Lectures 3 & 4 (pharmacology II- Spring 2023)

Malak Eljafari (MSc in pharmacology)

histamine and serotonin

i. Histamine
Histamine is a chemical messenger mostly generated in mast cells that
mediates a wide range of cellular responses, including allergic and
inflammatory reactions, gastric acid secretion, and neurotransmission in
parts of the brain.
Histamine has no clinical applications, but agents that interfere with the
action of histamine (antihistamines) have important therapeutic
applications.
Location:
Histamine occurs in practically all tissues, but it is unevenly distributed,
with high amounts found in lung, skin, and the gastrointestinal tract.
At the cellular level it is found at high concentration in mast cells and
basophils.
Non mast cell histamine occurs in histaminocytes in the stomach and in
histaminergic neuron in the brain.

Synthesis
Histamine is an amine formed by the decarboxylation of the amino acid
histidine by histidine decarboxylase, once formed histamine is either Stord
or rapidly inactivated, the major inactivation pathway involves the action of
diamine oxidase
Storage and release
In human mast cells and basophils, storage granules contain histamine
complexed with a sulfated polysaccharide, heparin or chondroitin sulfate,
and an acidic protein.
The bound form of histamine can be released through several
mechanisms:
1. Immunologic release
2. Chemical and mechanical release

Mechanism of action
Histamine released in response to various stimuli exerts its effects by
binding to one or more of four types of histamine receptors, H1, H2, H3,
and H4 receptors (G-protein coupled).
H1 and H2 receptors are widely expressed and are the targets of clinically
useful drugs. H3 and H4 receptors are expressed in only a few cell types,
and their roles in drug action are unclear.
The structures of the H 1 and H 2 receptors differ significantly and appear
to be more closely related to muscarinic and 5-HT 1 receptors,
respectively, than to each other.
• The H1-receptor drives cellular migration, nociception, vasodilatation,
and bronchoconstriction.
• The H1-receptor drives cellular migration, nociception, vasodilatation,
and bronchoconstriction.
• The H3-receptor plays an important role in neuro-inflammatory
diseases.
• The H4-receptor has also been shown to be involved in allergy and
inflammation where H4R-Mediated mast cell activation can regulate a
powerful inflammatory cascade by releasing several inflammatory
mediators. Ref: Histamine pharmacology: from Sir Henry Dale to the 21st century, British J Pharmacology, Volume:
177, Issue: 3, Pages: 469-489, First published: 19 October 2018, DOI: (10.1111/bph.14524) ]
Tissue and organ system effects of Histamine
i. Nervous system:
Histamine is a powerful stimulant of sensory nerve endings, especially
those mediating pain and itching.
H 1 and H 3 receptors play important roles in appetite and satiety
H 3 agonists reduce the release of acetylcholine, amine, and peptide
transmitters in various areas of the brain and in peripheral nerves.
ii. Cardiovascular system: In humans, injection or infusion of histamine
causes a decrease in systolic and diastolic blood pressure and an increase
in heart rate
iii. Bronchiolar smooth muscle: in humans, histamine causes
bronchoconstriction mediated by H 1 receptors.
iv. Gastrointestinal tract smooth muscle: Histamine causes contraction of
intestinal smooth muscle.
v. Other smooth muscle organs: In humans, histamine generally has
insignificant effects on the smooth muscle of the eye and genitourinary
tract.
vi. Secretory tissue: Histamine has long been recognized as a powerful
stimulant of gastric acid secretion and, to a lesser extent, of gastric pepsin
and intrinsic factor production. The effect is caused by activation of H 2
receptors on gastric parietal cells and is associated with increased adenylyl
cyclase activity.
vii. The “triple response”: Intradermal injection of histamine causes a
characteristic red spot, edema, and flare response that was first described
many years ago.
 A reddening appears due to dilation of small vessels.
 followed soon by an edematous wheal at the injection site.
 A red irregular flare surrounding the wheal
Clinical pharmacology of histamine:
The practical uses of histamine is limited to minor applications as
diagnostic agents and clinical trials of H1 antagonists.

Histamine antagonists
The effects of histamine released in the body can be reduced in several
ways:
1- Physiologic antagonists like epinephrine which have smooth muscle
actions opposite to those of histamine, but they act at different receptors.
2- Release inhibitors like Cromolyn and nedocromil which reduce the
degranulation of mast cells.
3- Histamine receptor antagonists, these compounds do not influence the
formation or release of histamine. Rather, they block the receptor-mediated
response of a target tissue.

