LaraibM.Phil pharamcologyAntianginal drugs

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Angina pectoris, the primary symptom of ischemic heart disease, is caused by transient episodes of myocardial ischemia

It is a characteristic sudden, severe, crushing chest pain that may radiate to the neck, jaw, back, and arms

ANGINA

Ischemia results due to an imbalance in the myocardial oxygen supplydemand relationship.

This imbalance may be caused by an increase in myocardial oxygen demand (which is determined by heart rate,ventricular contractility, and ventricular wall tension) or by a decrease in myocardial oxygen supply (primarily determined by coronary blood flow, but occasionally modified by the oxygen-carrying capacity of the blood) or sometimes by bothPATHOPHYSIOLOGY OF ANGINA

Stable angina, effort-induced angina, classic or typical angina

Unstable angina

Prinzmetal, variant, vasospastic, or rest anginaTYPES OF ANGINA

Classic angina reduction of coronary perfusion due to a fixed obstruction of a coronary artery produced by atherosclerosis.

Fixed obstruction the blood supply cannot increase, and the heart becomes vulnerable to ischemia whenever there is increased demand, such as that produced by physical activity, emotional stress or excitement, or any other cause of increased cardiac workloadA. Stable angina, effort-induced angina, classic or typical angina

Typical angina pectoris is promptly relieved by rest or nitroglycerin.

When the pattern of chest pain and effort needed to trigger the chest pains do not vary over time, the angina is named stable angina.

In some patients, anginal symptoms may occur without any increase in Myocardial O2 demand, but rather as a consequence ofan abrupt reduction inblood flow, as might result from coronary thrombosis

B. Unstable angina

Any episode of rest angina longer than 20 minutes,

any new-onset angina, any increasing angina, or

even sudden development of shortness of breath

The symptoms are not relieved by rest or nitroglycerin. Unstable angina is a form of acute coronary syndrome and requires hospital admission and more aggressive therapy to prevent progression to MI and death

uncommon pattern of episodic angina that occurs at rest and is due to coronary artery spasm ( localized vasospam)

Prinzmetal angina generally responds promptly to coronary vasodilators, such asnitroglycerin and calcium channel blockersC. Prinzmetal, variant, vasospastic, or rest angina

TREATMENT STRATEGIES

These compounds are effective in stable, unstable, and variant angina.

These include:

Nitroglycerine

Isosorbide dinitrate

Isosorbide mononitrate

Inhaled NO

ORGANIC NITRATES

Phosphorylation of the myosin light chain regulates the maintenance of the contractile state in smooth muscle.

Nitrites, organic nitrates, lead to the formation of the reactive gaseous free radical NO and related NO-containing compounds

NO can activate guanylyl cyclase, increase the cellular level of cyclic GMP, activate PKG, and modulate the activities of cyclic nucleotide phosphodiesterases (PDEs 2, 3, and 5) in a variety of cell types.

In smooth muscle, the net result is reduced phosphorylation of myosin light chain, reduced Ca2+ concentration in the cytosol, and relaxationMechanism of action

Nitrates such as nitroglycerin cause dilation of the large veins, which reduces preload (venous return to the heart) and, therefore, reduces the work of the heart

Nitrates also dilate the coronary vasculature, providing an increased blood supply to the heart muscle

Because of its rapid onset of action (13 minutes), sublingual nitroglycerin is the most frequently used agent for the immediate treatment of angina.

Because its duration of action is short (not exceeding 2030 minutes), it is not suitable for maintenance therapy

Significant first-pass metabolism of nitroglycerin occurs in the liver. Therefore, it is commonly administered via the sublingual or transdermal route (patch or ointment)Clinical Use & pharmacokinetics

Headache is the most common adverse effect of nitrates.

High doses of nitrates can also cause postural hypotension, facial flushing, and tachycardia.

Phosphodiesterase type 5 inhibitors such as sildenafil potentiate the action of the nitrates. To preclude the dangerous hypotension that may occur, this combination is contraindicatedAdverse effects

Tolerance to the actions of nitrates develops rapidly as the blood vessels become desensitized to vasodilation.

