Cardiac Medications
18.1 Angiotensin-Converting Enzyme Inhibitors
Nejm 2000;342:210; 1999;341:577
Drugs of this type: Benazepril (Lotensin), captopril (Capoten), enalapril (Vasotec), fosinopril (Monopril), lisinopril (Prinivil, Zestril), moexipril (Univasc), perindopril (Aceon), quinapril (Accupril), ramipril (Altace), trandolapril (Mavik)
Pharmacology: Prevent conversion of angiotensin I to angiotensin II (potent vasoconstrictor); decrease aldosterone secretion; increase bradykinin levels and thus stimulate prostaglandin synthesis; reduce peripheral vascular resistance; increase renal blood flow
Pharmacokinetics: See Table 18.1.
Effects on other organs: Trandolapril and ramipril are secreted in breast milk; whether other ACEIs are also secreted in milk is not known
Precautions and contraindications: Pts with renal artery stenosis may develop renal failure when treated with ACEIs.
ACEI use in the 2nd and 3rd trimesters of pregnancy is associated with fetal and neonatal injury and death.
Neutropenia developed in 0.2% ofpts with impaired renal function and no collagen vascular disease treated with captopril
and in 3.7% ofpts with both impaired renal function and collagen vascular disease.
and in 3.7% ofpts with both impaired renal function and collagen vascular disease.
Table 18.1 Pharmacokinetics of ACE Inhibitors | ||||||||||||||||||||||||||||||||||||||||||||||||
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The dose of most ACEIs needs to be reduced inpts with impaired renal function.
Adverse effects: Cough is the most commonly reported side effect (presumably due to decreased bradykinin degradation). Angioedema is reported in 0.1-0.5% ofpts treated with ACEIs.
Drug interactions: ACEIs increase serum digoxin and Li levels; administration of antacids decreases the bioavailability of ACEIs, and indomethacin reduces their hypotensive effects; phenothiazines increase their pharmacologic effects.
The effects of ACEIs are potentiated by the addition of thiazide diuretics.
Dosage and administration:
Benazepril (Lotensin): tablets 5 mg, 10 mg, 20 mg, 40 mg; HT: initial dose 10 mg qd, maximum dose 40-80 mg qd
Captopril (Capoten): tablets 12.5 mg, 25 mg, 50 mg, 100 mg; HT: initial dose 25 mg tid, maximum dose 150 mg tid; CHF: initial dose 6.25 mg tid, usual dose 50-100 mg tid; LV dysfunction post-MI: single dose 6.25 mg, if tolerated start 12.5 mg tid and titrate to target dose of 50 mg tid over several weeks; diabetic nephropathy: target dose 25 mg tid
Enalapril (Vasotec): tablets 2.5 mg, 5 mg, 10 mg, 20 mg; injection (enalaprilat) 1.25 mg/mL; HT: initial dose 5 mg qd, maximum dose 40 mg/day, iv dose 1.25 mg q 6 hr; CHF: initial dose 2.5 mg bid, maximum dose 20 mg bid
Fosinopril (Monopril): tablets 10 mg, 20 mg, 40 mg; HT: initial dose 10 mg qd, maximum dose 40-80 mg qd; CHF: initial dose 5-10 mg qd, maximum dose 40 mg qd
Lisinopril (Prinivil, Zestril): tablets 2.5 mg, 5 mg, 10 mg, 20 mg, 40 mg; HT: initial dose 10 mg qd, maximum dose 80 mg qd; CHF: initial dose 5 mg qd, usual dose range 5-20 mg qd; AMI: 2.5-5 mg within 24 hr of onset, 5 mg after 48 hr, then 10 mg qd
Quinapril (Accupril): tablets 5 mg, 10 mg, 20 mg, 40 mg; initial dose 10 mg qd; maximum dose 80 mg/d; CHF: initial dose 5 mg bid, usual dose 10-20 mg bid
Ramipril (Altace): capsules 1.25 mg, 2.5 mg, 5 mg, 10 mg; HT: initial dose 2.5 mg qd, maximum dose 20 mg/d; CHF: initial dose 1.25 mg qd or bid, target dose 5 mg bid
18.2 Aldosterone-Blocking Agents
Nejm 2003;348:1309
Drugs of this type: Eplerenone (Inspra)
Pharmacology: Binds to mineralocorticoid receptor and blocks binding of aldosterone
Pharmacokinetics: Bioavailability is unknown; 50% protein bound; metabolized by cytochrome P450 3A45; half-life is 4-6 hr
Precautions and contraindications: Contraindicated inpts with serum K+ > 5.5 mEq/L, creatinine clearance < 30 mL/min,pts receiving other cytochrome P450 inhibitors such as ketoconazole, itraconozole, clarithromycin, retonavir, nelfinavir. In rx of HT, contraindicated inpts with NIDDM and microalbuminuria, creatinine > 1.8 mg/dL, use of K+ supplements or potassium-sparing diuretics. Safety in pregnancy, children unknown.
