HISTAMINE SYNTHESIS

HISTIDINE
CH2CH(NH2)COOH

HISTAMINE
Histidine
Decarboxylase

CH2CH2NH2

9Once synthesized it is either stored or

rapidly inactivated.
9Widely distributed and found in most
tissues.

HISTAMINE SYNTHESIS.

HISTAMINE STORAGE
9The chief site of histamine storage in
most tissues is the mast cell and in the
blood it is the basophil (synthesized
and stored in secretory granules).

HISTAMINE STORAGE
9Other sites include histaminergic
neurons (in the brain), cells of the
epidermis and cells in regenerating or
rapidly growing tissues.

HISTAMINE RELEASE
9Bound form is biologically inactive.
9Release triggered by antigen binding,
neuropeptides, various drugs and
toxins.

HISTAMINE RELEASE

HISTAMINE RELEASE

9Mast cells and basophil - immunologic.

9Also requires energy and calcium.

9These cells if sensitized by IgE

antibodies attached to their surface
membranes degranulate when
exposed to the appropriate antigen.

9Other mediators also released.

HISTAMINE RELEASE
9Turnover rate of histamine in these
granules is slow and it may take weeks
before concns of it return to normal.

HISTAMINE RELEASE
9Turnover at the nonmast cell sites is
rapid as the histamine is continuously
released rather than stored.
9Non-mast cell sites contribute
significantly to the daily excretion of
histamine and its metabolites in the
urine.

HISTAMINE RELEASE
9Turnover at the nonmast cell sites is
rapid as the histamine is continuously
released rather than stored.

HISTAMINE RELEASE

ACH

HISTAMINE RELEASE

9Enterochromaffin like cells-endocrine

cells in the stomach lining---vagal
impulse (ACH) or gastrin.

9Histaminergic neurons (CNS)--- nerve

impulse.

9Histaminergic neurons (CNS)--- nerve

impulse.

DRUGS, POLYPEPTIDES AND

VENOMS CAUSING HISTAMINE
RELEASE

Histaminergic neuron

Histamine

9Tubocurarine, succinylcholine,
morphine, radiocontrast media and
certain carbohydrate plasma expanders.
9Vancomycin
9Basic polypeptides (e.g. polymyxin B)
9Snake venoms (contain polypeptides)

Histamine Metabolism

HISTAMINE METABOLISM
9Rapidly degraded after release.

MAO

MECHANISM OF ACTION
9Binds specific cellular receptors
located on the membrane.
9H1, H2 H3 and H4.

H1
H2
H3,4

H1 RECEPTORS
9Widespread, found in bronchial and
intestinal smooth muscle, cardiac
muscle, endothelial layer of small
vasculature, various regions of brain
(post-synaptic) and peripheral sensory
nerve endings.

Gq/11 PI hydrolysis, PKC, Ca2+

Gs
Stimulation of cAMP formation
Gi/o Inhibition of cAMP formation

H2 RECEPTORS
9Widespread-vascular smooth muscle,
cardiac muscle, gastric parietal cells,
various regions of brain and mast cells.

H3 Receptors

H4 Receptors

9 High expression in histaminergic neurons (especially

in the CNS).

9Similar signal transduction to H3.

9 Function as feedback inhibitors not only of histamine

but also of other neurotransmitters (ACH, dopamine,
NE and serotonin).

9Found mainly in blood cells in the bone

marrow and circulating blood.

9 Agonists promote sleep.

9May function in the differentiation of

myeloblasts and promyelocytes.

9 Antagonists are being studied for neuropsychiatric

diseases.

PHYSIOLOGICAL EFFECTS OF
HISTAMINE

CARDIOVASCULAR EFFECTS
9Dilation of small blood vessels resulting
in flushing, lowered total peripheral
resistance and a fall in systemic blood
pressure.

VASODILATION

HISTAMINE INDUCED
VASODILATION

9In humans this is the most important

vasculature effect of histamine (H1 and
H2 receptors).

INCREASED CAPILLARY
PERMEABILITY
9Classical effect on small blood vessels
resulting in loss of plasma protein and
fluid into the extracellular spaces
(formation of edema).
9Results from endothelial cell retraction
(H1 effect).

TRIPLE RESPONSE
9Used to quantify the extent of an
allergic response of an individual.

DIRECT CARDIAC EFFECTS

9Increased contractility and pacemaker
rate (H2 mediated).

ANAPHYLACTIC SHOCK
9Large scale systemic release of
histamine and other inflammatory
mediators

EFFECTS ON
EXTRAVASCULAR SMOOTH
MUSCLE
9Contraction of smooth muscle in
bronchi and gut (H1 effect).

