3 - Cardiovascular Therapies

Editors: Susla, Gregory M.; Suffredini, Anthony F.; McAreavey, Dorothea; Solomon, Michael A.; Hoffman, William D.; Nyquist, Paul; Ognibene, Frederick P.; Shelhamer, James H.; Masur, Henry

Title: Handbook of Critical Care Drug Therapy, 3rd Edition

Copyright 2006 Lippincott Williams & Wilkins

> Table of Contents > Chapter 3 - Cardiovascular Therapies

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Chapter 3

Cardiovascular Therapies

TABLE 3.1. Treatment of Acute Coronary Syndromes (Unstable Angina, Non-ST Segment Elevation, and ST Segment Elevation Myocardial Infarction)

All patients with ACS are candidates for antiplatelet and antithrombin therapies. STEMI are candidates for reperfusion therapy (fibrinolytic or catheter-based). NSTEMI are not candidates for fibrinolytic reperfusion agents but should receive catheter-based therapy when applicable. In treating ACS attention should also be paid to exacerbating factors such as fever, anemia, hypoxemia, hypertension, hypotension, and arrhythmias. If chest pain or hypotension remains refractory, intra-aortic balloon counterpulsation should be considered. In general, patients with ACS should undergo diagnostic coronary arteriography to evaluate for left main disease, triple vessel disease, proximal LAD disease or lesions amenable to PCI. Cocaine-induced ACS should be treated with intravenous nitroglycerin and a calcium channel blocker (e.g., diltiazem, verapamil) and coronary arteriography should be considered. There is evidence that -adrenergic blockade can enhance cocaine-induced coronary artery vasoconstriction.
Agent	Dosage	Indications	Comments
MONA(Morphine, O2, NTG, ASA)	See below	All patients with ACS.	Bedrest, IV access, telemetry, obtain serial ECGs and cardiac enzymes
Morphine sulfate	Initially 2 4 mg IV then increments of 2 8 mg IV q5 15 min prn pain	If pain not relieved with NTG then give until pain and anxiety relief is obtained or hypotension occurs	Reduces sympathetic tone; reduces preload; reduces myocardial O2 demand
Oxygen	Initially 4 L/min by nasal cannula or 28% by venti-mask (adjust to maintain SaO2 >90%)	Maximize O2 delivery to ischemic myocardium	SaO2 should be maintained over 90% and preferably over 95%
Nitrates (Contraindicated in patients on sildenafil or other PDE 5 inhibitors and patients with RV infarctions)
Nitroglycerin	SL: 0.4 mg q5min 3 Spray: 1 2 metered sprays (0.4 mg NTG/spray) onto or under the tongue; may repeat in 3 5 min, 3 IV: 20 g/min then titrate to effect (pain relief and/or to lower BP 10% to 20% if not hypotensive) Topical: 1 2 inches of 2% ointment q6h or equivalent patches	Nitrate preparations for acute use; initial pain relief; coronary vasodilation; reduces preload (predominant) and afterload	Causes headache; may increase myocardial O2 demand by causing unintended tachycardia or hypotension; rapid tachyphylaxis
Isosorbide dinitrate	10 60 mg PO q4 6h	Useful for chronic management	Daily nitrate-free interval may ameliorate tachyphylaxis to antianginal effects
Aspirin (ASA)	Immediate: 162 325 mg tablet (chewed or ground up) then 75 162 mg PO qd PCI: 75 325 mg prior to (300 325 mg at least 2 h and preferably 24 h before PCI if not on daily ASA) then 325 mg qd for at least 1 m if BMS, 3 m if sirolimus-eluting and 6 m if paclitaxel- eluting then 75 162 mg indefinitely	All patients with ACS without ASA allergy Effective for primary and secondary MI prevention	Irreversibly inhibits prostaglandin cyclo-oxygenase, preventing formation of platelet aggregating factor thromboxane A2 Immediate antiplatelet effect; reduces mortality
Clopidogrel	ACS: Initially 300 mg PO then 75 mg PO qd PCI: 300 mg PO before PCI (preferably 6 h prior), then 75 mg PO qd for at least 1 m if BMS, 3 m if sirolimus-eluting and 6 m if paclitaxel-eluting and ideally up to 12 m if bleeding risk not high	As a substitute for ASA in individuals with true ASA allergy May be beneficial when added to daily ASA in NSTEMI (CURE trial) In addition to ASA for planned PCI	Inhibitor of ADP-induced platelet aggregation May be associated with increased risk of bleeding in patients undergoing CABG within 5 7 d of receiving clopidogrel
Heparin (UFH)	If adjunct to fibrinolytic agents: 60 U/kg IV bolus (max 4,000 U) then 12 U/kg/h infusion (max 1,000 U/h) for at least 48 h (maintain aPTT 1.5 2.0 control) otherwise 60 70 U/kg IV bolus (max, 5,000 U) then 12 15 U/kg/h infusion (max 1,000 U/h) for at least 48 h (maintain aPTT 1.5 2.0 control)	For persistent or recurrent angina; for fibrin-specific lytics; for increased risk of systemic emboli (e.g., coexisting atrial fibrillation, LV thrombus, large or anterior MI)	Enhances the action of antithrombin III Should be avoided in cases of known HIT or whenever a pre-existing coagulopathy would increase risk over perceived benefit
Bivalirudin	PCI: 0.75 mg/kg IV bolus immediately before the procedure then 1.75 mg/kg/h infusion for the duration of the procedure. Five min after bolus, an ACT should be done, and if needed an additional bolus of 0.3 mg/kg may be given.	As an alternative to UFH in patients with ACS undergoing PCI With provisional use of GPI IIb/IIIa (given for complications) as an alternative to UFH + GPI IIb/IIIa in patients undergoing PCI	Direct thrombin inhibitor (synthetic analogue of recombinant hirudin) Except in the setting of PCI there are limited data on efficacy and safety Use in conjunction with ASA (325 mg PO); safety and
Bivalirudin (continued)	Continuation of the infusion for up to 4 h postprocedure is optional (after 4 h, an additional infusion may be continued at 0.2 mg/kg/h for up to 20 h)	(REPLACE-2 Trial) As a substitute for UFH with known HIT in patients undergoing PCI	efficacy have not been established when used in conjunction with platelet inhibitors other than ASA
Enoxaparin (LMWH)	30 mg IV bolus, then 1 mg/kg sq bid for 2 8 d (use with ASA 325 mg PO); avoid if age 75, serum Cr > 2 mg/dl in women or >2.5 mg/dl in men	Adjunctive therapy in ACS (age <75, and without clinically significant renal insufficiency) as an alternative to UFH	Direct thrombin inhibitor through complex with antithrombin III Avoid if pre-existing coagulopathy would increase risk over perceived benefit
Fibrinolytic Agents(For contraindications refer to Table 3.2)
Only for STEMI, including true posterior MI, or presumed new left bundle branch block and <12 hours from onset (ideally 3 h from symptom onset; goal: door to drug <30 minutes). Consider PCI as an alternative based on local resources. In general PCI preferred if door to balloon <90 minutes, or cardiogenic shock present or late presentation (>3 hours) or contraindication to fibrinolysis. If 3 hours from symptom onset and PCI without delay then no preference for either strategy. Reteplase and alteplase are not known to be antigenic nor hypotensive-inducing. Tenecteplase has shown infrequent development of antibody titer at 30 days and reuse should be undertaken with precaution. It is also not hypotensive-inducing. Tenecteplase, reteplase, and alteplase should be used in conjunction with ASA 162 325 mg PO and heparin bolus of 60 U/kg (max 4,000 U) then 12 U/kg/h infusion (max 1,000 U/h) for at least 48 hours (maintain aPTT of 1.5 2.0 times control).
Tenecteplase	IV bolus over 5 15 s <60 kg: 30 mg 60 69 kg: 35 mg 70 79 kg: 40 mg 80 89 kg: 45 mg 90 kg: 50 mg	Greater fibrin specificity then rtPA Give with ASA and heparin (see above)
Reteplase	10 U IV over 2 min, then repeat, 30 min later, 10 U IV over 2 min	Low fibrinolysis (relatively clot-selective) Give with ASA and heparin (see above)
Alteplase (rtPA)	>67 kg: 15 mg IV bolus, then 50 mg over 30 min, then 35 mg over 60 min >67 kg: 15 mg IV bolus, then 0.75 mg/kg over 30 min, then 0.5 mg/kg over 60 min	Low fibrinolysis (relatively clot-selective) Give with ASA and heparin (see above)
Glycoprotein IIb/IIIa Receptor Inhibitors (GPI IIb/IIIa) Platelet aggregation inhibitor; inhibits the integrin GP IIb/IIIa receptor in the platelet membrane; contraindications include active bleeding, bleeding diathesis (past 30 days), intracranial tumor, hemorrhage arteriovenous malformation, aneurysm, recent stroke or major surgery or trauma (past month), severe hypertension, aortic dissection, pericarditis, platelets <100,000. Major benefit in NSTEMI troponin positive group with signs of persistent or recurrent ischemia (used in addition to aspirin or heparin). Can be used as adjunctive therapy with PCI strategy. Eptifibatide and tirofiban preferred in patients with USA/NSTEMI managed medically and abciximab and eptifibatide preferred in patients with USA/NSTEMI undergoing PCI. For planned PCI start treatment prior to procedure as early as feasible.
Abciximab	0.25 mg/kg IV bolus (over 5 min) then 0.125 g/kg/min (max 10 g/min) infusion for 12 24 h	Consider for USA/NSTEMI undergoing PCI	A murine monoclonal antibody; readministration may result in hypersensitivity, thrombocytopenia, or diminished benefit due to formation of human antichimeric antibodies
Eptifibatide	0.18 mg/kg IV bolus (max 22.6 mg) then 2 g/kg/min (max 15 mg/h) infusion up to 72 h	Consider for USA/NSTEMI undergoing PCI Adjunct to ASA and heparin in high risk USA/NSTEMI managed medically	If CrCl <50 mL/min or Cr >2 mg/dL, decrease infusion to 1 g/kg/min (maximum 7.5 mg/h), contraindicated in renal dialysis
Tirofiban	0.4 g/kg/min IV for 30 min then 0.1 g/kg/min for 12 48 h	Adjunct to ASA and heparin in high risk USA/NSTEMI managed medically	CrCl <30 mL/min, decrease dose by half (0.2 g/kg/min IV for 30 min, then 0.05 g/kg/min)
Angiotensin Converting Enzyme Inhibitors (Refer to Table 3.4) Beneficial in setting of MI regardless of ejection fraction or presence of HF (oral route preferred). Avoid IV ACE-I within the first 24 hours of symptom onset due to risk of hypotension. -Blocking Agents (Refer to Table 3.5) Indicated as treatment in the setting of ACS. Statins(Refer to Table 3.6) For all patients with ACS without contraindication in first 24 hours. May reduce ACS associated inflammation, and increase nitric oxide level and thus may be useful irrespective of LDL-C level. Antiarrhythmic Agents (Refer to Tables 3.9 and 3.10) Do not give prophylactically and avoid Class IC agents.
Magnesium sulfate	1 2 g IV over 30 60 min, then 0.5 1 g IV q1 2 h for up to 24 h	Prophylactic use in ICU patients with ACS not recommended Some studies suggest reduction in mortality while others do not	Can cause conduction disturbances; mild hypotension; flaccidity; optimal dose unknown
Treatment of Complications of ACS Please see the following tables: Cardiogenic pulmonary edema and shock (Therapy; Table 3.3) Heart failure (Tables 3.3, 3.4, 3.5) Arrhythmia (antiarrhythmic agents Tables 3.9 and 3.10) Secondary Prevention After Acute MI ASA 75 162 mg PO qd indefinitely ACE inhibitor indefinitely (Table 3.4) -blocker indefinitely (Table 3.5) Statin indefinitely if LDL-C 100 mg/dl (Table 3.6)
ACS, acute coronary syndromes; ADP, adenosine diphosphate; aPTT, activated partial thromboplastin time; ASA, aspirin; BMS, bare metal stent; BP, blood pressure; CABG, coronary artery bypass graft; CURE, clopidogrel in unstable angina to prevent recurrent events; ECG, electrocardiogram; GPI IIb/IIIa, glycoprotein IIb/IIIa receptor inhibitor; HF, heart failure; HIT, heparin-induced thrombocytopenia; INR, international normalized ratio; IV, intravenous; LAD, left anterior descending coronary artery; LDL-C, low-density lipoprotein-cholesterol; LMWH, low molecular weight heparin; LV, left ventricle; NSTEMI, non-ST segment elevation myocardial infarction; NTG, nitroglycerin; O2, oxygen; PCI, percutaneous coronary intervention; PDE, phosphodiesterase; PO, by mouth; REPLACE-2, Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events-2; RV, right ventricle; SaO2, arterial oxygen saturation; STEMI, ST segment elevation myocardial infarction; UFH, unfractionated heparin; USA, unstable angina

