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DIURETICSThiazides:Chlorthalidone (Hygroton)Hydrochlorothiazide (Microzide, Diuril Loop:Bumetanide (Bumex)Furosemide (Lasix)Ethacrynic acid (Edecrin)K+ sparing:Spironolactone (Aldactone)Amiloride (Midamor)

Combos:Dyazide (Thiazide + K+ sparing)

ACE InhibitorsAngiotensin II Receptor Blockers (ARBs)CALCIUM CHANNEL BLOCKERSCaptopril (Capoten)Enalapril (Vasotec)Lisinopril (Prinivil, Zestril)Benazepril (Lotensin) & Lotensin HCT (Benazepril + HCTZ)Quinapril (Accupril)Losartan (Cozaar) & Hyzaar (Losartan + HCTZ)Valsartan (Diovan)Olmesartan (Benicar)Cardiac selective:Diltiazem (Cardizem)Verapamil (Calan)Vascular selective:Amlodipine (Norvasc) & Lotrel (Amlodipine + Benazepril)Nifedipine (Procardia)Nicardipine (Cardene)BETA BLOCKERSNon-selectivePropranolol (Inderal)

CardioselectiveMetoprolol (Lopressor, Toprol XL)Atenolol (Tenormin)Nebivolol (Bystolic)Bisoprolol (Zebeta)ISAPindolol (Visken)Acebutolol (Sectral)

Mixed alpha/beta blockersCarvedilol (Coreg)Labetalol (Trandate)

Alpha-1 Adrenergic Blockers (Peripheral Adrenergic Blockers)Alpha-2 Adrenergic Agonists (Centrally Acting Drugs)Direct Vasodilators

Doxazosin (Cardura)Prazosin (Minipress)Clonidine (Catapres) Methyldopa (Aldomet)Hydralazine (Apresoline)Minoxidil (Loniten)NITRATESShort ActingIV: Nitroglycerin, Nitroprusside (Nitropress), Nesiritide (Natrecor)Sublingual: Nitroglycerin (NTG, Nitrostat, Nitroquick)Sublingual: Isosorbide dinitrate (ISDN, Isodil, Nitrostat, Sorbitrate)Long Acting:Oral: Isosorbide mononitrate (ISMN, Ismo, Monoket, Omdur)Oral: Isosorbide dinitrate (ISDN, Isordil, Cedocard SR)Topical: Nitroglycerin (2% ointment, Nitro-bid; transdermal patch Minitran, Nitro-dur, etc; ointment Nitro-bid)Oral : BiDil (Hydralazine + ISDN)OTHER ANGINALPOSITIVE INOTROPESRanolazine (Ranexa)Disopyramide (Norpace, Rythmodan)Antiplatelet TherapyLow dose ASAClopidogrel (Plavix)Digoxin (Lanoxin) *Cardiac (digitalis) glycosideMilrinone (Primacor) *PDE inhibitorDobutamine (Dobutrex) *Beta agonist

BACKGROUNDAn estimated 30% of U.S. adults Almost 70 million Americans are hypertensive, according to an analysis based on surveys from 2003 to 2010 and included more than 20,000 individuals aged 18 and older.Among the other findings:More than half of hypertensive adults did not have their condition under control.Of those with uncontrolled hypertension, nearly 40% were not aware of their condition, 16% were aware but were not receiving medication, and 45% were aware and were being treated.Almost 90% of those with uncontrolled hypertension had a regular source of medical care! ANTIHYPERTENSIVE DRUG GROUPSDiuretics (3 classes: thiazides, loops, K+ sparing)ACE inhibitors (ACEIs)Angiotensin receptor blockers (ARBs)Beta adrenergic blockersAlpha1 adrenergic blocker Other adrenergic drugsCalcium channel blockersCentral alpha2 receptor activatorsDirect vasodilators Classification of Hypertension (HTN) Systolic BP Diastolic BP (mm Hg) (mm Hg)Normal 5mEq/L), acidosis, hirsutism, gynecomastia, menstrual irregularities.

LOOP DIURETICS LOOP DIURETICSInhibit Na+/K+/2Cl- transporter in thick ascending limb (TAL) of the loop of Henle.Bumetanide (Bumex) 0.5-5mg bid/tidEthacrynic acid (Edecrin) 25-100 mg bid/tid not a sulfa!Furosemide (Lasix) 20-320 mg qdEffective if creatinine clearance < 30mL/min, but should be avoided in anuria.While highly potent diuretics their use in hypertension is usually reserved for patients with chronic renal insufficiency.Adverse Effects: More likely than thiazides to cause dehydration, and hypokalemic alkalosis, but less likely to cause hyperglycemia and hyperlipidemia! Similar to thiazides in causing hyperuricemia. Renal actions can result in electrolyte disturbance including hypocalcemia & hypomagnesemia.Ethacrynic acid is potentially ototoxic.Relative contraindications: diabetes, gout, hyperlipidemia

4ACE INHIBITORS & ANGIOTENSIN BLOCKERS (ARBs) BLACK BOX WARNINGWhen used in the second half of pregnancy, ACEIs can cause reduced amniotic fluid (oligohydramniosis), fetal growth retardation, pulmonary hypoplasia, joint contractures, hypoplastic cranial bones (hypocalvaria) and neonatal renal failure, hypotension, and death. These effects result from blockade of the conversion of angiotensin I to angiotensin II in the developing fetal kidneys. A similar pattern of fetal anomalies has been reported after treatment of women in the second or third trimester of pregnancy with angiotensin IIreceptor antagonists. So the -prils & -sartans ARE ABSOLUTELY CONTRAINDICATED IN PREGNANCYACEI, ARB & DIURETIC COMBINATIONS When used alone, EITHER an ACE inhibitor or ARB improves outcomes in patients with diabetes, heart disease, or kidney disease. ACEI + ARB DOES give a little better BP lowering BUTthe combo may cause more adverse effects, such as hypotension, hyperkalemia, or increased serum creatinine. Consider more frequent monitoring of serum potassium and creatinine if you have a patient on both an ACE inhibitor and ARB.To increase antihypertensive effect consider the addition of a low dose of a thiazide diuretic (or calcium channel blocker, see below) to either an ACEI or ARB, rather than increasing the dose of the ACEI or the ARB! Angiotensin Converting Enzyme Inhibitors (ACEIs)Captopril (Capoten) 25-100 mg bid/tidEnalapril (Vasotec) 2.5 - 40 mg qd/bidLisinopril (Prinivil, Zestril) 10-40 mg qd .. and 7 or 8 more!

Mechanism: Block angiotensin II formation preventing stimulation of AT-1 receptors in kidney and vasculature aldosterone ( diuresis) & vasodilation) plus bradykinin degradation by ACE the vasodilating action of bradykinin.Uses in HTN: 1st choice drugs in patients with HF and compete with thiazides for initial treatment of HTN; especially good in patients with proteinuria including type 2 diabetics (But not if bilateral renal artery stenosis).Contraindications: Pregnancy (an absolute contraindication, see below), renal stenosis (bilateral).

Adverse effects: Cough (10-20% incidence enhanced bradykinin), loss of taste, rash, hyperkalemia, angioedema (? 1%), agranulocytosis (very rare)

Angiotensin II Receptor Blockers (ARBs)Losartan (Cozaar) 25-100 mg qd/bidValsartan (Diovan) 80-320 mg qd .. & 5-6 other sartans

Mechanism: Bind to AT-1 receptors in kidney and blood vessels preventing their activation by angiotensin II.

