Q: Make an easy and simple exam oriented notes and short notes and important notes from given source A: Here are comprehensive, exam-oriented notes from the Shanbhag Pharmacology source on Autacoids and Respiratory System Histamine, Antihistamines, 5-HT, Migraine, Prostaglandins & Leukotrienes: --- π AUTACOIDS & RESPIRATORY SYSTEM β EXAM NOTES Shanbhag Pharmacology --- PART 1: HISTAMINE & ANTIHISTAMINES β AUTACOIDS β Quick Definition - Produced by cells, act locally β also called "local hormones" - Examples: Histamine, Serotonin 5-HT, Prostaglandins, Leukotrienes, Angiotensin, Kinins, PAF --- β HISTAMINE β Key Points - Biogenic amine; synthesized by decarboxylation of histidine - Stored in mast cell granules skin, lung, liver, gastric mucosa, placenta - Mediator of inflammatory and hypersensitivity reactions HISTAMINE RECEPTORS β HIGH YIELD TABLE Receptor 2nd Messenger Effect --------- H1 β CaΒ²βΊ Smooth muscle contraction, β capillary permeability H2 β cAMP β Gastric acid secretion H3 presynaptic autoreceptor β cAMP β Histamine in brain, lung, skin, gastric mucosa H4 β cAMP Chemotaxis, cytokine secretion HISTAMINE LIBERATORS - AG:AB reaction, food crab, fish, bile salts - Drugs: Morphine, d-TC, dextran, hydralazine - Effects: itching, urticaria, flushing, hypotension, tachycardia, bronchospasm, angioedema BETAHISTINE Histamine Analogue - Used orally for vertigo in Meniere's disease - Mechanism: improves blood flow in inner ear - Side effects: nausea, vomiting, headache, pruritus - Avoid in: asthma, peptic ulcer --- β H1-RECEPTOR ANTAGONISTS ANTIHISTAMINES CLASSIFICATION First Generation Conventional: Diphenhydramine, Dimenhydrinate, Promethazine, Cinnarizine, Cyclizine, Meclizine, Hydroxyzine, Pheniramine, Chlorpheniramine maleate, Cyproheptadine, Clemastine, Triprolidine Second Generation Non-sedating: Cetirizine, Levocetirizine, Azelastine, Mizolastine, Loratadine, Desloratadine, Fexofenadine, Ebastine, Rupatadine --- MECHANISM OF ACTION - Competitive antagonism at H1 receptors - Histamine agonist β H1 Receptors β Antihistamines antagonists --- FIRST-GENERATION H1-BLOCKERS β Properties Pharmacological Actions: 1. CNS depression - sedation, drowsiness some have antiemetic, local anaesthetic, anti-parkinsonian effects 2. Antiallergic - suppress Type I reactions 3. Anticholinergic - dry mouth, blurred vision, constipation, urinary retention Pharmacokinetics: - Well absorbed orally and parenterally - Widely distributed, metabolized in liver, excreted in urine Adverse Effects: 1. Sedation, drowsiness, psychomotor incoordination β avoid while driving/operating machinery 2. GI: nausea, vomiting, loss of appetite 3. Anticholinergic: dry mouth, blurred vision, constipation, urinary retention 4. Teratogenic in animals 5. Allergic reactions contact dermatitis on topical use --- USES OF FIRST-GENERATION ANTIHISTAMINES Use Drugs ------ Allergic diseases urticaria, rhinitis, conjunctivitis All H1-blockers Common cold symptomatic relief Sedating antihistamines Preanesthetic medication Promethazine Antiemetic Promethazine, Diphenhydramine, Dimenhydrinate Parkinsonism Promethazine, Diphenhydramine, Orphenadrine Vertigo Meniere's Cinnarizine, Dimenhydrinate, Meclizine Sedation/Hypnotic children, minor surgery Promethazine, Diphenhydramine Blood transfusion reactions chills, rigors H1-blockers Anaphylaxis adjunct H1-blockers Antiemetic Mechanism: Motion β Vestibular apparatus M, H1 β Cerebellum β Vomiting centre M, H1 Parkinsonism: Due to imbalance between DA β and ACh β in basal ganglia --- SECOND-GENERATION H1-BLOCKERS β Properties 