2011 06 Pharmacology Anti Allergy Drugs

   2    1    0    2      1    1    0    2

Subject: Pharmacology Topic: Anti-allergy Drugs Lecturer: Dr. Ma. Luisa Delacruz Date of Lecture:06/29/2011 Lecture:06/29/2011 Transcriptionist: ChooOoosSs 01 Pages: 5

HISTAMINE Primary mediator of allergic of  allergic reactions  Drugs that are commonly used for allergic reactions (antihistamines) are intended to of histamine block the effects of histamine Formed by decarboxylation of histidine of  histidine by Lhistidine decarboxylase It is in the mast cell if it if  it is stored in the tissues, if  it is in the but it is stored in the basophils if it blood Other non-mast cell sites include the epidermis, gastric mucosa, neurons within the CNS and regenerating or rapidly growing tissues; these areas also contain some mast cells Before histamine is released from the mast cell to have manifested an allergic reaction, it has to have a sensitizing exposure.  Once exposed to the allergen, the body will produce antibodies against that allergen for the next exposure  Reaction occurs on second exposure: when allergen is re-introduce to the body, the antigen-anti body complex is now formed which attaches itself to itself  to the mast cell, then a series of processes of  processes occurs, leading to degranulation of that of  that mast cell to release mediators. Produces an effect by interacting with histaminergic receptors.

endothelial cells, CNS, peripheral nerve endings

y

y

   Y    S

H2

y

H3

Gastric parietal cells, heart, CNS

of  gastric Secretion of gastric acid

CNS: presynaptic neuron

Modulates neurotransmission -mediates feedback mechanism

Hematopoietic

Regulates

cells

responses

y

H4

immune

y

y

Histaminergic Histaminergic Receptors  G-protein coupled receptors H1  coupled to GS; the phosphoinositol pathway is involved; peripheral nerve ending, bronchial and intestinal smooth muscles, small blood vessels H2  linked to the cyclic AMP system that will release cyclic AMP as second messenger; primarily in gastric parietal cells H3  presynaptic autoreceptors in neurons that mediate feedback inhibition of the of  the release and synthesis of histamine of  histamine H4  similar to H3, expressed in cells of the of  the hematopoietic lineage y

y

y

y

Type

Major Tissue Locations Bronchial

H1

& intestinal smooth muscles,

Major Biologic Effects Acute allergic responses

HistamineEffects: 1. CVS a. Dilatation of resistance of  resistance vessels (arterioles) o H1 and H2 receptors distributed throughout the resistance vessels in most vascular beds o H1 (rapid in onset and short-lived), H2 (slow but more sustained) b. Decrease systemic blood pressure c. Increase capillary permeability o Effect on postcapillaryvenules o Outward passage of plasma of  plasma protein and fluid  edema formation o Mediated by H1 receptors on endothelial cells

1

d. Triple Response Lewis 1. Localized red spot Capillary dilatation (same as "petichiae: red spots) 2. Brighter red flush or flare around the area of the of  the red spot Axon reflex 3. Wheal Formed because of increase of  increase capillary permeability, the fluid and protein go out into interstitial area (edema formation)

Asthmatic attack due to allergic reactions d. Histamine-induced bronchospasm may involve an additional reflex component that arises from irritation of efferent of  efferent vagal nerve endings e. Contraction of intestinal of  intestinal smooth muscles y

y

y

y

4.

CNS

a. b. c. d. e. f.

Nociception  pain perception Arousal Satiation Cognitive function of  pituitary hormone release Control of pituitary Nausea & vomiting

*Fig. Produced by scratching the skin -> elicit the triple response lewis *Wheal- elevated area *Flare- reddened area surrounding th wheal

2. Heart o

H2:

(+) inotropic effect, (+) chronotropic effect of  contraction of atrial of  atrial Increase force of contraction & ventricular muscles promoting influx of  Ca++ (H2) Increase heart rate by hastening diastolic depolarization in the sinoatrial node (H2) H1: increase automaticity  arrhythmias Histamine shock In large doses (systemic anaphylaxis) causes a profound and progressive fall in blood pressure Resembles surgical or traumatic shock  Results in diminish effective blood volume, reduce venous return and marked decrease in cardiac output  Circulatory collapse = decrease in venous return  decreased cardiac output y

*Vestibular center and Chemoreceptor Trigger Zone has H1 receptor which when activated can produce nausea and vomiting, because they are linked to vomiting center. 5.

Dizziness, vertigo

6.