Do NOT block bradykinin metabolism by ACE.

Uses in HTN: Compete with prils as 1st choice drugs in patients with HF and in type 2 diabetics with nephropathy. Several ARBs are available in combinations with thiazides.

Contraindications: pregnancy, renal stenosis

Adverse effects: less than prils, less cough (do not affect bradykinin) and hyperkalemia, angioedema (very rare)

CALCIUM CHANNEL BLOCKERSBlock of membrane Ca2+ channels in the heart decreases contractility and in the vasculature causes relaxation in both cases the result is decreased BP. Cardiac selective drugs include Diltiazem (Cardizem et al) 180-480 mg qd Verapamil (Calan) 120-480 mg qdVascular selective drugs (dihydropyridines) include Amlodipine (Norvasc) 2.5 10mg qd Nifedipine (Procardia, Adalat) 30-60 mg qd Nicardipine (Cardene) 60-120 mg bidIn HTN CCBs are used in monotherapy, or as add-ons with thiazides (very effective in African Americans), especially if co-existing ischemic heart disease (IHD).Contraindications:Cardiac selective drugs accelerate HF (but amlodipine is safer) and should also be avoided in heart block or LV dysfunction. Short-acting forms of dihydropyridines (eg, nifedipine) have caused problems, including reflex cardiac stimulation, if used for hypertensive emergencies.Toxicity: Diltiazem & verapamil cause GI upset, constipation (verapamil), lupus-like rash, peripheral edema & cardiac depression.Dihydropyridines cause headache, flushing, gingival hyperplasia, reflex tachycardia & fluid retention.

BETA-ADRENERGIC BLOCKING AGENTS & ALPHA BLOCKERS BETA-ADRENERGIC BLOCKING AGENTS (1)Primary actions in HTN are antagonism of 1 receptors in the heart (decrease rate & contractility) and the kidney (decrease renin release). Several subgroups with distinctive characteristics

Nonselective - block all beta receptors including 2 receptors in lungs & some blood vessels the prototype Propranolol (Inderal) 40-160 mg bid

2. Selective 1 receptor blockers these drugs are safer in patients with asthma, COPD, or peripheral vascular disease Metoprolol (Lopressor, Topral XL) 50-100 mg qd/bid Atenolol (Tenormin) 25-100 mg qd

3. Blockers with intrinsic sympathomimetic activity minimal effect in resting states, but block CV responses with excessive SANS outflow (or if used at high doses) like partial agonists Pindolol (Visken) 10- 40 mg bid Acebutolol (Sectral) 200- 600 mg bid

4. Blockers of both alpha & beta receptors highly potent since they block 1 receptor mediated vasoconstriction - Carvedilol (Coreg) 12.5 50 mg bid Labetalol (Normodyne, Trandate) 200- 800 mg bid

Some beta blockers slow progression of HF - carvedilol & metoprolol have both been shown to decrease ventricular remodeling and carvedilol decreases mortality rate in HF patients! More laterIn HTN are generally considered 2nd to thiazides (or ACEIs), mostly as add-on. However they do have some advantages in patients with coexisting LVH, angina, or tachycardia & also in acute MI.

AVOID ABRUPT WITHDRAWAL REBOUND HYPERTENSION

Contraindications: 1st trimester of pregnancy, HF (except carvedilol & metoprolol), sinus bradycardia, asthma* & COPD*; relatively contraindicated in depression, diabetes, hyperlipidemia and peripheral vascular disease*.

Toxicity: bronchospasm, drowsiness, fatigue, NV are relatively common; more serious effects include AV conduction abnormalities & heart failure.

* 1 selective blockers safest

Alpha-1 Adrenergic Blockers (Peripheral Adrenergic Blockers) Alpha-2 Adrenergic Agonists (Centrally Acting Drugs)Act peripherally to relax vascular smooth muscle via block of NE activation of alpha-1 receptors on arterioles & veins. May decrease LDL-cholesterol modestly.

Also relax prostate sphincter smooth muscle to improve urine flow used in BPH +/- HTN! otherwise usually back-up drugs.

Doxazosin (Cardura) 1-16 mg qd Prazosin (Minpress) 2-20 mg bid/tid

Contraindications: Increase mortality in CV disease; watch the PDE5 inhibitors, the -afils like Viagra (sildenafil) additive hypotension.

Toxicity: First dose phenomena (syncope), postural hypotension, palpitations, fluid retention, CNS effects.Drugs that activate alpha-2 receptors in the CNS can decrease sympathetic outflow, which in turn results in a decrease in cardiac output & vascular peripheral resistance.

Clonidine (Catapres) 0.1-0.8 mg-tid or weekly transdermal patchGuanfacine (Tenex) 0.5-2mg qdMethyldopa (Aldomet) 250-1000 mg bid

Not for initial monotherapy they cause marked fluid retention so must be used with a diuretic.

AVOID ABRUPT WITHDRAWAL REBOUND HYPERTENSION

Toxicity: sedation, dry mouth, bradycardia, postural hypotension, decreased alcohol tolerance (guanfacine); in addition methyldopa also causes autoimmune disorders, colitis, hepatitis & hemolytic anemia ( veins.Their ability to block cardiac calcium channels is modest at doses used in angina so they may elicit a reflex tachycardia. Several agents are available for oral use in angina. Most are characterized by high first-pass metabolism. Elimination half-lives (& dosing regimens) vary.

Short-acting forms of dihydropyridines (eg, nifedipine) have caused problems, including reflex cardiac stimulation resulting in heart attacks, if used for hypertensive emergencies. A rapid-onset form of nifedipine was shown to increase the risk of MI in patients with HTN! Short-acting CCBs should be avoided in unstable angina they increase risk of cardiac events.

Dihydropyridines cause headache, flushing, gingival hyperplasia, reflex tachycardia & fluid retention. Edema, especially in the legs, may sometimes necessitate dosage reduction or discontinuance. Overall, amlopidine seems safer than other dihydropyridines in HF patients. Other dihydropyridine calcium channel blockers in the USA include felodipine (Plendil), isradipine (Dynacirc) & nisoldipine (Sular) though approved for HTN, they are also sometimes used in angina. Another dihydropyridine CCB, nimodipine (Nimotop, PO) improves neurological outcome in subarachnoid hemorrhage.This class of drugs is also used in the treatment of Raynauds disease.

CALCIUM CHANNEL BLOCKERSDrugCharacteristicsContraindicationsToxicityDiltiazem (Cardizem, generic): 30-80mg QID; extended release, (Cardizem CD, Dilacor XL, Tiazac): 180-420 mg qd: an IV prep is also available

Verapamil (immediate release (Calan, Isoptin): 80-320 mg bid; extended release (Calan SR, Isoprin SR) 120-480 mg qd

Diltiazem and verapamil are less selective than dihydropyridines since they block calcium channels involved in cardiac pacemaker activity i.e. they are cardiodepressant (V > D) and there is no reflex tachycardia. Diltiazem causes more vasodilation than verapamil.

This pair of CCBs also have well-documented clinical use in treatment of supraventricular tachycardias. Verapamil blocks P-glycoprotein drug transporters (involved in drug resistance) and has been used adjunctively in cancer chemotherapy.