Adverse effects: Hyperkalemia; elevations of triglyceride levels
18.3 Angiotensin II Receptor Antagonists
Nejm 1996;334:1649
Drugs of this type: Candesartan (Atacand); irbesartan (Avapro); losartan (Cozaar, Hyzaar); olmesartan (Benicar); telmisartan (Micardis); valsartan (Diovan)
Pharmacology: Bind selectively to AT1 receptor to block vasoconstrictor and aldosterone-secreting effects of angiotensin II
Pharmacokinetics: See Table 18.2.
Use: HT
Table 18.2 Pharmacokinetics of Angiotensin II Receptor Antagonists | ||||||||||||||||||||||||||||||||||||||||||
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Effects on other organs: Decreased hgb reported
Precautions and contraindications: May cause hypotension in NaCl/volume-depletedpts; may produce/worsen renal failure inpts with renal artery stenosis
Contraindicated in 2nd and 3rd trimesters of pregnancy
Adverse effects: Effects of some agents reported to be less in blacks
Drug interactions: Telmisartan may increase serum digoxin levels
Dosage and administration:
Losartan (Cozaar, Hyzaar): 25 mg, 50 mg, 100 mg tablets; usual dose 50 mg qd; maximum dose 100 mg qd
Addition of a thiazide diuretic may increase efficacy of all agents
18.4 α1 Adrenergic-Blocking Agents
Labetolol and carvediolol have both α- and β-blocker activity and are discussed in the section on β-blockers.
Drugs of this type: Doxazosin (Cardura), prazosin (Minipres), terazosin (Hytrin)
Pharmacology: Block postsynaptic α1 receptors, causing dilation of arterioles and veins
Pharmacokinetics: See Table 18.3.
Table 18.3 Pharmacokinetics of α1 Adrenergic Blockers | ||||||||||||||||||||||||||||
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Uses: HT; BPH
Precautions and contraindications: First-dose effect: hypotension, postural hypotension, syncope with first few doses or with change in dose; administer at bedtime when initiating rx
Adverse effects: Palpitations (2-5%), nausea (3-5%), dizziness (10-20%), headache (8-16%)
Drug interactions: May reduce antihypertensive effect of clonidine
Dosage and administration:
Doxazosin (Cardura): 1 mg, 2 mg, 4 mg, 8 mg tablets: initial dose 1 mg po qhs; maximum dose 16 mg/d; titrate dose q 2 wk
Prazosin (Minipres): 1 mg, 2 mg, 5 mg capsules; initial dose 1 mg po bid-tid; maximum dose 15 mg/d; titrate dose q 2 wk
18.5 Antiarrhythmic Agents
Nejm 1999;340:1910; 1998;338:35
Overview
Vaughn Williams classification (based on effect on action potential)
Class I: Local anesthetics of membrane-stabilizing agents; depress phase 0 (rapid depolarization)
Class IA (quinidine, procainamide, disopyramide): Depress phase 0; prolong action potential
Class IB (lidocaine, tocainide, mexiletine, phenytoin): Depress phase 0 slightly; may shorten action potential duration
Class IC (flecanide, propafenone): Depress phase 0 markedly; slight effect on repolarization
Note: Moricizine shares characteristics of Class IA, IB, and IC agents
Class II (propranolol, esmolol, acebutolol): β-Blockers; depress phase 4 (diastolic depolarization)
Class III (sotalol, bretylium, amiodarone, ibutilide): Prolong phase 3 (final rapid repolarization)
Class IV (verapamil): Depresses phase 4 depolarization; prolongs phase 1 (early rapid repolarization) and phase 2 (plateau)
Adenosine
Nejm 1991;325:1621
Drugs of this type: Adenosine (Adenocard)
Pharmacology: Slows conduction through AV node; interrupts reentrant pathways
Pharmacokinetics: Rapid uptake by erythrocytes, vascular endothelial cells; half-life < 10 sec
Uses: Conversion of PSVT, including those involving accessory bypass tracts (WPW syndrome); not effective in converting Aflut, Afib, but resulting transient AV block may facilitate diagnosis
Precautions and contraindications: May produce transient high-degree AV block
Adverse effects: Flushing (18%); headache (2%)
Drug interactions: Activity blocked by methylxanthines (theophylline, caffeine); potentiated by dipyridamole; carbamazepine also increases AV block
Class 1A Antiarrhythmic Agents
Nejm 1997;337:1383
Drugs of this type: Quinidine (Quinidex, Quinaglute); procainamide (Pronestyl, Procanbid); disopyramide (Norpace)
Pharmacology: Depress myocardial excitability and conduction velocity; prolong effective refractory period
Pharmacokinetics: See Table 18.4.