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TABLE 3.2. Fibrinolytic Therapy for ST-Segment Elevation Acute Coronary Syndrome: Contraindications

Absolute Contraindications to Fibrinolytic Therapy

• Active bleeding or recent bleeding diathesis (excluding menses).
• Intracranial/cerebral vascular legion (e.g., malignant intracranial neoplasm, arteriovenous malformation, or aneurysm).
• Prior intracranial hemorrhage.
• Major closed head or facial trauma within 3 months.
• Ischemic stroke within 3 months (except acute ischemic stroke <3 hours).
• Suspicion of aortic dissection.

Relative Contraindications to Fibrinolytic Therapy

• Chronic hypertension severe and poorly controlled.
• Presentation with severe uncontrolled hypertension (SBP >180 or DBP >110 mm Hg, consider absolute in low risk patients with STEMI).
• Prior ischemic stroke >3 months, dementia, or known intracranial pathology not covered under absolute.
• Recent internal bleeding (preceding 2 4 weeks) or active peptic ulcer disease.
• Noncompressible vascular punctures.
• Current anticoagulant use (bleeding risk proportional to INR).
• Pregnancy.
• Traumatic or prolonged cardiopulmonary resuscitation (>10 minutes) or major surgery (<3 weeks).

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TABLE 3.3. Treatment of Hypervolemia, Pulmonary Edema, Cardiogenic Shock and Decompensated Heart Failure Associated with Systolic Dysfunction