These drugs are more cardiodepressant than dihydropyridine CCBs and can cause problems in patients with LV dysfunction, conduction abnormalities, or in heart failure. Dizziness, flushing, nausea & constipation (esp. verapamil) may be troublesome. AV block, bradycardia, cardiac arrest & heart failure are all possible, but uncommon other than in overdose. Edema, especially in the legs, may sometimes necessitate dosage reduction or discontinuance. Diltiazem (like dihydropyridines) may cause gingival hyperplasia.

OTHER ANGINARANOLAZINE (Ranexa)

Anti-ischemic drug approved for chronic angina - used adjunctively with other anti-anginal drugs. Dose 500 mg PO bidMOA: Inhibits fatty acid oxidation in cardiac tissue; blocks late Na+ current in myocardial cells, prolonging QTc interval. Does NOT reduce blood pressure or heart rate! Modest efficacy, M > F?Kinetics: Hepatic metabolism (CYP 3A4)Contraindications: Pre-existing QT prolongation (or other QT-prolonging drugs); hepatic impairment; class C pregnancy.Interactions: Cardiotoxicity with drugs that prolong QT interval (eg, erythromycin, antiarrhythmics). May increase toxicity of dextromethorphan, digoxin & some statins!Toxicity: Nausea, constipation, dizziness, headache.ANTIPLATELET DRUGSASA (80-325 mg qd).Clopidogrel (Plavix, 75 mg qd)Antiplatelet drug treatment in patients with acute or chronic ischemic conditions decreases the incidence of MI. ASA is commonly used at low doses (80-325 mg qd) in classic angina. See past lectures on NSAIDs for reminders of ASA pharmacology such as side effects, contraindications & drug interactions.The ADP antagonist clopidogrel (Plavix, 75 mg qd) is an effective alternative if ASA is contraindicated and has less GI side effectsNitrates plus CCBsFOR VASOSPASTIC (VARIANT) ANGINANitrates plus CCBs are highly effective in abolishing attacks in >70% of patients and almost all remaining patients have reduced incidence and severity of attacks.Nitroglycerin or ISDN + Nifedipine, verapamil, or diltiazem (from Wells)Disopyramide (generic, Norpace and RythmodanThis is usually classified as an antiarrhythmic class IA drug (see Drugs for Cardiac Arrhythmias lecture, May 15). It has minimal effects on adrenergic receptors, but has a negative inotropic effect on the heart . Its usually considered to be a back-up drug in HCM, if beta blockers or verapamil are ineffective or contraindicated. Unfortunately disopyramide can have marked antimuscarinic effects, so it is advisable to use the drug together with low doses of a beta blocker. Side effects include blurred vision, constipation, dry mouth & urinary retention. TREATMENT OF ANGINARECOMMENDED TREATMENT OF ANGINA -1All patients diagnosed with angina should be prescribed a short-acting nitrate (eg, nitroglycerin) for aborting acute (or predictable) attacks. If episodes are infrequent and nitroglycerin works this may be adequate. If not effective, then start either a beta blocker (especially if symptoms relate to exercise) or a CCB (if symptoms are linked to coronary vasospasm) this may be adequate.If not try combinations, typically a beta blocker together with a long-acting nitrate (reflex tachycardia is neutralized) or a beta blocker + a CCB (as long as no cardiac conduction abnormality) may be adequate.If not consider a three drug regimen and get help eg, surgical revascularization by coronary artery bypass grafting or percutaneous coronary intervention (PCI, angioplasty) EFFECTS OF NITRATES ALONE & IN COMBINATIONS Nitrates Beta Blkrs or CCAs Combined

Heart rate (reflex)

Arterial Pressure

End diastolic vol. None or

Contractility (reflex) None

Ejection time None

Reflex effects are usually undesirable.TREATMENTPOTENTIAL VASODILATOR PROBLEMS?

Reflex sympathetic activation: With vasodilation reflex sympathetic output may lead to unwanted cardiac effects and to an increased release of renin from the kidney causing formation of the angiotensins.

The Steal phenomenon: Some data show that the ability of vasodilators to promote blood to ischemic tissue is limited because the small blood vessels there are already significantly dilated instead vessels in adjacent non-ischemic tissue dilate thus stealing blood from the ischemic tissue!

Effects on non-vascular smooth muscle:In Rx of HTN associated with toxemia in pregnancy, vasodilators may decrease the activity of uterine smooth muscle during labor.

Stable CAD- Treatment Guidelines

Intensive medical therapy (aspirin, beta-blocker, ACE inhibitor, or possibly ARB) Reduction of risk factors (lipid-lowering therapy, optimization of HDL, diabetes control) Lifestyle intervention (weight reduction, smoking cessation, exercise).

These are collectively known as optimal medical therapy. Despite this, 30-40% of patients (over 1 million annually) will ULTIMATELY undergo catheterization and PCI for stable CAD!

PERCUTANEOUS CORONARY INTERVENTION (PCI)The Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial compared the use of PCI plus optimal medical therapy with optimal medical therapy alone in patients with stable CAD. Boden et al: Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med 2007;356:1503-16.PCI is proven to reduce the risk of death and myocardial infarction (MI) in patients with acute coronary syndromes. HOWEVER these benefits of PCI have yet to be proven in those patients with stable coronary artery disease (CAD)!Clinical Outcomes Utilizing Revascularization In general and according to current guidelines and studies, the patients who will benefit from PCI include those who receive an immediate intervention for acute MI with ST-segment elevation or high-risk ACS without ST-segment elevation, and possibly that small group of patients who are post-MI and receive late PCI for silent ischemia. Those who are NOT likely to benefit from the addition of PCI to optimal medical therapy include initial therapy of patients with stable angina and late intervention for those who are post-MI with occlusion of the infarct-related artery.

Post-CAD Depression Linked to Higher Heart Failure Risk From Journal of the American College of Cardiology April 2009.Researchers prospectively followed, for roughly 6 years, nearly 14,000 patients with CAD who had no previous diagnosis of depression or heart failure at the time of their index angiography.In patients who had depression after CAD diagnosis, their incidence of heart failure was 4x higher than that of non-depressed patients. Heart failure was about as likely to occur among those with depression whether or not they received antidepressant drugs!The authors speculate on biological pathways between heart failure and depression: Both are associated with increased inflammatory levels and endothelial dysfunction, and both share such risk factors as smoking and being overweight. They conclude: "Although this association needs further investigation, its consequences and future interventions could have a significant public health impact.TREATMENT HYPERTROPHIC CARDIOMYOPATHY (HCM) -1

A genetic CV disorder with incidence about 1 in 500. Many patients are asymptomatic, but others may have severe limitations including dyspnea on exertion, chest pain (sometimes with normal arteriogram) and at worst sudden death after strenuous physical exercise the latter is more likely in children & young adults. In addition to the symptoms, diagnosis may be established via 2D echocardiography.HCM pathology involves impaired ventricular filling due to abnormal relaxation which can ultimately lead to diastolic heart failure. Drug therapy includes the use of beta blockers, verapamil & disopyramide.HYPERTROPHIC CARDIOMYOPATHY (HCM) -2

Beta Blockers: Advantage is taken of their cardio-depressant actions. Decreased heart rate allows increased diastolic filling decreased contractility lowers oxygen consumption of the myocardium. Propranolol is effective but may require high doses. Standard doses of atenolol or metoprolol are used more commonly. When used in children or adolescents with HCM the beta blockers may impair academic performance and lead to depression.Verapamil: The negative inotropic action of this calcium channel blocker improves ventricular filling in diastole and relieves chest pain. Recall its constipating actions! In addition, some HCM patients on verapamil may develop pulmonary edema or cardiogenic shock!

