Histamine and Antihistaminics

Dr. Sartaj Hussain

M.B.B.S., M.D.

1
 Autacoids
These are diverse substances produced by
wide variety of cells, having intense
biological activity, but act locally at the site
of synthesis and release

➢ Types of autacoids:
• Amine autacoids

- Histamine, 5-HT (Serotonin) 2

 Histamine - Introduction
• Meaning “tissue amine” (histos – tissue) –
abundantly present in animal tissues – also in
plants like “stinging nettle”
• Mediator of hypersensitivity and tissue injury
reaction– Physiological role
• The primary site the mast cell granules (or
basophils) – skin, intestinal and gastric
mucosa, lungs, liver and placenta
• Other sites
– central nervous system: neurotransmitter 3

– the fundus of the stomach: major acid

 Synthesis &
Storage
• Histamine is formed by the
decarboxylation of the
amino acid histidine by the
enzyme L-histidine
decarboxylase, found in
every mammalian tissue that
contains histamine.
• The chief site of storage in
most tissues is the mast cell;
in the blood, it is the
basophil.
• These cells synthesize
histamine and store it in
secretory granules. 4
Histamine – synthesis, storage and
release
• Metabolized by P450 system, 2 pathways:
– Methylation to N-methyl histamine (N-methyl
transferase), and to N-methyl imidazole acetic
acid (MAO) - eliminated in urine
– Oxidative deamination to imidazole acetic acid
(DAO), and to imidazole acetic acid riboside -
eliminated in urine
• In mast cells – held by acidic protein and
heparin (-ve charged) – histamine is +ve
charged
• Ineffective orally – liver destroys all absorbed
5
 Histamine Receptors
H1 H2 H3
Selective 2-Methylhistamine 4-Methylhistamine α-Methylhistamine
agonist
Selective Mepyramine Cimetidine Thioperamide
antagonist Ranitidine
Effector IP3/DAG cAMP Ca++ influx
Pathway K+ channel activation
Distribution •Smooth muscle (intestine, •Gastric glands – acid •Brain – inhibition of
airway, uterus)-contraction secretion Histamine release-
•Blood vessels – NO and PGI2 •Blood vessels (smooth sedation
release – Vasodilatation muscle) – dilatation •Lung, spleen, gatric
•Smooth muscle of large •Heart: Atria: + mucosa – decrease
vessels-vasoconstriction chronotropy and histamine release
• Afferent nerves – stimulation ventricles: + inotropy •Ileum – inhibition of Ach
•Ganglion cells – stimulation •Uterus – relaxation release
•Adrenal medulla – CA release •Brain (post synaptic)–
•Brain - transmitter impulse
6
 Pharmacological actions of Histamine
• CNS
- No BBB penetration
- On Intracerebrovascular injection:
* ↑ in BP, cardiac stimulation
* Vomiting, ADH release
• H3 agonists reduce the release of acetylcholine,
amine, and peptide transmitters in various areas of the
brain and in peripheral nerves
• Histamine is a powerful stimulant of sensory nerve
endings, especially those mediating pain and itching..

7
 Histamine - Pharmacological
• actions
Blood vessels: Dilatation of small vessels – arterioles, capillaries and
venules
– SC administration – flushing, heat, increased HR and
CO – little fall in BP
– Rapid IV injection: Fall in BP early (H1) and
persistent (H2) – only H1 effect with low dose
– Dilatation of cranial vessels
– H1 component vasodilatation – mediated indirectly by
EDRF .. But H2 component - mediation is directly on
smooth muscle of blood vessels
– Larger arteries and veins – constriction mediated by
H1 receptor
– Increased capillary permeability – exudation of plasma 8
 Histamine – The Triple Response

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

9
 Pharmacological actions
Heart :
• It increases the force of contraction of both atrial and
ventricular muscle
• slow atrioventricular (AV) conduction
• Atria: +ve chronotropy
• Ventricles: +ve inotropy
Due to H2 receptors
• Slowed AV conduction (-ve dromotropic effect)
which involves mainly H1 receptors
• If histamine is given i.v., direct cardiac effects of
histamine are overshadowed by baroreceptor reflexes
elicited by the reduced blood pressure
• Overall: H1 – decreased AV conduction; H2 - 10

Increased Chronotropy and automaticity

 Pharmacological actions (contd.)

• Visceral Smooth Muscles

- Bronchoconstriction

- Abd. Cramps & colic

• Glands

- ↑ in gastric secretion

• Sensory nerve endings 11

 Pathophysiological roles
• Gastric Secretion
• Allergic Phenomena
• As transmitter
• Inflammation
• Tissue growth and repair

12
 Uses Of Histamine
➢ No Therapeutic Use
• Diagnostic Uses:
* Secreting (Acid) capacity of stomach
* Pheochromocytoma
* Bronchial hyper-reactivity in Asthmatics
➢ H1 Selective Histamine Analogue:
Betahistine (used to control vertigo in Meniere’s disease)

13
 Antagonists of Histamine
➢ Physiological antagonists :
Adrenaline – effects are opposite to effects of
histamine

➢ Histamine release Inhibitors :

Mast cell stabilizers : Cromoglycate

➢ Histamine receptor blockers :

H1 blockers and H2 blockers
14
H1-RECEPTOR ANTAGONISTS
• 1st Generation:
– Highly sedatives: Diphenhydramine, Dimenhydrate,
Promethazine and Hydroxyzine
– Moderately: Pheniramine, Cyproheptadine, Meclizine,
Buclizine and Cinnarizine
– Mild: Chlorpheniramine, Dexchlorpheniramine,
Dimethindene, Cyclizine, Clemastine
• 2nd Generation: Fexofenadine, Loratidine,
Desloratidine, Cetrizine, Levocetrizine, Azelastine,
Mizolastine, Ebastine and Rupatidine

