8/11/14 ACMT Board Review 2014: Cardiovascular Toxins Russ Kerns, MD, FACMT Carolinas Medical Center Charlotte, NC Objectives: 2.1.6 Drugs that affect the cardiovascular system n 2.1.6.1 Antidysrhythmics n 2.1.6.1.1 calcium channel blockers n 2.1.6.1.2 cardiac glycosides n 2.1.6.1.3 potassium channel blockers n 2.1.6.1.4 sodium channel blockers n 2.1.6.2 Antihypertensives n 2.1.6.2.1 Angiotensin modulators n 2.1.6.2.2 β-adrenergic receptor antagonists n 2.1.6.2.3 central α-agonists n 2.1.6.2.4 diuretics n 2.1.6.2.5 vasodilators n 2.1.6.3 Inotropes n Provide key example toxins and visual stimuli Key Principles n Cardiac action potential n Sodium channels n Potassium channels n Na+-K+ ATPase n Electromechanical coupling n Calcium channels n Modulators n Β-adrenergic receptors 1 8/11/14 Cardiac Action Potential n Phase 0 n electrical stimulus n sodium influx via fast Na+ channels n ↑ resting membrane potential n depolarization Cardiac Action Potential n Phase 1 n Repolarization of membrane begins n Na+ channels close n Potassium efflux (outward rectifying current) Cardiac Action Potential n Phase 2 n plateau phase n calcium influx n potassium efflux 2 8/11/14 Cardiac Action Potential n Phase 3 n repolarization n Calcium channels close n Potassium efflux continues Cardiac Action Potential n Phase 4 n Resting state Sodium Channel 3 8/11/14 Na+ Channel Structure n Found in neurons, glial cells & myocytes n 9 subtypes n Tetrameric protein n Transmembrane n SCN gene n SCN5 – Brugada Syndrome n Voltage-gated (myocardial) n Ligand-gated (nicotinic) Na+ Channel Function n Resting (Closed) n Open n Inactivated (Closed) n Refractory to opening Na+ Channel Modulation n Agonists – channel openers n Aconitine (Monk’s Hood) n Batrachotoxin (Poison Dart Frog) n Grayanotoxin (Azalea and Rhododendron sp) n some are antagonists n Veratridine (Veratrum sp – False Hellebore) n Zygacine (Zygadenus sp – Death Camus) 4 8/11/14 Na+ Channel Agonists n Clinical consequences n Ventricular dysrhythmias n Bradycardia n Treatment n Na+ channel antagonists n Cardioversion/defibrillation Na+ Channel Modulation: Antagonists n Antidysrhythmics 2.1.6.1.4 n Ia Antidysrhythmics n Procainamide, quinidine, disopyramide n Ib Antidysrhythmics n Lidocaine, mexilitine, phenytoin n Ic Antidysrhythmics n Encainide, flecainide, propafenone Na+ Channel Modulation: Antagonists n Other sodium channel blocking drugs n Analgesics: propoxyphene n Anticonvulsants: carbamazepine n Antidepressants: cyclics, bupropion, venlafaxine n Antimalarials: quinine, chloroquine, hydroxychloroquine n Class II antidysrhythmics: propranolol, acebutolol n Class III antidysrhythmics: amiodarone n Local anesthetics n Phenothiazines: diphenhydramine, thioridazine n Others: cocaine, propylene glycol 5 8/11/14 Na+ Channel Modulation: Antagonists n Natural toxins n Grayanotoxins n Some are agonists n Taxine (Taxus sp – Yew) X Widened QRS 6 8/11/14 Wide QRS: ECG as Prognostic Tool for Cyclic Antidepressant OD n Reflects activity at the sodium channel n Limb lead QRS duration n > 100 ms risk of seizures n > 160 ms risk of ventricular dysrhythmias Boehnert. NEJM 1985;313:474-9 Na+ Channel Antagonism: Rate-dependent baseline 2:50 min QRS – 140 ms; BP - 145/78 mmHg QRS – 160 ms; BP - 151/68 mmHg 5:50 min 7:50 min QRS – 180 ms; BP -164/65 mmHg QRS – 220 ms; BP - 0 mmHg Terminal Axis Deviation 7 mm R’ 7 8/11/14 Sodium Channel Blockade: Rightward Terminal Axis normal right axis deviation n R’ wave in aVR > 3 mm n R’:S ratio in aVR > 0.7 Liebelt et al. Ann Emerg Med 1995;26:195-201 Brugada ECG Pattern u Terminal right axis deviation u Coved (saddle) ST segment elevation precordium Littmann et al. Am Heart J 2003;145:768-78; Beberta et al. Clin Toxicol 2007;45:186-8 Sodium Channel Blockade: Consequences ventricular tachycardia torsades de pointes n Treatment n Sodium bicarbonate n Lidocaine (?) n Cardioversion/defibrillation 8 8/11/14 Sodium Channel Blockade: Hypertonic Sodium Bicarbonate n Sodium ion n Reverses competative Na+ channel antagonism n Alkalinization n Increased drug-protein binding (↓ free drug) n decreased drug binding at the Na+ channel Sodium Channel Blockade Treatment: Why Lidocaine? n Class 1a n Blocks in resting state n Recovery: 1-10 ms n Class 1b n Blocks in inactive state n Recovery: <1 ms n Class 1c n Blocks in inactive state n Recovery: >10 ms Lidocaine is “fast on and fast off” so there is a greater chance of channel opening Antidysrhythmic Factoids n Class Ia: procainamide n Metabolism via acetylation n NAPA: K+ channel blockade n Polymorphic metabolism n Acute OD: seizures, dysrhythmias n Chronic use: SLE, myopathy, thrombocytopenia, agranulocytosis n False positive amphetamine on enzyme- based urine drug screens 9 8/11/14 Antidysrhythmic Factoids n Class Ia: quinidine n Torsades