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Pharma chemmediators

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  • 1. Chemical Mediators in Health & Disease Ma. Minda Luz M. Manuguid, M.D.
  • 2. Inflammatory Mediators & Antagonists Autacoids  Histamine  Serotonin  Angiotensin  Prostanoids Eicosanoids  Prostaglandins  Leukotrienes Chemokines & Cytokines
  • 3. Autacoids Autacoids – “self remedy” – derived from Gr. autos – “self” & akos – medicinal agent or “remedy” diverse group of endogenous mediators involved in homeostasis & in inflammation occur in minute amounts distinct biologic / pharmacologic activity act as “local hormones” mediators in aging, hypertension, allergy, asthma, acid peptic disease, anxiety, depression, hyperemesis
  • 4. Receptors Histamine: H1, H2, H3 Bradykinin: B1, B2 Serotonin: 5HT1A / 1B/ 1D/ 1E/ 1F/ 2A/ 2B/ 2C/ 3/ 4/ 5a/ 5b/ 6/ 7 Angiotensin: AT1A, AT1B, AT2 Prostanoids: DP, EP1, EP2, EP3, EP4, FP, IP, TP
  • 5. Histamine  actions:  vasodilatation;  ↑capillary permeability  mediation of cellular responses, including allergic & inflammatory reactions, gastric acid secretion  pain & itch mediator  bronchial & intestinal smooth muscle contraction  location: occurs in practically all tissues, with high amounts in the lungs, skin, GIT; stored in basophils & mast cells
  • 6. Histamine receptors receptor agonist antagonist H1 (~mine) 2-(m- fluorophenyl)- histamine Chlorpheniramine, Diphenhydramine, Meclizine(Bonamine ) H2 (~dine) 4-methyl histamine Cimetidine, Ranitidine, Famotidine H3 ⍺-methyl histamine Thioperamide
  • 7. clinical use of Anti-histamines H1 blockers –  anti-allergy,  anti-inflammatory,  anti-motion sickness.  common side effect: sedation H2 blockers – reduce secretion of gastric acid.  in peptic ulcer disease
  • 8. Serotonin  sources: vertebrates, molluscs, pineapple, banana, nuts, stings, venom; in man – 80% in GI chromaffin cells, rest in platelets & CNS  functions:  central chemical transmitter for tryptominergic neurons in the brain;  precursor for melatonin;  regulation of GI motility by increasing tone & peristalsis;  hemostasis – vasospasm & platelet activation/aggregation;  contraction of smooth muscle in the uterus, bronchi  synthesis: Tryptophan (tryptophan 5- hydroxylase)  5hydroxytryptophan(L-amino- decarboxylase) 5HydroxyTryptamine (5HT, Serotonin)
  • 9. 5HT receptor subtypes & effector systems recepto r mechanism effect 5HT1A Adenylyl cyclase stimulation direct vasodilatation & inotropic effect 5HT1A B 5HT1D Adenylyl cyclase inhibition inhibition of NE release 5HT1C Phospholipase C activation indirect vasodilation via EDRF release 5HT2 Phospholipase C stimulation vasoconstriction, ↑intracellular Calcium 5HT3 Calcium channel depolarization of
  • 10. 5HT Antagonists Ketanserin – blocks 5HT2 receptors –  lowers blood pressure by blocking 5HT-induced contraction of vascular smooth muscle & platelet aggregation;  minor side effects: sedation, dry mouth, dizziness, nausea;  clinical application: treatment of HTN & vasospastic disorders Methysergide (1-methy-d-lysergic acid butanolamide) -  inhibits vasoconstrictor & pressor effects of 5HT on vascular smooth muscle  clinical use: prophylaxis for migraine & vascular headaches
  • 11. Kinins  synthesis: HMWK & LMWK are acted upon by plasma & tissue Kallikrein to produce Bradykinin & Kallidin  metabolism: half-life=15 sec; inactivated by kininase or converting enzyme  functions:  inflammatory mediators  (also in rhinitis, hereditary angioneurotic edema, gout, endotoxic shock, DIC);  nociception;  composition/volume of urine;  BP regulation;  fetal to neonatal adjustment