Histamine receptor antagonists:

1.The H1-receptor blockers can be divided into first- and second-

generation drugs.
1-The older first-generation drugs are still widely used because they are
effective and inexpensive.(most of these drugs penetrate the CNS and
cause sedation.)Furthermore, they tend to interact with other receptors,
producing a variety of unwanted adverse effects.
Examples of 1st generation H1 receptor blockers:
Dimenhydrinate, Diphenhydramine, Cyclizine, Chlorpheniramine,
Promethazine and Cyproheptadin.
2-The second-generation agents are specific for H1 receptors, and,
because they carry polar groups, they do not penetrate the blood-brain
barrier, causing less CNS depression than the first-generation drugs.
Examples of 2nd generation H1 blockers:
Fexofenadine, lortadine and cetirizine.

a- Actions of antihistamines
The action of all the H1-receptor blockers is qualitatively similar. They are
much more effective in preventing symptoms than reversing them once
they have occurred. However, most of these blockers have additional
effects unrelated to their blocking of H1 receptors, which probably reflect
binding of the H1 antagonists to cholinergic, adrenergic, or serotonin
receptors and local anesthetic receptor sites.
Some of these actions are of therapeutic value and some are undesirable.
1. Sedation: A common effect of first-generation H 1 antagonists is
sedation, but the intensity of this effect varies among chemical
subgroups and among patients as well; Second generation H 1
antagonists have little or no sedative or stimulant actions. These
drugs (or their active metabolites) also have fewer autonomic effects
than the first-generation antihistamines.
2. Antinausea and antiemetic actions: Several first generation H 1
antagonists have significant activity in preventing motion sickness.
They are less effective against an episode of motion sickness already
present. Certain H 1 antagonists, notably doxylamine were used
widely in the past in the treatment of nausea and vomiting of
pregnancy
3. Antiparkinsonism effects: Some of the H 1 antagonists, especially
diphenhydramine , have significant acute suppressant effects on the
extrapyramidal symptoms associated with certain antipsychotic
drugs. This drug is given parenterally for acute dystonic reactions to
antipsychotics.
4. Anticholinoceptor actions: many first-generation agents,
especially those of the ethanolamine and ethylenediamine
subgroups, have significant atropine-like effects on peripheral
muscarinic receptors. This action may be responsible for some of the
(uncertain) benefits reported for nonallergic rhinorrhea but may also
cause urinary retention and blurred vision.
5. Adrenoceptor-blocking actions: A α-receptor blocking effects can
be demonstrated for many H 1 antagonists, especially those in the
phenothiazine subgroup, eg, promethazine . This action may cause
orthostatic hypotension in susceptible individuals. Beta-receptor
blockade is not observed.
6. Serotonin-blocking action: Strong blocking effects at serotonin
receptors have been demonstrated for some first-generation H 1
antagonists, notably cyproheptadine. This drug is promoted as an
antiserotonin agent and is discussed with that drug group.
Nevertheless, its structure resembles that of the phenothiazine
antihistamines, and it is a potent H 1 -blocking agent.
7. Local anesthesia: Several first-generation H 1 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. They are occasionally used to produce
local anesthesia in patients allergic to conventional local anesthetic
drugs.
8. Other actions: certain H 1 antagonists, eg, cetirizine, inhibit mast
cell release of histamine and some other mediators of inflammation.
This action is not due to H 1 -receptor blockade and may reflect an H
4 -receptor effect. The mechanism is not fully understood but could
play a role in the beneficial effects of these drugs in the treatment of
allergies such as rhinitis.

b- Therapeutic uses
1. Allergic and inflammatory conditions: H1-receptor blockers are useful in
treating allergies caused by antigens acting on immunoglobulin E antibody–
sensitized mast cells. For example, antihistamines are the drugs of choice
in controlling the symptoms of allergic rhinitis and urticaria because
histamine is the principal mediator.
The H1-receptor blockers are not used in treating bronchial asthma
because histamine is only one of several mediators of that condition.
2. Motion sickness and nausea: Along with the antimuscarinic agent
scopolamine, certain H1-receptor blockers, such as diphenhydramine,
dimenhydrinate (a chemical combination of diphenhydramine and a
theophylline derivative), meclizine, and hydroxyzine, are the most effective
agents for prevention of the symptoms of motion sickness. The
antihistamines prevent or diminish vomiting and nausea mediated by both
the chemoreceptor and vestibular pathways. The antiemetic action of these
medications seems to be due to their blockade of central H1 and
muscarinic receptors.
3- Somnifacients: Although they are not the medications of choice, many
first-generation antihistamines, such as diphenhydramine and doxylamine,
have strong sedative properties and are used in the treatment of insomnia.
They are both available over the counter (OTC).
c- Pharmacokinetics of antihistamines
H1-receptor blockers are well absorbed after oral administration.
H1-receptor blockers have high bioavailability and are distributed in all
tissues, including the CNS
All first-generation H1 antihistamines and some second-generation H1
antihistamines are metabolized by the hepatic cytochrome P450 system.
d- Toxicity of H1 antihistamines
 The non antihistaminic effects of the H 1 antihistamines is described
before.
 Several of these effects (sedation, antimuscarinic action) have been
used for therapeutic purposes, especially in over-the-counter
remedies.
 These two effects constitute the most common undesirable actions
when these drugs are used to block histamine receptors.
 Less common toxic effects of systemic use include excitation and
convulsions in children, postural hypotension, and allergic responses.
 Drug allergy is relatively common after topical use of H 1 antagonists.
The effects of severe systemic overdosage of the older agents
resemble those of atropine overdosage and are treated in the same
way.
 Overdosage of astemizole or terfenadine may induce cardiac
arrhythmias; the same effect may be caused at normal dosage by
interaction with enzyme inhibitors.