HYPERTROPHIC CARDIOMYOPATHY (HCM) -3Disopyramide (generic, Norpace and Rythmodan): This is usually classified as an antiarrhythmic class IA drug (see Drugs for Cardiac Arrhythmias lecture, May 15). It has minimal effects on adrenergic receptors, but has a negative inotropic effect on the heart . Its usually considered to be a back-up drug in HCM, if beta blockers or verapamil are ineffective or contraindicated. Unfortunately disopyramide can have marked antimuscarinic effects, so it is advisable to use the drug together with low doses of a beta blocker. Side effects include blurred vision, constipation, dry mouth & urinary retention. Summary of Vasodilators

Nitrates & nitroglycerin: form NO - cGMP, v; Rx CAD, HF, Raynauds disease

Hydralazine: a; Rx HF (with nitrate), HTN

Nitroprusside: a & v; Rx acute HF or HTN emergency

Captopril & other -prils: Inhibit ACE, a & v; Rx HF, HTN

Losartan & other -sartans: AT-1 receptor block; Rx HTN

Prazosin & other -osins: Alpha1 receptor block; a & v; Rx: HTN, Raynauds disease

Nifedipine & other dipines: Ca2+ channel block: a > v; Rx. CAD, HTN, Raynauds disease

Minoxidil: K+ channel activation; a; Rx refractory HTN

Sildenafil & other -afils: Inhibit PDE-5; a & v; Rx male impotence

a = arteriolar dilationv = venous dilationANTIARRHYTHMICSClass I Drugs NA+ CHANNEL BLOCKERS IA:QuinidineProcainamideDisopyramide (Norpace)IB:LidocaineIC: Flecainide (Tambocor)Propaphenone (Rythmol)Class II Drugs BETA BLOCKERSPropranolol (Inderal)Esmolol (Brevibloc)Metoprolol (Lopressor)Class III Drugs - K+ CHANNEL BLOCKERSAmiodarone (Cordarone)Dronederone (Multaq)Sotalol (Betapace)Dofetilide (Tikosyn)Class IV Drugs - Ca2+ CHANNEL BLOCKERSVerapamil (Calan)Diltiazem (Cardizem)Unclassified antiarrhythmic drugsAdenosine (Adenocard)Digoxin (Lanoxin)Magnesium sulfateAtropineOther/Misc DrugsEpinephrineVasopressin

BRENNER TABLE 14-1 Electrophysiologic Properties of Selected Antiarrhythmic Drugs

TERMSAbnormal automaticityPacemaker activity that originates anywhere other than in the sinoatrial (SA) node.Reentrant arrhythmiasArrhythmias of abnormal conduction; they involve the repetitive movement of an impulse through tissue previously excited by the same impulseAbnormal conductionConduction of an impulse that does not follow the normal path or re-enters tissue previously excited.Selective depressionThe ability of certain drugs to selectively depress areas of excitable membrane that are most susceptible, leaving other areas relatively unaffectedAtrial, ventricular fibrillation(AF & VF)Arrhythmias involving rapid re-entry and chaotic movement of impulses through the tissue of the atria or of the ventricles.

Ventricular fibrillation is fatal if not terminated within a few minutes.Supraventricular tachycardia (SVT)A reentrant arrhythmia that travels through the AV node; it may also be conducted through atrial and ventricular tissue as part of the reentrant circuitEffective refractory period (ERP)The period that must pass after the upstroke of a conducted impulse in a part of the heart before a new action potential can be propagated in that cell or tissueVentricular tachycardia(VT)An arrhythmia often associated with myocardial infarction. May involve abnormal automaticity or abnormal conduction which impairs cardiac output, and may deteriorate into ventricular fibrillation (with inadequate contraction); for these reasons it requires prompt managementGroup I, II, III, and IV antiarrhythmic drugsA method for classifyingantiarrhythmic drugs, sometimescalled the Vaughan Williamsclassification; based loosely on thechannel or the receptor that is the drug target

Sodium channel blockers Beta receptor blockers Potassium channel blockersCalcium channel blockers

See also Wells, Table 6-1 BACKGROUND: ARRHYTHMIASARRHYTHMIAS/DYSRHYTHMIASThese are any abnormal cardiac rhythms resulting from structural or electrical/conduction changes in the heart. Causes include chronic heart failure, electrolyte abnormalities, hypertension, hypoxemia, myocardial ischemia, thyroid dysfunction, valvular heart disease and drug side effects/ toxicities. The major mechanisms resulting in arrhythmias are abnormalities in impulse formation (increased automaticity) and abnormalities in impulse conduction (reentry).Management? Treat or correct abnormality if possible. Use antiarrhythmic drugs temporarily or chronically. Consider non-pharmacologic therapies.

TREATABLE CONDITIONS THAT MAY CAUSE ARRHYTHMIASElectrolyte imbalance Renal failure Hypovolemia MIThyroid dysfunction Metabolic acidosis Pulmonary embolism Fevers Valvular defects Drug/drug interactionsARRHYTHMIAS AMENABLE TO DRUG THERAPYParoxysmal supraventricular tachycardia (PSVT)Atrial fibrillation (AF)Atrial flutterVentricular premature contractions (VPC)Ventricular tachycardia (VT)

NON-PHARMACOLOGIC THERAPY OF ARRHYTHMIASRadiofrequency (RF) catheter ablation Implantable cardioverter-defibrillators (ICDs)DC cardioversion (Direct current cardioversion)The increasing use of these therapies has reduced the need for long-term drug therapy in many patients.

AUTOMATICITY Spontaneous depolarization (automaticity) occurs in cells of SA & AV nodes & in the HIS-Purkinje system. Order of rate of depolarization: SA node (the pacemaker) > AV node > His-Purkinje.Both SA & AV nodes are innervated by PANS (inhibitory, M2 receptors) & SANS (excitatory), but the cardiac muscle cells are mostly innervated by SANS (1 receptors).Increased automaticity can reflect functional changes in the molecular events underlying the ionic mechanisms of myocardial cell excitability.Abnormal impulse formation is usually due to after-depolarizations which generate new A.P.s. It can occur with intracellular calcium overload (eg, electrolyte imbalance) & with use of cardiotoxic drugs. BRIEF REVIEW OF CARDIAC PHYSIOLOGY RELEVANT TO ANTIARRHYTHMIC DRUG ACTIONS

4 FUNDAMENTAL CONCEPTS TO UNDERSTAND

Ionic basis of Action Potentials in Fast-Response fibers (cardiac muscle & the His-Purkinje system)

Ionic basis of Action Potentials in Slow-response fibers (SA & AV nodes)

Features of voltage-gated Na+ channels that render them susceptible to certain drugs

Actions of the 2ND messenger cAMP on cardiac function that are susceptible to drugs