Assess BP, heart rhythm, adequacy of oxygenation, mentation, heart and lung sounds. Cardiovert for VT or rapid AF; initiate anti-ischemic (coronary arteriography referral in appropriate individuals), antihypertensive, or inotropic therapies as indicated. Consideration should be given to guiding management with continuous arterial monitoring and RHC determined hemodynamics, especially in patients not responding to initial therapies. Management of compensated chronic HF associated with systolic dysfunction should routinely include oral vasodilator therapy (Table 3.4), -blockade (Table 3.5), and symptom relief with diuretics. In addition in selective patients with moderate to severe HF aldosterone antagonists (spironolactone [25 50 mg q24h for NYHA Class III IV] or eplerenone [25 50 mg for HF post-MI]) and digoxin (adjusted to serum levels of 0.5 0.9 ng/ml) can be beneficial. Cardiac resynchronization therapy should be considered in appropriate candidates on optimal medical therapy with NYHA Class III IV symptoms and LVEF 35%, QRS duration 0.12 s, and LV end diastolic dimension 30 mm (indexed to height). An implantable cardioverter defibrillator should be considered in selective HF patients per guidelines.
Agent	Dosage	Comments
3.3.1 Therapy of Pulmonary Edema or Significant Hypervolemia If patient not hypotensive then put head of bed at 60 90 . If patient is hypotensive then also refer to Table 3.8. For patients with hypoxemia, consider noninvasive ventilatory support with CPAP. For pulmonary edema associated with hypertensive crisis also see Table 3.11. If aortic dissection is a concern then -blockade should be instituted prior to starting other antihypertensive agents. For patients with decompensated HF the goal would be to obtain PCWP <18 and preferably 15 mm Hg while avoiding symptomatic hypotension and organ hypoperfusion.
Oxygen	Initially 4 L/min by nasal cannula or 28% by venti-mask (Adjust to maintain SaO2 > 90%)	SaO2 should be maintained over 90% and preferably over 95%
Morphine sulfate	Initially 2 4 mg IV then increments of 2 8 mg IV q5 15min prn pain and anxiety (avoid if hypotensive)	Reduces sympathetic tone; reduces preload; reduces myocardial oxygen demand
Nitroglycerin	IV: 20 g/min then titrate to effect (pain relief and/or to lower BP 10% to 20% if not hypotensive) Topical: 1 2 inches of 2% ointment q6h or equivalent patches	Increase venous capacitance; reduces preload (predominant) and afterload, and can reduce myocardial O2 demand; tachyphylaxis occurs Useful in patients with ischemia because of direct coronary vasodilation Causes headache and contraindicated in RV infarction or in patients on sildenafil or other PDE 5 inhibitors
Diuretics Reduce circulating blood volume; improve oxygenation; goal is to relieve symptoms without producing hypotension or azotemia. Initial therapy with IV loop diuretics is recommended for patients with pulmonary edema or anasarca or suspected GI edema, others may be tried on oral therapy. If GFR <30 cc/min then initial doses may need to be doubled. Poor response to traditional oral or IV bolus diuretic regimens may respond to IV infusions or sequential nephron blockade with a loop diuretic used in combination with either metolazone or hydrochlorothiazide or chlorothiazide. Diuretic refractory patients may be considered for ultrafiltration.
Diuretics Loop of Henle Primary diuretic agents used intravenously for patients with pulmonary edema or anasarca. Ototoxicity during therapy is most frequently associated with high doses and elevated blood concentrations. Furosemide 40 mg & torsemide 10 20 mg & bumetanide 1 mg.
Bumetanide	IV: Initial bolus: 0.5 1.0 mg Range: 0.5 6 mg titrate to effect q2 3 prn Infusion: 1 mg load then 0.5 2 mg/h Oral: Initial: 0.5 1.0 mg Range: 0.5 10 mg q24h, 12h, 8h, prn Max daily dose: 10 mg	Oral form duration of action 4 6 h; IV &4 h Maintenance doses should be given on an intermittent schedule, i.e., QOD or every 3 4 d alternating with a 1 2-d interval without drug
Furosemide	IV: Initial bolus: 20 40 mg Range: 20 250 mg titrate to effect q1 2 prn Infusion: 40 80 mg load then 5 20 mg/h Oral: Initial: 20 40 mg Range: 20 600 mg q12h, 8h, 6h, prn Max daily dose: 600 mg	Oral form duration of action 6 8 h; IV &2 h IV boluses are usually doubled until desired effect is obtained or maximal single dose range reached (250 400 mg)
Torsemide	IV: Initial bolus: 10 20 mg Range: 10 200 mg q24h titrate to effect Infusion: 20 mg load then 3 15 mg/h Oral: Initial: 10 20 mg q24h Range: 10 200 mg q24h Max daily dose: 200 mg	Oral and IV form duration of action &12 h Doses can be up-titrated by doubling until desired effect is obtained or maximal single dose reached (200 mg) IV dose = PO dose
Diuretics Thiazide (Distal Tubule) Primarily effects distal renal tubular mechanism of electrolyte reabsorption. Adjunctive diuretic agents for treatment of pulmonary edema or anasarca. May be used with loop diuretics to provide sequential nephron blockade.
Chlorothiazide	IV or oral: Initial: 250 mg q24h or q12h Range: 250 1,000 mg q24h, 12h Max daily dose: 1,000 mg	Oral or IV form duration of action 6 12 h
Hydrochlorothiazide	Initial: PO 25 mg q24h or q12h Range: PO 25 100 mg q24h, 12 h Max daily dose: 200 mg	Duration of action 6 12 h
Metolazone	Initial: PO 2.5 mg q24h Range: PO 2.5 20 mg q24h Max daily dose: 20 mg (If with loop diuretic for sequential nephron blockade then 2.5 10 mg 60 min before loop diuretic)	Duration of action 12 24 h Thiazide-like diuretic although primarily acts by inhibiting sodium reabsorption at the cortical diluting site
Diuretics Potassium Sparing (Aldosterone Antagonists) Adjunctive diuretic agents for treatment of pulmonary edema or anasarca. May be used with loop diuretics in patients with refractory hypokalemia. Beneficial in the treatment of chronic HF associated with systolic dysfunction. These agents combined with ACE inhibitors may lead to hyperkalemia (monitor potassium levels). Risk increases progressively with serum Cr >1.6 mg/dl. If baseline K 5.0 mg/dl then avoid aldosterone antagonists.
Eplerenone	Initial: PO 25 mg q24h Range: PO 25 100 mg q24h Max daily dose: 100 mg Max daily dose for chronic HF: 50 mg	For HF after MI, initially 25 mg q24h, increasing to 50 mg q24h within 4 wk if tolerated (EPHESUS). Selective aldosterone antagonist blocks mineralocorticoid but not glucocorticoid, androgen, or progesterone receptors
Spironolactone	Initial: PO 12.5 25 mg q24h Range: PO 12.5 200 mg q24h, 12h Max daily dose: 200 mg Max daily dose for chronic HF: 50 mg	Duration of action 48 72 h In severe HF, 25 50 mg q24h added to therapy with ACE-I and loop diuretics reduced risk of death or hospitalization (RALES).
Diuretics Proximal Tubule
Acetazolamide	IV or oral: Initial: 5 mg/kg (250 375 mg) Range: 250 500 mg q24h, 12h (Maintenance doses should be given on an intermittent schedule, i.e., qod or 2 out of every 3 d)	Oral form duration of action 6 12 h; IV & 4 5 h Carbonic anhydrase inhibitor, causes bicarbonaturia Adjunctive diuretic agent for treatment of pulmonary edema or anasarca; may be used with loop diuretics in patients with metabolic alkalosis
3.3.2 Therapy of Hypoperfusion (characterized by low CI due to systolic dysfunction and abnormally high afterload [elevated SVR]) For patients refractory to medical therapy consideration should be given to intra-aortic balloon counterpulsation (contraindications include severe aortic insufficiency, abdominal or aortic aneurysm, and severe calcific aortic-iliac disease or peripheral vascular disease). For patients with HF the goal would be to obtain SVR 1,200 while avoiding symptomatic hypotension and organ hypoperfusion. In appropriate medically refractory HF patients consideration should be given to referral for transplantation and/or evaluation for ventricular assist device placement.
Inodilators (Inotropy and Afterload Reduction)
In chronic HF, scheduled intermittent (i.e., 48 72 hours once a week) or continuous prolonged inotrope infusions may palliate symptoms but do not improve survival and can have an adverse impact on survival.
Dobutamine	Initial: 2.5 g/kg/min IV Range: 2.5 20 g/kg/min IV titrate to effect Usual: (in HF) 2.5 7.5 g/kg/min Wean: taper slowly (i.e., 1 g/kg/min q1h or slower)	Synthetic catecholamine with primarily -1 adrenergic activity; 3+ inotropic effect; 2+ chronotropic effect; 1+ vasodilation In HF patients with CAD or associated secondary pulmonary HTN, consider using with NTG In HF, if hypoperfusion and elevated SVR persist then consider adding nitroprusside or milrinone May precipitate or worsen dysrhythmias
Milrinone	Load: 25 50 g/kg IV over 10 min (Controversial in HF several advocate no load, realizing initial effect will be delayed several h) then 0.25 or 0.375 g/kg/min IV Range: 0.25 or 0.375 or 0.5 or 0.75 g/kg/min IV Wean: taper slowly (i.e., adjust dose downward q2 3h or slower elimination half-life is &2.3h)	Phosphodiesterase inhibitor; 2+ inotropic effect; 1+ chronotropic effect; 3+ vasodilation In refractory HF patients can be combined with dobutamine May precipitate or worsen dysrhythmias
Vasodilators
Hydralazine	IV: 5 40 mg q2 4h	Predominantly reduces afterload and often combined with nitrates to achieve balanced arterial and venous effects Can cause a lupuslike syndrome For oral dosing in HF see Table 3.4
Nesiritide	Load: 2 g/kg IV bolus over 60 s then Initial: 0.01 g/kg/min IV Range: 0.01 0.03 g/kg/min IV Titration: Increase by 0.005 g/kg/min (after a bolus of 1 g/kg IV) no more frequently than every 3 h up to a max dose of 0.03 g/kg/min IV (limited experience with infusion durations >48 h)	Recombinant human B-type natriuretic peptide; natriuretic and vasodilatory (arterial and venous) effects Limit use to acutely decompensated HF with dyspnea at rest or with minimal activity (VMAC trial); sufficient evidence does not exist to recommend its use as an agent to replace diuretics or enhance diuresis Should not be used as primary therapy for cardiogenic shock or in patients with systolic BP <90 mm Hg May be associated with a dose-dependent increase in serum Cr
Nitroglycerin	IV: 0.25 4 g/kg/min (20 300 g/min)	Useful with dobutamine in HF patients with CAD or associated secondary pulmonary HTN Useful in patients with ischemia because of direct coronary vasodilation Increase venous capacitance; reduces preload (predominant) and afterload Causes headache and contraindicated in RV infarction and in patients on sildenafil and other PDE 5 inhibitors For dosing of isosorbide dinitrate in CAD see Table 3.1 and in HF see Table 3.4
Nitroprusside	Initial: 0.2 g/kg/min IV (10 15 g/min) Usual: 1 4 g/kg/min IV Titrate to effect in increments of 0.2 0.5 g/kg/min IV q10 30min or slower Max: 10 g/kg/min IV Wean: Taper slowly to prevent rebound increase in filling pressures and decrease in cardiac output	Onset of action <1 min; duration of action 1 10 min; usually used with invasive monitoring Preload and afterload reduction (balanced venous and arterial vasodilation); very effective for decreasing pulmonary congestion and increasing CI Methemoglobin levels should be monitored and elevated or rising levels are indications for discontinuing Be alert for thiocyanate toxicity (confusion, nausea, weakness, anion-gap acidosis, seizures), especially in renal insufficiency. Monitor thiocyanate levels if infusion >48 h Solution is light-sensitive
ACE-I, angiotensin converting enzyme-inhibitor; BP, blood pressure; CAD, coronary artery disease; CI, cardiac index; CPAP, continuous positive airway pressure; EPHESUS, Eplerenone Post MI Heart Failure Efficacy and Survival Study; GFR, glomerular filtration rate; HF, heart failure; HTN, hypertension; LVEF, left ventricle ejection fraction; MI, myocardial infarction; NTG, nitroglycerin; NYHA, New York Heart Association; O2, oxygen; PCWP, pulmonary capillary wedge pressure; PDE, phosphodiesterase; PO, by mouth; RALES, Randomized Aldactone Evaluation Study; RHC, right heart catheterization; RV, right ventricle; SaO2, arterial oxygen saturation; SVR, systemic vascular resistance; VMAC, Vasodilation in the Management of Acute Congestive HF

