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  2. 2. • The term derived from Greek word Autos= Self Akoid (Akos)= Medicinal agent or Remedy
  3. 3. • Produced by wide variety of cells in the body and released locally • Act at site or near the site of their release so called as local hormones
  4. 4. Classical autacoids are • Amine autacoids:- • Histamine (H), • 5- Hydroxy tryptamine (Serotonin, 5HT) • Lipid derived autacoids:- • Prostaglandins (PG) , • Leuckotrines (LT), • Platelet activating factors (PAF) • Peptide hormones :- • Plasmakinin (Bradykinin,Kalliidin), • Angiotensin (AT). Others:- VIP Gastrin Somatostatin Cytokines
  5. 5. HISTAMINE • Histamine tissue amine (Histo=Tissue), also called as biogenic amine • It was identified in 1907 • Pharmacology studied by Dales 20th century. N N NH2 H 1 2 3 45 Histamine Heterocyclic amine
  6. 6. • Naturally occurring imidazole derivative (ß- imidazole ethylamine) • synthesized locally & Storage granules of mast cells. • Tissues rich in histamine are skin, Intestinal mucosa, Lungs, Liver and placenta • Non mast cell histamine occurs in brain, epidermis, gastric mucosa.
  7. 7. L-Histidine Synthesis Histamine Histidine de carbosylase α Fluromethyl hisitidine + Gastrin, Nicotine, stress L-A.A decarboxylase Stored in mast cells N- Methyl histamine Imidazole N- methyl transferees Di amine oxidase Imidazole acetic acid MAO-B Ribose N- Methyl imidazole acetic acid Imidazole acetic acid riboside
  8. 8. Storage • In mast cell histamine (+ve) and get ionically complexed with acidic –ve protein and heparin high molecular weight. • Bounded form is biologically inactive • Non mast cells stored in histaminocytes in the stomach and histaminergic neuron in brain. Histamine Heparin/ protein
  9. 9. Release • The stored histamine from the mast cells released by 2 ways mechanisms. – Immunological release (anaphylactic) – Chemical mediators (anaphylactoid)
  10. 10. Immunological release Allergen enter (Forgein body) Immunological reaction (AG:AB Complex formation) Circulation in blood Basophiles, Neutrophilis engulf Cause neutralization Contd.,
  11. 11. Whenever same allergen re-exposed Activation of AG:AB complex Reacts with mast cells (Degranulation of mast cells) Spasmogens release (Like Histamine,5HT,PGs,LT4, Cytokines) Mast Cell Degranulation
  12. 12. Chemical Release • Chemical mediators: Chemical injures mast cell (Granules exposed)
  13. 13. Drugs or chemicals release histamine • Morphine Hydralazine • d-TC Dextran • Pentamidine Bilesalts • Trimethophan Detergents • Tolazoline Substance –P • Polymyxin –B Bradykinin • SCh, component 48/80 • Polyvinylprolidone (PVP)
  14. 14. • Drugs decrease release of Histamine:- – ß-Agonists – Mast cell stabilizers – Negative feed back control on mast cells.
  15. 15. Histamine receptor classification • Histamine receptor were classified by Asch and Schild (1966) into H1, H2. • H3 receptor was postulated by Schwartz 1983, confirmed by Arang in 1987. • H4 receptors also present , but clinical less important.
  16. 16. Receptor Distribution Post receptor mechanism H1 Post synaptic a)Smooth muscle ( Intestine, bronchi, Uterus) b) Blood vessels c) CNS d) Sensory nerve ending e) Adrenal medulla Gq IP3, DAG Release Ca+ PKC activation H2 Post synaptic a) Gastric gland b) Blood vessels c) Heart d) Brain Gq IP3, DAG Release Ca+ PKC activation H3 Pre synaptic a) Brain presynaptic b) Lung, Spleen, Gastric mucosa c )Blood vessels Gi CAMP, Ca+2 influx , opening K+ channels H4 a) Eosinophils b) Neutrophils CD4T Cells. Gi CAMP, Ca+2 influx , opening K+ channels
  17. 17. Pharmacological actions H1 mediated pharmacological actions:- Sensory nerve endings:- Powerful stimulant on sensory nerve endings especially those mediating pain and itching. H1 mediated effect is an important component of utricarial response to insect bites and stings.
  18. 18. Smooth muscle:-Bronchial:- Histamine cause broncho constriction. • GIT:-cause contraction of intestinal smooth muscle result in intestinal cramps and diarrhoea. • Uterus:- spasmodic contractions of uterus and ileum • Glands:-Increases secretions of endocrine glands in bronchioles, pancreas, salivary and lacrimal glands.
