Calcium Channel Blocker O.D.

1. Calcium Channel Blocker O.D. Dennis P. McKenna Albany Medical Center Hospital

2. 28 y.o. Male • Arrives at AMCH ED 1345 • Admitted to taking approx 30 Verapamil tabs last PM • Intentional suicide attempt • Pt denies other co-ingestions • H/O prior suicide attempts in past • Began vomiting ~ 0300 • Pt c/o diaphoresis and occasional lightheadedness

3. PMHx: LVH, Depression, Suicide attempts Meds: Verapamil, Albuterol Allergies: Keflex Soc: Tob 1 ppd, Denies ETOH Occupation: RN

4. VS on arrival: T 97.3 HR 48 RR 30 106/52 PE: Awake,alert Slightly dry MM CV – Regular, Brady Lung – CTA Abd – TTP RUQ Ext – No c/c/e Neuro – Nonfocal

5. ED Timeline: 1344 Pt arrives 1349 EKG done 1355 Atropine 1 mg IV 1400 10% CaCl 1 amp IV 1400 Phenergan 12.5 mg IV 1500 Inapsine 0.625 mg IV 1530 D/W CCA Dr. Nelson—Admit to CCU 1540 10% CaCl 1 amp IV 1645 10% CaCl 1 amp IV 1738 Central Line placed 1830 10% CaCl 1 amp IV

6. ED vital Signs: HR BP 1350 48 106/52 1410 41 116/48 1600 46 104/54 1700 68 135/65 1740 44 121/57 1830 38 114/72 CaCl given @ 1400, 1540, 1645, 1830 Atropine given @ 1355

7. Physiologic Role of Calcium • Ca driven intracellular • Across large concentration and electric gradient • Through Ca-specific, voltage sensitive channels • Influx is critical for cardiac and smooth muscle • Little physiologic influx for skeletal muscle • In myocardial cells, slow Ca influx creates plateau phase (Phase 2) • Causes additional Ca to be released from sarcoplasmic reticulum • “Calcium-induced Calcium release” • Ca binds Troponin C actin and myosin bind • Results in contraction • Plays additional role in spontaneous depolarization (Phase 4)

8. Mechanism of Action: Calcium Channel Blockers (CCBs) • Antagonize slow Ca channels • Impairs Ca influx into cells • In vascular smooth muscle relaxation and arterial vasodilatation • In myocardium decreased force of contraction and negative inotropy • Also inhibits SA and AV nodes reduced HR

9. Mechanism of Action: Calcium Channel Blockers Eleven CCBs available in U.S. Class Specific Compounds Phenylalkylamine Verapamil (Calan) Benzothiazepine Diltiazem (Cadizem, Dilacor, Tiazac) Dihydropyridines Nifedipine (Procardia, Adalat) Isadipine (DynaCirc) Amlodipine (Norvasc) Feldopine (Plendil) Nimodipine (Nimotop) Nisoldipine (Sular) Nicardipine (Cardene) Diarylaminopropylamine ether Bepridil (Vascor) T Channel blocker Mibefradil (Posicor)

10. Mechanism of Action: Calcium Channel Blockers Verapamil most profound inhibitory affects on SA and AV nodes most potent at decreasing HR, CO and BP Diltiazem only moderate myocardial depressant effects significant cardiovascular effects, but not as potent as verapamil Nifedipine very little affinity for myocardial Ca channels greatest effect upon peripheral vascular smooth muscle greatest decrease in SVR

11. Mechanism of Action: Calcium Channel Blockers Potential therapeutic roles for each CCB • Verapamil and Diltiazem Tx HTN, Reduces myocardial O2 demand, Rate control in Afib, Aflutter, and Tx SVT • Nifedipine Tx disease with increased peripheral vascular tone e.g. HTN, Raynaud’s, Prinzmetal’s angina, Esophageal spasm, vascular HA, post-SAH vasospasm

12. Pharmakokinetics of CCBs • All CCBs absorbed well orally • Verapamil undergoes hepatic metabolism and is renally eliminated as inactive metabolites • Diltiazem undergoes extensive first-pass effect, deacylated into acetyldiltiazem, eliminated via biliary tract • Nifedipine undergoes extensive hepatic metabolism, without production of active metabolites All CCBs highly protein bound Volume of Distribution (VD) large for Verapamil (5.5 L/kg) and Diltiazem (5.3 L/kg) VD small for Nifedipine (0.8 L/kg) High protein bound + Large VD = Limited use HD

13. Epidemiology of CCB OD 1986 1200 Exposures 7 deaths 1995 8300 Exposures 69 deaths • As a class of drug, only cyclic antidepressants and opiods were associated with more deaths • In 1989 Verapamil, Diltiazem and Nifedipine all in Top 20 of Rx • Increase in death also associated with introduction of sustained-release preparations

14. Physiologic Manifestations of CCB Poisoning Mostly cardiovascular system • Myocardial depression and peripheral vasoldilation -Bradycardia and hypotension • AV conduction abnormalities • Idioventricular rhythms • Complete Heart block • Junctional escape rhythms • May present initially asympomatic • May deteriorate rapidly into severe cardiogenic shock