15
SECOND GENERATION
ANTIHISTAMINICS

The second generation antihistaminics

(SGAs) may be defined as those H1
receptor blockers marketed after 1980
which have one or more
of the following properties:
• Absence of CNS depressant property.
• Higher H1 selectivity : no 16
17
 Antihistaminics
(Pharmacokinetics)
• Absorption: Antihistaminics (H1 receptor antagonists) are well
absorbed from oral and parenteral routes

• Distribution: widely in the body and enter brain. Newer

compounds penetrate the brain poorly.

• Metabolism: In liver

• Excretion: In urine

18
 Pharmacological Actions
• CNS depression: (More with first generation)
– Sedation and drowsiness
– Some have antiemetic and antiparkinsonian effects
• Antiallergic action: Type- I reactions are
suppressed
• Anticholinergic actions (More with first
generation)
– Dryness of mouth , Blurring of vision
– Constipation
– Urinary retention
19
 Pharmacological Actions
• BP
-Fall in BP with IV injection (all) but not
with Oral
• direct smooth muscle relaxation or α
adrenergic blockade
• Antagonism of Histamine
- Effectively block:
* Bronchoconstriction
* Contraction of sm. Mus.
* Triple response 20
21
22
 Pharmacological Actions
• Antimotion sickness effect: Dimenhydrinate,
Promethazine
• Antiemetic: Promethazine
• Antiparkinsonism: Diphenhydramine,
orphenadrine, promethazine(IV)
• Antivertigo: cinnarizine

23
 Antihistaminics
(Uses)
• Allergic disorders,
• Other conditions involving histamine: Insect bite, Ivy
poisoning etc.
• Pruritides
• Common cold
• Motion sickness
• Vertigo
• Pre anesthetic medication
• Cough
• Parkinsonism
• Acute muscle dystonias
24
• As sedative, hypnotic, anxiolytic
 H2 receptor antangnists
• Cimetidine , Ranitidine, Famotidine
Clinical uses-
• Peptic Ulcer and Duodenal Disease
• Gastric Ulcer: reduce symptoms promote healing for benign
gastric ulcers
• Gastroesophageal Reflux Disorder (erosive esophagitis)
Hypersecretory Disease:
• Zollinger-Ellison syndrome: acid hypersecretion -- caused by
gastrin-secreting tumor
• Systemic mastocytosis and multiple endocrine adenomas

25
 H3 Receptor Antagonists
• The H3 receptors are presynaptic autoreceptors on
histaminergic neurons that originate in the
tuberomammillary nucleus in the hypothalamus and
project throughout the CNS
• H3 agonists decrease histaminergic transmission, and
antagonists increase it.
• Inverse agonist or antagonist of these receptors may
increase histamine leading to wakefulness.
• Pitolisant (tiprolisant) is such a drug approved for
Narcolepsy
• Thioperamide was the first “specific” H3
antagonist/inverse agonist available experimentally, 26
12. A 25-year-old man suffering from hay fever
started treatment with an over-the-counter
antihistamine preparation. Which of the
following statements best explains the molecular
mechanism of act ion of the prescribed drug to
treat this patient’s hay fever?
A. Reversible binding to H3 receptors
B. Irreversible binding to H3 receptors
C. Reversible binding to H2 receptors
D. Irreversible binding to H2 receptors
E. Reversible binding to H1 receptors
F. Irreversible binding to H1 receptors 27
13 A 34-year-old man presented to his physician
complaining
of dry mouth, constipation, and difficulty in
urination. He
also noticed an increase in appetite. The man had
started a
therapy with cyproheptadine 2 weeks earlier to
treat cold induced urticaria. Drug-induced
blockade of which of the following pairs of
receptors most likely mediated the patient’s
symptoms?
A. Dopaminergic and α1-adrenergic 28

B. H2-histaminergic and muscarinic

23. A 53-year-old man presented to the clinic
complaining of itching, ushing, arthralgia,
heartburn, and diarrhea. Further exams led to the
diagnosis of systemic mastocytosis. Which of the
following pairs of drugs should be included in
the therapeutic treatment of this patient?
A. Aspirin and ergotamine
B. Misoprostol and ergotamine
C. Loratadine and famotidine
D. Loratadine and diphenhydramine
E. Aspirin and famotidine
29
30. A 21-year-old woman suffering from
seasonal allergic conjunctivitis started a
treatment with eye drops of azelastine, a second-
generation histamine H1 antagonist. Second-
generation H1 antagonists are used locally in the
conjunctiva instead of first-generation H1
antagonists to provide which of the following
therapeutic advantages?
A. Negligible effects on pupil size and
accommodation
B. Negligible penetration into the central nervous
system
C. Higher dilating activity on conjunctival
30
31. An 8-year-old girl was diagnosed with
seasonal allergic conjunctivitis triggered by
exposure to airborne pollen. She started a topical
therapy with cromolyn sodium. Which of the
following actions most likely mediated the
therapeutic effectiveness of cromolyn in this
patient?
A. Blockade of H1 receptors
B. Blockade of mediator release from mast cells
C. Inhibition of prostaglandin biosynthesis
D. Blockade of leukotriene receptors
E. Constriction of conjunctival vessels 31
THANK YOU

32