Diabetic nephropathy



2.5-4Q mg daily in \-7

divided doses



10 SO rng daily in 1 2

divided doses

I V l-.— il

HTN, 1 IF, post-Ml

?.i>-40 mg daily



4™3 nig daily


1 IT'N, 1 IF, post-Ml

mg twice daily


HTN. high-risk for

2.5—10 mg daily in 1-2

IHD, HF, post-Mi

divided doses


H1N, Hh post-Mi

1-4 mg daily



4-32 rng: daily


HTN, HF, post-Mi

30 -320 rng daily in )-2

divided doses

ACE, ¿angiotensin-converting enzyme; ARB, angiotensin-receptor blockers; HR heart failure; HTN, hypertension; IHD, ischemic heart disease ML myocardial infarction.

Reduce initial dose and gradually titrate upward as tolerated in renal impairment.

Nitroglycerin to Relieve Acute Symptoms

Short-acting nitrates are first-line treatment to terminate acute episodes of angina. All patients with a history of angina should have sublingual nitroglycerin tablets or spray to relieve acute ischemic symptoms. Nitrates undergo biotransformation to nitric oxide. Nitric oxide activates soluble guanylate cyclase and leads to increased intracellular concentrations of cyclic guanosine monophosphate, and ultimately, to smooth muscle relaxation. Nitrates primarily cause venodilation, leading to reductions in preload. The resultant decrease in ventricular volume and wall tension leads to a reduction in myocardial oxygen demand. In higher doses, nitrates may also cause arterial dilation and reduce after-load. In addition to reducing oxygen demand, nitrates increase myocardial oxygen supply by dilating the epicardial coronary arteries and collateral vessels, as well as relieving vasospasm.

Short-acting nitrates are available in tablet and spray formulations for sublingual administration. Sublingual nitroglycerin tablets are most commonly used to alleviate angina and are less expensive than the spray. However, the spray is preferred for patients who have difficulty opening the tablet container or produce insufficient saliva for rapid dissolution of sublingual tablets. At the onset of an angina attack, a 0.3 to 0.4 mg dose of nitroglycerin (tablet or spray) should be administered sublin-gually, and repeated every 5 minutes until symptoms resolve. Sitting or standing enhances venous pooling and the effectiveness of nitroglycerin. Sublingual nitroglycerin can also be used to prevent effort-induced angina (i.e., angina that occurs with exertion). In this case, the patient should use sublingual nitroglycerin 2 to 5 minutes prior to an activity known to cause angina, with the effects persisting for approximately 30 minutes. Isosorbide dinitrate, also available in a sublingual form, has a longer half-life with antianginal effects lasting up to 2 hours. The use of short-acting nitrates alone, without concomitant long-acting antianginal therapy, may be acceptable for patients who experience angina symptoms once every few days. However, for patients with more frequent attacks, long-acting antianginal therapy with P-blockers, CCBs, or long-acting nitrates is recommended.

The use of nitrates with phosphodiesterase type 5 inhibitors (e.g., sildenafil, varde-nafil, and tadalafil), commonly prescribed for erectile dysfunction, is contraindicated. Phosphodiesterase degrades cyclic guanosine monophosphate (GMP), which is responsible for the vasodilatory effects of nitrates. Concomitant use of nitrates and phosphodiesterase type 5 inhibitors enhances cyclic GMP-mediated vasodilation and can result in serious hypotension and even death. All patients with IHD should receive a prescription for sublingual nitrates and education regarding their use. Points to emphasize when counseling a patient on nitroglycerin use include:

• The seated position is generally preferred when using nitroglycerin because the drug may cause dizziness.

• Call 911 if symptoms are unimproved or worsen 5 minutes after the first dose.

• Keep nitroglycerin tablets in the original glass container and close the cap tightly after use.

• Nitroglycerin should not be stored in the same container as other medications since this may reduce nitroglycerin's effectiveness.

• Repeated use of nitroglycerin is not harmful or addictive and does not result in any long-term side effects. Patients should not hesitate to use nitroglycerin whenever needed.

• Nitroglycerin should not be used within 24 hours of taking sildenafil or vardenafil or within 48 hours of taking tadalafil because of the potential for life-threatening hypotension.