1. No anticholinergic effects 2. Lack antiemetic effect 3. Do not cross BBB β minimal/no drowsiness 4. Do not impair psychomotor performance 5. Relatively expensive SECOND-GEN DRUGS β INDIVIDUAL FEATURES HIGH YIELD Drug Route/Duration Key Features --------- Cetirizine p.o., 12-24 hr Also inhibits histamine release; good skin concentration; poorly crosses BBB; may cause drowsiness Levocetirizine p.o., 12-24 hr More potent, fewer adverse effects than cetirizine Loratadine/Desloratadine p.o., 24 hr Long-acting, nonsedating; no cardiac arrhythmias Fexofenadine p.o., 12-24 hr Active metabolite of terfenadine; nonsedating; avoid in prolonged QT interval Azelastine Topical nasal spray, eye drops Also inhibits histamine release; rapid onset, long duration; taste alteration, burning sensation Rupatadine p.o. H1-blocker + blocks platelet-activating factor Uses of 2nd-gen: Rhinitis, dermatitis, conjunctivitis, urticaria, eczema, drug/food allergies - For allergic rhinitis: fexofenadine, cetirizine, mizolastine, rupatadine oral; azelastine nasal spray - Eye drops for allergic conjunctivitis: azelastine, levocabastine --- β ANTIVERTIGO DRUGS β Summary - Cinnarizine 1st-gen H1, decreases CaΒ²βΊ entry into vestibular cells - Promethazine, Diphenhydramine H1-blockers - Hyoscine anticholinergic - Prochlorperazine phenothiazine - Betahistine H1-analogue - Acetazolamide, thiazides, furosemide diuretics - Diazepam - Amitriptyline TCA - Glucocorticoids --- PART 2: SEROTONIN 5-HT β AGONISTS & ANTAGONISTS β KEY FACTS ABOUT 5-HT - Synthesized from tryptophan amino acid - High concentration in: intestine, platelets, brain - 7 subtypes of receptors 5-HT1β7; all G-protein coupled except 5-HT3 ligand-gated ion channel 5-HT RECEPTOR TABLE HIGH YIELD Receptor Location Actions Drugs ------------ 5-HT1 CNS, cranial blood vessels β 5-HT release autoreceptors; constriction of cranial blood vessels Buspirone partial agonist; Triptans selective 5-HT1B/1D agonists; Ergotamine 5-HT2 Platelets, smooth muscles, cerebral cortex, fundus, choroid Platelet aggregation, smooth muscle contraction, neuron activation, CSF production Ketanserin antagonist; Cyproheptadine antagonist; Methysergide; Atypical antipsychotics 5-HT3 CTZ, NTS, parasympathetic nerve terminals GIT Vomiting, peristalsis Ondansetron, Granisetron antagonists 5-HT4 GIT, CNS Peristalsis Metoclopramide, Prucalopride agonists --- 5-HT ANTAGONISTS β SUMMARY Drug Action Use/Notes --------- Cyproheptadine H1 + 5-HT2A blocker; anticholinergic Carcinoid syndrome, postgastrectomy dumping; increases appetite; side effects: dry mouth, drowsiness, weight gain Ketanserin 5-HT2A antagonist + Ξ±1-blocker Antihypertensive effect Ondansetron/Granisetron 5-HT3 antagonists Antiemetics Clozapine, Olanzapine, Quetiapine, Risperidone 5-HT2 blockers Schizophrenia atypical antipsychotics Methysergide 5-HT2A/2C antagonist Prophylaxis of migraine long-term use β abdominal and pulmonary fibrosis --- ERGOT ALKALOIDS Drug Receptor Action Effects Use ADR --------------- Ergotamine natural Partial agonist/antagonist at Ξ±, 5-HT1, 5-HT2 Smooth muscle contraction blood vessels, uterus, gut Acute migraine oral, sublingual, suppository, rectal Vomiting, diarrhoea; overdose β severe vasospasm β gangrene Dihydroergotamine DHE Predominant Ξ±-blockade; weak 5-HT and Ξ±-agonist Less vasoconstriction than ergotamine Acute migraine oral, i.m., s.c. Nausea, vomiting Ergometrine natural Partial agonist at 5-HT2; weak action at Ξ±-receptors Major action: uterine contraction; minimal vasoconstriction Postpartum haemorrhage