Danil hammoudi

· Beta-adrenergic blockers and calcium channel blockers were developed during the early 1960's and these two classes of agents have also become important in the therapy of angina

Background

· Types of Angina

o Stable angina (exertional angina, typical or classic angina, angina of effort, atheroscelorotic angina)

§ The underlying pathology is usually atherosclerosis

§ Anginal episodes can be precipitated by exercise, cold, stress, emotion, or eating

§ Therapeutic rationale: Decrease cardiac load (preload and afterload) and increase myocardial blood flow

o Vasospastic angina (variant angina, Prinzmetal's angina)

§ Caused by transient vasospasm of the coronary vessels

§ Usually associated with underlying atheromas

§ Chest pain may develop at rest

§ Therapeutic rationale: Decrease vasospasm of coronary vessels

o Unstable angina (preinfarction angina, crescendo angina, angina at rest)

§ Caused by recurrent episodes of small platelet clots at the site of a ruptured atherosclerotic plaque which can also precipitate local vasospasm

§ Associated with a change in the character, frequency, and duration of angina in patients with stable angina and when there are prolonged episodes of angina at rest

§ Unstable angina requires vigorous therapy as it signals the imminent occurrence of a myocardial infarction

§ Therapeutic rationale: Inhibit platelet aggregation and thrombus formation, decrease cardiac load, and vasodilate coronary arteries

· Factors that Affect Myocardial Oxygen Demand

o The major determinants of myocardial oxygen consumption include ventricular wall stress, heart rate, and inotropic state (contractility)

o Both preload and afterload affect the stress on the ventricular wall

§ Preload

§ Preload is the pressure that distends the ventricular wall during diastole (ventricular-end diastolic pressure, VEDP) and is determined by venous return

§ Peripheral venodilation increases venous capacitance and thereby reduces venous return and preload

§ Decreasing preload also reduces ventricular end-diastolic volume (VEDV) which reduces ventricular wall tension as described by Laplace's law (Tension = Pressure x Radius)

§ An added benefit of reducing preload is improvement in subendocardial perfusion as a result of increasing the pressure gradient for perfusion across the ventricular wall

§ Afterload

§ Afterload is the impedance against which the ventricle must pump

§ Decreasing peripheral arteriolar resistance reduces myocardial work and therefore myocardial oxygen consumption

o A commonly used non-invasive index of myocardial oxygen demand is the "double product" (Heart Rate x Systolic Blood Pressure)

· Factors that Affect Myocardial Oxygen Supply

o Coronary artery blood flow is the primary determinant of myocardial oxygen supply since myocardial oxygen extraction from the blood is nearly complete, even at rest

o Coronary blood flow is essentially negligible during systole and is therefore determined by perfusion pressure (aortic diastolic pressure), duration of diastole, and coronary resistance

o Coronary vascular resistance is determined by numerous factors including:

§ Metabolic products that vasodilate coronary arterioles

§ Autonomic activity

§ Extravascular mechanical compression

§ Atherosclerosis

§ Intracoronary thrombi

Pharmacology

Three categories of pharmacological agents are used in the treatment of angina:

1. Organic nitrates (reduce preload, reduce afterload, vasodilate coronary arteries, inhibit platelet aggregation)

2. Calcium channel blockers (reduce afterload, vasodilate coronary arteries, may inhibit platelet aggregation; some also decrease heart rate, decrease contractility)

3. Beta-adrenergic antagonists (decrease heart rate, decrease contractility, decrease afterload due to decrease in cardiac output, may inhibit platelet aggregation)

Organic Nitrates (Nitrovasodilators)

Organic nitrates have been used for more than 100 years, and are still widely used in the treatment of angina pectoris

Chemistry

All these agents lead to the formation of the reactive free radical, nitric oxide (NO)
Most of these agents are simple nitric and nitrous acid esters of polyalcohols:

Glyceryl trinitrate (GTN, nitroglycerin, Nitro-Bid)
Isosorbide dinitrate (ISDN, Isordil)
Isosorbide-5-mononitrate (5-ISMN, Ismo)
Amyl nitrate (highly volatile liquid which is administered by inhalation)

Nicorandil (Icorel) is a derivative of nicotinamide possessing a terminal nitrate group

Mechanism of Action

Nitrovasodilators are enzymatically converted to NO in the target tissues

Veins and large arteries appear to have greater enzymatic capacity than resistance vessels, resulting in greater effects of organic nitrates on these vessels