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TABLE 3.4. Oral Vasodilator Therapy for the Treatment of Heart Failure Associated with Systolic Dysfunction or Postmyocardial Infarction

ACE-I are considered first line therapy with ARB a suitable alternative in patients intolerant of ACE-I, particularly in those with ACE-I induced incessant cough. For HF associated with systolic dysfunction in patients intolerant of ACE-I and ARB, the combination of HYZ and ISDN is a reasonable alternative. In addition the combination of HYZ and ISDN when added to standard HF therapy that includes ACE-I (or ARB), -blocker, and diuretic (many also received digoxin) has been shown to produce a further survival benefit in black patients with NYHA Class III IV HF.
Agent	Dosage	Comments
Angiotensin Converting Enzyme Inhibitors Survival benefit in NYHA Class II IV HF patients and quality-of-life benefit in NYHA Class I patients (asymptomatic LV dysfunction). Beneficial in setting of MI regardless of ejection fraction or presence of HF. Cautiously begin low doses in setting of hypovolemia, hyper K, azotemia, or serum Na <130. In patients with uni or bilateral renal artery stenosis, ACE-I can increase serum Cr or BUN. Has been associated with angioedema, rash, hyperkalemia, and incessant cough.
Captopril	Initial: PO 6.25 mg q6h Range: PO 12.5 50 mg q8h (advance over 24 72 h to max tolerated dose)	Reduction in HF or cardiac events following MI Beneficial in patients with LV dysfunction and prior or current HF symptoms
Enalapril	Initial: PO 2.5 mg q12h Range: PO 5 20 mg q12h	Beneficial in NYHA Class I IV HF
Fosinopril	Initial: PO 5 mg qd Range: PO 10 40 mg qd	Beneficial in patients with LV dysfunction and prior or current HF symptoms
Lisinopril	Initial: PO 2.5 mg qd Range: PO 5 40 mg qd	Reduction in HF or cardiac events following MI Beneficial in patients with LV dysfunction and prior or current HF symptoms
Quinapril	Initial: PO 5 mq q12h Range: PO 10 20 mg q12h	Beneficial in patients with LV dysfunction and prior or current HF symptoms
Ramipril	Initial: PO 1.25 mg q12h Range: PO 2.5 5 mg q12h	Reduction in HF or cardiac events following MI
Trandolapril	Initial: PO 0.5 mg qd Range: PO 1 4 mg qd	Reduction in HF or cardiac events following MI
Angiotensin Receptor Blockers Use cautiously and start in low doses in setting of hypovolemia, hyperkalemia, and azotemia.
Candesartan	Initial: PO 4 mg qd Range: PO 8 32 mg qd	Beneficial in patients with LV dysfunction and prior or current HF symptoms
Losartan	Initial: PO 25 mg qd Range: PO 25 50 mg q12h	Beneficial in patients with LV dysfunction
Valsartan	Initial: PO 20 mg q12h Range: PO 40 160 mg q12h	Reduction in HF or cardiac events following MI Beneficial in patients with LV dysfunction and prior or current HF symptoms
Combined Arterial and Venous Vasodilatation
Hydralazine (HYZ) and Isosorbide Dinitrate (ISDN)	Initial: HYZ 10 20 mg PO q6 8h ISDN 10 20 mg PO q6 8h Range: HYZ 25 75 mg PO q6 8h ISDN 20 40 mg PO q6 8h	For HF associated with systolic dysfunction in patients intolerant of ACE-I and ARB and in addition to ACE-I in black patients Use cautiously and start in low doses in setting of hypovolemia Also available in a fixed dosage form of HYZ 37.5 mg and ISDN 20 mg. Starting dose to 1 tablet tid with max dose 2 tablets tid HYZ can cause a lupuslike syndrome; ISDN can cause headache and is contraindicated with sildenafil and other PDE 5 inhibitors
ACE-I, angiotensin converting enzyme-inhibitors; ARB, angiotensin receptor blocker; BUN, blood urea nitrogen; HF, heart failure; HYZ, hydralazine; ISDN, isosorbide dinitrate; K, potassium; LV, left ventricular; MI, myocardial infarction; Na, sodium; NYHA, New York Heart Association; PDE, phosphodiesterase

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TABLE 3.5. -Blockade Therapy for the Treatment of Heart Failure Associated with Systolic Dysfunction or Acute Coronary Syndrome

-blockade is indicated as treatment in the setting of ACS and for secondary prevention post-MI. It is beneficial in the setting of MI regardless of EF or presence of HF. -blockade with either carvedilol or bisoprolol or metoprolol (CR/XL) is indicated for HF associated with systolic dysfunction. There is sufficient evidence from multiple randomized trials to recommend these agents in NYHA Class II IV HF. Many experts would also advocate these agents in NYHA Class I HF. Appropriate candidates should be in a relatively compensated state with resting HR >60, and absence of 2nd- or 3rd-degree AV block or bronchospastic disease. -blockers can cause bradycardia, hypotension, bronchospasm, worsened conduction disturbances, worsened HF in a decompensated HF patient, and rebound ischemia after discontinuation. There is evidence that -adrenergic blockade augments cocaine-induced coronary artery vasoconstriction.
Agent	Dosage	Comments
Atenolol	IV (for ACS): 5 mg over 5 min, then 5 mg 10 min later then begin PO Range PO: 25 100 mg qd	Reduction in HF or cardiac events following MI 1 cardioselective at usual dose; long half-life allows qd dosing
Bisoprolol (HF indication)	HF therapy: Initial: PO 1.25 mg qd Range: PO 1.25 10 mg qd (Initial dose doubled after 1 wk then titrate over 1 4 wk intervals to max tolerated) Anti-ischemic range: PO 5 20 mg qd	Beneficial in patients with LV dysfunction and prior or current HF symptoms (NYHA Class III IV HF) 1 cardioselective
Carvedilol (HF indication)	HF therapy: Initial: PO: 3.125 mg q12h Range: PO: 6.25 25 mg q12h (max dose 50 mg q12h if wt >85 kg) (Initial dose doubled after 1 2 wk then titrated as tolerated every 2 wk) Anti-ischemic range: PO 25 50 mg qd	Beneficial in patients with LV dysfunction and prior or current HF symptoms. (NYHA Class II IV HF) Reduction in HF or cardiac events following MI Not cardioselective
Esmolol	IV: 250 500 g/kg over 1 min then 50 g/kg/min; rebolus and increase q5min by 50 g/kg/min to max of 300 g/kg/min	1 cardioselective; its 7-min half-life allows effects to subside quickly Consider reducing loading dose in marginally or poorly compensated patients Use 100 mg vial for loading dose
Metoprolol (HF indication)	Succinate (HF therapy): Initial: (NYHA II) PO 25 mg qd Initial: (NYHA III IV) PO 12.5 mg qd Range: PO 25 200 mg qd (Initial dose doubled after 1 2 wk then titrated as tolerated every 2 wk) Anti-ischemic range: PO 100 400 mg qd Tartrate (ACS therapy): IV: 5 mg q5min up to 15 mg then begin PO therapy 15 min after final IV dose Initial: PO 25 50 mg PO q6h for 48 h Range: PO 50 200 mg q12h	Succinate form beneficial in patients with LV dysfunction and prior or current HF symptoms (NYHA Class II IV) Tartrate form associated with reduction in HF or cardiac events following MI 1 selective at daily doses totaling 200 mg
Nadolol	Range: PO 40 240 mg qd	Not cardioselective; long half-life allows qd dosing
Propranolol	Short acting: Range: PO: 10 80 mg q6h Long acting: Range: PO: 80 320 mg qd	Reduction in HF or cardiac events following MI Prototype -blocker; not cardioselective
Timolol	Range: PO 5 20 mg bid	Reduction in HF or cardiac events following MI; not cardioselective
ACS, acute coronary syndrome; AV, atrioventricular; EF, ejection fraction; HF, heart failure; LV, left ventricular; MI, myocardial infarction; NYHA, New York Heart Association; O2, oxygen

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TABLE 3.6. Statins (HMG-CoA Reductase Inhibitors)

