1. BACK TO BASICS: PHARMACOLOGY CHAD C. CRIPE, MD Department of Anesthesiology & Critical Care Medicine Division of Cardiothoracic Anesthesiology The Children’s Hospital of Philadelphia

2. DISCLOSURE Nothing to disclose

3. OBJECTIVES Review the pharmacology & implications for the pediatric perfusionist of medications commonly used in patients with congenital heart disease – cardiovascular-Renal therapeutics – cardiac glycoside – antiarrhythmics – medications used in the treatment of pulmonary hypertension – antidepressants

4. CARDIOVASCULAR-RENAL THERAPEUTICS Common therapeutic classes – ACE inhibitors – angiotensin II blockers – aldosterone blockers – diuretics – beta blockers – calcium channel blockers

5. RENIN-ANGIOTENSIN- ALDOSTERONE

6. ACE INHIBITORS ACE inhibitors- differ with respect to potency, presence of prodrug and pK effects (renal elimination) – Captopril – Enalapril (Vasotec ® ) – Lisinopril (Zestril ® ) ACE inhibitors effective: – treatment of HTN – chronic renal disease in diabetes (diabetic nephropathy) – systolic heart failure: slow progression with improved survival prevent hypertrophy & remodeling after MI ↓ SVR, ↓ PCWP, ↓ PVR, ↑ CO, and ↑ exercise tolerance = reduction in mortality in HF patients Side effects: hypotension, ARF, ↑ K – cough, angioedema, anaphylactoid reaction r/t kinins kinins metabolized by ACE

7. CARDIOVASCULAR-RENAL THERAPEUTICS

8. ANGIOTENSIN II RECEPTOR BLOCKERS Angiotensin II blockers – Losartan (Cozaar ® ) – Candesartan – Valsartan (Diovan ® ) ATII blockers effective for: – treatment of HTN – diabetic nephropathy – heart failure to slow progression and improve survival prevent hypertrophy & remodeling after MI Side effects: similar to ACE inhibitors – lower rate of cough, angioedema – higher risk hypotension Both ACE and ARB contraindicated in pregnancy

9. ALDOSTERONE BLOCKERS Aldosterone blockers – Spironolactone (Aldactone ® ) – Eplerenone Aldosterone blockers used in treatment of – severe HF – HTN – edema RALES trial – 1663 NYHA class III/IV with LVEF <35% – given placebo or spironolactone – after 24 months, study d/c because 30% reduction in overall mortality with Spironolactone Side effects: hyperkalemia, renal dysfunction, endocrine irregularities-gynecomastia The use of ACE, ARB & AB (especially in combination) with CPB, blood loss or vasodilating effects of anesthetic vapors may result in significant hypotension

10. DIURETICS

11. Loop diuretics – Furosemide (Lasix ® ) – Bumetanide (Bumex ® ) – Torsemide (Demadex ® ) Act by inhibit reabsorb of NaCl in loop of Henle Used in the treatment of HTN and edema Side effects: ototoxicity, Ca excretion (renal calculi), gout, hypokalemic metabolic acidosis, allergy w/sulfonamide Thiazide diuretics – Hydrochlorothiazide (Diurel ® ) Act by inhibit Na transport in DCT (less effect than loop) Used in the treatment of HTN and edema Side effects: hypokalemic metabolic acidosis, gout, hyperlipidemia

12. BETA ADRENERGIC RECEPTORS B 1, B 2, B 3 receptors Excited by epinephrine and norepinephrine Beta Receptor – vasodilation (B 2 ) – cardioacceleration (B 1 ) – increased cardiac inotropy (B 1 ) – intestinal and uterus relaxation (B 2 ) – bronchodilation (B 2 ) – calorigenesis (B 2 ) – glycogenolysis (B 2 ), lipolysis (B 1 ), bladder wall relaxation (B 2 ), thermogenesis (B 3 )

13. BETA BLOCKERS B-Blockers – non-selective: Carvedilol, Labetalol, Sotalol, Propranolol, Nadolol – B 1 -Selective: Esmolol, Metoprolol, Atenolol – bioavailability may be variable: Propanolol & Metoprolol highly lipid soluble, hepatic metabolism, CNS effects Atenolol & Sotalol water soluble, eliminated in kidney, longer half life Used in treatment of – systolic heart failure: symptom improvement, reduced hospitalization and enhanced survival – HTN, angina, arrhythmia prevention – migraine prophylaxis – glaucoma – hyperthyroidism Side effects: bradycardia, hypotension, RAD, PVD, worsening of HF Recommendation from ACC/AHA continue beta blockers through periop period – implications for CPB: bradycardia, hypotension

14. CALCIUM CHANNEL BLOCKERS CCB inhibit L-type Ca channel found in cardiac and vascular smooth muscle – dihydropyridines: vasodilators, little effect on heart. Nifedipine, Nicardipine, Amlodipine – non-dihydropyridines: cardiac depressant. Verapamil, Diltizem Used in treatment of – HTN – angina – cardiac arrhythmias Side effects-short acting CCB – Increased mortality after MI – Increased GIB, cancer in elderly

