Autocoids
• Amine : Histamine, Serotonin
• Lipid derived: Prostaglandins,
Leukotrienes
• Peptide : Plasma Kinins, Angiotensin
Synthesis, storage & metabolism of histamine
• Synthesized by
decarboxylation of amino acid
histidine
• Histamine is present in storage
granules of mast cells & also
found in skin, lungs, liver,
gastric
Histamine
Distribution:
• Histamine –storage granules of mast cells
• Tissues rich in histamine skin, gastric and
intestinal mucosa, lungs, liver and placenta.
• Non-mast cell histamine occurs in brain,
epidermis, gastric mucosa.
Histamine: storage and release
Immunologic release: immunological stimulus
• In mast cells , sensitized by surface IgE antibodies,
degranulate when exposed specific antigen
• Degranulation is involved in the immediate type I allergic
reaction
Histamine: storage and release
MoA of Histamine Receptors
Histamine
H3 receptors
H1 receptors H2 receptors
cAMP
Ca 2+ cAMP
Smooth muscle contraction
Decrease in Histamine
Increased capillary Gastric acid secretion release
permeability Blood vessels: &
Vasodilation Increased capillary Secretion
Sensory nerve ending pain & permeability
itching
Pharmacological actions
stimulating H1, H2, H3 Receptors
• CVS:
• Dilates arterioles, capillaries. Venules
Histamine- the triple response
Subdermal histamine injection
causes:
1. Red spot in seconds: direct vasodilation
effects, H1 receptor mediated
2. Flare (1 cm 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
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
H2 component vasodilatation - mediated indirectly by EDRF ..
But H2
component - mediation is directly on smooth muscle of blood
Pharmacological actions (Contd)
• Visceral smooth muscles:
- Bronchospasm, abdominal cramps
• Secretions:
- Increased gastric secretion (H2)
- Increased nasal secretion (H1)
• Sensory nerve ending: Itching
• CNS:
Histamine agonists:
Betazole: isomer of histamine and acts on H2 receptor.
It is used for diagnosis of gastric acid secretion but it
is contraindication in case of bronchial asthma
Betahistamine: it is analogue of histamine and acts on
HI receptor, it is used in the treatment of Meniere, s
disease. IT should be used cautiously in patients with
bronchial asthma and pheochromocytoma
Adverse effects of histamine release
Itching, urticaria
Flushing
Hypotension
Tachycardia
Bronchospasm
Angioedema
Wakefulness
Increased acidity (gastric acid secretion)
Therapeutic uses
Beta-histamine
- To control vertigo in Meniere’s disease 8 mg tab ½ tablet
QID
HISTAMINE RELEASERS
• Stings and venom
• Ag-Ab reaction
• Drugs
D-tubocurarine
Morphine
Classification of H1 Antagonists
Antihistamines
Mechanism of Action: Competitive inhibitors for histamine at H1
receptors (structural analogs)
They antagonize all actions of histamine except for he gastric acid
stimulation & H2-mediated vasodilatation
Pharmacokinetics:
Well absorbed orally, max serum level in 1-2 hrs
Old first-generation agents have wide tissue distribution including CNS
Newer 2nd generation are not (non-sedative)
Duration of older members:
4-6 hrs, piperazine derivatives & 2nd generation drugs have a long duration
of >24 hrs
Anti-Histamines
H1 ANTAGONISTS
PHARMACOLOGICAL ACTIONS
1. Antagonism of histamine
Block – bronchoconstriction-contraction of intestinal & smooth
muscle and triple response wheal, flare and Redness.
Anti-Histamines
H1ANTAGONISTS
PHARMACOLOGICAL ACTIONS
2. Antiallergic action -immediate hypersensitivity (type I
reactions) are suppressed
3. CNS- variable degree of CNS depression
4. Anticholinergic action- antagonize muscarinic
actions of Ach
5. Local anesthetic - pheniramine, promethazine ,
diphenhydramine
Anti-Histamines
SECOND GENERATION ANTIHISTAMINICS
Absence of CNS depressant property
Higher H, selectivity: no anticholinergic side effects
Also inhibit late phase allergic reaction by acting on
leukotrienes or by antiplatelet activating factor effect
Anti-Histamines
SECOND GENERATION ANTIHISTAMINICS
Fexofenadine:
active metabolite of Terfenadine.
Terfenadine withdrawn
PVT(Torsades de pointes)
+
CYP3A4 inhibitors(Erythromycin, Clarithromycin,
Ketoconazole, Itraconazole, etc.)
Uses:
o Allergic rhinitis
o Urticaria
o Other skin allergies
o Free of arrhythmogenic potential.
Anti-Histamines
SECOND GENERATION ANTIHISTAMINICS
Loratadine:
Another long-acting selective peripheral H1 antagonist.
Lacks CNS depressant effects and is fast acting.
Uses-
Urticaria
Atopic dermatitis
Anti-Histamines
SECOND GENERATION ANTIHISTAMINICS
Desloratadine- active metabolite of loratadine effective at half
the dose.
Cetirizine-
metabolite of Hydroxyzine
Affinity for peripheral H1 receptors:
penetrates brain poorly, but mild sedation
inhibits release of histamine and of cytotoxic mediators from
platelets as well as eosinophil chemotaxis during the secondary
phase of allergic response.
Levocetirizine-
Active R(-) enantiomer of cetirizine.
Anti-Histamines
Uses
• Allergic disorders.
• Other conditions- insect bite and ivy poisoning
• Abnormal dermographism is suppressed
• Blood/saline infusion induced rigor
• Purities- antipruritic action
• Command cold
Anti-histamines
Uses
• Preanesthetic medication. Promethazine
• Cough-chlorpheniramine, diphenhydramine and
promethazine
• Parkinsonism- promethazine
• Acute muscle dystonia- promethazine,
diphenhydramine or hydroxyzine
Differences between first & second generation H1
antihistamine
First generation H1 antihistamine Second generation H1 antihistamine
Usually administered in 3 to 4 daily doses Usually administered once or twice a day
Cross the blood brain barrier (lipophilicity, low molecular Do not cross the brain barrier (lipophilicity, low
weight, lack recognition by the P-glycoprotein efflux molecular weight, lack recognition by the P-glycoprotein
pump) efflux pump)
Potentially caused side effects (sedation/ Do not cause relevant side effect
hyperactivity/insomnia/convulsions) (sedation/fatigue/hyperactivity/convulsions), in the absent
of drug interactions
Case reports of toxicity are regularly published No reports of serious toxicity
No randomized, double blind, placebo-controlled trials in Some randomized, double blind, placebo-controlled
children studies in children
Lethal dose identified for infants/ young children Do not cause fatality in overdose
