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1 HISTAMINE AND HISTAMINE ANTAGONISTS Emel Songu-Mize

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Presentation on theme: "1 HISTAMINE AND HISTAMINE ANTAGONISTS Emel Songu-Mize"— Presentation transcript:

1 1 HISTAMINE AND HISTAMINE ANTAGONISTS Emel Songu-Mize

2 2 Objectives Know the anatomic localization and function of histamine H1, H2, H3 and H4 receptorsKnow the anatomic localization and function of histamine H1, H2, H3 and H4 receptors Distinguish between the 1 st and 2 nd generation H1-antihistaminesDistinguish between the 1 st and 2 nd generation H1-antihistamines Know prototypical agents for 1 st and 2 nd generation antihistamines (underlined)Know prototypical agents for 1 st and 2 nd generation antihistamines (underlined) Describe the diversity of desired and undesired actions associated with 1 st generation H1- antihistaminesDescribe the diversity of desired and undesired actions associated with 1 st generation H1- antihistamines

3 3 Histamine: is an endogenous substance synthesized, stored and released in (a) mast cells, which are abundant in the skin, GI, and the respiratory tract, (b) basophils in the blood, and (c) some neurons in the CNS and peripheral NS

4 4 Histamine exerts its effects on many tissues and organs: It is not a drug but is important due to its physiological and pathophysiological actions. Therefore, drugs that inhibit its release or block its receptors have therapeutic value. Physiological Actions of Histamine Primary stimulant for gastric acid and pepsin secretion (H2) (acid secretion is enhanced by gastrin and vagal stimulation) Has a role as a neurotransmitter (H3) (both in the CNS and peripheral sites)

5 5 Pathophysiological Actions of Histamine Cellular mediator of immediate hypersensitivity reaction and acute inflammatory response Anaphylaxis Seasonal allergies Duodenal ulcers Systemic mastocytosis Gastrinoma (Zollinger-Ellison Syndrome)

6 6 Synthesis and Metabolism 1) Synthesized in the cell from L-histidine L-histidine L-histidine decarboxylase Histamine 2) Metabolized by P450 system, 2 pathways: a)Methylation to N-me histamine (N-me transferase), and to N-me imidazole acetic acid (MAO) - eliminated in urine b)Oxidative deamination to imidazole acetic acid (DAO), and to imidazole acetic acid riboside - eliminated in urine

7 7 HA Y Y Non-immune Releasers (opioids, tubocurarine, vancomycin etc ) IgE ANTIGEN PGs & LTs PROTEASES HISTAMINE OTHER MEDIATORS (PAF,TNF,ILs) IgE - Antibody Induced Release (food, penicillin, venoms, etc) ACUTE INFLAMMATORY RESPONSE IMMEDIATE HYPERSENSITIVITY REACTION Inhibitors of Release (Cromolyn, Albuterol) HA

8 8 IgE - Mediated Releasers Food: eggs, peanuts, milk products, grains, strawberries, etcFood: eggs, peanuts, milk products, grains, strawberries, etc Drugs: penicillins, sulfonamides, etcDrugs: penicillins, sulfonamides, etc Venoms: fire ants, snake, bee, etcVenoms: fire ants, snake, bee, etc Foreign proteins: nonhuman insulin, serum proteins, etcForeign proteins: nonhuman insulin, serum proteins, etc Enzymes: chymopapainEnzymes: chymopapain

9 9 Morphine and other opioids, i.v.Morphine and other opioids, i.v. Aspirin and other NSAIDs in some asthmaticsAspirin and other NSAIDs in some asthmatics Vancomycin, i.v. (Red man syndrome), polymixin BVancomycin, i.v. (Red man syndrome), polymixin B Some x-ray contrast mediaSome x-ray contrast media Succinylcholine, d-tubocurarine, 48/80Succinylcholine, d-tubocurarine, 48/80 Anaphylotoxins: c3a, c5aAnaphylotoxins: c3a, c5a Cold or solar urticariaCold or solar urticaria Non-immune Releasers

10 10 mild/cutaneousmild/cutaneous mild to moderatemild to moderate severe/anaphylacticsevere/anaphylactic erythema, urticaria, and/or itchingerythema, urticaria, and/or itching skin reactions, tachycardia, dysrhythmias, moderate hypotension, mild respiratory distressskin reactions, tachycardia, dysrhythmias, moderate hypotension, mild respiratory distress severe hypotension, ventricular fibrillations, cardiac arrest, bronchospasm, respiratory arrestsevere hypotension, ventricular fibrillations, cardiac arrest, bronchospasm, respiratory arrest Clinical Symptoms Associated With Histamine Release

11 11 Pharmacological Effects of Histamine Pharmacological Effects of Histamine Ranges from mild allergic symptoms to anaphylactic shockRanges from mild allergic symptoms to anaphylactic shock Involves both the H1 and H2 receptorsInvolves both the H1 and H2 receptors  dilatation of small blood vessels  flushing (H1)  decreased TPR and BP (H1 initial response, H2 sustained reaction)  increased capillary permeability, edema (H1)

