histamine & bradykinin
TRANSCRIPT
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AUTOCOIDS : HISTAMINE AND BRADYKININ
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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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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
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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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• 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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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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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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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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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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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
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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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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
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THERAPEUTIC USES
• Betahistine hydrochloride is an antivertigo drug
• For the treatment of Menieres disease
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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
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HISTAMINE ANTAGONIST
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CONT…
1. Physiologic antagonists: Epinephrine has smooth muscle actions opposite to
histamine but by actiong on different types of receptors2. Histamine release inhibitors:Reduce immunologic release of histamine from mast cellsa) Mast cell stabilizers: Cromolyn and nedocromilb) Beta 2 adrenergic agonists --- used in Bronchial
Asthma3. Histamine receptor antagonists
Compounds that competitively block histamine, mainly H1& H2 receptors.
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HISTAMINE ANTAGONIST
• Selective antagonist for H1:Mepyramide
Chlorpheniramine• Selective antagonist for H2:Cimetidine
Ranitidine • Selective antagonist for H3:Thioperamide
Impromidine
Clobenpropit
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Classification of H1-Receptor Antagonists
A)FIRST GENERATION (Sedating , Shorter DOA 4-6 hrs.)
Alkylamines –Chlorpheniramine–Brompheniramine
Ethylaminediamine: – Tripelennamine
Ethanolamines:– Diphenhydramine – Dimenhydrinate– Carbinoxamine
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CONT..
Piperazines–Cyclizine –Meclizine –Hydroxyzine
Phenothiazines derivatives
Promethazine HCl
Misc:– Cyproheptadine
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CONT…
B)SECOND GENERATIONNON-SEDATING, LONGER DOA (12 -
24hrs)
Piperidines:
Fexofenadine
Miscellaneous
Cetirizine
Loratadine
Desoratadine
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MECHANISM & EFFECTS
1. H1-Receptor Blockade 2. Sedation3. Antinausea and antiemetic actions: preventing
motion sickness
4. Antiparkinsonism effects5. Anticholinoceptor action: atropine-like effects
on peripheral muscarinic receptors.
6. Adrenoceptor-blocking actions7. Serotonin-blocking actions8. Local anesthesia: block Na+-channel
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PHARMACOKINETICS
1- First Generation Agents:Rapidly absorbed from the GITWidely distributedCross blood-brain barrier
Extensively metabolized by the cytochrome P450 and metabolites are active and are excreted by the kidneyDuration of action 4-6 hours
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PHARMACOKINETICS
2- Second GenerationRapidly absorbed from the GITWidely distributedDo not cross the blood-brain barrier (less
lipid soluble)Elimination: Cetirizine (urine) and
fexofenadine (bile)
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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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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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H2 RECEPTOR ANTAGONIST
• H2 receptors are widely present on parietal cell of gastric mucosa . Their antagonists are
• Cimetidine • Famotidine• Oxmetidine• Ranitidine• Nizatidine • SKF 93474
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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
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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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THERAPEUTIC USES
• Peptic ulcer• Duodenal ulcer• Zollinger Ellison syndrome
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SIDE EFFECT & TOXIC EFFECT
• Skin rash• Headache• Gynecomastia• Impotence• Mental confusion• Hepatotoxicity
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H3 ANTAGONIST
• Thioperamide• Clobenpropit• JNJ 5207852• ABT 239
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Contd..
• Centrally acting H3 antagonists are under study
• JNJ 5207852 increase wakefullness ,and ABT-239 is being evaluated for cognitive disorders
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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)
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Bradykinin
• Bradykinin formed by proteolytic cleavage of circulating proteins termed kininogens.
• Synthesis and metabolism of bradykinin
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KininsReceptors, 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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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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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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KininsActions & Therapy
• Kinins produce broncho-constriction & itching in respiratory system .
• Therapeutic Use:No current use of kinin analoguesIncreased bradykinin is possibly involved in
the therapeutic efficiency & cough produced by ACEIs
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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.
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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
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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.
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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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Thank you !!!!
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• 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
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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
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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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