Pharmacology II

CARDIOVASCULAR DRUGS A.

POSITIVE INOTROPES: CONTRACTILITY

1.

DRUGS

THAT

IMPROVE

CARDIAC

Use of positive inotropes revolves around the following factors: a. b. c. d. e.

2.

All of these drugs have the potential to increase myocardial oxygen consumption. All increase intracellular calcium levels or increase sensitivity of contractile myofibrils to intracellular calcium. None can significantly alter the underlying pathologic conditions that caused the heart to fail. Efficacy of most of these drugs is uncertain in many clinical settings and most have narrow therapeutic index. These drugs can cause symptomatic improvement and enhance the quality of life of the patient. Specific Agents

a. b. c. d. 3.

Catecholamines Phosphodiesterase inhibitors Anticholinergics Digitalis glycosides Catecholamines (Beta-adrenergic Blockers)

a.

Beta-1 receptors are mostly located in the heart and stimulation of these receptors results in positive inotropic and chronotropic response 1)

Beta-2 receptors are mostly found in vascular and bronchial smooth muscles and their stimulation can cause relaxation (vasodilatation and bronchodilation) 2) Alpha-1 receptors are found primarily in vascular smooth muscle and myocardium and their stimulation results in vasoconstriction and a positive inotropic response b.

Catecholamines increase contractility by the following process. 1)

Stimulation of Beta-1 adrenoreceptors stimulates adenylate cyclase.

2)

This increases intracellular cyclic AMP concentration which in turn activates CAMP-dependent protein kinase.

3)

CAMP-dependent protein kinases catalyze phospphorylation of membrane protein in the sarcolemma and sarcoplastic reticulum. 4) This phosphorylation regulates the movement of Ca++ ions across the sarcolemma and sarcoplasmic reticulum. 5) This increases intracellualar calcium which stimulates contractility of the heart. c.

Commonly used catecholamine 1)

Epinephrine a.

Drug of choice for positive inotropic and circulatory support following cardiac arrest. b. It is a potent alpha-1, beta-1, and beta-2 agonist. c. Increases contractility, heart rate, blood pressure, and cardiac output. 2)

Isoproterenol a. b.

The prototype beta agonist. Used in emergency treatment of complete AV nodal block that is unresponsive to anticholinergics. c. Not used in the management of cardiac arrest or myocardial failure because of its arrythmo-genecity and hypotensive effects. d. Desirable for acute management of heart failure. 3)

Dopamine a. b.

Biosynthetic precursor to norepinephrine. Acts on beta-1 and dopaminergic receptors (in renal, mesenteric, coronary and vascular beds) and also stimulates norepinephrine release. c. Vasodilatory effects improve renal blood flow. d. Desirable for acute management of heart failure. 4)

Dobutamine a. b. c.

A synthetic analog of dopamine, but a beta-1 agonist. Currently most useful in treating heart failure. Positive inotropic effects similar to dopamine but does not cause vasodilatation of renal, coronary, cerebral and mesenteric vascular beds. d. Contraindicated in patients with heart disease characterized by ventricular hypertrophy. e. Side effects similar to dopamine

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i) ii) iii) iv) 4.

Tachyarrhythmias Vomiting Nervousness Seizures (cats)

Phosphodiesterase Inhibitors a.

Phosphodiesterase enzymes are responsible for inactivation of Cyclic AMP 1)

Inhibition of these enzymes leads to increase intracellular calcium concentration. 2) Drugs that inhibit phosphodiesterases a) Xanthine derivatives b) Bipyridine derivatives 3) Xanthine derivatives a) May evoke changes in the cardiovascular system (slight increases in blood pressure, heart rate and stroke volume). b) Tolerance may develop within a few days of chronic intake. c) May also cause CNS stimulation and diuresis. 4)

Bipyridine derivatives a. i. ii. iii.

Amrinone Increases cardiac contractility and causes vasodilatation, decreasing preload and after load. May cause hypotension, arrhythmia, or G.I. distress. Associated with thrombocytopenia and liver function abnormalities

b. Milrinone i) Possess 20 to 50 times the potency of amrinone. ii) Approved for use in dogs. c. Pimobendan i) ii)

A relatively new product in this category Increases sensitivity of myocardial calcium-regulatory proteins to calcium.

5) a. b.

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Anticholinergic Drugs MOA: deny access of acetylcholine to receptors Ach causes

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i.

Negative inotropic effect (decrease force of contraction). Negative chronotropic effect (decrease rate of contraction). Vasodilatation.

ii. iii. 6) a. i. ii.

Cardiac glycosides (Digitalis), Digitoxin and Digoxin. Chemical structure Consist of a steroid nucleus bound to an unsaturated lactone ring (combination called aglycone) The number of sugar molecules attached to the aglycone account for their pharmacokinetic differences.

b.

Source: Dried leaf of foxglove plant (Digitalis lanata and Digitalis purpurea)

c.

Mechanism of Action 1)

Positive inotropic effect: binds to and inhibit sodium pump (Na+-K+-ATPase) at the myocardial cell membrane. a)

Inhibition causes reduction of Na+ transport out of the cell.

b)

This causes a transient increase in intracellular sodium concentration. c) Na+ ions move out of the cell via sodium-calcium exchange mechanism. d) Results to accumulation of Ca++ in the cell. 2)

Negative chronotropic effect (antiarrhythmia): via parasympathetic stimulation (vagus nerve). a)

SA node (increased sensitivity to Ach) i.

Increased slope of phase 4.

ii.

Toxic

levels

slow down heart rate. iii.

In diseased heart, may cause atrial arrhythmias. b) AV node i) Slow AV nodal conduction. ii) Increase AV nodal refractory period d. Pharmacokinetic 1) 2)

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Disposition of drugs varies with the formulation. Digitoxin is more lipid-soluble than digoxin.

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3) 4) 5)

Plasma protein binding: digoxin (25%), digitoxin (90%). Half-life in dogs: digoxin (1-7 days), digitoxin (8-12 hrs.). Excretion and metabolism a) Digoxin primarily eliminated via the kidney unchanged. b) Digitoxin is metabolized by the liver.

6) 7)

Digoxin should not be given IM (causes pain necrosis). Concurrent use with a) Quinidine increases toxin effects of digitalis due to displacement from plasma protein binding. b) Diuretics and amphotericin result to hypokalemia. c) Beta-adrenergic agonist increases likelihood arrhythmias. e. Toxicity 1) Stimulation of CTZ (early signs of toxicity) a) Vomiting b) Nausea c) Anorexia d) Diarrhea 2) CNS: drowsiness and malaise 3) Potentiated by hypokalemia 4) Treatment a) Discontinuation of digitalis therapy b) Discontinuation of K+-depleting diuretics c) Use of antiarrhythmics d) Potassium administration f. Clinical Uses 1) To restore adequate circulation in animals. 2) To slow down supraventricular arrhythmias. g. Digitalization 1) Rapid administration of a loading dose followed by maintenance dose 2) Slow giving of a maintenance dose. B. ANTIARRYTHMICS 1. Arrhythmia refers to any deviation from the normal cardiac rate and rhythm. 2. This deviation refers to variation from the normal. a. cardiac rate or regularity of heart rate. b. Site of origin of initial impulses (ectopic) c. Sequence of activation of atria and ventricles. 3. In general, cardiac arrhythmias can be considered to arise from either of the following or both: a. Abnormal impulse initiation 1. Normal automaticity is enhanced due to increased responsiveness to catecholamine.

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2. Abnormal automaticity is enhanced due to decreased oxygen supply to myocardium. 3. Triggered activity caused by after depolarization that reach threshold potential, probably due to large increase in intracellular calcium. 4. Sick-sinus syndrome wherein vagal activity increases K+ conductance out of the cell causing repolarization. b. Abnormal impulse condition 1. Re-entry phenomenon: an impulse that enters a slowly conducting region of the heart goes back to reactivate it again. 2. Condition for re-entry a) There must be blockade in the conduction pathway. b) There must be slow conduction over an alternate route to a point beyond the block. c) There must be delayed excitation beyond the block. 4. Therapy of arrhythmias a. Antiarrhythmic drugs have been classified into four groups based on their predominant effect on AP. b. General Classification: 1) Class I (membrane-stabilizing drugs) 2) Class II (beta adrenergic blockers) 3) Class III (repolarization prolonging drugs) 4) Class IV (calcium-entry blockers ventricular tachycardia with long Q-T intervals, myasthenia gravis, and severe hepatic failure) c. Procainamide i. Similar cardiac effects with quinidine but has less ability to induce hypotension and increase AV conduction. ii. Use with quinidine and other class agents and beta-blockers in treating refractory arrhythmias. d. Disopyramide i. Second-line drug for refractory arrhythmias ii. Possess strong negative inotropic tendencies. iii. Contraindicated in CHF, pulmonary edema, glaucoma, urinary retention, advanced AV block and SA node dysfunction. e. Class IB 1. Characteristics a. Shorten APD and effective refractory period. b. Decrease slope of phase 0. c. Depress automaticity. d. Increase threshold for ventricular fibrillation. e. Act selectively on inactivated Na+ channels present in diseased or ischemic tissues. 2. Specific Agents a. Lidocaine

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i. Used for acute, life threatening ventricular arrhythmias. ii. Causes significant suppression of automaticity, conduction velocity and prolongs refractoriness in diseases cardiac cells. iii. Intoxication seizures (controlled by diazepam and short-acting barbiturates). b. Tocainamide i. May be used to follow-up lidocaine . ii. Causes progressive corneal edema in Doberman pinschers. c. Mexiletine i. Synergistic with other class I A drugs ii. Needs further clinical evaluation. d. Phenytoin i. Similar to lidocaine but more effective in controlling supraventricular tachycardia ii. Indicated for controlling digitalis induced arrhythmias iii. Has minimal hemodynamic effects, wide therapeutic range, and rare adverse reaction f. Class IC ( flecainide, encainide) 1. Characteristics a) Causes profound depression of phase 0 and conduction velocity. b) Less effect in refractoriness or APD. c) Seriously depress contractility, cardiac output, and systemic blood pressure. 2. Indicated for supraventricular and ventricular, tachyarrhythmia and those involving accessory pathways. 3. Contraindicated in AV block, bundle branch block and myocardial depression. g.

Class II Antiarrhythmia 1. MOA: Blockade of cardiac Beta-I receptors leading to slow opening of calcium channels and rate of pacemaker discharge. 2. Characteristics a) Decrease conduction velocity. b) Increase AV nodal refractory period. c) Suppress tachyarrhythmia and ectopic pacemakers which are due to sympathetic-mediated increased in automaticity. d) Reduction in cardiac output is due to negative inotropic and chronotropic effects. 3. Indications a) Supraventricular tachycardia. b) Pre-excitation tachyarrhythmia. c) Atrial flutter and fibrillation. d) Contraindicated in AV block and sick-sinus syndrome. e) Those with Beta-2 blocking activity may cause bronchial smooth muscle constriction. 4. Specific agents

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a) Propranolol i. The standard beta blocker used in veterinary medicine. ii. Blocks Beta-1 and Beta-2 receptors. b) Atenolol (Beta-1 blocker, cardio selective) c) Esmolol (Beta-1 blocker, cardio selective) h. Class III Antiarrhythmics 1. MOA: Inhibition of K+ channel (inhibition of repolarization) prolonging APD and refractory period. 2. Characteristics a) Modify velocity of conduction. b) Effective for arrhythmias dependent on re-entry. c) Increase threshold for atrial and ventricular fibrillation. 3. Specific agents a) Amiodarone i. Control supraventricular and ventricular tachyarrhythmia. ii. Can be used with class IA or IC drugs. iii. Increase serum levels of digoxin b) Bretylium (not used in veterinary medicine). i. Class IV Antiarrhythmics 1. MOA: Block calcium channels, inhibiting calcium entry across the membrane during phase 1 and 2 of AP. 2. Characteristics a) Slow down sinus rate and AV conduction. b) Interrupt arrhythmia resulting from abnormal automatically and triggered mechanism. 3. Indicated for control of most supraventricular arrhythmia. 4. Contraindicated in arrhythmia due to AV blockade (wide QRS) sinus bradycardia, myocardial failure. 5. Specific agents a) Verapamil (used in dogs to slow sinus rate, increased AV conduction time, or decrease ventricular response). b) Diltiazem c) Nifedipine C. VASODILATOR DRUGS 1. The use of vasodilator drugs in the therapy of heart failure is relatively common in veterinary medicine. 2. Vasodilators are classified based on their primary site of action. a) Drugs that dilate systemic veins are called venodilators. b) Drugs that dilate systemic arterioles are arteriolar dilators. c) Drugs that dilate both systemic arterioles and veins are called mixed or balanced vasodilators. 3. Underlying heart failure a) Heart failure is characterized by inability of the heart to deliver normal amounts of blood at a rate required for tissue metabolism.

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b) It is represented clinically as 1) Backward failure: congestion or edema (congestive heart failure). 2) Forward failure: poor tissue perfusion (low – cardiac – output failure). c) The amount of blood pumped out of the heart per minute is influenced by the ff: 1) Preload (ventricular end – diastolic volume and pressure), reflects how much the heart is stretched before contraction. 2) After load refers to the pressure of force that the ventricular muscle must overcome to pump blood into the aorta. 3) Heart rate and rhythm 4) Size of the ventricles. d) These factors can be adjusted to compensate for the failing cardiovascular system. e) Cardiac compensatory mechanisms 1) Heart dilates or stretches to increase force of contraction and size of stroke volume. 2) This stretches myofibrils causing hypertrophy and increases metabolic requirements of the heart. 3) With accompanying increase in blood volume, the failing heart is strained 4) Eventually, the stroke volume and cardiac output decrease leading to death. 4. Arteriolar dilators decrease resistance to systemic arterial or forward blood flow (reduce after load). a. Dilation of systemic arterioles lowers arterial blood pressure. b. This decrease intraventricular pressure and tension during systole. c. This also decreases after load leading to shortening of myocardial fibers and greater expulsion of blood. d. Hydralazine. 5. Venodilators decrease venous return to the heart, intracardiac blood volume and diastolic intracardiac pressure (reduce preload) a. Through pooling of the blood in the peripheral veins, they decrease intraventricular pressure during diastole, and reduce edema formation. b. Examples: nitroglycerin, isosarbide dinitrate 6. Mixed or balanced vasodilators decreased preload and after load in patients with CHF. a. Examples: sodium nitroprusside, prazosin, angiotensin converting enzyme (ACE) inhibitors 7. Adverse side effects a. Hypotension, anorexia, dizziness, vomiting, diarrhea. b. ACE inhibitors: azotemia, inability to maintain GFR. c. Nitroprussides: headache, flushing 8. Specific vasodilators a. ACE inhibitors effects are based on decreased concentration of circulating Angiotensin II 1) Angiotensin actions

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a) Potent vasoconstrictor b) Stimulates release of aldosterone from adrenal gland c) Stimulates vasopressin (ADH) release from posterior pituitary gland d) Preserves glomerular filtration rate (GFR) when renal blood flow is decreased. 2) Inhibition of angiotensin-converting enzyme reduces aldosterone and ADH release, promotes NA+ and water loss thereby reducing edema and causing systemic vasodilation. 3) Examples: captopril, lisinopril b. Hydralazine 1) Used in the treatment of CHF unresponsive to conventional therapy with cardiac glycosides and diuretics. 2) Direct-acting peripheral arteriolar vasodilator. 3) Action: not know presumed to cause local increases in prostacylin concentration 4) Rapidly absorbed PO. IM: widely distributed mostly metabolized by GI mucous and liver (t1/2-8 hrs.) c) Prazosin 1) Mechanism of action a) Blocks postsynaptic alpha-1 adrenergic receptors (dilate both arteries and veins) b) Inhibits phosphodiesterase in vascular smooth muscle (decreased contractions) 2) Effects: lowering of blood pressure; decreased preload and after load. 3) Partial absorption after oral administration; wide distribution; extensively metabolized in the liver d) Nitrates and nitroprusside 1) MOA: stimulate quanylate cyclase to produce cGMP (cyclic guanosine monophosphate) a) cGMP accelerates Ca++ loss from vascular smooth muscle cells. b) Causes vasodilation 2) Nitroglycerin a) Dilate coronary arteries and improve collateral flow to ischemic regions of the heart. b) Produces vasodilation (venous > arterial ) c) Decrease preload d) Reduces myocardial oxygen consumption 3) Nitroprusside a) Produces peripheral vasodilation by direct action on venous and arteriolar smooth muscle b) Rapidly lowers blood pressure c) Decrease cardiac preload and after load 4) Isosarbide dinitrate a) Produces vasodilation (venous > arterial) b) Decreases preload

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c) Reduces myocardial oxygen consumption d) Dilate coronary arteries and improve collateral flow of ischemic regions e) Relieves anginal attacks and increases cardiac output D. ANTIANEMIC DRUGS (HEMATINIC DRUGS) 1. The oxygen-carrying capacity of blood depends on the adequate number of erythrocytes and hemoglobin concentration. 2. Anemia occurs when there is excessive loss or decreased replacement of erythrocytes and also when the circulating erythrocytes have inadequate hemoglobin (Hgb). 3) Causes: a. Chronic blood loss b. Abnormal shape or size of erythrocytes c. Nutritional deficiencies d. Chronic disease or malignancies 4) Anemia can be treated by a. Providing the necessary components of RBC production b. Stimulating bone marrow formation of RBC (erythrocytes) 5) Iron a. Necessary for hemoglobin formation b. Distribution 1) It is an integral part of hemoglobin 2) Stored in the body as hemosiderin and ferritin 3) In the blood, it is bound to transferrin 4) About 70% od body iron is functional (hemoglobin, myoglobin, or enzymes) 5) The amount stored in tissues can replace about half the circulating Hgb c. Absorption, metabolism and excretion 1) Absorption, metabolism and excretion 2) Absorption is influenced by gastric acidity, reducing agents like ascorbic and food intake. 3) Majority of the iron released via Hgb break down in the liver is reused 4) Demands increased by a) Rapid growth b) Blood loss (hemorrhage or menstruation) c) Pregnancy d. Signs of deficiency 1) Paleness of skin and mucous membrane 2) Fatigue/weakness 3) Loss of appetite e. Treatment 1) Ferrous salts (sulfate gluconate, fumarate) – PO 2) Iron dextran IM injectable – a complex of ferric hydroxide with dextran f. Side effects and toxicity (dose-related)

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1) Oral preparations may cause GIT irritation (eg. abdominal cramping and diarrhea) 2) Parenteral preparations can cause a) Iron overload b) Anaphylactic shock c) Cardiovascular collapse 6. Vitamin B12 (Cyanocobalamin) a A cobalt-containing compound necessary for DNA synthesis. b. It can be derived from microbial synthesis and ingestion of animal products in the food chain. c. Vitamin B12 is converted to biologically active forms 1) Methylcobalamin: a cofactor in the conversion of hemocysteine to methionine. 2) Adenosylcobalamin: participates in the conversion of methylmalonyl coenzyme A to succinyl coenzyme A. d. Absorption depends on a thermolabile glycoprotein, known as the intrinsic cofactor which binds to and protects B12 from digestion. 1) Factors that cause loss of intrinsic-factor-secreting gastric cells limit B12 absorption. 2) H-2 receptor antagonists (eg. cimetidine) decrease secretion of intrinsic factor 3) Concurrent administration of drugs (eg. Vitamin C may limit absorption) e. B12 is stored in the liver, slowly released as needed: released into the bile but undergoes hepatic recycling. f. Therapeutic use 1)Megaloblastic or pernicious anemia (delayed nuclear maturation due to inadequate DNA synthesis; thymidine) 2) Demyelinating neuropathies (inability to synthesize myelin) g. Deficiency is rare and is usually due to 1) Gastrectomy gastric mucosal lavage 2) Malabsorption 3) Parasitic infestation (eg. fish tapeworm) 7. Folic acid a. This is pteroyglutamic acid (combination of pteridine, PABA, and glutamic acid) needed for the synthesis of DNA thymine. b. Essential in tissues where rapid DNA synthesis occurs and the turnover is also rapid (eg. hematopoeitic tissues, developing embryo). c. The form 5-methyltetrahyhdrofolic acid serves as a methyl donor in the conversion of hemocysteine to methionine by Vitamin B12. d. It is well absorbed in the proximal intestine and conserved by enterohepatic recycling. 8. Anabolic steroids a. Mechanism of Action 1) Increases erythropoietin production (ERP)

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2) Promote differentiation of stem cells into ERP-stimulating-factorsensitive cells. 3) Directly stimulates erythroid-progenitor cells. b. Effectiveness in treating anemia depends on 1) The cause of anemia 2) Number of functional RBC 3) Adequate ERP levels 4) Responsiveness of bone marrow c. Cells generally classified into two categories 1) Alkylated a) Oxymetholone b) Stanozolol 2) Nonalkylated a) Nandrolone decanoate E. AGENTS AFFECTING BLOOD COAGULATION 1) Hemostasis – refers to the prevention of blood loss or spontaneous arrest of bleeding from damaged blood cells. 2) This involves vascular spasms, platelets, plug formation, and coagulation or blood clotting. 3) Blood loss at the site of breakage is permanently prevented when fibrous tissue grows into the clot and seals the hole in the blood vessel. 4) The clotting mechanism is responsible of the formation of fibrin which involves a cascade of reactions which are either intrinsic or extrinsic in origin. a. Intrinsic system is initiated by the activation of factor x 11 (Hageman factor) which occurs in vivo when the blood is exposed to collagen fibers of the damaged endothelium of blood vessels. b.Extrinsic system is triggered by factor 111 tissue thromboplastin/released from damaged tissues. c. Both lead to the formation of prothrombin activator that converts prothrombin to thrombin which in turn converts fibrinogen to fibrin. 5) Hemostatics are agents that arrest the flow of blood. a. Local or topical hemostatics 1) Physiological a) Thromboplastin USP b) Thrombin USP c) Human fibrinogen USP 2) Surgical a) Fibrin foam (human) b) Absorbable gelatin response USP c) Oxidized cellulose USP d) Calcium alginate 3) Astringent metals a) Ferric chloride b) Alum c) Tannic acid

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4) Adrenergics (used as sprays) a) Epinephrine b) Norepinephrine b. Systemic hemostatics 1) Whole blood or blood components 2) Vitamin K 3) Protamine sulfate 6. Vitamin K a. MOA: activates carboxylase which mediate synthesis of gammacarboxyglutamic acid used in the synthesis of factor II, VII, IX, X in the liver. b. Clinical Use 1) Antidote to coumarin group of anticoagulants (eg. warfarin) 2) Used in birds under sulfonamide therapy to counteract Vitamin K deficiency. 3) Excessive hemorrhage due to liver failure. c. Not effective against heparin-induced hemorrhage d. Preparations 1) Menadione (Vitamin K3) a) Slowly absorbed b) Useful for chronic therapy 2) Phytomenadione (Vitamin K1) – from plants a) Very toxic, can cause dyspnea, backpains, death b) Slowly administered IV to avoid hypotension (not faster than 510 mg/min 7) Protamine sulfate a. Low MW protein in sperm of certain fish b. Forms stables salt with heparin (acidic) c. Antagonize only heparin-induced hemorrhages d. Excess can cause coagulation due to interference with the reaction of thrombin and fibrinogen 8. Anticoagulants are agents that prevent blood coagulation. 9. Anticoagulants for blood samples a. For laboratory examination 1) Sodium oxalate (20%) 2) Sodium citrate (25%) 3) Disodium EDTA 4) Heparin sodium b. For blood transfusion 1) Sodium citrate solution 2) Acid citrate dextrose solution c. MOA: chelate calcium ions 10. Systemic anticoagulants a. Heparin sodium (parenteral anticoagulant) 1) MOA: combines with antithrombin III (an alpha globulin) and increases its effectivity in removing thrombin

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a) Requires the presence of antithrombin III to mediate its anticoagulant effect b) Antithrombin III combines with thrombin and blocks its effect on fibrinogen c) It then inactivates the bound thrombin (on fibrin threads) during the next 12-20 minutes d) The heparin-antithrombin III-thrombin complex is completely undissociable 2) Also inhibits active forms of factors IX, X, XI. 3) Can inhibit both the generation of thrombin and the formed thrombin 4) Rapidly metabolized in the liver by heparinase 5) Endogenous heparin is present in most cells along with histamine and serotonin b. Vitamin K antagonists/coumarin derivative (oral anticoagulants) 1) Toxicological effect is of primary importance in veterinary medicine. 2) Clinical Use a) Prophylaxis of venous thrombosis and laminitis in horses. b) Oral rodenticide c) Pulmonary thromboembolism in dogs 3) Agents include warfarin and bishydroxycoumarin. 4) Absorbed in the gut and stored in the liver. 5) Inhibit hepatic utilization of Vitamin K. c. Aspirin 1) An antithrombotic (agent which prevents or reduce formation of platelet thrombi in arterial system) 2) MOA: inhibit cyclooxygenase enzyme responsible for prostaglandin synthesis from arachidonic acid that has been released into cell and platelets. a) Inhibit formation of prostaglandins and thromboxane (potent platelet aggregator and vasoconstrictor) b) Reduce ADP (adenosine diphosphate) release by platelets impairing their aggregation and formation of platelet plugs. d. Fibrinolytics (thrombolytics) 1) MOA: increase activity of plasmin/fibrinolysin in dissolving clots 2) Agents commonly used: a) Streptokinase and streptodornase b) These are synthesized by streptococci 3) Used for chronic wounds that are unresponsive to other drugs. 4. Available as powder for oral and systemic administration.

