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

2. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Calcium channel blockers  Phenylalkylamines –verapamil  Benzothiazepines –diltiazem  Dihydropyridines –nifedipine, felodipine, nimodipine, nicardipine, amlodipine, lercanidipine

3. 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

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

5. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Antidotes  Correction of acidosis  Calcium loading  Glucagon  Insulin-dextrose euglycaemia  Atropine  Inotropic agents  Cardiac pacing  Bay K 8644 (calcium channel agonist)

6. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Correction of acidosis  Correct acidosis to a pH within the normal range –L calcium channel function is impaired when the pH falls outside the physiological range –acidosis enhances the effect of verapamil and decreases the effect of calcium –sodium bicarbonate significantly improved myocardial contractility and cardiac output in a swine model of verapamil poisoning

7. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Calcium loading  Calcium loading is the most logical and appears to be the most effective agent to use in calcium channel blocker poisoning  It is primarily indicated in patients with heart block (who have usually taken verapamil or diltiazem)

8. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Glucagon  Glucagon is a well-accepted antidote for beta-blocker poisoning  The rationale for its use in CCB poisoning is that it activates myosin kinase independent of calcium flux  Clinical experience suggests it is less effective in this setting than in beta- blocker poisoning

9. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Insulin-dextrose euglycaemia  Insulin infusions should be used to treat hyperglycaemia or hyperkalaemia  Insulin-dextrose euglycaemia is more effective in animal models than calcium, adrenaline or glucagon  Effective in a case series of clinically serious poisonings  Hypotension that is refractory to volume loading, correction of acidosis and calcium salts

10. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Insulin-Euglycaemia  Insulin as an inotrope –myocardial ischaemia/infarction –endotoxic shock –cardiogenic shock post cardiopulmonary bypass –CCB and  –blocker induced myocardial depression  Yuan TH, Kerns WP, Tomaszewski CA,Ford MD, Kline JA. Insulin-glucose as adjunctive therapy for severe calcium channel antagonist poisoning. J Tox Clin Tox 1999; 37(4): 463–474

11. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Insulin-Euglycaemia  Rationale –In unstressed, aerobic state the myocardium relies primarily on free fatty acids (FFAs) for mechanical energy –During shock, substrate preference shifts from FFAs to carbohydrate oxidation

12. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Insulin-Euglycaemia  In the presence of –inhibition of insulin release –insulin resistance –poor tissue perfusion l impaired glycolysis and carbohydrate delivery  Systemic hyperglycaemia and inefficient myocardial energy transfer –myocardial depression

13. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Insulin-Euglycaemia  Hypokalaemia –Shift of extracellular K + to intracellular via Na + /K + pump –Na + shift means resting membrane potential becomes more negative (hyperpolarisation) l decrease arrhythmias –Prolongs plateau phase of action potential l increases calcium entry –Aim for K + 2.8–3.2 l Replace if K + < 2.5

14. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Atropine  Vagal tone is increase by vomiting and gastrointestinal decontamination  Atropine should be given to all patients who are vomiting or having GI decontamination  Atropine should be given to all patients with bradycardia  A response may only occur after calcium loading

15. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Inotropic agents  Dopamine is the initial pressor agent of choice (75% response) for diltiazem overdose  Isoprenaline produces a therapeutic response in 50% of patients  Action is predominantly through increasing the frequency of impulses originating in the SA node  These agents are often ineffective as chronotropic agents when there is a high degree of conduction block

16. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Cardiac pacing  Ventricular rather than atrial pacing  In severe poisoning the heart may fail to capture and pharmacological therapy will still be required

17. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Calcium channel agonists  Calcium channel agonists (eg. Bay K 8644) would appear to be a logical antidote  Animal studies using these compounds have not been very promising