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

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

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

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

8. IgE - 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

9. 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: c3a, c5a
Cold or solar urticaria

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

11. Pharmacological Effects of Histamine
Ranges from mild allergic symptoms to anaphylactic shock
Involves 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. Histamine Receptors
All are part of the super family of G-protein coupled receptors:
H1 - Gq coupled to Phospholipase C (PLC)
H2 - Gs coupled to Adenylyl Cyclase (AC)
H3 - Gi/o coupled to AC, also to K- channels and reduce Ca influx, inhibit presynaptic neurotransmitter release
H4 - available data consistent with coupling to Gi/o in mast cells, as well as eosinophils, that can trigger calcium mobilization  mast cell chemotaxis

13. Receptors: Distribution and Function
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.
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 & NE
H4 - Highly expressed in bone morrow and white blood cells. Mediate mast cell chemotaxis.

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

15. Selected Actions of Histamine in Humans
Vascular
H1 – in vascular endothelium NO and PG release  vasodilation. In coronary vessels  vasoconstriction. Increased permeability of post capillary venules
H2 – in vascular s.m. cells  vasodilation mediated by cAMP

16. Selected Actions of Histamine in Humans
Heart
H1 - decreased AV conduction
H2 - increased chronotropy,
decreased inotropy
H1, H2 - increased automaticity

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+, 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 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.

18. Selected Actions of Histamine in Humans
Lung
H1 – bronchoconstriction, increased mucus viscosity
H2 - slight bronchodilation, increased
mucus secretion
H1 - stimulation of vagal sensory nerve
endings: cough

19. Selected Actions of Histamine in Humans
Gastrointestinal System
H2 - acid, fluid and pepsin secretion
H1 - increased intestinal motility
and secretions
Cutaneous Nerve Endings
H1 - pain and itching

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

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

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

23. First Generation Agents
Uses:
Adjunctive in anaphylaxis and other cases where histamine release can occur (H2 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)

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

25. First Generation Agents
Adverse Effects:
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

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

27. 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)

28. 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)
Uses
Antiallergy

29. 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”)
fexofenadine is active metabolite of terfenadine

30. 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.

31. 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 P450 liver enzymes

32. Reading
Goodman and Gilman
11th edition
Chapter 24