Class IV Antiarrhythmic Agents Calcium Channel Blockers Jen

Class IV Antiarrhythmic Agents: Calcium Channel Blockers Jen Foley and Quincey Melonakos

CCB as Antiarrhythmic Agent • Originally introduced as antianginal agents • Verapamil and Diltiazem (non-dihydropyridines) have antiarrhythmic effects • Dihydropyridines (nifedipine) do not have antiarrhythmic effects and may cause arrhythmias • Indicated for use in A fib, A flutter, and SVT (Katzung & Trevor, 2015; Therapeutic Research Center, 2016 b).

CCB Effect on Action Potential • Blocks activated and inactivated L-type calcium channels (slow calcium channels) • Slows Phase 4 Depolarization and conduction velocity of SA and AV nodes • Lengthens antegrade and retrograde refractory periods of AV node • Slows sinus rate and increases PR interval on ECG via slowing of conduction through AV node (Up. To. Date, 2017 a)

Pharmacokinetics Verapamil • Half-life (oral form) 4 -7 hrs. • Onset of action Diltiazem • Half-life (oral form) 3 -9 hrs. • Onset of action • Oral IR: 30 -60 min. • IV Bolus: 3 -5 min. • IV Bolus: 3 min. • Absorption: well absorbed • Protein bound 90% • Protein bound 70 -80% • Bioaivailabilty 20% • Bioavailability 40% • Metabolized by liver by CYP enzymes • Metabolized by liver by CYP 450 • Excreted in urine: 70% metabolites, 3 -4% unchanged drug, >16% in feces • Excreted in urine (2 -4% unchanged drug) and feces (Katzung & Trevor, 2015; Up. To. Date, 2017 c, Up. To. Date, 2017 d)

Side Effects/Adverse Drug Reactions • • Headache Lightheadedness Flushing Peripheral Edema Nervousness Constipation CCB Poisoning: Bradycardia, atrioventricular block, cardiac arrest, and heart failure *Largely dose dependent (Up. To. Date, 2017 a; Up. To. Date, 2017 b)

Drug-Drug Interactions CYP 450 Inhibitors • Acyclovir • Caffeine • Ciprofloxacin • SSRIs • Beta-blockers • Oral Contraceptives • Famotidine CYP 450 Inducers • Omeprazole • Phenobarbital • Phenytoin • Rifampin • Amiodarone • Prednisone • Montelukast MANY drug interactions!!! Always check for drug interactions before starting CCB (Therapeutic Research Center, 2016 b).

Brief scenario cc: 55 -year-old male c/o fluttering in his chest, light headed, SOB. HPI: 55 -year-old male presented to the ER this evening after feeling what he describes as a fluttering in his chest, light-headed, and SOB. Onset of symptoms x 3 days ago, worse with activity, nothing improves the symptoms. PMHx: Depression FHx: Father HTN, AAW 80 yr. Mother Depression, AAW 78 yr SHx: Current smoker 1 pk/day x 20 years 0 smokeless tobacco ETOH occasional, 1 -3 beers every weekend 0 recreational drug use MEDS: None Allergies: None

Brief scenario cont. . . EXAM: Patient in mild distress, anxious. ROS w/o abnormal findings except cardiac exam. Irregular rhythm noted on auscultation, rate 160 bpm, (-) for murmur or rub. Pulses +2 all extremities, cap refill <2 seconds, skin warm and dry. See vs. VS: 140/80 (RUE) mm. Hg, 145/79 (LUE), HR 160 bpm, RR 22, Sp 02 95% RA, Temp 36. 6 temporal. Pain 0/10. WT: 250 lb, Ht 5’ 5”. BMI 41. 6 12 lead EKG = atrial fibrillation with rapid ventricular response (RVR). Rate 160 bpm.

12 -lead EKG Atrial Fibrillation c RVR (Image retrieved from Healio, n. d. )

Brief scenario cont. . . Assessment/Plan: The patient is diagnosed with new onset atrial fibrillation and he is admitted to the telemetry floor. Atrial Fibrillation with RVR Admit to telemetry NPO p MN ECHO in am r/o thrombus Heparin gtt per protocol Labs in am: PTT, CBC, BMP, BNP, CK, Troponin Interventional Cardiology consult for possible heart cath and cardioversion in am *Diltiazem gtt 5 mg-15 mg IV for rate control. Stop for SBP <100 mm. Hg, HR< 60 bpm. Rhythm change to wide complex. Call provider if gtt stopped. (Phang & Olshansky, 2017). PTs Risk Factors for Afib Obesity Smoking ETOH ? Unknown CV Hx ? Sleep apnea

Use of Diltiazem: Why CCB for this Scenario? Diltiazem is used to slow the ventricular response in atrial fibrillation, atrial flutter, or atrial tachycardia. CCBs work on myocardial tissue mediating electrical conduction with slow action potential (calcium current driven). SA & AV node. The patient does not have any known contra-indications such as heart failure, LV failure, s/s acute STEMI w/impaired ventricular function, hypotension, wide complex arrhythmia. Not taking a beta blocker. · (-) inotropic – force of contraction · (-) chronotropic –heart rate Emergent cardioversion is not indicated at this time because the patient is relatively stable. ECHO is needed to r/o thrombus (prevent stroke) prior to cardioversion Rate control benefits: Decrease the workload of the heart Oxygen demand, consumption Increase diastole coronary artery perfusion Symptom improvement - SOB, b/p, perfusion, palpitations, CP, weakness Spontaneous conversion Avoid demand ischemia, tachycardia-associated cardiomyopathy (Podrid, 2017).

