Autocoids Antihistaminics Neural pharmacology

Histamines and antihistamine

1. Histamine and
Anti-histaminics
REAGAN KABUKA
(B.Pharm, MPH, MscPharmacology PG2)
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2. Autacoids
Thesearediversesubstancesproducedbywidevarietyofcells,having
intensebiologicalactivity,butactlocallyatthesiteofsynthesisandrelease
Typesofautacoids:
• Amineautacoids
-Histamine,5-HT(Serotonin)
• Peptideautacoids
-Plasmakinins(Bradykinin,Kallidin),Angiotensinogen
• Lipidautacoids
-Prostaglandins,Leukotrienes,PAF
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3. Histamine -Introduction
•Meaning “tissue amine” (histos–tissue) –abundantly
present in animal tissues
•Physiological role-mediator of hypersensitivity and tissue
injury reaction–The primary site the mast cell granules (or
basophils) –skin, intestinal and gastric mucosa, lungs, liver
and placenta
•Other sites
–central nervous system: neurotransmitter
–the fundus of the stomach: major acid secretagogues, epidermis,
gastric mucosa and growing regions
–also blood, body secretions, venoms & pathological fluids
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4. 4
Synthesis & Storage
•Histamine is formed by the
decarboxylation of the amino
acid histidineby the enzyme
L-histidinedecarboxylase
•The chief site of storage in
tissues is the mast cell; in the
blood, it is the basophil.
•These cells synthesize
histamine and store it in
secretory granules.
•Ineffective orally –liver
destroys all absorbed from
intestine. CYP 450 enzymes

5. Histamine Receptors
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H1 H2 H3
Selective
agonist
2-Methylhistamine 4-Methylhistamineα-Methylhistamine
Selective
antagonist
Mepyramine Cimetidine
Ranitidine
Thioperamide
Effector
Pathway
IP3/DAG cAMP Ca++ influx
K+channel activation
Distribution•Smooth muscle (intestine,
airway, uterus)-contraction
•Blood vessels –NO and
PGI
2release–
Vasodilatation
•Smooth muscle of large
vessels-vasoconstriction
•Afferent nerves –
stimulation
•Ganglion cells –
stimulation
•Adrenal medulla –CAT
release
•Brain-transmitter
•Gastric glands–
acid secretion
•Blood vessels
(smooth muscle) –
dilatation
•Heart: Atria: +
chronotropyand
ventricles: +
inotropy
•Uterus–relaxation
•Brain(post
synaptic)–impulse
•Brain–inhibition of
Histamine release-
sedation
•Lung, spleen, gatric
mucosa –decrease
histamine release
•Ileum–inhibition of
Ach release

6. Pharmacological actions of Histamine
•CNS
-No BBB penetration
-On Intracerebrovascular injection:
* ↑ in BP, cardiac stimulation
* Vomiting, ADH release
•Histamine is a powerful stimulant of sensory nerve
endings, especially those mediating pain and itching
•H
3agonists reduce the release of acetylcholine,
amine, and peptide transmitters in various areas of
the brain and in peripheral nerves
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7. Histamine -Pharmacological actions
•Blood vessels: Dilatation of small vessels –
arterioles, capillaries and venules
•Flushing, heat, increased HR and CO –little fall in BP
•Dilatation of cranial vessels
•Larger arteries and veins –constriction mediated by H1
receptor
•Increased capillary permeability –exudation of plasma
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8. Pharmacological actions
Heart :
•Atria: +vechronotropydue to H2 receptors
•Ventricles: +veinotropydue to H2 receptors
•AV conduction (-vedromotropic effect) due to H1
receptors
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9. Pharmacological actions
•Visceral Smooth Muscles
-Bronchoconstriction
-Abd. Cramps & colic
•Glands
-↑ in gastric secretion
•Sensory nerve endings
-IV –itching , Pain
•Autonomic ganglia & Adrenal medulla
- Release of Adrenaline → secondary ↑ in BP
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10. Pathophysiologicalroles
• Gastric Secretion
• Allergic Phenomena
• As transmitter
• Inflammation
• Tissue growth and repair
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11. Uses Of Histamine
 No Therapeutic Use
•Diagnostic Uses:
* Secreting (Acid) capacity of stomach
* Pheochromocytoma
* Bronchial hyper-reactivity in Asthmatics
H1 Selective Histamine Analogue:
Betahistineused to control vertigo in Meniere’s disease
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12. 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
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13. H
1-RECEPTOR ANTAGONISTS
•1
st
Generation:
•Highly sedatives: Diphenhydramine, Dimenhydrate,
Promethazineand Hydroxyzine
•Moderately: Pheniramine, Cyproheptadine, Meclizine,
Buclizineand Cinnarizine
•Mild: Chlorpheniramine, Dexchlorpheniramine,
Dimethindene, Cyclizine, Clemastine
•2
nd
Generation: Fexofenadine, Loratidine,
Desloratidine, Cetrizine, Levocetrizine, Azelastine,
Mizolastine, Ebastineand Rupatidine
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15. Antihistaminics(Pharmacokinetics)
•Absorption:Antihistaminics(H
1receptorantagonists)arewell
absorbedfromoralandparenteralroutes
•Distribution:widelyinthebodyandenterbrain
•Metabolism:Inliver
•Excretion:Inurine
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16. Pharmacological Actions
•CNSdepression:(Morewithfirstgeneration)
•Sedationanddrowsiness
•Somehaveantiemeticandantiparkinsonianeffects
•Antiallergicaction
•Anticholinergicactions(Morewithfirstgeneration)
•Drynessofmouth,Blurringofvision
•Constipation
•Urinaryretention
•Fall in BP with IV injection (all) but not with Oral
•direct smooth muscle relaxation or α adrenergic
blockade
•Contraction of sm. Muscles-Bronchoconstriction
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17. 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
•As sedative, hypnotic, anxiolytic
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18. Pharmacological Actions
•Antimotionsickness effect: Dimenhydrinate,
Promethazine
•Antiemetic: Promethazine
•Antiparkinsonism: Diphenhydramine, orphenadrine,
promethazine(IV)
•Antivertigo: cinnarizine
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20. H
2receptor antagonists
•Cimetidine , Ranitidine, Famotidine
Clinical uses-
•Peptic Ulcer and Duodenal Disease
•Gastric Ulcer: reduce symptoms and promote healing for
benign gastric ulcers
•GastroesophagealReflux Disorder (erosive esophagitis)
HypersecretoryDisease:
•Zollinger-Ellison syndrome: acid hypersecretion--caused by
gastrin-secreting tumor
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21. QUESTIONS???
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