de pointes (K+ channel blockade) n Qunidine syncopy n Cinchonism (abdominal pain, tinnitus, AMS) n d-isomer of quinine n Hypoglycemia n dis-inhibited pancreatic insulin release due to K+ channel blockade n Class 1a: disopyramide n Anticholinergic n Hypoglycemia (pancreatic K+ blockade) Antidysrhythmic Factoids n Class Ib: lidocaine n Acute toxicity: CNS and dysrhythmias n Lidocaine wraps and liposuction n Metabolism n Hepatic CYP3A4 (saturable/drug interactions) n Active metabolite (MEGX) n Adverse drug event risks: n Advanced age n Hepatic insufficiency n Prolonged infusion (>3 mg/min for 24-72 hr) Antidysrhythmic Factoids n Class Ib: tocainide n ADRs limit clinical use n Rash, heptatoxicity, blood dyscrasias n Class 1b: mexiletine n CYP2D6 interactions n False positive amphetamine on enzyme-based urine drug screens 10 8/11/14 Antidysrhythmic Factoids n Class Ic: flecainide n Procainamide derivative n Prolonged PR and QRS duration with minimal QT prolongation n Negative inotrope n Class 1c: propafenone n Also β-blocker and calcium channel antagonist n Bradycardia, wide QRS, negative inotropy Ca2+ Channels n L-type n N-type (neuronal) n P-type (Purkinje) n T-type (muscular) L-type Ca2+ Channel n Four proteins n Span cell membranes n Regulates calcium entry n Closed in resting state n Require activation to open n Channel location determines the functional result of calcium entry 11 8/11/14 L-type Ca2+ Channel endocrine non-vascular smooth muscle Ca2+ Channel Activation - Myocardial n Ca2+- mediated Ca2+ - release n Result n éHR n écontractility n Modulators n Catecholamines n G protein n cAMP n protein kinase Ca2+ Channel Activation - Vascular n Result n vasoconstriction n Maintenance of BP n Modulators n α1 stimulation n β2 stimulation n angiotensin n endothelin 12 8/11/14 Ca2+ Channel Antagonism Consequences: X Hypotension Bradycardia Poor cardiac output Cardiogenic Shock Ca2+ Channel Agonist n Levosimendan n Directly opens Ca2+ channel n Heart failure treatment n Experimental treatment of CCB toxicity n No human overdose Ca2+ Channel Antagonism n Class IV drugs n Nifedipine (dihydropyridine) n Diltiazem (benzothiazepine) n Verapamil (phenylalkylamine) n Bepridil (diarylaminopropylamine) n Cyclic antidepressants n Class 1c agent Propafenone 13 8/11/14 Calcium Channel Blocker Factoids n Class IV observations n Pharmacokinetics n Hepatic metabolism n Highly protein bound n Drug interactions X n CYP3A4 and P-glycoprotein inhibitors n Digoxin, theophylline, OTHERS!!! n Acute toxicity n Bradycardia, hypotension, decreased contractility n Diabetogenic state Class IV Toxicity: Treatment n Decontamination n Charcoal for sustained release formulations n Pharmacotherapy n Calcium salts n Glucagon n High-dose insulin n Intravenous lipid emulsion (too recent for exam) n Phosphodiesterase inhibitors n Vasopressors n Technological therapy – novel (except pacing) n Aortic balloon pump, ECMO, MARS, Pacing, LVADs Potassium Channels 14 8/11/14 K+ Channel Structure n Tetrameric protein in the cell membrane n Central pore through which K+ flows n Normally closed n Opening leads to K+ efflux from the cell K+ Channel Function n Inhibition of cell function n Acts to prevent overuse of the cell n Opening stimuli n êintracellular energy molecules (ATP) n éintracellular Na+ n éintracellular Ca2+ Normal Function: Myocardial K+ Channel 2+ Ca + mV Na+ - mV 15 8/11/14 Normal Function: Myocardial K+ Channel n Effective Refractory Period n Depolarization not possible n Relative Refractory Period n Depolarization possible with sufficient electrical stimulus ERP RRP K+ Channel Modulation n K+ channel inhibition n Prolongs action potential (phase 3) n Equalizes refractoriness of ischemic and non- ischemic tissues without slowing conduction n ↑RRP allows for dysrhythmias (TdP) Na+ X Prolonged QTc / TdP n Antidysrhythmic n Class I (procainamide, quinidine and quinine) n Class II (sotalol) n Class III (amiodarone, bretylium, dofetilide, ibutilide) n Antidepressants n Serotonin agonists n Antihistamine n terfenadine, astemizole n Antipsychotic n haloperidol - butyrophenone n thioridazine - phenothiazine n sertindole - atypical 16 8/11/14 Prolonged QTc / TdP n GI agents n cisapride n Metabolic n hypokalemia (diuretics) n hypomagnesemia (diuretics) n Metals n arsenic www.torsades.org Antidysrhythmic Factoids n Class III: Amiodarone n Pharmacology n Structurally similar to T3 and is 40% iodine n Class Ic, II, IV activity n Competes for p-glycoprotein n ↑ digoxin and cyclosporine concentrations n ↑ warfarin anticoagulation 17 8/11/14 Antidysrhythmic Factoids n Class III: Amiodarone n ADRs with chronic therapy n Pneumonitis n dose dependent >400 mg/day n Oxygen sensitive n Hypo- or hyperthyroidism n Hepatic transaminitis n Corneal deposits n Sun-sensitive