2. INTRODUCTION
Naturally occuring substances – termed as local
harmones which originate from diffuse tissues &
produce intense pharmacological action near their
site of formation & release.
Auto’s=Self ; akos= remedy/ medicinal agent.
4. HISTAMINE
Tissue amine.
Histos- Tissue.
DISTRIBUTION: Widely distributed in almost all
mammal tissues & in venom of bees & wasps.
SYNTHESIS: In mammals formed by Decarboxylation
of Histidine in prescence of Histidine decarboxylase.
STORAGE: Present in platelets, leucocytes, basophills
& mastcells.
Mainly in mastcells & basophills due to presence of
his.decarboxylase, specialised storage granules.
5. MECHANISM OF ACTION
Acts through 4 receptors viz : H1, H2, H3, H4 – all
belonging to family GPCR.
Activation of H1 receptors :
Activation of H2 receptors:
6. PHARMACOLOGICAL ACTIONS
CVS: (A). BLOOD VESSELS: In herbivores – Sys & Pul
vasoconstriction.
In humans Pul.vasodilation.
Acts by 3 ways: (a).Activation of H1 receptors on the
endothelial cells cause rapid- short lived vasodilation.
(b).Activation of H2 receptors in the vascular smooth
muscle causes slower but prolonged vasodilation.
(c).Relaxation of smooth muscle of capillaries &
venules leading to their dilation and fall in BP.
7. PHARMACOLOGICAL ACTIONS
(B).BP: Therapeutic doses induces hypotension, short
lived.
Large doses –prolonged hypotension.
Hypotension left untreated may cause irreversible
shock & death.
Histamine induced hypotension is partially reversed
by anti-histaminics & completely reversed by
adrenaline.
8. PHARMACOLOGICAL ACTIONS
TRIPLE RESPONSE; When given (20mcg) ID develops
a triple response :
(a).FLUSH(RED REACTION): Red line r spot develop
with in 10sec, due to local dilation of capillaries &
venules.
(b).WHEAL: Local swelling due to edema, mottled
reddening around injury.
Lasts about 1 1/2min.
Due to increased permeability of capillaries 7 post
capillary venules with consequent xtravasation of
fluid.
9. PHARMACOLOGICAL ACTIONS
(c).FLARE: Redness with irregular margins spreads out
from injury.
Triple response is part of normal reaction to injury.
Its prevention is used to evaluate anti-histaminic activity
of a new drug.
(C).HEART:Increases sinus rate (+ve chronotropic action)
Increases the amplitude of ventricular contraction
(+inotropic effect)
Decreases AV conduction time & increases coronary blood
flow, high conc. induce ven.fibrillation.
10. PHARMACOLOGICAL ACTIONS
(D)SMOOTH MUSCLE: Stimulates smooth muscles
of various tissues by direct action(H1).
Bronchial & Uterine smooth muscle – highly sensitive.
GIT & Ureteral smooth muscle – respond moderately.
Thru H1 receptor – gall bladder contraction ,
H2 receptor – gall bladder relaxation.
‘H’ –induced bronchospasm – antagonised by
adrenaline, isoprenaline & aminophylline but not by
anti-histaminics r atropine.
11. PHARMACOLOGICAL ACTIONS
ENDOCRINE GLANDS: Important physiological
mediator of gastric acid secretion.
CNS: Doesn’t cross BBB, ‘H’ constituted in 2types of
cells – Histaminergic neurones & Mast cells.
Considered as ‘Waking amine’- increase in sensitivity
of large cerebral areas to excitatory inputs.
IMMUNOMODULATION: Increases Humoral &
Cellular immunity by various receptors , H1- cellular
immunity , H2- Humoral immunity.
12. A,D,M,E:
Stable compound & absorbed from all sites .
Rapidly under go first pass metabolism in liver.
Metabolism varies acc.to: animal spcs, sex , organ
studied.
Chemically it is B-Imidazolyl etylamine.
End products of metabolism include N-Methyl
imidazole aectic acid, N-acetyl histamine.
13. ADR
Due to pharmacological actions: hypotension, visual
disturbances, dyspnea, diarrhoea.
Man, Gunea pig- extremely sensitive.
Rats & Mice – highly resistant.
