Katzung Board Review Cardiovascular Drugs

CARDIOVASCULAR DRUGS DRUGS USED IN HYPERTENSION Diuretics Thiazides Mild hypertension Loop Diuretics Moderate, Severe and Malignant HPN Sympathoplegics Alpha 2 selective agonists (Clonidine, Methlydopa)

Decrease in sympathetic outflow Methyldopa  Methyl NE in brain Major compensatory response: salt retention

Toxicity Sudden discontinuation of clonidine: Rebound Hypertension Reinstitute clonidine therapy Give alpha blockers (Phentolamine) Methyldopa causes hematologic immunotoxicity (+ Coombs) Methyldopa causes more sedation than clonidine Ganglion Blocking Drugs Nicotinic blockers: obsolete due to AE Hexamethonium Extremely powerful blood pressureTrimethaphan lowering drugs Major compensatory response: salt retention Toxicity: parasympathetic blockade -blurred vision, constipation, hesitancy, sexual dysfunction - sympathetic blockade: sexual dysfunction, orthostatic hypotension Postganglionic Sympathetic Nerve Terminal Blockers Reserpine: Major compensatory response: depelete NE stores at adrenergic salt retention nerve terminal Guanethidine: block release of NE stores Reserpine: penetrates CNS Both have long duration of action Toxicity Reserpine: behavioral depression (most serious) Guanethedine: sexual dysfunction, orthostatic hypotension MAO inhibitors: Decreased vascular responses Form false transmitter (less NE with octopamine) (octopamine) Large doses of indirect acting sympathomimetics (tyramine) may result in hypertensive crisis  MAO inh no longer used for HPN Adrenoceptor Blockers Alpha 1 selective agents (Prazosin) Beta blockers (Propranolol)

Reduce vascular resistance and venous return Initially reduce CO Decrease vacular resistance (reduced angiotensin levels – due to reduced renin release) Nonselective alpha blockers of no use: d/t compensatory tachycardia Beta blockers: slightly elevated glucose, LDL, TG

Vasodilators Act directly on smooth muscle cells through non autonomic mechanisms Mechanisms o Release of NO o Open K channels : hyperpolarization o Block Ca channels o Activate D1 receptors Marked compensatory mechanisms o Minoxidil and Hydralazine o Salt retention and tachycardia Hydralazine: - Effect on arterioles > veins acts on the release of NO from - Suitable for chronic therapy endothelial cells Toxicity Compensatory responses: salt retention, tachycardia Drug-induced SLE (reversible, increased risk if dose >200mg/d) Minoxidil: - Severe hypertension -Converted to active Minoxidil sulfate (K channel opener) - hyperpolarization Toxicity Compensatory responses Hirsutism Pericardial abnormalities Calcium Channel Blocking Agents Nifedipine - Effective vasodilators Verapamil - Suitable for chronic use in any Diltiazem severity of HPN - Fewer compensatory response Parenteral vasodilators ( used in hypertensive emergencies) Nitroprusside: - Short acting Release of NO - infused continuously Toxicity Excessive hypotension, tachycardia Accumulationof cyanide or thiocynate if infusion continued over days Diazoxide: -IV or bolus Open K channels -duration of action: hours Hyperpolarization -also reduces insulin release (can be treated for hypoglycemia from insulin secreting tumors) Toxicity Hypotension Hyperglycemia Salt and water retention Fenoldepam: Prompt marked arteriolar D1 receptor activation vasodilation IV infusion Short duration of action Angiotensin Antagonists ACE inhibitors: Inhibit angiontensinconverting enzyme, kininase II and peptidyl dipeptidase Captopril

- More extensively used - Reduced blood levels of A-II and aldosterone - Increase in bradykinin - Protect diabetic kidney - CI in pregnancy

Adverse Effects Minimal compensatory response Cough (30% of patients) Renal damage with preexisting vascular disease Renal damage in fetus Angiotensin II blockers: Reduce aldosterone Competitively inhibit A-II at levels it’s AT1 receptor site Cause K retention CI in pregnancy Losartan Adverse Effects Lower incidence of cough Fetal renal toxicity Clinical Uses Usual stepwise treatment of HPN: 1) Lifestyle measures 2) Diuretics 3) Sympathoplegics – usually B blocker first 4) ACE inhibitors 5) Vasodilators – usually Ca channel blocker first Malignant Hypertension Accelerated phase of severe hypertension Rising blood pressure and rapidly progressing organ damage Managed with powerful vasodilators (nitroprusside, fenoldopam or diazoxide) with diuretics (furosemide) and B blockers Lower BP to 140-160/90-110 within few hours