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DRUGS AFFECTING RENAL FUNCTION DIURETIC AGENTS 1. Diuresis refers to increased excretion of urine. 2. Diuretic is a substance that increases the rate of urine output or the volume of urine. a. Act by suppressing the total amount of fluid absorbed from the renal tubules b. Reduce the amount of fluid in the body c. May promote loss of sodium into the urine (natriuresis) 3. The functional unit of the kidney is the nephron. a. Glomerulus b. Bowman's capsule c. Proximal convoluted tubules d. Loop of Henle

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e. Distal convoluted tubule f. Collecting ducts 4. Diuretic mechanisms and site of action a. Glomerular filtration (glomerulus) 1) Blood from afferent arterioles enter the glomerular capillaries and filtered in the Bowman's capsule 2) Glomerular filtrate goes to the tubule of the nephron b. Tubular reabsorption 1) Proximal tubular reabsorption of Na+ depends on sodium pump and carbonic anhydrase isotonic absorption 2) Loop of Henle: only water is reabsorbed 3) Thick ascending limb of loop:

impermeable to water, active co

transport of Na+, K+ and Cl-, passive Ca+++ and Mg+ absorption (hyper osmotic) 4) Distal convoluted tubule: Na+ and Cl- reabsorption with little or no water, Ca++ reabsorption

dependent

on

parathyroid hormone

(PTH) 5)

Collecting

duct:

permeability

(vasopressin), aldosterone promotes

to

water influenced by ADH uptake of Na+

into

the

interstitium, K+ secreted back to lumen, Cl- follow Na+ or K+ c. Tubular secretion primarily occurs in the proximal convoluted tubules 5. Diuretic agents a. Classification 1) Minor diuretics (osmotic diuretics) are agents that increase glomerular filtration rate (GFR) a) Mannitol b) Xanthine derivatives c) Cardiac glycosides 2) Major diuretics

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a) Carbonic anhydrase inhibitors (weak) b) Potassium-sparing diuretics (weak) c) Thiazides (moderately potent) d) Loop diuretics (potent diuretics) b. Minor diuretics 1) Mannitol (most useful osmotic diuretic) a) Filtered at the glomerulus but not reabsorbed by the tubules b) Remains in renal tubules and osmotically attracts large volume of water which is flushed through the kidney c) Clinical use i. Edematous states (eg. Cerebral edema) ii. Clinical

evaluation of

acute oliguria

iii. Hasten excretion of certain poisons d) May cause cardiovascular overload if not excreted 2) Xanthine derivatives a) Increase GFR b) Inhibit Na+ reabsorption c) Causes mild diuresis and potency varies with species of animal d) Side effects include slight CNS and cardiac stimulation, bronchodilation c. Major diuretics 1) Carbonic anhydrase inhibitors a) Carbonic anhydrase generates H+ that exchange with sodium on the luminal side of tubule b) MOA:

inhibition of carbonic anhydrase in the proximal

tubule i. Depresses bicarbonate ion absorption from the tubular urine (HC03 - remains in the lumen) ii. Inhibit Cl- reabsorption (remains in lumen)

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iii. Causes decreased production of H+ for the H+/Na+ exchange so Na+ remains in the tubular urine (Na Cl or MaHC03) iv. These ions in tubular urine attract water c) Clinical effects i. Large loss of Na+ and water ii. Formation of alkaline urine iii. Systemic acidosis iv. Decreased rate of production of aqueous humor in the eye (lowers in intraocular pressure) v. CNS depression and antiepileptic action d) Clinical use i. Glaucoma ii. Adjunct to a more powerful diuretic in treatment of certain edematous states iii. Udder edema iv. Non-heart

failure

conditions

where negative Na+

balance or sodium loss is unimportant v. Alkalinization of urine e) Inhibition of sodium bicarbonate absorption at proximal tubule causes K+ wasting because bicarbonate

acts

as a

non

reabsorption at anion and it can draw K+ into the tubular lumen. f)

Specific

agents:

acetazolamide,

dichlorphenamide,

methazolamide, ethoxolamide 2) Potassium-sparing diuretics a) Spironolactone i. Competitive inhibitor or aldosterone in the collecting duct ii. Block

Na+/K+

exchange, converting K+

promote Na+ excretion iii. Useful when combined with more potent diuretics

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and

iv. Onset of action is 2-3 days; tolerance rapidly develops b) Triamterene i. Acts on collecting duct .

ii.

Inhibits Na+ reabsorption and limits

K+ and H+

secretion in distal tubules iii. Action not associated with aldosterone iv. More effective when combined with thiazides c) Amiloride i.

Directly

impairs the entry of

Na+

and promote

conservation of K+ ii. Action not associated with aldosterone iii. Rarely used alone, often used with thiazides or loop diuretics d)

Significance of potassium ~ sparing

effect: hypokalemia

increases contractility and automaticity of the heart 3) Thiazides a) Highly protein bound and mainly excreted in the proximal renal tubules b) MOA: inhibits Na+ and Cl~ reabsorption at distal convoluted tubules (little effect at proximal c) Action may be related to ATPase activity d) Tend to increase Ca++ absorption (slight) but promote loss of K+ and Mg+ e) Uses: hypertension and CHF f) Effects i. Pronounced diuresis ii. Hypokalemia iii. Metabolic alkalosis iv. Inhibition of insulin (hyperglycemia Glycosuria) v. Hypercalcemia

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g) Agents:

chlorthiazide and hydrochlorthiazide

4) Loop diuretics a) Most potent of the listed diuretics with sustained effects b) Actively excreted in the proximal tubule c) MOA: inhibit

sodium-potassium-chloride co transporter

i. Inhibit reabsorption of these ions in the thick ascending loop of Henle (lead to Na+, K+, Cl- loss into tubular urine ii. Increase excretion of K+, Mg++ and Ca++ ions d) Diuretic effect within 30 min. after

oral administration/

10-15 min. after IM or IV e) Specific agents i . Fu rose nude ii. Bumetanide iii. Ethacrynic acid iv. Muzolimine f) Clinical use i.. Edematous conditions ii. Hypercalcemia iii. Anion or cation overdose iv. Acute renal failure g) Toxicity i. Hypokalemic metabolic acidosis ii. Magnesium loss iii. Ototoxicity (dose-related, not always reversible) FLUID THERAPY OBJECTIVES 1. To restore the volume and composition of body fluids to normal. 2. To correct dehydration, hypokalemia,

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and metabolic acidosis.

10/23/2013

3. For specific correction of abnormalities in acid-base balance. 4. To replace essential electrolytes and nutrients. 5. To serve as a vehicle for the infusions of certain intravenous infusions. PHYSIOLOGY OF THE FLUID COMPARTMENTS OF THE BODY 1. Water composes 55 to 80 percent (60% on the average) of the weight of an adult animal. 2. Neonates have higher content (as much as 80 total body water (TBW) to 90%) 3. Obese animal has less body water than a thin animal (fat associates with little water). 4. Body water is distributed into two major compartment a. The intracellular fluid (ICF) compartment - composed of approximately 2/3 of TBW b.

The extracellular fluid (ECF) compartments:- composed of

approximately 1/3 of TBW 5. The ICF is the fluid contained in cells and constitute about 40 percent, of body weight. 6. The ECF is about 20 to 25 percent of body weight and is divided into plasma (5 to 8%) and interstitial fluid (15%) a-

Plasma is contained in blood vessels and

is separated from the

interstitial fluid by the vascular endothelium. b. Interstitial fluid occupies the interstitial space outside the blood vessels and bathes the cell membranes. c. Interstitial fluid includes: 1) lymph 2) volume 3) intestinal fluid volume 4) transcellular fluid a) found in the GIT

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b) aqueous humor c) CSF d) synovial fluid e) pleural and peritoneal fluids f) bile 7. Changes in the osmolality of ECF can change the size of the ICF: a. When ECF osmolality is high, water moves from ICF to ECF and the cells shrink in size b. When ECF osmolality is low, water is absorbed by cells and cells swell or enlarge 8. Sodium (Na+) and chloride (Cl-) are the major electrolytes in the ECF and contribute much to the osmolality of this compartment. 9. Potassium (K+) and phosphates ar.e the principal electrolytes in the ICF. 10. Thirst and renal control of sodium ions (major cation in ECF) and water excretion play a minor role in maintaining external fluid balance. C. REQUIREMENT TO DETERMINE - DEGREE FLUID IMBALANCE PRIOR TO TREATMENT 1. History - obtain information on food and water intake, vomiting

or diarrhea),

urine output,

recent

GI

losses

(through

exercise, exposure to heat,

trauma, hemorrhage,, excessive panting, fever, and use of diuretics 2. Physical, examination - determine hydration -status of patient 3. Laboratory tests - these are vital in establishing the nature and extent of fluid imbalances and in monitoring treatment (eg. elevations in PCV/ TPP, urine specific gravity) D. CAUSES OF DEHYDRATION 1. Decreased water intake due to a. Lack of food intake b. Depression of appetite and thirst centers in systemically ill animals c. Accidental or deliberate deprivation of adequate water and food

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2. Increased losa a . Urinary (polyur i a) b, Gastrcintestinal (vomiting, diarrhea) c. Respiratory (panting, fever) d. Skin (burns/ large wounds) e. Excessive salivation f. Peritoneal dialysis E. TYPES OF DEHYDRATION

(based

on

Na+

ion concentration)

1. Isotonic dehydration a. Most common type of dehydration b. Serum Na+ concentration is normal at the time of dehydration (145 to 157 mEq/L) c. Isotonic

loss (loss of water

and electrolytes in proportion to

those found in normal serum 2. Hypertonic dehydration a. The next most common type b. There is an elevation of serum Na+ concentration (158) c. Hypotonic loss (predominantly water loss or water lost in excess of solute found in normal serum) 3. Hypotonic dehydration a. The least common type b. Characterized by low serum Na+ concentration (143 mEq/L or less) at the time of dehydration c. Theoretical mechanism: Hypertonic loss of solute in excess of concentration in normal serum) d. Most probable mechanism: Loss of isotonic fluid with subsequent intake of hypotonic fluids that diluted Na+ concentration to below normal F. DETECTION OF DEHYDRATION 1. History - information obtained leads the clinician to suspect dehydration

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2. Physical examination - provides guidelines for detecting dehydration Normal skin pliability or turgor depends on hydration of tissues in the area tested: a. Normal skin returns immediately to its initial position. b. Dehydrated skin shows varying rates of slow return to its original position. Degree of

Signs

Dehydration < 5%

not

detectable; history

may suggest dehydration (eg.

vomiting/ diarrhea) 5%

subtle loss of skin elasticity, dry oral mucuous membranes

6 - 8%

definite delay in return of skin to normal position, eyes may be sunken in orbits, slightly prolonged CRT (capilla refill time), dry mucous membranes

10 - 12%

tented

skin stands

in

place, prolonged

CRT, eyes

sunken, in orbits, dry mucous membranes, signs of shock (increased heart rate, weak pulse) may be observed, moderate 12 - 15%

to

marked

mental depression

signs of shock, collapse, severe depression, death imminent

G. CORRECTION OF DEHYDRATION 1. Replacement % dehydration x weight in kg x 1,000 = ml of fluid to be replaced or % dehydration x weight in Ibs x 500 = ml of fluid to be replaced Note: 1 Ib water = 500 ml 1 kg water = 1,000 ml 2. Maintenance Requirement - this is the volume of fluid that must be taken in on a daily basis to keep the TBW content normal.

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a. Insensible loss (1 respiratory evaporation, feces, sweat) 1) estimated at 10 ml/lb/day (22 ml/kg/day) 2) increases during febrile states, panting high environmental temperature b. Sensible loss (urine production) 1) estimated at 10-20 ml/lb/day (22 to 44 ml/kg/day) in normal animals 3. Contemporary Losses - on-going losses

from insensible and sensible

mechanisms (fluid loss from vomitus and diarrhea are estimated. Total 24-hour need: _________ml = rehydration/replacement _________ml = sensible losses _________wl = insensible losses _________ml = contemporary losses H. ROUTE OF DELIVERY 1. Oral (PO) a. Indications and advantages 1) For the anorrectic patient that has short term illness 2) More conducive for animals < 20 kg body weight 3) Very conducive for neonates b. Complications and contraindications 1) Aspiration pneumonia 2) Not useful for hypovolemic shock 3) Should not be used in vomiting animals 2. Subcutaneous (SC, SO)

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a. Indications and advantages 1) For correction of mild to moderate dehydration 2) For maintenance in the not too severely ill patient 3) Conductive for animals weighing > 10 kg 4) Use only isotonic fluids b. Complications and contraindications 1) Do not deposit > 10 to 12 ml/kg bodyweight per injection site 2) Do not deposit fluid under infected or devitalized skin 3) Not useful for hypovolemic shock 4) Do not use irritating solutions 3. Intraperitoneal a. Indications and advantages 1) When IV access is unavailable 2) Relatively rapid absorption 3) For delivering ample volumes of fluid in a short time b. Complications and contraindications 1) Hypertonic

fluids

will

worsen dehydration.

2) Do not use in cases of abdominal, spesis, ascites or peritonitis and those with pending abdominal surgery 4. Intravenous a. Indications and advantages 1) Best route for correcting hypotension 2) Preferred route for severely dehydrated and hypovolemic patients 3) Rapid delivery at the most precise dosage b. Complications and contraindications

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1) Avoid IV overload due to excess fluid delivery 2) Avoid catheter sepsis and phlebitis 3) Avoid

catheter

displacement and inadvertent extravascular

placement of the fluid infusion I. SOLUTIONS AVAILABLE FOR FLUID THERAPY 1. Saline solutions a. Isotonic saline solution (0.9%) normal or physiologic saline 1) Indications a) Volume expansion b) Correction of hyponatremia c) Treatment of metabolic acidosis 2) Contraindications a) Borderline CHF b) Sodium-restricted conditions 3) All stay in the ECF (2/3 interstitial fluid; 1/3, intravascular space) b. Hypertonic saline solutions (3% and 5%) 1) For severe sodium loss and water excess 2) Give IV c. Half normal saline (0.45%) - hypotonic 1) Can be used as maintenance solution 2) 1/3 in ECF; 2/3 in ICF 2. Saline-lactate solutions (isotonic) a. Aimed to supply bicarbonate ions b. Useful in metabolic acidosis c. Types

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1)

Lactated Ringer's solution - metabolized

by

the

liver

bicarbonate ions 2) Acetated Ringer's solution –acetate is metabolized by muscles and peripheral tissues 3) Ringer's solution 3. Dextrose solutions a. DSW (5% dextrose solution) – hypotonic 1) 2/3

goes

to

ICF, 1/3

in

ECF

¾ intercellular; 1/4

intravascular) 2) Indications a) Hypernatrernia and primary water depletion states b) As CHO source to concommitantly

used solution

c) As a fluid supplement for with sodium intolerance 3) Does not supply electrolytes 4) Not for SC administration

J. BICARBONATE THERAPY 1. Metabolic acidosis is the most common acid-base disturbance

encountered

in small animal practice. 2. Causes a. Accumulation of acid (H+) in the body depletes HC03-levels b. Excess loss of HC03 - GIT or kidneys c. Rapid expansion and dilution of ECF (rare) 3. Defined as the primary change in bicarbonate that produces a fall in the HC03; PC02 ration/ thus depressing the pH 4. Categories of metabolic acidosis a. Those associated with a normal anion gap (hyperchloremia, primary loss of HC03-) 1) Diarrhea 2) Chronic vomiting (HC03-rich fluid

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3) Renal HC03- loss b. Those

associated

with

a

high

anion

gap (normochloremic,

increased unmeasured anions) 1) Diabetic ketoacidosis 2) Uremia and renal failure 3) Increased lactic acid (severe exercise, hypoxemia, shock) 4) Exogenous toxins (ethylene glycol, salicylic acid) 5. The anion gap reflects the difference between major measured cations (Na+, K+) and major measured anions (Cl- HC03-) a. Increases when there is accumulation of anions of acids which partially replace plasma bicarbonate. b. Remains normal if there is no accumulation of anions, such as when there is primary loss of bicarbonate (diarrhea) 6. Calculating bicarbonate requirements a. Guidelines HC03~

0.3

Body

x excess (mEq

space)

Base dose = (treatable.- x weight (kg)

(mEq/L)

b. Administer half this dose and then reevaluate the patient and the blood pH and gas volume.

DRUG THERAPY OF INFLAMMATION MEDIATORS OF INFLAMMATION A. Inflammation 1. Basic reaction of tissues to injury a. Directed at neutralization of noxious agents as well as repair of tissue injury. b. Necessary

for survival; but if

poorly controlled, it can cause

more harm than good.

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2. Involves vascular and cellular response a. Signs of inflammation 1) Increased temperature 2) Redness 3) Swelling 4) Pain 5) Loss of function b. Early phase 1) Brief duration 2) Associated

with vascular

changes (vasodilation, increased

capillary ipermeability to plasma proteins) c. Delayed phase 1) Prolonged duration (hours or days) 2) Characterized by cellular involvement or leukocytic infiltration of the site of inflammation,

slowed blood

flow, hemorrhage,

tissue damage 3. Vascular events a. Aterioles in the vicinity of the noxious agent of irritant constrict b. This causes increased blood flow to the area c. Capillary sphincters open and blood is shunted to the capillary side. d. Vascular permeability is increased and this leads to edema. e. These changes causes extravasation of plasma proteins. f. Leukocytes, platelets, and erythrocytes begin to adhere to the vascular endothelium g. Vascular lumen eventually narrows and blood flow slows down h. Further decrease in the blood flow leads to deposition of cell debris and penetration of neutrophils. 4. Cellular events a. Adhesion of more granulocytes to endothelial wall

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b. Blood flow is further reduced and metabolism becomes anaerobic c. Necrosis of tissues ensues d. Degenerative or regenerative changes in the tissue occurs depending on the quality of the irritant and the ability of the body's defense system to eliminate the offending agent e. Tissue proliferation may occur with mild irritants while tissue destruction occurs with intense irritants 5. Vasoactive substances a. Also referred to as AUTACOIDS b. Autocoids are circulating or locally acting hormone-like substances which originate from diffuse tissues; they are often called local hormones c. They act on the walls of blood .vessels d. They mediate vascular and cellular responses in inflammation.

6. Common mediators of inflammation a. Precursor molecules in the plams: kinins b. Preformed and stored in cell: histamin, serotonin c.

Precursor

molecule

in

cell

membrane phospholipids:

prostaglandins, leukotrienes B. Histamine 1. Properties a.. A 2- (4-imidazoyl) ethylamine b. Found in most tissues, but unevenly distributed c. Stored in bound formed in granules of mast cells or basophils d. In granules, histamin complexes with heparin and an acidic protein

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2. Functions a.

An important mediator of immediate

allergic and inflammatory

reactions b. Plays an important role in gastric acid secretion c. Neutrotransmitter in certain areas of the brain 3. Mechanisms of 'release a. Displacement of histamine from the heparin-protein complex by drugs (eg. Morphine, tubocurarine) b. Loss of granules from mast cell leads to rapid displacement of histamine from the complex by the Na+ in ECF c. Chemical and Mechanical injury to mast cells d. Sensitization of mast cells and basophils by IgE leading to degranulation and release of histamine

4. Mechanism of action a. HI receptor (in endothelial and smooth muscle cells) activation elicits an increase in phosphoinositol hydrolysis and an increase in intracellular calcium b. H2 receptor (gastric mucosa, cardiac muscle, immune cells) activation leads to increase in intracellular cAMP c. H3 receptor (in CNS) activation causes a decrease in associated with Ca++ influx 5. Tissue and organ system effects a. Cardiovascular system (HI, H2) 1) Decreased systolic and diastolic blood pressure 2) Increased contractility and activity (increased HR) b. GIT (HI) - contraction

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.

c. Bronchiolar

smooth muscle organs contraction (eg. uterus)

d. Other smooth muscle organs - contraction (eg. uterus) e. Nerve endings - stimulate sensory nerve endings (causes pruritus) f. Secretory tissue - powerful stimulant of gastric acid via H2 activation on parietal cells (leading to increased adenylcyclase activity, cAMP concentration,

and intracellular sodium concentration)

g. Triple response 1) Flush -- a reddening appears owing to dilatation of the small vessles. 2) Flare – a bright red

flush

with irregular outline extending

from the original red spot due to reflex dilatation of adjacent small vessels. 3) Wheal - localized edema fluid 6. Antagonists a. Physiologic antagonist: epinephrine b. Release inhibitors: cromolyn sodium, beta-2 adrenoceptor stimulants c. Receptor antagonists 7. HI receptor antagonists a. MOA: Competitively block histamin action on smooth muscles b. Effects not related to Hi (receptor blockade) 1) Sedation 2) Prevent nausea and vomiting/motion sickness 3) Anticholinoceptor actions (atropine-like) 4) Antiadrenoceptor actions (alpha blocking effects) 5) Antiserotonin action 6) Local anesthesia c. Uses 1) Allergic reactions 2) Motion sickness and vestibular disorders 3) Nausea and, vomiting of pregnancy (humans) d. Toxicity

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1) Excitation and convulsion in children 2) Postural hypotension 3) Allergic responses e. HI antihistaminic drugs in clinical use 1) Ethanolamines a) Dimenhydrinate (Dramamine) b) Diphenhydramamine (Benadryl) 2) Ethylenediamines a) Antazolin b) Pyrilamine (Neo-antergan) 3) Piparazine derivatives a) Cyclinizine (Marezine) b) Meclizine (Bonamine) 4) Alkylamines a) Brompheniramine (Dimetine) b) Chlorpheniramine (Chlortrimeton) 5) Phenothiazine derivatives: Promethazine Phenergan) 6) Piperidines a) Astimizole (Hismanal) b) Terfenadine (Seldane) 7) Miscellaneous a) Cryptoheptadine (Periactin) b) Loratidine (Claritin) 8) H2 receptor antagonists a) Used to block the gastric acid section that occur as a response to histamine b) Valuable in conditions concerning overproduction of gastric acid c)

Examples:

Cimetidine,

Ranitidine,

Famotidine,

Nizatidine C. SEROTONIN

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1. Properties a. An indoleethylamine formed from L-tryptophan

'

b. Found in plant and animal tissues, venoms, and stings c. Oxidized by the enzyme monoamine oxidaze d. In mammals, serotoin is found in 1) Enterochromaffin cells o GIT 2) Platelets 3) Brain 4) Mast cells (rodents and bovine) 2. Effects a. Cardiovascular system 1) Contraction of smooth muscles/vasoconstriction 2) Dilation of blood vessels supplying the heart and skeletal muscles 3) Venoconstriction 4) Platelet aggregation 5) Reflex bradycardia b. GIT 1) Contraction of GI smooth muscles 2) Increase tone and peristalsis c. Respiration 1) Bronchoconetriction 2) Hyper ventilation d. Nervous system 1) Stimulation of pain and itch sensory nerve endings 2) Regulation of sleep,

teraperature/ appetit®, blood pressure

3. Antagonists a. Cyproheptadine b. Ritan serin

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c. Ergot alkaloids d. Keataserin e. Cmdansetroa 4. Ergot alkaloids a. Produced bu Claverceps-purpiirea, a fungus that infects grain b. MOA: act on several receptors 1) actions

Agonist, at

partial,

agonist,

and

antagonist

alptsa adrenoceptors and dopamine

Eeceptors c. Organ system affects 1) CNS: hallucinations (eg. LSD) 2) Vascular smooth muscles: vasoconstriction on (ergotamine) 3) Uterine smooth muscles: prolonged and powerful contracture (ergonovine) d. Types 1) Asnine alkaloids a) 6-M.ethylergoliae b) Lysergic acid c) Lysergic acid diethylaniicie d) Ergonovin® (ErgoRieitr ia®) `

e) Methylsergicide 2) Peptide alkaloids a) Ergotaiflirsie b) a - E r go c r ypt i n® c) Bromocriptine e. Uses 1) Margarine 2) Hyperprolacteaeraia (pituitary turoor) 3) Postpartum Iieriaorrhage

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f. Toxicity/adverse effects 1) GI: diarrhea, nausea,vomiting 2) Prolonged vasoapasm D. KININS

1. A group of potent vasolator peptide formed from kinogens by kallekreins 2. Kallekreins a. Are proteases present in plasma and tissues (kidneys, pancreas, intestine, sweat glands, salivary glands) 1) Tissue kallekreins a) Have MW from 25,000 to 40, 000 b) Convert LMW kinenogen to kallidin 2) Plasma kallekreins a) Have 100,000 MW b) Convert BMW kinenogen to bradylcinin b. Plasma prekallekrein is produced by the liver 3. Kinenogens a. Precursor of kinins b. Present

in the plasma, lymph and interstitial fluid

c. HMW, kininogen is confined to the blood stream d. LMW kinenogen crosses the capillary walls and served as substrate for tissue kallikreins 4. Effects of kinins a. Cardiovascular system 1) Vasodilation in several beds (favors edema formation) 2) Release catecholamines from the adrenal medulla

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b. Kinins participate in the inflammatory process 1. Biologically active lipid and peptidolipid acids formed from polyunsaturated fatty acids with 18-, 20-, and 22-carbon skeletons. 2. Include the thromboxanes (TX), hydroperoxyeicosatetraenoic acid (HPETEO, hydroxyeicosatetraenoic 3. Arachidonic acid a. The most common important precursor for biosynthesis of eicosanoids b. Formed from linoleic acid in most mawaaals c. Released from membrane lipids and other lipid esters by phospholipasas d. Release can be initiated by a variety of physical, chemical, hormonal, and neurochemical stimuli 4. Prostaglandin a. A family of naturally occurring lipids characterized by a unique oxygenated fatty acid structure incorporating a 5-membered ring b. Biosynthesized from aracheidonate (AA) via cyclooxygenase enzyme system c. PGs are classified by letters, according to the specific functional groups attached to the 5 membered ring (cyclopentane ring) d.. The important factor which determines the rate of synthesis is the enzyme system (phospholipases) that liberates AA e. Phospholipase A2 activators: tissue injury; chemical mediators f. PG effects 1) Wide array of metabolic effects 2) Enhanced vascular permeability leading to edema 3) Chemotaxis for leukocytes g. Released during fever and can themselves produce fever h. They do not cause pain but sensitize pain receptors to mechanical and chemical stimulation

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5. Biosynthesis of prostaglandin from arachidonic acid a. Begins

with

cycloxogenase reaction (inhibited by NSAIDs)

which yields PGG2 b. This

step

is followed

by reaction, converting PG G2 to

(PGH) c. Both steps are catalyzed the single eazyme prostaglandin endoperoxidase, (PGH) synthetase d. Endoperoxides (PGG2, PGH2) provide intermediate substrate for the tissue specific synthesis of various prostaglandins e. The presence of the enzyme determine which endoperoxide product predominates in a specific tissue. 6. Biosynthesis of prostacyclin and thromboxane a. Thromboxane (TX) 1) In platelets (thrombocytes), PGH2 is converted to TXA2 by thromboxane synthetase. 2) TXA2 (t1/2 = 30 seconds) spontaneously hydrolyzes to inactive TXB2 3) Thromboxane contracts smooth muscle and induce platelet aggregation even at low concentration. b. Prostacyclin (PGI2) 1) Derived from PGH2 by the action of membrane-bound enzyme, prostacyclin synthetase 2) Relaxes smooth muscle and inhibits platelet aggregation 3) PGI2 (t 1/2) = 3 minutes) is converted to its inactive form: G-keto-PG Flalpha 7. Biosynthesis of HPETE and LT a. Mediated by lipoxygenases b. Arachidonic acid is converted to HPETE which eventually yield their corresponding HETE derivatives.

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c. Leukotrienes are synthesized from 5-HPETE by 5-lipooxygenase in neutrophils, monocutes, macrophages, mast cells, keratinocytes, lung, spleen, brain, and heart. d. These are potent vasoconstrictors, cause increased mucus secreting. e. LTC4, LTD4, and LTE4 mixture was earlier recognized as the slow reacting substance for anaphylaxis (SRS-A) f. Potency: LTD4 > LTC4 > LTE4 >>> Histamine g. LTB4 is produced mainly by neutrophils and has chemotactioc as, well as chemokinetic properties:

.

1) Causes adhesion of WBCs to endothelial walls. 2) Extravasation of leukocytes 8. Effects of eicosanoids a. Vascular smooth muscles 1) Vasodilation - PGI2, PGD2 2) Vasoconstriction - TXA2, PGF2 alpha b. GI smooth muscles 1) Contraction of longitudinal s.m. – PGE2 and PG F2alpha 2) Contraction of circular s.m. - PGI2 and PG F2alpha 3) Relaxation of circula smooth muscle c. Airways saooth muscle 1) Relaxed br PGEl, PGE2, and PGI2 2) Contracted by TXA2 and PG F2alpha d. Platelet aggregation 1) Inhibited by PEG1 and PGI2 F. PLATELET ACTIVATING FACTOR 1. Potent lipid inflammatory mediator (acetylglycerol ether phosplaorylcholine) derived from membrane phospholipids. 2. Produced by endothelial cells and by WBCs at the site of inflammation

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3. Effects: a. Vasodilation. b. Increased permeabillty c. Hyperalgesia d. Bronchoconstriction e. Platelet aggregation f. Degranulation g. Superoxide production in granulocytes NONSTEROIDAL ANTIINFLAMMATORY DRUG INSAIDS A. INTRODUCTION 1. These drugs are used to reduce the vascular and cellular response of the inflammatory process. 2. They reduce the concentration of inflammatory mediators, suppress the release of lysosomal enzymes, counteract vasodilation and reduce the tendency of cell to migrate to the lesion. 3. They generally act by inhibiting the formation of prostaglandins and thromboxane at the level of cyclooxygenase. 4. Their effects generally include antipyrexia and analgesia a. antipyrexia 1) Fever occurs as a response to minute doses of pyrogenic substances particularly interleukin (an endogenous pyrogen released by WBCs due to the presence of bacterial toxins). 2) Pyrogens induce the synthesis of PGE in the hypothalamus. 3) PGE then acts on the hypothalamic regular causing the generation of heat thus elevating body temperature. 4) NSAIDS prevent this effect by inhibiting the hypothalamic cyclooxygenase.