15. Physiologic Manifestations of CCB Poisoning Most common physical finding is Hypotension Early symptoms - Dizziness and fatigue More severe - Lethargy, syncope, AMS, coma and death GI symptoms (N/V) uncommon Szs, CVAs, ischemic bowel and renal failure occur

16. Physiologic Manifestations of CCB Poisoning All CCBs can produce severe bradycardia, hypotension and death • Verapamil has the most significant myocardial effect – Negative inotropic and chronotropic • Prospective, poison control center study showed Verapamil caused the most AV nodal block • Nifedipine can cause tachycardia initially, and develop bradycardia only w/ substantial ingestion • Death from Nifedipine class very uncommon

17. Physiologic Manifestations of CCB Poisoning Non-cardiovascular • Hyperglycemia Insulin release from islet cells dependent upon Ca influx • Noncardiogenic pulmonary edema Precapillary vasodilation causes increase in transcapillary hydrostatic pressure

18. Severity of Poisoning • Agent used and dose affect severity of poisoning • Coingestion of Beta Blockers or Digoxin potentiate conduction abnormalities • Co-morbid conditions and age have negative impact • Regular release formulations – Toxicity present in 2-3 hrs • Sustained-release products – Initial sxs delayed to 6-8 hrs, maybe as long as 15 hrs Toxicity may last as long as 48 hrs

19. Initial Approach to Management of CCB Ingestion Evaluate all suspected CCB regardless of VS or Sxs ABCs as indicated • O2 and Airway • Intravenous access • If hypotensive then Fluid Bolus (check for CHF) • Continuous cardiac monitoring • EKG, and repeat Q 2 hrs

20. Initial Approach to Management of CCB Ingestion Gastrointestinal decontamination • Avoid syrup of ipecac • Orogastric lavage if early (1-2 hrs) and particularly if large ingestion or sustained release • Activated charcoal 1-2 g/kg • Multiple doses charcoal (MDAC) without cathartic in all significant ingestions • Whole bowel irrigation (WBI) for sustained release ingestions dose till rectal effluent is clear *Goldfrank emphasizes MDAC and WBI*

21. Pharmacologic Treatment Options in CCB O.D. • Focus on improvement of CO and PVR • No single agent has demonstrated efficiency • Little prospective research done to date

22. Pharmacologic Treatment Options in CCB O.D. Atropine • Drug of choice for all patients with symptomatic bradycardia • Improves HR and CO in dog study • Little proven benefit in human studies • Initial improvement with Ca may improve efficacy of Atropine • Ease of availability and safety profile • Consider as initial therapy • Anticipate treatment failures

23. Pharmacologic Treatment Options in CCB O.D. Calcium • Treatment w/ Ca improves BP more than HR • Increase extracellular Ca concentration • Increase intracellular Ca gradient • Drives Ca through unblocked Ca channels • Reverses negative inotropy, impaired conduction and hypotension in poisoned human patients • Effect of Rx often short-lived in CCB O.D.

24. Pharmacologic Treatment Options in CCB O.D. Calcium (cont.) 13.4 mEq Ca in 1 gm CaCl 4.3 mEq Ca in 1 gm Ca gluconate • Initial bolus of 13-25 mEq Ca (10-20 cc 10% CaCl) • Repeat bolus every 15 to 20 minutes up to 4 doses OR Continuous infusion of 0.5 mEq/kg/hr • Digoxin toxicity worse with elevated intracellular Ca • Avoid Rx w/ Ca in setting of cardiac glycoside O.D. unless Fab used

25. Pharmacologic Treatment Options in CCB O.D. Catecholamines • Experimentally, no single agent has been consistently effective • Beta1-adrenergic receptors on myocardium • Alpha1-adrenergic receptors on peripheral vascular smooth muscle • Formation of cAMP leads to chain of events that allows for greater influx of Ca

26. Pharmacologic Treatment Options in CCB O.D. Glucagon • Endogenous polypeptide secreted by pancreas • Bypasses the beta-adrenergic receptors and activates adenyl cycles • No advantage pharmacologically over traditional vasopressors • Initial dose 2 to 5 mg IV over 30 to 60 seconds • Follow by 4 to 10 mg over 10 minutes if no response • Initial pediatric dose 50 mcg/kg • Short half-life • Maintenance infusion dosing at “response dose”

27. Pharmacologic Treatment Options in CCB O.D. Amrinone • Nonncathecholamine inotropic agent • Does not increase myocardial O2 demand • Traditionally used in CHF • Inhibits breakdown of cAMP • Increases intracellular Ca and inotropy • May cause hypotension • Use only as second agent with other inotropic agent

28. Other Treatment Options in CCB O.D. • Transthoracic cardiac pacing • Intravenous cardiac pacing • IABP • Emergent cardiopulmonary bypass • Extracorporeal membrane oxygenation (ECMO) • Experimental: Insulin and Digoxin