CARDIOVASCULAR DRUGS DRUGS USED FOR ANGINA PECTORIS Types of Angina Atherosclerotic -classic angina -angina of effort

Vasospastic -rest angina, variant angina - Prinzmetal’s angina Unstable -crescendo angina -acute coronary syndrome

- atheromatous plaques that partially occlude coronaries - rest leads to relief of pain within 5-15 minutes - 90% of angina cases - reversible spasm of coronaries -occur at any time -increased frequency and severity of attacks -immediate precursor of MI -medical emergency

Determinants of Cardiac Oxygen Requirement Major determinant: myocardial fiber tension (higher tension, higher O2 requirement) Preload (diastolic filling Function of blood volume and venous tone pressure) Afterload Determined by arterial BP and large artery stiffness Heart rate Time-integrated fiber tension (faster HR, more time at systolic) Double product: SBP x HR Cardiac contractility Controlled by sympathetic outflow Ejection time Inversely related to force of contraction Increased Ejection time, increase O2 requirement Therapeutic strategies -defect: inadequate coronary O2 delivery relative to O2 requirement Increase O2 delivery Decrease O2 requirement Drugs that reduce O2 Requirement Nitrates -release NO (inc cGMP) Reduced preload, CO, afterload -increase coronary flow via collaterals -reduce vasospasm Venodilation -Decreased diastolic heart size and fiber tension

Smooth muscle relaxation Most sensitive: Veins > arteries> arterioles Rapidly denatured in liver and smooth muscle (large first pass effect 90%) Vasodilating effect: Dinitrate> mononitrate

Arteriolar dilation -dec PR and BP Adverse Effects Reflex tachycardia Increased force of contraction Toxicity Most common: reflex tachycardia, orthostatic hypotension Headache from meningeal artery vasodilation Interact with Sildenafil (potentially dangerous

hypotension) Cause methemoglobinemia at high blood concentration Monday disease: headache, tachycardia, dizziness Other forms Nitroglycerin: most important Range of duration of action 10-20 min (sublingual) 8-10 hr (transdermal) IV nitroglycerin: reduce platelet aggregation Isosorbide dinitrate Isosorbide mononitrate Amyl nitrate: volatile, inhalatational Nitrites in the treatment of Cyanide Poisoning Immediate exposure to amyl nitrite IV Na nitrite: increase methemoglobin level IV Na thiosulfate: convert cyanomethemoglobin to thiocynate and methemoglobin Ca channel Blocking Drugs (Nifedipine, Diltiazem, Verapamil) - Block voltage gated L - All are orally active type Ca Channels - Nifedipine: greater - Decrease Ca influx, vasodilation reduce muscle - Reduce BP and double product contractility

Clinical Use - Prophylactic (Nifedipine abort acute angina attacks) - Nimodipine: approved only for stroke associated with SAH - Verapamil, Diltiazem: AV nodal arrhythmias Toxicity - Constipation, pretibial edema - Nausea, flushing, dizziness - Bepridil: greater CV toxicity than other Ca channel blockers (torsades pointe) - Verapamil: AV block, sinus node depression B Blocking Drugs - decrease HR, BP, cardiac force -reduce the double product

Summary Nitrates Ca blockers B blockers

-effective in prophylaxis of atherosclerotic anginas -used only for prophylactic therapy of angina, no value in acute attack -prevent exercise-induced angina, no effect in vasospastic form

- Useful in all 3 types of angina - Treatment for angina of effort and vasospastic angina - Refractory unstable angina - Prophylaxis of angina of effort - Not useful for vasospastic angina - Not useful for acute attack of angina of effort - Emergency treatment of acute coronary syndrome

CARDIOVASCULAR DRUGS DRUGS USED IN HEART FAILURE Cardiac Glycosides Digitalis -foxglove plant Digoxin (P)

- Steroid nucleus and lactone ring - Increased ventricular ejection - Increased renal perfusion - Decreased CO - Decreased preload, afterload, HR

