Commonly Used Veterinary Cardiac Drugs Vicky Yang 8/30/12

Can I possibly make this topic interesting???

CHF – What to Give? Diuretic Positive Inotrope ACE inhibitor

Diuretics

Loop Diuretics Furosemide Torsemide

Furosemide – Lasix/Salix Pharmacologic effects Inhibits Na+/K+/2Cl- co-transporter on ascending limb Drug exerts effect intraluminally (Na+, Cl-, K+) Dose 1-8 mg/kg bolus IV or IM 1 mg/kg/hr CRI Peak effect 30 min after IV dose, 1-2 hrs after oral dose Short duration of action (4-5 hours) Side effects Hyponatremia, hypochloremia, hypokalemia Alkalosis Ototoxicity especially with aminoglycosides Azotemia

Torsemide Longer duration of action Can persist for 12 hrs Approximately 10 times potency than furosemide More potassium-sparing Use as an adjunct to furosemide treatment

Thiazide Diuretics With or without spironolactone Hydrochlorothiazide Aldactazide

Hydrochlorothiazide Pharmacologic effects Dose Side effects Inhibits Na+, Cl- co-transporter at early distal nephron Longer duration of action (16-24 hrs in humans) Dose 2 mg/kg q12 hrs Aldactazide: dose according to spironolactone 25 mg/25 mg Side effects Hypokalemia, hyponatremia, hypochloremia Hypercalcemia: increase reabsorption at proximal tubule

Aldosterone Receptor Blockers Adverse effects of aldosterone Na+ retention by inhibiting Na+/K+ exchanger Promotes cardiac fibrosis Nephron growth Promotes endothelial dysfunction Inhibits release of NO Spironolactone RALES: 30% reduction in mortality Epleronone EPHESUS: 15% reduction in mortality

Spironolactone Pharmacologic effects Dose Side effects Aldosterone-receptor blocker at distal tubule Increase Na+ excretion K+ sparing Dose 1-2 mg/kg q12 hrs Use as adjunct treatment with furosemide Side effects Hyperkalemia, hyponatremia Facial dermatitis in cats

Aquaretics Arginine vasopressin (AVP) V2 receptor antogonists “Vaptans” Conivaptan Tolvaptan Lixivaptan

Diuretic Resistance Can occur even after 1 dose of diuretic Intravascular fluid contraction RAAS activation Aldosterone induced nephron growth Increase Na+ reabsorption Excessive circulating catecholamine Poor renal perfusion

Pimobendan Pharmacologic effects Dosing Side effects Ca+ sensitizer PDE III inhibitor Dosing 0.25-0.3 mg/kg Side effects GI (rare) Pro-arrhythmic

ACE Inhibitors RAAS stimulation Chymase Tissue specific ACE b-adrenergic system Low BP Hyponatremia Hypovolemia Chymase Tissue specific ACE

Adverse Effects of RAAS Vasoconstriction AT-1 receptor a1-receptor bradykinin breakdown Myocardial remodeling Endothelial dysfunction aldosterone Na+ retention

ACE Inhibitors: Benefits Vasodilation Aids in diuresis Myocardial remodeling Potential anti-arrhythmic effects

Enalapril Pharmacologic effects Dose Side effects Converted to enalaprilat by liver (active form) Competes with angiotensin 1 for ACE Long duration of action (12 hrs) Renal clearance Dose 0.5 mg/kg q12 hrs Side effects Hypotension hyperkalemia

Other ACEi Benazepril Lisinopril Benazeprilat active metabolite Renal and hepatic clearance 0.25-0.5 mg/kg q12 hrs Lisinopril No conversion needed Renal excretion Long half life 0.5 mg/kg q24 hrs

Other Methods of RAAS Blockage Angiotensin II receptor blockage Losartan Candesartan Valsartan Renin inhibition Aliskiren Aldosterone blocker for ACE inhibition “escape”

And Then Things Get Exciting… I used furosemide (lots!), pimobendan (overdose!), ACEi but…. we‘re still in the O2 cage!!

