Lecture 16
Autocoids
Terms
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- Histamine
- Autacoid (see notes for general actions) Aerosol form sometimes used as a provocative test of nonspecific bronchial hyperactivity Adverse Effects: Flushing, hypotension, tachycardia, headache, wheals, bronchoconstriction, GI upset DO NOT give to asthmatics or patients with ulcer disease/GI bleeding Epinephrine (Physiological Antagonist) can reverse Anaphylaxis (massive release of histamine by mast cell degranulation)
- Cromolyn and Nedocromil
- Release inhibitors that reduce degranulation of mast cells that results from immunologic triggering by antigen-IgE interaction (thus inhibit LT and histamine release) Use: treatment of asthma (by aerosol) Orally--> preventing food allergy and hay fever Local drops--> conjunctival and nasopharyngeal allergies Adverse effects: cough and irritation of respiratory tract may occur NOTE: β2-agonists can also reduce histamine release
- Chlorpheniramine, Dimenhydrinate, Diphenhydramine, Doxylamine, Hydroxyzine, Meclizine, Promethazine
- First generation H1 receptor antagonists (actually inverse agonists). Have sedative effects and are more likely to block autonomic receptors (cholinergic, α-adrenergic, serotonin and local anesthetic receptor sites) Uses: Allergic conditions--> allergies caused by antigens acting on IgE-antibody sensitized mast cells (control symptoms of allergic rhinitis and urticaria) Capable of completely blocking histamine-induced contraction of bronchiolar and GI muscle. Diphenhydramine, dimenhydrinate, promethazine, cylizine, and meclizine can be used to prevent motion sickness Some (especially Diphenhydramine)--> can cause sedating effects capable of treating insomnia Ineffective in treating bronchial asthma, does not influence gastric acid secretion Adverse Effects: sedation, dry mouth (due to anti-cholinergic)
- Astemizole, Fexofenadine, Terfenadine, Loratadine, Cetirizine
- 2nd generation H1 receptor antagonists (actually inverse agonists). NOTE: Astemizole and Terfenadine have been withdrawn due to inducing potentially ventricular arrhythmias when used with drugs that inhibit CYP3A4 action--> blocking HERG K+ channels in the heart responsible for repolarization. Fexofenadine = safe metabolite of terfenadine Less liposolubile, therefore less sedating than the 1st generation. Also act as substrates of the P-glycoprotein transporter (limiting brain penetration) Uses: Allergic conditions--> allergies caused by antigens acting on IgE-antibody sensitized mast cells (control symptoms of allergic rhinitis and urticaria) Capable of completely blocking histamine-induced contraction of bronchiolar and GI muscle. Ineffective in treating bronchial asthma, does not influence gastric acid secretion Adverse Effects: dry mouth MN: C-FLat
- Cimetidine, Ranitidine, Famotidine, Nizatidine
- H2 Receptor Antagonists (competitive, reversible) (See Cimetidine flashcard for more info) Inhibit gastric acid secretion Uses: peptic ulcers (promote healing of duodenal and gastric ulcers), acute stress ulcer management, GERD prevention/treatment Adverse Effects: headache, dizziness, diarrhea, muscular pain, CNS effects in elderly, rarely cause blood dyscarsias, rapid IV infusion may cause bradycardia and hypotension, rarely cause liver chemistry abnormalities Cross the placenta! (but no harmful effects yet shown)
- Sumatriptan, Zolmitriptan
- 5-HT (1D/1B) Receptor Agonists--> Triptans 1st-line therapy for acute severe migraine attacks Mechanism--> Reduce both sensory activation in the periphery and nociceptive transmission in the trigeminal nucleus. Cause vasoconstriction, opposing vasodilation involved in pathophysiology of migraines
- Migraine Prophylaxis
- β-blockers, amitriptyline, valproic acid, topiramate, and calcium channel blockers
- Metoclopramide
