Dr Tehniat Zahra

Receptors

Histaminergic Adrenergic Cholinergic

receptors receptors receptors

H1 M2
receptor M1 M3
H2 α receptor M4
s β receptor receptors
receptors Receptors s receptors
receptor s (exocrine
(smooth (Stomach (Blood (heart & (bronchial
s (Parietal gland &
vessels ) vessels) cardiac smooth
cell) smooth
Heart) cells) muscle) muscles)

β1 receptors β 2 receptors
(Heart) (Lungs &
uterus)
HISTAMINE
• First autacoid to be discovered. (Greek: autos=self; akos=cure) Synthesized in
1907 Demonstrated to be a natural constituent of mammalian tissues (1927)
• Involved in inflammatory and anaphylactic reactions.
• Local application causes swelling redness, and edema, mimicking a mild
inflammatory reaction.
• Large systemic doses leads to profound vascular changes similar to those seen
after shock or anaphylactic origin
HISTAMINE (Synthesis, Storage, and
Metabolism)
• Formed by the decarboxylation of the amino acid histidine by the
enzyme L-histidine decarboxylase
• The chief site of histamine storage in most tissues is the mast cell; in
the blood, it is the basophil.
• Metabolized to N-methylhistamine by histamine-N- methyltransferase
• These metabolites have little or no activity and are excreted in the urine
HISTAMINE (Release and functions)
• It is released from storage granules as a result of the interaction of antigen with
immunoglobulin E (IgE) antibodies on the mast cell surface,
• Histamine plays a central role in immediate hypersensitivity and allergic
responses.
• The actions of histamine on bronchial smooth muscle and blood vessels account
for many of the symptoms of the allergic response.
• In addition, certain clinically useful drugs can act directly on mast cells to release
histamine, thereby explaining some of their untoward effects.
 • Smooth Muscles
H1 • Vascular endothelium
• GIT
H2 • Vascular Smooth Muscle Tissue

• CNS
H3
• Bone marrow, Small intestine , colon
H4 spleen
HISTAMINE (Pharmacological Effects)
1 Cardiovascular system .
a. Triple effect on terminal vasculature (itching & pain):
– reddening at injection site due to vasodilation
– wheal or disk of edema within 1 to 2 min
– a large, bright crimson flare or halo surrounding the wheal
b. IV Histamine: fall in blood pressure, cutaneous flushing, over the
face and upper trunk, rise in skin temperature, intense headache.
2 Smooth muscle of bronchioles; Contraction of nonvascular smooth
muscle.
H1-RECEPTOR ANTAGONISTS
(Conventional Antihistaminic)
1. First generation Antihistaminics
a) Highly sedative: Diphenhydramine, Dimenhydrinate, Promethazine,
Hydroxyzine
b) Moderately sedative: Pheniramine, Cyproheptadine, Meclizine,
Buclizine, Cinnarizine
c) Mild sedative: Chlorpheniramine, Dexchlorpheniramine,
Dimethindene, Triprolidine, Mebhydroline, Cyclizine, Clemastine
2. Second generation Antihistaminics
Fexofenadine, Loratadine, Desloratadine, Cetrizine, Levocetrizine,
Azelastine, Mizolastine, Ebastine, Rupatadine
ANTIHISTAMINIC(Pharmacokinetics)
Absorption: Antihistaminic (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
 Antihistaminic (Pharmacological actions)
Smooth Muscle: Inhibit most of the effects of histamine on
smooth muscles, especially the constriction of respiratory
smooth muscle
Capillary Permeability: H1 antagonists strongly block the
increased capillary permeability, formation of edema and wheal
brought about by histamine.
Flare and Itch. The flare component of the triple response and
the itching caused by intradermal injection of histamine are two
different manifestations of the action of histamine on nerve
endings. H1 antagonists suppress both.
 Cont.…
Immediate Hypersensitivity Reactions (Anaphylaxis and Allergy):
Oedema formation and itch are effectively suppressed. Other effects,
such as hypotension, are less well antagonized. Bronchoconstriction is
reduced little, if at all.
Central Nervous System: The first-generation H1 antagonists can both
stimulate and depress the CNS. – Stimulation  Restless, nervous,
sleeplessness & convulsions – Central depression  Diminished
alertness, slowed reaction times, and somnolence are common
manifestations. The second-generation ("nonsedating") H1 antagonists do
not cross the blood-brain barrier appreciably.
 Cont.….
Local anesthetics: some drugs like Pheniramine have
strong membrane stabilizing property. But not used
clinically.
Antihistaminic (Side effects and toxicity)
• Side effects are frequent but mild.
• Sedation, diminished alertness and concentration, light headedness,
motor incoordination, fatigue and tendency o fall asleep.
• Second generation antihistaminic are largely free of CNS effects.
• Anticholinergic properties.(Dryness of mouth, alteration of bowel
movement, urinary hesitancy and blurring of vision)
• Epigastric distress and headache.
• Acute overdose causes excitation, tremors, hallucinations, muscular
incoordination, convulsions, flushing, hypotension, death.
Antihistaminic (Uses)
• Allergic disorders,
• Other conditions involving histamine: Insect bite, Ivy poisoning etc.
• Pruritis
• Common cold
• Motion sickness
• Vertigo
• Pre anesthetic medication
• Cough
• Parkinsonism
• As sedative, hypnotic, anxiolytic
Drug interactions
• Increased effect of CNS depressants
• MAO inhibitors increase anticholinergic effect of antihistaminic
• First generation antihistaminic can decrease effectiveness of
cholinesterase inhibitors used in Alzheimer`s disease like donepezil and
rivastigmine
H2 RECEPTOR ANTAGONISTS
These drugs are still used for treatment and maintenance therapy of peptic ulcer disease,
treatment of gastroesophageal reflux disease, and management of dyspepsia. However,
they achieve less acid suppression than proton pump inhibitors.
MOA: H2 receptor antagonists (H2RAs) inhibit acid secretion by blocking SECRETION
OF HITAMINE FROM histamine H2 receptors on the parietal cell In the stomach.
Four H2RAs are used in the United States:
• Cimetidine
• Ranitidine
• Famotidine
• Nizatidine
 Cimitidine Ranitidine Femotidine
Drug
Structure Imidazole ring Furan ring Thiazole ring

Lipid solubility LS V poor LS Most poor LS

Potency Less potent (healing power 50%) More potent (healing power Most potent (healing power
75%) 90%)

Duration of Action 4-6 hr 8-12hr 24hr

Specificity Non specific (H1& H2) Specific (only H1) Specific (only H1)

Enzyme Inhibition Inhibit Cyt P450 Donot Inhibit Cyt P450 Donot Inhibit Cyt P450

Sexual impotency Yes No No

Mental confusion Yes (cross BBB) No No
Gynecomastia Yes(both male and female) No No
Interaction with antacid antacid interfere with its No interaction No interaction
absorption
Other side effect Headache dizziness skin rash Headache dizziness skin rash Headache dizziness skin rash

Dose(Gastric ulcer) 200mg 400mg tab 150mg tab BID 20mg Tab BID
200mg/ml injection 40 mg Tab OD
200mg tab TID
Thank you