Pharmacology of AUTOCOIDS : HISTAMINE & ITS SYNTHETIC ANALOGUES

1. Guided By :- Prepared By :-
Dr. Tarique Mahmood Abu Raihan Shams
(Associate Prof. & Head) Pharm. D , 2nd
Mrs. Arshiya Shamim
Assistant Professor

2. TOPIC
PHARMACOLOGY OF AUTOCOIDS – HISTAMINE
& ITS SYNTHETIC ANALOGUES

3. Autocoids
Introduction
 The term Autocoid is derived from Greek word “autos”
means “self” & “akos” means “Healing substances / Remedy/
medicinal agents”.
 These are naturally occuring compound produced by wide
variety of cells in the body, having intense biological activity
, but generally act locally (e.g. Within inflammatory pockets)
at the site of synthesis and release.

4.  They have also been called ‘local hormones’.
However , they differ from circulating hormones that they
are produced by many tissues rather than in specific
endocrine gland.

5. Classification of Autocoids
The Classical autocoids are:-
Amine autocids: Histamine , 5-Hydroxytryptamine/5-
HT(Serotonin)
Lipid derived autocoids: Prostaglandins(PGs),
Leukotrienes , Somatostatin , Platelet activating factor
Peptide autocoids: Plasma kinins(Bradykinin ,
Kallidin) , Angiotensin

6. Histamine
 Histamine meaning ‘tissue amines’ (Histos-tissue)
 Histamine is a chemical messenger mostly generated in
mast cells that mediates a wide range of cellular responses
including allergic & inflammatory reactions , gastric acid
secretion , and neurotransmission in parts of brain.
It has no clinical application , but agents that interfare
with action of histamine(antihistamins) have imp
therapeutic applications.

7. Location
 Unevendistributionthroughoutthebody.
Mostly within storage granules of mast cells & WBC(Basophil
andEosinophils).
Tissue rich in histamines like skin , gastric and intestinal
mucosa,lungs,liver&placenta.
Tissue fluids like blood, most of the body secretions , venoms
andpathologicalfluids.

8. Synthesis

9. Degradation of Histamine

10. HISTAMINE
RECEPTOR
H1
RECEPTOR
H2
RECEPTOR
H3
RECEPTOR
H4
RECEPTOR
Receptor type G Protein
Coupled
G Protein
Coupled
G Protein
Coupled
G Protein
Coupled
Location Intestinal,
bronchial,
uterine smooth
muscles, CNS,
endothelial
cells, sensory
nerve endings
On parietal
cells of GIT,
Blood vessels,
heart, brain
On brain,
lungs, spleen,
skin, gastric
mucosa, certain
blood vessels
On thymus
gland, small
Intestine,
spleen, colon,
Bone marrow,
Present on
surace of
basophils
HISTAMINIC RECEPTORS

11. HISTAMINE
RECEPTOR
H1
RECEPTOR
H2
RECEPTOR
H3
RECEPTOR
H4
RECEPTOR
Specific
agonist
2 methyl
histamine,
2 thiazolyl
etylamine,
2 pyridyl
etylamine
Dimaprit,
Impromidine,
4 –methyl
histamine
α-Methyl
histamine
Imetit,
Clozapine
Specific
antagonist
Chlorphenir
amine,
Mepyramine
Rantidine,
cimetidine
Thioperamide,
Clobenpropit,
burimamide
thioperamide

12. HISTAMINE
RECEPTOR
H1
RECEPTOR
H2
RECEPTOR
H3
RECEPTOR
H4
RECEPTOR
Mechanism of
action
 Hydrolysis of
PIP2 Increases
IP3 and DAG
levels
 Release of
intracellular
calcium levels
 Activation of
protein kinase
C.
 Increase in
cAMP Levels
 Phosporylati
on of proteins
 Decrease in
cAMP and
calcium levels
 Causes
opening of
potassium
channels
Decrease in the
levels of cAMP
and calcium
influx
PIP2: Phosphatidyl Inositol bisPhosphate IP3: Inositol triPhosphate
DAG: DiAcylGlycerols

13. PHARMACOLOGICAL ACTIONS OF
RECEPTORS
H1 RECEPTORS
Contraction of smooth muscles
Vasodilation of blood vessels
Increase in capillary permeability
H2 RECEPTORS
Increases gastric secretion from gastric glands
Vasodilation of blood vessels
Relaxation of uterine smooth muscles
Positive inotropic and chronotropic effects on heart

14. H3 RECEPTORS
Vasodilation of blood vessels
Decreases neurotransmitter release
H4 RECEPTORS
Causes chemotaxis of WBC

15. PATHOPHYSIOLOGICAL ROLE
 PATHOLOGICAL ROLE
In Hypersensitivity reactions
In Inflammation
 PHYSIOLOGICAL ROLE
Gastric secretion
Neuronal Transmission
Tissue growth and repair

16. PHARMACOLOGICAL ACTIONS
1. On blood vessels
Dilatation of smaller blood vessels like arterioles ,
capillaries & venules.
On S.C. Injection: Flushing , heat , HR & CO.
I/V injection causes fall in BP which has early short
lasting H1& slow but more persistent H2 component.
(At low dose H1 has higher affinity)
Dilatation of cranial vessels causes pulsatile headache.

