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

1
 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
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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
3 in the CNS and peripheral sites)
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)
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 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
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 IgE - Antibody ANTIGEN
Induced Release IgE Y Y
(food, penicillin, Non-immune
venoms, etc) Releasers
HA HA
(opioids,
tubocurarine,
Inhibitors HA vancomycin etc)
HA
of HA
Release HA
(Cromolyn,
HA
Albuterol)

PGs & LTs PROTEASES HISTAMINE OTHER MEDIATORS (PAF,TNF,ILs)

ACUTE INFLAMMATORY RESPONSE

6 IMMEDIATE HYPERSENSITIVITY REACTION
 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

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 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

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 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/anaphylactic • severe hypotension, ventricular
fibrillations, cardiac arrest,
bronchospasm, respiratory arrest

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

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 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
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 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
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 Selected Actions of Histamine in
Humans

Heart
 H1 - decreased AV conduction
 H2 - increased chronotropy,
decreased inotropy
 H1, H2 - increased automaticity
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 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.
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 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
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 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

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 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)

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 Histamine H1- Antagonists

First Generation:
Sedating

Second Generation:
Nonsedating
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 First Generation Agents
Examples

Ethanolamines: DIPHENHYDRAMINE (Benadryl)

CLEMASTINE (Tavist)
Ethylenediamine: TRIPELENNAMINE
Alkylamine: CHLORPHENIRAMINE (Chlortrimeton)
Phenothiazine: PROMETHAZINE (Phenergan)
Piperazines: HYDROXYZINE (Vistaril)
CYCLIZINE (Antivert)
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 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)

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

• Antitussive (diphenhydramine)

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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

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 First Generation Agents
Drug interactions:
• Additive with classical antimuscarinics
• Potentiate CNS depressants
• opioids
• sedatives
• general and narcotic analgesics
• alcohol
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 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)
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 Second Generation Agents
Examples Uses
• CETIRIZINE (Zyrtec) • Antiallergy
• FEXOFENADINE (Allegra)
• LORATADINE (Claritin)
• DESLORATADINE (Clarinex-
FDA Approved In 2002)
• LORATADINE (Claritin Hives
Relief - FDA Approved In 2004)
• AZELASTIN (Intranasal Spray)

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 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

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 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.
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 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

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 Reading

Goodman and Gilman

11th edition
Chapter 24

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