- 5-HT4 Receptor Agonist. Prokinetic agent--> coordinated contractions of the SM of GI that enhance transit Content Below was not in Slides, only in Written Notes: Facilitates Ach release from enteric neurons--> accomplished both by 5-HT4 agonism and 5-HT3 antagonism Has both central (antinauseant and antiemetic properties) and peripheral (prokintetic activity by counteracting the inhibitory effects of dopamine, mediated by D2 receptors on cholinergic enteric neurons) antidopaminergic actions Adverse Effects: somnolence, nervousness, and dystonic reactions, Extrapyramidal effects, TARDIVE dyskinesia, galactorrhea (rarely)
- Cisapride
- 5-HT4 Receptor Agonists. Once used as a prokinetic agent for GERD and gastroparesis Was found to cause severe cardiac effects: extended AP and QT interval, serious cardiac arrhythmias and deaths from ventricular tachycardia, Vfib, torsades de point. Only available on a LIMITED BASIS
- Cyproheptadine
- 5-HT2 Receptor Antagonist with potent H1 blocking actions. Prevents smooth muscle effects of both serotonin and histamine; has significant muscarinic effects and causes sedation Uses: perennial and seasonal allergic rhinitis, vasomotor rhinitis, allergic conjunctivitis, cold urticaria, dermatographism Treatment carcinoid syndrome and serotonin syndrome (overstimulation of 5-HT1A and 5-HT2 receptors)
- Ondansetron
- 5-HT3 Receptor Antagonist. Used as an anti-emetic drug, particularly with cancer chemotherapy NOTE: The 5-HT3 is the only receptor that is a ligand-gated ion channel
- Ergot Alkaloids: Ergotamine, Dihydroergotamine, Bromocriptine, Cabergoline, Ergonovine, Methylergonovine
- Agonist, partial agonist, and antagonist actions at α-adrenergic and 5-HT receptors; also agonist or partial agonist actions at CNS dopamine receptors. Some act presynaptically, others act postsynaptically Uses: Migraine (Ergotamine, Dihydroergotamine), Hyperprolactinemia (Bromocriptine, Cabergoline), Diagnosis of variant angina by provoking coronary artery spasm (Ergonovine). Postpartum hemorrhage (Ergonovine, methylergonovine) Only use to control late uterine bleeding, NEVER given before delivery Adverse Effects are minimal: HTN, headache, seizures... Contraindications: Angina pectoris, MI, pregnancy, HTN, transient ischemic attack, history of cerebrovascular accident PRESENT IN MILK--> can cause fetal gangrene, do not use long term NOTE: Triptans are preferred for migraine treatment, and oxytocin is preferred for control of postpartum hemorrhage
- Dinoprostone
- PGE2 Used to ripen cervix before induction of labor Can be used as an abortifacient in the 2nd term Management of benign H mole evacuation of uterine contents in the management of missed abortion Administration: Vaginal insert, vaginal suppository, and cervical gel
- Carboprost tromethamine
- 15-methyl-PGF2α Used as an abortifacient in the 2nd trimester Control of postpartum hemorrhage (3rd Line) after oxytocin or ergonovine Administration: IM
- Misoprostol
- PGE1 derivative Used with mifepristone (progesterone antagonist) or with methotrexate as an abortifacient combination Effective also for cervical ripening and labor induction. Used also in the treatment of postpartum hemorrhage Administration: Orally or vaginally Used to prevent peptic ulcers in pateints who take high doses of NSAIDs (for arthritis)--> FDA approved only for this
- Alprostadil
- PGE1 Given as an infusion to maintain patency of the ductus arteriosus in infants (transposition of the great vessels) Treatment of impotence (Injection into penis).
- Prostacyclin
- PGI2 Lowers peripheral, pulmonary and coronary resistance Used for severe pulmonary HTN and to prevent platelet aggregation in dialysis machines Must use IV Contraindicated in pregnancy
- Latanoprost
- PGF2α derivative Used for treatment of glaucoma (Gold Standard)
- Zileuton
- Inhibits 5-lipoxygenase, preventing leukotriene synthesis MOA: Blocks conversion of arachidonic acid to leukotrienes Given orally Treatment of asthma--> antigen, exercise, and aspirin induced Adverse Effects: Elevation of liver enzymes
- Zafirlukast, Montelukast
- Inhibition of binding of LTD4 to its receptor in target tissues, preventing its action Given orally Treatment of asthma--> antigen, exercise, and aspirin induced, NOT acute Not as effective as steroid and β2-agonists Adverse effects: very safe, may produce Churg-Strauss Syndrome and allergic granulomatous angiitis