BACKGROUND: ARRHYTHMIAS DRUGS THAT ACT ON FAST-RESPONSE CARDIAC CELLS(Present in atrial & ventricular cardiac muscle & the His-Purkinje system)DRUGS THAT ACT ON SLOW-RESPONSE CELLS (SA & AV nodes)

Class I Antiarrhythmics (Na+ channel blockers) slow or block phase 0 (depolarization phase) this class has 3 drug subclasses (A, B & C)

Class II Antiarrhythmics ( blockers) slow phase 3 (the delayed rectifier current) prolonging the ERP and AP duration

Class III Antiarrhythmics (K+ channels blockers) also slow phase 3 prolonging the ERP and AP duration

Class II Antiarrhythmics ( blockers) - slow both phase 0 and phase 4 currents* PLUS they also decrease the delayed rectifier currents (phase 3)

Class IV Antiarrhythmics (Ca2+ channel blockers) slow phase 0 and phase 4 (pacemaker currents*)

*Pacemaker currents are the basis for automaticity. They involve a complex of an increased influx of Na+ and Ca2+ and a decreased efflux of K+The double-gated Na+ channels can exist in 3 states resting, open, or refractory. Most class I antiarrhythmic drugs block these channels when the M gate is open a state-dependent action.

Depolarization (phase 0) in the slow-response fibers of the SA & AV nodes as well as the pacemaker currents (phase 4)) are slowed by beta blockers (class II) and by calcium channel blockers (class IV).

BACKGROUND: ARRHYTHMIASDRUGS & ANS REGULATION OF HEART RATE SA & AV nodes have M2 receptors (which decrease cAMP) & 1 receptors (which increase cAMP).

Vagal stimulation (via ACh) increases outward K+ current thus inhibiting depolarization M receptor agonists & AChE inhibitors enhance these effects and thus cause bradycardia, while M receptor blockers oppose these effects and cause tachycardia.

Activation of 1 receptors(1) increases the slope of phase 4, (2) increases the upstroke velocity in pacemakers, and (3) shortens AP duration by increasing the delayed rectifier currents.

Beta activators (eg, isoproterenol) initiate this action, causing tachycardia - the beta blockers (Class II antiarrhythmics) antagonize these effects and cause bradycardia!

CARDIAC EFFECTS OF SERUM POTASSIUM LEVELS

Changes in serum potassium can have effects on cardiac function that are somewhat paradoxical they do not follow simply from considering the electrochemical gradient and the role of the ion in the repolarization phase of the cardiac action potential.

Hyperkalemia can reduce action potential duration, slow conduction and decrease pacemaker rate!

Hypokalemia can prolong action potential duration, increase pacemaker rate & increase pacemaker arrhythmogenesis.

The bottom line?

Maintain plasma K+ between 3.5-5.0 mEq/L

CLASS IA NA+ CHANNEL BLOCKERS Intermediate OnsetCLASS IA: increase Action Potential Duration (APD)block fast Na+ channels (state-dependent) decreasing slope of phase 0 & also block K+ channels decreasing slope of phase 3; APD & ERP1A drugs have a broad spectrum are used in both supraventricular & ventricular arrhythmias.Quinidine*(Quinidex, Quinaglute, Cardiqion):*optical isomer of quinine200-600 mg PO qid, as sulfate or gluconate salt. Broad activity & as been used in atrial flutter, AF & AV nodal re-entry. The IV form has been used in VT. Also blocks cardiac M receptors so need initial beta blocker (or verapamil) to slow AV nodal conduction. Causes peripheral vasodilation via an alpha blocking action hypotension Toxicity: GI distress (common), cinchonism (dizziness, tinnitus, blurred vision), hypersensitivity, thrombocytopenia; QT interval (torsades); heart block.

Procainamide (generic, Pronestyl, Procanbid): Both IV & PO forms, with doses depending on specific circumstance

Broad activity - like quinidine in its actions, but no M block. Metabolism via N-acetyltransferase (genetic variations) to an active metabolite, NAPA, which has class III actions; short half-life requires frequent dosing; PO & IV forms.Used in both atrial (SVTs) & ventricular arrhythmias (used in CCU as back-up to lidocaine post-MI). Toxicity: GI distress; SLE-like syndrome is common (especially in slow acetylators); agranulocytosis; CV toxicity includes torsades (more likely in fast acetylators). Serum levels must be monitored. Contraindicated in renal dysfunction.Disopyramide (generic, Norpace, PO):Use limited due to marked M receptor block, hypoglycemia & possible ventricular arrhythmias!

CLASS IB NA+ CHANNEL BLOCKERS Fast OnsetCLASS IB: decrease Action Potential Duration (APD)Block fast Na+ channels especially in ischemic cells, bundle of His, Purkinje fibers & ventricular myocardium. (Interestingly, they shorten APD in normal cardiac cells!)1B drugs are more effective in ventricular arrhythmias.Lidocaine (generic, Xylocaine)IVuse for ventricular arrhythmias especially post-MI; also used in heart surgery & in digoxin OD. No therapeutic effect in most SVTs.Toxicity: Least cardiotoxic drug BUT causes CNS toxicity (sedation, dizziness, paresthesias, seizures, respiratory arrest), especially if used >24h and especially in elderly.CLASS IC NA+ CHANNEL BLOCKERS Slow OnsetCLASS IC: No effects Action Potential Duration (APD)Block fast Na+ channels (esp. His-Purkinje); no effects on APD or on the ANS. Several drugs in this class, but problems 1C drugs can be used in both supraventricular & ventricular arrhythmias BUT there is a risk of pro-arrhythmic action!Flecainide (generic, Tambocor, PO)Approved for VTs, but shown in CAST* to increase mortality! Now used mainly for pharmacologic cardioversion of AF (if no form of structural heart disease or HF) the so-called pill in the pocket approach. Toxicity: pro-arrhythmogenic (sudden death)Propafenone (generic, Rythmol, PO)Similar, but also has nonselective beta blocking actions (type II). Approved for VTs, but mainly used in SVTs and for cardioversion in AF. Not studied in CAST, but suspicions linger * CAST = Cardiac arrhythmia suppression trial32CLASS II ANTIARRHYTHMIC DRUGS: BETA BLOCKERSMetoprolol (Lopressor): 25 mg bid or 50mg SR form qd also IV

Propranolol (Inderal): 10-20 mg tid PO as tabs or soln - also IV

Esmolol (Brevibloc): IV only

SA & AV nodal activity; slope of phase 4 in pacemakers; negative inotropic effects (decrease contractility & oxygen consumption). Also treat underlying causes of some arrhythmias (eg, ischemic heart disease; exercise or stress-related sinus tachycardia). Wide range of Rx uses with established efficacy: SVTs, AF & atrial flutter, VTs, post-MI.Drugs: Most drugs have equivalent efficacy based on CAST resultsToxicity: bradycardia, bronchospasm, depression, fatigue, hypotension, impotenceCLASS III ANTIARRHYTHMIC DRUGS: K+ CHANNEL BLOCKERS delayed rectifier current slowing repolarization APD & ERP (effective refractory period)Amiodarone (Cordarone): PO & IV forms; dosing (may require initial hospitalization!) depends on both specific arrhythmia and the need for loading & maintenance regimens - its half-life is > 2 months!