Uses: Treatment of paroxysmal SV tachycardia, Aflut, Afib (including maintenance rx after cardioversion); PSVT (see precautions)
Effects on other organs: All 3 agents cross the placenta and are excreted in breast milk.
Precautions and contraindications: Contraindicated in myasthenia gravis, digitalis toxicity, complete heart block, long QT syndrome orpts with h/o drug-related torsades de pointes, or inpts who develop QRS or QT prolongation; administration in Aflut may decrease AV block and produce rapid ventricular response; pre-treatment with digitalis recommended; may produce complete heart block inpts with lesser degrees of conduction disturbance
Disopyramide has a significant negative inotropic effect and is contraindicated in CHF
Adverse effects: Thrombocytopenia, hemolytic anemia, hepatotoxicity, and fever reported with quinidine, and periodic CBC, liver studies recommended; most common side effects are gi
Procainamide: Agranulocytosis, neutropenia, thrombocytopenia seen in ˜0.5% ofpts; usually occurs within first 12 wk. Procainamide can produce a positive ANA test and lupus-like sx and is contraindicated inpts with lupus.
Table 18.4 Pharmacokinetics of Antiarrhythmic Agents | ||||||||||||||||||||||||||||||||||||||||||||||||
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Disopyramide: Dry mouth (32%), headache (3-9%), urinary hesitancy (14%), constipation (9%), muscle discomfort (3-9%)
Drug interactions: Amiodarone, antacids, cimetidine, and verapamil may increase serum quinidine levels. Hydantoins, nifedipine, rifampine, and sucralfate may reduce serum quinidine levels. Quinidine may potentiate effects of warfarin, digoxin, propafenone, and succinylcholine.
Cimetidine and ranitidine increase procainamide bioavailability. Trimethoprim increases serum procainamide levels.
Erythromycin increases disopyramide levels. Hydantoins and rifampin decrease disopyramide levels.
Dosage and administration:
Quinidine sulfate: 200 mg, 300 mg; quinidine gluconate: 324 mg; maintenance rx: 300-600 mg po q 8 hr; may administer 200 mg po as test dose
Procainamide: 250 mg, 375 mg, 500 mg tablets; 500 mg, 750 mg, 1000 mg sustained-release tablets; 100 mg/mL, 500 mg/mL injection; initial po dose up to 50 mg/kg/d in divided doses (q 4 hr standard formulation, q 6-12 hr timed-release formulation); initial iv dose 500 mg at infusion rate < 50 mg/min
Class IB Antiarrhythmic Agents
Drugs of this type: Lidocaine (Xylocaine); tocainide (Tonocard); mexiletine (Mexitil)
Pharmacokinetics: See Table 18.4.
Uses:
Lidocaine: Acute short-term management of ventricular arrhythmias
Tocainide and mexiletine: Treatment of documented life-threatening ventricular arrhythmias
Effects on other organs: Lidocaine crosses the placenta. Mexiletine crosses the placenta and is excreted in breast milk.
