Module: Autacoids
Subject: Pharmacology
Lecture:

Autacoids-Histamine
& Antihistamines-1 &

2
Dr Biswadeep Das

Associate Professor(Pharmacology)
AIIMS Rishikesh

Autacoids-Overview
n Histamine, serotonin, prostaglandins, & some vasoactive

peptides belong to a group of compounds called autacoids
n They all have the common feature of being formed by the

tissues on which they act; thus, they function as local
hormones

n The word autacoid comes from the Greek:
¨autos (self) &
¨akos(medicinal agent, or remedy)

n The autacoids also differ from circulating hormones in that
they are produced by many tissues rather than in specific
endocrine glands

Histamine-Pharmacology
n First autacoid to be discovered
n Synthesized in 1907
n Demonstrated to be a natural constituent of

mammalian tissues(1927)
n Involved in inflammatory & anaphylactic reactions
n Local application causes redness, swelling, & edema

mimicking a mild inflammatory reaction
n Large systemic doses leads to profound vascular

changes similar to those seen after shock or
anaphylaxis

Histamine-Pharmacology(contd.)
n Histamine is a chemical messenger that mediates a

wide range of cellular responses, including:
¨Allergic and inflammatory reactions
¨Gastric acid secretion, &
¨Neurotransmission in parts of the brain

n Histamine has no clinical applications, but
n Agents that interfere with the action of histamine

(antihistamines) have important therapeutic
applications

Histamine-Biosynthesis
n Histamine occurs in plants as well as in animal tissues & is

a component of some venoms & stinging secretions
n Biosynthesized in mammalian tissues
n Decarboxylation of the amino acid L-Histidine yields

Histamine

Histamine-Storage
n In mast cells, histamine(positively charged) is held

by an acidic protein and heparin(negatively
charged) within intracellular granules

n Stored in complex with:
¨Heparin
¨Chondroitin sulphate
¨Eosinophilic Chemotactic Factor
¨Neutrophilic Chemotactic Factor
¨Proteases

Histamine-Degradation
n Degraded rapidly by

oxidation to imidazole
acetic acid

n Degraded rapidly by
methylation to N-
methyl histamine

n Very little histamine is
excreted unchanged

Histamine-Conditions causing Release

n Tissue Injury
n Allergic Reactions
n Drugs & other foreign compounds

Histamine-Conditions causing Release
n Tissue Injury

¨Any physical(mechanical) or chemical agent that
injures tissue, skin or mucosa are particularly
sensitive to injury and will cause the immediate
release of histamine from mast cells

¨Chemical and mechanical mast cell injury causes
degranulation & histamine release

¨Compound 48/80, an experimental drug,
selectively releases histamine from tissue mast
cells by an exocytotic degranulation process
requiring energy & calcium

Histamine-Conditions causing
Release
n Allergic Reactions

¨Exposure of an antigen to a previously
sensitized(exposed) subject can immediately
trigger allergic reactions

¨If sensitized by IgE antibodies attached to their
surface membranes, mast cells will degranulate
when exposed to the appropriate antigen &
release histamine, ATP and other mediators

Histamine & Allergic Reaction

Histamine-Conditions causing
Release(contd.)
n Drugs & other foreign compounds:

¨Morphine/Dextran/Antimalarial drugs/Dyes/Antibiotic
bases/Alkaloids/Amides/Quaternary ammonium
compounds/Enzymes(PL-C)/Penicillins/Tetracyclines/
Basic drugs(Amides/Amidines/Diamidines)/Toxins/
Venoms/Proteolytic enzymes/Bradykin/Kallidin &
Substance P

¨Displace histamine from its bound form within cells
¨This type of release does not require energy and is not

associated with mast cell injury or degranulation

Histamine-Receptors
n 4 Types of Histamine Receptors(all GPCR’s):

¨H1 receptors:
n Mediate effects on smooth muscle leading to vasodilation

(relaxation of vascular smooth muscle), increased
permeability & contraction of non-vascular smooth muscle

¨H2 receptors:
n Mediate histamine stimulation of gastric acid secretion & may

be involved in cardiac stimulation
¨H3 receptors:

n Feedback inhibition in CNS, GIT, Lungs & Heart
¨H4 receptors:

n Eosinophils, Neutrophils & CD4 T-cells

Histamine-Receptor Subtypes
Receptor Mechanism Function Antagonists
H1 Gq, ↑ IP3 & nIleum contraction Diphenhydram