For all patients with ACS without contraindication in first 24 hours. May reduce ACS associated inflammation, and increase nitric oxide level and thus may be useful irrespective of LDL-C level. For secondary prevention in patients with LDL-C >100 mg/dl. Reduction in LDL-C 18% to 55%, TG 7% to 30%, and increase in HDL-C 5% to 15%. Contraindicated in active or chronic liver disease. Side effects: Myopathy (monitor CK) or increased liver enzymes (monitor AST and ALT). Liver enzyme tests should be performed before and at 2 3 months following both the initiation of therapy and dose elevations, and periodically (e.g., semiannually) on chronic therapy. Reduce dose or discontinue if serum transaminase levels of 3 times the upper normal limit persist. Temporarily hold or discontinue if a condition suggestive of or predisposing to myopathy or renal failure develops. Concomitant therapy with cyclosporine, macrolides, protease inhibitors, azole antifungals, nefazodone, fibrates, or niacin may increase the risk of myopathy.
Agent	Equipotent Dosages (mg) (once-daily oral-dosing)
Atorvastatin	5	10	20	40	80
Fluvastatin	40	80	N/A	N/A	N/A
Lovastatin	20	40	80	N/A	N/A
Pravastatin	20	40	80	N/A	N/A
Rosuvastatin	2.5	5	10	20	40
Simvastatin	10	20	40	80	N/A
ACS, acute coronary syndrome; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CK, creatine kinase; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein-cholesterol; N/A, not applicable; TG, triglyceride

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TABLE 3.7. Calcium Channel Antagonists

In general, calcium channel antagonists are not used in the treatment of acute coronary syndromes. Used for treatment of hypertension. Nondihydropyridine forms are used for treatment of atrial arrhythmias.
Agent	Dosage	Comments
Nondihydropyridine
Diltiazem	IV: 0.25 mg/kg over 2 min (typically 15 20 mg IV) (may repeat once in 15 min with 0.35 mg/kg, typically 25 mg IV) then 5 15 mg/h PO: 30 90 mg q6h	Compared to verapamil, slightly more vasodilator potency and less antiarrhythmic potency; relatively little negative inotropy
Verapamil	IV: 2.5 10 mg over 2 3 min (repeat in 15 30 min prn), Max cumulative = 20 mg PO: 40 160 mg q6h	Verapamil has the strongest antiarrhythmic potency, the most negative inotropy, and the weakest vasodilator potency; side effects include conduction disturbances, heart failure, hypotension, and constipation
Dihydropyridine
Amlodipine	PO: 2.5 10 mg qd	Peripheral and coronary arterial vasodilator; acts directly on vascular smooth muscle; does not affect myocardial contractility or cardiac conduction; can cause dizziness and edema; once-daily dosing
Nicardipine	Initial: 5 mg/h IV Titrate: 2.5 mg/h every 5 15 min Range: 5 15 mg/h IV PO: 20 40 mg tid	Effects intermediate between amlodipine and nifedipine
Nifedipine	PO: 10 30 mg q8h	Minimal inotropic, antiarrhythmic, or conducting system effects; relative to verapamil or diltiazem, acts more as a pure vasodilator, including coronary vasodilatation; side effects include dizziness, headache, and flushing

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TABLE 3.8. Intravenous Vasoactive Agents

Vasoconstrictors usually are administered by central vein and should be used in conjunction with adequate volume repletion. All can precipitate myocardial ischemia. All except phenylephrine can cause tachyarrhythmias. Cautions should be used to avoid extravasation of vasoconstrictors. If extravasation occurs, 10 15 ml of 0.9% NaCl containing 5 10 mg of phentolamine should be infiltrated liberally throughout the affected area.
Agent and Dose	Systemic Vasoconstriction	Inotropy	Systemic Vasodilation	Comments
Vasoconstrictors
Phenylephrine Start at 30 g/min IV and titrate	++++ Alpha	0	0	Pure vasoconstrictor without direct cardiac effects; may cause reflex bradycardia Doses up to 350 g/min may be required in some settings
Vasopressin Start at 0.01 U/min and titrate; doses should be limited to 0.04 U/min	+++	0	0	May be beneficial in patients with refractory shock despite adequate fluid resuscitation and high dose conventional vasopressors Exact mechanism of BP increase is unknown
Vasoconstrictors and Inotropes
Dopamine 2 20 g/kg/min Dopaminergic effects (++++)	+ Alpha	++++ Beta	0	Doses >20 30 g/kg/min usually produce no added response Increases in BP mainly due to increases in inotropy and HR
Epinephrine Start at 2 g/min and titrate	+ Alpha	++++ Beta	0	Increases in BP mainly due to increases in inotropy and HR Doses up to 0.5 g/kg/min may be required in some settings
Norepinephrine Start at 2 g/min and titrate	++++ Alpha	+ Beta	0	Increase in BP primarily due to increase in peripheral vasoconstriction Doses up to 3 g/kg/min may be required in some settings
Vasodilators and Inotropes
Dobutamine 2.5 20 g/kg/min	0	++++ Beta	++	Useful for acute management of low cardiac output states Can be combined with nitroprusside, NTG, or milrinone
Milrinone
Loading dose 25 50 g/kg over 10 min, then 0.25 0.75 g/kg/min	0	++	+++	Useful for acute management of low cardiac output states Can be combined with dobutamine
Vasodilators
Nesiritide Load 2 g/kg bolus, then 0.01 g/kg/min and increase by 0.005 g/kg/min (after 1 g/kg bolus) no sooner than every 3 h Range: 0.01 0.03 g/kg/min	0	0	++	Recombinant human B-type natriuretic peptide Use limited to acutely decompensated HF with dyspnea with minimal activity Should not be used for intermittent outpatient infusion, scheduled repetitive use, to improve renal function, to enhance diuresis, or as primary therapy for cardiogenic shock
Nitroglycerin 0.25 4 g/kg/min (20 300 g/min)	0	0	++	Predominantly reduces preload; increases venous capacitance Useful in patients with ischemia due to direct coronary vasodilation Contraindicated with sildenafil and other PDE 5 inhibitors
Nitroprusside Initial: 0.2 g/kg/min (10 15 g/min) Usual: 1 4 g/kg/min Max: 10 g/kg/min	0	0	++++	Preload and afterload reduction (venous and arterial vasodilation) Useful for acute management of low cardiac output states Methemoglobin levels should be monitored and elevated or rising levels are indications for discontinuing
BP, blood pressure; HF, heart failure; HR, heart rate; NTG, nitroglycerin; PDE, phosphodiesterase

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TABLE 3.9. Antiarrhythmic Agents