Precautions and contraindications: Lidocaine is contraindicated in WPW syndrome, severe SA node or AV node block, or Stokes-Adams attacks. Mexiletine is contraindicated in cardiogenic shock, preexisting 2nd- or 3rd-degree AV block.
Adverse effects: CNS effects are seen in lidocaine toxicity.
Blood dyscrasias, pulmonary fibrosis, and interstitial fibrosis have been reported with tocainide and usually occur 3-18 wk after initiation of therapy. Vertigo (15%), nausea (15%), parasthesias (9%), and tremor (8%) have also been reported. Mexiletine may cause liver enzyme abnormalities, palpitations (7.5%), dizziness (26%), tremor (13%), coordination abnormalities (10%), and gi upset (40%).
Drug interactions: β-Blockers and cimetidine may increase serum lidocaine levels. Rifampin and cimetidine decrease bioavailability of tocainide. Antacids slow and metoclopramide increases mexiletine absorption. Hydantoins and rifampin increase mexiletine clearance. Mexiletine can increase serum theophylline levels.
Dosage and administration:
Mexiletine: 150 mg, 200 mg, 250 mg capsules; initial dose 200 mg po q 8 hr; increase dose 50-100 mg q 3-5 d; maximum dose 1200 mg/d; may use bid dosing in stablepts
Class IC Antiarrhythmic Agents
Drugs of this type: Flecanide (Tambocor); propafenone (Rhythmol)
Pharmacokinetics: See Table 18.4.
Effects on other organs: Flecanide is excreted in breast milk.
Precautions and contraindications:
Flecanide: preexisting 2nd- or 3rd-degree AV block; bifascicular block; cardiogenic shock; sick sinus syndrome; CHF; recent MI (CAST study: 5.1% mortality/nonfatal VF rate)
Propafenone: Above plus bronchospasm; may cause positive ANA titer
Both drugs may increase pacing threshold. Both have negative inotropic effects and should be used with caution in combination with other negative inotropic agents.
Adverse effects:
Flecanide: Dizziness (19%); dyspnea (10%); nausea (9%); fatigue (8%); palpitations (6%); chest pain, asthenia, fever (5%)
Propafenone: Unusual taste (7%); dizziness (7%); 1st-degree AV block (4.5%); headache (4.5%); constipation (4%)
Drug interactions: Cimetidine increases flecanide and propafenone bioavailabilty. Flecanide and propafenone increase digoxin levels. Propafenone increases warfarin, β-blocker, and cyclosporine blood levels.
Dosage and administration:
Flecanide: 50 mg, 100 mg, 150 mg tablets; SVT/Afib: initial dose 50 mg po q 12 hr, maximum 300 mg/d; VT: initial dose 100 mg po q 12 hr; maximum dose 400 mg/d; reduce dosage to q 24 hr in renal failure
Moricizine
Drugs of this type: Moricizine (Ethmozine)
Pharmacology: Class I antiarrhythmic; has characteristics of Class IA, IB, and IC drugs; prolongs PR interval, AV nodal, and His-Purkinje conduction time; prolongs QRS interval, and QTc slightly
Pharmacokinetics: See Table 18.4.
Uses: Ventricular arrhythmias
Effects on other organs: Moricizine does not have negative inotropic effects; excreted in breast milk; no adequate studies on use in pregnancy
Precautions and contraindications: Contraindicated inpts with 2ndor 3rd-degree AV block, bifascicular block, cardiogenic shock; use with caution in sick sinus syndrome; has proarrhythmic potential; CAST study failed to demonstrate definite benefit and adverse trend in use with MIpts
Adverse effects: Dizziness (15%); nausea (10%); headache (8%); fatigue (6%); dyspnea (6%); palpitations (6%); proarrhythmia (3.7%)
Drug interactions: Cimetidine increases moricizine plasma levels. Digoxin produces increased PR prolongation. Moricizine decreases theophylline half-life.