Pharmacotherapy to Prevent Recurrent Ischemic Symptoms

The overall goal of antianginal therapy is to allow patients with IHD to resume normal activities without symptoms of angina and to experience minimal to no adverse drug effects. The drugs traditionally used to prevent ischemic symptoms are P-blockers, CCBs, and nitrates. These drugs exert their antianginal effects by improving the balance between myocardial oxygen supply and demand, with specific effects listed in Table 7-6. P-Blockers, CCBs, and nitrates decrease the frequency of angina and delay the onset of angina during exercise. However, there is no evidence that any of these agents prevent ACS or improve survival in patients with chronic stable angina. Ran-olazine is a newer molecular entity indicated for the treatment of chronic stable angina in patients unresponsive to traditional antianginal medications. Combination therapy with two or three antianginal drugs is often needed.


Stimulation of the Pi-and P2-adrenergic receptors in the heart increases heart rate and cardiac contractility. P-Blockers antagonize these effects and decrease myocardial oxygen demand. P-Blockers may also reduce oxygen demand by lowering blood pressure and ventricular wall tension through blockade of plasma renin release. However, with marked reductions in heart rate, P-blockers may actually increase ventricular wall tension. This is because slower heart rates allow the ventricle more time to fill during diastole, leading to increased left ventricular volume, end-diastolic pressure, and wall tension. However, the net effect of P-blockade is usually a reduction in myocardial oxygen demand. P-Blockers do not improve myocardial oxygen supply.

Table 7-6 Effects of Antianginal Medications on Myocardial Oxygen Demand and Supply

Oxygen Demand

Heart Wall Antianginal Agent Rate Tension

Cardiac Oxygen

Contra ctiMty Supply



or t


Calcium channel







Dihydropyri dines

or T







Table 7-7 Properties and Dosing of P-Blockers in Ischemic Heart Disease

I, decreases: no change; T. increases.

Table 7-7 Properties and Dosing of P-Blockers in Ischemic Heart Disease

Drug flmpter Af1 ii ■:I m ri mk 1-y m^i hornlinetle Acilvi [>■ Liu j1 [>oifi Fid n-.; ■

Acebutolol Atenolol BetuoH Eiiojxiobl

Nadolol Penbutolol pintkAil Pnopfjnobl

Timolol ft-Selective ft-SeleeilYS


ICO-IOOdig twice daiy*

25-100 mg oncedjil}*

2.5-10 mg once da

^Js-Js img twice dUily"

100-400 "ig (wiicdjily*

50 100 mq twkS(tHy (OoCt daiy ft» ettenefed


■ 120 mg once djily* 10-10 my once daily" 10-40 lyij mitt dtiily-

20-60 mg daily (50-160 mg once daily 1m

ILVHJ-JI 1—(J IohhuLIIkjiiI' I0-J0 mg (wke daily1'

I ime odiust in htfwtk "npairmeiil f™.1- adjust imcnJ impairment AvufeJ in pilk'rus l-fUMlk- irnf^illW-TH.

The properties and recommended doses of various P-blockers are summarized in Table 7-7. P-Blockers with intrinsic sympathomimetic activity have partial P-agonist effects and cause lesser reductions in heart rate at rest. As a result, P-blockers with intrinsic sympathomimetic activity may produce lesser reductions in myocardial oxygen demand and should be avoided in patients with IHD. Other P-blockers appear equally effective at controlling symptoms of angina. The frequency of dosing and drug cost should be taken into consideration when choosing a particular drug. Agents that can be dosed once or twice daily are preferred. Most P-blockers are available in inexpensive generic versions. P-Blockers should be initiated in doses at the lower end of the usual dosing range, with titration according to symptom and hemodynamic response. The P-blocker dose is commonly titrated to achieve the following:

• Resting heart rate between 50 and 60 beats per minute (bpm).

• Maximum heart rate with exercise of 100 bpm or less or 20 bpm above the resting heart rate.