MOA: - inhibition of Na/K ATPase -increase intracellular Ca Clinical Uses Traditional positive inotropic agent used in CHF Improves functional status but does not prolong life Atrial fibrillation and Atrial Flutter -reduce the conduction velocity -increase the refractory period of AV node -ventricular rate is controlled with efficient filling and ejection Interactions Quinidine : reduction in digoxin clearance Extracellular K and Mg: inhibit digitalis effect -loop diuretics may precipitate digitalis toxicity Extracellular Ca: facilitate digitalis effect Digitalis toxicity Arrhythmias – most serious manifestation Nausea, vomiting, Diarrhea Chronic intoxication: Ca overload ( increased automaticity) Treatment -correct K or Mg deficiency (not for acute toxicity) -antiarrhythmic drugs (not for acute toxicity) - Lidocaine -Digoxin antibodies

Other Drugs used in Heart Failure Diuretics Furosemide - Immediate reduction of pulmonary congestion and severe edema Thiazides - Mild chronic failure Spironolactone/ Epleronone - Long term benfits Angiontensin Antagonists - reduce morbidity and mortality in CHF -no direct positive inotropic action -reduce aldosterone secretion, salt and water retention and vascular resistance Beta 1 Selective Adrenoceptor Agonists Dobutamine - Acute heart failure - Not appropriate for CHF Dopamine (tolerance, lack of oral efficacy, arrhthmogenic effects) Beta Adrenoceptor Antagonists Carvedilol, Labetalol, - Reduce progression of CHF Metoprolol - No value in acute heart failure Phosphodiesterase Inhibitors Amrinone and Milrinone - Increase cAMP, Increase in intracellular Ca - Vasodilation - Not used in CHF Vasodilators Nitroprusside - Acute severe failure with congestion - Reduced cardiac size, reduced resistance to ventricular Nitroglycerin ejection Nesiritide - Vasodilation - Natriuretic effects - For acute failure only Hydralazine - Chronic Heart Failure ISDN

Hyperkalemia increase cardiac toxicity Tocainide: agranulocytosis IC: Flecainide (P) - Powerful depressants of Na current Normal Electrical Activity in Cardiac Cell Encainide, Moricizine, Propafenone - Approved only for refractory Na current - Dominates the upstroke of the action potential phase ventricular tachycardias and (Phase 0)in most parts of heart - No effect on AP duration or QT intractable SVT - Most important determinant of conduction of AP interval - Markedly slow conduction velocity Ca current - Dominates in the AV node - Increase QRS duration on ECG - Plateau of phase 2 Toxicity K current - Rapid repolarization Refractory - Function of rapidly Na channels recover from inactivation -proarrhythmic effect (more likely to exacerbate or precipitate arrhythmias) – CAST Trial period -restricted to use in arrhythmias that fail to respond to other drugs -contraindicated for post MI Drug Class Amiodarone: Class III drug with IA effects, greatest AP prolonging effect Class I - Sodium channel blockers Phenytoin: reverse digitalis induced arrhythmias, classified with IB Class II - Beta adrenoceptor blockers ARDIOVASCULAR DRUGS ANTI ARRHYTHMIC DRUGS

Class III Class IV

- Potassium channel blockers - Calcium channel blockers

Class I Antiarrhythmics (Local Anesthetics) -MOA: slow or block conduction - slow or abolish abnormal pacemakers - use dependent or state dependent in their action -reduce both phase O and phase 4 Na currents IA: Procainamide (P) - All types of arrhythmias - Affect both atrial and ventricular Quinidine, Disopyramide arrhythmias - Also block K channels (phase 3) - Block Na - Slow conduction velocity - Prolong the AP (block - Slow AV conduction (high dose) K), increase effective - Increased QRS duration on ECG refractory period - Commonly used in acute phase of MI Increase in QT interval (Procainamide) Toxicity All may precipitate new arrhythmias Torsades pointes (particularly quinidine, except amiodarone) Hyperkalemia: exacerbates toxicity -Na lactate: given to reverse drug induced arrhythmias -Sympathomimetics: to reverse drug induced hypotension Procainamide Hypotension Induces Lupus like / SLE reaction Quinidine Cinchonism (headache, vertigo, tinnitus) Cardiac depression, GI upset (diarrhea) Autoimmune reactions (thrombocytopenia) Reduce digoxin clearance, increase serum digoxin Disopyramide Antimuscarinic effects, precipitate HF IB: Lidocaine (P) - -ventricular > atrial - Atrial arrhythmias not Mexiletine, Tocainide responsive unless caused by digitalis - Shorten the AP - No significant effect on ECG - does not shorten effective - Prefer ischemic tissues (for refractory period or increase post MI) contractility - reduces abnormal automaticity Toxicity May precipitate arrhythmias (less than IA)