Tolerance can be overcome by providing a daily nitrate-free interval to restore sensitivity to the drug.

This interval of 10 to 12 hours is usually taken at night because demand on the heart is decreased at that time.

However, variant angina worsens early in the morning, perhaps due to circadian catecholamine surges. Therefore, the nitrate-free interval in these patients should occur in the late afternoonTolerance

Ca2+ CHANNEL ANTAGONISTS

Voltage-sensitive Ca2+ channels (L-type or slow channels) mediate the entry of extracellular Ca2+ into smooth muscle and cardiac myocytes in response to electrical depolarization.

In both smooth muscle and cardiac myocytes, Ca2+ is a trigger for contraction, albeit by different mechanisms

Calcium entry into the myocyte first triggers intracellular calcium release; the released calcium then binds the regulatory protein troponin, resulting in a calcium-troponin complex which allows actin and myosin to interact and contract.

The sequence of events is the same in vascular smooth muscle cells, except that a calcium-calmodulin complex instead of calcium-troponin.

The net effect is vasodilatation; the ensuing fall in blood pressure decreases cardiac work and may contribute to the efficacy of these drugs in the patient with angina.Mechanism of action

Exertional Angina increase in blood flow owing to coronary arterial dilation, from a decrease in myocardial oxygen demand (secondary to a decrease in arterial blood pressure, heart rate, or contractility), or both

vasospastic angina due to relaxation of the coronary arteries

Clinical uses

A. Dihydropyridine calcium channel blockers

B. Nondihydropyridines

Most common ADR is constipation

Othes include:

Headache, flushing, peripheral edema, hypotension, rebound tachycardiaAdverse effects

BETA-BLOCKING DRUGSThe -adrenergic blockers decrease the oxygen demands resulting in decreased heart rate, contractility, cardiac output, and blood pressure.

These agents reduce myocardial oxygen demand during exertion and at rest. As such, they can reduce both the frequency and severity of angina attacks.

-Blockers are recommended as initial antianginal therapy in all patients unless contraindicated.The exception to this rule is vasospastic angina, in which -blockers are ineffective and may actually worsen symptoms

Propranolol is the prototype for this class of compounds, but it is not cardioselective Thus, other -blockers, such as metoprolol and atenolol, are preferred.

Nonselective -blockers should be avoided in patients with asthma. All -blockers are nonselective at high doses and can inhibit 2 receptors

-Blockers should be avoided in patients with severe bradycardia.

It is important not to discontinue -blocker therapy abruptly. The dose should be gradually tapered off over 2 to 3 weeks to avoid rebound angina, MI, and hypertension

Bradycardia

Worsen peripheral vascular disease

Sleep distubances

Inhibit beta-2 mediated bronchodilation in asthamaticsAdverse effects

A decreased efflux or increased influx of sodium may cause cellular sodium overload

The peak sodium current underlies excitability and conduction in heart muscle, but a late sodium current flowing after the peak contributes to maintaining and prolonging the action potential plateau, and also to intracellular sodium loading, that in turn increases intracellular calcium with consequent effects on arrhythmia and diastolic function.

Late sodium current is pathologically increased in both genetic and acquired heart disease, making it an attractive target for therapy to treat arrhythmia, heart failure, and angina. Late INa may represent a major source for increased intracellular sodium during ischemia.

Sodium channel blocker

Ranolazine inhibits the late inward sodium current in heart muscle. Inhibiting that current leads to reductions in elevated intracellular calcium levels. This in turn leads to reduced tension in the heart wall, leading to reduced oxygen requirements for the muscle

It is indicated for the treatment of chronic angina and may be used alone or in combination with other traditional therapies.

It is most often used in patients who have failed other antianginal therapies.

Ranolazine is extensively metabolized in the liver, mainly by the CYP3A family and also by CYP2D6.

