Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Calcium channel blockers Professor Ian Whyte Hunter Area Toxicology Service

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Cardiac arrhythmia  Primary –quinidine–like drugs, sympathomimetic drugs, calcium channel blockers, β– blockers, digitalis, chloroquine  Secondary to metabolic/electrolyte abnormalities –salicylates, methanol, ethylene glycol

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Cardiotoxic drugs  All patients should have –oxygenation and protection of airway –decontamination of the GIT l atropine pre–medication –correction of electrolyte abnormalities l acid base balance –cardioversion when appropriate –consultation l PIC

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Cardiac arrest  Successful resuscitation has been well documented after 8 hours of CPR  Overdose patients usually have –a reversible cause for their arrest –good general health –novel treatments for arrhythmias –cerebral protection

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Calcium channel blockers  Block calcium channels (L-type) in heart and blood vessels –prolong depolarisation l ↑QRS width –block SA and AV node conduction l heart block l asystole –vasodilators –cerebral protection

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Calcium channel blockers  Hypotension –peripheral vasodilatation and myocardial depression  Bradycardia –AV and SA node block

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital CCB case  18 yo female admitted 3 hours after self– poisoning with –3.5 g of slow release verapamil (Isoptin SR) –6 g of paracetamol –4.5 g of tetracycline –1 g of pseudoephedrine

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital CCB case  On arrival in ED –PR 120, BP 110/80, RR 20, afebrile –drowsy but oriented and cooperative

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital CCB case  GI decontamination –emesis before arrival –lavaged with return of green tablets –50 g of charcoal with sorbitol repeated 4 h later

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital CCB case  Investigations –ECG l sinus tachycardia with normal QRS width –serum paracetamol at 4 h was 38 µmol/l l hepatotoxicity > 1300 µmol/l at 4 hours

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital CCB case  16 hours post overdose –BP fell to 70/40 and then 50/30 –PR 50 –oxygen saturation dropped to 75 %

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital CCB case  16 hours post overdose –ECG l absent p waves l prominent u waves l normal QRS duration and QT interval

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital CCB case  Treatment –IV atropine 0.6 mgs – no response

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital CCB case  Treatment –IV calcium gluconate l 6 g over 20 minutes l further 6 g over the next hour –pr 60, sinus rhythm, BP 100/80 –oxygen saturation > 95 % –infusion of 10% calcium gluconate at 2 G/h for 10 hours –she was also given 2.5 L IV fluids

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital

CCB case  Outcome –non–cardiogenic pulmonary oedema –twenty four hours post admission l largely recovered, sinus rhythm PR 60, BP 115/70

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital CCB case  Outcome –peak serum Ca was 4.8 (2.18–2.47 mmol/l) –serial verapamil levels at 6, 18, 22 and 46 hours were 616, 2374, 2518 and 1006 ng/ml l range during usual therapy –100–300 ng/ml

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital CCB case  A thirty one-year-old female is brought to the Emergency Department by relatives  She states that she ingested 25 x 240 mg sustained-release diltiazem tablets approximately one hour earlier as a suicide attempt

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital CCB case  The tablets do not belong to her and she has no significant intercurrent illnesses  She appears upset but otherwise well  Her pulse is 70/minute, her blood pressure 125/70 mmHg and her ECG shows normal sinus rhythm

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital CCB case  Outline your initial management

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital CCB case  Despite the relatively benign presentation, this is a life-threatening overdose  Aggressive gastrointestinal decontamination using whole bowel irrigation before clinical effects of poisoning develop

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital CCB case  Give oral polyethylene glycol solution (GoLYTELY) at a rate of 15–20 mL/kg/h  Few patients can drink it this fast so it is best to place a nasogastric tube (premedicate with atropine!)

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital CCB case  Then sit the patient on a commode chair and continue until the rectal effluent looks like the GoLYTELY solution  This may take several hours

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital CCB case  Institute appropriate monitoring  This includes establishing IV access, continuous ECG monitoring and frequent non-invasive blood pressure monitoring  This patient will need a minimum of 16 hours monitoring even if she remains completely asymptomatic

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital CCB case  Admission should be to a monitored bed and personnel should be available who are capable of placing an arterial line, transvenous pacemaker and Swan-Ganz catheter

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital CCB case  Some six hours later, the patient is noted to be drowsy with a pulse rate of 45/minute (first degree heart block) and blood pressure of 80/40 mmHg  How do you respond now?

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital CCB case  Despite the excellent decontamination, sufficient drug has been absorbed to result in a toxic syndrome  There is no way of knowing at present how severe it is going to be  Best to assume the worst  Management at this point includes

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital CCB treatment  Normal saline bolus (10–20 mL/kg)  Calcium –5–10 mL of 10% calcium chloride or 10–20 mL of 10% calcium gluconate over 5 minutes –repeat every 3–5 minutes up to 3 to 5 doses –if response institute calcium infusion of 1–10 mL/h of 10% calcium chloride –monitor serum calcium after 30 mL of calcium chloride or equivalent

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital CCB treatment  Glucagon 0.05 mg/kg IV –repeat every 5–10 minutes as needed –if response consider infusion of 0.075– 0.15 mg/kg/h  Atropine, isoprenaline and/or pacing may be tried if associated symptomatic bradycardia  Dopamine infusion if still persistent hypotension

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital CCB treatment  If no response to the above consider –insulin bolus 1 unit/kg with glucose 25 mL of 50% dextrose IV followed by –insulin infusion of 0.5 units/kg/hr with 50% dextrose infusion at 0.5 g/hr adjusted according to hourly glucose checks

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital

Cardiopulmonary bypass  As a last resort extracorporeal blood pressure support eg cardiopulmonary bypass may be considered

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Antidotes: asystole & bradycardia  Atropineeverything  Bicarbonate tricyclic antidepressants  Calcium calcium channel blockers  Diazepamchloroquine, organochlorines  Epinephrineeverything, β–blockers  Fab fragmentsdigoxin  Glucagonβ–blockers, CCBs