O ft-Blockers are first-line therapy for preventing ischemic symptoms, particularly in patients with a history of MI. In the absence of contraindications, ft-blockers are preferred because of their potential cardioprotective effects. Specifically, ft-block-ers may prevent cardiac arrhythmias by decreasing the rate of spontaneous depolarization of ectopic pacemakers. Second, while the long-term effects of ft-blockers on morbidity and mortality in patients with chronic stable angina are largely unknown, certain ft-blockers have been shown to decrease the risk for reinfarction and improve survival in patients who have suffered an Ml.30 Specific P-blockers associated with mortality reductions in clinical trials include metoprolol, propranolol, and carvedilol.30,31 In a meta-analysis of 82 clinical trials investigating the use of P-

blockers in patients following MI, the relative risk of death was reduced by 23% in pa-

tients treated with P-blockers compared to control subjects. Long-term therapy (for at least 6 months) was associated with greater mortality benefit compared to short-term P-blockade (6 weeks or less).

P-Blockers are contraindicated in patients with severe bradycardia (heart rate less than 50 bpm) or AV conduction defects in the absence of a pacemaker. P-Blockers should be used with particular caution in combination with other agents that depress AV conduction (e.g., digoxin, verapamil, and diltiazem) because of increased risk for bradycardia and heart block. Relative contraindications include asthma, bronchospas-tic disease, and severe depression. Pi-Selective blockers are preferred in patients with asthma or chronic obstructive pulmonary disease. However, selectivity is dose dependent, and P1-selective agents may induce bronchospasm in higher doses.

There are several precautions to consider with the use of P-blockers in patients with diabetes or heart failure. All P-blockers may mask the tachycardia and tremor (but not sweating) that commonly accompany episodes of hypoglycemiain diabetes. In addition, nonselectiveP-blockers may alter glucose metabolism and slow recovery from hypoglycemia in insulin-dependent diabetes. P1-Selective agents are preferred because they are less likely to prolong recovery from hypoglycemia. Importantly, P-blockers should not be avoided in patients with IHD and diabetes, particularly in patients with a history of MI who are at a high risk for recurrent cardiovascular events. P-Blockers are negative inotropes (i.e., they decrease cardiac contractility). Cardiac contractility is impaired in patients with left ventricular systolic dysfunction. Therefore, P-blockers may worsen symptoms of heart failure in patients with left ventricular systolic dysfunction (i.e., ejection fraction less than 40%). While certain P-blockers are indicated in patients with heart failure because they have been shown to reduce morbidity and mortality in this population, they must be used cautiously. In particular, when used for management of IHD in a patient with heart failure, P-blockers should be initiated in very low doses with slow up-titration to avoid worsening heart failure symptoms. The initiation of a P-blocker in a patient with acute cardiac decompensation should be delayed until the patient has stabilized.

Other potential adverse effects from P-blockers include fatigue, sleep disturbances, malaise, depression, and sexual dysfunction. Abrupt P-blocker withdrawal may increase the frequency and severity of angina, possibly because of increased receptor sensitivity to catecholamines after long-term P-blockade. If the decision is made to stop P-blocker therapy, the dose should be tapered over several days to weeks to avoid exacerbating angina.

Calcium Channel Blockers

CCBs inhibit calcium entry into vascular smooth muscle and cardiac cells, resulting in the inhibition of the calcium-dependent process leading to muscle contraction. Inhibition of calcium entry into the vascular smooth muscle cells leads to systemic vasodilation and reductions in afterload. Inhibition of calcium entry into the cardiac cells leads to reductions in cardiac contractility. Thus, CCBs reduce myocardial oxygen demand by lowering both wall tension (through reductions in afterload) and cardiac contractility. In addition, the nondihydropyridine CCBs, verapamil and diltiazem, further decrease myocardial oxygen demand by slowing cardiac conduction through the AV node and lowering heart rate. In contrast, dihydropyridine CCBs, nifedipine in particular, are potent vasodilators that can cause baroreflex-mediated increases in sympathetic tone and heart rate. Because of their negative chronotropic effects, verapamil and diltiazem are generally more effective antianginal agents than the dihydropyrid-ine CCBs. In addition to decreasing myocardial oxygen demand, all CCBs increase myocardial oxygen supply by dilating coronary arteries, thus increasing coronary blood flow and relieving vasospasm.