Agents (Listed by Vaughan Williams Classification)	Indications	Dosage	Comments
Class IA (Infrequently Used)
Procainamide	Malignant ventricular ectopy; conversion of A fib and A flutter to NSR; WPW	12 17 mg/kg at 20 30 mg/min IV, then 2 5 mg/min (or 500 1,000 mg PO q4 6h)	N-acetyl procainamide is active metabolite and tends to accumulate in renal failure; lupuslike syndrome; fever; rash; agranulocytosis; QT interval prolongation; mild negative inotropy
Quinidine sulfate	Malignant ventricular ectopy; conversion of A fib and A flutter to NSR; WPW	6 10 mg/kg at 20 mg/min IV, then 1 3 mg/min (or 200 400 mg PO q6h)	Diarrhea; thrombocytopenia; hemolysis; fever; hepatitis; rash; cinchonism; QT interval prolongation; increased digoxin level; IV causes hypotension; PO route preferred
Disopyramide	Malignant ventricular ectopy; conversion of A fib and A flutter to NSR; WPW	100 200 mg PO q6h	Anticholinergic effects; negative inotropy; QT interval prolongation
Class IB (Infrequent Use Except Lidocaine)
Lidocaine	Malignant ventricular ectopy; WPW	1 1.5 mg/kg IV over 2 min IV May repeat 0.5 0.75 mg/kg IV to a max 3 mg/kg, then infusion 1 4 mg/min	Seizures; paresthesias; delirium; levels increased by cimetidine; minimal hemodynamic effects
Mexiletine	Malignant ventricular ectopy; less effective than IA and IC agents	150 300 mg PO q6 8h with food	Nausea; tremor, dizziness; delirium; hepatitis; dose-related bradycardia, but minimal hemodynamic effects; levels increased by cimetidine
Class IC
Flecainide	Life-threatening ventricular arrhythmias refractory to other agents	100 200 mg PO q12h IV formulation not available in the U.S.	Proarrhythmic effects; moderate negative inotropy; dizziness; conduction abnormalities Contraindicated if conduction abnormalities, coronary disease, HF Avoid if electrolyte abnormalities or liver disease
Propafenone	Life-threatening ventricular arrhythmias refractory to other agents Used for supraventricular arrhythmias	IV formulation not available in the U.S. 150 300 mg PO q8h 600 mg po single dose used for cardioversion of recent onset A fib	Proarrhythmic effects; negative inotropy; dizziness; nausea; bronchospasm; conduction abnormalities Avoid if structural heart disease, conduction abnormalities, or abnormal electrolytes
Class IA/IB (Hybrid Electrophysiologic Effects, Rarely Used)
Moricizine	Life-threatening ventricular arrhythmias refractory to other agents	100 300 mg PO q8h	Proarrhythmic effects; dizziness; nausea; rash; headache
Class II ( -Blocking Agents)
Metoprolol	Slowing ventricular rate in A fib, A flutter, SVT, and MAT	5 mg q5min IV up to 15 mg, then 25 100 mg PO q8 12h	Cardioselective at low doses; hypotension; negative inotropy
Esmolol	Slowing ventricular rate in A fib, A flutter, SVT, and MAT	250 500 g/kg over 1 min IV, then 50 g/kg/min; rebolus and increase q5min by 50 g/kg/min to maximum of 300 g/kg/min	Cardioselective at low doses; hypotension; negative inotropy; very short half-life Use 100 mg vial for loading dose
Propranolol	Slowing ventricular rate in A fib, A flutter, and SVT; suppression of PVCs	Up to 0.15 mg/kg over 20 min IV, then 3 mg/h (or 10 80 mg PO q6h)	Not cardioselective; hypotension; bronchospasm; negative inotropy
Class III
Amiodarone	Life-threatening ventricular arrhythmias refractory to other agents Used for atrial arrhythmias Drug of choice for reduced LV function	PO: 800 1600 mg qd for 1 3 wk, then 600 800 mg qd for 4 wk, then 100 400 mg qd IV: 150 mg over 10 min, then 1 mg/min for 6 h, then 0.5 mg/min maintenance infusion; switch to PO when possible; for recurrent ventricular arrhythmias, supplement with infusions of 150 mg over 10 min IV: 300 mg for VF refractory to 1 2 shock-CPR cycles and one vasopressor agent	Half-life >50 days; pulmonary fibrosis; corneal microdeposits; hypo/hyperthyroidism; bluish skin; hepatitis; photosensitivity; conduction abnormalities; mild negative inotropy; increased effect of warfarin sodium; increased digoxin level ARDS has been reported With IV administration, hypotension, bradycardia, and AV block can occur
Ibutilide	Conversion of A fib and A flutter to NSR	60 kg: 1 mg IV over 10 min; wait 10 min; then if needed, another 1 mg IV over 10 min <60 kg: same protocol, using 0.01 mg/kg doses	Can cause QT interval prolongation, torsade, and transient heart block Avoid if abnormal electrolytes, prolonged QT interval Use with caution in patients with EF <35%
Sotalol	Life-threatening ventricular arrhythmias; conversion of A fib and A flutter to NSR	PO: 80 mg q12h; may increase up to 160 mg PO q8h IV formulation not available in the U.S.	-blocker with Class III properties; proarrhythmic effects; QT interval prolongation, torsade de pointes
Class IV (Calcium Channel Antagonists)
Verapamil	Conversion of SVT to NSR; slowing ventricular rate in A fib, A flutter, and MAT	5 10 mg IV over 2 3 min (repeat in 30 min prn), then 0.1 5 g/kg/min IV (or 40 160 mg PO q6h)	Hypotension; negative inotropy; conduction disturbances; increased digoxin level; contraindicated in WPW; avoid combination with -blockade, digoxin, amiodarone
Diltiazem	Conversion of SVT to NSR; slowing ventricular rate in A fib, A flutter, and MAT	0.25 mg/kg IV over 2 min (may repeat once in 15 min with 0.35 mg/kg IV), then 5 15 mg/h (or 30 90 mg PO q6h)	Hypotension; less negative inotropy than verapamil; conduction disturbances; rare hepatic injury; contraindicated in WPW; avoid combination with -blockade, digoxin, amiodarone
Miscellaneous Agents
Adenosine	Conversion of SVT, to NSR	6 mg rapid IV bolus; if ineffective, 12 mg rapid IV bolus 2 min later; follow bolus with saline flush; use smaller doses (3 mg) if giving through central venous line	Flushing; dyspnea; nodal blocking effect increased by dipyridamole and decreased by theophylline and caffeine; very short half-life (&10 s)
Atropine	Initial therapy for symptomatic bradycardia	0.5 mg IV bolus; repeat q5min prn to total of 3 mg IV	May induce tachycardia and ischemia
Digoxin	Slowing AV conduction in A fib and A flutter	0.5 mg IV bolus, then 0.25 mg IV q2 6h up to 1 mg; maintenance 0.125 0.375 PO/IV qd	Heart block; arrhythmias; nausea; yellow vision; numerous drug interactions; generally contraindicated in WPW Monitor level
Isoproterenol	Rarely used for torsade de pointes	Start at 2 g/min, increase as needed (usually >10 g/min)	Tachycardia; ischemia; hypotension
Magnesium sulfate	Torsade de pointes; adjunct for VT and VF	2 g IV over 10 min, then 1 g IV q6h	Can cause conduction disturbances; mild hypotension; flaccidity; optimal dose uncertain
A fib, atrial fibrillation; A flutter, atrial flutter; ARDS, acute respiratory distress syndrome; AV, atrioventricular; CPR, cardiopulmonary resuscitation; HF, heart failure; IV, intravenous; MAT, multifocal atrial tachycardia; NSR, normal sinus rhythm; PO, by mouth; PVC, premature ventricular contraction; SVT, supraventricular tachycardia; VF, ventricular fibrillation; VT, ventricular tachycardia; WPW, Wolff-Parkinson-White

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TABLE 3.10. Antiarrhythmics of Choice

Rhythm	Treatment	Prevention of Recurrence
Paroxysmal supraventricular tachycardia	If unstable, electrical cardioversion initially 100 J monophasic synchronized, or biphasic equivalent If stable 1st choice: vagal maneuvers such as carotid sinus massage 2nd choice: IV adenosine Alternatives: IV verapamil; IV diltiazem; IV -blocker If reduced LVEF, amiodarone preferred to calcium channel antagonists Consider electrical cardioversion; rapid atrial pacing, or IV ibutilide if normal LVEF	Assess need for drug therapy 1st choice: PO -blocker, PO verapamil, or PO diltiazem 2nd choice: PO digoxin 3rd choice: Class IA/C or Class III drugs If reduced EF, amiodarone preferred
Atrial flutter or fibrillation	If unstable, electrical cardioversion A flutter, initially 50 J monophasic synchronized or biphasic equivalent; A fib, initially 100 J monophasic synchronized or biphasic equivalent If stable For rate control: IV diltiazem, -blocker, amiodarone, or digoxin depending on clinical setting? For restoring sinus rhythm: 1st choice: IV/PO Class IC or Class III drugs Class IA drugs rarely used If CAD, sotalol preferred over Class IC If HF, amiodarone preferred over Class IC	Determine whether rate control only or rhythm control is necessary; correct electrolyte abnormalities Rate control with oral drugs: -blockade, verapamil, diltiazem, digoxin, or amiodarone Rhythm control with oral drugs: Class III or Class IC or Class IA (rarely used) drugs depending on clinical setting Prophylactic warfarin and/or aspirin should be prescribed for paroxysmal or chronic A fib/flutter unless contraindicated Notes: (1) If A fib persists >24 48 h, anticoagulate prior to conversion; (2) use type IA antiarrhythmic agents only after blocking the AV node with digoxin or a calcium channel or -blocker; (3) prior to cardioversion, consider whether TEE or several weeks anticoagulation is necessary
Multifocal atrial tachycardia	1st choice: Treat the underlying condition, e.g., metabolic or electrolyte abnormalities or rarely digoxin toxicity 2nd choice: IV diltiazem or IV verapamil 3rd choice: IV esmolol or IV metoprolol (use caution despite -1 selectivity)	Avoid hypoxemia; correct metabolic derangements; avoid aminophylline and theophylline if possible -blockade may be contraindicated because of pulmonary disease Note: Digitalis and electrical cardioversion are both ineffective for this rhythm
Wolff-Parkinson-White syndrome with atrial fibrillation or flutter	1st choice: electrical cardioversion (initially 100 J monophasic synchronized or biphasic equivalent)	1st choice: catheter ablation of accessory pathway 2nd choice: PO, Class IC, or Class III agents
	2nd choice: IV procainamide, amiodarone, ibutilide, or flecainide	Note: If wide complex (antidromic), avoid drugs that block AV node such as adenosine, -blockers, calcium channel antagonists, and digoxin
Paroxysmal junctional tachycardia	May respond to Class II, III, or IC Catheter ablation may be necessary	Rare arrhythmia
Nonparoxysmal junctional tachycardia	Correct underlying abnormality, e.g., digoxin toxicity, electrolyte abnormalities, myocardial ischemia, hypoxia	Rarely consider -blockade or calcium channel antagonists
Ventricular tachycardia	If unstable, defibrillation Initially 200 J unsynchronized monophasic or biphasic equivalent If stable with pulse Drug choices: 1st: IV amiodarone 2nd: IV lidocaine 3rd: IV procainamide 4th: -blockade, Mg Electrical: Synchronized cardioversion	Consider electrophysiologic assessment and need for defibrillator Drug therapy should be tailored to circumstance. It may include -blockade, amiodarone, sotalol, or LV remodeling regimen in heart failure Other antiarrhythmic agents may be proarrhythmic Note: Symptomatic ventricular tachycardia requires evaluation and treatment. Asymptomatic ventricular arrhythmias may require evaluation especially if reduced LV function. Therapy is not usually needed for premature ventricular contractions.
Torsade de pointes	If unstable, defibrillation Initially 200 J unsynchronized monophasic or biphasic equivalent If stable 1st choice: IV magnesium sulfate 2nd choice: increase heart rate with atrial pacing, isoproterenol, or atropine	Discontinue precipitating drugs (e.g., type IA agents, tricyclic antidepressants, nonsedating antihistamines, phenothiazines)
Ventricular fibrillation	Per ACLS algorithm, shock-CPR (2min) sequences (200/300/360 J monophasic or biphasic equivalent), followed by vasopressor such as epinephrine or vasopressin	Give drugs while continuing CPR After 1 2 shocks, consider epinephrine 1 mg IV at 3 5 min intervals. May give vasopressin 40 U IV once, instead of 1st or 2nd dose epinephrine Consider amiodarone 300 mg IV over 10 min Other possible drugs include IV lidocaine, procainamide, or Mg
A fib, atrial fibrillation; A flutter, atrial flutter; ACLS, advanced cardiac life support; CAD, coronary artery disease; IV, intravenous; HF, heart failure: LVEF, left ventricular ejection fraction; PO, by mouth

