HISTAMINE AND HISTAMINE ANTAGONISTS Emel SonguMize emizelsuhsc edu

HISTAMINE AND HISTAMINE ANTAGONISTS Emel Songu-Mize emize@lsuhsc. edu 1

Objectives • Know the anatomic localization and function of histamine H 1, H 2, H 3 and H 4 receptors • Distinguish between the 1 st and 2 nd generation H 1 -antihistamines • 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 H 1 antihistamines 2

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 3

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. 4 Physiological Actions of Histamine • Primary stimulant for gastric acid and pepsin secretion (H 2) (acid secretion is enhanced by gastrin and vagal stimulation) • Has a role as a neurotransmitter (H 3) (both in the CNS and peripheral sites)

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

Synthesis and Metabolism 1) Synthesized in the cell from L-histidine decarboxylase Histamine 2) Metabolized by P 450 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 6

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

Ig. E - Mediated Releasers • Food: eggs, peanuts, milk products, grains, strawberries, etc • Drugs: penicillins, sulfonamides, etc • Venoms: fire ants, snake, bee, etc • Foreign proteins: nonhuman insulin, serum proteins, etc • Enzymes: chymopapain 8

Non-immune Releasers • Morphine and other opioids, i. v. • Aspirin and other NSAIDs in some asthmatics • Vancomycin, i. v. (Red man syndrome), polymixin B • Some x-ray contrast media • Succinylcholine, d-tubocurarine, 48/80 • Anaphylotoxins: c 3 a, c 5 a • Cold or solar urticaria 9

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

Pharmacological Effects of Histamine • Ranges from mild allergic symptoms to anaphylactic shock • Involves both the H 1 and H 2 receptors Ødilatation of small blood vessels flushing (H 1) Ødecreased TPR and BP (H 1 initial response, H 2 sustained reaction) Øincreased capillary permeability, edema (H 1) 11

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

Receptors: Distribution and Function • H 1 – Smooth muscle, endothelium, CNS. Bronchoconstriction, vasodilation, separation of endothelial cells, pain and itching, allergic rhinitis, motion sickness. • H 2 – gastric parietal cell, vascular s. m. cell, basophils. Regulate gastric acid secretion, vasodilation, inhibition of Ig. E-dependent degranulation. • H 3 - 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 • H 4 - Highly expressed in bone morrow and white blood 13 cells. Mediate mast cell chemotaxis.

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

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 c. AMP 15

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

Effects on Human Heart (ref: G & G) 17 • 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 Ca 2+, and • 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. • With the exception of slowed AV conduction, which involves mainly H 1 receptors, all these effects are largely attributable to H 2 receptors and c. AMP accumulation. • If histamine is given i. v. , direct cardiac effects of histamine are overshadowed by baroreceptor reflexes elicited by the reduced blood pressure.

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

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

Histamine-related Drugs • Mast Cell Stabilizers (Cromolyn Na, Nedocromil – Tilade -, Albuterol) • H 1 Receptor Antagonists (1 st and 2 nd generation) • H 2 Receptor Antagonists (Ranitidine, Cimetidine) • H 3 Receptor Agonist and Antagonists (potential new drugs being developed) 20

Histamine H 1 - Antagonists First Generation: Sedating Second Generation: Nonsedating 21

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

First Generation Agents Uses: • 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) • Sedative/sleep aid • To prevent motion sickness (meclizine, cyclizine) 23

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

First Generation Agents Adverse Effects: • • • 25 Sedation (Paradoxical Excitation in children) Dizziness Fatigue Tachydysrhythmias in overdose - rare Allergic reactions with topical use Peripheral antimuscarinic effects • dry Mouth • blurred Vision • constipation • urinary Retention

First Generation Agents Drug interactions: • Additive with classical antimuscarinics 26 • Potentiate CNS depressants • opioids • sedatives • general and narcotic analgesics • alcohol

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

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

Second Generation Agents Adverse effects: • 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”) 29 • fexofenadine is active metabolite of terfenadine

Second Generation Agents Adverse effects: • 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. 30

Second Generation Agents Pharmacokinetics: Cetirizine (C), loratadine (L), fexofenadine (F) • well absorbed and are excreted mainly unmetabolized form. • C and L are primarily excreted in the urine • F is primarily excreted in the feces • They induce Cyt P 450 liver enzymes 31

Reading Goodman and Gilman 11 th edition Chapter 24 32