EFFECTS ON GASTRIC ACID

SECRETION
9Histamine is a powerful stimulant of
stomach acid secretion.(pepsin also)
(H2 receptors).
9Acid secretion is also stimulated by
vagal nerve activity and gastrin.

CNS
9 Neurotransmitter in the CNS.
9 Found in the hypothalamus and other brain
regions.

NERVE ENDINGS
9Powerful stimulant of sensory nerve
endings especially those mediating pain
and itching (H1).

9 May play a role in many CNS functions

(wakefulness, body temp.)
9 H1 and H2 receptors.

ALLERGIC INFLAMMATION AND

IMMUNE MODULATION

Role in allergic inflammation and

immune modulation

9Increased release of histamine and

other mediators from mast cells.

9Increased cytokines and cellular

adhesion molecule expression.

9Most effects occur through H1

receptors.

9Role in autoimmunity and malignant

disease.

OTHER BIOLOGICAL EFFECTS

OF HISTAMINE
9Cell proliferation and differentiation.

HISTAMINE ANTAGONISTS
9Epinephrine is a physiological
antagonist.

9Hematopoiesis.
9Embryonic development.

9Histamine release inhibitors cromolyn, nedocromil and some $2

adrenergic agonists.

9Regeneration and wound healing.

RECEPTOR BLOCKERS

H4 BLOCKERS
9Inhibitors of inflammation (allergic
rhinitis, asthma and rheumatoid
arthritis)

H3 BLOCKERS
9Thioperamide,clobenpropit,ciproxifan

H2 BLOCKERS
9Cimetidine, famotidine, nizatidine,
ranitidine.

and proxifan.
9Arousal from sleep, improve attention
and learning effects, suppress food
intake, increase locomotion and
increase anxiety.

H1-RECEPTOR BLOCKERS
9 Inverse agonists. Shift equilibrium towards
inactive state.
9 Traditionally classified into 6 chemical
groups (see syllabus).
9 Like histamine many of these are substituted
ethylamines. Most have a tertiary amino
group linked by a 2 or 3 atom chain to two
aromatic substituents.

H1-RECEPTOR ANTIHISTAMINES
9Often classified into first and second
generation compounds.

CH3
X Y

C N
CH3

X is C or N
Y is C,O, or omitted

H1 Receptor Blockers

PHARMACOKINETICS
9Rapidly absorbed following oral
administration with an onset of action
of 1-3 hrs and peak blood
concentrations occurring in 2-3 hrs.
9Widely distributed throughout the body
(1st. genrn drugs enter the CNS
readily).

PHARMACOKINETICS
9Extensively metabolized by
microsomal systems in the liver (CYP
3A4) (some may induce microsomal
enzymes).

PHARMACOKINETICS
9Duration of action is usually 4-6 hrs.,
but several are longer-acting with a
duration of 12-24 hrs.

PHARMACOLOGICAL
PROPERTIES
9Inhibit most responses of smooth
muscle to histamine.
9Strongly block the action of histamine
that results in increased permeability
and formation of edema and wheal.

PHARMACOLOGICAL
PROPERTIES

PHARMACOLOGICAL
PROPERTIES
9Antiallergic and anti-inflammatory
activities
-Decreased allergic inflammation, itching,
sneezing, rhinorrhea and wheal formation.
-Decreased antigen presentation, expression
of cell-adhesion molecules, chemotaxis
and proinflammatory cytokines.
-Inhibition of mediator release.
-Block some parts of anaphylaxis.

DRUG INTERACTIONS

9Effects on the CNS

9Anticholinergic effects
9Local anesthetic effects

COMMON THERAPEUTIC USES

9Second generation compounds have
been well studied in RCTs.
9Best to take H1 antihistamines on a
regular basis rather than prn.
9Tolerance does not develop.

COMMON THERAPEUTIC USES

9Dose response curve for efficacy is
flat in contrast to curve for adverse
effects (especially 1st.gen).
9Relief from symptoms may be
incomplete.

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Seasonal allergic rhinitis and conjunctivitis

Seasonal allergic rhinitis and

conjunctivitis
9Relieve nasal itching, sneezing,
rhinorrhea and congestion etc.
9Various H1 cpds have similar efficacy.
9Topical intranasal or ophthalmic agents
have a more rapid onset.

Seasonal allergic rhinitis and

conjunctivitis

OTHER AIRWAY DISORDERS

9Choice of drug depends on safety,

patients preference, formulation and
route of administration.

9Widely used for symptoms of upper

RTIs , otitis media and sinusitis ( but
evidence doesnt support use).

9Many are available in fixed dose

combos with pseudoephedrine (or
phenylephrine).

9Same for persistent asthma.

9Effective in patients with allergic
inflammation throughout upper and
lower airways.