  • 12. Receptors & effector systems B1 Contraction of arteries & most veins pain B2 Arteriolar vasodilation via EDRF or H release; contraction of endothelial cells in venules ↑Capillary permeability, edema B1 & B2 Contraction of bronchial smooth muscle; stimulate nerve endings pain
  • 13. KKK Antagonists Receptor antagonists  Non-selective: blocks both B1 & B2 Selective: blocks B1 effects Kallikrein inhibitors  Aprotinin
  • 14. the Renin – Angiotensin system  precursor: Angiotensinogen  enzyme: Renin  Angiotensin I  converting enzyme: Kininase  Angiotensin II – arteriolar vasoconstriction ↑BP  aminopeptidase  Angiotensin III  angiotensinase  inactive peptide fragments
  • 15. Angiotensin II actions  stimulates synthesis & secretion of Aldosterone  stimulates the heart & sympathetic nervous system  increases ADH secretion  stimulates thirst center  powerful vasoconstrictor  increases BP
  • 16. Angiotensin Antagonists ACE inhibitors –  Captopril  Enalapril  Lisinopril Angiotensin II receptor blockers (ARBs)  Losartan  Valsartan  Temisartan
  • 17. Eicosanoids  def. unsaturated fatty acid derivatives locally synthesized & released as needed, widely distributed in the body, very short duration of action, rapidly metabolized to inactive products  receptors: DP1, DP2 (PGD2); EP1, EP2, EP3, EP4 (PGE2); FP (PGF2); IP (PGI2); TP (TXA2)
  • 18. Synthesis of Eicosanoids Phospholipids  Phospholipase A2 Arachidonic acid  Lipooxygenase ▪ Cyclooxygenase Leukotrienes Prostacyclin Prostaglandins Thromboxane
  • 19. Eicosanoids Mechanism of action – activation of cell surface receptors that are coupled by G proteins to adenylyl cyclase (producing CAMP) or to phosphatidylinositol (producing IP3 & DAG 2nd messengers) Physiologic effects:  LTB4 – chemotactic factor  PGE2 & PGI – vasodilators  PGE2 & PGF2a – induce labor  PGE1 & derivatives – smooth muscle relaxation, protect gastric mucosa
  • 20. Therapeutic uses of Eicosanoids Eicosanoi d effects clinical uses PGE2 & PGF2a increase uterine activity induction of labor / abortion PGE1 Relax vascular smooth muscle Maintain a patent ductus arteriosus PGE bronchodilates PGF Bronchoconstricts
  • 21. Clinical uses of Eicosanoids eicosanoi d effects clinical use PGE & PGI2 Decrease gastric acid secretion; sensitize afferent nerve endings in pain Misoprostol – to reduce gastric ulcerations from NSAIDS PGI2 Vasodilation Tx of 1º pulmonary HTN TXA2 & PGI2 Control of microcirculation Alprostadi vasodilaton Induce penile
  • 22. Clinical Application of Autacoids autacoid agonist antagonist enzyme inhibitor Histamine Allergy diagnostic challenge Anti-allergy, Sedation, ulcer Rx Serotonin Migraine therapy Appetite stimulation, GERD, HTN, depression, asthma Angiotensin Hypertension hypertension Prostanoids (PGE, PGF) Ulcer Rx, stimulation of labor Anti-inflammatory, anti-platelet, anti- asthma
  • 23. Chemokines & Cytokines Chemokines – small proteins (90-130 AAs) containing 4 conserved Cysteines  CC chemokines: 2 consecutive cysteine pairs  CXC chemokines: 2 cysteine pairs separated by other AA  over 50, produced by a wide variety of cell types  major regulators of Leukocyte traffic; chemotactic; bind to proteoglycans on the endothelial cell surface & within the extracellular matrix & set up chemokine gradients for the migrating leukocytes to follow