DAG nModulate circadian cycle ine/Loratadine
nItching /Cetirizine/

Fexofenadine
nSystemic vasodilatation
nBronchoconstriction

H2 Gs, ↑cAMP, nSpeed up sinus rhythm Cimetidine/
↑Ca2+ nStimulation of gastric secretion Ranitidine/

nSmooth muscle relaxation Famotidine/
Nizatidine

nInhibit antibody synthesis, T-
cell proliferation & cytokine
production

Histamine-Receptor Subtypes

Receptor Mechanism Function Antagonists
H3 Gi, ↓cAMP nDecrease Acetylcholine, ABT-239/

Serotonin and Norepinephrine Ciproxifan/
neurotransmitter release in the Clobenpropit/T
CNS hioperamide
nPresynaptic autoreceptors

H4 Gi, ↓cAMP nMediate mast cell chemotaxis Thioperamide/
JNJ 7777120

Histamine-Pharmacological
Actions(H1)
n Exocrine Excretion(H1)

¨ ↑ Production of nasal + bronchial mucus
n Bronchial Smooth Muscle(H1)

¨ Bronchiolar constriction
¨ Asthmatic symptoms
¨ ↓ Lung capacity

n Intestinal Smooth Muscle(H1)
¨ Contraction Intestinal cramps &

diarrhea
n Sensory Nerve Endings(H1)

¨ Itching & pain

Histamine-Pharmacological
Actions(H1&2)
n Cardiovascular System(H1&2)

¨ ↓ Peripheral resistance ↓Systemic BP
¨ +ve chronotropism(H2)
¨ +ve inotropism

n Skin(H1&2)
¨ Dilatation & ↑ permeability of the

venules
¨ Leakage of fluid + proteins into the

tissues
¨ Classic “triple-response”(wheal

formation+ reddening due to local
VD(<1-2 min)+ flare(halo)

Histamine-Pharmacological
Actions(H2)

n Stomach(H2)
¨ ↑ Gastric HCl secretion

Histamine Antagonists
n The effects of histamine released in the body can be

reduced in several ways
n Physiologic antagonists, especially epinephrine, have

smooth muscle actions opposite to those of histamine, by
acting at different receptors

n This is important clinically because injection of epinephrine
can be lifesaving in systemic anaphylaxis/other conditions
in which massive release of histamine(and other more
important mediators)occurs

Adrenoceptor Agonists(Sympathomimetics)- Major
Effects Mediated By Alpha & Beta Adrenoceptors for
Epinephrine in the Management of Anaphylaxis

Epinephrine

Adrenoceptor Agonists(Sympathomimetics)-
Use of Epinephrine in Anaphylaxis
n Anaphylaxis

¨Epinephrine is the drug of choice for the
immediate treatment of anaphylactic shock

¨It is an effective physiologic antagonist of many
of the mediators of anaphylaxis

¨Epinephrine is sometimes supplemented with
antihistamines and corticosteroids, but these
agents are neither as efficacious as
epinephrine nor as rapid acting

Histamine Antagonists-Release
Inhibitors
n Release inhibitors reduce the degranulation of mast

cells that results from immunologic triggering by antigen
-IgE interaction

n Cromolyn and nedocromil appear to have this effect
and have been used in the treatment of asthma,
although the molecular mechanism underlying their
action is not fully understood

n Beta2-adrenoceptor agonists also appear capable of
reducing histamine release

Histamine Release Inhibitors-
Therapeutic Uses
n Mild to moderate bronchial asthma

¨ To prevent acute attacks
¨ Effective in children
¨ Reduces need of steroids or bronchodilators
¨ Ineffective for an acute attack
¨ Becomes effective over time(e.g., 2-3 weeks)

n Allergic rhinitis
n Atopic diseases of the eye
n Giant papillary conjunctivitis

H1 Antihistamines-Overview
n The term antihistamine, refers to the classic H1-

receptor blockers
n These compounds do not influence the formation or

release of histamine; rather, they block the receptor-
mediated response of a target tissue

n This contrasts with the action of cromolyn &
nedocromil, which inhibit the release of histamine
from mast cells and are useful in the treatment of
asthma