Large dose causes – severe nausea, gripping, headache
& sweating.
USES:Study of gastric acid secretion.
14. ANTI-HISTAMINICS
Certain phenolic ether – anti-histaminic properties.
CLASSIFICATION: By two ways Clinically &
Chemically.
(A).CLINICAL CLASSIFICATION:
1.POTENT & SEDATIVE: Diphenhydramine,
Promethazine.
2.POTENT & LESS SEDATIVE: Cyclizine, Meclizine.
3.LESS POTENT & LESS SEDATIVE: Antazoline,
Cinnarizine.
4.NON SEDATIVE: Loratidine, Cetirizine.
15. CHEMICAL CLASSIFICATION
General formula:
Based on configuration of ‘X’ classified as :
1. ETHANOLAMINES(X=‘O’): Diphenhydramine,
Doxylamine.
2.ETHYLENE DIAMINES(X=‘N’): Mepiramine, Antazoline.
(show negligible anti-cholinergic & anti-emetic efcts)
3.ALKYL AMINES (X=‘C’): Chloropheneramine,
Triprolidine.
4.PIPERAZINES: (X=‘C’ in conjunction with piperazine
ring): Cinnarizine, Cetirizine.
16. CHEMICAL CLASSIFICATION
5.PHENO THIAZINES (X=‘N’ as apart of
phenothiazine nucleus): Promethazine, Trimeprazine,
show potent anti-emetic effect.
6.PIPERIDINES: Loratadine, Fexofenadine.
7.DIBENZOXYPINES: Doxepine (Tricyclic anti
depressant) shows potent anti-histaminic properties.
17. ‘H’- ANTAGONISTIC ACTIONS
1.ANTI-HISTAMINIC ACTIONS: Competatively block
‘H’ at various sites.
Antgonize stimulant action of ‘H’ on: Smooth muscle
of GIT, bronchi, uterus & bld.ves.
Reduce ‘H’ induced triple response.
Anti-allergic & anti-inflammatory actions involve:
(a). Inhibition of release of mediators from mastcells,
basophills.
(b).Down regulation of H1-receptors.
Don’t antgonize CVS actions of ‘H’.
18. ANTAGONISTIC ACTIONS
OTHER ACTIONS: Related to their blocking of 5-HT
& A1-Adreno receptors.
1.SEDATION & HYPNOSIS: CNS depression –
common side effect.
Induce varying degrees of sedation, drowsiness &
sleep.
2.CNS STIMULATION: Stimulation is less ,
conventional doses of Promethazine cause
restlessness, tremors & insomnia.
19. ANTAGONISTIC ACTIONS
3. ON ANS: First gen. anti-histaminics show
muscarinic blocking activity, second gen. anti-
histaminics doesn’t show these actions.
4.ANTI-EMETIC & ANTI-MOTION SICKNESS:
Diphenhydramine & Promethazine block
histaminergic signals from the vestibular nucleus to
vomiting center.
5.ANTI-PARKINSONIAN EFFECTS: Central anti-
muscarinic actions useful in treating parkinsonism.
20. ANTAGONISTIC ACTIONS
6.CVS: Rapid IV administration of Diphenhydramine,
Antazoline may produce dose related prolongation of
QT interval due to membrane stabilising effect.
7.LOCAL ANAESTHESIA: Promethazine,
Diphenhydramine exhibit local anaesthetic activity.
A,D,M,E: Well absorbed orally & parenterally.
Anti-histaminic effect starts with in 15-30 min, peaks
by 1hr & lasts for 3-6hrs.
Meclizine- action persists for 12-24hrs.
21. ANTAGONISTIC ACTIONS
A,DM,E: First gen compounds metabolised by
CYP3A4 in liver.
H1-antagonists induce hepatic microsomal enzymes,
facilitating their own metabolism.
ADR: Mild,
1.CNS: Sedation & Hypnosis, Fatigue.
In children less than 2yrs- Promethazine cause
Apnoea.
ANTI-MUSCARINIC EFFECTS: Dry mouth, blurred
vision, bladder disturbances & rarely impotence.
22. ADR:
GIT: Nausea, vomiting, epi-gastric distress.
MISC: May produce allergic manifestations despite of
their anti-allergic & anti-inflammatory properties.