12 12 Histamine Receptors All are part of the super family of G-protein coupled receptors: 1.H1 - G q coupled to Phospholipase C (PLC) 2.H2 - G s coupled to Adenylyl Cyclase (AC) 3.H3 - G i/o coupled to AC, also to K- channels and reduce Ca influx, inhibit presynaptic neurotransmitter release 4.H4 - available data consistent with coupling to G i/o in mast cells, as well as eosinophils, that can trigger calcium mobilization  mast cell chemotaxis

13 13 Receptors: Distribution and Function H1 – Smooth muscle, endothelium, CNS. Bronchoconstriction, vasodilation, separation of endothelial cells, pain and itching, allergic rhinitis, motion sickness.H1 – Smooth muscle, endothelium, CNS. Bronchoconstriction, vasodilation, separation of endothelial cells, pain and itching, allergic rhinitis, motion sickness. H2 – gastric parietal cell, vascular s.m. cell, basophils. Regulate gastric acid secretion, vasodilation, inhibition of IgE-dependent degranulation.H2 – gastric parietal cell, vascular s.m. cell, basophils. Regulate gastric acid secretion, vasodilation, inhibition of IgE-dependent degranulation. H3 - CNS cells, and some in peripheral NS. Presynaptic, feedback inhibition of histamine synthesis and release. They also control release of DA, GABA, ACh, 5-HT & NEH3 - CNS cells, and some in peripheral NS. Presynaptic, feedback inhibition of histamine synthesis and release. They also control release of DA, GABA, ACh, 5-HT & NE H4 - Highly expressed in bone morrow and white blood cells. Mediate mast cell chemotaxis.H4 - Highly expressed in bone morrow and white blood cells. Mediate mast cell chemotaxis.

14 14 Triple Response of Willis Subdermal histamine injection causes: 1.Red spot (few mm) in seconds: direct vasodilation effect, H1 receptor mediated 2.Flare (1cm beyond site): axonal reflexes, indirect vasodilation, and itching, H1 receptor mediated 3.Wheal (1-2 min) same area as original spot, edema due to increased capillary permeability, H1 receptor mediated

15 15 Selected Actions of Histamine in Humans Vascular  H 1 – in vascular endothelium  NO and PG release  vasodilation. In coronary vessels  vasoconstriction. Increased permeability of post capillary venules  H 2 – in vascular s.m. cells  vasodilation mediated by cAMP

16 16 Selected Actions of Histamine in Humans Heart  H 1 - decreased AV conduction  H 2 - increased chronotropy, decreased inotropy  H 1, H 2 - increased automaticity

17 17 Effects on Human Heart (ref: G & G) Histamine affects both cardiac contractility and electrical events directly. It increases the force of contraction of both atrial and ventricular muscle by promoting the influx of Ca2+, andHistamine affects both cardiac contractility and electrical events directly. It increases the force of contraction of both atrial and ventricular muscle by promoting the influx of Ca2+, and it speeds heart rate by hastening diastolic depolarization in the sinoatrial (SA) node. it speeds heart rate by hastening diastolic depolarization in the sinoatrial (SA) node. It also acts directly to slow atrioventricular (AV) conduction, to increase automaticity, and in high doses especially, to elicit arrhythmias.It also acts directly to slow atrioventricular (AV) conduction, to increase automaticity, and in high doses especially, to elicit arrhythmias. With the exception of slowed AV conduction, which involves mainly H1 receptors, all these effects are largely attributable to H2 receptors and cAMP accumulation.With the exception of slowed AV conduction, which involves mainly H1 receptors, all these effects are largely attributable to H2 receptors and cAMP accumulation. If histamine is given i.v., direct cardiac effects of histamine are overshadowed by baroreceptor reflexes elicited by the reduced blood pressure.If histamine is given i.v., direct cardiac effects of histamine are overshadowed by baroreceptor reflexes elicited by the reduced blood pressure.

18 18 Lung  H 1 – bronchoconstriction, increased mucus viscosity  H 2 - slight bronchodilation, increased mucus secretion  H 1 - stimulation of vagal sensory nerve endings: cough endings: cough Selected Actions of Histamine in Humans

19 19 Gastrointestinal System  H 2 - acid, fluid and pepsin secretion  H 1 - increased intestinal motility and secretions and secretions Cutaneous Nerve Endings  H 1 - pain and itching Selected Actions of Histamine in Humans

20 20 Histamine-related Drugs Mast Cell Stabilizers (Cromolyn Na, Nedocromil – Tilade -, Albuterol)Mast Cell Stabilizers (Cromolyn Na, Nedocromil – Tilade -, Albuterol) H1 Receptor Antagonists (1 st and 2 nd generation)H1 Receptor Antagonists (1 st and 2 nd generation) H2 Receptor Antagonists (Ranitidine, Cimetidine)H2 Receptor Antagonists (Ranitidine, Cimetidine) H3 Receptor Agonist and Antagonists (potential new drugs being developed)H3 Receptor Agonist and Antagonists (potential new drugs being developed)

21 21 First Generation: Sedating Second Generation: Nonsedating Histamine H1- Antagonists

