HISTAMINE AND HISTAMINE

ANTAGONISTS
Emel Songu-Mize
emize@lsuhsc.edu

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 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

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 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
4 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

7 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
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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 (contd)
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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