i.m., i.v. Nausea, vomiting, rise in BP Bromocriptine semi-synthetic D2-agonist Decreases prolactin release Parkinsonism, galactorrhoea oral Vomiting, hypotension Contraindications of Ergot Alkaloids: Ischaemic heart disease, hypertension, peripheral vascular disease, renal disease --- PART 3: DRUG THERAPY OF MIGRAINE β Migraine Attack: aura visual disturbance β severe throbbing headache with photophobia, nausea, vomiting --- DRUGS FOR ACUTE ATTACK 1. NSAIDs mild-moderate migraine: Paracetamol, aspirin, ibuprofen, naproxen, diclofenac, mefenamic acid 2. Antiemetics oral/parenteral: Metoclopramide, Domperidone, Prochlorperazine, Promethazine, Diphenhydramine 3. Ergot Preparations: - Ergotamine: partial agonist at 5-HT1B/1D β constricts dilated cranial blood vessels + decreases inflammation - Combined with caffeine increases absorption + vasoconstriction - DHE Dihydroergotamine: safer for parenteral use i.m., i.v., s.c. 4. Triptans DRUGS OF CHOICE for moderate-severe migraine: Examples: Sumatriptan, Rizatriptan, Eletriptan, Almotriptan, Zolmitriptan, Naratriptan, Frovatriptan Mechanism: Selective 5-HT1B/1D agonists - Abnormal dilatation of cranial blood vessels β Cerebral ischaemia β Migraine attack - Triptans β constrict dilated cranial blood vessels + AV shunts β Restore cerebral blood flow - Also: decrease 5-HT and vasoactive peptide release from presynaptic nerve endings - Inhibit extravasation of plasma proteins in perivascular space Route: All oral; Sumatriptan also s.c. and nasal; Zolmitriptan also nasal Half-life: Sumatriptan = 2 hours; Frovatriptan and Naratriptan = longer half-life Adverse Effects of Triptans: Paraesthesia, tightness/flushing/dizziness in chest, nausea, rise in BP, coronary vasospasm Contraindications of Triptans: - Pregnancy - Ischaemic heart disease - Peripheral vascular disease - Hypertension - Risk factors for coronary artery disease - Triptan + Ergot = NOT together neither within 24 hours of ergot derivative --- PROPHYLAXIS OF MIGRAINE Note ABCD β HIGH YIELD Letter Drug Class Examples --------- A Antidepressants TCAs Amitriptyline B Beta-blockers Propranolol, Timolol, Atenolol, Metoprolol Propranolol most effective C Calcium channel blockers Verapamil, Flunarizine selective for cerebral; also NaβΊ channel blocking D Anticonvulsants "D"rugs for epilepsy Gabapentin, Sodium valproate, Topiramate Others Methysergide, Cyproheptadine rarely used Note: CCBs should NOT be co-administered with Ξ²-blockers. Flunarizine is selective for cerebral CaΒ²βΊ channels. --- PART 4: PROSTAGLANDINS PGs & LEUKOTRIENES β KEY FACTS - Products of long-chain fatty acids - Precursor: Arachidonic acid - Enzyme: Cyclooxygenase COX forms PGs from arachidonic acid - COX-1: Constitutive always present; widely distributed - COX-2: Inducible during inflammation by cytokines and endotoxins; also constitutively found in brain and kidney - Leukotrienes: obtained from arachidonic acid by lipoxygenase LOX PHARMACOLOGICAL ACTIONS & USES HIGH YIELD 1. GI Tract: - PGE2 and PGI2: β acid secretion, β mucus secretion cytoprotective - Misoprostol PGE1 analogue: used for prevention of NSAID-induced ulcers 2. Cardiovascular: - PGD2, PGE2, PGI2: vasodilation - PGF2Ξ±: constricts pulmonary veins and arteries - TXA2: vasoconstrictor - PGE1 Alprostadil: maintains patency of ductus arteriosus before surgery 3. Pulmonary hypertension: - Prostacyclin PGI2 β decreases peripheral, pulmonary, coronary resistance - PGI2 Epoprostenol: treats pulmonary hypertension; analogues: Treprostinil, Iloprost 4. Platelets: - PGI2: inhibits platelet aggregation useful