Vasodilators Preload reducers Afterload reducers Mixed agents Venodilators Diuretics Nitrates (nitroglycerin) Afterload reducers Decrease vascular resistance Hydralazine Calcium channel blockers Mixed agents Nitroprusside

Nitroprusside Phomocologic effects Dose Side effects NO donor  cGMP  Ca2+  vasodilation Dose 0.5-10 mg/kg/min Fast acting Side effects Metabolized to thiocyanate by liver, cleared by kidneys CNS signs Hypotension

Nitroglycerin Pharmocologic effects Dose Side effects Exogenous source of NO Dose ¼” - 1” q6-12 hrs Side effects Hypotension Nitrate tolerance

Hydralazine Pharmacologic effects Dose Side effects Potassium channel opener (Opie) Interferes with Ca2+ movement in smooth muscles (Plumb) Arteriole vasodilation Dose 0.5-3 mg/kg PO q12 hrs Side effects Hypotension

Or Things Get Really Bad… Poor cardiac output – Cardiogenic shock!! Circulatory shock from cardiac causes Peripheral constriction (cold peripheries) Anuria or oliguria Low systolic BP (<90 mmHg) Treatment goal Reduce cardiac load (preload reduction) Preserve cardiac function (positive inotropes) Maintain BP

Acute Inotropes Dobutamine (b1 > b2 > a) at 2-20 mg/kg/min Dopamine (a at high doses) at 1-10 mg/kg/min Pimobendan Epinephrine (b1 = b2 > a) at 0.01 mg/kg Norepinephrine (b1 > a > b2) Vasopressin (V1, V2 receptors) at 0.01-0.04 U/min Side effects Arrhythmias Tachycardia Hypertension

The Dreaded Arrhythmias

Class I – Na+ Channel Blockers IA Quinidine, disopyramide, procainamide Inhibits fast Na+ channels Prolongs APD and QT interval IB Lidocaine, mexiletine, tocainide, phenytoin Inhibits fast Na+ channels (inactivated channels) Shortens APD in non-diseased tissue (no QT prolongation) Acts selectively on diseased/ischemic tissue Use dependency

Class I – Na+ Channel Blockers IC Flecainide, propafenone, moricizine Inhibits fast Na+ channels Variably prolongs APD Good for supraventricular tachyarrhythmias

Class II – b-Blockers If (pacemaker current) L-type Ca-channel Non-selective Propranolol, sotalol Risk of bronchiol spasm b1-selective Atenolol, metoprolol, bisoprolol, esmolol b1, b2, a-blockade Carvedilol Bradycardia

Class III – K+ Channel Blockers Amiodarone Class I, II (a and b), III, IV Slow onset, loading required (10 mg/kg q12 hrs) Side effects: Liver toxicity Sotalol Class II, III 1-2 mg/kg q12 hrs Reverse use dependence (greater effects at low HR) Ibutilide, dofetilide, bretylium QT prolongation

Class IV – Ca+ Channel Blockers Dihydropyridine (DHP) Amlodipine Greater effects on vessels Non-DHP Diltiazem (1 mg/kg q8 hrs, 1.5 mg/kg q12 hrs for ER) Verapamil (1-5 mg/kg q8 hrs) Greater effects on myocardium L-type channels T-type channels (SA and AV node) Negative ionotrope

Digoxin Pharmacologic effects Dose Side effects Inhibits Na+/K+ ATPase Parasympathetic activation Decrease renin release Dose 0.003 mg/kg q12 hrs Side effects Nausea, vomiting, anorexia (parasymapathomimetic effects)

Supraventricular Tachycardia Esmolol (II) Atenolol (II) Metoprolol (II) Carvedilol (II) Sotalol (III) Amiodarone (III) Verapamil (IV) Diltiazem (IV) Digoxin

Ventricular Tachycardia Quinidine (IA) Procainamide (IA) Lidocaine (IB) Mexiletine (IB) Sotalol (III) Amiodarone (III)

Anti-Thrombotics

Thrombus Formation Subendothelial tissue factor exposed Coagulation factors activated Platelet adhesion, activation, aggregation Thrombus formation from fibrin cross-linking

Platelet Inhibitors Aspirin ADP receptor antagonists Irreversibly inhibits COX-1 ↓TXA2, no effect on PGI2 ADP receptor antagonists Prevent platelet aggregation, promote disaggregation Clopidogrel Glycoprotein IIb/IIIa receptor antagonists Blocks platelet activation and fibrinogen cross-linking abciximab

Anticoagulants Unfractionated heparin Low-molecular weight heparin Binds thrombin Low-molecular weight heparin Dalteparin (Fragmin) Enoxaparin (Lovenox) Factor Xa inhibitors Rivaroxaban (Xeralto) Fondaparinux (Arixstra) Vitamin K antagonists Warfarin

Thrombolytics Tissue plasminogen activator Tenecteplase Streptokinase Longer half-life of tPA Streptokinase

Thank goodness there’s no coronary artery disease!