CCB Poisoning 101/11/04Calcium Channel Blocker PoisoningJohn Gualtieri, PharmDClinical Assistant ProfessorDept. of Experimental and Clinical PharmacologyCollege of Pharmacy, University of MinnesotaI. Objectives1.) Described the classic clinical manifestations of CCB poisoning.2.) Describe the mechanisms by which CCBs exert their toxic effects in the setting of drug overdose.3.) Be able to discuss patient disposition for cases of CCB overdose (i.e. when and where should these patients be admitted,how long should they be observed).4.) Provide appropriate GI decontamination guidelines for the management of CCB overdose patients.5.) Describe the pharmacological interventions available for the treatment of CCB poisoning, and be able to list them in orderof importance or priority.6.) Understand the mechanisms by which the treatments listed in objective 5 may potentially reverse the toxic effectsproduced by CCB poisoning.7.) Describe the appropriate dosing guidelines for the administration of CaCl2 and glucagon in the treatment of CCBpoisoning.8.) Be familiar with how to appropriately monitor a CCB poisoned patient.II. IntroductionSerious calcium channel blocker (CCB) overdoses are nasty cases to manage often requiring a numberof prolonged and aggressive critical care interventions. It is not uncommon for small hospitals to runout of calcium as well as vasopressor and intotropic drugs during the course of managing a CCBpoisoned patient. The mortality rate in cases of CCB overdose is one of the highest of all the prescriptiondrugs available in the United States. Only TCAs and opiates are typically associated with more drug-related deaths in the USA, annually. The fact that many of the dispensed CCB drugs are sustainedrelease preparations is also a major contributing factor to the high mortality rate associated with CCBoverdose. With overdoses of sustained-release CCB preparation, not only are the patients typicallytaking extremely large doses of the CCB, the duration is often protracted and wrought withcomplications requiring relatively long ICU stays. Acute TCA and opiate poisonings are relatively quickin onset and short in duration. An overdose of a sustained release CCB preparation may not displayevidence of toxicity for several hours after an ingestion and may last for 24 hours or longer afterexposure.III. Pharmacology/ToxicologyAll CCBs bind dihydropyridine (DHP) receptors on cardiac and smooth muscle cellmembranes, which inhibits the movement of calcium from extracellular sites through cellmembrane-based voltage sensitive L-type calcium channels. This pharmacodynamicaction decreases cardiac automaticity and myocardial contractility, and produces dilationof the vascular smooth muscle. Hemodynamic shock with the classic triad ofbradycardia, conduction blocks and systemic hypotension are the hallmarks of severeCCB poisoning.CCBs Four Primary Mechanisms of Toxicity1) Dilation of vascular smooth muscle: Caused by CCB-induced inhibition of the calciuminflux. Interference with intracellular binding and release of calcium may also contribute.2) Decreased cardiac automaticity: Calcium entry into SA and AV nodal cells provides thecurrent that results in depolarization. Inhibition of the inward calcium current intomyocardial cells slows the heart rate and prolongs AV conduction (PR intervallengthening and bradycardia are seen on EKG).3) Decreased myocardial contractility: Calcium entry during phase 2 of cardiacdepolarization triggers release of calcium bound by sarcoplasmic reticulum, which inCCB Poisoning 201/11/04turn results in attachment of actin and myosin to cause muscular contraction. CCB’simpede the inward calcium current responsible for triggering contraction and may alsoaffect binding of calcium within the cell.4) Impaired carbohydrate utilization: CCB intoxication is also associated with altered carbohydratemetabolism resulting hyperglycemia, lactic acidosis, and metabolic derangements similar to diabeticketoacidosis. CCBs shift normal cardiac metabolism away from free fatty acid utilization and forcesmyocardial cells to become carbohydrate-dependent. Yet, CCBs at the same time preventadequate myocardial utilization of carbohydrates due to three additional mechanisms of toxicity.i. CCBs inhibit calcium mediated insulin release by the pancreatic islet cells.ii. Insulin resistance appears to occur during CCB intoxicationiii. There is poor insulin and substrate delivery due to poor cardiac output.v This is a vicious cycle in that not only do CCBs directly inhibit myocardial contractility, reduce cardiacoutput, and reduce peripheral vascular resistance, leading to poor tissue perfusion, but CCBs alsoimpair carbohydrate utilization at the tissue level where carbohydrate utilization is critical during shock.• CCBs are classified into three major classes with the recent introduction of Bepridil as a new fourthclass called a diarylaminopropylamine ether.CLASSDRUGSPharmacology/ToxicologyPhenylalkylamineVerapamil• May produce profound SA and AV nodal inhibitionproducing severe cardiac conduction defects.• Reduces myocardial contractility.• Reduces peripheral vascular resistance but not to thedegree of the dyhyrdropyridines.• Most potent agent at decreasing heart rate, cardiacoutput, and blood pressure verses the other CCBclasses.BenzothiazepineDiltiazem• Moderate effects on myocardial contractility andconduction relative to verapamil.• Similar effect on vascular smooth muscle when comparedto verapamil.DihydropyridinesNifedipine,isradipine,amlodipine,felodipine,nimodipine,nicardipine,nisoldipine• Preferentially binds vascular smooth muscle andpredominantly decreases systemic and coronary vascularresistance leading to profound hypotension in the settingof DHP overdose.• Produce reflex increases in heart rate at therapeutic levelsby the unloading of the baroreceptors.• Cardiac contractility and bradycardia may still occur incases of severe overdose.Diarylaminopropylamine etherBepridil• Seldom used; reserved for tx of refractory angina pectoris• In addition to calcium blockade, it blocks the fast sodiumchannels and potassium channels resulting in prolongedQT intervals and potentially ventricular arrhythmiasincluding Torsades de Pointes.IV. PharmacokineticsAbsorption:• Rapid GI absorption with the immediate release products with an onset of action of 0.5-3hours and a duration of action of 6-10 hours.• Sustained