Dosage and administration: Moricizine (Ethmozine): 200 mg, 250 mg, 300 mg tablets; starting dose 200 mg q 8 hr; usual dose 600-900 mg/d; ifpts well controlled, may change to q 12 hr dosing; reduce dosage inpts with impaired hepatic function. When changing from another agent, start moricizine 6-12 hr after last dose of
quinidine or disopyramide; 3-6 hr after last dose of procainamide; 12-24 hr after last dose of flecanide; 8-12 hr after last dose of tocainide, propafenone, or mexiletine.
quinidine or disopyramide; 3-6 hr after last dose of procainamide; 12-24 hr after last dose of flecanide; 8-12 hr after last dose of tocainide, propafenone, or mexiletine.
Class II Antiarrhythmic Agents
See β-blockers.
Class III Antiarrhythmic Agents
Drugs of this type: Bretylium (Bretylol), amiodarone (Cordarone, Pacerone), ibutilide (Corvert); dofetilide (Tikosyn)
Sotalol (Betapace) also has class III antiarrhythmic properties.
Pharmacology: Bretylium inhibits norepinephrine release.
Pharmacokinetics: See Table 18.4.
Uses: Life-threatening ventricular arrhythmias (bretylium, amiodarone, sotalol); treatment of Aflut/Afib and PSVT (amiodarone, sotalol); conversion of Aflut/Afib (ibutilide)
Effects on other organs: Amiodarone can produce pneumonitis, liver disease, optic neuropathy, and corneal microdeposits, and it blocks peripheral conversion of T4 to T3. It may cause hyper- or hypothyroidism. CXR, PFTs, ophthamologic exam, and thyroid and liver function studies are required before initiation and periodically thereafter.
Precautions and contraindications: Amiodarone: Severe sinus node dysfunction or marked sinus bradycardia, 2nd- or 3rd-degree AV block
Adverse effects:
Amiodarone: Above plus neurologic (20-40%) and gi (25%) complaints; 10% ofpts develop photosensitivity
Because of the risk of life-threatening arrhythmias, dofetilide requires 3-d hospitalization for initiation of rx by a certified practitioner with reevaluation at 3 mon based on QTc interval and renal function.
Drug interactions: Amiodarone increases levels of digoxin, warfarin, cyclosporine, hydantoins, methotrexate, quinidine, procainamide, and theophylline.
Dosage and administration:
Bretylium: 2 mg/mL, 4 mg/mL, 50 mg/mL injection; 5-10 mg iv loading dose over 10 min (rapid injection possible but may produce vomiting), 1-2 mg/min maintenance infusion
Amiodarone: 200 mg tablets, 50 mg/mL injection; loading dose 400-800 mg po bid pc for 1-3 wk, then 600-800 mg/d for 1 mon, then 200-400 mg po qd; for iv loading, give 150 mg over 10 min, then 360 mg/6 hr (1 mg/min), then 540 mg/18 hr (0.5 mg/min), then 0.5 mg/min maintenance infusion
Iv amiodarone is incompatible with aminophyline, cefazolin, cefamandole, heparin, NaHCO3
18.6 Anticoagulants
Warfarin
Nejm 1991;324:1865
Drugs of this type: Warfarin (Coumadin)
Pharmacokinetics: 97-99% protein bound; half-life 1-2.5 d
Uses: Treatment and prophylaxis of thrombosis and thromboembolic complications
Precautions and contraindications: Contraindicated in pregnancy, hemophilia, h/o bleeding diathesis, thrombocytopenic purpura, leukemia, major active bleeding, recent major surgery or trauma, cerebral or dissecting aortic aneurysm, hemorrhagic CVA, pericarditis, severe HT, severe renal or hepatic disease, infectious endocarditis
Adverse effects: Hemorrhage, “purple toe syndrome” (systemic cholesterol microembolization)
Drug interactions: Anticoagulant effect increased by acetaminophen, aminoglycosides, amiodarone, androgens, β-blockers, cephalosporins, chloral hydrate, chloramphenicol, chlorpropamide, cimetidine, cyclophosphamide, D-thyroxine, disulfiram, erythromycin, fluconazole, gemfibrozil, glucagon, hydantoins, influenza vaccine, INH, ketoconazole, loop diuretics, metronidazole, miconazole, moricizine, omperazole, NSAIDs, penicillins, propafenone, propoxyphene, quinine and quinidine, quinolones, salicylates, SMX-TMP, streptokinase, sulfinpyrazone, sulfonamides, tamoxifen, tetracyclines, thyroid hormone, urokinase, vitamin E