17. 2. On Heart
 H2-Positive chronotropic and inotropic effect.
 H1-decrease AV conduction
3. On Smooth muscles
 H1-stimulant effect on smooth muscles.
 Contraction of smooth muscles causing
bronchoconstriction and increased motility of intestinal
mucosa.

18. 4. On gastric glands
H2 increase in gastric secretion
Other secretions may also be increased.
5. Sensory nerve endings
Itching occurs when histamine is injected I/V or
intracutaneously.
Higher concentrations causes pain.

19. 6. Autonomic ganglia and adrenal medulla
Stimulation and release of Adr.
7. CNS (H1 & H2)
Does not penetrate BBB
No central effects on I/V infusion
Rise in BP on intraceberoventricular administration
Cardiac stimulation
Behaviour arousal
Hypothermia
Vomitting
ADH release

20. THERAPEUTIC USES
Positive control injection in skin hyper reactivity
testing.
Test acid secreting capacity of stomach.
Clinical diagnosis of Pheochromocytoma.

22. SYNTHETIC ANALOGUES
 H1 : Betahistine
 H2: Betazole , Impromidine ,
 H3: α-Methyl histamine
 H4: Imitit , Clozapine

23. Betahistine
 Betahistine is an orally active , H1 selective histamine
analogue, which is used to control vertigo in patients of
Meniere’s disease.
 It possibly acts by causing vasodilation in the internal ear.
Pharmacokinetics of Betahistine
 Absorption: It is very rapidly absorbed after oral
administration.
 Metabolism: Betahistine is rapidly metabolised in the liver to
2-pyridylacetic acid. Excretion: Excreted mainly in urine

24. Onset of Action for Betahistine
Within 1 hr.
Duration of Action for Betahistine
6-12 hours.
Half Life of Betahistine
3.5 hours

25. Side Effects of Betahistine
 Headache
 Rashes
 Pruritis
 Gastrointestinal disturbances
 Nausea
 Urticaria
 Dizziness
 Insomnia
 Dyspepsia
Contra-indications of Betahistine
 Hypersensitivity to Betahistine
 Pheochromocytoma
 Asthmatic & Ulcer patient.

26. Betazole
Betazole is a histamine analogue.
It produces the same effects as histamine, binding the
H2 receptor which is a mediator of gastric acid
secretion.
This agonist action thereby results in an increase in
the volume of gastric acid produced.

27. Use
 It has been used as a gastric stimulant to test for maximal
production of gastric secretion .
 The test can be used in diagnosis of diseases such
as Zollinger-Ellison syndrome where there is excess acid
production, in this case driven by over production
of gastrin.
 The volume of acid secretion is measured following
administration of betazole.

28. α-Methyl histamine
α-Methylhistamine is a histamine agonist selective
for the receptor subtype H3.
It causes lowering of blood pressure and a decrease
of heart rate in animal models.

29. Clozapine
Clozapine is a histamine agonist selective for the
receptor subtype H4.
Is is a medication of the atypical antipsychotic type.
It is mainly used for schizophrenia that does not
improve following the use of other antipsychotic
medications.
In those with schizophrenia and schizoaffective
disorder it may decrease the rate of suicidal behavior.
It is more effective than typical antipsychotics and
effective for those who are treatment resistant.

30. Side Effects
 constipation,
 drooling (especially at night),
 sleep problems,
 increased sweating,
 weight gain,
 dry mouth,
 blurred vision,
 drowsiness,
 dizziness,
 spinning sensation,
 headache, or
 shaking (tremor).

31. REFERENCES
Tripathi KD, ESSENTIALS OF MEDICAL
PHARMACOLOGY, 7th edition, page no: 158-163
THE PHARMACOLOGICAL BASIS OF
THERAPEUTICS, Goodman and Gilman’s, 12th
Edition.
Lippincott’s Pharmacology , 5th edition, page no: 549-
551
Wikipedia
Slideshare.net