It is also a substrate of P-glycoprotein. As such, ranolazine is subject to numerous drug interactions

Constipation

Headache

Edema

QT interval prolongationAdverse effects

Aspirin reduces the incidence of MI and death in patients with unstable angina.

In addition, low doses of aspirin appear to reduce the incidence of MI in patients with chronic stable angina.

aspirin inhibits prostaglandin action and therefore avoid clotting followed by preventing thromboxane A2, the platelet-aggregating substance, formation

ANTI-PLATELET

Prevention doses: 81 to 325mg daily or every other day;Treatment doses: 160 to 325mg once daily

One of the main adverse effects of aspirin is gastric upset. Especially when taken in high doses the risk of gastrointestinal bleeding increases.

Other side effects include:

Nausea, heartburn, thrombocytopenia, prolonged bleeding time Rey's syndrome, anaphylaxis and angioedema.

Atorvastatin Fluvastatin LovastatinPravastatin Simvastatin

The most effective impact of statins on the patients suffering from anginal attacks is believed to be through lowering the LDL cholesterol level in plasma Statins or HMG CoA reductase inhibitors

HMG CoA reductase is an enzyme responsible for mevalonate production.

In lipid forming pathway, mevalonate is finally transformed to cholesterol.

Statins which have some structural similarities with this HMG CoA reductase, can competitively attach to the enzyme and block it.

Therefore, the speed of cholesterol biosynthesis will decline. Mechanism of action

statins

Stenting or "percutaneous coronary intervention" ( PCI)

Is a procedure that uses a flexible plastic catheter with a tiny balloon at the end to dilate narrowed arteries in the heart.

A metal stent is then placed at the site of a major blockage to hold the artery open.

This procedure (which also used to be called "angioplasty")Interventional treatments

CABG , is a surgery used to treat narrowed or blocked arteries that supply blood to the heart.

This is accomplished by going around or bypassing the blocked artery with a healthy vessel called a graft that is taken from the leg, arm or chest.

The graft will now carry the blood around the blockage to improve the blood flow to the heart.

Coronary artery bypass grafting

The university of chicago chronic angina program considering for alternative methods to treat chronic ischemic heart disease.

One option currently under investigation involves "angiogenesis," the formation of new blood-flow pathways.

Physicians are studying the use of gene therapy to trigger the creation or enlargement of blood vessels to the heart; thereby improving previously impaired blood flow.

These substances are delivered directly into the arteries. If successful, this gene therapy treatment may either reduce or stop angina, and decrease the severity of heart disease.

Angiogenesis/Gene Therapy

Cardiac Center heart surgeons are using lasers to reduce cardiac chest pain.

Transmyocardial laser revascularization (TMR) is an FDA-approved surgical technique that uses lasers to create small holes in heart muscle.

These laser "channels" may destroy nerve fibers that cause pain or they may stimulate new blood vessels to growTransmyocardial Laser Revascularization

Crataegus hawthorn, has acquired the reputation in modern herbal literature as an important tonic for the cardiovascular system that is particularly useful for angina.

Crataegus leaves, flowers, and fruits contain a number of biologically active substances, such as oligomeric procyanins, flavonoids, and catechins.

From current studies, Crataegus extract appears to have antioxidant properties and can inhibit the formation of thromboxane as wellMedicinal plants

Crataegus extract antagonizes the increases in cholesterol, triglyceride, and phospholipid levels in low-density lipoprotein (LDL) and very low-density lipoprotein in rats fed a hyperlipidemic diet; thus, it may inhibit the progression of atherosclerosis.

In recent decades, research has focused on garlic's use in preventing atherosclerosis.

Garlic, like many of the other herbalmedicines discussed previously, has demonstrated multiple beneficial cardiovascular effects.

A number of studies have demonstrated these effects that include lowering blood pressure, inhibiting platelet aggregation, enhancing fibrinolytic activity, reducing serum cholesterol and triglyceride levels

Garlic (Allium sativum)

Useful as an antianginal drug because It has been shown to dilate coronary arteries

S. Miltiorrhiza also inhibits platelet aggregation

Salvia miltiorrhiza