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TABLE 3.11. Parenteral Antihypertensive Agents Pharmacologic Characteristics (See Table 3.12 for Therapy of Specific Conditions)

Agent	Dosage/Onset/Duration	Comments
Parenteral Vasodilators
Nitroprusside	Dosage: IV Infusion 0.2 10 g/kg/min Onset: <1 min Duration: 1 10 min	Thiocyanate toxicity (serum level >10 mg/dL) usually occurs after >48 h especially in presence of renal dysfunction; treat with sodium thiosulfate Methemoglobinemia Cyanide toxicity
Nitroglycerin	Dosage: IV infusion 0.25 4 g/kg/min (20 300 g/min) Onset: 1 2 min Duration: 3 10 min	Tachyphylaxis, headache, methemoglobinemia
and Adrenergic Blocker
Labetalol	Dosage: 20 mg IV over 2 min, then 40 80 mg IV q10min to a total of 300 mg or IV infusion starting at 0.5 2 mg/min; titrate to effect, max 4 mg/min Onset: 5 min Duration: 2 12 h	Bronchospasm, conduction disturbances, bradycardia
Adrenergic Blocker
Phentolamine	Dosage: IV infusion 1 5 mg/min or IV bolus 5 10 mg q5 15min Onset: 1 2 min Duration: 3 10 min	Indicated for pheochromocytoma Tachycardia, GI stimulation, hypoglycemia
Adrenergic Blockers
Side-effects include bronchospasm, negative inotropy, HF, conductive disturbances
Metoprolol	Initial: 5 mg IV Range: 5 15 mg IV Onset: 5 10 min Duration: 3 6 h
Esmolol	Dosage: IV 250 500 g/kg over 1 min then 50 g/ kg/min; rebolus and increase q5min by 50 g/kg/min to max of 300 g/kg/min Onset: 1 3 min Duration: 1 2 min for -blockade	Careful BP monitoring because hypotension is common The bolus dose should be withdrawn from the 100-mg vial Infusion doses >300 g/kg/min have not been studied
Propranolol	Dosage: IV 1 10 mg load then 3 mg/h Onset: IV 2 3 min Duration: 1 6 h
Angiotensin Converting Enzyme Inhibitor
Enalaprilat	Dosage: IV 0.625 5 mg slowly over 5 min q6h Onset: 15 min Duration: 4 6 h	Effective in renin-dependent hypertension Initial dose in pt on diuretics: 0.625 mg
Calcium Channel Antagonists
Nicardipine	Initial: 5 mg/h IV Titrate: 2.5 mg/h every 5 15 min Range: 5 15 mg/h Onset: 1 5 min Duration: 30 min	IV substitute for PO nicardipine therapy: 20 mg PO q8h = 0.5 mg/h 30 mg PO q8h = 1.2 mg/h 40 mg PO q8h = 2.2 mg/h
Diltiazem	IV: 0.25 mg/kg over 2 min (typically 15 20 mg IV) (may repeat once in 15 min with 0.35 mg/kg, typically 25 mg IV) then 5 15 mg/h	Compared to verapamil, relatively more vasodilator potency and less antiarrhythmic potency
Dopamine-1 Receptor Agonist
Fenoldopam	Initial: 0.1 0.3 g/kg/min; increase by 0.05 0.1 g/ kg/min; maximum 1.6 g/kg/min	Increases renal blood flow Tachycardia; monitor for hypokalemia q6 Can worsen glaucoma; contains sulfites; effect of dialysis unknown; avoid in intracranial hypertension
Central Sympatholytic
Methyldopa	Dosage: IV 250 1000 mg q6h Onset: 4 6 h Duration: 10 16 h	Sedation, CNS depression
BP, blood pressure; CNS, central nervous system; GI, gastrointestinal; HF, heart failure;IV, intravenous; PO, by mouth

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TABLE 3.12. Antihypertensive Therapy

For hypertension associated with neurologic disorders, see chapter 9 Rate of BP reduction and final BP goal depends on diagnosis. In general BP should not be reduced more than 10% to 15% over 4 6 hours and then a more gradual reduction over the ensuing days. Rapid control of BP is indicated in aortic dissection. Diuretic only for pa- tient with clinically evident fluid overload.
Type	Recommended Therapy	Comments
Central/Peripheral Nervous System
Hypertensive encephalopathy	1 : Nitroprusside Alt: Labetalol Alt: Calcium channel blocker	Drugs to avoid: methyldopa, clonidine, other central nervous system depressants
Aortic dissection	1 : -blocker and then add nitroprusside Alt: Labetalol	Increases in heart rate, cardiac output, and dP/dT could be deleterious; so always give -blocker first Drugs to avoid: hydralazine, minoxidil, nifedipine
Postcardiopulmonary bypass	1 : Nitroprusside + narcotics	First exclude postoperative pain/distress as reason for hypertension/tachycardia
Post-major vascular surgical procedure	1 : Nitroprusside Alt: Labetalol	First exclude postoperative pain/distress as reason for hypertension/tachycardia
Malignant Hypertension
Grade III or IV fundoscopic changes	1 : Nitroprusside and -blocker or labetalol Alt: Calcium channel blockers	Drugs to avoid: clonidine, methyldopa
Eclampsia (BP > 140/90 mm Hg, edema, proteinuria, seizures in pregnancy)	1 : Hydralazine + delivery Alt: Labetalol Alt: Calcium channel blockers	Drugs to avoid: trimethaphan, diuretics, pure -blockers ; nitroprusside has potential risk to fetus and is reserved for refractory hypertension
Renal
Renal parenchyma disease; Renovascular hypertension; Vasculitis	1 : Nitroprusside and -blocker or labetalol Alt: Calcium channel blockers Alt: ACE inhibitors	Avoid ACE inhibitors if renal artery stenosis suspected, or significant renal insufficiency
Endocrine
Pheochromocytoma	1 : Phentolamine or phenoxy-benzamine -blockers after -blockade Alt: Labetalol Alt: Nitroprusside	Must provide -blockade first and then -blockade
Drug-induced
Monoamine oxidase inhibitors	1 : Phentolamine Alt: Nitroprusside Alt: Labetalol
Sympathomimetics (cocaine, amphetamines, phencyclidine, tricyclics, diet pills)	1 : Labetalol or nitrates Alt: Phentolamine Alt: Nitroprusside
Withdrawal of centrally acting antihypertensive (clonidine, -blockers)	1 : Labetalol Alt: Nitroprusside Alt: Phentolamine Alt: Resume clonidine or -blocker	Restart agent that was discontinued if possible
ACE, angiotensin converting enzyme; BP, blood pressure; ICP, intracranial pressure

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TABLE 3.13. Treatment of Pulmonary Arterial Hypertension

