histamine and bradykinin

AUTOCOIDS : HISTAMINE AND BRADYKININ

PRESENTED BY : CHAUDHARY NEHADEPARTMENT OF PHARMACOLOGY

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

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

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)

• 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

• Injected intradermally, histamine causes the 'triple response':

• reddening (local vasodilatation),• wheal (direct action on blood vessels) • flare (from an 'axon' reflex in sensory nerves

releasing a peptide mediator)

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

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

HISTAMINE AGONIST

• Selective agonist for H1:2-methylhistamine• Selective agonist forH2:4-methylhistamine

Dimaprit

impromidine• Selective agonist for H3:(R) α-

methylhistamine

Imetit

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

PHARMACOKINETIC

• 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

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

THERAPEUTIC USES

• Betahistine hydrochloride is an antivertigo drug

• For the treatment of Menieres disease

• 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

HISTAMINE ANTAGONIST

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.

HISTAMINE ANTAGONIST

• Selective antagonist for H1:Mepyramide

Chlorpheniramine• Selective antagonist for H2:Cimetidine

Ranitidine • Selective antagonist for H3:Thioperamide

Impromidine

Clobenpropit

Classification of H1-Receptor Antagonists

A)FIRST GENERATION (Sedating , Shorter DOA 4-6 hrs.)

Alkylamines –Chlorpheniramine–Brompheniramine

Ethylaminediamine: – Tripelennamine

Ethanolamines:– Diphenhydramine – Dimenhydrinate– Carbinoxamine

CONT..

Piperazines–Cyclizine –Meclizine –Hydroxyzine

Phenothiazines derivatives

Promethazine HCl

Misc:– Cyproheptadine

CONT…

B)SECOND GENERATIONNON-SEDATING, LONGER DOA (12 -

24hrs)

Piperidines:

Fexofenadine

Miscellaneous

Cetirizine

Loratadine

Desoratadine

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

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

PHARMACOKINETICS

2- Second GenerationRapidly absorbed from the GITWidely distributedDo not cross the blood-brain barrier (less

lipid soluble)Elimination: Cetirizine (urine) and

fexofenadine (bile)

THERAPEUTIC USES• Allergic rhinitis• Allergic conjunctivitis• Allergic dermatological conditions (contact

dermatitis)• Urticaria , Angioedema Diarrhea

Anaphylactic or anaphylactoid reactions—adjunct only

• Nausea and vomiting • Sedation

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

H2 RECEPTOR ANTAGONIST

• Cimetidine • Famotidine• Oxmetidine• Ranitidine• Nizatidine • SKF 93474

PHARMACOKINETIC

• Absorbed orally well• Oral bioavaibility of nizatidine-90% ,

where as ,others have 50% because of first pass metabolism

Peak effect is reached within 2 hours

Excreted unchanged in kidney by tubular secretion

THERAPEUTIC USES

• Peptic ulcer• Duodenal ulcer• Zolliger ellison syndrome

SIDE EFFECT & TOXIC EFFECT

• Skin rash• Headache• Gynecomastia• Impotence• Mental confusion• Hepatotoxicity

Bradykinin

• Bradykinin formed by proteolytic cleavage of circulating proteins termed kininogens.

• Synthesis and metabolism of bradykinin

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)

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)

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.

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

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.

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• 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.

REFERENCES

• Essentials of medical pharmacology;KD Thripathi;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;

Thank you !!!!

• 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

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

CONTRAINDICATIONS

• Betahistine is contraindicated for people with peptic ulcers or tumours of the adrenal gland(pheochromocytoma)

• People with bronchial asthma should be closely monitored.

histamine and bradykinin

Health & Medicine