Brief scenario cont. . . the plot thickens You are the night shift provider for the telemetry unit and you receive a page that your patient has deteriorated. Upon arriving at the bedside you assess the patient. The patient is cool to the touch and is lethargic but protecting his airway, pulses thready and weak. . As you move the patient to the ICU the staff report that the IV pump had delivered the entire bag of Diltiazem in less than an hour. The patient has received 100 mg of Diltiazem and is now in cardiogenic shock. VS: 60/40 mm. Hg, HR 30, RR 16, Sp 02 93% on 6 L NC. As a provider, you recognize that a CCB overdose requires aggressive supportive care. Assessment/Plan: Cardiogenic shock IVF bolus Vasopressors/Vasoactives/Inotrope Calcium IV myocardial function vascular tone Glucagon *off label use, CCB induced myocardial depression (Glucagon, 2017). Produces (+) inotropic & (+) chronotropic effects (Glucagon, 2016). Hyperinsulinemia/euglycaemia therapy Lipid emulsion therapy (refractory shock) ECMO (refractory shock) (Reitens, de Lange, Donker, & Meulenbelt, 2016).

Hyperinsulinemia-euglycemia Therapy Mechanism not completely understood CCBs appear to disrupt fatty acid metabolism (accumulation, insulin signaling interference) = insulin resistance within the myocardium (no glucose uptake) state of carbohydrate dependence and insulin resistance “theoretically be overcome with high-dose insulin” (Barrueto, 2017). Also, Calcium is needed to facilitate exocytosis of insulin from the beta-islet cells of the pancreas CCBs block the influx of calcium = prevent insulin release from the beta-islet cells. High-dose insulin therapy to compensate for the decreased secretion of insulin. (Barrueto, 2017).

References Barrueto, F. (2017). Calcium channel blocker poisoning. Up. To. Date. Retrieved from https: //www-uptodate-com. ezproxy. lib. utah. edu/contents/calcium-channel-blockerpoisoning? source=search_result&search=mechanism%20 Hyperinsulinemia%20 euglycaemia%20 therapy%20 in%20 calcium% 20 channel%20 poisoning&selected. Title=1~150 Glucagon. (2016). Glucagon. Dyna. Med. Retrieved from http: //web. a. ebscohost. com. ezproxy. lib. utah. edu/dynamed/detail? vid=2&sid=7 fde 1516 -95 b 6 -4573 -9 aa 4 e 8 fc 781 c 64 c 9%40 sessionmgr 4007&bdata=Jn. Npd. GU 9 ZHlu. YW 1 l. ZC 1 sa. XZl. Jn. Njb 3 Bl. PXNpd. GU%3 d#AN=356454&db=dme Glucagon. (2017). Glucagon: Drug information. Up. To. Date. Retrieved from https: //www-uptodatecom. ezproxy. lib. utah. edu/contents/glucagon-drug-information? source=see_link#F 176460 Healio. (n. d. ). Healio Learn the Heart. Image Retrieved from https: //www. healio. com/cardiology/learn-the-heart/ecgreview/ecg-archive/atrial-fibrillation-with-rvr-ecg-5 Katzung, B. , & Trevor, A. (2015). Basic & Clinical Pharmacology, (13 th ed. ). Pennsylvania: Mc. Graw Hill Education. Phang, R. & Olshansky, B. (2017). Management of new onset atrial fibrillation. Up. To. Date. Retrieved from https: //wwwuptodate-com. ezproxy. lib. utah. edu/contents/management-of-new-onset-atrial-fibrillation? source=search_result&search =treatment%20 of%20 new%20 onset%20 atrial%20 fibrillation&selected. Title=1~67#H 8

References Podrid, P. J. (2017). Calcium channel blockers in the treatment of cardiac arrhythmias. Up. To. Date. Retrieved from https: //www-uptodate-com. ezproxy. lib. utah. edu/contents/calcium-channel-blockers-in-the-treatment-of-cardiacarrhythmias? source=search_result&search=diltiazem%20 for%20 arrhythmia&selected. Title=2~150#H 1428150565 Rietjens, S. J. , de Lange, D. W. , Donker, D. W. , Meulenbelt, J. (2016). Prtactical recommendations for calcium channel antagonist poisoning. The Netherlands Journal of Medicine, 74(2). Retrieved from http: //www. njmonline. nl/getpdf. php? id=1674 Therapeutic Research Center. (2016 a). Comparison of calcium channel blockers. Pharmacist’s Letter/Prescriber’s Letter. Retrieved from https: //utah. instructure. com/courses/452422/assign ents/4083542 Therapeutic Research Center. (2016 b). Cytochrome P 450 drug interactions. Pharmacist’s Letter/Prescriber’s Letter. Retrieved from https: //utah. instructure. com/courses/452422/pages/course-resources Up. To. Date. (2017 a). Calcium channel blockers in the treatment of cardiac arrhythmias. Retrieved from https: //www-uptodate -com. ezproxy. lib. utah. edu/contents/calcium-channel-blockers-in-the-treatment-of-cardiacarrhythmias? source=search_result&search=class%20 iv%20 antiarrhythmic%20 drugs&selected. Title=1~150

References Up. To. Date. (2017 b). Calcium channel blocker poisoning. Retrieved from https: //www-uptodate-com. ezproxy. lib. utah. edu/con tents/calcium-channel-blockerpoisoning? source=search_result&search=calcium%20 channel%20 blocker%20 poisoning&selected. Title=1~15 Up. To. Date. (2017 c). Diltiazem: Drug information. Retrieved from https: //www-uptodate-com. ezproxy. lib. utah. edu/contents /diltiazem-drug-information? source=search_result&search=diltiazem&selected. Title=1~150 Up. To. Date. (2017 d). Verapamil: Drug information. Retrieved from https: //www-uptodatecom. ezproxy. lib. utah. edu/contents/ver apamil-druginformation? source=search_result&search=verapamil&selected. Title=1~150