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