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When Cardiovascular Medications Become Toxins Sami Alsolamy ICU Fellow When Cardiovascular Medications Become Toxins Sami Alsolamy 5/23/2017 Objectives Discuss the pathophysiology and pharmacokinetics of digoxin, ß-blockers, and CCBs. Recognize and treat patients poisoned by CV toxins, based on properties of the specific agent(s) involved. When Cardiovascular Medications Become Toxins Sami Alsolamy 5/23/2017 Introduction Cardiovascular agents were the fourth most common pharmaceutical agent involved in poisoning fatalities in the US. CCBs ( 60 %), ßblockers (17% ), and digoxin (17%. When Cardiovascular Medications Become Toxins Sami Alsolamy 5/23/2017 Cardiac Glycosides Cardiac glycosides became widely accepted as a medical treatment for heart failure. Digoxin, Derived from the foxglove plant Is the most commonly pre scribed cardiac glycoside in north amarica . When Cardiovascular Medications Become Toxins Sami Alsolamy 5/23/2017 ß-blockers At least 15 different ß-blockers are commonly used in the North America They have proven effective for the treatment of ischemic heart disease, hypertension, congestive heart failure, and certain dysrhythmias Nonspecific ß- blockers that also block α 1 receptors eg : Labetalol and carvedilol Nonspecific ß- blockers that blocks both ß 1 and ß 2 receptors eg : Propranolol Selective for ß 1 receptors eg : metoprolol When Cardiovascular Medications Become Toxins Sami Alsolamy 5/23/2017 CCBs Due to their negative inotropic and chronotropic effects, CCBs are used for the treatment of hypertension, dysrhythmias, and angina. 10 CCBs approved for clinical use, each belonging to 1 of 4 classes: the phenylalkylamine class (verapamil), the benzothiazepine class (diltiazem), the diarylaminopropylamine class (bepridil), The dihydropyridine class (nicardipine, nifedipine, isradipine, amlodipine) When Cardiovascular Medications Become Toxins Sami Alsolamy 5/23/2017 Pharmacokinetics When Cardiovascular Medications Become Toxins Sami Alsolamy 5/23/2017 Pharmacokinetics : Digoxin Digoxin is typically dosed orally at 0.125 to 0.5 mg/day It is well absorbed orally, with a bioavailability of about 70 to 80%. Clarithromycin, erythromycin, and tetracycline alter gut flora and may lead to elevated serum levels of digoxin. Drugs that decrease absorption, such as antacids, cholestyramine, metoclopramide, and neomycin. When Cardiovascular Medications Become Toxins Sami Alsolamy 5/23/2017 Pharmacokinetics : Digoxin….(2) • Distribution of digoxin follows a 2-compartment model • Followed by a slower distribution to cardiac tissue over a period of 6 to 8 hours Serum peak 2-3 h When Cardiovascular Medications Become Toxins Sami Alsolamy 5/23/2017 Pharmacokinetics : Digoxin….(3) • Digoxin is approximately 25% protein-bound. • It has a volume of distribution in adults of 6 to 7 L/kg • Digoxin is metabolized to a very small extent via hydrolysis, oxidation, and conjugation. • About 50 to 70% is excreted unchanged by the kidney, and dosing should be adjusted according to the patient’s creatinine clearance. • Smaller amounts of the drug are excreted in bile, with enterohepatic recycling occurring. • The elimination half-life ranges from 36 to 51 hours. When Cardiovascular Medications Become Toxins Sami Alsolamy 5/23/2017 Pharmacokinetics : ß-blockers When Cardiovascular Medications Become Toxins Sami Alsolamy 5/23/2017 Pharmacokinetics : ß-blockers Equally important properties, which vary from one beta-blocker to another, include cardioselectivity, membrane-stabilizing effect, lipophilicity, and intrinsic sympathomimetic activity. There is also large variation in the volume of distribution among ß-blockers When Cardiovascular Medications Become Toxins Sami Alsolamy 5/23/2017 ISA, intrinsic sympathomimetic activity; MSE, membrane-stabilizing effect ; Vd, volume of distribution; VT, ventricular tachycardia Hoffman, Robert S..Goldfrank’s of Toxicologic Emergencies When CardiovascularManual Medications Become Toxins Sami Alsolamy 5/23/2017 Pharmacokinetics : CCBs When Cardiovascular Medications Become Toxins Sami Alsolamy 5/23/2017 Pharmacokinetics : CCBs Onset of action following an oral dose of an immediate releas preparation usually occurs within 30 to 60 minutes. All CCBs are highly protein-bound, and most have large volumes of distribution. Elimination half-lives range from 1.3 to 64 hours. Increased elimination half-life may develop in the setting of an overdose When Cardiovascular Medications Become Toxins Sami Alsolamy 5/23/2017 Pharmacokinetics : CCBs