H1 Antihistamines-2
Generations
n The H1-receptor blockers can

be divided into first- & second-
generation drugs

n The older first-generation
drugs are still widely used
because they are effective
and inexpensive

n However, most of these drugs
penetrate the CNS and cause
sedation

H1 Antihistamines-2
Generations
n By contrast, the second-

generation agents are specific
for H1 receptors

n Because they do not penetrate
the blood-brain barrier, they
show less CNS toxicity than the
first-generation drugs

n Among these agents loratadine/
desloratadine/fexofenadine
produce the least sedation

Histamine Receptor Blockers-
Classification

General Structure of H1 Antagonist Drugs
& examples of the Major Subgroups

n First Generation
¨ Alkylamines

n Pheniramine/Chlorphen
iramine/Dexchlorphena
mine/Brompheniramine
/Triprolidine

¨ Ethanolamines
n Carbinoxamine/

Clemastine/
Diphenhydramine/
Dimenhydrinate/
Doxylamine

General Structure of H1 Antagonist Drugs
& examples of the Major Subgroups

n First Generation(contd.)
¨ Ethylenediamines

n Antazoline/Mepyramine
(Pyrilamine)

¨ Piperazines
n Cyclizine/Chlorcyclizine

/Hydroxyzine/Meclizine
¨ Tricyclics

n Alimemazine(Trimepra
zine)/Azatadine/
Cyproheptadine/
Ketotifen/Promethazine

General Structure of H1 Antagonist Drugs
& examples of the Major Subgroups

n Second Generation
¨ Acrivastine(modification

of Triprolidine)
¨ Azelastine
¨ Cetirizine(Piperazine)
¨ Desloratadine(Piperidine)
¨ Fexofenadine(Piperidine)
¨ Loratadine(Piperidine)
¨ Levocabastine

Antihistamines-Mechanism of Action(PD)
n Actions

¨ The action of all the H1-receptor blockers is qualitatively
similar(block action of histamine at H1 receptors)

¨ However, most of these blockers have additional effects unrelated
to their blocking of H1 receptors

¨ These effects probably reflect binding of the H1 antagonists to
cholinergic, adrenergic, or serotonin receptors

Antihistamines-Mechanism of Action(PD)

n Sedation
¨A common effect of first-generation H1 antagonists is

sedation, but the intensity of this effect varies among
chemical subgroups

¨Second-generation H1 antagonists have little or no
sedative or stimulant actions

¨These drugs (or their active metabolites) also have far
fewer autonomic effects than the first-generation
antihistamines

Antihistamines-Mechanism of Action(PD)

n Antinausea and Antiemetic Actions
¨Several first- generation H1 antagonists have significant

activity in preventing motion sickness
¨They are less effective against an episode of motion

sickness already present

Antihistamines-Mechanism of Action(PD)

n Antiparkinsonian Effects
¨H1 antagonists, especially diphenhydramine, have significant

acute suppressant effects on the EPS associated with
certain antipsychotic drugs

¨Given parenterally for acute dystonic reactions to
antipsychotics

Antihistamines-Mechanism of Action(PD)

n Anticholinoceptor Actions
¨First-generation agents, especially those of ethanolamine

and ethylenediamine subgroups, have significant atropine-
like effects on peripheral muscarinic receptors

¨Benefits reported for nonallergic rhinorrhea
¨May also cause urinary retention and blurred vision

Antihistamines-Mechanism of Action(PD)

n Adrenoceptor-Blocking Actions
¨Alpha-receptor blocking effects demonstrable for many

H1 antagonists, especially phenothiazine subgroup, e.g.,
promethazine

¨This action may cause orthostatic hypotension in
susceptible individuals

Antihistamines-Mechanism of Action(PD)

n Serotonin-Blocking Action
¨Strong blocking effects at serotonin receptors have been

demonstrated for some first-generation H1 antagonists,
notably cyproheptadine

¨ Its structure resembles that of the phenothiazine
antihistamines, and it is a potent H1-blocking agent