in haemodialysis - TXA2: promotes aggregation 5. Eye: - PGF2Ξ± analogues Latanoprost, Bimatoprost, Travoprost, Unoprostone: used in glaucoma topical eye drops, β IOP 6. Uterus: - PGE2 low conc. and PGF2Ξ±: contract pregnant uterus - Used in mid-trimester abortion, missed abortion, hydatidiform mole - PGE2 and PGF2Ξ±: induce labour at term; promote cervical ripening 7. Male reproductive system: - PGE1 Alprostadil: used in erectile dysfunction --- PROSTAGLANDIN ANALOGUES β TABLE HIGH YIELD Drug Type Route Use ------------ Dinoprostone PGE2 PGE2 Vaginal tab/gel Induction of labour, mid-term abortion, termination of pregnancy Dinoprost PGF2Ξ± PGF2Ξ± Intra-amniotic injection Mid-term abortion Carboprost 15-methyl PGF2Ξ± PGF2Ξ± analogue i.m. Mid-term abortion, control of PPH Gemeprost PGE1 PGE1 Vaginal pessary Cervical priming in early pregnancy Alprostadil PGE1 PGE1 i.v. infusion, intracavernosal Maintain ductus arteriosus; erectile dysfunction Misoprostol PGE2 PGE2 analogue Oral, vaginal pessary Peptic ulcer, abortion, PPH Epoprostenol/Treprostinil/Iloprost PGI2 PGI2 i.v. infusion Pulmonary hypertension Latanoprost/Bimatoprost/Unoprostone/Travoprost PGF2Ξ± PGF2Ξ± Topical eye drops Glaucoma THERAPEUTIC USES IN OBSTETRICS 1. Abortion: Dinoprostone, Misoprostol +mifepristone/methotrexate, Carboprost 2nd trimester, Gemeprost and Dinoprost 2. Induction of labour: PGE2 softens cervix 3. PPH: Carboprost i.m. and Misoprostol oral Adverse Effects of PGs: Nausea, vomiting, diarrhoea, fever, flushing, hypotension, backache due to uterine contractions; injections painful due to nerve sensitization --- LEUKOTRIENES - Obtained from arachidonic acid by lipoxygenase - Leukotriene antagonists: see p. 259 Montelukast, Zafirlukast β used in asthma --- β QUICK-FIRE HIGH YIELD FACTS EXAM SHORTCUTS Fact Answer ------ Histamine is synthesized from Histidine Histamine stored in Mast cell granules H1 receptor 2nd messenger CaΒ²βΊ H2 receptor 2nd messenger cAMP β H3 receptor Presynaptic autoreceptor; β cAMP Betahistine used for Vertigo in Meniere's disease 1st-gen antihistamine for antiemetic Promethazine, Dimenhydrinate 1st-gen antihistamine for vertigo Cinnarizine, Dimenhydrinate, Meclizine 2nd-gen antihistamine causing drowsiness Cetirizine mildly Only 5-HT receptor that is NOT G-protein coupled 5-HT3 ligand-gated 5-HT3 antagonists antiemetics Ondansetron, Granisetron Drug of choice β acute severe migraine Triptans 5-HT1B/1D agonists Triptan with shortest half-life Sumatriptan 2 hours Triptan + ergot contraindication Never within 24 hours of each other Best beta-blocker for migraine prophylaxis Propranolol COX-1 vs COX-2 COX-1 = constitutive; COX-2 = inducible by inflammation Precursor for PGs and leukotrienes Arachidonic acid Enzyme for PGs COX Cyclooxygenase Enzyme for Leukotrienes Lipoxygenase Misoprostol used for NSAID-induced ulcers, abortion, PPH Alprostadil PGE1 used for Ductus arteriosus patency, erectile dysfunction PGI2 analogue for pulmonary hypertension Epoprostenol, Treprostinil, Iloprost PGF2Ξ± eye drops for glaucoma Latanoprost, Bimatoprost, Travoprost Carboprost used for Mid-term abortion + PPH control Methysergide long-term side effect Abdominal and pulmonary fibrosis Rupatadine unique feature H1-blocker + blocks platelet-activating factor Fexofenadine is active metabolite of Terfenadine --- Exam Tip: Remember migraine prophylaxis as "ABCD" β Antidepressants, Beta-blockers, Calcium channel blockers, Drugs anticonvulsants. Triptans are preferred for acute moderate-severe attacks. Never combine Triptans with Ergot preparations.