Hoffman, RobertWhen S., Goldfrank’s Manual of Toxicologic Emergencies Cardiovascular Medications Become Toxins Sami Alsolamy 5/23/2017 Pathophysiology When Cardiovascular Medications Become Toxins Sami Alsolamy 5/23/2017 Pathophysiology: Digoxin Increase in vagal tone Inhibits the Na / K ATPase. (1) increasing the force of myocardial contraction to increase cardiac output (2) decreasing atrioventricular (AV) conduction to slow the ventricular rate i.. When Cardiovascular Medications Become Toxins Sami Alsolamy 5/23/2017 Pathophysiology: Digoxin Block SA and AV node Paralyzes the Na-K pump, Increase cardiac automaticity, When Cardiovascular Medications Become Toxins Sami Alsolamy 5/23/2017 Digoxin : ECG Atrial fibrillation with slow, regular ventricular rate (AV dissociation). Nonparoxysmal junctional tachycardia (rate 70– 130 beats/min). Bidirectional ventricular tachycardia When Cardiovascular Medications Become Toxins Sami Alsolamy 5/23/2017 Pathophysiology : ß-blockers When Cardiovascular Medications Become Toxins Sami Alsolamy 5/23/2017 Pathophysiology GDP cAMP: augments myocardial contraction , enhances cardiac conduction , and accelerates heart rate . When Cardiovascular Medications Become Toxins Sami Alsolamy 5/23/2017 Complex beta2 effects include vascular (smooth muscle relaxation and vasodilation) and liver (glycogenolysis, gluconeogenesis). When Cardiovascular Medications Become Toxins Sami Alsolamy 5/23/2017 Propranolol Propranolol's toxicity derives from its lipophilic nature and membrane-stabilizing effect that allow it to penetrate the CNS, leading to obtundation, respiratory depression, and seizures. When Cardiovascular Medications Become Toxins Sami Alsolamy 5/23/2017 Sotalol : Potassium Channel Blockade Sotalol is a nonselective antagonist that is unique because of its ability to block the delayed rectifier potassium current (I Kr ) responsible for repolarization. This prolongs the action potential duration and is manifested on the electrocardiogram by a prolonged QTc. When Cardiovascular Medications Become Toxins Sami Alsolamy 5/23/2017 Pathophysiology: Calcium channel blockers When Cardiovascular Medications Become Toxins Sami Alsolamy 5/23/2017 Pathophysiology : CCB Phase 2 (plateau phase ) When Cardiovascular Medications Become Toxins Sami Alsolamy 5/23/2017 Pathophysiology : CCB Reduce cardiac contractility, depress SA nodal activity, and slow AV conduction In smooth muscle, CCBs cause vasodilation and lead to hypotension. Each group binds a slightly different region of the calcium channel and thus has different affinities for the various L-type calcium channels both in the myocardium and the vascular smooth muscle. Nifedipine overdose more commonly causes reflex sinus tachycardia from peripheral vasodilation. When Cardiovascular Medications Become Toxins Sami Alsolamy 5/23/2017 ICU Managements When Cardiovascular Medications Become Toxins Sami Alsolamy 5/23/2017 ICU Management: Digoxin Acute Vs Chronic Marx: Rosen's Emergency Medicine, 7th ed When Cardiovascular Medications Become Toxins Sami Alsolamy 5/23/2017 ICU Management: Digoxin Serum digoxin level. It must be interpreted in relation to the clinical condition of the patient, the relationship of the time of obtaining the blood sample to that of the last dose and metabolic abnormalities. - It is inaccurate to use the therapeutic range of digoxin of 0.5– 2.0 ng/mL as the sole indicator of toxicity. In general, patients with pharmaceutical digoxin toxicity have clinical findings and mean serum concentrations above 2 ng/mL, measured at least 6 hours postingestion for digoxin. When Cardiovascular Medications Become Toxins Sami Alsolamy 5/23/2017 ICU Rx :Digoxin (3) There is no evidence to support gastric emptying for the treatment of digoxin overdose Multidose charcoal has historically been used for digitoxin toxicity because of its prominent 6% enterohepatic circulation. Antman EM, et al: Treatment of 150 cases of life-threatening digitalis intoxication with digoxin-specific Fab antibody fragments: Final report of a multicenter study. Circulation 1990; 81:1744 When Cardiovascular Medications Become Toxins Sami Alsolamy 5/23/2017 Fab Fragments (Digibind or Digifab) Intravascular Interstitial space 1- Bind intravascular free digoxin When Cardiovascular Medications Become Toxins 3- A concentration gradient is then established to facilitate movement of digoxin that is dissociated from its binding sites Sami Alsolamy 5/23/2017 Fab Fragments (Digibind or Digifab) Hoffman, Robert S..Goldfrank’s Manual of Toxicologic Emergencies When Cardiovascular