Treatment of Ischemic Heart Disease (IHD)

TREATMENT

DESIRED OUTCOME:

The short-term goals of therapy for IHD are to reduce or prevent anginal symptoms that limit exercise capability and impair quality of life. Long-term goals are to prevent CHD (Coronory Heart Disease) events such as MI (Myocardial Infarction), arrhythmias, and heart failure and to extend the patient's life.

RISK-FACTOR MODIFICATION:

• Primary prevention through the modification of risk factors should significantly reduce the prevalence of IHD. Secondary intervention is effective in reducing subsequent morbidity and mortality.
• Risk factors for IHD are additive and can be classified as alterable or unalterable. Unalterable risk factors include gender, age, family history or genetic composition, environmental influences, and, to some extent, diabetes mellitus. Alterable risk factors include smoking, hypertension, hyperlipidemia, obesity, sedentary lifestyle, hyperuricemia, psychosocial factors such as stress and type A behavior patterns, and the use of drugs that may be detrimental (eg. progestins, corticosteroids, and cyclosporine). Although thiazide diuretics and BETA blockers (nonselective without intrinsic sympathomimetic activity) may elevate both cholesterol and triglycerides by 10% to 20%, and these effects may be detrimental, no objective evidence exists from prospective well-controlled studies to support avoiding these drugs.

BETA-Adrenergic blocking agents:

• Decreased heart rate, contractility, and blood pressure reduce MVO2 and oxygen demand in patients with effort-induced angina. BETA-blockers do not improve oxygen supply and, in certain instances, unopposed BETA-adrenergic stimulation may lead to coronary vasoconstriction.
• BETA blockers improve symptoms in about 80% of patients with chronic exertional stable angina, and objective measures of efficacy demonstrate improved exercise duration and delay in the time at which ST-segment changes and initial or limiting symptoms occur. BETA blockade may allow anginal patients previously limited by symptoms to perform more exercise and ultimately improve overall cardiovascular performance through a training effect.
• Ideal candidates for BETA blockers include patients in whom physical activity is a prominent cause of attacks; those with coexisting hypertension, supraventricular arrhythmias, or post-MI angina; and those with anxiety associated with anginal episodes. BETA blockeers may be used safely in angina and heart failure.
• Beta blockade is effective in chronic exertional angina as monotherapy and in combination with nitrates and/or calcium channel antagonists. BETA blockers are the first-line drugs in chronic angina requiring daily maintenance therapy because they are more effective in reducing episodes of silent ischemia and early morning peak of ischemic activity and improving mortality after Q-wave MI than nitrates or calcium channel blockers.
• If BETA blockers are ineffective or not tolerated, then monotherapy with a calcium channel blocker or combination therapy may be instituted. Reflex tachycardia from nitrates can be blunted with BETA-blocker therapy, making this a useful combination. Patients with severe angina, rest angina, or variant angina may be better treated with calcium channel blockers or long-acting nitrates.
• Initial doses of BETA-blockers should be at the lower end of the ususal dosing range and titrated to response. Treatment objectives include lowering the resting heart rate to 50 to 60 beats/min and limiting maximal exercise heart rate to about 100 beats/minute or less. Heart rate with modest exercise should be no more than about 20 beats/minute above resting heart rate (or a 10% increment over resting heart rate).
• There is little evidence to suggest superiority of any particular BETAblocker. Those with longer half-lives may be administered less frequently, but even Propranolol may be given twice a day in most patients. Membrane stabilizing activity is irrelevant in the treatment of angina. Intrinsic sympathomimetic activity appears to be detrimental in patients with rest or severe angina because the reduction in heart rate would be minimized, therefore limiting a reduction in MVO2. Cardioselective BETA blockers may be used in patients to minimize adverse effects such as bronchospasm, intermittent claudication, and sexual dysfunction. Combined nonselective BETA and BETA ± blockade with Labetalol may be useful in some patients with marginal left ventricular (LV) reserve.
• Adverse effects of BETA blockade include hypotension, heart failure, bradycardia, heart block, bronchospasm, peripheral vasoconstriction and intermittent claudiaction, altered glucose metabolism, fatigue, malaise, and depression. Abrupt withdrawal in patients with angina has been associated with increased severity and number of pain episodes and MI. Tapering of therapy over about 2 days should minimize the risk of withdrawal reactions if therapy is to be discontinued.