Rx Uses:mimics all 4 classesnot a negative inotrope safe in patients with left ventricular dysfunction.effective in atrial and ventricular arrhythmiasused in AF in patients with structural heart disease.QT prolongation (Torsades) is rare despite amiodarone being a K+ channel blocker that can prolong QT interval!Toxicity: Most serious is pulmonary toxicity which can be life-threatening (baseline lung function tests & chest X-ray needed annually) Black Box Warning!Contains 38% iodine and may cause hypo- or hyperthyroidism (test baseline & q. 6 months). Benign corneal & lens opacities, but with long-term use vision-threatening optic neuritis may occur (test baseline & annually). Increases LFTs, but hepatitis is rare. Photosensitivity reactions occur (use sunscreens) and blue-gray skin discolorations. Drug interactions: Inhibits several CYP450 isoforms eg, increases blood levels of warfarin (commonly used in AF) and several statins used in hyperlipidemias.

Dronederone (Multaq)

Like amiodarone, but contains no iodine! It has a much shorter half-life (24h), does not require a loading dose and is reported not to affect the thyroid, visual functions, or warfarin activity (its labeling states no Interaction!). has been used commonly in atrial fibrillation (though 4x more costly than amiodarone) and is reported to reduce hospitalization & mortality. Only to patients with normal sinus rhythm

However, the drug increases mortality in severe heart failure! Some warfarin patients report INR increases and there have also been warnings of liver failure (check liver enzymes at 6 months) and reports of renal toxicity & torsades. risk of serious cardiovascular events, including death, in patients with atrial fibrillation monitor ECG every 3 months with appropriate antithrombotic therapyDrug Interactions: digoxin, beta-blockers, calcium channel blockers, some statins, strong 3A4 inhibitors, grapefruit, and others.

33CLASS III ANTIARRHYTHMIC DRUGS: K+ CHANNEL BLOCKERS delayed rectifier current slowing repolarization APD & ERP (effective refractory period)Sotalol (Betapace, Betapace AF): PO 80mg bid, or qd if CCl < 60 mL/min

Consist of 2 isomers - one IK (potassium current) & the other is a nonselective beta blocker (class II). Renal elimination.Rx Uses: Both atrial & ventricular arrhythmias. Need hospitalization when starting treatment to monitor & possibly to resuscitate!Toxicity: Torsades (dose-dependent) is NOT rare! Avoid if QT interval > 440 msec. Black Box warning.Watch renal function and diuretics since hypokalemia and hypomagnesemia can both increase the risk of torsades. Contraindications: LV dysfunction, HF, asthmaDofetilide (Tikosyn): 500 mg bid PO (lower in renal dysfunction).

Most selective drug in this class, with few hemodynamic effects & no negative inotropy (safe in LV dysfunction). Used for conversion and/or maintenence in atrial flutter and AF.

Toxicity: May cause headache or dizziness. Torsades problematic (like sotalol) avoid if QT interval > 440 msec. Suggest initiate Rx for 3 days where cardiac monitoring & resuscitation facilities are available!Drug Interactions: Levels increased by azoles, cimetidine, diltiazem, erythromycin, grapefruit juice, ketoconazole and SSRIs.

CLASS IV ANTIARRHYTHMIC DRUGS: Ca2+ CHANNEL BLOCKERSBlock slow calcium channels: phases 0 & 4 in nodal pacemakers.Decrease AV nodal conductionVerapamil (generic, Calan, Isoptin): PO & IV.

Diltiazem (generic, Cardizem, Dilacor):PO/IVRx Uses: SVTs mainly of re-entry origin.

Toxicity: Dizziness, headache, flushing, hypotension, peripheral edema, bradycardia, AV block & constipation (verapamil).Contraindications: Heart block, LV dysfunction; careful in SA nodal disease, or if used with beta blockers.UNCLASSIFIED ANTIARRHYTHMIC DRUGSDigoxin (generic. Lanoxin)Vagotomimetic action slows AV conduction in atrial flutter or AF.Though ok in LV dysfunction, with exercise it elicits SANS stimulation limiting its effectiveness! Interactions:Check Heart Failure lecture for more re toxicity & drug interactions.Adenosine (generic Adenocard) IV administration (half-life < 20s)inhibits AV & SA node activity and is effective in PSVTs & AV nodal arrhythmias. May cause bronchoconstriction & flushingAdverse EffectsMay cause bronchoconstriction & flushingMagnesium sulfate:IV Used IV in digoxin-caused arrhythmias & in torsades, even if Mg levels normal. Mechanism unclear!Atropine:IVOnly used (IV) in monitored clinical setting for slow arrhythmias causing symptomatic bradycardia. 34ARRHYTHMIASLong QT SyndromeOccurs as a familial condition with increased risk of ventricular arrhythmias. Etiology unclear, but some evidence of mutations in certain genes encoding cardiac K+ channels.Risk of problems is increased by class IA & class III antiarrhythmic drugs (and by many other drugs including tricylic antidepressants see next frame. Higher risk in females, elderly, bradycardia, low K+, low Mg2+

TreatmentCorrect hypokalemia & hypomagnesemiaDiscontinue QT-prolonging drugsShorten APD with isoproterenol or electrical pacingMg sulfate 1g/IV

DRUGS ASSOCIATED W/ QTc PROLONGATIONAntibioticsazithromycinclarithromycin*erythromycinlevofloxacinmetronidazoleOfloxacinAntifungalsfluconazole(in cirrhosis)Itraconazole*ketoconazoleAntiviralsnelfinavir Antimalarialschloroquinemefloquine AnaestheticshalothaneAntiarrhythmicsamiodarone*disopyramideflecainide procainamidequinidinesotalol*Antidepressants amitriptylinecitalopramclomipramine fluoxetineimipraminetrazodone Antipsychoticsclozapine* fluphenazinehaloperidolrisperidonethioridiazine*ziprasidonepimozideBronchodilatorsalbuterolsalmeterolAntiemeticsondansetron et al

*Black box warnings Rx ATRIAL FIBRILLATION/FLUTTERAtrial fibrillation (AF) is a common form of arrhythmia that affects over 2 million Americans. Risk of developing AF increases with age, is more prevalent in men, and often is associated with underlying heart disease. Severe symptoms are usually managed by direct current cardioversion (DCC).Options for the drug management of AF are rhythm control and rate control strategies. The rhythm control strategy (restores sinus rhythm) involves cardioversion with antiarrhythmic drugs or DC electrical current, followed by drugs for maintenance of sinus rhythm. With the rate-control strategy, the ventricular rate is controlled by the use of drugs without restoring sinus rhythm.See algorithm Fig 6-1 in Wells (p.70)Rx ATRIAL FIBRILLATION/FLUTTER (1)Ventricular rate-control drugs: Diltiazem, verapamil, beta blocker, or digoxin if LVEF > 40%; digoxin or amiodarone are preferred drugs if LVEF < 40%Drugs for conversion to sinus rhythm rhythm control: amiodarone, dofetilide, flecainide, propafenone, or ibutilide. Most are available both PO and IV.CAUTION: Antiarrhythmic drugs (or DC cardioversion) should NOT be used in persistent AF (> 48h ?) or recurrent AF BEFORE anticoagulation Rx, due to a high risk of thromboembolism strokes.Management of patients with atrial fibrillation also includes antithrombotic therapy which may include aspirin, warfarin or newer antithrombotic agents (see below). WHY USE DRUGS IN AF?