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5) Fever-reducing doses of NSAIDs have no significant effect on normal by temperature. b. Analgesia 1) Depend on their ability to prevent the sensitization of pain receptors. 2) Some analgesic effects are attributed to the anti-inflammatory activity of NSAIDS. B. SALICYLATES 1. These include a. Sodium Salicylate - one of the early synthetic antipyretics b. Salicylic acid - keratolytic agent c. Methylsalicylate - active component of oil of wintergreen d. Acetylsalicylic acid (Aspirin) - most widely used anti-inflammatory 2. Aspirin a. Administered by mouth to attain a systemic effect b. Rapidly absorbed in stomach because ionization is prevented by stomach acid c. During and after absorption acetylsalicylate is hyrolized and salicylic acid is liberated d. Widely distributed in the body e. Bound in plasma proteins and can displace other substances f. metabolized by conjugation with glucuronic acid or glycine g. Rapidly excreted unchanged in the alkaline urine h. These drugs have lower analgesic properties than narcotic analgesia i. Do not cause dependence and tolerance j. valuable for mild to moderate pain, eg.head, post-surgical, and k. Musculoskeletal pain - Uses

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1) Antipuretic - reduce distress in patients with fever 2) Ant inflammatory - reduce postsurgical or traumatic edema and some inflammatory conditions 3) Analgesic - reduce pain through its antiinflammatory activity -Side effects and toxicity 1) Irritation, bleeding and ulceration, of gastric mucosa 2) Hyperpnea followed by respiratory depression and acidosis 3) Impairment of hemostatis 4) Hepatotoxicity 5) Metabolic acidosis 6) Hyperthemia -Plasma half-life Man

1-1 1/2 hours

Horse

5 hours

Dog

8 hours

Cat 30 hours

Use with caution in cats because of the poor ability of this species to metabolize aspirin. C. ANILINE DERIVATIVES 1. These drugs include: a. Acetanilde b. Phenacetin c. Paracetamol 2. More toxic than salicylates, less irritant to the stomach and possess no antiinflammmatory activity. (usually not considered as NSAID) 3. Acetanilide converts hemoglobin to methemoglobin resulting to hypoxia, shorten the longevity of RBCs, and causes frank hemolysis (anemia). 4. Phenacetin causes necrosis of renal palilla in man and so is no longer used. 5. Paracetamol is the least toxic member of this group and at therapeutic doses, is free from all the side effects and adverse reactions of aspirin.

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6. Poisoning with paracetamol can still be encountered in cats following "treatment" by owners. 7. Cats poorly biotransform this drug and signs of toxicity include paleness, cyanosis, and facial edema. 8. Antidote include methionine cystein, which are glutathione precursors. 9. Antioverdose regimen include: a. Vitamin C b. Oxygen therapy for hypoxia c. Use of diuretics d. Acetylcysteine D. PYRAZOLONE DERIVATIVES 1. They have more powerful antipyretic, and antiinflammatory properties. 2. Can elicit hypersensitivity reactions in man and has now been banned for human use. 3. Phenylbutazone a. Shorter plasma half-life in animals than in man (72 hours) b. Binds extensively to plasma proteins and may displace other drugs (eg. warfarin) c. Biotransformed in the liver to oxyphenbutasone d. Rate of elimination depends on concentration. e. Relatively nontoxic to dogs and horses tl / 2 dog

= 2 1/2 to 6 hours

tl / 2 bourse = 3 1/2 to 8 hour a f. MOA: 1) Inhibit cyclooxygenase 2) Trap or scavenger toxic oxygen radicals g. Side effects: 1) Man

- hypersensitivity reactions - sodium retention with edema

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- increased plasma volume - kidney and liver damage - leukopenia 2) Horse - edema - erosions of buccal mucosa - gut ulcerations - necrostic phlebitis of portal vein 3) Dog

- GIT ulceration - biliary phlebitis - necrotic phlebitis - hemorrhage - kidney damage

h. Dosing recommendations should not exceed in quantity and duration. i.

Drug

is contraindicated in the presence of`heart, liver of kidney

disease.

4. Dipyrone a. One of the original pyrazolone derivatives b. Slight antiinflammatory, analgesis and antipyretic potency c. Relaxes smooth muscle particularly that of the GIT in a not well understood mechanisms d. Widely used in the management of equine colic and other conditions of GI spasms or hypermotility in both large and small animals e. Sometimes used with a spasmolytic agent to treat spasmodic colic f. Toxic effects same as phenylbutazone g. Overdose may lead to convulsions E. MODERN NSAIDSs

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1. Neclofenamic acid a. Derivative of anthranilic acid b. Antiinflammatory effect is more powerful that of phenylbutazone c. Antagonizes PGF2 alpha d.

Toxicity:

4x the recommended dose

produces colic, diarrhea,

anorexia, bloody feces, lowered PCV value e. Chronic toxic dosage signs: 1) CNS depression 2) Ulcer in the mouth 3) Diarrhea 4) SC edema 5) Tachycardia 6) Weight loss f. Fate in the body 1) Well absorbed per os 2) Biotransformed in the liver 3) Excreted in the urine 2. Flunixine a. Has significant analgesic potent antiinflammatory effect b. Short 1/2 in horses but prolonged duration of action (24-36 hours) c. Should not be used in horses or cattle intended for human consumption without observing the recommended withdrawal period d. Treatment should not exceed 5 consecutive days e. Available preparations for PO, IV, and IM 3. Naproxen a. Deprived from propionic acid b. Analgesic effect is a consequence of antiinflammatory action c. tl / 2 in plasma is 4 hours and so requires to docing twice daily d. Completely eliminated in 48 hours

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e. Effective on soft tissue (ex. myositis, tying-up syndrome in horses f. Reduce pain and inflammatory in muscle damage and brings complete relief from pain and lameness in 5-6 days g. Good only for horses; too toxic for use in dogs specially beagles (tl / 2 as 72 hours) because it is slowly metabolized F. MISCELLANEOUS AGENTS 1. Dimethylsulphoxide (DMSO) a. Organic solvent which is extremely hygroscopic b. Used as anti-inflammatory agent particularly for relief from pain and swelling in limb injuries in horses and dogs and for treatment of some very acute traumatic injuries. c. Analgesic action: reduction or interference with pain impulse conduction in peripheral nerves d. Rapidly absorbed following application e.

May enhance percutaneous absorption of many substances and potentiates activity of atropine and some endogenous steroids

f. MOA: scavenger of free hydroxul radicals of oxygen g. Recommendation: for topical application in dogs and horses 2 ml/day of a 7-9% solution q. 6-8 hours for not more than 2 weeks h. Precautions: 1) Apply with rubber gloves 2) Should not be used simultaneously with, before or after a few days of treatment consisting of anticholinergic drugs 3) Do not bandage or cover topical applications 4) Contraindicated i dogs and horses for breeding purposes (teratogenic) 5) Side effects: a) Transient and local erythema b) Burning effect c) Dry skin

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d) Occular changes-myopia, cataract 2. Selenium a. Available with toeopherol (Vit. E.) b. MOA: inhibit formation, of peroxides c. Maintain cellular integrity d. Toxic effects: nausea, GIT irritation muscle weakness, respiratory depression, initial CNS stimulation and later depression e. Chronic use: pathological changes in hearty kidney and pancreas f. Administered IM or SC 3. Sodium Hyaluronate a. Free Ka+ of hyaluroRic acid b. Hyaluronic acid is a component of synovial fluid and is responsible of giving its characteristics viscious lubricating properties; it is lacking in inflamed joints c. Used for treatment of joint disfunctions d. Labelled for use in horses (return to normal function may follow just one injection) 4. Polysylphated Glycosaminoglycan a. Resembles the ground substance of cartilage b. Inhibit inflawnation and protect cartilage from degeneration by inhilating lycosomal enzymes c. Reduce PG release and inhibits hyaluronidase and other enzymes capable of degrading proteoglycans on articular surfaces d. Used for repair of cartilage and promote integrity of synovial fluid e. Stimulate metabolism of chondrocytes and synovial cells f. Indicated for treatment of noninfectious joining dysfunction (lameness) or

intraarticularly (contraindicated) in actively inflamed or infected

joints) DOSES

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Sodium Salicylate: Large Animals 15-20 g PO Aspirin: Cat

10 mg/kg q. 48h PO

Dog

10 mg/kg q. 8-12h PO

Horse

30 mgkg q. 12h PO

Cattle

100mg/kg q. 12h PO

Pig

10 mg/kg q. gh

Phenylbutazone: Dog

10 mg/kg q. 12h PO (progressively decrease dose) 10-15 mg/kg q. 12h slow IV (adm. not more than 2 days)

horse

1-2 g/454 kg daily in 3 divided doses IV for a maximum of 5 days 2-4 g/454 kg PO but not to exceed 4 g/animal/day

Dipyrone: Horse

28 mg/kg PO 5-10 g/anmal IV, SC, IM. (may be repeated SID or BID q. 8h)

dog

0.6 mg/kg of 50% soln. (1-2 doses q. 8h daily)

cat

0.3 ml/kg of 50% soln. (1-2 doses g. 8h daily)

Meclofenamic acid: Horse

2.2 mg/kg PO SID x 5-7 days

Dog

1.1 mg/kg PO SID x 5-7 days

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Flunixin horse

1.1 mg/kg IM/IV daily (max. 5 days)

cattle

2.2 mg/kg IV daily (max. 5 days)

dog

0.5-10 mg/kg IM/IV daily (max. 3 days) or 1.0 mg/kg PO daily {max. 3 days)

Naproxen: horse 10 mg/kg PO BID x 14 days

GLUCOCORTICOIDS A. ADRENAL GLANDS 1. These are small, ellipsoidal organs found bilaterally at the anterior portion of the kidneys. 2. The mammalian adrenal glands is divided into an outer cortex and an inner medulla. 3. The adrenal cortex secretes corticosteroids and have three anatomical divisions: a. Zona glomerulosa b. Zona fasciculata c. Zona reticularis 4. The adrenal medulla is relatively homogenous and contain chromaffin cells which secretes epinephrine. B. CHEMISTRY OF ADRENOCORTICAL HORMONES 1. Adrenocortical hormones are derivatives of the 21- C pregnane nuclei called cyclopentanoperhydrophenatrene ring. 2. Endogenous corticosteroids differ in structure only in three positions:

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C-11, C-13, and C-17 3. Presence of hydroxyl or deteone group on C-ll indicates greater glucocorticoid activity with respect to carbohydrate metabolism 4. Absence of substituents on C-ll enhances mineral mineralocorticoid activity (effect on electrolyte metabolism) C. METABOLISM OF STEROIDS 1. Steroids are synthesized from cholesterol within the adrenal gland. 2. ACTH promotes conversion of adrenocortical cholesterol to glucocorticoids, mineralocorticoids and sex steroids 3. Steroid hormones are biotransformed in the liver, kidney and target tissues themselves, and are eliminated in the bile or urine. D. MECHANISM OF GLUCOCORTICOID REGULATION 1.Stress in any form, stimulates the hypothalamus to produce corticotropiN releasing factor (CRF). Stressors. include the following: a. trauma b. infection c. intense cold/heat d. sympathomimetic drugs e. surgical operations f. toxins g. restraint of the animal h. debilitating disease 2. The CRF signals the anterior pituitary to release adrenocorticotropic hormone (ACTH) 3. The ACTH then acts on the adrenal cortex and stimulates steroido-genesis. 4. Cortisol an endogenous glucocorticoid is released in the process

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5.

Increased cortisol levels send negative feedback signals to the anterior pituitary

and hypothalamus (+)

(-)

- - > - - - - - - - - - - - - - Hypothalamus < - - - - - - - - - - - - - - - - - - - - - -

B. GLUCOCORTICOID HORMONES 1. Examples a. Cortisone betamethasone b. Fluemethasone prednisone c. Flurocynolone dexamethasone d. Hydrocortisone e. Methylprednisolone f. Paramethasone Comparison of the corticoid bases: ANTI-

SODIUM

INFLAMATORY RETENTION

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DURATION (Hour)

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of Acting 1. Short Acting

1

++

48 >0

Hydrocortisone / Cortisone Cortisone 2. Intermediate-Acting Prednisone Prednisolone Methylprednisone Triamiconolone 3. Long-Acting Paramethasone Betamethasone Dexamethasome

F. PHARMACOLOGICAL EFFECTS 1. Carbohydrates Metabolism a. Enhancement of gluconeogenesis 1) Enzymes involved in gloconeogenesis are inceased in hepatocytes 2) Amino acids from extrahepatic tissues are mobilized b. Decreased utilization of glucose by cells c. Elevated blood glucose concentration/hyperglycemia d. Increased glycogen synthesis and accumulation in the liver 2. Protein Metabolism a. Reduction in cellular protein of extrahepatic cells 1) Decreased protein synthesis b. Increased blood amino acid 1) Mobilization of amino acid from cells

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c. Reduced amino acid

transport

into extrahepatic cells

d. Increased liver protein and plasma protein 1) Enhanced utilization of amino acids by liver cells 2) Increased liver protein synthesis 3) Increased formation of plasma proteins by hepatocytes 4) Increased formation of amino acids to glucose e. Advantage: conservation of glucose f. Disadvantage: muscle wasting 1) Delayed wound healing 2) Increased urea production 3) Negative nitrogen balance 3. Fat Metabolism a. Adepolinesis 1.) Mobilization of fatty acids from adipose tissues 2) Increased fatty acid plasma concentration b. Lipolysis 1) Due to decreased alpha-glycerophosphate concentration (derived from

glucose) which is necessary for deposition of

triglycerides in adipose cells c. Increased oxidation of fatty acids in cells d. Advantage: shift in utilization of glucose to fatty acid for energy by cells in time of starvation and other stresses e. Disadvantage: ketogenic effect particularly when insulin is deficient 4. Ions a. Increased retention of sodium b. Increased excretion of potassium c. Increased water retention d. Increased RCF volume, leading to edema e. Increased calcium mobilization f. Prolonged therapy causes

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1) Tendency towards alkalosis 2) Increased K+ secretion in exchange of increased sodium reabsorptions in kidney tubules 3) Polyurea (frequent urination) - due to antagonism of ADH in kidney and increased water intake 4) Polydipsea (increased water consumption) 5. I nflammmation-related Responses a. MOA: Inhibit membrane phospholipase A2 that mediate the release of arachidonic acid from the membrane phospholipids thereby inhibiting the synthesis of prostaglandin's and leukotrienes b. Effects: 1) Increased stability of lysososial merebranes (proteolytic enzymes are released very alow) and cellular insult due to toxins 2) Enhanced integrity of capillary walls (decreased leateinesis and prevention of the loss of plasma into the tissues) 3) Decreased chemotaxis of WBCs and phagocytosis of damaged cells 4) Reduced inflammatory edema fibrin deposition 5) Depressed capillary and fibroblast proliferation 6) Depressed activation of compliment system components 7) Inhibition of Kellikrein-Kinin system and plasminogen activation. 8) Suppression of tissue response to injury 9) Prevention or inhibition of acute and often undersirable reaction of tissue cells to insult such as trauma and crash 6. Blood Cells and Lymphatic System a. Lymphocyte function 1) Lymphocytopenia 2) Inhibition of T cells response to antigens 3) Temporary redistribution of circulating lymphocytes to bone marrow and lymphoid tissues

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a) Suppression of lymphocyte proliferation (interleukein 2 or T cell growth factor synthesis is impaired) b) Monocyte and macrophage function i. Monocytopenia in most species (monocytosis in dogs) ii. Diminished response to chemotactic factors and lyrophokines iii.Temporary redistribution of circulatory monocytes to lymphoid tissues iv. Inhibition of interleukein 1 production v. Impaired clearance of opsonized and non-opsonized substances c. Neutrophil function 1) Neutrophilia due to: a) Increased rate of release from the bone roar row b) Reduced migration out of the circulation c) Inhibition of margination in the capillaries 2) Diminished response to chemotactic agents a) Increased random migration b) Inhibition of neutropliil cellular metabolism c) Impaired antibody-dependent cell mediated cytotoxicity d) Decreased phagocytosis d. Increased RBC production (erythropoiesis) 7. Immune Reaction a. Inhibition of antibody produotiora (species dependent)

'

b. Inhibition of interferon (IFN) production c. Advantage of immunosuppression: 1) Prevent immunologic logic rejection of organ transplants d. Disadvantage of immunosuppression: 1) Infection and death from diseases which are not otherwise lethal 8. Cardiovascular System a. (+) Ionotropic action on the heart b. Increased blood pressure

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c. Increased perfusicm (opening up of capillary beds and prevention of sludging) d. Increased venous return to the heart e. Increased cardiac output and urine output 9. Central nervous System a. Enhanced neuronal activity b. Decreased

threshold

for

convulsion (contraindicated in epilepsy)

c. Produce ephciiria d. Decrease or prevent cerebral edema G. ENDOCRINE INTERACTION AFTER PROLONGED TREATMENT 1. Decreased secretion of ACTH 2. Atrophy of adrenal cortex 3. Increased insulin requirement of the animal 4. Tendency to cause androgenic effect (male sec hormone) 5. Induce parturition in late stages of pregnancy a. GCCs have been used in the induction of parturition in, the ruminants/ but this also favors the retention of placenta 6. Male Animals; it may inhibit spermatogenesis 7. Female animals; it may inhibit ovulation 8. Inhibition of linear growth and skeletal maturation in children 9. Stimulation of appetite 10. Peculiar central deposition of fat in the face, neck and abdomen H. EXOCRINE INTERACTION 1. Predispose to hypothyroidism 2. Decrease milk production in cattle 3. Decrease secretion of gastric acids 4. Increase secretion of sweat, salivary, sebaceous glands but decrease mucus formation in gastrointestinal and reproductive tracts

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I. ADVERSE REACTIONS 1. Single dose, no adverse effect (24-48 hours) 2. Prolonged administration can cause iatrogenic hyperadrenocorticism a. Increased serum sodiuto ions b. Decreased serum potassium ions c. Muscular weakness d. Hyperglycemia e. Deterioration of muscle mass f. Osteoporosis g. Decreased body defense mechanism h. Decreased interferon production i. Decreased amount of connective tissues ground substance j. Delayed wound/fracture healing k. Loose bowel l. Borderline diabetes mellitus 3. Sudden withdrawal after prolonged administration can cause HypothalamusPituitary-Adrenal (HPA) axis suppression due to the inability of the adrenal cortex to produce cortisol 4. Exogenous glucocorticoids should be removed slowly to restore normal adrenocortical function 5. Clinical adverse signs: a. Dullness b. Easy fatigability c. General unthriftiness d. Mental depression e. Incoordination f. Weight loss 6. Drug interactions a.

Potent

stimulator

of

barbiturate

metabolism,

insecticides

phenylbutazone, chlorinated hydrocarbons

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J. CONDITIONS FOR CONTRAINDICAT ION 1. Cushing's syndrome (hyperadrenocorticism) 2. Diabetes mellitus/hyperglycemia 3. Later stages of pregnancy 4. Epilepsy 5. Congestive heart failure 6. Renal insufficiency K. CLINICAL INDICATIONS 1. Replacement therapy especially for a. Addison's Disease b. Adrenolectomy 2. Therapy for metabolic abnormalities a. Functional hypoglyceinia b. Bovine ketosis c. Puerperal tetany eclampsia in bitches 3. Therapy of tissue insult a. Skin-dermatitis, otitis externa b. Respiratory 1) Chronic obstructive pulmonary disease 2) Dyspnea due to chronic edema c. Cardiovascular 1) Anaphylactic shock 2) Anesthesia 3) Hemorrhage 4) Trauma d. GIT 1) Colitis (granulomatous)

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2) Eosinophilic gastroenteritis e. Musculoskeletal 1) Arthritis, Bursitis, Laminitis 2) Bosinophilic myositis 3) Lameness f. Kidney 1) Gloroerulonephritis g. Eye-Chemosis, Keratitis, Uveitis h. Blood-aplastic anemia 1) Hemolytic anemia 2) Thrombocytopenia i. Brain 1) Cerebral edema j. Male reproductive organ 1) Phimosis

(to suppress formation of excessive granulation

tissue)

DRUGS ACTING ON THE RESPIRATORY SYSTEM A. EXPECTORANT These agents increase the fluidity and volume of respiratory secretions. 1. Inhalant Expectorants a. These agents are either heated or dissolved in steaming water for inhalation on a confined air space. b. Useful for small animals c. They either exposed to steam for repeated short periods or to an aerosol or water generated by pump and fed into a small, enclosed space.

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Examples : Benzoin

Camphor

Eucalyptus oil

Pine oil

Turpenteine

Lemon oil

2. Ingested expectorants/secretory expectorants a. Administered by mouth b. Some can induce vomiting but are given in subemetic doses while others are absorbed in gut and partly excreted in the brochial mucosa. Examples: 1) Reflex or Nauseant Expectorants a) Ipecacuania b) Squill c) Balsam of Tolu d) Cocillana 2) Locally acting, systemically administered expectorants a) Sodium iodide/Ammonium carbonate b) Potassium iodide/Potassium citrate c) Ammonium chloride guaifenesin/glyceryl guiacolate 3. Mucolytic expectorants a.

Regarded as expectorants although their action involves

liquifaction of mucus b. Assist on preventing and removing mucus plugs which may cause atelectasis and bronchiectasis Example: 1) Sodium Acetylcysteine a) Sulphydryl group breaks disulfide bonds of the glycoproteins in exudate b) Inhaled in the form of spray or aerosol 2) Bromhexine a) Increases volume and decreases visicidity of mucus

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b) Available in solution or powder, either alone or in combination with an antibacterial agent (eg. oxytetracycline) c) Improves lysosomal function causing hydrolysis of mucopoly saccharide fibers of mucus d) Dose: 1 mg/kg BID PO (small animals) 3) Dembrexine a) More recent addition into the equine market b) Modifies mucus consistency, decreasing its viscidity 4) Carbocysteine B. ANTITUSSIVES - Agents that reduces the incidence of coughing by acting locally or by Central depression of the cough center - Should not be used in cases where there is profuse respiratory secretion 1. Direct-acting Antitussives (Demulcents) a. These are sweet, syrupy vehicles in which other cough remedies are dissolved. b. They protects, coat, and sooth, inflamed respiratory mucosa for a short period. Example: Honey Syrup 2. Centrally Acting Antitussives a. Depress cough centers in the medulla oblungata 1) Narcotic Antitussives a) Codeine (Methylmorphines) i. A naturally occuring alkaloid which has been used as a major antitussive for years ii. Shares others action and effects of morphine iii. Do not usually cause dependence at doses for cough control but addiction is possible.

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iv. Dose: 1-2, g/kg PO 2) Others: a) Morphine/Dihydrocodeine b) Heroin (Diamorphine)/Dihydrocodeinone 2) Non-narcotic antitussives 1) Develop to increase the safety of these drugs, retain the ability to suppress the cough center but eliminate the CNS effects of narcotic antitussives Example: Dextromethorphan Noscapine Butorphanol Tartrate Trimeprazine Pholcodine C. BRONCHODILATORS 1. Bronchoconastriction is part of the complex series of events that initiate cough 2. It may induce by the release of chemical mediators in hypersensitivity and inflammatory reactions as well as drugs that cause contraction of the bronchial muscles 3. The resistance to the flow of air through the respiratory tract is increased and this causes difficulty in expiration 4. Drugs that cause bronchial dilation (bronchodilators) are therefore useful in the mana-gement of respiratory diseases which are accompanied by coughing and dyspnea a. Spasmolytics/Anticholinergics 1) These agents block the muscarainic chlorinoceptor-mediated bronchoconstriction Example:

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Atropine Eucatropine Ipratropiume Bromide b. Sympthomimetics 1)

Sympathetic stimulation brings about relaxation of the

bronchiolar smooth muscle 2) Sympathomimetic agents block the B2 receptors in the lungs Example.: Isoproterenol/Terbutaline Albuterol/Clenboterol Metaproterenol/Epinephrine (1:1,000 soln. for injection) Dose: large animals 2-4 ml c. Clenbuterol 1) Along acting B2 agonist for bronchospasm in horses 2)

Used chronic allergies, bronchitis, chronic, obstructive,

pulmonarydisease, equine influenza 3) Dose: 0.8 ug/kg BID for 10 days PO or parental

D. MEMBRANE-SHRINKING DRUGS 1. These agents cause shrinkage of the swollen respiratory mucous and reduce sections. a. Decongestants (Alpha-adrenergic Stimulants) 1) Have vasoconstricting properties utilized to decrease respiratory mucosa and shrinkage of swollen nasal tract 2) Effect is attained locally through the use of nasal sprays or systematically by oral administration Example: Phenylephrine/Phenylpropanolamine Propylhexedrine/ Oxymethazoline

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Tuaminopheptane b. Corticosteroids 1) Used in humans in the treatment of severe bronchodilator-resistant asthma 2) Anti-inflammatory activity include a. Stabilization of lysosoroal membranes b. Reduction of antibodies synthesis c. Reduction/prevention of release of inflammatory mediators d. Lessened fibrosis e.

Blockade of uptake 2 an extension of the half-life (t1/2) of

Endogenous sympathomimetics 3) Used to control chronic allergic-type summer coughs in dogs 4) Chronic use yield undesirable/unwanted side effects Example Prednisolone c. NSAIDS 1) Suppress productions of chemical mediators of inflammation thereby reducing structural damage and functional impairment of pneumonic lung 2) Improve ventilation, gaseous exchange and pulmonary hemorrhage Example: Flunixin d. Antihistamines 1) Counteract activity of histamine in bronchoconstriction 2) These agent also possess parasympatholytic, local anesthetic and they may be given for long periods without ill effects Example: Diphenhydramine

HCl/Chlorphenylamine maleate

Promethazine Pyrilamine maleate Tripelenamine HCl

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RESPIRATORY STIMULANTS 1. Ammonia a. Causes reflex stimulation of the respiratory and vasomotor centers so that both respiratory and circulatory improvement follow if the degrees of CNS depression is not deep 2. Analeptics a. These agents stimulate the respiratory and vasomotor centers in the medulla b. Administered IM or IV and are more effective than ammonia Example: Doxapram 3. Physiologic Stimulants a. Oxygen 1) Essential for life 2) Counteracts anoxia which can cause irreversible brain cell damage and death 3) Usually used to combat hyperemic hypoxia caused by anesthetic respiratory depression and other conditions that decrease adequate oxygenation in the tissue and blood a) Adequate oxygenation in the tissues and blood b) Adequate oxygenation with effective C02 removal is necassary during anesthesia because elevation of body CO2 levels (hypercapnia) leads to acidosis, a condition,

and decreases

ionization of barbiturates in the blood promoting the entry to their cells c) Administered only for short periods because of its tendency to cause hypocapnia with alkalosis resulting to mark fall in blood pressure and cardiac arrest d) Optimum concentration is 40-60% 2-3x than normal air concentration

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b. Oxygen 1) Stimulates the respiratory center and chemoreceptors 2) Usually administered at 5% concentration with oxygen 3) Prevents respiratory alkalosis that accompanies hyperventilation 4) In alkalosis, oxygen slowly dissociates from hemoglogin; the administration of carbon dioxide improves the oxygen supply to the tissues DRUGS AFFECTING GASTROINTESTINAL FUNCTION A. GENERAL CONSIDERATION The treatment of the gastrointestinal diseases presents a number of special challenges that arise from the following characteristics of the digestive system: 1. The gastrointestinal tract is the usual route of administration of most drugs, which may have effects on the gastrointestinal mucosal lining. 2. The therapeutic effect of a drug can be achieved without the drug entering the circulation. 3. The entero-hepatic cycle can be exploited in the design of the therapeutic regimen. 4. The GIT harbors a rich microbial flora and fauna. Some drugs may require microbial action to attain their full therapeutic activity. 5. Drugs-to-drug and drug-to-food interactions can influence the absorption and effectiveness of various therapeutic regimens. 6. The GIT is one of the richest endocrine organs of the body. 7. Any dysfunction of the GIT influences the effectiveness of orally administered drugs. B.