Medications Become Toxins Sami Alsolamy 5/23/2017 Cont… Electrolyte Correction: K , Mg and Na Atropine is generally used for severe bradycardia and advanced AV block. Pacing: Transvenous pacing: may induce ventricular tachydysrhythmias in a myocardium made irritable by digitalis Cardioversion Can cause asystole. Phenytoin and lidocaine are the safest of the antidysrhythmic drugs for controlling tachydysrhythmias When Cardiovascular Medications Become Toxins Sami Alsolamy 5/23/2017 ICU Managements: Beta-adrenergic blockers When Cardiovascular Medications Become Toxins Sami Alsolamy 5/23/2017 Rx B.B : Hypotension and Bradycardia Catecholamines less effective : higher doses are usually needed Glucagon : Acts by stimulating adenylate cyclase GDP When Cardiovascular Medications Become Toxins Sami Alsolamy 5/23/2017 Rx B.B : Hypotension and Bradycardia The first step in the treatment of beta-blocker overdose : atropine, glucagon, and crystalloid fluids. A dose of atropine may quickly wear off or be ineffective, so infusion of more potent drugs or cardiac pacing is usually necessary. Glucagon: because of its short (20-minute) halflife, an infusionshould be started immediately after the bolus. Taboulet P, et al: Pathophysiology and management of self-poisoning with beta-blockers. Clin Toxicol 1993; 31:531. When Cardiovascular Medications Become Toxins Sami Alsolamy 5/23/2017 Rx B.B : Hypotension and Bradycardia Insulin and Glucose high-dose insulin infusion (in combination with glucose administration to maintain serum glucose levels) has been reported to improve outcomes The mechanism of action is via the positive inotropic effects of insulin. Inotropes and chronotropes Isoproterenol, Dopamine, or Epinephrine : Higher doses are usually needed Holger JS, Engebretsen KM, Fritzlar SJ, et al: Insulin versus vasopressin and epinephrine to treat beta blocker toxicity. Clin Toxicol 2007; 45:396. When Cardiovascular Medications Become Toxins Sami Alsolamy 5/23/2017 Rx B.B : Hypotension and Bradycardia Refractory cases of bradycardia external or transvenous pacemaker Phosphodiesterase inhibitors such as, amrinone and milrinone. Raise intracellular cyclic AMP levels and stimulate contractility Hypotension secondary to peripheral vasodila tion Intraaortic balloon pump or extracorporeal circulation Tsuji Sato, Okubo N, Naito H: Milrinone versus glucagon: Comparative hemodynamic effects in canine propranolol poisoning. Clin Toxicol 1994; 32:277. When Cardiovascular Medications Become Toxins Sami Alsolamy 5/23/2017 ICU Managements: Calcium channel blockers When Cardiovascular Medications Become Toxins Sami Alsolamy 5/23/2017 Hypotension and Bradycardia Atropine Calcium - Lead to increase the extracellular Ca 2+ concentration, which increases the transcellular concentration gradient, driving Ca 2+ intracellularly - Poor effect on peripheral vasodilation When Cardiovascular Medications Become Toxins Sami Alsolamy 5/23/2017 Rx CCB : Hypotension and Bradycardia Inotropes and Vasopressors Norepinephrine appears to be an appropriate initial catecholamine to use in hypotensive CCBpoisoned patients* Insulin and Glucose animal evidence * Buckley NA, Whyte IM, Dawson AH: Overdose with calcium channel blockers [letter]. BMJ 1994; 308:1639. When Cardiovascular Medications Become Toxins Sami Alsolamy 5/23/2017 Hemodialysis When Cardiovascular Medications Become Toxins Sami Alsolamy 5/23/2017 Hemodialysis CCBs: - Large volume - Hige plasma protein binding Optimal drug characteristics for removal: Relative molecular mass < 500 Water soluble Small Vd Minimal plasma protein binding Single compartment kinetics When Cardiovascular Medications Become Toxins Sami Alsolamy 5/23/2017 ? When Cardiovascular Medications Become Toxins Sami Alsolamy 5/23/2017 When Cardiovascular Medications Become Toxins Sami Alsolamy 5/23/2017 Hemofiltration Hemofiltration is useful for removal of substances with : Large volume of distribution Hemofiltration membranes are permeable to substances weighing up to 20,000 d. Brett AS, Rothschild N, Gray R, et al. Predicting the clinical course in intentional drug overdose: implications for the use of the intensive care unit. Arch Intern Med 1987; 147:133–137 When Cardiovascular Medications Become Toxins Sami Alsolamy 5/23/2017 Hemoperfusion Drug clearance is not limited by: Low water solubility, High molecular weight Increased protein binding But need central compartment Rommes JH. Haemoperfusion, indications and side-effects. Arch Toxicol 1992; 15:S40 –S49 When Cardiovascular Medications Become Toxins Sami Alsolamy 5/23/2017