The results of DC cardioversion in patients with chronic atrial fibrillation indicate a high initial effectiveness, but poor long-term effectiveness.70-90% patients with chronic atrial fibrillation will convert to sinus rhythm with application of DC cardioversion.BUT! 60-75% of successfully cardioverted patients will revert to atrial fibrillation within one year! Rx ATRIAL FIBRILLATION/FLUTTER (2) Warfarin (INR 2-3) is usually given for 3-4 weeks before attempted cardioversion and for at least 4 weeks after. In high risk patients anticoagulants become a chronic necessity. Dabigatran (Pradaxa) a direct thrombin inhibitor (DTI) & rivaroxaban (Xarelto) a direct factor Xa inhibitor are alternatives to warfarin. (see Anticoagulants lecture Jan 30 2014 & a recent Prescribers Letter, May 2014).ARRHYTHMIAS TREATMENT OF PSVTs

Paroxysmal supraventricular tachycardia is usually due to activity of AV nodal reentrant circuits.

1. First approach: Vagal stimulation (cough, carotid sinus massage, valsalva, etc.)

2. Second approach: Adenosine IV

3. Third approach:If LVEF > 40% : IV diltiazem, or verapamil, or beta blocker or digoxin. If no good try DC cardioversion. If that fails try IV amiodarone or procainamide.If LVEF 40% procainamide (IV), LVEF 10%), leukopenia, angioedema (can be life-threatening), agranulocytosis ( 5.5 mEq/L, creatinine > 3 mg/dL, systemic BP < 80 mm Hg

Symptomatic improvement may take several months, despite which the risk of HF progression is reduced.

ACEIs also decrease mortality if given post-MI.

DRUG INTERACTIONS WITH ACEIs

Antacids decrease GI absorption of captopril & possibly others

Aspirin antagonizes hemodynamic effects of ACEIs

Capsaicin triggers or worsens the cough

Lithium ACEIs increase lithium toxicity

NSAIDs increase salt & water retention

K+ supplements increased risk of hyperkalemia

K+ sparing diuretics - increased risk of hyperkalemia

Rifampin decreases effects of enalapril

Tetracycline GI absorption is decreased by ACEIsAngiotensin II Receptor Blockers (ARBs)MORE ABOUT ARBs IN HFIn one large study of efficacy in heart failure losartan was shown equivalent to the ACE inhibitor enalapril in terms of effectiveness judged by similar clinical endpoints in terms of exercise tolerance, dyspnea-fatigue index, lab evaluations, etc and like the other -sartans was less likely to cause cough! In several recent clinical studies ARBs (like ACEIs) were shown to decrease hospitalizations in HF.In addition there have been reports that certain ARBS (eg, candesartan) decreases mortality in HF, so the ARBs seem to be equivalent to the ACEIs in this regard!

WHAT ABOUT ACEIs & ARBs IN HF DUE TO DIASTOLIC DYSFUNCTION?Although diastolic dysfunction (stiff heart) is an important clinical problem, its treatment is less well-defined than for systolic dysfunction. Theheartmuscles do not relax in a normal manner and theheartmay fill too slowly, asynchronously or with an elevation in filling pressure only.Diastolic dysfunction can result in HF, though not generally as severe as systolic dysfunction. However, subsequent morbidity and mortality rates are quite high.

Control of hypertension & coronary artery disease is a requirement in most patients. Evidence so far suggests ACEIs and ARBs can reduce symptoms and hospitalizations, but these drugs have NOT been shown to decrease mortality in diastolic heart failure (yet!).DrugCharacteristicsAdverseLosartan (Cozaar) 25-100 mg qd/bid

Valsartan (Diovan) 80-320 mg qd

Candesartan (Atacand)

Mechanism:Bind to AT-1 receptors in kidney and blood vessels preventing their activation by angiotensin II. Do NOT block bradykinin metabolism by ACE!

Uses in HF:ARBs are increasingly competitive with prils as 1st choice drugs in patients with HF

Contraindications: Pregnancy (category D), bilateral renal stenosis

Adverse effects: Somewhat less than prils eg, less cough and hyperkalemia; angioedema (very rare)

THIAZIDE DIURETICSInhibit the Na+/Cl- co-transporter in the distal convoluted tubule (DCT)

Thiazides: In past were often the first drug type used in HF. Most effective if CrCL > 30 mlL/min. Now mostly adjunctive to ACEIs.

Chlorthalidone (Hygroton): 12.5-50 mg qdHydrochorothiazide (Diuril): 12.5 50 mg qd Metolazone (Zaroxolyn): 2.5-10 mg qd

Contraindicated in anuria (creatinine clearance < 30mL/min). Adverse effects:

Hypokalemia (note this may balance the effects of ACEIs if used adjunctively!), hyperuricemia, hyperglycemia, hyperlipidemia, hypercalcemia, rash. K+ leads to cardiac toxicity Ca2+ leads to cardiac toxicity

POTASSIUM-SPARING DIURETICS Spironolactone (Aldactone) 12.5 50 mg qdBlocks aldosterone receptors in collecting ducts. Valuable adjunctive use (at low dose) with ACEIs in HF 36% decrease in hospitalization and 27% reduction in mortality.Toxicity: GI distress, hyperkalemia (avoid if K+ > 5mEq/L), acidosis, hirsutism, gynecomastia, menstrual irregularities

Amiloride (Midamor) 5-20 mg qd/bid

Triamterene (Dyrenium) 50-150 mg qd/bidBlock Na+ channels in collecting ducts. Rx use: to offset hypokalemia caused by other diureticsToxicity: Hyperkalemia (as above, avoid if K+ > 5mEq/L), acidosis, nephrolithiasis.

LOOP DIURETICS LOOP DIURETICS

Bumetanide (Bumex): 0.5-5 mg qdEthacrynic acid (Edecrin): 25-100 mg, bid-tidFurosemide (Lasix): 20-32- mg, bid-tidTorsemide (Demadex)

Effective even if CrCl < 30 mL/minCan monitor effects by weight change. IV administration may be needed with persistent volume overload

Adverse effects: Dehydration (?circulatory collapse), hypokalemia (note may balance the effects of ACEIs!), hypocalcemia, hypomagnesemia, hyperuricemia, hyperglycemia, metabolic alkalosis

Interactions: NSAIDs may antagonize the diuresis & necessitate dose increase. Potential enhanced ototoxicity with drugs like aminoglycosides.

46BETA BLOCKERS FOR HFBETA BLOCKERS IN HF (1)

How can drugs that decrease heart rate, decrease cardiac contractility and even possibly oppose peripheral vasodilation be of any value in HF? Good question!

Carvedilol (Coreg) was the 1st beta blocker approved for HF it slowed disease progression, decreasing both hospitalization and mortality (a 65% reduction) was its efficacy due to the drug also being an alpha blocker?

Apparently not! a long-acting form of metoprolol (generic, Lopressor, a selective 1 receptor blocker) decreases mortality in HF and this drug has no alpha receptor blocking action!

Bisoprolol (generic, Zebeta) has also been shown to decrease mortality in HF it too lacks any alpha antagonism! BETA BLOCKERS IN HF (2)

Increased sympathetic tone occurs in HF and it has been suggested that chronic SANS activation of the heart accelerates the progression of HF. This idea may originate more from the fact that some beta blockers work in HF than from direct evidence for the connection between SANS activation and heart deterioration!