This form includes familial and idiopathic ( primary ) PAH and PAH associated with congenital systemic-to-pulmonary shunts, portal hypertension, collagen vascular diseases (e.g., scleroderma), certain drugs and toxins (e.g., anorexic agents), HIV disease, and hemoglobinopathies (e.g., sickle cell disease). IPAH has a mPAP >25 mm Hg at rest and a PCWP or LA pressure 15 mm Hg. Treatments below are not being recommended for PH due to postcapillary etiologies (e.g., left-sided heart disease), hypoxic etiologies (e.g., sleep disordered breathing, chronic high altitude), airway or parenchymal lung diseases (e.g., COPD, ILD), and chronic thrombotic and embolic etiologies. Progressive evaluation may include EKG, chest x-ray, echocardiogram, 6-minute walk, pulmonary function studies, chest CT, polysomnogram, serologies (e.g., ANA, RF, Scl 70, HIV), liver sonogram, VQ scan, pulmonary angiography, and RHC. Anticoagulant therapy based on risk benefit analysis should be considered to reduce risk of pulmonary thrombo-embolism or systemic embolism. Consider lung transplant evaluation or balloon atrial septostomy in appropriate refractory candidates.
Agent	Dosage	Comments
Oxygen	Inhaled (l/min) to maintain SaO2 >90%	Controversial in patients with PAH associated with large right-to-left shunts due to congenital heart disease (Eisenmenger physiology)
Spironolactone	Range 25 200 mg/d PO in single or divided doses (max 400 mg/d)	For symptoms of right heart volume overload Monitor serum K and renal function
Nitric oxide (NO)	Range 5 80 ppm inhaled Vasoreactivity testing: 10 or 20 ppm inhaled (2 3 sets of baseline hemodynamics over 1 h then NO dose given over 6 10 min with hemodynamics determined) Doses >20 ppm increase risk of methemoglobinemia; monitor methemoglobin levels prior to and at 1 and 6 h after initiating prolonged therapy and after each dose increase, otherwise daily. NO dose should be reduced for methemoglobin concentration 5%	An endogenous chemical messenger acting via guanylate cyclase to cause vasodilatation Used to test pulmonary vasoreactivity in IPAH: Positive response = decrease of 10 mm Hg in mPAP to mPAP 40 mm Hg without a decrease in CO May be useful as continuous inhalation therapy in ventilated patients with PH and right HF Interruptions in delivery during chronic administration or large dose reductions may cause symptoms of rebound PAH May increase bleeding risk due to inhibitory effects on platelet aggregation
Calcium Channel Blocker Reserved for IPAH with a positive vasodilator test (see NO above). Maintenance of response defined as NYHA Class I II and near normal resting hemodynamics should be re-evaluated in 6 months. If response not maintained then patient should be considered for therapy with prostanoids or an endothelin-1 receptor antagonist. There are limited data on dose ranges and optimal dosing.
Nifedipine (immediate release)	Initial: 10 mg PO q8 Usual IPAH range 30 180 mg q8h	Preferred over diltiazem if HR 100 Should be up titrated cautiously
Diltiazem (regular release)	Initial: 30 60 mg PO q6 8 Usual IPAH range: 120 720 mg q6 8h	Preferred over nifedipine or amlodipine if HR >100 Should be up titrated cautiously
Amlodipine	Initial: 2.5 5 mg PO qd Usual IPAH range: 2.5 30 mg PO qd	Diltiazem preferred if HR >100 Limited data and should be up titrated cautiously
Prostanoids
Epoprostenol is produced in the vascular endothelium. Treprostinil and iloprost are stable analogues of epoprostenol. These agents are vasodilators with platelet antiaggregating properties. Adverse reactions associated with initiation and up titration of prostanoid therapy include jaw pain, flushing, headache, nausea, diarrhea, rash, anxiety, hypotension, and musculoskeletal pain. In addition epoprostenol therapy carries the risk of catheter-related infections and thromboembolic events, treprostinil can cause pain and induration at the infusion site, and iloprost has been associated with trismus and cough.
Epoprostenol	Initially 2 ng/kg/min IV with increases of 1 2 ng/kg/min no faster than hourly or until unacceptable (dose-limiting) pharmacologic effects occur Average discharge dose after a 3-d initial titration was 6.5 ng/kg/min Adjustments: Increases or decreases of 1 2 ng/kg/min are usually based on symptoms or excessive side effects Plateau dose usually 20 40 ng/kg/min	Recommended for NYHA Class III IV PAH with advanced disease; considered first line therapy for NYHA Class IV PAH Chronic overdosing can result in high-output HF Requires a central venous catheter for administration; interruptions in delivery or large dose reductions may cause symptoms of rebound PAH
Treprostinil	Initially: 1.25 ng/kg/min SC infusion; (decrease to 0.625 ng/kg/min if not tolerated) Adjustments: increase by >1.25 ng/kg/min per wk for the first 4 wk then 2.5ng/kg/min per wk based on symptoms; similar decreases are made based on excessive side effects	Reserved for NYHA Class III IV PAH, particularly those without significant benefit on oral therapy Limited data with >40 ng/kg/min Avoid interruptions in delivery Liver disease: initial dose should be decreased to 0.625 ng/kg/min and increased cautiously
Iloprost	Initially: 2.5 g inhaled; if tolerated, increase to 5 g 6 9 times per day ( q2h) while awake, according to need and tolerability; max dose studied, 45 g daily (5 g 9 times per d)	Reserved for NYHA Class III IV PAH, and may be useful as adjunct to oral therapy Liver disease: give 2.5 g at intervals 3 h to max of 6 times daily; dose may be cautiously increased or given more frequently per patient response
Endothelin Receptor Antagonist Endothelin-1 is a vasoconstrictor and smooth muscle mitogen. Bosentan may cause hepatotoxicity. If elevated AST or ALT with symptoms or Bili of 2 UNL, then stop. If AST or ALT >3 and 5 UNL, then reduce or hold and monitor AST/ALT; if levels return to pretherapy values, then continue or reintroduce (starting dose); and monitor levels. If ALT or AST >5 and 8 UNL, then stop and monitor levels; if levels return to pretherapy values, then consider reintroduction (starting dose) and monitor levels. If ALT or AST >8 UNL, then stop and should avoid reintroducing.
Bosentan	Initial, 62.5 mg PO q12h for 4 wk Maintenance, up to 125 mg PO q12h Adults <40 kg: initial and maintenance, 62.5 mg PO q12h (monitor liver function [monthly] and hemoglobin [1 mo, 3 mo, every 3 mo]) Should avoid if elevated AST or ALT >3 the UNL at baseline	Reserved for NYHA Class III IV PAH Adverse reactions include hepatotoxicity, anemia, edema, headache, hypotension, nausea, emesis, dyspepsia, palpitations, and flushing
Phosphodiesterase (Type-5) Inhibitor Limited data on long-term efficacy and safety alone or in combination with prostanoids or bosentan.
Sildenafil	Range 25 100 mg q8 12h Dose increases of 25 mg q8 12h every 2 4 wk, based on symptoms (limited data on dosing, particularly maximal efficacious dose) Increased plasma levels can occur in the elderly (age >65) and with renal impairment (Cr clearance <30 mL/min), hepatic impairment and concurrent use of cytochrome P450 inhibitors	Reserved for NYHA Class III PAH Inhibitor of cGMP specific phosphodiesterase; lengthens and enhances effects of inhaled NO Hypotension can result with the coadministration of nitrates Adverse reactions include headache, flushing, periorbital edema, and priapism
ALT, alanine aminotransferase; AST, aspartate aminotransferase; Bili, bilirubin; CO, cardiac output; COPD, chronic obstructive pulmonary disease; CT, computed tomography; EKG, electrocardiogram; HF, heart failure; ILD, interstitial lung disease; IPAH, idiopathic pulmonary arterial hypertension; K, potassium; LA, left atrium; mPAP, mean pulmonary artery pressure; NO, nitric oxide; NYHA, New York Heart Association; PAH, pulmonary arterial hypertension; PCWP, pulmonary capillary wedge pressure; PH, pulmonary hypertension; PO, by mouth; RHC, right heart catheterization; SaO2, arterial oxygen saturation; UNL, upper normal limit; VQ, ventilation-perfusion

P.70

TABLE 3.14. Drugs Associated with QT Interval Prolongation^a

Antiarrhythmic Agents
Sotalol
Ibutilide, dofetilide, sematilide
Disopyramide
Procainamide
Quinidine
Amiodarone^b
Nonantiarrhythmic Agents
Erythromycin, clarithromycin, telithromycin, azithromycin
Ketoconazole, itraconazole
Quinolones (sparfloxacin, moxifloxacin, gatifloxacin, gemifloxacin, levofloxacin)
Phenothiazines (chlorpromazine, droperidol, haloperidol, thioridazine)
Fosphenytoin
Methadone
Pentamidine
Probucol
Quetiapine
Risperidone
Arsenic trioxide
Astemazole^c
Bepridil, mibefradil
SSRI (venlafaxine)
Terfinadine^c
Tricyclic antidepressants
Trimethoprim-sulfamethoxazole

^aAdditional information available at www.qtdrugs.org.
^bRisk of torsade is low.
^cNot available in the U.S.