d. Drug interactions:
Interaction of H1-receptor blockers with other drugs can cause serious
consequences such as:
a- potentiation of the effects of all other CNS depressants, including
alcohol.
b- MAOIs can exacerbate the anticholinergic effects of the
antihistamines
 c- The first-generation antihistamines have considerable
anticholinergic actions. These actions would decrease the
effectiveness of cholinesterase inhibitors

2.Histamine H2-receptor blockers

Histamine H2-receptor blockers have little affinity for H1 receptors, but it
competitively block the binding of histamine to H2 receptors in the gastric
parietal cells.
Their chief clinical use is as inhibitors of gastric acid secretion in the
treatment of ulcers and heartburn.
Examples: cimetidine, ranitidine, famotidine, and nizatidine

3. H3 and H4 receptor blockers

No selective H 3 or H 4 ligands are presently available for general clinical
use, there is great interest in their therapeutic potential.
H 3 -selective ligands may be of value in sleep disorders, narcolepsy,
obesity, and cognitive and psychiatric disorders.
H 4 blockers have potential in chronic inflammatory conditions such as
asthma, in which eosinophils and mast cells play a prominent role.
 ii. Serotonin (5-hydroxytryptamine (5-HT)
Serotonin is an important neurotransmitter, a local hormone in the gut, a
component of the platelet clotting process, and is thought to play a role in
migraine headache and several other clinical conditions, including carcinoid
syndrome.
Location
Serotonin is widely distributed in nature, being found in plant and animal
tissues, venoms, and stings
Synthesis
It is synthesized in biologic systems from the amino acid L-tryptophan by
hydroxylation of the indole ring followed by decarboxylation of the amino
acid, serotonin is metabolized by MAO, and the intermediate product is
further oxidized by aldehyde dehydrogenase to 5-hydroxyindoleacetic acid
(5-HIAA).

Storage and release

After synthesis, the free amine (5-HT) is stored or is rapidly inactivated,
usually by oxidation by monoamine oxidase (MAO).
In the pineal gland, serotonin serves as a precursor of melatonin (a
hormone that regulates sleep and wakefulness)
In mammals (including humans), over 90% of the serotonin in the body is
found in enterochromaffin cells in the gastrointestinal tract.
In the blood, serotonin is found in platelets, which are able to concentrate
the amine by means of an active serotonin transporter mechanism (SERT)
similar to that in the membrane of serotonergic nerve endings.
Once transported into the platelet or nerve ending, 5-HT is concentrated in
vesicles by a vesicle-associated transporter (VAT) that is blocked by
reserpine.
Serotonin is also found in brainstem, which contain cell bodies of
serotonergic neurons that synthesize, store, and release serotonin as a
transmitter.

Mechanisms of Action
Serotonin exerts many actions and, like histamine, displays many species
differences, making generalizations difficult.
The actions of serotonin are mediated through a remarkably large number
of cell membrane receptors.
The serotonin receptors that have been characterized are seven families of
5-HTreceptor subtypes (those given numeric subscripts 1 through 7) have
been identified.
Six subtypes involving G protein-coupled receptors of the usual 7-
transmembrane serpentine type and one a ligand gated ion channel.
5-HT 3 receptor is ion channel linked receptor (Na + /K + channel)
Effect of 5-HT on tissues and Organs
1. Nervous system:
A multitude of brain functions are influenced by 5-HT, including sleep,
cognition, sensory perception, motor activity, temperature regulation,
nociception, mood, appetite, sexual behavior, and hormone secretion.
Repinotan, a 5-HT 1A agonist currently in clinical trials, appears to have
some antinociceptive action at higher doses while reversing opioid-induced
respiratory depression.

