1. AUTOCOIDS : HISTAMINE
AND BRADYKININ
Page 1

2. AUTOCOIDS
• Autocoids are naturally ocurring substances
that produce wide range of pharmacological
actions in small amounts
• They are also termed as local hormone since
they produced locally in response to some
stimulus (e.g. during inflamation)
• The term autocoid derived from
auto=self and akos=remedy or medicinal agent
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3. HISTAMINE
• Histamine is a basic amine , stored in granules
within mast cells & basophils
• Secreted when complement components C3a
& C5a interact with specific membrane
receptors or when antigen interact with cell-
fixed IgE
• It produce effect by acting on H1,H2 or H3
receptors on target cells
Page 3

4. Main Action In Human
• Stimulation of gastric secretion(H2)
• Contraction of smooth musle other than that of
blood vessels(H1)
• Cardiac stimulation(H2)
• Vasodilation(H1)
• Increased vascular permeability(H1)
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5. • The main pathophysiological roles of
histamine are:
– as a stimulant of gastric acid secretion (treated
with H2-receptor antagonists)
– as a mediator of type I hypersensitivity reactions
such as urticaria and hay fever (treated with H1-
receptor antagonists).
• H3 receptors occur at presynaptic sites and
inhibit the release of a variety of
neurotransmitters
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6. Contd..
• Injected intradermally, histamine causes the
'triple response':
• reddening (local vasodilatation),
• weal (direct action on blood vessels)
• flare (from an 'axon' reflex in sensory nerves
releasing a peptide mediator)
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7. Page 7

8. What is agonist???
• An agonist is a drug that once bound to the
receptor, initiates a change in cellular activity.
• The binding of the agonist often triggers a
series of biochemical events which ultimately
lead to the alteration in function
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9. CONT…
• Agonist  Receptor  Generation of secondary
messenger  Change in cellular activity
• Some important secondary messenger systems
activated by the binding of agonists to cell
surface receptors include:
• 1) The cyclic AMP and GMP systems
• 2) Calcium and calmodulin
• 3) Phosphoinositides and diacylglycerol
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10. HISTAMINE AGONIST
• Selective agonist for H1:2-methylhistamine
• Selective agonist forH2:4-methylhistamine
Dimaprit
impromidine
• Selective agonist for H3:(R) α-
methylhistamine
Imetit
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11. BETAHISTINE
• A histamine analogue and H1 receptor agonist
that serves as a vasodilator
• Betahistine has a very strong affinity for
histamine H3 receptors and a weak affinity for
histamine H1 receptors
Page 11

12. PHARMACOKINETICS
• Protein binding : Very low
• Metabolism : To 2-(2-aminoethyl)pyridine and
2-pyridylacetic acid
• Half-life: 3–4 hours
• Excretion : complete in the urine within 24
hours
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13. SIDE EFFECTS
• Low level of gastric side effects
• Nausea can be a side effect
• Decreased appetite, leading to weight loss
• Patients taking betahistine hydrochloride may
experience several hypersensitivity and
allergic reactions
• Headache
Page 13

14. THERAPEUTIC USES
• Betahistine hydrochloride is an antivertigo
drug
• For the treatment of Menieres disease
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15. Contd..
• Antagonists can bind to receptors but do not
initiate a change in cellular function.
• However, occupation of the receptor can
prevent the binding and actions of agonists.
• Antagonists are also referred to as blockers
Page 15

16. HISTAMINE ANTAGONIST
Page 16

17. CONT…
1. Physiologic antagonists:
Epinephrine has smooth muscle actions opposite to
histamine but by actiong on different types of receptors
2. Histamine release inhibitors:
Reduce immunologic release of histamine from mast cells
a) Mast cell stabilizers: Cromolyn and nedocromil
b) Beta 2 adrenergic agonists --- used in Bronchial
Asthma
3. Histamine receptor antagonists
Compounds that competitively block histamine, mainly
H1& H2 receptors.
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18. HISTAMINE ANTAGONIST
• Selective antagonist for H1:Mepyramide
Chlorpheniramine
• Selective antagonist for H2:Cimetidine
Ranitidine
• Selective antagonist for H3:Thioperamide
Impromidine
Clobenpropit
Page 18