In randomized, controlled, clinical trials, CCBs were as effective as P-blockers at preventing ischemic symptoms. CCBs are recommended as initial treatment in IHD when ft-blockers are contraindicated or not tolerated. In addition, CCBs may be used in combination with ft-blockers when initial treatment is unsuccessful. However, the combination of a P-blocker with either verapamil or diltiazem should be used with extreme caution since all of these drugs decrease AV nodal conduction, increasing the risk for severe bradycardia or AV block when used together. If combination therapy is warranted, a long-acting dihydropyridine CCB is preferred. P-Blockers will prevent reflex increases in sympathetic tone and heart rate with the use of CCBs with potent vasodilatory effects. For patients with variable and unpredictable occurrences of angina, indicating possible coronary vasospasm, CCBs may be more effective than P-blockers in preventing angina episodes. The dosing of CCBs in IHD is described in Table 7-8.

Verapamil and diltiazem are contraindicated in patients with bradycardia and preexisting conduction disease in the absence of a pacemaker. As noted above, verapamil and diltiazem should be used with particular caution in combination with other drugs that depress AV nodal conduction (e.g., P-blockers and digoxin). Because of their negative inotropic effects, CCBs may cause or exacerbate heart failure in patients with pre-existing left ventricular systolic dysfunction and should be avoided in this population. The exceptions are amlodipine and felodipine, which have less negative inotropic effects compared to other CCBs and appear to be safe in patients with left

32 33

ventricular systolic dysfunction. ' Finally, there is some evidence that short-acting CCBs (particularly short-acting nifedipine and nicardipine) may increase the risk of cardiovascular events.34 Therefore, short-acting agents should be avoided in the management of IHD.

Table 7-8 Dosing of CCBs in Ischemic Heart Disease


Usual Dose Range

Diltiazem, extended

120-360 rng once daily: consider dose


adjustment in hepatic dysfunction

Verapamil extended-

13Q-4S0 mg once daily; use initial dose


of 120 mg in hepatic dysfunction



5-Tp mg once daily


S-10 rng once daily; use initial dose

of 2.5 mg once daily in hepatic


Nifedipine, extended

30 90 mg once daily; dose adjust


and monitor closcly in hepaLic



70-40 mg 3 x daily; dose twice daify

in hepatif dysfunct on and t trate

slowly in both hepatic and renal


CCBr calcium channel blockers.

Long-Acting Nitrates

Nitrate products are available in both oral and transdermal formulations for chronic use. Commonly used products are listed in Table 7-9. All nitrate products are equally effective at preventing the recurrence of angina when used appropriately.

The major limitation of nitrate therapy is the development of tolerance with continuous use. The loss of antianginal effects may occur within the first 24 hours of continuous nitrate therapy. While the cause of tolerance is unclear, several mechanisms have been proposed, including the generation of free radicals that degrade nitric oxide. The most effective method to avoid tolerance and maintain the antianginal efficacy of nitrates is to allow a daily nitrate-free interval of at least 8 to 12 hours. Nitrates do not provide protection from ischemia during the nitrate-free period. Therefore, the nitrate-free interval should occur when the patient is least likely to experience angina. Generally, angina is less common during the nighttime hours when the patient is sleeping and myocardial oxygen demand is reduced. Thus, it is common to dose long-acting nitrates so that the nitrate-free interval begins in the evening. For example, isosorbide dinitrate is typically dosed on awakening and again 7 hours later.

Monotherapy with nitrates for the prevention of ischemia should generally be avoided for a couple of reasons. First, reflex increases in sympathetic activity and heart rate, with resultant increases in myocardial oxygen demand, may occur secondary to nitrate-induced venodilation. Second, patients are unprotected from ischemia during the nitrate-free interval. P-Blockers and CCBs are dosed to provide 24-hour protection from ischemia. Treatment with long-acting nitrates should be added to baseline therapy with either a ft-blocker or CCB or a combination of the two. P-Blockers attenuate the increase in sympathetic tone and heart rate that occurs during nitrate therapy. In turn, nitrates attenuate the increase in wall tension during P-block-er therapy. As a result, the combination of P-blockers and nitrates is particularly effective at preventing angina and provides greater protection from ischemia than therapy with either agent alone. Monotherapy with nitrates may be appropriate in patients who have low blood pressure at baseline or who experience symptomatic hypotension with low doses of P-blockers or CCBs.

Table 7-9 Nitrate Formulations and Dosing for Chronic Use




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