2. Respiratory system: Serotonin has a small direct stimulant effect on

bronchiolar smooth muscle in normal humans, probably via 5-HT 2A
receptors
It also appears to facilitate acetylcholine release from bronchial vagal
nerve endings.
But In patients with carcinoid syndrome, episodes of bronchoconstriction
occur in response to elevated levels of the amine or peptides released from
the tumor.
3. Cardiovascular system: Multiple direct and indirect effects:
 1. Direct vasoconstriction (large arteries) and indirect vasodilation (due
to NO release in the presence of vascular endothelial cells.
2. Heart: direct inotropic and chronotropic effects (no clinical
significance)
3. Reflex mechanisms due to change in BP
4. Stimulation of sensory nerve endings in baroreceptors and in vagal
afferents in coronary circulation → bradycardia and hypotension.
4. Gastrointestinal tract: serotonin is a powerful stimulant of gastrointestinal
smooth muscle, increasing tone and facilitating peristalsis.
Overproduction of serotonin (and other substances) in carcinoid tumor is
associated with severe diarrhea.
Serotonin has little effect on gastrointestinal secretions, and what effects it
has are generally inhibitory.

5. Skeletal muscle and the eye: 5-HT 2 receptors are present on skeletal
muscle membranes, but their physiologic role is not understood.
Studies in animal models of glaucoma indicate that 5-HT 2A agonists
reduce intraocular pressure. This action can be blocked by ketanserin and
similar 5-HT2 antagonists.

 Serotonin syndrome
Is a condition associated with skeletal muscle contractions and
precipitated when MAO inhibitors are given with serotonin agonists,
especially antidepressants of the selective serotonin reuptake inhibitor
class (SSRIs).
Although the hyperthermia of serotonin syndrome results from excessive
muscle contraction, serotonin syndrome is probably caused by a central
nervous system effect of these drugs.
Clinical pharmacology of serotonin
Serotonin has no clinical applications as a drug (no pharmacological use)
Several receptor subtype-selective agonists have proved to be of value:
1-Buspirone a 5-HT 1A selective agonist, has received wide attention for
its usefulness as an effective nonbenzodiazepine anxiolytic.
2- Dexfenfluramine selective 5-HT2c agonist, was widely used as an
appetite suppressant but was withdrawn because of cardiac valve toxicity.
3- triptans: e.g sumatriptan are mixed 5-HT1B/1D agonist are used almost
exclusively for migraine headache.
4-Cisapride a 5-HT4 agonist, was used in the treatment of
gastroesophageal reflux and motility disorders. Because of toxicity, it is
now available only for compassionate use in the USA.
5-Tegaserod, a 5-HT 4 partial agonist, is used for irritable bowel syndrome
with constipation.

Serotonin antagonists
Serotonin antagonism is clearly desirable in those rare patients who have
carcinoid tumor and may also be valuable in certain other conditions.
1- p-chlorophenylalanine and p-chloroamphetamine are serotonin synthesis
inhibitors and they are too toxic for general use.
2- Reserpine inhibit serotonin storage
3- Cyproheptadine is a potent 5-HT2 antagonist as well as H 1
acetylcholine blocking agent, used in treatment of the smooth muscle
manifestations of carcinoid tumor and in cold-induced urticaria. It is of some
value in serotonin syndrome, but because it is available only in tablet form,
cyproheptadine must be crushed and administered by stomach tube in
unconscious patients.
4-Ketanserin is 5-HT 2 receptors blocker works on smooth muscle and
other tissues and has little or no reported antagonist activity at other 5-HT
or H 1 receptors. This drug potently blocks vascular α 1 adrenoceptors
,and drug blocks 5-HT 2 receptors on platelets and antagonizes platelet
aggregation promoted by serotonin.
 5-Ritanserin is 5-HT 2 antagonist, has little or no α-blocking action. It has
been reported to alter bleeding time and to reduce thromboxane formation,
presumably by altering platelet function.
6-Ondansetron is the prototypical 5-HT 3 antagonist. This drug and its
analogs are very important in the prevention of nausea and vomiting
associated with surgery and cancer chemotherapy.
7-Ergot Alkaloids are molecules based on a complex aromatic acid
(lysergic acid) produced by fungus that infects cereal corps, most of ergot
alkaloids act as partial agonist or antagonist on 5-HT receptors, in addition
to its effect on α adrenoceptors and dopamine receptors.

The most important ergot alkaloids:

a. ergotamine and dihydroergotamin used in acute migraine attack
b. ergometrine used to prevent postpartum hemorrhage
c. methylsergide used to treat carcinoid syndrome and occasionally for
migraine prophylaxis
d. bromocriptine used in parkinsonism and endocrine disorders