19. Classification of H1-Receptor
Antagonists
A)FIRST GENERATION (Sedating , Shorter
DOA 4-6 hrs.)
Alkylamines
– Chlorpheniramine
– Brompheniramine
Ethylaminediamine:
– Tripelennamine
Ethanolamines:
– Diphenhydramine
– Dimenhydrinate
– Carbinoxamine Page 19

20. CONT..
Piperazines
– Cyclizine
– Meclizine
– Hydroxyzine
Phenothiazines derivatives
Promethazine HCl
Misc:
– Cyproheptadine
Page 20

21. CONT…
B)SECOND GENERATION
NON-SEDATING, LONGER DOA (12 -
24hrs)
Piperidines:
Fexofenadine
Miscellaneous
Cetirizine
Loratadine
Desoratadine
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22. MECHANISM & EFFECTS
1. H1-Receptor Blockade
2. Sedation
3. Antinausea and antiemetic actions: preventing
motion sickness
4. Antiparkinsonism effects
5. Anticholinoceptor action: atropine-like effects
on peripheral muscarinic receptors.
6. Adrenoceptor-blocking actions
7. Serotonin-blocking actions
8. Local anesthesia: block Na+-channel
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23. PHARMACOKINETICS
1- First Generation Agents:
Rapidly absorbed from the GIT
Widely distributed
Cross blood-brain barrier
Extensively metabolized by the cytochrome
P450 and metabolites are active and are excreted
by the kidney
Duration of action 4-6 hours
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24. PHARMACOKINETICS
2- Second Generation
Rapidly absorbed from the GIT
Widely distributed
Do not cross the blood-brain barrier (less
lipid soluble)
Elimination: Cetirizine (urine) and
fexofenadine (bile)
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25. THERAPEUTIC USES
• Allergic rhinitis
• Allergic conjunctivitis
• Allergic dermatological conditions (contact
dermatitis)
• Urticaria , Angioedema Diarrhea
Anaphylactic or anaphylactoid reactions—
adjunct only
• Nausea and vomiting
• Sedation
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26. SIDE EFFECTS & TOXICITY
• Sedation, drowsiness & euphoria
• Dryness of mouth, headache, dizziness, skin
rashes, distress , tremors , g.i. muscle
incordination
• Acute dose produce central excitation,
hallucination,convulsion,flushing, fever
• Death due to respiratory & cardiovascular
failure
• α-blocking actions may cause orthostatic
hypotension
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27. H2 RECEPTOR ANTAGONIST
• H2 receptors are widely present on parietal cell of
gastric mucosa . Their antagonists are
• Cimetidine
• Famotidine
• Oxmetidine
• Ranitidine
• Nizatidine
• SKF 93474
Page 27

28. PHARMACOKINETICS
• Absorbed orally well
• Oral bioavaibility of nizatidine-90% & with a
t1/2 of 1.5 hours ,where as ,others have 50%
because of first pass metabolism.
• Peak effect is reached within 2 hours
Excreted unchanged in kidney by tubular
secretion
Page 28

29. Contd…
• Fomotidine
• It has inverse agonistic action on H2 receptor &
half life is 2.5-3.5 hr.
• Oral bioavailability is 40-50 % and 70 %
excreted unchanged in urine
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30. THERAPEUTIC USES
• Peptic ulcer
• Duodenal ulcer
• Zollinger Ellison syndrome
Page 30

31. SIDE EFFECT & TOXIC EFFECT
• Skin rash
• Headache
• Gynecomastia
• Impotence
• Mental confusion
• Hepatotoxicity
Page 31

32. H3 ANTAGONIST
• Thioperamide
• Clobenpropit
• JNJ 5207852
• ABT 239
Page 32

33. Contd..
• Centrally acting H3 antagonists are under
study
• JNJ 5207852 increase wakefullness ,and
ABT-239 is being evaluated for cognitive
disorders
Page 33