15. CARDIAC GLYCOSIDE

16. DIGOXIN Clinical effects – vagomimetic effects which decrease conduction through SA and AV node- rate control – improved LVEF- function – attenuation of the renin-angiotensin-aldosterone system – reduced PCWP & SVR – increased CO – Reduction in plasma NE levels with Digoxin Pharmacokinetic differences between Digoxin and Digitoxin Digoxin has a narrow therapeutic window 0.8-2 ng/ml – arrhythmias (bradycardia/PVC), conduction disturbances, nausea/vomiting, visual changes – Digoxin toxicity with ↓ K or Mg – Digoxin specific antibody (Fab) used to treat overdose – Digoxin not removed via extracorporeal circulation

17. ANTIARRHYTHMICS

18. Class Ia- Na channel blockers – Quinidine, Procainamide, Disopyramide Class Ib – Lidocaine, Phenytoin, Mexiletine, Tocainide Class Ic – Flecainide, Propafenone Class II- Beta blockers – Propranolol, Esmolol, Metoprolol, Atenolol Class III-Potassium channel blockers – Amiodarone, Sotalol Class IV-Calcium channel blockers – Verapamil, Diltiazem Miscellaneous – Magnesium

19. CLASS I: NA CHANNEL BLOCKERS Class Ia- Na channel blockers (lengthen AP, intermed interact) – Procainamide slows conduction velocity and pacemaker rate, prolongs AP used for atrial and ventricular arrhythmias given oral or IV Hepatic metabolism, renal elimination toxicity: hypotension, lupus-related symptoms, pancytopenia Class Ib (shorten AP, rapid interact) – Lidocaine used to terminate VT or VF. Reduce dose in liver failure. Toxicity: CNS & cardiovascular symptoms – Mexiletine oral active congener of lidocaine used in ventricular arrhythmias & chronic pain syndromes (off label) Class Ic (min effect AP, slow interact) – Flecainide used in supraventricular arrhythmias, long half life toxicity: proarrhythmic

20. CLASS II, III, IV ANTIARRHYTHMICS Class II- Beta blockers – Propranolol slows SA automaticity & AV node conduction used for atrial arrhythmias, long QT syndrome toxicity: asthma, AV node blockade, acute heart failure Class III-Potassium channel blockers – Amiodarone prolongs AP duration and QT interval, slows HR and AV node conduction used for ventricular and supraventricular arrhythmias oral or IV route, hepatic metabolism toxicity: bradycardia, heart block, peripherial vasodilation, pulmonary and hepatic failure, hyper- or hypothyroidism – Sotalol isomer which has both K channel and beta blocking activity used for ventricular and atrial arrhythmias, drug of choice in fetal atrial flutter toxicity: bradycardia and proarrhythmic effects Class IV-Calcium channel blockers – Verapamil slows SA automaticity and AV node conduction, decrease cardiac contractility and decrease BP used in supraventricular tachycardias

21. MISCELLANEOUS ANTIARRHYTHMICS Magnesium – mechanism poorly understood, interacts with Na + K + ATPase, K and Ca channels – off-label use as drug of choice for torsades de pointes – toxicity: may see muscle weakness in overdose, CNS depression, heart block with digoxin

22. TARGETED PULMONARY HYPERTENSION THERAPY Prostanoids (prostacyclins) – Epoprostenol (Flolan ® ) IV, inhaled – Treprostinil (Remodulin ® ) IV, SQ, inhaled iNO Endothelin receptor antagonists – Bosentan (Tracleer ® ) – Ambrisentan (Letaris ® ) Phosphodiesterase type 5 inhibitor – Sildenafil (Revatio ® ) – Tadalafil

23. PROSTACYCLINS Epoprostenol (Flolan ® ) IV – strong vasodilator of all vascular beds & potent inhibitor of platelet aggregation, inhibit proliferation of vascular smooth muscle – dose: start IV @ 2ng/kg/min, titrate mean dose 11ng/kg/min – half life 6 minutes, rebound effects if abruptly withdrawn – complications: catheter related sepsis, heart failure, pulmonary edema, bleeding Treprostinil (Remodulin ® ) SQ, IV – uses: PAH NYHA class II-IV – vasodilator of pulmonary & systemic arterial beds via increase of cAMP – side effects: hypotension, antiplatelet effects, flushing, headache, GI bleed, pain with SQ admin – half life 4 hours

24. INHALED NITRIC OXIDE Originally named endothelium-derived relaxing factor – natural occuring vasodilator – supression of smooth muscles and platelet aggregation – produced from L-arginine in endothelial cells by eNOS Selective dilator of pulmonary vasculature Half life of 0.1-5 seconds Adverse effects – methemoglobinemia – cytotoxicity, DNA mutagenesis – immunosupression – may become a pulmonary irritant – interfere with surfactant function – decreased platelet function Delivered inhalation 5-40 ppm