22 22 First Generation Agents Examples Ethanolamines: DIPHENHYDRAMINE (Benadryl) CLEMASTINE (Tavist) Ethylenediamine:TRIPELENNAMINE Alkylamine:CHLORPHENIRAMINE (Chlortrimeton ) Phenothiazine:PROMETHAZINE (Phenergan) Piperazines: HYDROXYZINE (Vistaril) CYCLIZINE (Antivert)

23 23 Uses: Adjunctive in anaphylaxis and other cases where histamine release can occur (H 2 antagonist, and epinephrine must also be used in anaphylaxis)Adjunctive in anaphylaxis and other cases where histamine release can occur (H 2 antagonist, and epinephrine must also be used in anaphylaxis) Antiallergy (allergic rhinitis, allergic dermatoses, contact dermatitis)Antiallergy (allergic rhinitis, allergic dermatoses, contact dermatitis) Sedative/sleep aidSedative/sleep aid To prevent motion sickness (meclizine, cyclizine)To prevent motion sickness (meclizine, cyclizine) First Generation Agents

24 24 Uses (cont’d)Uses (cont’d) Antiemetic: prophylactic for motion sickness ( promethazine )Antiemetic: prophylactic for motion sickness ( promethazine ) Antivertigo (meclizine)Antivertigo (meclizine) Local anesthetic: (diphenhydramine)Local anesthetic: (diphenhydramine) Antitussive ( diphenhydramine )Antitussive ( diphenhydramine ) First Generation Agents

25 25 First Generation Agents Adverse Effects: Sedation (Paradoxical Excitation in children)Sedation (Paradoxical Excitation in children) DizzinessDizziness FatigueFatigue Tachydysrhythmias in overdose - rareTachydysrhythmias in overdose - rare Allergic reactions with topical useAllergic reactions with topical use Peripheral antimuscarinic effectsPeripheral antimuscarinic effects dry Mouthdry Mouth blurred Visionblurred Vision constipationconstipation urinary Retentionurinary Retention

26 26 Drug interactions: Additive with classical antimuscarinicsAdditive with classical antimuscarinics Potentiate CNS depressantsPotentiate CNS depressants opioidsopioids sedativessedatives general and narcotic analgesicsgeneral and narcotic analgesics alcoholalcohol First Generation Agents

27 27 First Generation Agents Pharmacokinetics: Well absorbed from the GI-tractWell absorbed from the GI-tract Widely distributedWidely distributed Cross BBBCross BBB Placental transferPlacental transfer Hepatic transformation, renal elimination of the metabolites (induce hepatic microsomal enzymes)Hepatic transformation, renal elimination of the metabolites (induce hepatic microsomal enzymes)

28 28 Uses Uses AntiallergyAntiallergy Examples CETIRIZINE (Zyrtec)CETIRIZINE (Zyrtec) FEXOFENADINE (Allegra)FEXOFENADINE (Allegra) LORATADINE (Claritin)LORATADINE (Claritin) DESLORATADINE (Clarinex- FDA Approved In 2002)DESLORATADINE (Clarinex- FDA Approved In 2002) LORATADINE (Claritin Hives Relief - FDA Approved In 2004)LORATADINE (Claritin Hives Relief - FDA Approved In 2004) AZELASTIN (Intranasal Spray)AZELASTIN (Intranasal Spray) Second Generation Agents

29 29 Adverse effects: in general, these agents have a much lower incidence of adverse effects than the first generation agents.in general, these agents have a much lower incidence of adverse effects than the first generation agents. terfenadine (seldane) and astemizole (hismanal) were removed from the market due to effects on cardiac K+ channels - prolong QT interval (potentially fatal arrhythmia “torsades de pointes”)terfenadine (seldane) and astemizole (hismanal) were removed from the market due to effects on cardiac K+ channels - prolong QT interval (potentially fatal arrhythmia “torsades de pointes”) fexofenadine is active metabolite of terfenadinefexofenadine is active metabolite of terfenadine Second Generation Agents

30 30 Adverse effects: Cetirizine appears to have more CNS actions (sedative) than fexofenadine or loratadine. recommended that cetirizine not be used by pilots.Cetirizine appears to have more CNS actions (sedative) than fexofenadine or loratadine. recommended that cetirizine not be used by pilots. Erythromycin and ketoconazole inhibit the metabolism of fexofenadine and loratadine in healthy subjects, this caused no adverse effects.Erythromycin and ketoconazole inhibit the metabolism of fexofenadine and loratadine in healthy subjects, this caused no adverse effects. Second Generation Agents

31 31 Second Generation Agents Pharmacokinetics: Cetirizine (C), loratadine (L), fexofenadine (F) well absorbed and are excreted mainly unmetabolized form.well absorbed and are excreted mainly unmetabolized form. C and L are primarily excreted in the urineC and L are primarily excreted in the urine F is primarily excreted in the fecesF is primarily excreted in the feces They induce Cyt P450 liver enzymesThey induce Cyt P450 liver enzymes

32 32 Reading Goodman and Gilman 11 th edition Chapter 24


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