Class II Antiarrhythmics (Beta Blockers) - -MOA: B adrenoceptor blockade Reduction in cAMP, Na and Ca currents No effect in AP - AV node is particularly sensitive to B blockers - PR interval prolonged Esmolol (P) - Short acting B blocker - Used exclusively in acute arrhythmias Propranolol (P), Timolol, - Prophylactic drugs in patients who have Metoprolol MI - Protective effect (2 years or longer after infarct) Toxicity Patients with arrhythmias more prone to B blocker induced depression of cardiac output Judicious use: reduces progression of CHF, reduce incidence of potentially fatal arrhythmias Class III Antiarrhythmics (K Channel Blockers) -Hallmark: prolongation of AP duration -due to blockade of phase 3 K channels -reduce outward phase 3 K current -main effect: prolong refractory period -same toxicity as in Class IA -eliminated in tears -phase 4 K current NOT affected -increase QT interval on ECG Sotalol (P) - Chiral compound Toxicity May precipitate torsade pointes, B blockade (sinus bradycardia or asthma) Ibutilide (P), Dofetilide - Atrial flutter, atrial fibrillation Toxicity: induction of torsade de pointes Amiodarone - Markedly prolongs AP, block Na -most efficacious among channels antiarrhythmic drugs - Only for arrhythmias resistant to other -blocks Na, K, Ca channels drugs and B adrenoceptors - Cyp inhibitor (ex. increase antithrombotic effects of warfarin) Toxicity: Microcrystalline deposits in cornea and skin Thyroid dysfunction Paresthesias, tremor Pulmonary fibrosis Rarely cause new arrhythmias Bretylium - Combines general sympathoplegic

-used only in the with K channel blocking effect in treatment of refractory ischemic tissue post MI arrhythmias - Acts on ischemic cells, little change on (recurrent VFib) ECG - May precipitate new arrhythmias or marked hypotension Class IV Antiarrhythmics (Ca Channel Blockers) -state and use dependent selective depression of Ca current in tissues that require L type ca channels -converting AV nodal reentry to NSR (nodal arrhythmias) - decrease conduction velocity at AV node - increased ERP (refractoriness prolonged) - increased PR interval (consistently) -reduce inward calcium current during AP and phase 4 Verapamil (P) - Major toxicity: excessive pharmacologic effect - Contractility, AV conduction, blood pressure depressed - Nifedipine and other dihydropyridines not useful as antiarrhythmic due to compensatory sympathetic discharge Miscellaneous Antiarrhythmic Drugs Adenosine - slows or completely blocks conduction in the AV node - activates Ik1 K channels in AV node (hyperpolarize) - effective in abolishing AV nodal arrhythmias (DOC) - short duration of action (15s) - only antiarrhythmic drug that consistently alters the resting potential of AV node Toxicity: flushing and hypotension chest pain and dyspnea overcome by short duration of action Digitalis - treatment of rapid atrial or AV nodal arrhythmias - slows AV conduction in atrial flutter or fibrillation Potassium Ion depresses ectopic pacemakers including those caused by digitalis toxicity Magnesium Ion similar effects as potassium on digitalis-induced arrhythmias Nonpharmacologic Treatment of Arrhythmias External defibrillation Implanted defibrillators Implanted pacemakers Radiofrequency ablation of arrhythmogenic foci