PHARMACOLOGICAL

PRINCIPLES

IN

THE

THERAPY

GASTROINTESTINAL DISORDERS

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OF

1. The pathophysiology of the symptoms in individual patient should be well understood so that therapy will be more selective and therefore more effective. 2. Sometimes therapy may be directed at the symptoms during diagnostic evaluation, or when diagnostic analysis fails to yield a full understanding of the cause of the symptoms. This is done to alleviate the discomfort of the patient but should not be considered as specific and the only treatment. 3. Some symptoms may be eliminated by withdrawal of the offending agents, and may not require further pharmacological treatment. 4. Gastrointestinal therapeutics may require interruption of normal or abnormal physiological process. 5. Therapy is often aimed reducing the functional stimulus to inflame or diseased organs. 6. When treating chronic disease, diagnose first. 7. Always consider the negative effects of the drugs to be used. SOURCE: Landicho, E.P. lecture handouts in Vet.

Pharma. 142

(Clinical

Pharmacology). College of Vet. Med. UPLB, College, Laguna. C. CLASSIFICATIONS OF DRUGS ACTING ON THE GASTROINTESTINAL SYSTEM 1. Sialogogues/Salivary Stimulants a. Increase the flow of salivary b. MOA:

stimulation of taste buds or parasympathetic stimulation

c. No therapeutic benefit 2. Antisialogues/Salivary Inhibitors a. Indicated where salivary secretion is undesirable (eg. presurgical medication to reduce bronchial and salivary secretions) b. Consistency of salivary secretions: 1) Watery-parasympathetic stimulation

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2) Vicious-sympathetic stimulation Ex. Atropine is the most commonly used antisialogogue and preanesthetic medication to reduce salivation. 3. Emetics a. Agents that induces vomittng b. Emesis is a protected reflex that occurs effectively is some species of animals c. True emesis is not possible in: 1.) horses 2) ruminants 3) rabbits 4) rodents d. Regurgitation of stomach contents occur with these species E.Vomiting can be induce in dogs and cats f. Indications: 1) Evacuation of stomach contents prior to anesthetic 2) Reduce absorption of poisons a. CENTRALLY-ACTING EMETICS 1) MOA: they stimulate the chemoreceptor trigger zone in the area postrema of the medualla oblongata. The CTZ then stimulates the vomiting center and emesis follows. The CTZ is sensitive to drugs and metabolic disturbances. 2) APOMORPHINE HYDROCHLORIDE a) An alkaloid derived from morphine but is no longer classified as narcotic b) A dopamine agonist c) Reliable emetic for dogs: vomiting occurs occurs in 2-3 minutes after administration and may continue for 5-15 minutes d) Causes CNS excitation in cats e) Should not be used in advanced cases of toxicity because additional shock can kill the patient

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f) Dose in dogs: 0.04 mg/kg IM of SC 3) IPECUC SYRUP a) Has been used as emetic but the vomiting is not consistent b) They cause toxic effects and even death c) An old drug but may still be apart of some drugs presently used 4) XYLAZINE a) A sedative-analgesic b) Do not use in shock animals where its sedative effect may aggravate condition c) Dose:

0.05-1.0 mg/kg IM (emesis in cats, sometimes in dogs 1-3

mg/kg IM (dogs) 5) PROSTAGLANDIN F2 a.) Causes vomiting and defecation when given in high doses and may also cause bronchoconstriction b) Usually used in reproductive disorder in the dog or in estrus synchronization in large animals. a. LOCALLY ACTING EMETICS/IRRITANT EMETICS These agents irritate the stomach - this will stimulate the vomiting center via the autonomic nervous system. a. Hydrogen Peroxide (3%) 1) Induces vomiting within 5-10 mins. 2) Dose: 5 ml (1 tsp.) given orally b. Sodium Chloride 1) Used as solid and deposited at the back of the tongue or as a solution of 1-2 tsp. in 1 cup water swallowed 2) Causes vomiting in about 15 mins. c. Copper Sulfate, Zinc Sulfate, freshly ground mustard seed 4. Antiemetics

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a. Agents that prevent or stop vomiting b. The control of emesis is necessary because prolonged vomiting can cause exhaustion, dehydration, hypochloremia and metabolic alkalosis. c. Indications 1) motion sickeness 2) vomiting associated with metabolic diseases CENTRALLY-ACTING ANTIEMETICS a. MOA:

they raise the threshold of excitability of the CTZ or the vomiting

center I) Antihistamines a) Dimenhydrinate (DramamineR) - Dose: 8 mg/kg 0.8 hrs. PO (dog & cat) b) Diphenhydramine (BenadrylR) - Dose: 2-4 mg/kg 0.8 hours PO (dog & cat) 1-2 mg/kg 0.8-12 hours IM c) Cyclizine - Dose: 25-100 mg daily in divided doses (dog & cat) d) Miclizine (BonamineR) 2) Tranquilizers a) Chlorpromazine - Dose: 0.5 mg/kg PO IM (dog & cat) b) Acepromazine - Dose: 1 mg/kg (PO, IM (dog & cat) c) Promethazine - Dose: 2 mg/kg an hour before travelliag (dog & cat) 3) Haloperidol Dose: 0.02-0.1 mg/kg IM (dog)

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LOCALLY-ACTING ANTIEMETICS a) MOA: diminish irritating stimulant that begins in the stomach 1) Oral Antacids (a) Indicated in dogs and cats to lessen gastric acidity on conditions like ulcer disease, acid hypersecretion due to renal failure, histamine release from mast cell tumors. (b) Often incorrectly used as antiemetics because of their capability to reduce vomiting caused by gastric hyperacidity. (c) They are not absorbed and therefore they do not cause systemic alkalosis. (d) Excess may cause catharsis (increased peristalsis) (e) Aluminum salts depletion of phosphates, which is characterised by weakness and demineralization (f) May decrease asorption of other drugs from the stomach (eg. tetracyclines) (g) Decrease the secretion of pepsin so these should be given concurrently with inhibitors of gastric acid secretion (h) Should be administered 0.4-6h to ensure control of gastric acidity Example: Magnesium Oxide Magnesium Hydroxide Magnesium Silicate Calcium Carbonate Calcium Hydroxide Almninum Hydroxide Ammonium Carbonate - Dose: Magnesium hydroxide 5-10 ml PO 0.4-8 h Aluminum hydroxide 5-10 ml PO 0.4-8 h

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2) Histamine-2 Antagonists/Inhibitors of Gastric Acid Secretion (a) These also referred to as ulcer- healing drugs (b) They block H2 receptors found in the gastric mucosa which mediate acid secretion (c) Causes inhibition of cytochrome P-450 (cimetidine and ranitidine) (d) Inhibit glucuronidation of acetaminophen (ranitidine) (e) Inhibit renal clearance of basic drugs secreted by the renal tubules (f) Cimetidine has antiandrogen effects - Doses: CIMETIDINE 5-10 mg/kg BID-OID PO, IM, IV, 0.6-8 h (dogs & cats) RANITIDINE 1-2 mg/kg BID PO, IM 0.12 h (dogs & cats) FAMOTIDINE* 0.5-1 mg/kg SID PO IV NIZATIDINE*

5 mg/kg SID PO

*Doses currently used in dogs but not yet established. OTHER ANTI-EMETICS 1) Metoclopramide a. Has a dual mode of action b. It possesses parasympathomimetic activity and promotes gastric emptying. c. It is also a dopamine receptor antagonist with a direct depressant effect in the CTZ. d. Has been used treating emesis such as those associated with cancer therapy, pasvovirus infection recovery from gastric dilatation, chronic gastritis, esophageal reflux e. In dogs it is 35 x more potent than chlorpramazine - Dose:

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Dog and Cat = 0.25-0.5 mg/kg PO SC, IM, IV 0.6-2 h or 1-2 mg/kg/day constant for infusion 2) Atropine a. A cholinergic blocker b. MOA: competes with acetylcholine for muscarinic receptor sites c. Decreases gut motility, tone, and secretory activity of gut - Dose: 0.4 mg/kg SC, IM 5. Antidiarreal Drugs a. Adsorbents 1) Absorb dissolved or suspended substances such as gases, toxins, and bacteria a) KAOLIN (Hydrated Aluminum Silicate) (1) Usually in combination with pectin, a protectant (2) Generally safe but gastric carcinoma may be produced with prolonged use (3) Prevents absorption of certain drugs: tetracycline (4) May not is able to absorb E. coli enterotoxin, its use in the treatment of neonatal diarrhea is not satisfactory (5) Do not administer together with other drugs - Dose: horse/cow 50-200 g PO Foal/Calf 15-60 g PO Dog up to 8 g PO 2) Activated Charcoal a) Residue of destructive distillation of various organic materials and treated in such a way as to increase the surface area of the particles. b) One of the components of the so-called "universal antidote", other components are magnesium oxide (antacid) and tannicacid (astringent) 3) Attapulgite a) Absorb enterotoxines, especially in activated form b) Heating carries out activation

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b. Protectants 1) Form a thin layer over skin or mucous membrane in order to prevent contact with possible irritants a) PECTIN (1) A purified carbohydrate from citrus or apple rinds b) BISMUTH SALTS (CARBONATE, SALICYLATE) (1) Also antisecretory (2) Use in the treatment of diarrhea (3) Carbonate has antacid effect (4) Salicylate has local ant inflammatory effect (5) Can absorb E. coli enterotoxins (6) Bismuth Subsalicylate 1-2 ml/kg q. 6-8 h for 1-2 days

c) SUCLRALFATE (1)

A nonabsorbable sulfate sucrose complex that protects denuded mucosa by adhering rightly to it.

(2) Indicated for gastroduodenal ulceration/erosion/ esophagitis, stress ulceration (3) Other orally administered drugs should be used 1-2 h before after administration (4) Side effect constipation - Dose: 1/4-1 g PO TlD OID, depending on patient size d) MISOPROSTOL (1) For treatment and prevention of gastroduodenal ulceration, particularly associated with NSAIDs (2) A newer cytoprotective drug c. Motility Reducers/Inhibitors (Antispasmodics) 1) Drugs that prolongs transit time 2) Cholinergic Blockers: a) Atropine

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b) Methscopolamine - Dose: 0,3-1.5 mg/kg 0.6-8 h for 1-2 days 3) Opiate Derivatives a) MOA:

Increase segmental motility and sphinchter muscle tone

decrease peristalsis and movement of intestinal contents in the lumen b) Indicators: treatment of one specific acute and chronic diarrhea c) May increase the risk for proliferation of pathogenic bacteria in the intestinal lumen (1) DIPHENOXYLATE

(+ atropine = lomotilR)

(a) May be a sedative in dog (b) Well absorbed in GIT and metabolized in liver - Dose: 0.5-0.1 mg/kg PO 0.6-8 h (dog) (2) LOPERAMIDE HYDROCHLORIDE (Lormide®, Immodium®) - Dose: 0.8 mg/kg PO 0.8 h (dog) (3) PAREGORIC (a) Camphorated tincture of opium (b) Traditional remedy for diarrhea 6. Other Drugs acting on the GIT a. Astringents 1) Produce protein-precipation acting limited to the surface of the cells (the permeability of the cells is reduced but the cells remain viable) Effects: a) Protection of tissue form irritation substances b) Reduction of intestinal secretion c) Reduction of absorption of toxic materials - Doses: Tannic acid, Krameria, Gambir, Nutgal, Querium, Geranium b. Carminatives

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Effects: expulsion of gas and reduction of foam formation Examples: Simethecon, Poloxalene, Turpentine, Camphor, Peppermint, Capsicum, and Ginger 7. Laxatives/Cathartics a. Purgatives/cathartics/aperient:

cause intensification of intestinal activity

resulting in the expulsion of intestinal content from the colon and rectum b.

Laxatives: cause similar action but the effect is milder

c.

Both hasten the rate of passage of materials through the GIT and promote defecation - indications: constipation 1) Removal of toxic materials from the GIT 2) Soften stool in cases when straining may be detrimental eg.:

rectal, vaginal/ or uterine prolapse) sometime to remove edema fluid)

a) STIMULANT LAXATIVES 1)

Increase the propulsive motility of the bowel by a variety of mechanisms.

2)

Contraindicated in the presence of obstructive lesions and not appropriate for long term use.

(A) Direct Irritant (1) Phenopthalein (a) Direct acting irritant cathartic (b) Has prolonged action due to ricinoleic acid, which stimulate colonic motility and secretion - Dose:

Dr. Elmer Q. Abillar

pig's

1-2 g

Dog

0.03-0.2 g

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Cat

15-65 rog

(2) Castor Oil (a) Hydrolyzed in the intestine to ricinoleic acid which stimulates colonic motility and secretion (3) Linseed Oil (a) Metabolized to linoleic acid which has less irritant effect than ricinoleic acid (B) Indirect Irritant - requires absorption and metabolism before they can exert their irritant action and stimulate intestinal movement 1) Danthron a) An anthraquinone laxative b) A snythetic analogue of emodin c) Slow-acting (effective within 6-14 h in dogs and cats, and within 12-36 hours in horses and cattle) d)

Prolonged use may lead to degeneration of the myenteric plexus leading to loss of intestinal motility

e) Excreted into milk and may affect offspring f) Commonly recommended for horse - Dose: horse 15-40 g cattle

20-45 g

dog

300-400 mg

cat

100-250 mg

2) Bisacodyl a) Stimulates colonic smooth muscle and myenteric plexus Dose: 5 mg/day 10 mg/day

(cats and small dogs) (medium-sized dogs)

15-20 mg/day (large dogs) 3) Senna 4) Cascara Sargada b) SIMPLE BULK FORMING LAXATIVES 1) Milder than that of stimulation laxative

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2) Added to the food to promote soft feces and normal cooling motility for the prevention and control of constipation 3) Insoluble fiber laxatives derived from cereal grains and seed coats 4) MOA:

absorb water, increase bulk of fecal content and soften fecal

consistency due to its hydrophilic properties --> bowel distention — > increase pressure stimulus--> stimulates reflex contraction of intestinal musculature leading to increase in power and speed of peristalsis Example:

Methylcellulose PsyIlium compounds Bran Agar

5) Mainly used small animals for their mild stimulant effects Indications: Constipation - due to diets consisting of concentrated food with low fiber content Diarrhea -

gel laxatives trap large amounts of water so they are useful in the symptomatic treatment of diarrhea and under this condition they decrease the fecal fluid content --> decreased speed of intestinal transit

c) SALINE BULK FORMING/OSMOTIC LAXATIVES 1) Ionic compounds which are poorly absorbed from the GIT that retain and absorb water from the tissues into the intestinal lumen. The resulting bowel distention promotes peristalsis. (a) Magnesium Sulfate (Epsom Salt) Dose: as purgative

as laxative

Cow 0.24-0.48 kg

Horse 30-60 g

Sheep 60-120 g

Cow 60-120 g

Sheep 7.7-15 g

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Pig 15-30 g Dog 5-25 g Cat 2-5 g Effect within 3-12- hours in simple stomached animals and after Approximately 18 hours in ruminants 2) Contraindicated in dehydrated patients and those with renal disease 3) Fluid should be available throughout the treatment 4) Absorption of appreciate amount of Epsom's salt may cause CNS 5) Depression and neuromuscular blockade 6) In cases of poisoning with epsom’s salt, give patient activated charcoal and a stimulant cathartic (magnesium adsorbs to activated charcoal) (b) Sodium Sulfate (Glauber's Salt) (c) Sodium Potassium Tartrate d) LUBRICANT LAXATIVES 1) Lubricates intestinal mucosa and interferes with water absorption 2) These group have laxative rather than purgative action and their effect I entirely mechanical. 3) Their oily and lubricant character enable them to coat the entire mucosa and intestinal contents thereby smoothens the passage of fecal material and reduce water absorption. 4) Prolonged use may interfere with absorption of nutrients. (a) Mineral Oil Dose: large animals small animals

0.5 to 2.0 liters 2.0 to 50 ml

(b) Liquid Paraffin Dose: horses, cattle foals, calves

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0.5-2.0 liters 60-120 ml

10/23/2013

Dogs

2-60 ml

Cats

2-10 ml

e.) EMOLLIENT LAXATIVES 1) These are surfactants, wetting agents or detergents 2) Reduce surface tension of intestinal contents by allowing fecal matter to be easily penetrated by water 3) Have slowly onest of action (1-2 days) 4) The induce hypovolemic shock in horses 5) May enhance toxicity of toxic drugs 6) Should not used with mineral oil because they can increase the undesirable absorption of mineral oil. The mineral oil reduces the emollient effect of the also docusate. (a) Dioctyl Sodium Sulfosucciaate (Docusate Sodium) (b) Dioctyl

calciuia

(Docusate Calcium) Dose: Cattle & Horse

5 – 10 g/animal

Dogs

15 – 120 mg/animal

Cats

5 – 30 mg/animal

8. Motility Modifiers/GIT Secretion Inhibitors a. Prokinetics (Cholinergics) 1) ARECOLINE - used as purgatives for the expulsion of taperworros NEOSTIGMINE, OHYSOSTIGMINE, CARBAMYLCHOLINE, BETHANNECHOL METOCLOPRRAMIDE 2) MOTILITY REDUCERS/INHIBITORS - opiates and their derrivatives 9. Inhibitors of GIT Fluid Secretion a. Anticholinergics

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b. Phenothiazine tranquilizers 1) Mechanism may involve inhibition of calimodium, a calcium-binding protein required in intestinal ion and fluid secretion c. Optiates d. Prostaglandin inhibitors (NSAIDS) 10. Enemas a. Refer to infusion of large volumes of warm fluid per return or warm, soapy water or glyceryl to soften fecal mass and float out impacted materials (eg. undigested bone) b. For removal impacted rectal and colonic contents in does or in the treatment of colic 11. Cholagogues a. Drugs that stimulates bile flow b. Menbutone INTRODUCTION TO CHEMOTHERAPEUTIC DRUGS DEFINITION OF TERMS Chemotherapy

-

refers to the use of drugs

and chemicals to treat or prevent

disease caused by infectious organisms and-neoplastic cells. Chemotherapeutic Agents - are the drugs or chemicals used for chemotherapy and are classified according to the kind of disease or infection they are used for. Those used against infectious organisms are also called ANTIINFECTIVE AGENTS. Antimicrobial Agents - are substances of natural, semi-synthetic, or synthetic origin that kills or inhibits the growth of a microorganism, but cause little or no host damage. Antibiotic

- is a substance propduced by a miroorganism that at low concentrations inhibit or kill other organisms.

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Antifungal/Antimycotic

Agents

-

are substances intended to treat fungal (myotic)

infections. Antiparasitic Agents - are those substances used against internal and external parasites. a. Antiprotozoans - are used against protozoan diseases. b. Antihelmentics - are used against worms. 1) Antinematodal - vs. roundworms 2) Anticestodal —vs. taperworms 3) Antitrematodal - vs. trematodes Antiviral Agents - are used against viral infections. Antineoplastic - are used against cancer cells.

GENERAL PRINCIPLES OF ANTIBACTERIAL THERAPY 1. Possible Responses or Effects a. No Effect b. Super infection; New infection arising from the use of broadsprectrum antibacterials c. Development of bacterial resistance d. Toxicities e. Adverse interactions with other drugs concurrently used f. Allergic response h. Killing or bacterial growth inhibition

2. Considerations in the Choice of Antibiotics

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a. Etiology (bacteria) 1) What causes the disease? 2) Is an antibiotic required or would another drug cure the disease?' 3) It is possible to use a narrow-spectrum antibiotic which is more selective? b. Animal Host 1) Age

3) Clinical condition

2) Size

4) Drugs concurrently taken

c. Antibacterial Agent 1) Pharmacodynamic and pharmacokinetic properties 2). Ability of the drug to penetrate tissues 3) Drug interaction d. Duration of Treatment 1) Safety and economics 2) How long should the drug be given and at what dosage rate? 3) Bacterial are more effectively killed in the early logarithmic phase of growth. 4) Majority of antibiotics are better administered at large doses while bacterial number is still low (exceptions are polymyxins and penecillin because

their activity is not affected by the number of bacteria

present) 3 . Essential for Anbacterial Therapy a. The drug must come in contact with the infecting organisms. b. The drug

must be present in levels above the minimum inhibitory

concentration (MIC) in the plasma. 1) MIC refers to the lower effective concentration of the drug that will inhibit the growth of a specific bacterial species. 2) MIC of a a drug for a bacterial species may not be the same for the other species.

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c. The drug must be present at the site of infection for a sufficient length of time in order to give time for effective drug-bacteria interaction. d. The microorganism must be sensitive to the drug at usual doses. 4. Criteria for Selecting Antibacterial Agents a. Selectivity and Effectivity 1) Drug must be effective against the bacteria in question 2) Determined by sensitivity testing 3) If laboratory identification of bacteria is not possible, treatment should be directed to the disease that is most likely to cause the observed symptoms. b. Low Toxicity to Host c. Good Therapeutic Ration. No adverse effect when given in high doses. d. Good Storage Properties e. Stable in the presence of body fluids, exudates and necrotic tissue debris. Antimicrobial efficacy must not be significantly reduced. f. Effective in various routes of administration g. Good blood and tissue levels attained after administration h. Affordable or available at reasonal cost i. Does not induce development of bacterial resistance 5. Bacterial Resistance to Antibiotics a. There are several ways by which bacterial become resistant to antibiotics. b. These microorganisms are already considered to be resistant to antimicrobial compounds when they are no longer susceptible. c. There are also several ways by which bacterial protect themselves against the harmful effects of antimicrobial agents and these involve the following: 1)

Inactivation of drug by elaboration or increased synthesis of drug metabolizing enzymes.

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a) Bacterial have enzymes that degrade the antibiotic b) Eg. Staphylococci can produce betalactamase (penicillinase/ cephalospo rinase) which render them resistant to beta-lactam antibiotics 2) Altered configuation or structure as well as concentration of a receptor or target sites. a)

This results to the decrease in affinity of the antibiotic to the

receptor. 3) Alteration in the permeability of the drug in the resistant cells a) eg. inability of the drug to penetrate the bacteria due to development of impermeable cell walls 4) Utilization of alternate metabolic pathways a) Bacterial develops another metabolic pathway which will not be blocked by the antimicrobial agent b) eg. sulphonamide-resistant bacteria develop the ability to use preformed folic acid 5) Induction of membrane transport system that can remove antibacterial agents 6) Decreased enzyme affinity a)

eg.

in

sulfonamide-resistant

bacterial

strains,

their

tetrahydrofolate enzymes have lesser affinity for sulfonamides than for PABA as compared with that sulfanamide- susceptible bacteria d. Resistance of genetic origin 1) Chromosomal resistance - involves R factor or plasmids a) More complex than chromosomal resistance b) Plasmid mediated resistance c) Can be passed to another cell via transformation, transduction, conjugation

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e. Mechanisms of development of resistance 1) Mutation - alteration in the genes; there is selective multiplication of resistant genes 2) Genetic Recombination or Gene Transfer Reactions: a) Transduction - bacteriophage is capable of transfering resistant gene; passes a gene carrying resistance from, one strain to another b) Transformation - bacterial cell acquires from its environment particles of chromosomal

material released from a

lyzed

resistant bacterial cell c) Conjugation - Involves the transfer of a resistant gene through sex pilus; also transfer of plasmids or R factor f. Types of bacterial resistance: 1) Innate Resistance a) Certain bacteria have innate (intrinsic) characteristics which enable them to resist the lethal effects of antimicrobials (eg. cell wall) 2) Acquired Resistance a)

Occurs when a previously susceptible population becomes resistant following exposure to the antibiotic

b) When resistant bacteria are contained in original susceptible population, they rapidly multiply and replace the susceptible population g. Guidelines to minimize bacterial resistance: 1) Avoid using broad-spectrum antibacterials if a narrow-spectrum is effective against the causative agent 2) Seek information about the endemic infection and sensitivity of the antibiotic used 3) Follow appropriate doses

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4) When combination therapy is required to prevent the development of resistance, use individual agents in full dosage. 5) Use antibacterial agents for topical application which does not cause resistance 6) For prophylaxis, use antibacterial that prevents colonization of specific organism or eradicates it after it has become established 7) Use antibiotics when the medical indications are clear 6. Factors that Influence Clinical Use of Antibiotics a. Use of combined antibiotics or use of antibiotics other chemotherapeutic agents 1) Bacterial plus bactericidal - may be synergic 2) Bacteriostatic plus bacteriostatic usually additive 3) Bacteriostatic plus bacteriostat -

may be antagonistic because the

former suppress growth or bacterial division while the latter usually act on actively dividing cells b. Blood and tissue levels of available antibiotics 1). These influence the route of administration and the nature of formulation of the antibiotic c. Reaction with blood and tissue fluids 1) The potency of some antibiotics are not altered by the presence of these fluids while some are affected unfavorably 2) Absorption of some antibiotics from the gut may be inhibited by the presence of other chemical substances in the intestinal contents d. Physiological barriers 1) Blood-brain barrier a) This is a physiological division between the blood and the CSF b) Some

antibiotics

(eg. penicillin, oxytetracycline) can only

pass through this barrier when the meninges are inflammed

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c) Antibiotics like chloramphenicol can penetrate the barrier relatively easily 2) Placental barrier a) Does not normally resist the passage of antibiotics 3) Intestinal barrier a) Limit the absorption of some orally administered antibiotics into the circulation 4) Serous membrane a) Penicillin does not readily pass through normal pleural or peritoneal membranes while chlortetracycline does 5) Milk a) Concentration of antibiotic in milk depends on the type of the antibiotic b) Penicillin concentration in the milk is generally lower than that in the plasma except in mastitis cases where as the concentration of other antibiotics in milk is much higher than their concentration in the plasma e. Intestinal flora of herbivores 1) Ruminants largely depend on the integrity of their ruminal microflora f. Immunity 1) Use of broadspectrum antibiotics usually causes rapid elimination of infectious agents and development of immunological reactions. 2) Further infection may develop once the antibiotic is withdrawn 7. Reasons for Failure of Antimicrobial Therapy a. Drug 1) Inappropriate drug a) Organism is not susceptible to the antimicrobial agent used b) Use of expired or substandard product 2) Inadequate dosage or incorrect dosage

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3) Improper route of administration 4) Adverse side effects of drug 5) Interaction with concurrently administered drugs (use of incompatible drugs in the therapy) 6) Accelerated drug excretion 7) Poor penetration of drug into the site of infection b. Host 1)

Compromised host defenses (due to disease, malnutrition, or concurrent therapy)

2) Inadequate drainage of pus and other cellular debris 3) Retained infected foreign body 4) Presence of dead tissue 5) Lack of owner compliance to therapy (dosage regimen not followed) 6) Inadequate supportive therapy 7) Uncorrected nutrition deficits 8) Substandard nursing care and stress c. Pathogen 1) Development of drug resistance 2) Super-infection by a resistant, opportunistic pathogen 3) Reinfection by original or other pathogenic bacteria 4) Initial multiple infections (only one organism was detected and treated) d. Laboratory 1) Incorrect diagnosis 2) Erroneous report of the susceptible pathogen 8. Combination Therapy a. Antimicrobial combinations have been employed in the treatment of some cases b. Objectives of this type of treatment are to 1) Treat mixed bacterial infection in which organisms are not susceptible to a common antibacterial agent

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2) Achieve synergestic antimicrobial activity against particularly resistant strains (eg. Psuedomonal aeruginosa) 3) Overcome bacterial tolerance 4) Prevent the emergence of drug resistance 5) Minimize toxicity of toxic antibiotics 6) Prevent inactivation of antibiotics by enzymes that are present c. Examples: 1) Clindamycin, metronidazole or semisynthetic penicillins + aminoglycosides 2) Carbenicllin or ticarcillin + gentamicin or tobramycin 3) Penicillins or cephalosporins + clavulanic acid or sulbactam 9. Interbacterial Drug Interactions a. Antimicrobial, are genrally classified as bacteriostatics and bactericidal. b. Bacteriostatics often act in additive fashion while bactericidals are often synergestic. c. Additive or syaergestic effects occur when these agents are used in combination but antagonism may occur with serious consequences. d. Effectivity of bactericidals may be impaired with concurrent use of bacteriostatics but there are now exceptions and other factors also play a role. e. Additive - if the combined effects of the drugs equal the sum of their independent effects. f. Synergestic - if the combined effects are significantly greater than the independent effects. g. Antagonistic – if the combined effects are significantly less than their independent effects h. Synergium in antimicrobial combinations usually involves. 1) Sequential inhibition of successive steps in metabolism (eg. trimethopimsulfonamide) 2) Sequential inhibition of cell wall synthesis (eg. Moxillinam-ampicillin)

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3) Facilitation of entry of one antibiotic by another (eg. beta-lactamaminoglycosides) 4) Inhibition of inactivating enzymes (eg. ampicillin - clavulanic acid) 5) Prevention

of

emergence

of

resistant population of bacteria (eg.

erythromycin-rifampin) i. Antagonism may be due to any of the following: 1) Bacteriostatic drug prevents the activity of a bactericidal drug 2) Competition for drug-binding sites (eg. macrolide - chloramphenicol 3) Inhibition of cell permeability mechanism 4) Depression of resistance enzymes j. Careful

consideration in the

use

of antibacterial combinations should be taken

into account because of the possible toxic effects of the drugs which may be at least additive and may be synergestic. k. Bacterial drugs at usual concentrations: Penicillins

Aminoglycoside

Cephalosporin

Trimetophrim sulfonamide

Nitrofurans

Quinolones Metronidazole

l. Bacteriostatic drugs at usual concentrations: Tetracydlines

Macrolides

Chloramphenicol

Lincosamides

Spectinomycin

Sulfonamides

REQUIREMENTS FOR SUCCESSFUL ANTIBACTERIAL THERAPY 1.