Peripheral nerve endings

y

o o

y

y

3. Extravascular Extravascular smooth muscle a. Contraction due to H1 activation Histamine induces bronchoconstriction b. Relaxation due to H2 activation c. Intense bronchoconstriction in patients with asthma and other pulmonary diseases y

i. Perception of itchiness of  itchiness & pain is due to the activation of  H1 receptors in the nerve endings a. Stimulation of various of  various nerve endings and sensory effects f  released in the epidermis (superficial b. If released stimulation)  itch c. If released f  released in the dermis (deep stimulation)  pain sometimes accompanied by itching Narrow margin for itch and pain perception y

2

Widely distributed throughout the body including the CNS Metabolized in the liver by CYP enzymes  isoenzymes not yet identified Excreted in small amounts in breast milk Small amount excreted unchanged in the urine Therapeutic Uses: 1. Type 1 hypersensitivity reaction - Acute allergic reaction  Secondary to food, drugs, insect bites, etc.  Seasonal rhinitis & conjunctivitis - Limited efficacy in asthma since in asthma, other mediators are involved not just histamine) (not just 2. Adjunct role to epinephrine in the treatment of severe of  severe allergic reactions/anaphylaxis Epinephrine - reverses the effect of histamine of  histamine but needs anti histamine to prevent further inflammatory reactions 3. Antipruritic 4. Motion sickness, vertigo - Meclizine (aka Bonamine) is an antihistamine widely used for motion sickness 5. Prophylaxis & treatment 6. Anti-emetic of  vomiting - Prevention of vomiting 7. Parkinson's disease - Diphenhydramine (Benadryl®) has been used to decrease muscle stiffness and tremors, which are associated with the disease. (Wellness.com) 8. Drug-induced extrapyramidal adverse effects Adverse Effects 1. CNS Drowsiness (often transient) o May be a good thing, when trying to avoid scratching and the feeling of itchiness of  itchiness Sedation, dizziness, faintness, disturbed coordination 2. GIT of  appetite, epigastric Loss of appetite, distress, constipation or diarrhea 3. Hematologic Hemolytic anemia, leukopenia, thrombocytopenia, agranulocytosis 4. Metabolic - not very common Increased appetite, weight gain Some drug preparations (H1 receptor blocker; Pizotifen) for children contain appetite stimulants y

y

y

y

y

y

ANAPHYLAXIS of  allergic reaction Severe form of allergic Potentially fatal Manifestations:  Angioderma, pruritus  Dyspnea  Tachycardia  Hypotension  of  consciousness Loss of consciousness

y y y

lassification of Classification

Anti-allergy Drugs (H1 receptor antagonists, antagonists, epinephrine, histamine release inhibitors, corticosteroids) corticosteroids) I. H1 Receptor Antagonists (Classical Antihistamines) a. 1st generation o Chlorpheniramine o Cyclizine o Dimenhydrinate o Hydroxyzine o Meclizine o Promethazine st o Diphenhydramine HCl: prototype of  1 generation drugs Pharmacokinetics  Rapidly absorbed after oral administration Usually given orally but also y has parenteral administration  Peak plasma concentration in 1-2 hours half  life is 4-8 hours Elimination half life y

y

y

y

y

y y

y

3

5.

Respiratory

Thickening of  bronchial secretions; chest tightness; wheezing Not useful for asthma because it can make the mucus more viscid, making it more difficult to expel 6. Others Hypersensitivity reactions, photosensitivity, in asthma (anti-histamine) - dry secretions 7. Cardiovascular Fatal ventricular arrhythmia (torsade des pointes) with Terfenadine and Astemizole  nd both are 2 generation antihistamines and are now withdrawn from the market Enhanced with simultaneous administration of  Ketoconazole and Macrolide antibiotics Precautions: 1. Avoid driving a motor vehicle or operating machinery  since taking this drug makes you drowsy 2. Avoid taking Alcohol and other CNS depressants y

y

y

y

y

y

y

y

b. 2nd generation drugs Characteristics (2nd gen. - useful as anaprophylaxis) o Improved H1 selectivity and selectivity is not absolute o Decreasedlipophilicity o Interfere with mediator release from mast cells and can prevent histamine release Acrivastine Cetirizine Fexofenadine Loratadine* Characteristics: y o Non-sedating o Does not impair psychomotor performance - not impair cognition o Does not produce excessive mucosal drying o No anti-cholinergic effect Prototype for 2nd generation y antihistamines Pharmacokinetics y o Rapidly absorbed after oral administration  Given only once a day (longer half -life) o Peak plasma levels is attained in 1 hour o Does not cross the blood brain barrier appreciably y