NO is an important endogenous diffusible mediator of smooth muscle contraction and neuronal transmission

NO is very short-lived (half-life of a few seconds)
Endogenous NO produced by vascular endothelium in response to acetylcholine is known as EDRF (endothelium-derived relaxing factor)

NO activates a cytosolic form of guanylate cyclase by binding to iron in the heme prosthetic group of the enzyme

Activated guanylate cyclase catalyzes the formation of cyclic GMP (cGMP), which subsequently activates cGMP-dependent protein kinase
Activation of cGMP-dependent protein kinase in smooth muscle results in relaxation through several possible mechanisms, all of which involve protein phosphorylation:

Activation of Ca²⁺-ATPases which increases Ca²⁺ efflux
Inhibition of Ca²⁺ channels which decreases Ca²⁺ influx
Hyperpolarization of the sarcolemmal membrane by stimulation of Ca²⁺-activated K⁺ channels

Nicorandil (Icorel) acts by two separate mechanisms that both result in lower intracellular Ca²⁺ in vascular smooth muscle

Generation of NO and the subsequent stimulation of cGMP in vascular smooth muscle
Activation of the ATP-dependent potassium channel which hyperpolarizes the plasma membrane

Pharmacological Effects

Peripheral vasodilation

Dilation of veins predominates over that of arterioles, resulting in a large reduction in preload and a lesser reduction in afterload
Reduction in preload and afterload decreases myocardial workload and results in decreased myocardial oxygen demand
Nicorandil has a more pronounced effect on afterload and coronary flow than conventional nitrovasodilators

Effects on coronary blood flow

Large epicardial coronary arteries are dilated without impairing autoregulation in small coronary vessels
Collateral flow may be increased, improving perfusion of ischemic myocardium
Decreased preload improves subendocardial perfusion
Although organic nitrates can relax vasospastic coronary arteries, they have little or no effect on total coronary blood flow in patients with typical angina due to atherosclerosis

Inhibition of platelet function

Platelet aggregation is reduced by nitrovasodilators which may contribute to their effectiveness in the treatment of unstable angina
The mechanism involves stimulation of platelet guanylate cyclase

Pharmacokinetics

Hepatic first-pass metabolism is high and oral bioavailability is very low for the traditional organic nitrates, GTN and ISDN
Sublingual administration, which avoids the first-pass effect, is therefore preferred for administration of GTN and ISDN
The plasma clearance value of GTN (50 L/min) greatly exceeds that of cardiac output, indicating extra-hepatic metabolism also plays an important role in its inactivation
Oral ISDN is completely absorbed, but only about 20% of the dose enters into the systemic circulation as intact drug, the rest being converted (at least initially) to its active mononitrate metabolites (primarily 5-ISMN)
Oral 5-ISMN is not subjected to first-pass metabolism, and is therefore 100% available following oral administration
A high-capacity hepatic glutathione-organic nitrate reductase, which sequentially removes nitrate groups from the parent drug, is a major mechanism for inactivation of the organic nitrates

The enzyme converts the lipid soluble organic nitrate esters into more water-soluble denitrated metabolites and inorganic nitrite
The denitrated metabolites are considerably less potent vasodilators than are the parent compounds
Excretion of the metabolites is predominantly via the kidney

The kinetics of hepatic denitration of the organic nitrates is influenced by hepatic blood flow and the presence or absence of hepatic disease

Pharmacokinetics of Prototypical Nitrovasodilators in Man

Property	GTN	ISDN	5-ISMN
Half-life (min)	3	10	280
Plasma clearance (L/min)	50	4	0.1
Apparent volume of distribution (L/kg)	3	4	0.6
Oral bioavailability (%)	< 1	20	100

· Routes of Administration

o Amyl nitrate, a gas at room temperatures, can be administered by inhalation and has a very rapid onset and very short duration of action (3 - 5 min)

o The sublingual route of administration is rapid (onset of action 1-3 min) and effective for the treatment of acute attacks of angina pectoris and avoids first-pass effects

§ The short duration of action (20-30 min) is not suitable for maintenance therapy

o Intravenous nitroglycerin may be useful in the treatment of severe recurrent unstable angina because the onset of action is also rapid

o Slowly absorbed preparations (oral, buccal, transdermal) can be used to provide prolonged prophylaxis against angina attacks (3 - 10 hrs), but can lead to the development of tolerance

o Nicorandil can be given orally (twice daily) or i.v. and exhibits little or no tolerance

