Subject: Pharmacology Topic: Anti-allergy Drugs Lecturer: Dr. Ma.

Luisa Delacruz Date of Lecture:06/29/2011 Transcriptionist: ChooOoosSs 01 Pages: 5

HISTAMINE y Primary mediator of allergic reactions  Drugs that are commonly used for allergic reactions (antihistamines) are intended to block the effects of histamine y Formed by decarboxylation of histidine by Lhistidine decarboxylase y It is in the mast cell if it is stored in the tissues, but it is stored in the basophils if it is in the blood y 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 y 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-antibody complex is now formed which attaches itself to the mast cell, then a series of processes occurs, leading to degranulation of that mast cell to release mediators. y Produces an effect by interacting with histaminergic receptors. Histaminergic Receptors G-protein coupled receptors y H1 coupled to GS; the phosphoinositol pathway is involved; peripheral nerve ending, bronchial and intestinal smooth muscles, small blood vessels y H2 linked to the cyclic AMP system that will release cyclic AMP as second messenger; primarily in gastric parietal cells y H3 presynaptic autoreceptors in neurons that mediate feedback inhibition of the release and synthesis of histamine y H4 similar to H3, expressed in cells of the hematopoietic lineage Major Tissue Locations Bronchial & intestinal smooth muscles, Major Biologic Effects Acute allergic responses

endothelial cells, CNS, peripheral nerve endings H2 Gastric parietal cells, heart, CNS CNS: presynaptic neuron Hematopoietic cells Secretion of gastric acid Modulates neurotransmission -mediates feedback mechanism Regulates immune responses

H3

H4

Type

H1

HistamineEffects: 1. CVS a. Dilatation 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 protein and fluid edema formation o Mediated by H1 receptors on endothelial cells

SY 2011-2012

d. Triple Response Lewis 1. Localized red spot y Capillary dilatation (same as "petichiae : red spots) 2. Brighter red flush or flare around the area of the red spot y Axon reflex 3. Wheal y Formed because 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 vagal nerve endings e. Contraction of intestinal smooth muscles
y

4. CNS a. Nociception pain perception b. Arousal c. Satiation d. Cognitive function e. Control of pituitary hormone release f. 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 y Increase force of contraction of atrial & ventricular muscles promoting influx of Ca++ (H2) y Increase heart rate by hastening diastolic depolarization in the sinoatrial node (H2) o H1: increase automaticity arrhythmias o Histamine shock y In large doses (systemic anaphylaxis) causes a profound and progressive fall in blood pressure y 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 3. Extravascular smooth muscle a. Contraction due to H1 activation y Histamine induces bronchoconstriction b. Relaxation due to H2 activation c. Intense bronchoconstriction in patients with asthma and other pulmonary diseases

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

ANAPHYLAXIS y Severe form of allergic reaction y Potentially fatal y Manifestations:  Angioderma, pruritus  Dyspnea  Tachycardia  Hypotension  Loss of consciousness Classification of Anti-allergy Drugs (H1 receptor antagonists, epinephrine, histamine release inhibitors, corticosteroids) I. H1 Receptor Antagonists (Classical Antihistamines) a. 1st generation o Chlorpheniramine o Cyclizine o Dimenhydrinate o Hydroxyzine o Meclizine o Promethazine o Diphenhydramine HCl: prototype of 1st generation drugs y Pharmacokinetics  Rapidly absorbed after oral administration y Usually given orally but also has parenteral administration  Peak plasma concentration in 1-2 hours y Elimination half life is 4-8 hours

Widely distributed throughout the body including the CNS y Metabolized in the liver by CYP enzymes isoenzymes not yet identified y Excreted in small amounts in breast milk y Small amount excreted unchanged in the urine y 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) 2. Adjunct role to epinephrine in the treatment of severe allergic reactions/anaphylaxis y Epinephrine - reverses the effect of histamine but needs antihistamine 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 - 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 y Drowsiness (often transient) o May be a good thing, when trying to avoid scratching and the feeling of itchiness y Sedation, dizziness, faintness, disturbed coordination 2. GIT y Loss of appetite, epigastric distress, constipation or diarrhea 3. Hematologic y Hemolytic anemia, leukopenia, thrombocytopenia, agranulocytosis 4. Metabolic - not very common y Increased appetite, weight gain y Some drug preparations (H1 receptor blocker; Pizotifen) for children contain appetite stimulants
y

5. Respiratory y Thickening of bronchial secretions; chest tightness; wheezing y Not useful for asthma because it can make the mucus more viscid, making it more difficult to expel 6. Others y Hypersensitivity reactions, photosensitivity, in asthma (anti-histamine) - dry secretions 7. Cardiovascular y Fatal ventricular arrhythmia ( torsade des pointes ) with Terfenadine and Astemizole both are 2nd generation antihistamines and are now withdrawn from the market y Enhanced with simultaneous administration of Ketoconazole and Macrolide antibiotics y 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 b. 2nd generation drugs y 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* y Characteristics: o Non-sedating o Does not impair psychomotor performance - not impair cognition o Does not produce excessive mucosal drying o No anti-cholinergic effect y Prototype for 2nd generation antihistamines y Pharmacokinetics 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

 Less lipid-soluble 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 o

c. 3rd generation drugs y Desloratadine y Characteristics 1. Anti-inflammatory and immunomodulatory activities 2. Direct effects on inflammatory mediators: y Inhibition of intracellular adhesion molecules-1 (ICAM1) expression by nasal epithelial cells y Metabolite of loratadine y H1 receptor blocker y Reversible, competitive inhibitor of the interaction of histamine with the H1 receptors y Do not prevent histamine release y Do not reverse effects of histamine y Prevents further histamine effects y Pharmacologic Effects a. Smooth muscles o Prevents contraction of bronchial smooth muscles partially because other mediators such as leukotrienes and PAF are also involved y 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 more rapid vasodilator effects that are mediated by activation of H1 receptors on endothelial cells 4

b. Capillary permeability o 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: Kapagmalikotyungmgabata, parents sometimes give them antihistamines to make them fall asleep. ); restlessness, nervousness, insomnia o 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 y Not an H1 receptor blocker; sympathomimetic o Mimics the effects of the sympathetic nervous system o Acts on the adrenergic receptors y Physiologic antagonist to histamine o Physiologic antagonist: substance that can reverse the action 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 by acting on 1 adrenergic receptors (found in peripheral blood vessels), resulting to vasoconstriction

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

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

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