Clinical Diagnosis - a specific diagnosis or at least

reasonable

preliminary

diagnosis is required.

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2. Microbiological Diagnosis - Treatment should be aimed at a specific pathogen whenever possible. Examination of direct smears with Gram-stain is helpful to establish at least the general type pathogens involved especially in cases of – mixed infections. 3. Sensitivity Test - Provides a good basis for the selection of antibacterial agent and dose regimen but it is not aways advantage to wait for the results of this test before starting antibiotic therapy. 4. Appropriate Selection of Antibacterial Agents Consider the microorganisms involved, results of sensitivity testing (if any), pathogenicity of organisms, pathological lesions, acuteness of infection, pharmacokinetic properties of drug being considered, potential drug toxicity, organic

dysfunction of the host,

drug

interaction, and expense. 5. Correct Dosage Route of Administration - Dose must be adequate at therapeutic levels a the site of infection and maintained at sufficient period, of time without causing side-effects. 6. Supportive Therapy - Ancillary treatments, nutritional support and nursing care

CLASSIFICATION OF ANTIBACTERIAL AGENTS 1. According to spectrum of activity Gram + bacteria Gram - bacteria a. Broad-spectrum:

some penicillin,

tetracyclines, treroethopriBi-sulfonamide

combinations b. Narrow-spectrum: Aminoglycoside 2. According to effect of bacteria

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a. Bacteriostatic - inhibit bacterial growth and multiplication; but may become bactericidal at high concentrations and during which, toxic signs on the host may appear b. Bactericidal - kills bacteria at the minimum inhibitory concentration (MIC); below MIC levels, bactericidal agents may

become bacteriostatic

3. According to mechanisms of action a. Inhibitors of cell wall synthesis Penicillins

Bacitracins

Cephalosporins

Vancomycins

b. Disrupters of cell membranes Polymyxins

novobiocin

c. Inhibitors of protein synthesis 1) Bacteriostatic Tetraclines

Macrolides

Lincosamides

Chloramphentcol

2) Bactericidal Aminoglycosides d. Inhibitors of nucleic acids Nalidixic acid

Novobiocin

Rifampins

Metronidazole

Fluoroquinolonss

Dimetridazole

e. Inhibitors of folate synthesis Sulfonamides Trimethoprim f. Inhibitors of energy metabolism Nitrofurans

ANTIBACTERIAL AGENTS

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I. INHIBITORS OF CELL WALL SYNTHESIS Beta-lactam Antibiotics These are a group of antibiotics which share a common structure, the beta-lactum ring.

These groups include the penicillins, cephalosporins and cephamycins,

monobactams and carbapenems Penicillins 1. Penicillins are the most popular in this group of antibiotics. 2. These impair bacterial cell wall development because of their ability to inhibit transpeptidase

enzymes involved in

the

cross linking of the

peptidoglycan strands in the final stage of cell wall synthesis. 3. The net effect is bactericidal due to formation of defective cell walls and osmotic-lysis of the bacterial cell. 4. Penicillins are most active when applied during the period of rapid bacterial growth (logarithmic phase)). 5. These drugs have little effect on formed bacterial cell walls and require that organisms must be actively multiplying or growing. 6. Pharmacokinetic features: a. Absorption is enhanced in a slightly acidic environment (pH) 5.5-6.5) b. Penicillins in aqueous solutions are generally rapidly absorbed parenterally. c. Following absorption/ these are distributed in fluids and tissues. d. Penicillins do not readily traverse normal physiological barriers but high concentrations and inflammatory coaditions of these barriers permit the passage of effective penicillin levels into the protected areas.

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e. Penicillins are generally eliminated unchanged but small fractions are metabolized (usually less than 20%) and the formed metabolites (penecilloic acid derivatives) are allergenic. f. About 60-90% of a parenterally administered penicillin is excreted in urine; of these, about 20% occurs by glomerular filtration and the rest by tubular secretion. 7. Physicochemical properties: a. Poorly soluble, weak organic acids b. Unstable and sensitive to heat, light, pH extremes, heavy metals, oxidizing and reducing agents c. Easily deteriorate in aqueous solutions (therefore reconstitution with diluents is necessary just before injection d. Usually administered parenterally as suspension in water, oil, or as water-soluble salts. e. Only acid- stable penicillins are administered orally 8. Side-effects: a. Organ toxicity is rare b. Hypersensitivity reactions to occur (particularly in cattle) 1) skin reactions

5) vasculitis

2) agioedema

6) eosinophilia

3) drug fever

7) anaphylaxis

4) serum sickness 9. Interactions a. Displaced

by salicylates, phenylbutazone, sulfonamides, and other

weak acids concurrently administered from plasma-protein binding. b. Absorption or ampicillin is impaired by presence of food. c. Some never generation should penicillins not be mixed with aminoglycosides. d. Pen G and ampicillin are not compatible with other drugs and should not be mixed. 10. Some important penicillins:

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a. Penicillin G (benzylpenicillin) 1) This is commonly employed in Vet. Med. 2) Predominantly active against gram-positive and anaerobes and a few gram-negative bacteria like Hemophilus sp. 3) Available in a variety of formulations. 4) Disadvantages: a) Susceptible to acid hydrolysis in stomach and so is not administered orally b) Destroyed by beta-lactamase (penicillinase) enzymes b. Ampicillin and Amoxicillin 1) Modified semi-synthetic penicillins. 2) Have less marked acitivity against gram-positive than does Pen G but has significant activity against gram-negative organism B including some enterobacteria. Activity against Proteus spp., Pseudomonas aeruginosa and Klebsiella spp. is poor. 3) Both are resistant to acid-hydrolysis and so can be given PO. 4) Both are susceptible to beta-lactamase. 5) Both are pharmacologically equivalent but amoxycillin is pharmacokinetically superior because it is absorbed more rapidly and plasma peak concentration is achieved earlier than ampicillin. 6) Amoxycillin also has a more rapid bactericidal action than ampicillin. Cephalosporins 1. The physical and chemical properties of these drugs are similar to the penicillins. 2. These are also weak acids and are more stable to pH and temperature changes. 3. Contain beta-lactass nucleus which is susceptible to beta-lactamase (cephalosporinase).

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4. The cephalospirinases that hydrolyze cephalospins may or may not attack penicillins. 5. The mechanism of action is similar to penicillins. 6. Pharmacokinetic properties: a. Absorption - orally administered cephalosporins are acid-stable - well absorbed orally or parenterally - peak plasma levels can be reached in about 30 minutes b. Distribution - widely distributed in tissues and fluids - poorly penetrates the CSP even in inflammation c. Biotransformation

- actively deacetylated primarily in the liver but are also biotransformed in other tissues

d. Excretion - excreted in the kidneys mainly by renal tubular secretion biliary exceretion is employed largely by newer cephalosporins e. Plasma half-lives - 30-120 minutes - third generation cephalosporins have longer halflives 7. Side effects a. Relatively nontoxic but cephaloridine may be nephrotoxic in some species. b. Hypersensitivity reactions may be encountered particularly in animals with history of penicillin allergy c. Superinfection 8. Source: isolated from Cephalosporium acremonium (a marine fungus) 9. First Generation (Narrow Spectrum) Oral

Parenteral

Microbiologic

Activity Cephradrine

Cefacetrile

- every active vs. Grant + mod.

Cefadroxil

Dr. Elmer Q. Abillar

vs. Gram - bacteria

Cefapirin

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Cephalexin

Cephazolin

- relatively susceptible to cephalosporinases

Cephaloglycin

Cephalothin

- not effective vs. anaerobes - no activity vs. Proteus and Psuedomonas (rapidly dev. resistance

10. Second Generation (Moderate Spectrum) Oral Cefachlor

Parenteral Cefamandole

Microbiologic Activity - active vs. Gram + and – org.

Cefonicid Ceforanide

- relativelyresistantto cephalosporinase

Cefoxitin Cefuroxime

- ineffective vs. enterococci, Pseudomonas,

Cefotiam

Actinomyces, and obligate anaerobes

11. Third Generation (Broad Spectrum) Oral

Parenteral

Microbiologic Activity

Ceftriaxones

Cefotaxime

- moderate activty vs. Gram +

Ceftizoxime

Cefoperazone

Ceftazidine

Cefsulodin

- active vs. gram – bacteria

Cefmenoxime

Moxalactam

including Proteus, Pseudomonas

( Latamoxef) **

Citrobacter -

very good activity vs. enterobacter

-

high resistance to cephalosporinase

Legend: * a cephamycin (from Streptomycin) ** a cephamycin (synthesis form)

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Note: 1. Cephalosporins discovered before 1975 are spelled with "ph' and after 1975, with an "f. 2. First and second generation cephalosporins are not capable of penetrating the outer roeroberanes of Pseudomonas aeruginosa BETA-LACTAMASE INHIBITORS 1. Introduced in Vet. Med. in combination with penecillin to produce broadspectrum antibacterial activity and overcome limitations of these drugs. 2. Synergestic with a number of penicllins and cephalosporines that are easily hydrolyzed by plasmid-mediated beta-lactamases. 3. MOA:

irreversibly inhibit beta-lactamase enzymes allowing the beta-lactam

antibiotics to act on the bacterial pathogens.

.

4. Effect: Beta-lactum antibiotics are protected from the enzymatic destruction by beta-lactamases and their antibacterial activity is extended. 5. Most commonly used beta-lactamase inhibitors: a. clavulanic acid b. sulbactam 6. Clavulanic acid: a. Produced Streptomyces clavigerus b. Resembles penicillin in structure but has no significant antibacterial activity. c. Has good activity against plasmid-mediated beta-lactamases and chromosomally mediated penicillinases. d.

Has

little

activity

against

chromosomally

mediated

cephalosporinases. 7. Sulbactam (penicillinic acid sulfone) a. A synthetic derivative of aminopenicillanic acid. b. Affinity to beta-lactarnases is less than that of clavulanic acid. c. Binds to B-lactamases of Citrobacter, Enterobacter, Proteus, and Serratia sp. to which calvulanic acid does not.

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8. Examples of potentiated beta-lactams: a. Clavulanic acid - armoxicillin (2:1) (Coamoxiclav) b. Clavulanic acid - ticarcillin (15:1) c. Sulbactam - ampicillin d. Sulbactam - cefoperazone 9. The combination is useful in situations wherein the organisms have developed resistance to the beta-lactam alone but sensitive to the combination. 10. Contraindications: a. Oral administration in herbivores b. Injection to horses, rabbits, guinea pigs, hamsters, and gerbils MONOLACTAMS 1. Monolactams possess the monocyclic beta-lactam ring amd do not have the thialodine ring. 2. Aztreonam was the firstdrug of this group to be introduced in human medicine. 3. It is synthetic analogue of an antibiotic isolated from Streptomyces sp. 4. MOA:

It binds to the PBP3 (penicillin binding protein) causing disruption of cell

wall synthesis 5. It is not susceptible to the action of most beta-lactamases. 6. May also be hydrolyzed by beta-lactamase that hydrolyze group II parenteral cephalosporins. 7. Activity

is limited to

gram-negative aerobic bacteria including the fastidious

Haemophilus spp., Pasteurella.spp and Enterobacteriaciae 8. Resistant organisms include gram-positive bacteria and anaerobic bacteria, some (Pseudomonas spp., Citrobacter spp and. Enterobacter spp.) 9. Pharmacokinetics: a. Not absorbed following oral administration. b Widely absorbed after IM administration. c. Penetrates the CSF when meningitis is present d. Excreted mainly in the kidneys. 10. Side effects:

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a. Toxicity similar to B-lactam antibiotics. b. No apparent cross-allergic reactions. 11. Exhibits synergistic.with aminoglycoside antibiotic 12. Main use in human medicine is for treatment of urinary tract infections. CARBAPENEMS 1. These are newer beta-lactam antibiotics. 2. Imipenem is used in human medicine in combination with cilastin, a drug that inhibit hydrolysis in the kidney. 3. It is highly active against almost all clinically important gram-positive, gram negative and aerobic bacteria. 4. There is rapid development of resistance against Psuedomonas aeroginosa. 5. Pharroacokinetics: a. Mot absorbed following oral administration. b. Widely

distributed

to

following

IV administration, including the

CSF in meningitis. c. Mainly excreted in the kidneys and metabolized in the renal tubules. d. Renal metabolism is inhibited by cilastin. 6. Side effects: a. Gastrointestinal disturbances (most common) b. Hypersensitivity reactions (rash) c.Seizures (associated with high doses, renal failure underlying neurological abnormalities) 7. Use

in human medicine in treating

nasocomial infections, infections caused by

resistant organisms and mixed infections. OTHER CELL WALL INHIBITORS Bacitracin 1. Discovered in 1945 by Johnson and his colleagues. 2. Was isolated from a Bacillus sp. of.bacteria taken from the fractured tibia of Margaret Tracy, hence the name bacitracin. 3. Chemistry: a. These are basically polypeptides.

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b. Also contains a thiazolidine ring present in penicillin. 4.. Pharmacokinetics a. Fully absorbed from the gut. b. Absorbed drug is excreted via glomerular filtration. 5. Spectrum of activity: a. A narrow-spectrum antibiotic b. Bactericidal in nature c. Activity is not affected by organic materials d. Effective against: aerobic and anaerobic gram-positive rods, spirochaetes, penicillin-resitant organism. e. Often combined with aminoglycosides or .with polymyxin B for broadspectrum activity in treating minor skin wounds. 6. MOA: Interferes with the phospholipid which carries the wall materials from the center of the cell to the cell-wall structure. 7. Toxicity:

strongly nephrotoxic when

given parenterally

8. Resistance develops slowly and is rare. 9. Clinical applications; a. Feed additive, of pigs, poultry, and cattle b. For growth promotion purposes c. Prevention

and

treatment of Clostridium perfringens and C.

spiroforme (rabbits) d. Topical treatment of superficial infections of skin and mucosal surfaces Vancomycin 1. A glucopeptide produced by Streptomyces orientalis. 2. MOA: inhibits peptidoglycan synthesis by binding with D-alanyl-D-alanine terminal of muramyl dipeptide. 3. Spectrum of activity; narrow (limited to gram-positive organisms) 4. Pharmacokinetics: a. Fully absorbed from the gut b. Fully penetrates tissue and CSF, except when inflamed

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c. Half-life in man is 6 hours, in dogs 2 hours 5. Used in humans, hamsters, and guinea pigs for treatment of antibiotic-induced Clostridium deficile infections. II. DISRUPTORS OF CELL MEMBRANE FUNCTION Polymyxins 1. Are antibiotic products of Bacillus polymyxa 2. These are basic cyclic decapeptides 3. The two known members of this family are: a. Polymyxin B - available as a sulphate for oral and parenteral administration b. Colistin (Polymyxin E - available as Colistin sulphate (oral) and Colistin sulfomethate parenteral) 4. These are stable, highly water-soluble drugs 5. Mechanism: Disrupt cell membrane phospholipids and increase permeability by a detergent-like action a. Being cationic, these drugs bind to the anionic lipid. A region causing disorganization of the outer membrane of the gram (-) bacteria. b. The gram negative bacteria are sensitive to the effects of polymyxins because of their larger phospholipid content in the cytoplasmic and outer membranes. 6. Spectrum of activity a. Both drugs have similar antibacterial acitivity b. They are bactericidal and are active against many gram (-) bacteria while gram (+) bacteria are relatively resistant. c. Have

good activity against Pseudomonas aeruginosa

7. Resistance a. Acquired resistance does not develop (rare) – in susceptible gram (-) bacteria and usually occurs among P. aeruginosa b. Resistance is due to decreased permeability of the drug into the cell c. Complete cross-resistance among polymyxins occur but not with other antibiotics

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8. Pharmacokinetics a. Very slowly absorbed from the GIT b. Parenteral administration is necessary to obtain systemic effects c. Diffuse poorly across biologic membranes d. Slowly excreted unchanged in urine via glomerular filtration 9. Interactions, synergestic with many other antimicrobial agents (eg. Trimethoprim-sulfonamide Amphotericin) 10. Toxicity a. Systemic use causes nephrotoxicity, neurotoxicity, and neuromuscular blockade b. IM injection of polymyxin B and Colistin or their sulfates produces tissue necrosis. c. Colistin is less toxic than polymyxin B d. These are not recommended for parenteral IV administration in animals e. .Their ability to inactivate endotoxins is offset by their toxic-effects 11. Clinical applications a. Treatment of neonatal colibacillosis in calves and swine b. Bovine mastitis c. Local treatment of superficial infections of eyes and uterus in horses as well as otitis externa and other skin infections in dogs and cats III. INHIBITORS OF PROTEIN SYNTHESIS A. Bacteriostatic: Inhibitors of Protein Synthesis 1. TETRACYCLINES a. One of the classic broad-spectrum antibiotics b. These are derivatives of polycyclic naphthacenecarboxamide c. Tetracyclines

(TCNs)

are a group of amphoteric substances that are only

slightly soluble in water at neutral pH. d. Mechanism of action: bind reversibly to the 30S ribosomes e. Effect of the binding: 1) Interference on the attachment of the aminoacyl-tRNA on the A site (acceptor site) on the mRNA-ribosome complex

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2) Prevents the addition of armino acid to the growing peptide chain thus inhibiting protein synthesis (stopping of the elongation of peptides) f. Groups 1) Naturally occuring TCNs a) Chlortetracycline (from Streptomyces aureofaciens) b) Oxytetracycline (from S. rimosus) c) Demethylchlortetracycline 2) Semisynthetic TCNs a) Tetracycline b) Rolitetracycline c) Methacycline d) Minocycline e) Doxycycline f) Lymicycline g. Classification (based on duration) 1) Short-acting a) Tetracycline b) Chlortetracycline c) Oxytetracycline 2) Intermediate-acting a) Demethylchlortetracycline b) Methacycline 3) Long-acting a) Doxycycline b) Minocycline h. Antimicrobial activity: 1 Differences in clinical efficacy are largely due to their pharmacokinetic properties and not to the difference in susceptibility of microorganisms. 2) Generally bacteriostatic requires a responsive host defense system. 3) May become bactericidal at high concentration due to impaired cell membrane function (disruption of bacterial cell)

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4) Effective against aerobic and anaerobic gram-positive and gram-negative bacteria, mycoplasma, rickettsiae, chlamydiae, amoebiases. 5) Doxycycline and minocycline are active against Staphylococci 6) TCNs enter microorganisms by: a) Diffusion through the cell membrane b) Active transport (via energy-dependent carrier transport system) 7) Resistance to TCNs is-based on the decreased penetration of the drug into the previously susceptible microorganism through interference with active transport system. . a) Mutant strains may not posses the necessary transport system leading to impaired uptake of the drug. b) Acquired

plasmid-mediated

resistance •confers

in the property of

either diminished uptake of the antibiotic or active efflux of TCN from the bacterial cell. c) Acquired

via

transduction or conjugation.

8) Resistance- develops slowly, but is already widespread because of the extensive use of low levels of TCNs. 9) Complete cross-rsistance among tetracyclines occur. i. Pharmacokinetics: 1) Oral and parenteral preparations are available. 2) Oral TCNs a) Absorption

can

be impaired

by

food, especially milk and milk

products, antacids, kaopectate, and other solutions containing calcium (chelate with TCNs). b) Minocycline and doxycline:

lipophilic absorption not impaired by

the presence of food; 90% absorbed from the gut, others 35- 65%. c) Effective blood levels reached .in 2-4 hours. 3) Parenteral a) Given intravenously or intramuscularly. b) Oxytetracycline; slow absorption from IM sites leads to its prolonged effect (depends on the carrier or vehicle) c) May cause tissue necrosis and pain at the site of injection

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d) Distributes rapidly and extensively and enter body tissues and fluids except the CSF, unless the meninges are inflamed e) May cross placental barrier and reach fetus leading to deposition of the drug in the fetal bone and teeth. g) Can be secreted in, mills, (pose a daiiger to suckling neonates) 4 Deposition of TCNs in the bones and teeth of young animals lead to: a) Improper calcification of bones. b) Brown and yellowish (yellow-brown) discoloration of teeth which become susceptible to erosions. 5) TCNs are excreted unchanged into the urine (except minocycline-partly metabolized) or into the intestine via the bile (Doxycycline and Minocycline) and undergo enterohepatic circulation (long half life) 6) Doxycycline is not excreted in the kidneys and is safe for patients with renal insufficiency. j. Toxicity and adverse effects: 1) Superinfection with nonsusceptible pathogens particularly in horses due to broadspectrum

inhibition

the

of colonic microflora (diarrhea)

2) Necrosis and pain at the site of injection 3) Ability to bind to calcium (harmful deposits in bones and teeth) 4) Rapid IV is dangerous; this may cause collapse of the animal due to the calciumbinding property of TCNs and consequent depression of the cardiovascular function. 5) Recommendation: administer slowly/ greater than 5 minutes and pre-treat animals with calcium gluconate 6. Catabolic in nature: combination with glucocorticoids can lead to weight loss. 7) Hepatotoxic in large doses and potentially nephrotoxic. 8) Use of expired TCNs, is not recommended because the drug undergoes degradation and the degradation products are toxic; may cause acute tubular necrosis. 9) May also cause photosensitization (phototoxic dermatitis) 10) Very' high concentration inhibit .leukocyte chemotaxis.. k. Drug interactions: 1) Chelation

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2) Nephrotoxicity enhanced by using methoxyflurane. 3) Enzyme enducers (phenytoin, phenobarbital) shorten tl/2 of TCN 4) Inactivated by alkaline urine into the intestine via the bile (Doxycycline and Minocycline)

and

undergo

enterohepatic circulation (long t 1/2)

5) Very high concentration inhibits leukocyte chemotaxis and phagocytes.

k. Drug interactions: 1) Chelation 2) Nephrotoxicity enhanced by using methoxyflurane 3) Enzyme enducers (phenytoin, phemobarbital) shorten tl/2 of TCN. 4) Inactivated by alkaline urine. CHLORAMPHENICOL a. A simple, neutral nitrobenzene derivative with a bitter taste b. Isolated from Streptomyces venezuelae c. Congeners: Thiamphenicol and florfenicol (not yet used in Vet.Med.) d. MOA: binds reversibly with the 50S ribosomal subunit e. Effects of binding: 1) Interferes with the formation of new peptide by blocking the action of peptidyltransferase.. 2) Also prevents the binding of aminoacyl-tRNA to the active site of peptidyltransferase. f, Peptidyltransferase mediates the transfer of peptides carried by peptidyl tRNA to the amino acid attached to the aminoacyl-tRNA. g. Usually bacteriostatic, but can be bactericidal at high concentrations. h. Inhibition of protein synthesis occurs in both prokaryotes and eukaryotic ribosomes. i. Spectrum of activity: "gram-positive and gram-negative

bacteria

anaerobes,Bacteroides fragilis. rickettsiae, chlamydiae, Salmonella

and several spp. (resistant

strains include Pseudomonas spp.) j. Resistance:

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1) Plasmid-mediated (via conjugation). 2) Resistance gene codes for acetyltransferase which which is directed towards the inactivation of chloramphenicol, 3) Resistance can also be due to the decreased permeability of the organism to the drug. k. Pharmacokinetics 1) Stable and highly lipid soluble, hence widely distributed to most body fluid compartments CSF, intraocular, intracellular) 2) Forms available: a) Chloramphenicol palmitate (oral) b) Chloramphenical

sodium

succinate (parenteral)

3) Well absorbed in the GIT, even in the presence of food; decreased ration will however decreased or hinder absorption 4) Biotransformation in the liver, primarily by glucuronide conjugation 5) Cats and very young animals slowly biotransform chloramphenicol. a) Cats have genetic deficiency in glucuronyl transferase b) Young animals do not yet have the full microsomal enzyme capabilities

except

in foals (drug metabolism is particularly rapidin

horses) 6) Excretion a) In the urine via tubular secretion; about 5-15% of original dose is excreted in its active form via glomerular filtration (useful for treating urinary infections) b) Via the bile: pronounced enterohepatic recycling occurs 1. Toxicity and adverse effects: 1) Bone marrow suppression a)