· Tolerance and Dependence

o Continuous or frequent exposure to organic nitrates may lead to the development of complete tolerance (tachyphylaxis)

o For instance, transdermal administration of GTN may provide therapeutic blood levels for 24 hours or more, but efficacy does not persist for more than 8-10 hours

o Nitrate-free periods of at least 8 hours (e.g. overnight) are suggested to avoid or reduce the development of tolerance

o The mechanism of tolerance remains uncertain but several theories have been suggested:

§ Diminished ability to convert nitrate to NO (no cross-tolerance with acetylcholine)

§ Diminished release of NO because of depletion of endogenous sulfhydryl compounds (sulfhydryl-regenerating agents can partially reverse tolerance)

§ Alterations in guanylate cyclase activation

o Industrial exposure to organic nitrates has been associated with "Monday disease" and with the development of physical dependence manifest by variant angina occurring after 1-2 days "withdrawal" from source of organic nitrates

§ Myocardial infarction resulting from coronary vasospasm has occurred in the most severely affected individuals

§ There is no evidence that physical dependence occurs with therapeutic doses of short-acting organic nitrates, even at high doses

· Adverse Effects

o The major acute adverse effects of nitrovasodilators are due to excessive vasodilation:

§ Orthostatic hypotension

§ Tachycardia

§ Severe throbbing headache

§ Dizziness

§ Flushing

§ Syncope (fainting)

· Contraindications

o Organic nitrates are contraindicated if intracranial pressure is elevated

Calcium Channel Blockers

· Chemistry

o Four chemically distinct classes of calcium channel blockers are currently used to treat angina

§ Phenylalkylamines: Verapamil (Calan)

§ Benzothiazipines: Diltiazem (Cardizem)

§ Dihydropyridines: Nifedipine (Procardia), nimodipine (Nimotop), nicardipine (Cardene)

§ Diarylaminopropylamine ethers: Bepridil (Vascor)

· Mechanism of Action

o The primary action of the calcium channel blockers is to block voltage-sensitive calcium channels

o Dihydropyridines, verapamil, and diltiazem block L-type calcium channels which are abundant in cardiac myocytes, arteriole smooth muscle cells, SA nodal tissue, and AV nodal tissue

o Bepridil blocks L-type channels, but also has significant sodium and potassium channel blocking activity in the heart

· Pharmacological Effects

o All of the calcium channel blockers vasodilate coronary arterioles and reduce afterload, but each class has different effects on heart rate and cardiac contractility

§ Verapamil, diltiazem, and bepridil have direct negative inotropic, chronotropic, and dromotropic effects

§ The dihydropyridines have negligible direct effects on heart rate or contractility, but reflex increases in sympathetic tone (due to decreased arterial pressure) can increase heart rate and contractility which may aggravate angina

o The calcium channel blockers have little effect on preload

o Calcium channel blockers may inhibit platelet aggregation

o The desired therapeutic effects of calcium channel blockers in treating angina are to:

§ Reduce myocardial oxygen consumption by reducing afterload

§ Reduce myocardial oxygen consumption by reducing heart rate and contractility (except for the dihydropyridines which have minimal effects on contractility)

§ Improve oxygen delivery to ischemic myocardium by vasodilating coronary arteries and by reducing heart rate (increased time spent in diastole)

§ May also inhibit platelet aggregation

· Pharmacokinetics

o The calcium channel blockers are orally active

o The calcium channel blockers exhibit high first-pass metabolism and high protein binding

o Most of the channel blockers used to treat angina are active within about 30 minutes after oral administration and have plasma half-lives of several hours

§ Bepridil and the newer dihydropyridines have longer half-lifes (24-50 hours)

· Adverse Effects

o The major adverse effects of calcium channel blockers are typically direct extensions of their therapeutic actions and are relatively rare:

§ Depression of contractility and heart failure

§ Bradycardia

§ AV block

§ Cardiac arrest

o Short-acting dihydropyridines have been associated with an increased incidence of sudden death (cardiac arrhythmia), perhaps by increasing sympathetic tone

o Minor toxicities include:

§ Hypotension

§ Dizziness

§ Edema

§ Flushing

o Because of its ability to block potassium channels, bepridil can prolong the cardiac action potential and cause torsades de pointes (drug-induced long QT syndrome)