  19. 19. • Autonomic ganglia:- Stimulates, cause release adrenaline. • CNS:- Histamine does not penetrate BBB. No central effect. • Intra cerebroventricular administration produces BP, cardiac stimulation, behavioral arousal, hypothermia, vomiting and ADH release. • H1 mediate the maintenance of wakefulness.
  20. 20. H2 mediated action:- • powerful stimulant of gastric acid on activation of H2 receptors on gastric cells. • It associated with cAMP & intracellular Ca+2 concentration H3 mediated action:- CNS and ANS , presynaptic H3 receptors act as feed back inhibitor for the release of histamine, NE and Ach. • H3 receptor activation by histamine, it inhibits gastric acid release and block inflammatory process.
  21. 21. H1 and H2 actions:- • Stimulation of both receptor cause dilatation of arterioles and post capillary venules. Result remarkable fall in BP. • Vasodilation is mediated by the release of Endothelium Derived Relaxing Factor (EDRF). • Dilatation of post capillary venules cause headache due to stretching of sensory nerve fibers around the cranial arteries.
  22. 22. • Histamine inj intradermally, atypical triple response is produced • It characterized by an immediate redding of skin (Flush) , formation of edematous patch (Wheal) and a red irregular halo surround the wheal (Flare) Flare Wheal Flush
  23. 23. • Flush:- Due to vasodilatation • Wheal:-Exudation of fluid from capillaries and venules due to inc. permeability • Flare: Consequence of axon reflex causing vasodilatation through the release of vasodilatory neuromediators.
  24. 24. CVS:- + ve chronotrophic (H2) and positive inotropic effect (H1+ H2) on heart • These effect occurs reflexly due to fall in BP.
  25. 25. Receptor Distribution Function H1 Post synaptic a)Smooth muscle ( Intestine, bronchi, Uterus) b) Blood vessels c) CNS d) Sensory nerve ending e) Adrenal medulla Contraction Dilatation NT Stimulation( Pain) Release catecholamines H2 Post synaptic a) Gastric gland b) Blood vessels c) Heart d) Brain Inc. acid secretion Dilatation Atria +ve chronctrophic Ventricle +ve inotrophic NT H3 Pre synaptic a) Brain presynaptic b) Lung, Spleen, Gastric mucosa c )Blood vessels Inhibitor dec.Ach, NE, H, release Dilatation H4 a) Eosinophils b) Neutrophils CD4T Cells.
  26. 26. Histamine antagonists • Histamine released in the body reduced by 3ways. • Release inhibitors:-Disodium cromoglycate, Nedocromic sodium prevent the degranulation of mast cell. • Prevent the release of histamine & other inflammatory mediators from mast cells. • Iodoxasmide, Tromethamine are newer mast cell stabilizers. • Ketotifen fumarate H1 blcoker + Mast cell stabilizer
  27. 27. Physiological antagonists:- Ex:- Epinephrine It have smooth muscle action opp. to histamine; but they acts at different receptors. Histamine receptor antagonists: These are antagonize the effect of histamine by competitively blocking the receptors.
  28. 28. H1 antagonists • Called as conventional anti histamines. (Old) • These are introduced at 1930s. • These are conveniently divided into 1st & 2nd generations • These group are distinguished by the relatively strong side effects most 1st generations.
  29. 29. 1st generation 2nd generations • Short to intermediate action • BBB cross • Sedative action • Produce anti muscurnic side effects • Also block auonomic receptors • Cheap • Long acting • Poor penetration • No • No • No • Relatively expensive
  30. 30. Name Adult dose Oral in mg Duration of action (hr) Anti cholinergic activity Uses Highly sedative Dimenhydrinate Diphenhydramine Doxylamine Hydroxyzine Promethazine 25-50 25-50 15-25 25-50 10-25 4-6 4-6 4-6 4-6 +++ +++ ++ +++ +++ Anti motion sickness activity Anti motion sickness activity Sleep aid Antiemetic Antiemetic Moderate sedative Pyralamine Tripelennamine Cyproheptadine Carbinoxamine(Clistin) Clemastine 25-50 25-50 4 4-8 2-6 4-6 4-6 4-6 4-6 12 + + ++ +++ +++ Sleep aid - Anti serotonin effects - - Mild sedatives Cyclizine Meclizine Chlorphenaramine Dexchlorphenaramine Triprolidine 25-50 25-50 4-8 4-6 2.5-65 4-6 12-20 4-6 4-6 4-6 ++ ++ + + + - - - Anti motion sickness activity -
  31. 31. Pharmacological actions • Antagonism of histamine:- Blocks • Histamine induced broncho constriction • Contraction of intestinal other smooth muscle • Triple response. • Fall in BP is blocked, but H2 antagonists are required. • Release of Adr form adrenal medulla in response to histamine is abolished.