CARDIOVASCULAR DRUGS DIURETIC AGENTS -most enter in luminal end (except aldosterone receptor antagonist who enter from the basolateralside) Proximal - Reabsorption of AA, glucose and cations Convoluted Tubule - Major site of NaCl and NaHCO3 - 60-70% of total reabsorption of Na - Weak acid transport: most in S2 segment - Weak base: transported in S1 and S2 - Transport of uric acid - Target of carbonic anhydrase inhibitors Thick Ascending - Pumps Na, K, Cl out of the lumen into the interstitial Loop of Henle of kidney - Major site of Ca and Mg reabsorption -due to net positive selective channel - Na-K-Cl transporter: 20-30% of reabsorption of sodium (gradient for counter current concentrating mechanism) --target of Loop diuretics Distal Convoluted - 5-8% of Na reabsorption Tubule - NaCl active transport: target of thiazide diuretics - PTH mediated Ca reabsorption Cortical Collecting - 2-5% of Na reabsorption via Na channels Tubule - Controlled by aldosterone - Primary site of acidification of urine - Primary site of K excretion - Site of K sparing diuretics Medullary - Water reabsorption (ADH mediated) Collecting Tubule Carbonic Anhydrase Inhibitors Acetazolamide (P) MOA: inhibit carbonic anhydrase (brush border) and intracellular carbonic anhydrase in PCT

- Sulfonamide derivatives - Self-limiting within 2-3 days - treatment of glaucoma : reduce IOP - prevent acute mountain sickness acidosis in CSF results in hyperventilation which can protect mountain sickness - only used as a diuretic if edema is accompanied by significant metabolic acidosis

Major renal effect: bicarbonate diuresis  metabolic acidosis - Significant K wasting Toxicity drowsiness and paresthesia alkalinization of urine may cause precipitation of Ca salts and form renal stones marked renal K wasting hepatic encephalopathy in patients with hepatic impairment (increased ammonia reabsorption) Loop Diuretics Furosemide (P) MOA: inhibit cotransport of Na, K and Cl Bumetanide, Torsemide - Significant increase of Ca excretion - Significant K wasting - Proton excretion - Hypokalemic alkalosis

- sulfonamide derivatives - Ethacrynic Acid: phenoxyacetic acid derivative - Relatively short acting - Diluting ability of nephron is reduced - Loss of lumen-positive potential (reduce reabsorption of cations) - Inhibition of prostaglandin synthesis (NSAIDS) decreases efficiency of loop diuretics - Treatment of edematous states - Acute pulmonary edema (pulmonary vasodilating action)

- Treatment of severe hypercalcemia Toxicity: Hypokalemic metabolic alkalosis Hypovolemia Ototoxicity Thiazide Diuretics Hydrochlorthiazide (P) MOA: inhibit NaCl transport in DCT

- Sulfonamide derivatives - Longer duration of action than loop diuretics - Dilutionalhyponatremia - Major application in HPN - Can be used for chronic renal calcium stone formation (reduce urine Ca concentration)

-moderate but sustained Na and Cl diuresis -hypokalemic metabolic alkalosis - increased Ca reabsorption Toxicity Massive sodium diuresis with hyponatremia Chronic therapy: K wasting Significant hyperglycemia in diabetic patients Synergistic effect with loop diuretics

K sparing Diuretics -increase in Na clearance -decrease in K and H ion excretion -cause hyperkalemic metabolic acidosis Spironolactone - Steroid derivatives - Pharmacologic antagonists of Epleronone aldosterone in collecting tubules - Reduce gene expression controlling Na ion channel synthesis Amiloride - Block Na channels Triamterene Clinical Uses Indicated in aldosteronisms Spironolactone and Epleronone: long term effects in HF Toxicity Hyperkalemia (most important) Never be given with K supplements Caution with use of ACE inhibitors and ARBS Spironolactone: gynecomastia, antiandrogenic effects Osmotic Diuretics -increased volume of urine -increased Na excretion Mannitol (P) Glycerin, Isosorbide, Urea

- Given IV - Holds water by virtue of isosmotic effect - Major location : PCT - Reduce brain volume/ ICP - Useful in acute glaucoma and in neurologic conditions (reduce ICP)

Toxicity Hyponatremia and pulmonary edema Headache, nausea and vomiting Antidiuretic Hormone Agonists and Antagonists ADH agonists ADH and Desmopressin (P) - Peptides , IV - Reduce urine volume

- Increase urine concentration - Useful in pituitary diabetes insipidus Toxicity Dangerous hyponatremia Large doses, hypertension ADH antagonists Demeclocycline and Lithium ion

- Oral - Demeclocycline : Useful for SIADH

Toxicity Lithium with greater toxicity Lithium : cause nephrogenic diabetes insipidus (never used to treat SIADH Demeclocycline in Children