Non-regenerative anemia - disturbed

thrombocytopenia

RBC maturation

with

and leukocytopenia

i) Dose related; animals have

high tolerance except cats

ii) Toxic

to interference of rRNA synthesis in very

effects

are related

Actively dividing cells in the bone marrow

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b) Aplastic anemia - more serious consequence i. Not dose-related; occurs in 1:40,000 (incidence) ii. Pancytopenia iii. Signs: bleeding tendencies, secondary infections, throrobocytopenia iv. Due to toxic intermediates of the nitro group c) Because

of

those

possible

effects, chloramphenicol has been

banned for use in food animals because of the drug residues which might cause aplastic anemia in humans 2) Suppression of antibody synthesis (anamnest ic immune response) - animals under treatment should not be vaccinated 3) Gray baby' syndrome (neonatal humans and young cats) a) Occurs

in premature babies exposed

to high concentrations of

chloramphenicol b) Death due to cardiovascular collapse 4) Superinfection m. Drug interactions 1) Chloramphenicol is a potent noncompetitive microsomal enzyme inhibitor that can prolong the duration of action of other

drugs concurrently administered (eg.

pentobarbital, codeine, phenytoin, NSAIDs) 2) Causes hepatic damage when combined with sulfamethopyridazine 3) Delays response of anemia to hematinics 4) Interfere with actions of many bactericidal drugs 5) Should not be used concurrently with other antibacterial agents that bind to the 50s ribosomal subunit 3. MACROLIDES a. Contain a microcyclic lactone ring attached to 2 or more sugar moieties b. Are organic barrier whose action is favored by alkaline pH c. These are generally effective against rapidly dividing gram positive bacteria, mycoplasma, and rickettsiae d. Primarily bacteriostatics; but bactericidal at high concentrations

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e. MOA: binds reversibly to 50s ribosoraal unit on the donor site (P site) and prevents the translocation of petidyl tRNA) f. Pharmacokinetics: 1) Absorbed well from the GIT but are acid stable 2) Oral preparations are available as enteric coated tablets or stable salts or esters 3) Can be administrered IV or IM but pain and swelling may occur at injection sites 4) Widely distributed in tissues; high concentration may reach in milk and can exceed plasma concentration but cannot reach the CSF unless the meninges are inflamed 5) Biotransformed in the liver and excreted mainly via the bile (often undergo enterohepatic recycling) 6) Used for systemic and local infections often used as alternative to penicillins in the treatment of staphylococcal

and streptococcal infections

g. Toxicity 1) Rare 2) Contraindicated in horses (adult esp.) because these may cause gastrointestinal disturbance that may be fatal. h. Drug interactions 1) Should

not be used together

with chloramphenicol and lincosamides because

of their similarity in their MOA (they compete for binding site) 2) A microsomal enzyme inhibitor; can depress the metabolism of other drugs i. Examples: 1) Erythromycin -gram positive, including penicillinase-producing Staph. The prototype drug for this group 2) Spiromomycin

more active than erythromycin in vivo used for cryptosporidiosis

same applications as tylosin in pigs and poultry 3) Tilmicosin - antibacterial and antimycoplasma

activity intermediate

between

erythromycin and tylosin used only in treating bovine respiratory diseases 4) Tylosin- from Streptomyces fradiae active vs. Treponema hyodysenteriae and mycoplasm administered IM, intramamniary, and in feed also used as gr6wth promoter in swine to improve weight gain

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5) Newer Macrolides: (similar activity to erythromycin and tylosin) a) Oleandomycin

(used

in

treating toxoplasmosis in dogs and cats)

b) Josamycin c) Kitamycin d) Rosamycin e) Roxithromycin (an acid-stable oxime derivative of erythromycin) 4. LINCOSAMIDES a. Derivatives of an amino acid and a sulfur-containing octose b. Similar MOA with chloramphenicol and raacrolides c. Bactericidal depending on the concentration d. Effective vs. gram-positive cocci, including the penicillinase-producing Staphylococcus e. Has limited spectrum of activity vs. aerobic pathogens but has broadspectrum of activity vs. anaerobic pathogens f. Can be administered orally or parenterally but orally

administered

drugs are incompletely absorbed from the GIT g. Has a wide volume of distribution; well distributed in tissues and fluids including the bone, but not in the CSF even if the meninges are inflamed h. Often used for treating skin infections, like the secondary bacterial infection in demodectic mange i. Adverse reactions: 1) May produce skeletal muscle paralysis at high concentrations 2) Hypersensitivity reactions may occur j. Contraindications: 1) Neonates

- because of their limited ability to metabolize the drug

2) Animals with liver diseases 3) Horses - may cause severe or fatal colitis in this species 4) Cattle - inappetence, diarrhea, ketosis, decreased milk production 5) Rabbits, guinea pigs, hamsters - may cause fatal typhlitis due to overgrowth of Clostridium diffcile/Clostridium pisiforme.

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k. Safe for use in cat and dogs as well as swine (control dysentery and mycoplasma infections) 1. Examples: 1) Lincomycin

(fermentation

product

of Streptomyces lincolensis var lincolensis

2) Clindamycin (chlorinated lincomycin) - used for treatment of toxoplasmosis in dogs and cats 5. PLEUROMUTILIN a. The prototype drug is Tiamulin B.Tiamulin has very good activity vs, anaerobic bacteria and mycoplasma c. Used exclusively in animals and largely in swine d. Also utilized in swine as growth promoter e. Should not be administered together with ionophores (monensin, narasin, salinomycin) to pigs and poultry because of dose-dependent fatal effects of such combinations f. Should not be administered to horses and other herbivores with expanded LI (rabbits, guinea pigs) because of the danger of destruction of large bowel flora and predisposition to colitis g. Used extensively in swine vs. mycoplasma, leptospirosis

(better

swine dysentery,

than lincomycin)

B. Bactericidal Inhibitors of Protein Synthesis 1. AMINOGLYCOSIDES a. Chemistry 1) Contain characteristic amino sugars joined to a hexose nucleus in a glycosidic linkage 2) Amino groups contribute to the basic nature of drug 3) Hydroxyl groups in the sugar moieties add to the high aqueous solubility and poor lipid solubility of these drugs 4) Removal of these hydroxyl groups increases antibiotic activity b. Mechanism of action 1) Inhibit protein synthesis by acting directly on the ribosome (30s)

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2) Interfere with -the proper attachment of the mRNA to the ribosome and induces misreading of the genetic code on the mRNA template 3) Result: wrong amino acid will be carried to the template and cause decreased or abnormal protein synthesis 4) A bacterial protein synthesis inhibitor, but the precise nature of bactericidal activity is however not yet known c. Classes 1) Narrow spectrum vs. aerobic, gram negative bacteria a) Streptomycin b) Dihydrostreptomycin 2) Broad spectrum a) vs. gram (+) and gram (-) aerobic bacteria (1) Neomycin (2) Framycetin (Meomycin B) (3) Paromomycin (4) Kanamycin b) Also have good activity vs. Pseudcmonas aerucrinos (1) Gentamycin (2) Tobramycin (3) Amikacin (4) Sisomicin (5) Netilmicin d. Antimicrobial activity 1) More effective against rapidly multiplying organisms 2) Need only a short contact with bacteria to kill them 3) These are polar organic bases which require a specialized transport process for the drug to enter the cell and reach the ribosoroes 4) The driving force for this transfer is probably the membrane potentials but these processes are more efficient if the energy that is utilized is aerobically generated. 5) This does not occur in anaerobic condition; therefore the drug is not effective for anaerobes or the effect is diminished because of decreased oxygen tension

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6) Effective concentrations of the antibiotic must be present outside the bacterial cell 7) Anaerobic bacteria and mutants lack appropriate transport systems 8) Transfer of the drug inot the bacterial cell is decreased in hypoxic conditions 9) Divalent cations (Ca+-»- and Mg^+) compete with amino glycosides in the transport process 10) Alkaline pH will facilitate transport of drug across bacterial cell membranes 11) Synergistic

with beta-lactam antibiotics (penicillins and cephalosporins) because

wall injury caused by beta-lactam compound allow increased uptake of aminoglycosides 12) Cell membrane effect: lysis as a result of altered cell membrane function due to increased concentration inside the cell. e. Bacterial resistance: plasmid-mediated on due to mutation 1) Impaired transport of drug into

bacterial cell

2) Impaired ribosomal binding 3) Producing of aminoglycoside-hydrolyzing enzymes 4) Cross-resistance to other aminoglycosides may occur f. Pharmacokinetics 1)

Poor GIT absorption except when enteritis or other pathological changes, eg.

ulceration occur which increases absorption 2) Well absorbed parenterally; rapid and complete absorption

except in hypotensive

states where blood is stagnant 3) IV injection may cause acute fatal atomic reactions,

thrombophlebitis,

and shock

(in septicemic states) 4)

Given

as

intramammary infusion

for

mastitis, intrauterine infusion for

endomertritis, topical for eye and ear infections because antibiotic has

limited

capacity to enter cells and penetrate barriers due to its polar nature 5) Effective

levels are not reached in

CSF, bronchial secretions, bile, milk,

intestinal fluids, and poorly penetrates fetal barrier 6) It has a tendency to accumulate in renal cortex 7) It is not metabolized; excreted unchanged in the urine via glomeruiar filtration 8) Fracture of filtered drug gets reabsorbed in renal tubules

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g. Untoward effects 1) All aminoglycosides have similar spectrum of toxicity 2) Ototoxicity and nephrotoxicity are the most serious side effects a) Nephrotoxicity (1) Acute tubular necrosis leading to renal failure (2) Monitor renal function when using these drugs (3) Cats and young animals are more sensitive to the nephrotoxic effects of this drug (4) Gentamicin is the most nephrotoxic (5) Nephrotoxic effects are potentiated by nephrotoxic drugs (eg. Amphotericin B) b) Ototoxicity (1) Damage to the auditory and vestibular components of the cranial nerve 11 (2) In coordination and lost of righting reflex (3) Ototoxicity

potentiated by

loop diuretics

(4) Ototoxic effects higher in gentamicin, sisomicin, and neomycin (5) Cats are particularly sensitive to ototoxic action c) Neurotoxicity:

neuromuscular

junction blockade

(1) Dose related (2) Occurs as an acute effect and may give rise to respiratory failure due to the ability of the aminoglycoside to chelate calcium (3) Nondepolarizing-type or flaccid paralysis (curare-like) (4) Treatment (a) Neostigmine/physostigmine (potentiate ACh activity) (b) IV

administration

of

calcium borogluconate

(c) IPPV (intermittent possitive pressure ventilation) h. Important aminoglycosides 1) Streptomycin and Dihydrcstreptomycin a) The most commonly used aminoglycosides b) Used with caution in cats, particularly kittens, aged animals, and in those with renal disease

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c) Course of treatment should be as short as possible and not longer than 7 days as with other aminoglycosides d) In UTI: genitourinary activity can be increased by alkalinizing the urine e) Often used leptospirosis to eradicate the carrier state 2) Gentamicin a) Comes from Micromonospora purpurea (fungus) hence the spelling "micin" indicating that it does not come from Streptomyces b) The most active in this group c) Has good activity vs. Pseudomonas aeruginosa and Proteus spp. d) Mainly

used in the

treatment

of localized respiratory tract

infections caused by these agents and E. Coli as well as life-threatening gram (-) septicemia e) Endotoxemia:

may be combined

with ampicillin

3) Weomycin a) Major use is for topical apllication but this is also a potent sensitizing agent b) Very toxic if absorbed c) Systemic administration raay cause

acute respiratory failure; or

chronic toxicity with renal and VIII nerve damage may develop 4) Kanamycin a) May be used for the treatment of systemic infections by Proteus spp. , E. coli, Mycoplasma, and Mycobacteria b) Same precautions should be taken with gentamicin 2. AMICYCLITOL: SPECTINOMYCIN a. Spectinomycin is a nonglycosidic aminocyclitol but is often classified under aminoglycosides because of its close similarity with these antibiotics b. A product of Streptomyces spectabilis

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c. Usually bacteriostatic; bactericidal at higher doses d.

MOA:

binds to 30s ribosome and inhibits protein synthesis

by

preventing

elongation of the polypeptide chain e. Has limited application because of ready development of resistance f. Combination with lincosamides may enhance activity

vs. Mycoplasma and

Treponema hyodysenterae g. It

does

not

induce

ototoxicity

and nephrotoxicity

by may

cause

neuromuscular blockade h. pharmacokinetic i.

Used

in

properties

veterinary

similar

medicine

to aminoglycosides for

infections caused

by

mycoplasma,

enterobactericeae, and gram (-) bacteria (respiratory disease) IV. INHIBITORS OF NUCLEIC ACID SYNTHESIS V. Benzimidazoles a. Characteristics 1) Have

both

antiprotozoal

and antibacterial acitivity

2) Examples: Metronidazole, Dimetridazole, Ronidazole, Tinidazole, Ipronidazole 3) Metronidazole is the most popular and most studied in this group; also considered as the prototype drug of the group b. Metronidazole 1) Has been used against protozoans (Trichomonas, Giardia, Amoeba) and has striking effect on obligate anaerobic bacteria 2) Bactericidal at concentrations higher than MIC 3) MOA:

when drug enters a susceptible microorganism, it undergoes reduction

of the nitrogen and produces products that bind to the DNA causing extensive breakage of DNA strands and inhibition of DNA repair enzyme (DNAase ) 4) Only the susceptible organisms

can metabolize this drug; reduction occurs

under anaerobic condition 5) Pharmacokinetics a) A basic drug which is very lipid soluble b) Readily but variably absorbed from the

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GIT c) Widely distributed; penetrates blood- brain barrier and attains therapeutic concentration in abscess and emphysema fluid 6) Adverse reactions a) Neurotoxicity in dogs: tremor, muscle spasms, ataxia, convulsions b) Reversible bone marrow suppression c) May produce reddish brown discoloration of urine d) Kemorrhagic diathesis e) Rumen dysfunction 2. Quinolones a.

Synthetic antimicrobial agents that have

become more important in veterinary

medicine b. MOA: inhibit the A sub-unit DNA gyrase which is essential for DNA replication c. Examples: 4-Quinolone, Nalidixine^ Oxolonic acid, Nalidixic acid 1) Almost completely absorbed after oral administration extensively and rapidly metabolized; and excreted as inactive conjugate 2) Clinical use a) Bactericidal against most gram (-) aerobes except Pseudomonas aeroginosa; not active vs. gram (+) and anaerobic bacteria b) Treatment of UTI caused by gram (-) bacteria c) Toxic to dogs and cats; produced undesirable side effects d) Clinical use often accompanied by rapid emergence of resistance mutants 3) Interactions a) Absorption decreased by antacid b) Decreased efficacy if used

with nitrofurantoin in the treatment of UTI

c) Inhibit biotransformation of theophyline d) Food may delay absorption 4) Adverse reactions a) Serious CNS stimulation; seizures in dogs b) GIT:

nausea, vomiting,

diarrhea, hepatic necrosis

3. Fluoroquinolones

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a. Synthetic analogues of nalidixic acid b. Differ from the older quinolones and nalidixic acid in that they have a fluorine atome at position and a piperazinyl constituent at position. c. Enhanced activity against DHA gyrase d. MOA: inhibit the A sub-Uilit DNA gyrase e. Antibacterial activity 1) Active against enteric gram (-) bacilli, Pseudomonas, Aeromonas, Haemophilus 2) Penetrate intracellularly into phagocytic cells, allowing intracellular killing of bacteria f. Pharmacokinetics 1) Rapid

oral

abosprlton;

partially metabolized in liver and excreted in urine

and bile (unchanged/active metabolite) 2) Low protein binding and high lipid solubility 3) Long half-lives, allowing dose intervals of > or = 8 to 12 hours 4) Interaction a) Additive with beta lactam, macrolides, aminoglycosides b) Antagonistic with nitrofurans

and chloramphenicol

h. Uses 1) UTI, especially those caused by P. aeroginosa 2) Prostatitis;

severe

bacterial gastroenteritis; pneumonia and osteomyelitis

caused by gram (-) bacili 3) Examples:

Bnrofloxacin,

Perfolxacin, Ofoxacin,

4. Rifarepicins a. Examples: b. MOA:

Rifampicin

BV

Rifampicin (Rifampicin), Rifamide

interfere with the synthesis of RNA by binding to sub-units of the

sensitive DNA dependent RNA polymerase c. Antibacterial activity 1) Active

vs.

gram (+)

organisms,

some myobacteria, gram (-) cocci, some

anaerobes. reason, they are often administered with

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2) Resistance easily develop, and for this penicillins, erythromycin miconazoie, and amphotericin B 3) Used in man to treat TB; in foils to treat Rhodococcus equi-induced pneumonia 4) Brucella and other fastidious organisms are susceptible d. Pharmacokinetics 1) Readily but incompletely absorbed from the gut 2) Concurrent feeding may reduce or delay gut absorption 3) IV or IM administration; widely distributed in tissues and fluids because of its increased lipid solubility 4) Biotransformed in liver and primarily excreted in bile 5) Active against intracellular organisms e. Adverse reactions 1) Well tolerated and produces few side effects in animals 2) GI disturbances and abnormalities in liver dysfunction (not recommended in animals with liver disease) 3) May be teratogenic 4. Novobiocin a. Also called Streptonivicin, Cardelmycin b. Produced by Streptomyces niveus c. A narrow-spectrum antibiotic that may be bacteriostatic or bactericidal at higher concentration d. MOA: 1) Inactivates the B sub-unit of DNA gyrase 2) Also causes cell membrane disruption e. Well-absorbed from the gut and mainly excrete in the bile f. Active against Staphylococcus aureus g. Less active vs. Streptococcus, and more fastidious gram (-) bacteria h. Mycoplasmas are moderately susceptible i. Resistance easily develops j. Synergestic effect with tetracyclines k. Adverse reactions

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1) Inhibition of liver metabolism 2) Eosinophilia,

Thrombocytopenia,

Leukopenia 3) Skin rashes in cow treated with intramammary infusion of the drug 1. Current main use: In combinatiori with other agents for the treatment of bovine mastitis W. INHIBITORS OF FOLIC ACID COBNZYMB SYNTHESIS A. Sulfonamides 1. Chemistry a. Derivatives of sulfanilamide, an amide of sulfanilic acid (paraminobenzene sulfonic acid) b. Derivatives are made by substitution in the amide of the sulfanilamide c. Structural analogues of PABA (paraaminobenzoic acid) d. Have the basic structure related to the compound P-aminobenzoic acid (PABA) which is required by the bacteria as a precursor to the synthesis of essential coenzyme tetrahydrofolic acid (THFA) e. These are bacteriostatic

chemical antibacterial

substances,

not antibiotics

2. Properties a. These are white, crystalline

powders relatively soluble in water

b. Amphoteric substances, behaving as weak organic acids c. Commercial preparations come as sodium salts to increase their solubility d. incompatible 3.

with

Mechanism:

calcium-containing compounds

compete with PABA in the synthesis of folic acid coenzymes

(counterfeit incorporation) a. Competitively inhibit an enzymatic step which incorporates PABA in the synthesis b. The enzyme responsible for the incorporation of PABA in folic acid synthesis is dihydropterate synthestase c. Bacterial growth can resume once the concentration of PABA is increased (it is important that the host mounts an adequate immune response to eliminate the offending organism)

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4. Folic acid a. Responsible for 1) Mathylation reactions needed in the synthesis of thymidine (a purine base) 2) Formation of amino acids: methionine and glycine b. Inhibition of folic synthesis leads to 1) Inhibition of protein synthesis 2) Impairment of metabolic processes 3) Inhibition of growth, of susceptible organisms b. Resistance a. Resistant organisms are 1) Those which do not require folic acid are for growth 2) Those which can utilize preformed folic acid b. Development of resistance occur via 1) Alteration of enzyme structure thereby lowering the affinity of their enzyme to the drug 2) Hyperproduction of PABA c. Human and animal cells have exogenous sources requirement of folic acid from diet and can absorb this vitamin synthesized by intestinal microorganisms d. Susceptible organisms are those which cannot use the preformed folic acid; they have to use some other derivatives of PABA to synthesize folic acid e. Sulfonamides are more effective if used in the early stages of multiplication f. After dosing, a lag period occurs (effect is not yet observed) because the existing PABA needs to be used up before bacteriostatic effect takes place 6. Antibacterial activity a. Sulfonamides are generally bacteriostatic while

potentiated

Sulfonamides

are

bactericidal b. Have broad-spectrum activity but many

organisms have already developed

resistance c. Gram (-»-) (except Staph.) are generally more sensitive than gram (-) d. Also affect chlamydia, coccidia,

and toxoplasma

e. Antibacterial

by purulant materials in tissues

activity neutralized

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7. Pharmacokinetics a. Rapidly absorbed from the gut b. Administered orally and parenterally (M, IV, IP) c. Widespread distribution, can

penetrate

cellular barriers d. Second to chloramphenicol in lipid solubility e. Biotransformed in the liver 1) Primarily by acetylation of para-amino groups man > ruminants > horse > cats > (rone in dogs) 2) Aromatic hydroxylation 3) Glucoronide conjugation f. Precipitation of acefcylation metabolites may lead to crystalluria and eventually renal damage g.

Excretion

occurs primarily in the urine

via glomerular

filtration and tubular

secretion of both unchanged drugs and metabolite forms 8. Undesirable or Toxic Effects a. Renal toxicity 1) Manifested as crystalluria, hematuria, obstruction 2) Minimized by a) Proper hydration of the patient b) Use cf most soluble forms of sulfonamides c) Alkalinizing

urine

(passive reabsorption of drug from distal

tubular fluid influenced by urine pH) b. Disturbance of normal microfloral balance c. Hypersensitivity reactions in the flora of fever, skin rashes, dermatitis, alopecia, photosynthesitization d. Hematopoietic

disorders:

anemia, granulocytopenia,

thrombocytopenia,

immunosuppression e.

Hemorthagic diathesis (bleeding

tendencies): antagonistic effect on Vitamin K

(disturbance of normal microflora)

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f. "Drug shock" - weakness, tremors, collapse (avoided in Doberman Pinschers because of idiosyncratic reactions) g. Goiterogenic in swine 9. Drug reactions a. Procaine Pen G antagonizes sulfa (procaine is an structural analogue of PABA and antagonizs activity of sulfonamide b. Do not use with calcium-containing compounds c. Antacids decrease absorption of sulfa from gut d. Urinary acidification increases risk

of crystalluria

10. Clinical uses a. For acute systemic or l^cal infections caused by susceptible organisms b.

Initiate

therapy

by

giving

priming

dose (loading

dose)

and then

give

maintenance dose (half the priming dose) c. Therapy should not last for 7 days 11. Classification a. Locally active sulfas 1) Enteric sulfas:

undergo bacterial hydrolysis in intestines before they

become active a) Phthalysulfathiazole b) Succinylsulfathiazole c) Sulfaquinoxaline 2) Sodium

Sulfacetamide - for

eye infections

3) Sodium Sulfadiazene - skin infections burns, wounds b. Systematically active sulfas 1) Short-acting (l-4x/day) a) Sulfacetamide b) Sulfisoxazole c) Sulfathiazole d) Sulfamethizole 2) Intermediate-acting a) Sulfapyrindine

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b) Sulfamethazine c) Sulfadiazine d) Sulfamethoxazole 3) Long-acting (q3-4 days) a) Sulfabromethazine b) Sulfadoxirae c) Sulfamethoxypyridazine (low release tablets) c. Potentiated sulfonamides 1) Trimethoprim-Sulfadiazine 2) Trimethoprim-sulfamethoxazole 3) Trimethoprim-sulfadoxin B. Trimethoprim 1. Characteristics a. A synthetic folic acid-antagonist widely used in combination with sulfonamides b. A weak base, pKa 7.6 c. Poorly soluble in water 2. Mechanism of action: Inhibit dihydrofolate reductase a. Has greater affinity for bacterial enzyme than mammalian enzyme b. Combination

with sulfonamide

inhibit sequently steps in the synthesis of folic

acid and thus of purines required of DHA sythesis c. Produces a synergestic and bactericidal effect with sulfonamides (pontentiates sulfonamide activity) 3. Resistance a. Usually due to transposon-encoded plasmid or chromosomal

synthesis

resistant dihyrofolate reductase b. Increasing in Snterobacteriaceae 4. Pharmacodynamic properties a. Widely distributed in body tissues b. 60% plasma protein binding c. Metabolized in the liver (oxidation and conjugation) 5. Toxicity

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of

a. Relatively non-toxic drug b. May be due to induced folic acid deficiency at high doses 6. Clinical applications a. Drug of choice (alone or in combination) or treating prostatic infections caused by gram(-) bacteria b. When combined with Dapsone may be prophylactic for Pneumocystis

cariini

pneumonia VI. INHIBITORS OF ENERGY METABOLISM: NITROFURANS , 1. Properties a. A group of

synthetic

nitrofurane derivatives

b. Stable and slightly soluble in water c. Primarily bacteriostatic but bactericidal at higher concentrations d. Also active against protozoan e. Weak acids; more active in acidic environments f. Clinical use is limited by poor solubility and toxicity g. Broadspectrum (bacteria, some protozoa and some fungi) 2. MOA: a. Inhibit

severe!

micorbial

enzymes, particularly those involved in

CHO

metabolism b. Inhibit nucleic acid function: degraded by bacterial nitro-reductase enzymes and these reduction products break up bacterial DNA strands 3. Compounds in Veterinary Medicine a. Nitrofurazone b. Nitrofurantoin - well absorbed after oral administration but is rapidly excreted in the urine c. Nitrofurantel d. Nitrofuroquine e. Furazolidone 4. Adverse effects a. High oral doses: CHS effects (excitement, tremors, convulsions peripheral neuritis)

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b. GIT disturbances (anorexia,

nausea; vomiting)

c. Chronic use of lower doses (in dogs and cats): bleeding tendencies VII. ANTIBACTERIAL GROWTH PROMOTERS 1. Uses a. To improve growth rato and/or feed conversion-efficiency b. Widely

used

in

poultry,

swine, intensively-reared cattle

2. Virginiamycin a. One of the depsopeptide group of antibiotics b. Isolated from Streptomyces virginiae c. MOA: Interferes with protein synthesis by distorting the ribosomal A site to inhibit the binding of aminoacyi tRNA and the peptidyltransferase reaction d. Mainly active against gram positive anaerobic and aerobic bacteria? also vs, Leptospira, Treponema e May

exhibit

hyodysenteriae, Haemophilus, Mycoplasma

cross-resistance

with macrolides and lincosamides

f. Used in pig and poultry 3. lonophore antibiotics a. MOA: 1) It complexes with sodium in the cell membrane to cause the passive transport of potassium ions out of the cell in exchange for hydrogen ions 2) The low intracellular pH kills the cell b. Monensin 1) Fermentation product of Streptomyces cinnamonensis 2) Active primarily against gram positive bacteria and coccidia 3) Primarily used as an anticoccidia in poultry 4) Used to improve feed conversion efficiency in ruminants 5) Fatal when used with tiamulin 6) Horses are susceptible to toxic effects of ionophores c. Salinomycin 1) Anticoccidial activity 2) Improves

efficiency of

Dr. Elmer Q. Abillar

ruminal fermentation

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3) Used as growth promoter in swine 4) Fatal when combined with tiamulin d. Others: Lasalocid, Maduromycin, Narasin 4. Tiamulin a. A pleuromutilin b. Used as growth promoter in swine 5. Macrolidae antibiotics a. Brythromycin

- growth promotion in cattle and swine

b. Spiramycin - growth promotion in calves c. Tyiosin - promote growth and improve weight gain in swine; poultry and ruminants 6. Quinoxalines a. Quinoxaline NN dioxide derivative existing DNA (similar to that of nitrofurans) b. MOA: Inhibit bacterial synthesis an denature pre-existing DNA (similar to that of nitrofurans) c. More effective in anaerobic condition d. Active vs. Clostridia and

Treponema, Chlamydia, and protozoan

q. Examples: Carbadox, Olaquindox 7. Bacitracin Zinc - growth promotion and disease prophylaxis in cattle and swine 8. Lincomycin - used in pig and poultry 9. Hitrofurans a. Nitrofurazone 1) Poorly soluble and not absorbed after oral administration 2) Used as feed additive (0.051) to control

enteric

bacteria

and coccidiosis

b. Furazolidone 1) Has the greatest antibacteral activity among nitrofurans 2) Poorly soluble and not absorbable after oral administration 3) Also

used for

prevention

of coccidiosis in poultry

10. Others: Bambermycin, Avilamycin, Flavomycin, Avoparcin, Arsenical:: (Arsanilic Acid, Sodium Arselinate), Mitrovin, Halquinol

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ANTIVIRAL AGENTS 1. ANTIVIRAL CHEMOTHERAPY a. Still in an early stage of development but has excellent long-term prospects b. Most of antiviral drugs used in humans as experimental drugs in human medicine are still further investigated for their potential veterinary use. 2. Mechanisms of action of various antiviral agents a. Inhibition of penetration of cells b. Inhibition of intracellular viral protein synthesis c. Inhibition of virus assembly or release d. Inhibition of assembly of viral particles e. Immunoenhancers 3. Inhibition of penetration to cells a. Gamma Globulins 1) Passive immunization in IgG (IM, IV, SC) can prevent entry of viruses into cells 2) Protection may last for several weeks butnot completely 3) May be used to control distemper, rabies, Aujesky's disease, TGE in swine 4) Offsprings that have taken colostrum from vaccinated dams are usually protected from enteric viral infections b. Araantadine 1) A synthetic tricyclic araine with a symmetric structure

.