  32. 32. Anti allergic action:- – Immediate hypersensitivity (type I) are suppressed. – Itching, angioedema are controlled. – Rhinitis, common cold CNS:- 1st generation anti histamines produce variable degree of CNS depression. – Dec. alertness – Inc. reaction time - 2nd generation antihistamine are poor penetration to BBB so no sedative action.
  33. 33. • Motion sickness:- – Some antihistamine drugs acts Labyrinthine (H1) and decrease motion sickness (Dimenhydrinate, Diphenhydramine) • Chlorpromazine (2-5mg ), Diphenhydramine(15-25mg) and promethazine(15-25mg) are added to antitussive agents. • Doxylamine is used to prevent nausea and vomiting due to pregnancy.
  34. 34. Pharmacokinetics :- • Well absorbed by oral and parental routes. • Metabolized in liver by microsomal system • Wide distribution and enter brain • Repeated use induce their own metabolism Side effects:- Sedation, diminished alteration and concentration, light headache, motor in coordination, fatigue, tendency to fall sleep are most common. • Acute overdose produce central excitation, tremors, convolutions, flushing, hypotension and fever. • Death is due to respiratory CVS failure.
  35. 35. 2nd generation (1980) Name Adult dose Oral in mg Duration of action (hr) Anti cholinergic activity Remarks Astemizole Fexofenadine Cetrizine Loratadine Desloratadine Levocetrizine Ebastine 10mg OD 120-180mg 10mg OD 10mg OD 5mg OD 5mg OD 10mg 24 12 12-24 24 24 24 - - - - - - - Anti inflammatory action
  36. 36. • Cetrizine is an active metabolite of hydroxyzine (1st G) • Levo cetrizine is L-isomer of cetrizine more potent less sedative . • Cetrizine:- poorly penetrate to BBB • Inhibits release of histamine and cytotoxic mediators from platelets and eosinophil chemotaxis during 2nd phase of allergic response • Once daily , Elimination t1/2 7-10hr • It is indicated for upper respiratory tract.
  37. 37. Fexofenadine • dose not cross BBB • free anti cholinergic side effect. • Rapidly absorbed, excreted in urine and bile. • t1/2 11-16hr, duration of action is 24hr. Astemizole:- • 97% plasma protein bound • t1/2 20hr. Its metabolite t1/2 is 12-19days • Excretion in faeces. • Used for maintenance therapy.
  38. 38. Uses • Allergic reactions:- effectively control – immediately type of allergies like itching, urticaria, – Allergic conjunctivitis – Angioedema (DOC glucocorti). – lay fever (2nd G), – symptomatic relief in insect bite • Pruritides:- first choice of drugs for idopathic pruritides. • Common cold:- produce symptomatic relief by sedative and anticholinergic actions
  39. 39. Motion sickness:- Promethazine, Dimenhydrinate useful for prophylaxis. • Used in morning sickness, drug induced and post operative vomiting. Preanaesthetic medication • promethazine used for its anticholinergic and sedative action (specially in childrens) Cough • Chlorpromazine , Diphenhydramine and promethazine are added to antitussive agents. Motion Vomiting centre M,H1 Vestibular apparatus M,H1 Cerebellum Anti cholinergic activity
  40. 40. • Parkinsonism • promethazine used due to anticholinergic activity and sedative action. • Acute muscle dystonia • parentral promethazine or hydroxyzine. • As a sedative, hypnotic, anxiolytic • CNS depressant action • Vertigo • Cinnarizine widely used • used to control mild blood transfusion and saline infusion reactions like rigors and chills and adjunct in anaphylaxis.
  41. 41. H2 antagonists These are over the counter drugs OTC • Mechanism of action:- competitively inhibit H2 receptors cells and suppress basal and food stimulated acid secretions. • They block the actions of histamine released from ECL • They inhibit stimulation of parietal cells. • Reduced cAMP levels
  42. 42. Clinical uses: • Peptic ulcer:- – H2 blockers are one of the commonly used drugs is peptic ulcer. – H2 blockers produce sympathetic relief within days and ulcer healing with in weeks. • Zollinger Ellison syndrome: – PPIs are drug of choice, H2 blockers are used to control hypersecretions. • GERD: – PPIs are used. H2 blcokers also effective. • Stress ulcers:- H2 blockers or PPIs are used
  43. 43. • Expect astemazole all are competitive blcokers • Antihistamines absorbed from gut. • Metabolised by liver • Metabolites are long half life