25. ENDOTHELIN RECEPTOR ANTAGONISTS Endothelin-1 effect – ET-A: potent vasoconstrictor & smooth muscle proliferator – ET-B: mediate release of prostacyclin & NO Meta-anaylsis of 5 RTC; ERA improved exercise capacity, dyspnea, and improved PAP, PVR, CI Bosentan (Tracleer ® ) – nonselective agent blocker of ET-A & ET-B – side effects: liver injury (monthly LFT’s), anemia, peripheral edema, angioedema, teratogenic Ambrisentan (Letairis ® ) – selective ET-A blocker (less risk hepatic injury) Liu C, Chen J. Endothelin receptor antagonists for pulmonary arterial hypertension. Cochrane Database Rev. 2006;3:CD004434.

26. PHOSPHODIESTERASE INHIBITORS Slow metabolism of cGMP leading to decrease intracellular calcium which will cause smooth muscle relaxation and arterioles vasodilation PDE 5 inhibitors have been shown to significantly increase exercise tolerance and hemodynamics with PH Sildenafil (Revatio ® ) – given by mouth 3 x day – side effects: headaches, vision/hearing loss, priapism – contraindicated with use of nitrates (hypotension) Tadalafil (Adcirca ® ) – once a day dose GalièN, Ghofrani HA, Torbicki A, Barst RJ, Rubin LJ, Badesch D, Fleming T, Parpia T, Burgess G, Branzi A, Grimminger F, Kurzyna M, Simonneau G, Sildenafil Use in Pulmonary Arterial Hypertension (SUPER) Study Group. N Engl J Med. 2005;353(20):2148.

27. ANTIDEPRESSANTS 1 st generation – Tricyclic antidepressants (TCA) Amitriptyline (Elavil ® ) – Monoamine oxidase inhibitors (MAOi) Phenelzine (Nardil ® ) 2 nd generation – Selective serotonin reuptake inhibitors (SSRI) Celexa ®, Lexapro ®, Prozac ®, Paxil ®, Zoloft ® – Serotonin-norepinephrine reuptake inhibitors (SNRI) Effexor ®, Cymbalta ®

28. ANTIDEPRESSANTS TCA – off label use for chronic pain, generalized anxiety, panic disorders, PTSD, eating disorders and insomnia – side effects and toxicity limit use prolongation of QT and other arrhythmias anticholingeric effects- blurred vision, drowsiness seizures hallucinations orthostatic hypotension weight gain – 10 x daily dose may be fatal MAOi – hypertensive crisis with tyramine containing foods & merperidine

29. ANTIDEPRESSANTS SSRI – inhibit serotonin reuptake pump and increase postsynaptic serotonin – used in MDD, OCD, bulimia, panic and bipolar disorder – warnings: neuroleptic malignant or serotonin syndromes Mental status changes: agitations, hallucinations, coma Autonomic instability: tachycardia, labile BP, hyperthermia Neuromuscular aberrations: hyperreflexia, incoordination GI symptoms: nausea, vomiting, diarrhea – side effects: increased risk abnormal bleeding, hypoglycemia, and hyponatremia (SIADH) SNRI – increased side effects at high doses: diaphoresis, dizziness – potential for more NE effects (hypertension) during CPB

30. REFERENCES Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG, Jessup M, Konstam MA, Mancini DM, Michl K, Oates JA, Rahko PS, Silver MA, Stevenson LW, Yancy CW. 2009 focused update incorporated into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: developed in collaboration with the International Society for Heart and Lung Transplantation. Circulation. 2009;119(14):e391. Brunton L, Chabner B, Knollman B. Goodman and Gilman’s The Pharmacological Basis of Therapeutics 12 th ed. McGraw-Hill, 2010. Katzung B, Masters S, Trevor, A. Basic and Clinical Pharmacology, 11 th ed. Lange, 2009. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 1999;341(10):709. Warnes CA et al. ACC/AHA 2008 guidelines for the management of adults with congenital heart disease. J Am Coll Cardiol. 2008 Dec 2;52(23):e1-121. Fuster V, Walsh RA, Harrington RA. Hurst’s The Heart, 13 th ed. McGraw-Hill, 2010. GalièN, Ghofrani HA, Torbicki A, Barst RJ, Rubin LJ, Badesch D, Fleming T, Parpia T, Burgess G, Branzi A, Grimminger F, Kurzyna M, Simonneau G, Sildenafil Use in Pulmonary Arterial Hypertension (SUPER) Study Group. N Engl J Med. 2005;353(20):2148. Liu C, Chen J. Endothelin receptor antagonists for pulmonary arterial hypertension. Cochrane Database Rev. 2006;3:CD004434.