Pharmacology for the Boards Dr. Cruz

Pharmacology for the ABA Part 1 Examination June 29, 2007 Elvin J. Cruz-Zeno, MD, MS Department of Anesthesiology Wilford Hall Medical Center Sodium Nitroprusside (Nipride, Nitropress) • • • • Mechanism of action: • Potent peripheral vasodilator (venous & arterial) • Converts OxyHgb to MetHgb, and decomposes into cyanide + NO (inside RBCs) Vasodilation a result of: • generation of Nitric oxide (endothelium-derived relaxing factor) which activates guanylyl cyclase • • Onset of action: • < 1 min Duration of action: • 5-10 min Administration requires: • Continous IV infusion • Careful BP monitoting (A-line) Toxicity usually avoided with doses: • < 10 mcg/kg/min From: Morgan & Mickail, Clinical Anesthesiology, 4th Ed Sodium Nitroprusside (Nipride, Nitropress) • Acute cyanide toxicity • • • • • Tachyphylaxis Metabolic acidosis Cardiac arrhythmias Increased venous O2 content From: Morgan & Mickail, Clinical Anesthesiology, 4 Treatment • Mechanical ventilation with 100% O2 • Sodium Thiosulfate (150mg/kg over 15 min) • 3% Sodium Nitrate (5mg/kg over 5 min) th Ed • Methemoglobinemia • Treatment • Methylene Blue (1-2 mg/kg of a 1% solution over 5min) reduces Methemoglobin to OxyHemoglobin (Keywords: Nitroprusside toxicity signs, Cyanide toxicity) Metoclopramide • Pheripheral action: • Cholinomimetic • Prokinetic – speeds gastric emptying • Increase lower esophageal sphincter tone • Central effects: • Dopamine antagonist (antiemetic) • Can cause sedation, nervousness, extrapyramidal side effects • Droperidol increases likelihood of extrapyramidal effects • Excretion: • Renal => reduced dose in renal dysfunction • Contraindications: • Complete intestinal obstruction • Pheochromocytoma (can induce a HTN emergency) • Parkinson’s dz (worsening sxs) (Keywords: Metoclopramide contraindications, Parkinsons dz: Metoclopramide effects) Cocaine • • • • 1855 – Isolated from coca plant From: Morgan & Mickail, Clinical Anesthesiology, 4 1884 – Koller topically for eye surgery; Halsted intradermal infiltration and nerve blocks 1898 – Bier for SAB Mechanism of action: • Ester local anesthetic • Local vasoconstrictor th Ed • • Used topically, available in 4% and 10%, Max dose 3mg/kg, duration of neural blockade ~ 1Hr Inhibits reuptake of Norepinephrine => HTN, ectopy • Contraindicated in patients with: • HTN • TCA or MAO-I (Keywords: Cocaine: Mechanism of action, Acute cocaine toxicity, Cathecols-chronic cocaine abuse) Local Anesthetic Potency • Primary determinant of LA potency • Lipid solubility - Ability to penetrate cell membranes • Inportant determinant of duration of action • Protein binding (related to lipid solubility) • Important determinant on the speed of onset of blockade • pKa • Why Chloroprocaine has such a rapid onset if it has the highest pKa? (Keywords: Local anesthetic potency-lipid solubility) Mivacurium (Mivacron) • Benzylisoquinolinium NMB • Histamine release • Intubating dose • 0.15-0.2 mg/kg • Infusion • 4-10 mcg/kg/min • Onset • 2-3 min • Duration • 12-20 min • Hydrolysis by: • Pseudocholinesterase (like Succinylcholine) • Increased duration of action in patients with: • Atypical plasma cholinesterase • Heterozygous – paralyzed twice as long • Homozygous – paralyzed for 3-4 hours (Keywords: Prolonged NMB w Mivacurium) Barbiturates • Depress reticular activating system (RAS) in the brain stem – controls consciousness • Enhance transmission of inhibitory neurotransmitters – GABA • CNS depression • Constrict cerebral vasculature => ↓ CBF, ICP => ↑ CPP • ↓ cerebral O2 consumption => EEG suppression • Potentiated by EtOH, benzos, opioids, antihistamines • Thiopental rapidly controls grand mal seizures (50-100mg) • Methohexital can induce involuntary skeletal muscle contractions • Acute tolerance and physiological dependence develops quickly • No reversal available (Keywords: Barbiturates - mechanism of action, Barbiturates - CNS effects) Propofol (Diprivan) • Depress reticular activating system (RAS) in the brain stem • Controls consciousness • Facilitation of inhibitory neurotransmission mediated by GABA • 1% aqueous solution contains: • soybean oil, glycerol, egg lecithin (from egg yolk) • Formulation supports bacterial growth: • Administration within 6 Hrs of opening ampoule • Hemodynamic effects: • Decrease in MAP, SVR, contractility, preload • Impairs arterial baroreceptor reflexes • • • • Anticonvulsant Antipruritic Antiemetic CNS depression • ↓ CBF, ICP • Exhitatory events: • Hiccups • Muscle twitching (Keywords: Propofol – CV effects, Propofol-CNS effects) Esmeraldas, Ecuador April, 2007 Etomidate • Depress RAS in the brain stem • Facilitation of inhibitory neurotransmission mediated by GABA • • • • • • • Disinhibition of extrapyramidal motor activity centers • Myoclonus (30-60%) – severity decreased with opioids Less ventilatory depression than Propofol, Barbiturates Pain on injection PONV common Effects on CV system • Minimal Endocrine: • Induction doses => transient inhibits enzymes of cortisol & aldosterone synthesis • Infusions => Adrenocortical supression CNS depression • ↓ CBF, ICP, CRMO • Enhances somatosensory evoked potentials (Keywords: Etomidate – Side effects) Dexmedetomidine (Precedex) • Selective α2-agonist • At higher doses it can also stimulate α1 adregenergic receptors • CNS: • Dose-dependent sedation anxiolysis • CV: • Blunts sympathetic response to surgery and stress • Respiratory: • No significant depression of respiratory drive • Excessive sedation might cause airway obstruction • Dosing: • Loading dose of 1 mcg/kg over 10 min • 0.2-0.7 mcg/kg/HR • Side effects: • Bradycardia • Heart block • Hypotension (Keywords: Dexmedetomidine – Cardiorespiratory effects Flumazenil • Competitive antagonist of benzodiazepines • Useful for: • Reversal of BZD sedation • Treatment of BZD overdose • Elderly more difficult to reverse • Dosing: • 0.2mg/min until reaching desired degree of reversal • May need redosing in 1-2 hrs • Side effects: • Rapid administration may cause anxiety reactions and withdrawal sxs in long term BZD users • N/V (Keywords: Benzodiazepine antagonism) Succinylcholine • • • • Two joined Ach molecules Rapid onset(30-60 sec) Short duration (10min) Metabolized by • Pseudocholinesterase • • • • High doses Low pseudocholinesterase levels – pregnancy, liver/renal dz Genetically aberrant enzyme (up to 4-8 Hr paralysis) Hypothermia – decreased rate of hydrolysis • Prolonged paralysis in: • Sinus bradycardia, junctional rhythm, sinus arrest: • Action of SCh at cardiac postganglionic muscarinic receptors (Ach-like) • Cardiac dysrhythmias more likely with 2nd dose at about 5 minutes • Hyperkalemia (Keywords: Succ induced bradycardia cause, Succ hyperkalemia tx) Doxorubicin (Adriamycin) • Anthracycline antibiotic used in chemotherapy • Cardiac side effects: • Transient dysrhythmias • ST-T wave abnormalities • Risk of irreversible cardiomyopathy and CHF increases with: • • • Cummulative doses > 550 mg/m2 Prior radiotherapy Concurrent cyclophosphamide treatment • Myelosuppression • • • Thrombocytopenia Leukopenia Anemia (Keywords: Doxorubicin toxicity) Ketorolac Parenteral NSAID – Non-selective COX inhibitor Inhibits prostaglanding synthesis Short-term pain management (<5 days) Ketorolac 30mg provides equivalent analgesia to 6-10mg of Morphine with similar time of onset • Duration of action 6-8 hrs • Side effects • • • Inhibits platelet aggregation => prolongs bleeding time Renal toxicity with long term use GI tract ulceration • • • • • Contraindicated on pts in renal failure, or those allergic to ASA, NSAIDS (Keyword: Ketorolac & postop risk) Heparin • • • Mucopolysaccharide organic acid present endogenously in the liver and granules of mast cells & basophils Commercially obtained from bovine lung and porcine intestinal mucosa Indirect anticoagulant: – Binds to antithrombin III (heparin co-factor), accelerating it’s binding and inhibition of thrombin, thus preventing new fibrin formation and the expansion of thrombi – It also inhibits activated factors IX, X, XI, and XII • • • • • Onset < 2min IV, 20-30min SC Duration of action 1-2 hours ( T1/2  ) Metabolized by reticuloendothelial system (prolonged effect in liver failure) Inactive metabolites and remaining heparin are excreted