  • 24. Chemokines & receptors Examples of Chemokines:  IL8 – interleukin 8  RANTES – regulated upon activation normal T cell expressed & secreted  MCP – monocyte chemoattractant protein “serpentine receptors” – polypeptide chain “snakes through” the cell membrane with 7 transmembrane segments  CCR – bind CC chemokines  CXCR – bind CXC chemokines
  • 25. Cytokines Soluble factors released by lymphocytes & monocytes : Interferons & Interleukins  have potent pro-inflammatory properties  IL 1, IL 6, TNF-⍺ : endogenous pyrogens
  • 26. Analgesics/Anti-inflammatory agents & Antipyretics Aspirin (ASA) NSAIDS: non-steroidal anti-inflammatory agents  Ibuprofen  Naproxen  Indomethacin Acetaminophen
  • 27. Aspirin Acetyl salicylic acid  irreversibly inhibits cyclooxygenase  effects: ↓manifestations of inflammation; analgesia; ↓body temperature  pharmacokinetics: readily absorbed; hydrolyzed in blood & tissues to Acetate & Salicylate (the active molecule);  elimination: low-dose – 1st order (half-life 3-5 h); high dose – zero order (half-life >15h)  excretion: kidney
  • 28. Aspirin  clinical use:  low dose = < 300mg/d = anti-platelet aggregation  intermediate = 300-2400 mg/d = antipyretic, analgesic  high dose = 2400-4000 mg/d = anti-inflammatory  toxicity:  G I disturbances  ↑risk of bleeding  ↓prothrombin synthesis  tinnitus, vertigo, hyperventilation, respiratory alkalosis
  • 29. Aspirin  hypersensitivity reactions  anaphylaxis  special precaution: use in children with viral infection is associated with Reye’s syndrome – hepatic fatty degeneration & encephalopathy  overdose: metabolic acidosis; dehydration; hyperthermia; collapse; coma; death  Tx of overdose: dialysis
  • 30. Aspirin Therapeutic dose: 0.5-1.0 gm./day Lethal dose: 2-4 gm./day in children 10-30 gm./day in adults Acute toxicity: initial alkalosis--- fluid & electrolyte imbalance--- metabolic acidosis--- death Chronic toxicity: (3 gm/day): dizziness, nausea, vomiting, diarrhea, drowsiness, hallucinations, convulsions, coma Known effects: analgesic; anti-platelet aggregation; gastric irritant--- acute erosive gastritis Unpredictable ADRs: hypersensitivity: rashes, urticaria, exfoliative dermatoses
  • 31. NSAIDs  representative drugs:  Ibuprofen – low potency; short acting; half-life = 2 hrs  Naproxen – intermediate potency;  Indomethacin – high potency; long-acting; half-life = 12-24 hrs  pharmacokinetics: good absorption after oral intake; excretion – kidney  toxicity:  GI disturbances, ↑ risk of bleeding;  significant risk of renal damage at high therapeutic dose, esp. in the presence of pre-existing renal disease
  • 32. Acetaminophen / Paracetamol  mechanism of action: unclear; weak cyclooxygenase inhibition in peripheral tissues, more effective in CNS  effects: antipyretic, analgesic. (no significant anti-platelet aggregation or anti- inflammatory effects)  pharmacokinetics: well-absorbed & metabolized in the liver; half-life = 2-3 hrs; unaffected by renal disease
  • 33. Acetaminophen  clinical use:  analgesic;  antipyretic;  Aspirin substitute in hypersensitivity cases & in children with viral infection  toxicity:  negligible in therapeutic dosage;  overdose  hepatotoxicity (Use with caution in Liver impairment)
  • 34. Acetaminophen therapeutic dose: 0.5 gm q 4 hrs.(up to 3gm/day) toxic dose: 15-25 gm;  toxicity: nausea, vomiting, diarrhea; shock; hepatic injury pathology: hepatic necrosis; renal/myocardial damage