34. H4 ANTAGONIST
• JNJ 7777120
• It block histamine induced chemotaxis in
mast cells & eosinophils
• Usefull in autoimmune inflammatory &
allergic disorders
• Nasal stuffness & blockage in allergic
rhinitis(Poor treatment by H1 & H2
antagonist, can be improve by H4
antagonist)
Page 34

35. Bradykinin
• Bradykinin formed by proteolytic cleavage of
circulating proteins termed kininogens.
• Synthesis and metabolism of bradykinin
Page 35

36. Kinins
Receptors, Actions & Therapy
• The activate B1, B2, B3 receptors linked to
PLC/A2
• Powerful Vasodilation→ decreased blood
pressure via B2 receptor stimulation (NO-
dependent)
• Increase in capillary permeability inducing
edema.
It produces inflammation & analgesia (B2)
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37. Pharmacological actions:
– vasodilatation
– increased vascular permeability
– stimulation of pain nerve endings
– stimulation of epithelial ion transport and fluid
secretion in airways and gastrointestinal tract
– contraction of intestinal and uterine smooth
muscle.
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38. CONT..
• Cardiac stimulation:
Compensatory indirect & direct tachycardia &
increase in cardiac output
• It produces coronary vasodilation
Bradykinin has a cardiac anti-ischemic effect,
inhibited by B2 antagonists (NO & PI2
dependent)
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39. Kinins
Actions & Therapy
• Kinins produce broncho-constriction & itching
in respiratory system .
• Therapeutic Use:
No current use of kinin analogues
Increased bradykinin is possibly involved in
the therapeutic efficiency & cough produced
by ACEIs
Page 39

40. kallekrein inhibitor
• Aprotinin (Trasylolol), a kallekrein inhibitor,
used in treatment of acute pancreatitis,
carcinoid syndrome & hyperfibrinolysis.
• Ecallantide :is a human plasma kallikrein
inhibitor injection for subcutaneous use in
inflammation.
Page 40

41. Bradykinin Antagonist
• Deltibant : It is a novel Bradykinin Antagonist used in
treatment of Severe Systemic Inflammatory Response
Syndrome and Sepsis.
• Icatibant :It is a synthetic decapeptide functioning as
a potent,competative antagonist of the bradykinin 2
receptor
• used in management of Heriditary angioedema
Page 41

42. pharmacokinetics
 Given by subcutaneous injection 3ml (30mg), half life1-
2 hours
 Rapid onset usually within an hour, systemic side effects
rare and local side effects at site of injection are common
but transient
 Drug interaction :
 ACE inhibitors like captopril block B(2) receptor
desensitization, thereby potentiating bradykinin
beyond blocking its hydrolysis.
Page 42

43. REFERENCES
• Essentials of medical pharmacology;KD
Tripathi;sixth edition;2008;published by
Jaypee brothers;page no:135-144
• Rang and Dale’s pharmacology;H.P.Rang,
M.M.Dale; sixth edition;2008;published by
Churchill Livingstone;
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44. Thank you !!!!
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45. Page 45

46. • Betahistine comes in tablet form and is
taken orally.
• It is rapidly and completely absorbed.
• The mean plasma half-life is 3-4 hours
• Excretion is virtually complete in the urine
within 24 hours.
• Very low Plasma protein binding
• Betahistine is transformed into
aminoethylpyridine & hydroxyethylpyridine
& excreted with the urine as pyridylacetic
acid
Page 46

47. Impromidine
• Potent and selective histamine H2
receptor agonist
• The role of histamine in the control of
gastric acid secretion and blood flow in
both healthy man and in patients with
peptic ulcer disease
Page 47

48. CONTRAINDICATIONS
• Betahistine is contraindicated for people
with peptic ulcers or tumours of the
adrenal gland(pheochromocytoma)
• People with bronchial asthma should be
closely monitored.
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49. Page 49