Other notions of how some beta blockers have efficacy in HF include slowing/reversing ventricular remodeling, blocking catecholamine-induced necrosis, decreasing HR & hence myocardial oxygen demand, and inhibiting the release of renin.

Whatever!

Selected beta blockers are recommended for stable NYHA class II-IV patients with LV dysfunction (EF < 35 - 40%) as add-ons to ACEIs, ARBs and diuretics. IMPORTANT: The three beta-blockers shown to improve survival in HF are metoprolol succinate, carvedilol, & bisoprolol. DrugCharacteristics/MechanismAdverse ReactionsCarvedilol (Coreg, Coreg ER): 3.125-50 mg bid; CR 10-80 mg qd.

Metoprolol ER (Toprol XL): 50-100 mg qd/bid

Bisoprolol (generic, ZeBeta): start 5 mg qd; range 5-20 mg

Are started slowly watching for 1 hr with each dose change

Toxicity: bradycardia, AV block, postural hypotension, dizziness, fatigue, depression, bronchoconstriction, hepatic dysfunction, fluid retention (check weight) if withdrawal is needed it is done slowly!

Contraindications: Asthma, heart block (unless pacemaker used), sinus bradycardia

VASODILATORS & NITRATESUsually considered as alternatives in combination therapy, with the following exception studies in African-American HF patients showed decreases in hospitalizations and in mortality rate in the long-term (>3y) and, if used together WITH ACEIs, they may further decrease mortality!

DrugCharacteristics/MechanismAdverse ReactionsIsosorbide dinitrate (ISDN, Isordil): 10-40 mg tidThe nitrate ISDN venodilates (decreases preload).May cause headache, flushing, postural hypotension, tachycardia, blurred vision. Need nitrate-free periods! Avoid in nitrate hypersensitivityHydralazine (Apresoline): 25-75 mg tid Hydralazine dilates arterioles (decreases afterload)May cause postural hypotension & tachycardia. May cause a lupus-like syndrome. Avoid in CAD or aortic stenosis.Nitroprusside (generic, Nitropress, IV infusion):Acts like other nitro-vasodilators. Can improve cardiac output in decompensated heart failure. Used short term

Used short-term, due to possible CN or SCN toxicity.

Nitroglycerin (IV):Coronary dilator used in severe HF & ischemic heart disease.

Tolerance may develop to these nitrates and rebound can occur with abrupt withdrawal.Nesiritide (Natrecor, IV): Recombinant form of human B-type natriuretic peptide increases cGMP causing rapid & intense vasodilation, but is very short-acting. Though approved for Rx of acute decompensated HF concerns have arisen recently over its nephrotoxic potential.

Bidil

Hydralazine (Apresoline)+Isosorbide dinitrate (ISDN, Isordil)

Marketed specifically for African-American patients*, the agent is a fixed combination of hydralazine (37.5 mg) and isosorbide dinitrate (20 mg). Use of the individual drugs in combination is less expensive but the dosage regimen of 2 tabs TID with need for a nitrate-free interval can make adherence difficult. *It remains uncertain whether this combination can improve survival in other HF patients, but it is an alternativeregimen if ACEIs and ARBS are contraindicated due to renal insufficiency, or hyperkalemia.

Headache dizziness and GI distress commonly occur.

POSITIVE INOTROPESCARDIAC GLYCOSIDESDigitalis glycosides (together with diuretics) had been the mainstay of treatment of HF until the ACEIs & ARBs arrived! Digitalis improved symptoms & quality of life and decreased hospitalizations, especially in HF patients with very low ejection fraction, or enlarged hearts.BUT digitalis glycosides do NOT decrease mortality in HF AND they have a narrow therapeutic index with risk of severe toxicity in overdose including myocardial infarction and cardiac arrhythmias ANDMany drug interactionsThe only glycoside now available in the USA is digoxin.DrugCharacteristics/MechanismAdverse ReactionsDigoxin (Lanoxin): 0.0625 - 0.25 mg qd. Recommended in HF due to LV systolic dysfunction in conjunction with ACEIs & diuretics.Kinetics: Long half-life (48 hr) reaching steady state in about 10 days check serum levels, electrolytes, BUN & creatinine at that time. Enters most tissues (high Vd) and eliminated mainly via the kidney. Narrow therapeutic window!Toxicity: Anorexia, nausea, headache, fatigue, ECG changes; higher doses cause disorientation & visual effects. Cardiac symptoms can take the form of most known arrhythmias and include paroxysmal atrial tachycardia, ventricular tachycardia & heart blockImportant: diuretics may alter electrolytes - potassium level is critical! K+ leads to cardiac toxicity Ca2+ leads to cardiac toxicity

Overdose toxicity is managed with Fab antibody (Digibind) + electrolyte adjustments & antiarrhythmic drugs avoid attempted cardioversion!

Contraindications: allergy, ventricular arrhythmias, renal dysfunction

Drug Interactions: Blood levels are increased by many drugs including anticholinergics, quinidine, spironolactone & verapamil. GI absorption may be decreased by antacids and kaopectateMechanismThe drug is a positive inotrope. It stimulates cardiac function by complex mechanisms including inhibition of the Na+-K+-ATPase that pumps out sodium in exchange for potassium. This leads to intracellular Na+ which in turn results in Na+/Ca2+ exchange intracellular Ca2+ which causes Ca2+ release from sarcoplasmic reticulum which increases the interaction between actin-myosin which leads to contractile force!Phew!Milrinone (generic, Primacor):Used primarily IV in acute decompensated failure, or for severe exacerbation in chronic failurePhosphodiesterase inhibitor that increase the levels of cAMP resulting in the enhancement of cardiac contractility plus vasodilation, the latter decreasing ventricular afterload. Less thrombocytopenia than the older drug amrinone; some hepatotoxic potential.

Dobutamine (Dobutrex) & Dopamine (Intropin): used IV in mgmt of acute decompensated failure, especially if there is a need to BP.These agents are sympathomimetics which activate cardiac beta receptors

HEART FAILURE RECOMMENDATIONSGENERAL RECOMMENDATIONS (1)An ACE inhibitor should be given to all patients with heart failure unless there are contraindications. An ARB is an alternative.In symptomatic patients with heart failure, specific beta-blockers are recommended to reduce mortality rates.The aldosterone antagonist (spironolactone) is recommended to reduce mortality rates in certain patients with heart failure. These include patients with current or recent history of dyspnea at rest, and patients with recent myocardial infarction who have systolic dysfunction with either clinically significant signs of heart failure or with concomitant diabetes mellitus.GENERAL RECOMMENDATIONS (2)For persistently symptomatic African-American patients with heart failure, direct-acting vasodilators (eg, isosorbide dinitrite) reduce overall mortality rates when added to background therapy with ACE inhibitors, beta-blockers, and diuretics (if needed). Direct-acting vasodilators are also an alternative for patients with heart failure who are intolerant of ACE inhibitors.For HF patients with volume overload, diuretics are recommended.TREATMENT RE HEART FAILURE STAGES

For Stage A patients the emphasis is on modifying risk factors including diet, smoking & treatments of HTN, diabetes mellitus & dyslipidemias. If hypertensive then ACEIs or ARBs are optimal.

For Stage B patients with prior MI (or ejection fraction