Autocrine-Paracrine System Pharmacology PDF

Autocrine – Paracrine System PHARMACOLOGY OF HIsTAMINE  Inflammation Chemical mediator Gastric acid secretion  Basophil Mast cells brain Enterochromaffin...

Autocrine – Paracrine System PHARMACOLOGY OF HIsTAMINE  Inflammation Chemical mediator Gastric acid secretion  Basophil Mast cells brain Enterochromaffin cells Skin Lungs 1 2 3 Morphine Venoms PHARMACOLOGICAL MODULATION OF HISTAMINE: PHARMACOLOGICAL ANTAGONISM OF HISTAMINE 1. Adrenaline is the Physiological Antagonist. 2. H1 and H2 blockers compete with histamine at its receptors. 3. Corticosteroids suppress the effects of antigen- antibody reaction and have anti-allergic, anti- inflammatory action.  H 1-blockers Antihistaminics Diphenhydramine  1st Generation 2nd Generation Effective, inexpensive Cross BBB Central antimuscarinic Anti motion sickness No sedation Cross BBB (sedation) Competitive Reversible Bronchoconstriction Pain & Itching Other actions (Not related to the anti-allergic action) Anti-emetic Sedation Anti-motion sickness Promethazine 1st generation Diphenhydramine Dimenhydrinate Cyclizine,Miclizine Other actions (Not related to the anti-allergic action) Anticholinergic α- blocking action Promethazine  Generations First Second Chlorpheniramine Cetrizine Examples Diphenhydramine Loratidine Block of Actions on other muscarinic and No receptors alpha-adrenergic No receptors Pharmacokinetics: Cross of BBB Yes No/minimal Pharmacodynamic  Anti-allergic Yes Yes  Sedation Yes Less sedating  Antiemetic Yes No  Anti-motion Yes No sickness  Histamine is the Drugs 1. Allergic conditions principle mediators Of Choice Nor effective Allergic Allergic rhinitis Urticaria Conjunctivitis Anaphylaxis Adrenaline 2. Motion sickness and nausea Diphenhydramine Dimenhydrinate Cyclizine Meclizine Most effective They prevent or diminish for nausea mediated by Prevention of symptoms chemoreceptor of motion sickness and vestibular pathway  Off-label treatment of insomnia with first-generation antihistamines 3.Somnificient (Sedation) OTC Diphenhydramine R/ Insomnia 4. Vertigo, vestibular disturbance and Meniere’s disease Antihistaminic 5. Common cold Anticolinergic 1. Sedation. 2. Anticholinergic manifestations. 3. GIT upsets: nausea, constipation or diarrhea 4. Teratogenic effects Pharmacology of serotonin  Serotonin (known as 5- hydroxytryptamine [5-HT]) is an endogenous amine that has no clinical application as a drug. 5-HT is formed from the amino acid L- tryptophan Serotonin receptors & actions: 5-HT1A receptor: located in the brain involved in the control of mood (inhibit serotonin liberation). 5HT2A receptor: It mediates platelet aggregation. It also mediates contractile responses of many vascular, urinary, gastrointestinal and uterine smooth muscles.. It is involved in diseases affecting learning & memory processes. 5HT2C receptor: in brain. Activation of these receptors is involved in the initiation of a migraine attack. 5-HT3 receptors: located centrally in vomiting center. They mediate stimulation of nausea & vomiting. 5-HT4 receptors: located in enteric neurons in GIT. It mediates increase in GIT propulsive activity. SEROTONIN AGONISTS 5HT2C receptor Mosapride SEROTONIN ANTAGONISTS 1. 5-HT3 antagonist: For example: Ondansetrone & granisetrone This group of drugs blocks 5-HT3 receptor both centrally in vomiting center and peripherally in afferent nerve terminals in GIT. Therapeutic Uses: Antiemetics used to prevent cancer chemotherapy-induced nausea and vomiting Drugs Inhibiting Serotonin Reuptake Selective Serotonin Reuptake Inhibitors (SSRIs): e.g.,Fluoxetine,…. They are used to elevate mood and treat depression. PHARMACOLOGY of eicosanoids (prostaglandins and leukotriens)  Synthesis of eicosanoids Membrane lipid Physical injury Immune reaction AA Lipoxygenase COX-1,COX-2 Endoproxides Hydroperoxides PGG,PGH Leukotriens Prostacyclin TXA LTB,LTC,LTD PGE,PGF  COX-1 (constitutive) found in many tissues and the PGs produced by it mainly share in normal physiological regulations. COX-2 (inducible) is found mainly in inflammatory cells and the PGs produced by it mainly share in pathological disorders inducing pain, fever, and inflammation Pharmacological uses of prostaglandins analogues  Obstetric uses: – Induction of abortion and treatment of postpartum hemorrhage: Carboprost(PGF2) – Induction of labour at term: Dinoprostone (PGE2).  Treatment of peptic ulcer :  Misoprostol (PGE1) is approved for use in patients taking high doses of Non-Steroidal Anti-inflammatory Drugs (NSAIDs) to reduce gastric ulceration.  Treatment of open angle glaucoma: Latanoprost (PGF2  Treatment of erectile dysfunction: Alprostadil (PGE1). Pharmacological antagonism of prostaglandins  Non-Steroidal Anti-inflammatory Drugs [NSAIDs] analgesic, antipyretic, and anti-inflammatory actions. Ketorolac Aspirin (Acetyl Salicylic Acid) Indomethacin All NSAIDs inhibit thromboxane A2, thus they must be stopped before surgery for risk of bleeding. Only Aspirin (in low dose) that is used specifically as an antiplatelet because, being an irreversible COX inhibitor, it decreases thromboxane though out the platelets’ life span without affecting prostacyclin synthesis. Therapeutic Uses: 1. Inflammatory disorders; as rheumatoid arthritis, gout, 2. Mild to moderate pain (headache, toothache, arthralgia, dysmenorrhea....) 3. Fever (non-specific) 4. Common cold (lower fever, relieve headache and muscle aches). 5. Thrombotic events: Aspirin(in low dose) is used as antiplatelet for protection against cardio- and cerebrovascular thrombotic insults; as myocardial infarction, stroke…etc. Adverse Reactions 1. Gastric irritation up to ulceration due to inhibition of gastric cytoprotective PGs 2. Tendency to blood pressure elevation or impairment of renal functions, inhibition of renal regulatory PGs 3. Bleeding tendencies due to inhibition of thromboxane specially with Aspirin. 4. Hypersensitivity reactions could be manifested in the form of bronchoconstriction, urticaria, angioneurotic edema, 5. Reye syndrome: an acute non-inflammatory fulminant liver injury with cerebral edema  Selective COX-2 Inhibitors; Celecoxib They are significantly more selective for inhibition of COX-2 than COX-1; that’s why COXIBs Mainly suppress PGs responsible for pain, fever, and inflammation Less liable to be associated with gastrointestinal adverse reactions in therapeutic dose. Selective COX-2 inhibitors do not affect platelet function. So they may increase the incidence of arterial thrombosis (myocardial infarction and stroke); that is why they must be used with caution in cardiac patients. Paracetamol Paracetamol (Acetaminophen) is an analgesic antipyretic drug that inhibits COX mainly centrally; it is not an anti-inflammatory agent. Due to its weak PGs inhibition in peripheral tissue, it does not inhibit gastric or renal PGs, therefore, it is safe on gastric mucosa. Also, it has no antiplatelet actions. Therapeutic Uses: Analgesic; in mild to moderate intensity pain. Antipyretic; the most common and the safest (in therapeutic dose) to be given even in children and pregnant women.