NITRATES:

• The action of nitrates appear to be mediated indirectly through reduction of myocardial oxygen demand secondary to venodilation and arterial-arteriolar dilation, leading to a reduction in wall stress from reduced ventricular volume and pressure. Direct actions on the coronary circulation include dilation of large and small intramural coronary arteries, collateral dilation, coronary artery stenosis dilation, abolition of normal tone in narrowed vessels, and relief of spasm.
• Pharmacokinetic characteristics common to nitrates include a large first-pass effect of hepatic metabolism, short to very short half-lives (except for Isosorbide mononitrate [ISMN]), large volumes of distribution, high clearance rates, and large interindividual variations in plasma or blood concentrations. The half-life of nitroglycerin is 1 to 5 minutes regardless of the route, hence the potential advantage of sustained-release and transdermal products. Isosorbide dinitrate (ISDN) is metabolized to Isosorbide-2 and 5-mononitrate (ISMN). ISMN has a half-life of about 5 hours and may be given once or twice daily, depending on the product chosen.
• Nitrate therapy may be used to terminate an acute anginal attack, to prevent effort- or stress-induced attacks, or for long-term prophylaxis, usually in combination with BETA blockers or calcium channel blockers. Sublingual, buccal, or spray nitroglycerin products are preferred for alleviation of anginal attacks because of rapid absorption. Symptoms may be prevented by prophylactic oral or transdermal products (usually in combination with BETA-blockers or calcium channel blockers), but development of tolerance may be problematic.
• Sublingual introglycerin, 0.3 to 0.4 mg, relieves pain in about 75% of patients within 3 minutes, with another 15% becomin pain free in 5 to 15 minutes. Pain persisting beyond 20 to 30 minutes after use of two or three nitroglycerin tablets suggests acute coronary syndrome, and the patient should be instructed to seek emergency aid.
• Chewable, oral, and transdermal products are acceptable for long-term prophylaxis of angina. Dosing of long-acting preparations should be adjusted to provide a hemodynamic response. This may require doses of oral ISDN ranging from 10 to 60mg as often as every 3 to 4 hours due to tolerance or first-pass metabolism. Intermittent (10 to 12 hours on, 12 to 14 hours off) transdermal nitroglycerin therapy may produce modest but significant improvement in exercise time in chronic stable angina.

Sr no.	Product	Onset (minutes)	Duration	Initial dose
1	Nitroglycerin IV	1-2	3-5 minutes	5 mcg/min
2	Nitroglycerin sublingual/lingual	1-3	30-60 minutes	0.3mg
3	Nitroglycerin oral	40	3-6 hours	2.5-9mg t.i.d
4	Nitroglycerin ointment	20-60	2-8 hours	1/2 -1 in
5	Nitroglycerin patch	40-60	>8 hours	1 patch
6	Erythritol tetranitrate	5-30	4-6 hours	5-10 mg t.i.d
7	Pentaerythritol tetranitrate	30	4-8 hours	10-20 mg t.i.d
8	Isosorbide dinitrate sublingual/chewable	2-5	1-2 hours	2.5-5 mg t.i.d
9	Isosorbide dinitrate oral	20-40	4-6 hours	5-20 mg t.i.d
10	Isosorbide mononitrate	30-60	6-8 hours	20mg qd, b.i.d.

• Adverse effects include postural hypotension with associated central nervous system symptoms, reflex tachycardia, headaches and flushing, and occasional nausea.Excessive hypotension may result in MI or stroke. Noncardiovascular adverse effects include rash (especially with transdermal nitroglycerin) and methemoglobinemia with high doses given for extended periods.
• Because both the onset and offset of tolerance to nitrates occurs quickly, one strategy to circumvent it is to provide a daily nitrate-free interval of 8 to 12 hours. For example, ISDN should not be used more often than 3 times a day to avoid tolerance.
• Nitrtaes may be combined with other drugs with complementary mechanisms of action for chronic prophylactic therapy. Combination therapy is generally used in patients with more frequent symptoms or symptoms that do not respond to BETA blockers alone (nitrates + BETA blockers or calcium channel blockers), in patients intolerant of beta blockers or calcium channel blockers, and in patients having an element of vasospasm leading to decreased supply (nitrates plus calcium channel blockers).

Calcium Channel Antagonists

• Direct actions include vasodilation of systemic arterioles and coronary arteries, leading to a reduction of arterial pressure and coronary vascular resistance as well as depression of myocaradial contractility and the conduction velocity of the SA and AV nodes. Reflex beta-adrenergic stimulation overcomes much of the negative ionotropic effect, and depression of contractility becomes clinically apparent only in the presence of LV dysfunction and when other negative chronotropic properties.
• Verapamil and Diltiazem cause less peripheral vasodilation than dihydropyridines such as nifedipine, but greater decreases in AV node conduction. They must be used with caution in patients with preexisting conduction abnormalities or in patients taking other drugs with negative chronotropic properties.
• MVO2 is reduced with all calcium channel channel antagonists primarily because of reduced wall tension secondary to reduced arterial pressure. Overall, the benefit provided by calacium channel antagonists is related to reduced MVO2 rather than improved oxygen supply.
• In contrast to the beta blockers, calcium channel antagonists have the potential to improve coronary blood flow through areas of fixed coronary obstruction by inhibiting coronary artery vasomotion and vasospasm.
• Good candidates for calcium channel antagonists include patients with contraindications or intolerance to beta blockers, coexisting conduction system disease (excluding the use of verapamil and possibley diltiazem), Prinzmetal's angina, peripheral vascular disease, severe ventricular dysfunction, and concurrent hypertension. Amlodipine is probably the agent of choice in severe ventricular dysfunction, and the other dihydropyridines should be used with caution if the ejection fraction is less than 40%.