Anticoagulant effect decreased by ascorbic acid, barbiturates, carbamezepine, cholestyramine, dicloxacillin, estrogens, ETOH, gluthethimide, griseofulvin, nafcillin, rifampin, spironolactone, sucralfate, thiazide diuretics, trazodone, vitamin K
Heparin and Low-Molecular-Weight Heparin
Nejm 1997;337:668
Drugs of this type: Heparin, dalteparin (Fragmin), enoxaparin (Lovenox)
Pharmacology: LMW heparins obtained by depolymerization of unfractionated heparin
Pharmacokinetics: Average half-life of heparin is 0.5-3 hr; terminal half-life is 3-5 hr for dalteparin, 4.5 hr for enoxaparin
Uses: Rx and prophylaxis of thrombosis
Effects on other organs: May induce lipoprotein lipase and increase serum free fatty acid levels
Precautions and contraindications: Active major bleeding, thrombocytopenia
Adverse effects: Bleeding; thrombocytopenia
Drug interactions: Use with caution in conjunction with platelet inhibitors
Dosage and administration:
Heparin: Prophylaxis: 5,000 U sc q 12 hr; continuous infusion: 3,000-5,000 U iv bolus and then 1000 U/hr; target PTT 55-85 sec for DVT (see Table 18.5), 55-70 sec with thrombolytics
Dalteprin (Fragmin): Systemic anticoagulation: 100 U/kg sc q 12 hr; hip replacement surgery: 2,500 U sc 2 hr before surgery, 2500 U sc after surgery, 5000 U sc qd thereafter; unstable coronary artery syndrome: 120 U/kg (maximum 10,000 U) sc q 12 hr for 5-8 d with ASA 81-160 mg qd
18.7 FACTOR Xa INHIBITORS
ARIXTRA (fondaparinux sodium) Injection Prescribing Information 2005
Drugs of this type: Fondaparinux (Arixtra)
Pharmacology: Fondaparinux selectively binds to antithrombin III and potentates the innate neutralization of Factor Xa by antithrombin III. It does not inactivate thrombin and has no effect on platelets.
Pharmacokinetics: Absolute bioavailability after SC injection is 100%; steady-state plasma concentration is reached ˜3 hr postdose. Fondaparinux is highly bound to antithrombin III and does not bind significantly to other plasma proteins or red cells. It is eliminated in urine mainly as unchanged drug; elimination half-life is 17-21 hr. Elimination time is prolonged in the elderly and inpts with renal impairment.
Uses: Prophylaxis of thromboembolic events following knee and hip replacement surgery (including extended prophylaxis), and abdominal surgery, as well as, for the treatment of deep vein thrombosis and acute pulmonary embolism (in conjunction with warfarin sodium when initial therapy is administered in the hospital).
Precautions and Contraindications: Agents that may enhance the risk of hemorrhage should be discontinued prior to initiation of treatment. Fondaparinux should be discontinued before initiation of epidural/spinal anesthesia.
Use with caution inpts who weigh less than 50 kg (prophylaxis only) and in those with moderate renal impairment. The drug should be discontinued immediately in patients who develop severe renal impairment.
Use with extreme caution in conditions with increased risk of hemorrhage (congenital/acquired bleeding disorders, active ulcerative and angiodysplastic disease, hemorrhagic CVA, recent
brain, spinal, or ophthalmological surgery,pts treated concomitantly with platelet inhibitors).
brain, spinal, or ophthalmological surgery,pts treated concomitantly with platelet inhibitors).
Fondapurinax is contraindicated inpts with active major bleeding or bacterial endocarditis.
PT and PTT are insensitive measures of activity. No monitoring is required with fondaparinux.
Adverse effects: Risk of hemorrhage.
Drug interactions: None known.
Dosage and administration: Fondaparinux (Arixtra) 2.5 mg, 5 mg, 7.5 mg, 10 mg pre-filled syringes; recommended dose for DVT prophylaxis is 2.5 mg SC QD.
For acute DVT and acute PE, the recommended dose is 5 mg (body weight <50 kg), 7.5 mg (body weight 50-100 kg) or 10 mg (body weight >100 kg) SC QD.
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