· Contraindications

o Verapamil, diltiazem, and bepridil can worsen cardiac performance in patients with overt heart failure

o Verapamil, diltiazem, and bepridil may depress contractility and produce AV block in patients receiving beta-blockers

o Verapamil may increase serum digoxin levels in digitalized patients

Beta-Adrenergic Blockers

· A variety of beta-blockers are now available with a spectrum of properties

· Propranolol (Inderal) is the prototypic beta-adrenergic blocker

· Mechanism of Action and Effects

o These agents block beta-adrenergic receptors in the cardiovascular system

o They have a negative chronotropic and inotropic effect and reduce afterload which:

§ Decreases myocardial oxygen consumption, especially during exercise

§ Improves myocardial perfusion due to lower heart rate

· Adverse Effects and Contraindications

o May dangerously reduce myocardial performance in patients with overt heart failure

o May depress contractility and produce AV block in patients receiving calcium channel blockers

Therapeutics

The goal of drug therapy is to reduce cardiac ischemia by:

Reducing oxygen demand (decrease preload, afterload, contractility, heart rate)
Increasing oxygen delivery to ischemic tissue (coronary vasodilation, decrease preload, decrease heart rate, minimize intracoronary thrombi)

In addition to specific drug therapies, it is important to modify risk factors associated with atherosclerosis (smoking, hypertension, hyperlipidemia)

Stable Angina (Angina of effort)

Maintenance therapy of chronic stable angina includes long-acting nitrovasodilators, calcium channel blockers, or beta-adrenergic blockers

In hypertensive patients, monotherapy with calcium channel blockers or beta-blockers may be sufficient
In normotensive patients, monotherapy with long-acting nitrovasodilators may be adequate
For patients with persistent hypertension, sinus bradycardia, or AV node dysfunction, nifedipine or a longer-acting dihydropyridine is the drug of choice

Combination therapy may be more effective than monotherapy in many patients

A beta-blocker with a dihydropyridine calcium channel blocker (e.g. propanolol and nifedipine)
Two calcium channel blockers with different selectivities (e.g. a dihydropyridine and verapamil)
Combinations that maximize beneficial reduction in work and minimize adverse effects

Surgical revascularization (coronary bypass) and angioplasty should be considered for patients refractory to drug therapy

Vasospastic Angina (Variant angina, Prinzmetal's angina)

Nitrates and the calcium channel blockers are much more effective than beta-adrenergic blocker therapy in relieving and preventing ischemic episodes in patients with variant angina

Angina attacks are completely abolished in 70% of patients treated with channel blockers plus nitrates; marked reduction in frequency of attacks is seen in another 20%

The calcium channel blockers all have similar efficacy in treating variant angina
Beta-blockers may worsen angina due to increased coronary resistance secondary to the unopposed effects of catecholamines acting at alpha-adrenergic receptors
Surgical revascularization and angioplasty are not indicated for patients with variant angina

Unstable Angina

Verapamil has been found to be more effective than propanolol in controlling unstable angina
Nifedipine alone is no more effective than nitrates or beta-blockers in reducing the frequency of rest angina
Adding nifedipine to beta-blocker and nitrate therapy can decrease the frequency of rest angina, the incidence of myocardial infarction, and the necessity for emergency revascularization
Aspirin has been shown to reduce the incidence of cardiac events in these patients
IV heparin or thrombolytic agents may also be indicated in some patients

Combination Therapy

Since nitrates, calcium channel blockers, and beta-adrenergic antagonists are each useful in the treatment of angina and reduce oxygen consumption by different mechanisms, concurrent therapy may be more beneficial than monotherapy (Table 2)

Table 2. Effects of Nitrovasodilators Alone and in Combination with Beta-Blockers or Calcium Channel Blockers (from Katzung, 7th edition)

Hemodynamic Parameter	Nitrates Alone	Beta-Blockers or Calcium Channel Blockers Alone	Nitrates Plus Beta-Blockers or Calcium Channel Blockers
Heart Rate	Reflex Increase	Decrease*	Decrease
Afterload	Decrease	Decrease	Decrease
Preload	Decrease	Increase	None or Decrease
Contractility	Reflex Increase	Decrease*	None
Ejection Time	Decrease	Increase	None

Undesirable effects are shown in italics

* Dihydropyridines have little direct effect on cardiac contractility but may cause an increase in contractility due to a reflex increase in sympathetic tone.