Urticaria

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OTHER ALLERGIC AND

IMMUNOLOGIC DISORDERS
9Ancillary treatment of anaphylaxis.
9Relief of itching and glucocorticoidsparing effect in atopic dermatitis.

(Dermatitis)

CNS AND VESTIBULAR

DISORDERS

ADVERSE EFFECTS

9 Insomnia
9 Perioperative sedation
9 For analgesia, akathisia, serotonin syndrome,
anxiety and other CNS conditions.
9 Antiemetic effects.
9 Prevention and treatment of motion sickness,
vertigo and related disorders.

CNS

APPETITE AND GI DISORDERS

9 Interference with neurotransmitter effects of

histamine.

9 Blockade of muscarinic, -adrenergic and

serotonin receptors

9 Daytime drowsiness and slowed reaction time, impair

psychomotor performance and interfere with learning
and decrease work productivity, dizziness, headache.

9 Constipation, diarrhea

9 CNS stimulation-nervousness, tremors,

hallucinations.
9 None or less with 2nd genern drugs.

9 Appetite stimulation and weight gain

9 Nausea and vomiting
9 None or less with 2nd generation cpds

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DRY MOUTH AND SINUSES

GLAUCOMA, PALPITATIONS,
HEADACHE,DYSURIA
9Urinary retention and hesitancy
9Erectile dysfunction

CARDIAC EFFECTS
9Dose-related sinus tachycardia
9Reflex tachycardia

Polymorphic Ventricular
Tachycardia
9Rarely terfenadine and astemizole
cause prolongation of the QT interval
with resultant polymorphic ventricular
tachycardia (torsades de pointes).
9The parent drug (but not the carboxy
metabolite) blocks delayed rectifier
potassium channels.

POLYMORPHIC VENTRICULAR
TACHYCARDIA
9It occurs with high doses or with
blockage of hepatic metabolism
(CYP3A4).

Polymorphic Ventricular
Tachycardia
9Most commonly associated with
combined use of macrolide antibiotics
and certain antifungal agents.

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ALLERGIC REACTIONS
9Dermatitis

TERATOGENICITY
9Doxylamine in bendectin was reported
to show teratogenic effects.

9Drug fever
9Photosensitization

CARCINOGENICITY AND
MUTAGENICITY
9Most studies with animals and clinical
experience do not suggest
carcinogenicity.

FIRST GENERATION H1
ANTAGONISTS
9Diphenhydramine.
9Chlorpheniramine.
9Promethazine, azelastine
dimenhydrinate, doxylamine,
pyrilamine, hydroxyzine, cyclizine,
brompheniramine, cyproheptadine.

ABUSE OF ANTIHISTAMINES
9Euphoria
9Hallucinations

DIPHENHYDRAMINE (Benadryl)
9Oral and topical preparations.
9Allergic rhinitis
9OTC sleep aids.
9Motion sickness (pronounced anticholinergic properties).
9Sedation is fairly prominent.
9Topical allergic responses.

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CHLORPHENIRAMINE
(Chlortrimeton)

AZELASTINE

9Oral preparation for treatment of

allergic symptoms (allergic rhinitis).

9Oral and nasal spray for treatment of

allergic rhinitis.

9Common in OTC cold remedies.

9May cause sedation due to systemic

absorption.

9Typically less sedation than with

diphenhydramine, but varies with the
patient.

PROMETHAZINE
9Oral
9Most commonly used as an antiemetic.
9Pronounced sedative effect.

LORATIDINE (Claritin)

SECOND GENERATION
ANTAGONISTS
9Loratidine
9Fexofenadine
9Terfenadine
9Astemizole
9Ebastine
9Cetirizine
9Desloratidine

FEXOFENADINE (Allegra)

9Prodrug, but no evidence for binding

to cardiac K+ channels.

9Effective for treating seasonal allergies

and urticaria.

9Effective for treating seasonal allergies.

9It is the active metabolite of terfenadine

so it avoids problems with cardiac
arrhythmias.

9otc

9Seems to offer the best combination of

effectiveness and safety.

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EBASTINE
9Well tolerated and effective treatment
for allergic rhinitis and urticaria.
9Prodrug with no evidence of binding
cardiac K+ channels.

CETIRIZINE (Zyrtec)
9 Most potent antihistamine.
9 Associated with more sedation than other
second generation compounds.
9 Minimal anticholinergic effects.
9 Active metabolite. Free of cardiac effects.

LEVOCETIRIZINE
9Rapid onset, long duration
9Lacks adverse effects

DESLORATIDINE
9Active metabolite of loratidine.
9No advantage over other 2nd. generation
cpds. including loratidine

ACRIVASTINE (Semprex)
9Effective in treating seasonal and
perennial allergic rhinitis and histaminemediated dermatoses
9Relatively non-sedating.

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