in urine (prolonged effect in renal insufficiency) Doesn’t cross placenta or into breast milk Heparin • Indirect anticoagulant – Binds to antithrombin III (heparin co-factor), accelerating it’s binding and inhibition of thrombin (IIa), thus preventing new fibrin formation and the expansion of thrombi – It also inhibits activated factors IX, X, XI, and XII From www.frca.co.uk/images/clotting_cascade.gif Heparin • • Monitor PTT or ACT for therapeutic effect Complications/Side effects: – Bleeding • Tx: Discontinuation of therapy &/or Protamine – Hypersensitivity reactions • Chills, fever, urticaria, anaphylaxis • Obtained form animal sources – Thrombocytopenia • Heparin-induced platelet aggregation • Antiplatelet antibodies • Contraindications: – – – – – Hypersensitivity HIT Severe thrombocytopenia Uncontrolled active bleeding not due to DIC Post-op for eye, brain, or spinal cord surgery Heparin • BEWARE: Heparin vials are available in many different concentrations From www.appdrugs.com/ProdJPGs/HeparinSodiumInjLg.jpg Protamine • • Protein derived from fish sperm or mature testes Antagonizes the anticoagulation effect of Heparin – Positively charged protein that interacts with negatively charged Heparin to form a stable complex devoid of anticoagulant activity • Protamine dosing – 1mg neutralizes about 100 units of Heparin in the circulation ( 1mL (10mg/mL) for every mL of Heparin 1,000 units/mL ) – Half dose at 1 hour – Quarter dose at 2 hours • • • Rapid IV infusion associated with histamine release, peripheral vasodilation, Hypotension, increased PulmVR Onset: 1 minute Duration of action 1-2 hours ( T1/2  ) Protamine • Increased risk of allergic reactions: – Allergy to fish – Previous use of Insulin preparations containing protamine (NPH) – Infertile men or s/p vasectomy • • • • When reversing large doses of heparin rebound might occur, requiring administration of more protamine Protamine itself can interfere with coagulation when given in the absence of Heparin by interactions with platelets and fibrinogen Incompatible with PCN, cephalosporins Protamine-Heparin complex degraded and excreted in urine Recombinant Factor VIIa (NovoSeven) • FDA approved for the treatment of bleeds in haemophilia A and B patients with inhibitors. • Recombinant protein is expressed from cloned human FVII genes in baby hamster kidney cells • Induces haemostasis in pharmacologic doses by converting FX to FXa on the surface of ‘activated’ platelets • Under normal circumstances, platelets only become ‘activated’ at the site of injury – thus preventing blood clots from forming in areas where they are not wanted. Recombinant Factor VIIa (NovoSeven) • Store NovoSeven at 2°C - 8°C (in a refrigerator) • • • • NovoSeven should be given as early as possible after the start of a bleeding episode. Dose: 15-90 μg per kg Dosing interval: – 2-3 hours initially until bleeding controlled – 4-12 hour afterwards After administration of NovoSeven, prothrombin time (PT) and activated partial thromboplastin time (aPTT) have been shown to shorten, however no correlation has been demonstrated between PT and aPTT and clinical efficacy of NovoSeven. Recombinant Factor VIIa (NovoSeven) • Drug used on wounded GIs could be fatal Linked to heart attacks, strokes By Robert Little Tribune Newspapers: The Baltimore Sun Published November 21, 2006 BAGHDAD -- American military doctors in Iraq have injected more than 1,000 of the war's wounded troops with a potent and largely experimental blood-coagulating drug despite mounting medical evidence linking it to deadly blood clots that lodge in the lungs, heart and brain… References • • • Stoelting & Dierdorf’s, Anesthesia and C0-Existing Disease, 4th Ed, 2002 Stoelting & Miller’s, Basics of Anesthesia, 5th Ed, 2007 Morgan, Mikhail, Murray’s, Clinical Anesthesiology, 4th Ed, 2006 • • • Omoigui’s, Anesthesia Drugs Handbook, 3 rd Edition, 1999 Mycek, et al, Lippincott’s Illustrated Reviews : Pharmacology, 2 nd Edition, 1997 Stoelting & Hillier, Handbook of Pharmacology & Physiology in Anesthetic Practice, 2 nd Edition, 2006 • White, Perioperative Drug Manual, 2nd Edition, 2005