2) Activity limited to Influenza A viruses in humans and animals 3) Most effective as^prophylactic; moderately effective early in the course od disease 4) Experiments as porphylactic in infected chickens and turkeys proved successful 4. Inhibition of intracellular viral protein synthesis a« Inhibition

of

early

protein

synthesis:benzimidazoles 1) Formation of RNA polymerase in inhibited 2) Ready development of resistance b. Inhibition of nucleic acid synthesis 1) Idoxuridine - vs. herpesvirus a) Converted into an iodonalogue of thymidilate b) Inhibit virus-specified DMA polymerase

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c) Defective viral proteins will be produced d) Topical use only e) Used for treatment of feline herpesvirus keratoconjunctivitis and herpatic keratitis in other species 2) Viradarabine a) An analogue of adenine deoxyriboside b) Acts by inhibiting viral DNA polymerase c) Effective /vs. viruses with DMA polymerase activity d) Low

solubility

and

rapid

systemic deamination makes it unsuitable for

systemic use in animals 3) Ribavirin a) Resembles guanosine and interferes

with formation of guanosine phosphate in

DNA and RNA viruses b) Has broad antiviral activity vs. many DNA and RNA viruses c) Clinical used does not induce viral resistance c) Clinical use does not induce viral resistance d) Low toxicity upon systemic administration e) Prolonged treatment in cats may produce profound thrombocytopenia 4) Acyclovir a) An acyclic nucleoside analogue of 2- deoxyguanosine b) One of the first new antivirals lincensed for use in humans c) Highly effective vs. herpesvirus

by inhibiting herpes-specified DNA polymerase

d) Potential in veterinary medicine needs further studies 5) Ganciclovir a)/ Active bs. all herpesviruses b) More active

than

ancyclovir

vs. cytomegalovirus

c) Outstanding activity vs .fequine herpesvirus 6) Trifluridine a) A halogenated thyroidine analogue b) Drug of choice for herpetic keratitis because of superior ability to penetrate the cornea

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7) Iodothyronine a) A dideoxynucleoside thymidine analogue b) Inhibits viral reverse transcriptase in retroviral replication c) HIV reverse transcriptase 100 x moresusceptible

than

mammalian

DNA

polymerase d) Prolongs survival in advanced cases if HIV-AIDS by 12-30 months and delays progression of asymptomatic infection e) Tested in FeLV and FIV infections 8) Phosphonofornate (Foscarnet) a) A pycophosphate analogue b) Inhibits DNA polymerase of herpesvirus and RNA polymerase of influenza viruses being investigated for treatment of herpesvirus infections and AIDS in humans c. Inhibition

of late

protein

synthesis:

Methisazone 1) Inhibits transcription of proteins required for development of mature virus 2) Effective

prophylactically vs. poxviruses (vaccinia, small pox)

3) Possible use as prophylactic in infectious canine hepatitis and bovine respiratory disease 5. Inhibition of virus assembly or release: 2-Deoxy-D-Glucose a. Inhibits a wide range of enveloped DNA and RNA viruses

(esp, .orthonyxo-,

paramyxon, and herpesviruses) b. A glucose analogue c. Interferes

with

the

synthesis

of oligosaccharides that are part of viral specific

surface glycoproteins d. Results to decreased infectivity of viruses because of their inability to penetrate cells or to become uncoated. Topically applied on to genital herpes in women f. Potential application as prophylaxis in CD, equine influenza, and parainfluenza infections 6. Interferons a. Families of glycoproteins with antiviral, immunomodulatory and antiproliferative effects b« Produced most animal species

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c. Indirect

antiviral

activity:

alter

host metabolism to impair synthesis and

assembly of viral components d. Immunomodulating activity: 1) Increased antibody production 2) Increased natural killer activity 3) Enhanced antigen expression on cell enhances recognition of virally infected cells e. Types: alpha (leukocyte) amd beta (fibroblast) are released in response to antigen or nitrogen stimulation f. Clinical application still under study g. Studies have also been conducted to stimulate endogenous interferon production but has not yielded satisfactory results 7. Inhibition of assembly of viral particles; Rifampin a. Inhibits DNA-dependent RNA polymerase in bacteria and mammalian cells b. Prevents assembly of enveloped mature particles in mammalian cells in poxviruses c. Effect is reversible upon remova.. of drug 8. Immunoenhancers a. Cytokines b. Inosiplex (Inosine Pranobex) 1) Claimed to a) Increase B and T lymphocyte activity b) Increase natural killer cell activity 2) No evidence of its value in veterinary medicine c. Bacterial adjuvants 1) Both

Bacilus Calmette-Guerin (BCG)

AMD Corynebacterium

parvum

are

nonspecific adjuvants that increase activation- of macrophages through an effect on T lymphocytes 2) Others require additional study ANTIFUNGAL AGENTS A. CLASSIFICATION OF FUNGAL INFECTIONS (L. Local a. Dermatophytes

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1) Most common mycotic infection 2) Involve the skin, hair and nails 3) Can be treated with topical antifungal agents b. Mucocutaneous infection 1) Involve the moist skin and mucous membranes 2) Can be treated with topical amphot'Jricin B, miconazole, clotrimazole, nystatin, and oral ketoconazole for chronic infection 2. Systemic a. Almost always fatal b. Occurs less frequently c. Usually chronic in nature and are rather difficult to diagnose d. Usually treated with parenteral amphotericin B and ketoconazole for chronic infection e. Drugs used for treatment of systemic mycoses may also be used for dermatophytes B. TOPICAL ANTIFUNGAL PREPARATIONS 1. Imidazoles - available for topical application to the skin as a cream, lotion, shampoo a. Clotrimazole

d. Ketoconazole

b. Econazole

e. Miconazole

c. Thiabendazole 1) Also has anthelmintic activity 2) Usually not for topical application 3) Can raduce aflatoxin formation in infected feed 4) Effective vs. Blastomyces, Fusarium, Candida, Penicillium, Trichophyton 2. Cycloprox Olamine a. Has a broad antifungal activity b. A synthetic antimycotic agent c. MOA: inhibits the uptake of precursors of macromolecular synthesis and the site of action of presumed to be the cell membrane d. Has limited penetration of epidermis and incidence of adverse reactions is low e. Available as 1% solution or cream 3. Naftifine a. An allylamine

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b. Has activity against dermatophytes but less active against yeasts c. MOA:

Selectively

inhibit

squalene epoxidase, which is the key enzyme in the

synthesis of ergosterol d. Available as 1% cream e. Adverse reactions:

local

irritation, burning sensation, and erythma; avoid

contact with mucous membranes 4. Tolnaftate a. A synthetic antifungal agent effective against

Microsporum,

Epidermophyton,

Trichophyton b. Not active against Candida c. May be administered with griseofulvin for a more immediate effect d. Well tolerated and rearely causes irritation or allergy e. Available as cream, solution, powder, or powder aerosol 5. Haloprogin a. Synthetic halogenated phenolic ether b. Active against Microsporum, Epidermophyton, Trichophyton, Candida c. Use is restricted to dermatophyte infections d. Available as 1% cream or solution e. Slight penetration of intact skin 6. Cuprimyxin a. Broadspectrum antifunfal with antibacterial activity b. After application, the myxin component is released from the copper complex c. Myxin component is active vs. Trichophyton, Microsporum, and Candida 7. Organic Acids a. Undecyclenic Acid 1) Fungistatic for superficial fungal infections 2) Usually

used

with

zinc

and salicylanilide to improve its efficiency

3) Available as powder or 10% alcoholic solution b. Caprylic Acid c. Propionic Acid

Dr. Elmer Q. Abillar

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1) Also incorporated in

manufactured animal feed to help control fungal

growth in feed 2) Prevent growth of toxin producing fungi by acidifying feed 3) Cannot neutralize the toxin already present in feed d. Benzoid Acid 1) Main ingredient of Whitfield's ointment, together with salicylic acid 2) Has

fungistatic

and

keratolytic properties

e. Salicylic Acid 1) Used in the treatment of chronic superficial dermatophyte infection 2) Has moderate fungistatic activity but good keratolytic action 3) Requires the presence of water to produce keratolytic effects 4) May cause skin irritation 8. Other Antifungals a. Candidicin b. lodochlorhydroxyquin c. Natamycin d. Iodine preparations e. Dyes: carbol-fuchsin and gentian violet C. ORAL ANT I FUNGAL AGENTS 1. Griseofulvin a. Properties 1) A fungistatic antibiotic derived from Penicillium griseofulvum 2) May exhibit cross-sensitivity with penicillin 3) Effective

against

dermatophyte infections

4) Ineffective against bacteria, Candida, and fungi responsible for deep mycotic infections 5) MOA: Inhibition of cell wall synthesis, nucleic acid synthesis, and mitosis 6) Primarily active vs. growing cells b. Pharmacokinetics 1) Administered orally; variable absorption from GIT

Dr. Elmer Q. Abillar

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2) Absorption depends on the physical state of the drug or its particle size and the presence of high-fat foods 3) Drug has affinity to diseased skin; binds to keratin and makes it resistant to fungal infection . 4) Highest new growth of nails and hair of the infection 5) Excreted in feces; few in urine c. Adverse reactions 1) Teratogenic and carcinogenic in laboratory animals; teratogenic in cats 2) Overall frequency of side-effeces is low d. Contraindicated in pregnant animals and kittens younger than 6 weeks of age 2. Nystatin a. A polyene macrolide antibiotic b. The first antifungal antibiotic to be discovered c. Has fairly broadspectrum of activity including Candida Aspergillus, Microsporum d. MOA:

Binds to fungal membrane Bterols, principally ergosterol

e. Effects 1) Altered permeability and transport features probably due to pore formation 2) Loss of cations and macromolecules from the cell 3) Cell destruction f. Pharmacokinetics 1) Can also be applied to skin or mucous membranes in forms of creams, ointir.ants, suppositories, suspensions, or powders 2) Orally administered nystatin is excreted in feces g. Adverse reactions 1) Local burning/itching sensatation 2) GI upset 3. Amphotericin B a. Properties 1) An

amphoteric

polyene

macrolind antibiotic

produced by

Streptomyces

nodosus 2) Fungistatic and fungicida

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3) Very effective in the treatment of systemic

fungal

infections

and candidiasis

when combined with other antifungal agents like ketoconazole and flucytoxine 4) Insoluble in water b. MOA:

Binds firmly to ergosterol causing disruption of fungal cell membrane

(similar to nystatin) c. Pharmacokinetics 1) Administered topically, orally, or IV for systemic effect 2) Poorly absorbed orally and is effective only on fungi within the lumen of GIT 3) Injected drug is widely distributed in tissues and about 2-3% reaches the CSF d. Adverse reactions 1) Impairment of renal and hepatocellular functions 2) Anemia, cardiac airhythmias, hypokelameia, phlebitis e. Concurrent use with flucytosine decreases the dose requirement f. Caution:

treatment with amphotericin is dangerous and complicated; specific

guidelines must be consulted 4. Flucytosine a. A fluorinated pyrimidine derivative b. MOA:

Converted to fluorouracil which inhibits thymidylate synthetase thereby

inhibiting DNA synthesis c. SpeTctrum of activity 1. Narrow; causes rapid development

of resistance

2) Often used with amphotericin b to offset this effect 3) Indicated for cryptococcal infection in cats d. Pharmacokinetics 1) Well-absorbed from the gut 2) Penetrates tissues and CSF 3) Excreted unchanged in the urine e. Pharmacokinetics 1) Hematologic, GI, and hepatic toxicities 2) Appears relatively nontoxic for mammalian cells but prolonged high levels can cause BM suppression, loss of hair and impaired hepatic function

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5. Ketoconazole a. Properties 1) An

imidazole derivative

synthetic antifungal

2) Insoluble in water but soluble in dilutes acid solutions 3) Incompatible with gastric antacids and anticholinergics b. MOA: 1) Inhibits fungal lipid synthesis, esp. ergcsterol 2) Bind to membrane phospholipid 3) Interfere with cytochrome C oxidase and peroxidase

(resulting

in

increased

intracellular peroxide and cell death) c. Effects: 1) Loss of membrane integrity 2) Increased permeability 3) Cell degeneration 4) Cell death d. Spectrum of activity 1) Wide: filamentous fungi; dermatophytes, yeasts, and dimorphic fungi 2) Delayed onset of action (5-10 days) 3) Often prescribed with amphotericin B in treating systemic infections e. Pharmacokinetics 1) Well

absorbed orally and widely

distributed in tissues 2) Does not readily cross the CSF 3) Biotransformed in the liver; excreted in bile and urine f. Adverse reactions 1) Dogs: inappetence, pruritus, alopecia, reversible lightening of hair 2) Cats: anorexia, depression, diarrhea, fever, cholangiohepatitis g. Contraindicated

in

pregnant

animals

(embryotoxic teratogenic)

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ANTHELMINTIC AGENTS A. ANTINEMATODALS 1. Arsenicals a. MOA: Trivalent arsenic salt binds to the sulphydryl (-SH) group of glycolytic enzymes 1) Alters tertiary structure of proteins and active sites of enzymes in host and parasite 2) Inhibits glycolysis leading to death of the parasite b. Thiacetarsemide 1) Also known as arsenimide sodium, an organic arsenical 2) Available as 1% buffered injectable solution (CaparsolateR ) 3) Use is limited to the renoval of adult Dirofilaria immitis (adulticide) 4) Thorough health evaluation of patient is necessary prior to treatment 5) Highly hepatotoxic and may cause swelling and sloughing of the skin when injected extravascularly. 6) Activity

of treated dogs

must

be restricted to reduce

danger of massive pulmonary emboli resulting from drying adult heartworms

c. Melarsomine 1) A relatively new trivalent arsenical marketed as immiticideR 2) Efficacy of adult Dirofilaria immitis from 92-98% 3) Less arsenic content than thiacetarsaraide and apparently less toxic patient 4) Well tolerated in dogs 2. Benzimidazoles a. Characteristics

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1) Broadspectrum anthelmentics 2) MOA: a) Bind to tubulin molecules and inhibit

the

formation

of microtubules and

distrupt cell division b) Inhibit fumarate reductase and block mitochondrial function depriving the parasite of energy resulting death 3) Poorly soluble and are genrally given per orem 4) More effective in horses and ruminants due to their slow transit through the cecum and rumen 5) Three members are teratogenic: albendazole, membendazole , and oxfendazole b. Albendazole 1) The

newest benzimidazole

with

potent broadspectrum anthelmentic

2) Used in the treatment of intestinal helmith infections, hydatid disease, and cysticercosis of man ( Zentel ) 3) Used in cattle and sheep (Valbazen ) to treat a wide variety of nematode parasites, including inhibited larval forms, cestades and lung and liver trematodes 4) Wide margin of safety in cattle but must not be used in female dairy wattle of breeding age and given to pregnant cows during the first 45 days of gestation and in sheep during the first 10-17 days of pregnancy 5) Withdrawal period in cattle is about 27 days; in sheep, 10 days c. Fenbendazole 1) Not embryotoxic and teratogenic 2) Formulated

as Sageguard

and

Panacur suspension, premix pellets, deworming

block, and free-choice mineral supplement for

oral administration

3) With activity against lung and GI nematodes and cestodes of cattle, sheep, swine, horses, dogs, and cats c. Mebendazole 1) Formulated as powder, paste, or suspension (Telmintic) for control of intestinal helminth parasites of dogs and horses 2) Has wide margin of safety fo domestic animals but was found to be teratogenic and embryotoxic in rats and mice

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e. Oxfendazole 1) Metabolized in ruminants to oxfendazole sulfone and fenbendazole 2) Approvced for use in cattle (Synanthic) Syntex Rumen Injector) and in horses (Benzelmin paste, suspension, or powder) f. Oxibendazole 1) Active

vs. benzimidazole-resistant

small strongyles in horses (Anthelcide ECy

paste or suspension) 2) Not effective vs. stomach bots in horses 3) Available in combination with diethylcarbamazine for dogs

ANTIPROTOZOAN AGENTS A.

Introduction 1. Considerations a. Many protozoan parasites require arthropod intermediate hosts. b. They have closer biochemical make-up to the mammalian cells than are pathogenic bacteria and fungi.

B.Anticoccidials 1. Amprolium – 1st generation schizonts a. Used as anticoccidial, especially against 1st generation schizonts b. MOA: Antagonism the physiological role of thiamine as a coenzyme. c. Effective in the early stages of infection d. Fed in poultry rations or drinking water, to prevent or treat cocidiosis e. Given as drench, mixed in drinking water, ot top dressed on the feed for treatment and prevention in cattl, goat, and sheep. 2. Arprinocid a. A purine analogue b. MOA: interfere with nucleic acid synthesis, especially the interconversion of purines, thereby blocking nucleic acid synthesis.

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3. Carbanilides a. Nicarbazine – 2nd generation schizonts 1) MOA: Unknown 2) Anticoccidial which has inhibitory effect on second generation schizonts. 3) Suitable for broilers and given for the first 12 weeks of the chicken life. 4) Not suitable for layers or breeding stock because of its effect on egg color and hatchability 5) Interrupts egg-laying period; reduces hatchability; mottled egg yolk b. Nitrophenide – E. tenella and E. necatrix (2nd generation schizonts) 1) Active vs. Eimeria tenella,, E. necatrix, E. acervulina, and E. maxima 2) Given at 0.025% in feed 3) Inhibits 2nd generation schizonts and reduces hatchability c. Trithiadol - E. tenella, necatrix, acervulina nad maxima 1) Active vs E. tenella, E. necatrix, E. acervulina, and E. maxima 2) Given at 0.06% to 0.09% in feed 3) Reduces hatchability; do not use in breeders 4. Clopidol – coccidiosis (broilers) a. MOA: unknown b. Used for prevention of coccidiosis in broilers and replacement birds c. Should not be given to birds producing eggs for human consumption. 5. Decoquinate a. A 4-hydroxyquinolone b. MOA: affects energy metabolism by interfering with cellular respiration c. Approved coccidiostatic drug for the control and prevention of Emeria infections in chicken, cattle, and goats. d. Indicated fro prevention of coccidiosis in cattle and goats e. Should not be fed to breeding animals or lactating dairy cows or goats. f. Bentonite should not be used indecoquinate feeds g. Co-members: Bequinolate, Methyl Benzoquate 6. 2, 4 – Diaminopyrimidines a. MOA: Inhibit dihydrofolate reductase b. Combinations with sulfonamides are synergestic c. Both block synthesis of tetrahydrofolic acid d. Diaveridine, Ormethoprim, Pyremethamine 7. Halofuginone a. Used for prophylaxis of coccidiosis. b. Not used in poultry > 8 weeks old c. Administered in feed. d. MOA: Unknown

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8. Ionophore antibiotics a. Characteristics. 1) MOA: Forms ionophores with sodium and potassium in the host and in the parasite. It renders the parasite membrane permeable to K+ and Na+ ions. Mitochondrial function is inhibited. 2) Acts on first sexual cycle by preventing development of 1st generation schizonts. 3) Continued use retards development of 1st generation schizonts. 4) Suitable for addition to feeds for broilers but not for laying birds. 5) Toxic to horses and other equines. 6) Not to be used 7 days before and after tiamulin administration (can be severe growth growth depression) b. Lasalocid 1) Closely related to monensin 2) The least toxic of the ionophores 3) Approved for use in cattle, sheep, and poultry fro control of coccidia and improve feed efficiency. 4) Should not be fed to claves processed for veal c. Monensin 1) Antibiotic product of Streptomyces cinnamonensis 2) Used in poultry and cattle (as feed additive) for its coccidiostatic and growth promoting activities. 3) Not approved for use in sheep but may be tolerable at low doses. d. Others: Salinomycin, Narasin, Maduramicin 9. Nitrobezamides a. Inhibit development of second generation schizonts but do not inhibit development of immunity. b. MOA: Unknown c. Dinitolmide (Zoalene), Nitromide. 10. Robenidine (Robenzilidine) 1st and 2nd generation schizonts a. For prophylaxis and treatment of coccidiosis in chickens b. Both coccidiostatic and cocciocidal c. MOA: Inhibits the respiratory chain phosphorylation and ATPase activity in rat liver mitochondria and may have similar action in coccidian. d. Affects the late first generation and second stage schizonts. 11. Sulfonamides and Substituted PABA a. MOA: Interfere with cofactor synthesis. As an analogue of the growth factor PABA, these block the synthesis of tetrahydrofolate synthetase b. Sulfadimethoxine 1) Useful in small animals 2) Therapy is continued until the animal is asymptomatic for at least 48 hours c. Sulfamethazine

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1) Its sodium salt may be administered in water or feed, or IV to cattle, sheep, and goats for control of coccidiosis 2) During outbreaks, it may be given in feed. 3) Animals should be provided with plenty of drinking water. 4) Withdrawal recommendations should be followed for food animals. d. Sulfaquinoxaline 1) Approved for use in poultry, cattle, and sheep 2) Administered in water for 3 – 5 days. 3) Do not give to lactating dairy cattle. e. Others: Sulfanilamide, Sulfamethoxine, Ethopabate (substituted PABA) C. MISCELLANEOUS ANTIPROTOZOALS 1. Metronidazole – Trichomonas, Giardia, Entamoeba a. A 5 – nitroimidazole b. MOA: Inhibits DNA synthesis by disturbing the helical structure causing DNA strand breakage and inhibition of DNA repair enzyme (DNAassel) c. Used in man (Flagyl) for treatment of Trichomonas vaginalis, Giardia lamblia, and Entamoeba hystolitica d. Indicated for the treatment of giardiasis and trichomoniasis in dogs. e. Causes pulmonary tumors in mice and increases incidence of neoplasms. 2. Dimetridazole – (blackheads) histomonas, swine dysentery and trichomoniasis in pigeons. a. Also a 5-nitromidazole b. Used to prevent and treat infections of Histomonas meleaqridis (blackhead) in poultry and game birds c. Also used for treatment and prophylaxis of swine dysentery and trichomonas in pigeons d. Should not be used in egg-laying birds. 3. Furaltadone – Histomoniasis (Chicken & Turkey) a. A nitrofuran (broadspectrum amtibiotic) b. Used to prevent histomoniasis in chickens and turkeys c. Administered in drinking water (10-40 g/100 L) for 7 days 4. Quinacrine – Giardia, Taenia, Diphyllobothrium a. MOA: Incorporated into DNA resulting to inhibition of RNA and DNA synthesis b. Originally used as antimalarial drug but has been replaced by other antimalarials c. Indicated in dogs for the control of Giardia, Taenia, and Diphyllobothrium infections ANTINEOPLASTIC AGENTS

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A.

CANCER THERAPHY 1. Treatment of Cancer involves a. Surgical excision b. Radiation c. Chemotheraphy 2. The apeutic goals are aimed to allow the patient to a. Live prolonged disease-free interval b. Have an improved quality of life c. Have an increased survival time 3. Surgical excision and/or radiation is usually used for localized, solid tumors (local and regional neoplasia) 4. Chemotheraphy involves the use of one or more combinations of antineoplastic agents to treat nonlocalized malignancies, advanced metastatic tumors, and for residual malignancies after surgery or radiation. 5. ANTINEOPLASTIC AGENTS are drugs used for the treatment of malignant diseases 6. Requirements prior to therapy a. Cytologic or histologic diagnosis of the tumor type b. Knowledge of drugs the tumor is sensitive to c. Measurable parameters by which to gauge the response 7. Neoplastic disease of veterinary importance that are responsive to chemotherapy include a. Canine lyphosarcoma b. Felome lymphosarcoma c. Mastocytoma d. Transmissable veneral tumor e. Multiple myeloma

B.

GENERAL PRINCIPLES 1. Normal and neoplastic cells follow the same cell division cycle 2. Tumor cells, even if they are immune from the attack by host defenses, still differ from the normal cells by virtue of their rapid rate of division and growth 3. Tumor cells may also reach the terminal stage of differentiation and may be temporarily quiescent or no longer divide 4. Actions of cytotoxic neoplastic agents are directed at the different stages of the cellular life cycle 5. Some chemotherapeutic drugs exert their greatest toxicity on rapidly dividing cells while some are effective during certain phases of the cell cycle

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6. Use of drug combinations in the therapeutic protocols increases the chance of killing resistant tumor cells and decreases the chance of temporarily dormant or become fully differentiated C.

CELL AND TUMOR KINETICS 1. Normal and neoplastic cells follow the same cell division cycle 2. Cell division cycles a. M (mitosis) phase (1) Period of mitosis where rapid cell division takes place (2) Lasts for about 30-90 minutes b. GO (gap 0) phase (1) The true resting phase (2) Cells are temporarily dormant or become fully differentiated (3) Cells may leave the dividing phase and enter the resting phase which can last for years (4) As tumors increase in mass, more cells enter this phase c. G1 (gap 1) phase (1) The period of increased biosynthetic activity (RNA and protein synthesis) before replication takes place (2) Variable duration (10-72) hours d. S (synthesis) phase (1) A period during which DNA synthesis (replication of DNA and chromosomes) takes place in preparation for the next mitosis (2) Lasts for about 6-8 hour e. G2 (gap 2)phase (1) Postreplication period (2) More RNA and protein synthesis takes place before the next M phase (3) Approximately 2 hours in duration 3. The number of tumor cells in the G0 phase increases as the mass of tumor cells increases 4. Malignant tumors are therefore more susceptible to antineoplastic agents when the masses are still small because majority of the cells are still dividing

D.