Antihistamines-Mechanism of Action(PD)
n Local Anesthesia

¨Several first-generation H1 antagonists are potent local
anesthetics

¨They block sodium channels in excitable membranes in
the same fashion as procaine and lidocaine

¨Diphenhydramine and promethazine are actually more
potent than procaine as local anesthetics

Antihistamines-PK
n Absorption

¨ These agents are rapidly absorbed after oral administration
¨ Peak blood concentrations occur in 1–2 hours

n Distribution
¨ Widely distributed throughout the body
¨ First-generation drugs enter CNS readily

n Biotransformation(Metabolism)
¨ Some of them are extensively metabolized, primarily by

microsomal systems in the liver
¨ Several of the second-generation agents are metabolized by the

CYP3A4 system and thus are subject to important interactions
when other drugs(such as ketoconazole) inhibit this subtype of
P450 enzymes

Antihistamines-PK(contd.)
n The newer agents are considerably less lipid-soluble

than the first-generation drugs and are substrates of the
P-glycoprotein transporter in the blood-brain barrier

n As a result they enter the CNS with difficulty or not at all
n Many H1 antagonists have active metabolites

Antihistamines-PK(contd.)
Parent Drug Active Metabolite Available as

Drug
Hydroxyzine Cetirizine Yes
Loratadine Desloratadine Yes
Terfenadine Fexofenadine Yes

n Elimination
¨Cetirizine is excreted largely unchanged in the

urine, &
¨Fexofenadine is excreted largely unchanged in

the feces

Antihistamines-Therapeutic Uses
n Allergic and inflammatory conditions
n H1-receptor blockers useful in treating allergies caused by

antigens acting on immunoglobulin E antibody–sensitized
mast cells

n Antihistamines are the drugs of choice in controlling the
symptoms of allergic rhinitis and urticaria, because
histamine is the principal mediator

n However, the H1-receptor blockers are ineffective in
treating bronchial asthma, because histamine is only one of
several mediators of that condition(LTs are the main
mediators)

Antihistamines-Therapeutic Uses
n Motion sickness/Nausea:
n Along with the antimuscarinic agent scopolamine, certain

H1-receptor blockers, such as diphenhydramine,
dimenhydrinate, cyclizine, meclizine, and hydroxyzine, are
the most effective agents for prevention of the symptoms of
motion sickness

n Prevent or diminish vomiting and nausea mediated by both
the chemoreceptor and vestibular pathways

n The antiemetic action of these medications seems to be
due to their blockade of central H1 + muscarinic receptors

Antihistamines-Therapeutic Uses
n Somnifacients:
n Although they are not the medication of choice,

many first-generation antihistamines, such as
diphenhydramine and doxylamine, have strong
sedative properties and are used in the treatment of
insomnia

n The use of first-generation H1 antihistamines is
contraindicated in the treatment of individuals
working in jobs where wakefulness is critical

Antihistamines-Therapeutic Uses
n Nausea and Vomiting of Pregnancy:
n Several H1-antagonist drugs have been studied for possible

use in treating “morning sickness”
n The piperazine derivatives were withdrawn from such use

when it was demonstrated that they have teratogenic
effects in rodents

Antihistamines-Adverse Effects &
Toxicity

n Sedation:
¨ First-generation H1

antihistamines, such as
chlorpheniramine,
diphenhydramine,
hydroxyzine, and
promethazine, bind to H1
receptors and block the
neurotransmitter effect of
histamine in the CNS

¨ The most frequently
observed adverse reaction
is sedation

Antihistamines-Adverse Effects &
Toxicity

n Sedation:
¨Sedation is less common

with the second-
generation drugs, which
do not readily enter the
CNS

¨Second-generation H1
antihistamines are
specific for H1 receptors
and penetrate the CNS
poorly

¨They show less sedation
and other CNS effects

Antihistamines-Adverse Effects &
Toxicity
n Other CNS actions:

¨Other central actions include tinnitus, fatigue,
dizziness, lassitude(a sense of weariness),
incoordination, blurred vision, and tremors

Antihistamines-Adverse
Effects & Toxicity

n Dry mouth:
¨Oral antihistamines also

exert weak anticholinergic
effects, leading not only to a
drying of the nasal passage
but also to a tendency to
dry the oral cavity

¨Blurred vision can occur as
well with some drugs