Less lipid-soluble o Metabolized in the liver by hepatic CYP3A4 to an active metabolite:  Desloratadine o Mean half -life of  Loratadine 8.4 hrs;Desloratadine 24 hrs o 98% protein bound o Excreted in the urine and feces, mainly as metabolite Therapeutic Uses: Acute allergic reactions o Allergic rhinitis o Allergic rhinitis o Drug/food allergy Chronic urticaria Atopic dermatitis Adverse effects, though not verycommon: 1. Fatigue, headache 2. Epigastric distress 3. Dry mouth 

c. 3rd generation drugs Desloratadine y Characteristics 1. Anti-inflammatory and immunomodulatory activities 2. Direct effects on inflammatory mediators: Inhibition of intracellular of  intracellular adhesion molecules-1 (ICAM1) expression by nasal epithelial cells of  loratadine Metabolite of loratadine H1 receptor blocker Reversi ble, competitive inhibitor of the of the interaction of  histamine with the H1 receptors Do not prevent histamine release Do not reverse effects of  histamine Prevents further histamine effects Pharmacologic Effects a. Smooth muscles o Prevents contraction of  bronchial smooth muscles partially because other mediators such as leukotrienes and PAF are also involved You have dilatation because it will prevent constriction. But the effect on bronchial smooth muscles is partial which means it cannot totally relax the smooth muscles because other mediators are involved o Inhibition of the of  the more rapid vasodilator effects that are mediated by activation of  H1 receptors on endothelial cells y

y

y

y

y

y

y

y

y

y

4

b. Capillary permeability o of  increased Blocks the reaction of increased capillary permeability and prevent further edema formation produced by histamine c. Central Nervous System (CNS) o Produce stimulation and depression o At therapeutic doses  depressant  diminished alertness, decrease reaction time, sedation, drowsiness, lethargy  More with 1st generation agents o High doses produce stimulation children are more sensitive to this effect (example of doc: of  doc: Kapagmalikotyungmgabata, parents sometimes give them anti histamines to make them fall asleep.); restlessness, nervousness, insomnia o of  overdose: Striking feature of overdose:  Marked stimulation  Agitation, convulsions, and coma in infants d. Anticholinergic o Atropine-like effects on muscarinic receptors  Atropine - muscarinic blocker o Promethazine has the strongest anticholinergic activity  Exhibits profound sedative effect  Used as pre-anesthetic medication to induce sedation in patients that would undergo surgery o Second generation H1 receptor blockers have no effect on muscarinic receptors e. Local Anesthetic effects o Diphenhydramine and Promethazine + o Blocks Na channels in excitable membrane o Alleviates pain and itchiness

Epinephrine Not an H1 receptor blocker; sympathomimetic y o of  the sympathetic Mimics the effects of the nervous system o Acts on the adrenergic receptors Physiologic antagonist to histamine o Physiologic antagonist: substance that can reverse the action of another of  another by acting on its own receptors o Histamine, by acting on the blood vessels, causes vasodilation o Epinephrine can rapidly reverse the action of histamine of  histamine by acting on 1 adrenergic receptors (found in peripheral blood vessels), resulting to vasoconstriction

2 bronchial smooth muscles, reverse bronchoconstriction Drug of choice of  choice for severe allergic reaction (anaphylaxis) o Desired effect is on 1 o of  anaphylaxis is laryngeal A feature of anaphylaxis edema, which is usually the cause of  fatality o Acting on the 1 receptors induces vasoconstriction, resolving the edema o

y

Histamine Histamine Release Inhibitors: used for prophylaxis to prevent chronic allergic conditions, especially asthma a. Nedocromil b. Cromolyn sodium o Inhibits histamine release from mast cells o Used to prevent hypersensitivity reactions o Indicated for asthma prevention Examples: o Spincapsule for asthma o Ophthalmic drops for allergic conjunctivitis Corticosteroids

a. Methylprednisolone b. Prednisone c. Hydrocortisone o Anti-inflammatory o Inhibits phospholipase A2 The enzyme is the rate-limiting step for almost all the chemical inflammatory mediators of phospholipase A2 inhibits Lack of phospholipase production of prostaglandins, of  prostaglandins, leukotrienes, platelet activating factor, TNF, interleukins Reduces expression of  cyclooxygenase 2 o Immunosuppression Decrease circulating lymphocytes, eosinophils, monocytes, basophils Increase circulating neutrophils Inhibit function of macrophages of  macrophages and other antigen-presenting cells y

y

y

y

y y

END OF TRANSCRIPTION

y

5