MECHANISMS OF RESISTANCE TO ANTINEOPLASTIC AGENTS 1. Pharmacokinetic a. The target cell is not able to maintain an effective drug concentration for a period of time sufficient for it to be destroyed by the agent b. This may be due to alteration in the pharmacokinetic of the drug

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c. Majority of tumor cells are in the G0 phase because of the marginal blood supply and poor nutrient supply 2. Cytokinetic a. Based on the growth rate and fraction of tumor cells b. Resistant tumors usually have lower growth rates and lower growth fraction than curable tumors 3. Biochemical a. Defective transport of antineoplastic drug into tumor cell b. Impaired drug activation within the cell c. Increased intracellular nucleotide pools d. Altered patterns of DNA repair e. Gene amplification and increased RNA coding for certain necessary enzymes that can biotransform and inacrivate the drug f. Altered receptor structure or decreased concentration of receptors g. Changes in the rate of cellular proliferation due to unknown factors E.

CONSIDERATIONS 1. Most chemotherapeutic drugs are dosed based on body surface area in square meters rather than the body mass 2. This correlates better than bodyweight does to the different sized patients 3. This is more physiologically accurate and is done to minimize the toxic effects of these agents (k) x (bodyweight in grams) 2/3 Body surface area (m²) = -------------------------------------------------------------------

104 where k = 10.1 (dogs); 10.0 (cats) 4. Effects of anticancer drugs on neoplastic cells follow the first order kinetics ( a constant proportion is killed) 5. Antineoplastic agents given at higher dose rates for short intermittent periods usually destroy more tumor cells than prolonged low dosage rates 6. Possible clinical responses to cancer chemotherapy a. Palliation (remission of secondary clinical signs) b. Regression c. Partial remission (decrease in size or amount of neoplastic tissue) d. Complete remission (disappearance of clinically detectable tumors) e. Cellular cure (complete elimination of all neoplastic cells) 7. Sources of failure a. Excessive chemotherapy-related side effecta

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F.

b. Progressive tumor growth due to (1) Intrinsic resistance (a) Tumors are found in sites which are protected (b) Tumor cell dormancy/insensitivity to specific drug actions (c) Insufficient drug delivery (2) Acquired resistance (a) Development of alternate metabolic pathways (b) Change in transport mechanisms (c) Initiate cellular repair (d) Inhibit drug activation (e) TOXICITY PATTERNS / COMPLICATIONS 1. Hematologic toxicity a. Bone marrow suppression is the most common toxicity associated with chemotherapeutic agents b. Characterized by (1) Leukocytopenia (increased incidence of infection) (2) Thrombocytopenia (uncontrolled bleeding, anemia) c. Normal life span of cells (1) Canine neutrophils = ²-8 hours (2) Canine platelets = ²-6 days (3) Canine RBC = 120 days 2. Gastrointestinal toxicity a. Less common than myelosuppression b. Major types of G1 complications (1) Nausea/vomiting (2) Gastroenterocolitis 3. Hypersensitivity a. Clinical signs similar to those of other hypersensitivity reactions b. Signs begin shortly after administration and include head shaking (due to ear pruritus), generalized urticaria and erythema, restlessness, occasional vomiting, and (rarely) collapse by hypotension c. May necessitate administration of H1 antihistamines 30 minutes prior to drug administration 4. Cardiotoxicity a. Often associated with use of doxorubicin in dogs b. Exhibited as arrhythmias c. Relatively rare in cats 5. Dermatologic Toxicity a. Delayed hair regrowth b. Hyperpigmentation

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c. Alopecia d. Tissue necrosis (when injected extravascularly) 6. Urinary Toxicity a. Nephrotoxicity b. Sterile hemorrhagic cystitis: pollakiuria, hematuria, dysuria c. Discontinue drug and administer furosemide (diuretic) and sulfadiazinetrimethoprim combination (vs. 2° bacterial infection) 7. Neurotoxicity a. Uncommon in dogs b. Frequent and fatal in cats c. Often seen with use of 5-flourouracil G.

CLASSIFICATION OF ANTINEOPLASTIC AGENTS 1. Different types of anticancer drugs act by different mechanisms a. Cell cycle-phase nonspecific drugs: act on several phases of the cycle b. Cell cycle-phase specific drugs: selectively kill tumor cells during a given phase of the cell cycle c. Cell cycle-nonspecific drugs: kill resting and dividing cells and are extremely myelosuppressive that they rarely used in Vet. Med. 2. Anticancer drugs are commonly classified in the following categories a. Alkylating agents d. Plant alkaloids b. Antimetabolites e. Hormones c. Antitumor antibiotics f. Miscellaneous 3. ALKYLATING AGENTS a. Examples (1) CYCLOPHOSPHAMIDE – most frequent used (2) CHLORAMBUCIL (3) BUSULFAN (4) MELPHALAN (5) TRIETHYLENETHIOPHOSPHORAMIDE (6) MECHLORETHAMINE HCI (7) CISPLATIN: platinum-containing compound fatal to cats b. Action: Crosslink DNA, preventing its replication c. Cell cycle-nonspecific 4. ANTIMETABOLITES: Structural analogues of normal metabolites of nucleic acids a. Purine analogues (1) 6-MERCAPTOPURINE (AZATHIOPRINE) and 6-THIOGUANINE (2) Actions: Feedback enzyme inhibitor of DNA synthesis (3) S-phase specific

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b. Pyramidine analogues (1) 5-FLUOROURACIL inhibits enzyme thymidylate synthetase (results in thymidine deficiency leading to inhibition of DNA synthesis) (2) CYTOSINE ARABINOSIDE (CYTARABINE): appears to inhibit DNA polymearse activity c. METHOTREXATE: Conpetitive enzyme inhibitor of folic acid reductase 5. VINCA (PLANT) ALKALOIDS (“Spindle Poisons”) a. VINCRISTINE – most frequent used - binds the mitotic spindle, arresting mitotic division in metaphase b. VINBLASTINE – affects cell energy production and disrupt mitotic spindle c. Both are M phase specific 6. ANTITUMOR ANTIBIOTICS a. Examples (1) BLEOMYCIN (2) DOXORUBICIN (3) MITOXANTRONE (4) DACTINOMYCIN (ASTINOMYCIN D) (5) PLICAMYCIN b. Action: Crosslink DNA and cause free-radical damages; inhibit RNA and protein synthesis; bind to membranes and alter ion transport c. Cell cycle nonspecific 7. HORMONAL AGENTS (often used for hemolymphatic malignancies or endocrine-related tumors) a. PREDNISOLONE’ and PREDNISOLONE – most common hormones used to treat tumors and are primarily used to treat lymphomas and mast cell tumors (1) Action: Penetrates to nucleus and affects RNA production (2) G1–phase specific b. DACARBAZINE (1) Action: Exhibits alkylating and antimetabolite activity (exact MOA unknown) (2) Cell cycle nonspecific c. HYDROXYUREA (1) Action: Inhibits DNA synthesis without interfering with mRNA and protein synthesis (2) S-phase specific ANTIVIRAL AGENTS 1. ANTIVIRAL CHEMOTHERAPY a. Still in an early stage of development but has excellent long-term prospects

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b. Most of antiviral drugs used in humans and experimental drugs in medicine are still further investigated for their potential veterinary use 2.

human

Mechanisms of action of various antiviral agents a. Inhibition of penetration of cells b. Inhibition of intracellular viral protein synthesis c. Inhibition of virus assembly or release d. Inhibition of assembly of viral particles

3. Inhibition of penetration to cells a. GAMMA GLOBULINS (1) Passive immunization in IgG (IM, IV, SC) can prevent entry of viruses into cells (2) Protection may last for several weeks but not complete (3) May be used to control distemper, rabies, Aujesky’s disease, TGE in swine (4) Offspring that have taken colostrums from vaccinated dams are usually protected from enteric viral infections b. AMANTADINE (1) A synthetic tricyclic amine with a symmetric structure (2) Activity limited to influenza A viruses in humans and animals (3) Most effective as prophylactic; moderately effective early in the course of disease (4) Experiments as prophylactic in infected chickens and turkeys proved successful 4.

Inhibition of intracellular viral protein synthesis Inhibition of early protein synthesis: Bisbenzimidazoles (1) Formation of RNA po;ymerase is inhibited (2) Ready development of resistance b. Inhibition of nucleic acid synthesis (1) IDOXURIDINE – vs. herpesvirus a. Converted into an iodoanalogue of thymidilate b. Inhibit virus-specified DNA polymerase c. Defective viral proteins will e produced d. Topical use only e. Used for treatment of feline herpesvirus keratoconjuntivitis and herpetic keratitis in other species (2) VIDARABINE a. An analogue of adenine deoxyriboside b. Acts by inhibiting viral DNA polymerase c. Effective vs. viruses with DNA polymerase activity d. Low olubility and rapid systemic deamination makes it unsuitable for systemic use in animals (3) RIBAVIRIN a. Resembles guanosine and interferes with formation of guanosine phosphate in DNA and RNA synthesis a.

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b. c. d. e. (4)

(5)

(6)

(7)

(8)

c. (1) (2) (3) 5.

Has broad antiviral activity vs. many DNA and RNA viruses Clinical use does not induce viral resistance Low toxicity upon systemic administration Prolonged treatment in cats may produce profound thrombocytopenia ACYCLOVIR a. An acyclic nucleoside analogue of 2’-deocyguanosine b. One of the first new antivirals licensed for use in humans c. Highly effective vs. herpesvirus by inhibiting herpes-specified DNA polymerase d. Potential in veterinary medicine needs further studies GANCICLOVIR a. Active vs. all herpesviruses b. More active than acyclovir vs. cytomegalovirus c. Outstanding activity vs. equine herpesvirus-1 TRIFLURIDINE a. A halogenated thymidine analogue b. Drug of choice for herpetic keratitis because of superior ability to penetrate the cornea AZIDOTHYMIDINE a. A dideocynucleoside thymidine analogue b. Inhibits viral reverse transcriptase in retroviral replication c. HIV reverse transcriptase 100x more susceptible than mammalian DNA polymerase d. Prolongs survival in advanced cases of HIV-AIDS by 12-30 months and delays progression of asymptomatic infection e. Tested in FeLV and FIV infections PHOSPHONOFORMATE (FOSCARNET) a. A pynophosphate analogue b. Inhibits DNA polymerase of herpesviruses and RNA polymerase of influenza viruses c. Being investigated for treatment of herpesvirus infections and AIDS in humans Inhibition of late protein synthesis: METHISAZONE Inhibits transcription of proteins required for development of mature virus Effective prophylactically vs. human poxviruses (vaccinia, small pox) Possible use as prophylactic in infectious canine hepatitis and bovine respiratory disease

Inhibition of virus assunbly or release: 2-DEOXY-D-GLUCOSE Inhibits a wide range of enveloped DNA and RNA viruses (esp. orthomyxo-,paramyco-, and herpesviruses) b. A glucose analogue a.

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c.

Interferes with the synthesis of oligosaccharides that are part of viral specific surface glycoproteins d. Results to decrease infectivity of viruses because of their inability to penetrate cells or to become uncoated e. Topically applied on to genital herpes in women f. Potential application as prophylaxis in CD, equine influenza, and parainfluenza infections 6. a. b. c. d.

e. f. g. 7.

8.

Interferons Families of glycoproteins with antiviral immuno-modulatory and antiproliferative effects Produced most animal species Indirect antiviral activity: alter host metabolism t impair synthesis and assembly of viral components Immuno-modulating activity: (1) Increased antibody production (2) Increased natural killer activity (3) Enhanced antigen expression on cell enhances recognition of virally infected cells Types: alpha (leukocyte) and beta (fibroblast) are released in viral infections while gamma (T-lymphocytes) are released in response to antigen or mitogen stinulation Clinical application still under study Studies have also been conducted to stimulate endogenous interferon production but has not yet yielded satisfactory results

Inhibition of assembly of viral particles: REFAMPIN a. Inhibits DNA-dependent RNA polymerase in bacteria and mammalian cells b. Prevents assembly of enveloped mature particles in mammalian cells in poxviruses c. Effect is reversible upin removal of drug Immunoenhancers Cytokines INOSIPLEX (INOSINE PRANOBEX) (1) Claimed to a. Increase B and T lynnphocyte activity b. Increase matural killer cell activity (2) No evidence of its value in veterinary medicine c. Bacterial adjuvants (1) Both Bacillus Calmette-Guerin (BCG) and Corynebacterium parvum are nonspecific adjuvants that increase activation of macrophages through an effect on T lymphocytes (2) Others require additional study a. b.

PESTICIDES

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A. PRINCIPLES OF THERAPY 1. Definition a. Compounds that destroy insect parasites b. Term usually applied to substances which are active against skin parasites or those which spend part of their life cycle in the body of animals 2. Characteristics of an ideal pesticide a. Effective against all stages of the parasite’s life cycle b. Fast-acting and prolonged c. Low or no toxicity to host d. Provide minimum residue in host e. Does not accumulate in the environment f. Minimal ecologic interference g. Inexpensive or economical h. Convenient to administer or use i. Well tolerated by the animal j. Cosmetically appealing to the pet owner 3. Route of entry a. Stomach poisons - need to be ingested or eaten by the parasites and become distributed within their bodies b. Contract poisons – enter the body of the parasites via the skin as these crawl on the surface to which pesticide has been applied c. Fumigants – released into the atmospheres as gas or as fine suspension and enter the respiratory system of the parasites d. Systemic pesticides – absorbed through the animal’s skin, stomach, or subcutaneous injection and become distributed throughout its body 4. Systems of parasiticidal application a. Prediluted sprays b. Emulsifiable concentrates c. Dips and washes d. Shampoos e. Dusts f. Foggers g. Systemics 5. A successful treatment program requires knowledge of the a. Life cycle of the parasite b. Habitat of the parasite c. Asymptomatic carrier state d. Contagiouness of the parasite to humans or other animals e. Recognized activity of the parasite

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B. FORMULATIONS AND ACTIVE INGREDIENT 1. Botanicals a. Characteristics (1) Derived from plant materials (flowers, leaves, stems, roots) (2) Have excellent toxic effects on a variety of crop and animal insect pests (3) Have very short persistence in the environment (4) Relatively have low toxicity to mammals b. ROTENONE (1) MOA: Inhibit mitochondrial respiratory enzymes (2) Insoluble in water but soluble in m any organic solvents (3) First used by natives of South America to paralyze fish, causing them to surface (4) Used in 1800s to control leaf-eating caterpillars (5) It is the insecticidal component of derris root, cube root, and several other leguminous shrubs (6) May be applied to cats and dogs as an ointment, dip, or in liquid form, for the control of a variety of arthropod parasites (7) Not for kittens less than four weeks old and suckling puppies (8) May induce vomiting once ingested by dogs and cats (9) Toxic to swine, fish, and snakes; carcinogenic in rats c. PYRETHRINS (1) MOA: Disrupt Na+ and K+ transport in nerve membranes thereby disrupting neurotransmission along the axon and at the synapse (2) Include six closely related insecticidal substances (pyrethrin I and II, cinerin I and II, jasmolin I and II) (3) Obtained from the flower head of pyrethrum plant Chrysanthemum cinerariaefolium (4) Rapidly biodegradable and are rapidly degradable in the presence of moisture, air, and light (5) Usually combined with synergists to increase their insecticidal activity ten to twenty times (6) Toxic to fish and arthropods (7) Should not be applied to kittens less than 4 weeks old or to suckling puppies d. Pyrethroids (1) Characteristics a. Synthethic pyrethrum-like substances b. MOA: Initially stimulate then depress nerve cell function and eventually cause rapid muscular paralysis c. More potent than plant pyrethrins, biodegradable, and are sufficiently stable when exposed to air and light d. Low mammalian toxicity but are toxic to fish (2) First generation pyrethroids

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a. Represented by ALLETHRIN, a synthetic duplicate of cinerin I b. Have similar properties with natural pyrethrins c. Formulated in an aerosol spray with synergists to control flies, mosquitoes, ticks, and fleas in animal quarters and also formulated into fles shampoo for removing fleas in dogs and cats (3) Second generation pyrethroids a. Potency 10-50x the natural pyrethrins b. Not much more stable in sunlight than natural pyrethrins c. Examples: RESMETHRIN, TETRAMETHRIN (4) Third generation pyrethroids a. Has increased potency and photostability b. Available in a variety of formulations for use on or around animals, and to livestock buildings or animal quarters c .Examples: CYFLUTHRIN, CYPERMETHRIN, LAMBDACYHALOTHRIN, ZETAMETHRIN 2. CARBAMATES a. Characteristics (1) MOA: Blind to and inactivate AChE leading to accumulation of Ach at neural synapses (2) Carbamate forms a carbamate-AChE complex thereby inactivating the enzyme but it is later cleaved away (3) Similar to organophosphates in activity but are more reversible and have lower mammalian toxicity (4) Antidote of choice is atropine (5) Not to be used with other AChE inhibiting chemicals b. CARBARYL (1) Also known as SEVIN (2) Introduced in 1956 and was first commercially successful carbamate (3) Used alone or in combination with other products (4) Formulated as sprays or dusts for use on animals and animal quarters (5) Not recommended on puppies and kittens under 4 weeks of age c. METHOMYL (1) Introduced in 1966 and more potent than carbaryl (2) Very toxic to mammals, fish, and honeybees (3) Has broadspectrum of activity vs. insects infesting vegetables and field crops (4) Used as fly bait together with a synthetic fly-attractant pheromone, (2)-9tricosene d. PROPOXUR (1) Introduced in 1959 (2) Has quick knockdown effect and residual effect of 4-6 weeks (3)Toxic to birds and honeybees but can be safely used and around domestic animals (BAYGON®, SENDRAN®)

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(4) Commonly used in flea collars for dogs and cats e. Others: MOBAN, ALDICARB, ZECTRAN 3. CHLORINATED HYDROCARBONS a. Characteristics (1) Have high lipid solubility and are very persistent (2) As a contact poisons (3) Stimulate the CNS causing incoordination and neuromuscular hyperexcitability (4) MOA: Believed to attach into the sodium gate causing inward flow of Na+ and prevent repolarization b. DDT (DICHLORO DIPHENYLTRICHLOROETHANE) (1) First drug introduced in this group (2) Its spectacular success in 1939 resulted in widespread use and overuse (3) Primarily used vs. mosquitoes that carry malaria, body lice that carry typhus, and fleas that are vectors for plague (4) Persisted in body fat, accumulated in the food chain thereby affecting wildlife species, and has caused thinning of eggshell among raptors c. LINDANE (1) A gamma isomer of hexachlorohexane (HCH) (2) Stimulates mammalian CNS resulting in hypertension, bradycardia, polypnea, restlessness, body tremors, salivation, grinding of teeth, and convulsions (3) High rate of biodegradability and high volatility (4 Available as aerosol spray for each ticks and screw worms on farm animals (5) Not approved for whole animal treatment, do not apply to humans, household pets, lactating animals, and young animals < 3 months old d. METHOXYCHLOR (1) A methoxy analogue of DDT (2) Has prolonged residual insecticidal activity (3) Little tendency to accumulate in animal fat (4) Available in combination with pyrethrin and synergists or with carbaryl (5) Can be sprayed or rubbed on animal or applied to premises or given as powder or dust in dogs and cats (6) Not to pregnant animals, nursing pups and kittens, or young animals < 4 weeks old 4. ENDECTOCIDES a. Developed from macrocyclic lactones produced by various Streptomyces b. Invermectin and milbemycin are currently used in veterinary dermatology c. MOA: Potentiate the release and effects of GABA which is peripheral neurotransmitter in susceptible arachnids and insects

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d. Main action is paralysisi of the parasite but can also suppress egg production and molting in ticks e. IVERMECTIN (1) Has good activity against nematodes, microfilariae, and mites (2) Not found to be effective against Demodex but has been advocated as beneficial when used concurrently with topical amitraz f. MILBEMYCIN (1) Similar to ivermectin in activity (2) Effective against amitraz-resistant generalized demodecosis 5. FORMAMIDINES a. Characteristics (1) Acaricidal comppunds effective vs. cattle ticks and mange mites of swine and dogs (2) MOA: a. Inhibit monoamine oxidase b. Inhibit voltage sensitive sodium gates in the nerve membrane (3) Found very effective vs. pests that have developed resistance to Ops and carbamates b

AMITRAZ (1) The only formamidine approved for use in animals (2) Well tolerated by dogs but many produce transient sedation, depression of rectal temperature, and elevation of blood pressure (3) Available as MITABAN® (19.9%) liquid and as diluted to a 0.025% solution in treating generalized demodicosis in dogs (3-6 treatments spaced 14 days apart) (4) Available as TACKTIK EC® (12.5%) emulsifiable concentrate for use vs. ticks, mange mites, and lice on beef cattle, dairy cattle, and swine (5) No slaughter withdrawal in beef cattle and no milk withdrawal in dairy cattle are required but swine must not be treated within three days of slaughter (6) Must not be used in horses since fatal colon impaction may occur (7) Mitaban concentrate is flammable, rubber gloves must be worn when preparing dilutions and applying these to dogs

6. INSECT GROWTH REGULATION / INHIBITION a. Characteristics (1) Break the life cycle by killing immature insects where they grow and develop (2) IGRs are juvenile hormone mimics that bind to juvenile hormone receptors in the immature insect and prevent survival to the next stage of development

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(3) Cannot have biologic response on the host because mammals have no analogons systems that can be affected (4) Effective in insect control programs when used properly (5) Use of these products also minimizes the use of toxic adulticides b. CRYOMAZINC (1) An IGR whose use is limited to the filth flies (eg. Houseflies) (2) No effect on most of other beneficial insects (3) MOA: Block the formation of new cuticle in fly larvae so that the insect cannot survive the molt from the first to the second instar stage (4) Formulated as a feed premix (LARVADEX 1% PREMIX®) and a liquid concentrate (LARVADEX 2 SL®) (5) As feed premix, it passes through the bird and is deposited in the manure where it controls developing filth flies (6) Surface sprays are for the control of fly larvae in breeding places like feed spills, dead bird piles, and manure storage areas c. DIFLUBENZURON (1) Is a contact and systemic insecticide and not a true IGR (2) MOA: Interferes with chitin deposition and prevents shedding of old skin leading to death of the l;arvae or pupae as well as hatching of eggs (3) Available as a bolus (VIGILANTE®) to beef and dairy cattle for the control of horn flies, stable flies, and houseflies (4) About 80% is eliminated unchanged in the feces and interfere growth of larvae in manure d. FENOXYCARB (1) A broadspectrum IGR classified chemically as carbamate but has no activity against AChE (2) MOA: Blinds to the juvenile hormone receptor and is not readily broken down by juvenile hormone esterases in the insect larvae (3) It is very stable in the environment (4) Larvicidal and ovicidal against fleas (5) For use against fleas (BASUS®, ECTOGARD®, IM[PASS®), cockroaches (TORUS®), AND FIRE ANTS (LOGIC®) (6) Available as fenoxycarb alone for use as flea preventive, and in combination with adulticides for the treatment of existing flea infestations e. LUFENURON (FLUFENACUR) (1) A benzoyl urea which inhibits insect development (2) MOA: Disrupts chitin synthesis and deposition on the immature flea (3) Chitin is a major component of flea exoskeleton (4) Given orally to dogs for 30 days and is deposited in fats which serves as storage for release into blood stream (5) Ingested by adult flea when they feed and is passed transovarially to the flea egg

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(6) Flea eggs exposed to lufenuron fail to hatch, those that hatch die during their first molt. f. METHOPRENE (1) MOA: Arrests larval development by acting as s juvenile hormone mimic (2) Sensitive to UV degradation (3) Formulated in combination with natural pyrethrins (OVITROL®, OVITROL FLEA EGG COLLAR®) for use on dogs and cats and with synthetic pyrethroids and chlorpyrifos (SIPHOTROL®) for indoor control of fleas (4) Ovicidal and larvicidal vs. fleas 7. ORGANOPHOSPHATES a. Characteristics (1) Yellow to deep brown oily liquids, or yellow to white crystalline powders which may have garlic odors (2) These are synaptic poisons that work by inactivating AChE enzymes in two steps (a) OP first binds reversibly to the active site of AChE (b) The phosphate later becomes irreversible bound to the AChE (c) Once bound, the inzyme cannot be regenerated and so the tissue must synthesize new enzymes (3) OP toxicity is a medical emergency and requires a) Treatment with activated charcoal and bathing to decrease absorption b) Pralidoxime (2-PAM) to reverse binding to the enzyme (first reaction) c) Atropine to decrease clinical signs of Ach excess (4) Groups (a) Aliphatic derivatives (b) Phenyl derivatives (c) Heterocyclic derivatives b. Aliphatic derivatives (1) Characteristics (a) Simple in structure (b) Rapidly broken down in the animal and in the environment (c) First group available commercially (2) DICHLORVOS (a) Has quick knockdown insecticidal action as contact, systematic, and fumigant agent, but little residual effect (b) Also available in slow-release pharmaceutical forms for use against nematodes of dogs, cats, swine, and horses (c) Used as spray or backrubbers in beef cattle; collars in dogs and cats; resin strips, baits, foggers, spray for the surrounding, resting, and breeding areas (d) Apply to animals q. 7-14 days; do not slaughter food animals within 1 day of treatment

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(3) TRICHLORFON (a) Hydrolyzed in vivo dichlorvos (b) Has high insecticidal activity and low mammalian toxicity (c) Treated animals must not be slaughtered for 21 days (d) Do not use milk treated animals for human consumption for 7 days c. Phenyl derivatives (1) Characteristics (a) Have a benzene ring in their structure (b) Longer lasting than aliphatic derivatives (2) CYTHIOTE (a) Effective systematically vs. adult fleas when given PO in dogs (b) Safe for oral administration (c) May be useful vs. Demodex, Otodectes, lice, and ticks (3) PENTHION (a) A potent and highly persistent insecticide (b) Applied as pour-on over back of cattle: ear tags (1-5 months) (c) Given PO to control Hypoderma (d) Withdrawal period is about 35 days (e) Should not be given in cows within 28 days of calving, lactating cows, calves < 3 mos. Old, or in animal under stress (4) TETRACHLORVINPHOS (a) A phenyl derivatives OP with low mammalian toxicity (b) Available as wettable powder, dust, and in emulsifiable concentrate d. Heterocyclic derivatives (1) Characteristics (a) The last group to be developed (b) All have ring structure where at least one of the atoms in the ring is oxygen, nitrogen, or sulfur (c) Heterocyclic ring may have 3, 5, or 6 atoms (d) The longest lasting of all Ops (2) CHLORPYRIFOS (a) Moderately persistent in the environment (b) Useful for control of mosquito and fly larvae, fire ants, and termites (c) Available as premise sprays and dips; flea and tick collars for dogs only; ear tags (d) Should not be administered to pregnant bitches and pups < 10 weeks old (e) Should not be used in veal calves, dairy cattle of any age, cows within 21 days before or 14 days after calving, or cattle for slaughter within 14 days of slaughter (3) COUMAPHOS (a) Relative low toxicity for mammals; mice are very sensitive (b) Hydrolyzes slowly under alkaline conditions (c) Rapidly degraded in liver of cattle

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(d) Available as emulsifiable concentrate, wettable powder, dust for use on animals and premises (4) DIAZINON (a) Relatively safe with good record of safety (b) Available as flea collar (dogs), ear tags (beef and non-lactating dairy cattle) (5) PHOSMET (a) Used as spray for control of horn flies and ticks in cattle (b) Available in aromatic petroleum solvents for control of fleas, ticks, sarcoptic mange mites in dogs and cats (c) Calves < 3 months old, dairy cattle, and beef cattle within 21 days of slaughter, and dogs