Antianginal DrugsAngina Pectoris• Defined as a characteristic sudden,

severe, pressing chest pain radiating to the neck, jaw, back, and arms.

• It is caused by coronary blood flow that is insufficient to meet the oxygen demands of the myocardium.

Antianginal Drugs• The imbalance between the oxygen

requirement of the heart and the oxygen supplied to it may result during exertion, from a spasm of the vascular smooth muscle, or from obstruction of blood vessels caused by atherosclerotic lesions.

Types of AnginaA.Stable Angina (Typical Angina)o Most common form o Characterized by burning, heavy, or

squeezing feeling in the chesto Caused by reduction of coronary

perfusion due to fixed obstruction produced by coronary atherosclerosis

o Relieved by rest or nitroglycerin

Types of AnginaB. Unstable Anginao A type of acute coronary syndromeo Present when episodes of angina occur at

rest and when there is an increase in the severity, frequency, and duration of chest pain in patients with previously stable angina

o Caused by episodes of increased epicardial coronary artery resistance or small platelet clots occurring in the vicinity of an atherosclerotic plaque

Types of AnginaB. Unstable Anginao Not relieved by rest or nitroglycerino Requires hospital admission and

more aggressive therapy to prevent death and progression to myocardial infarction

Types of AnginaC. Prinzmetal’s/Variant/Vasospastic AnginaoUncommon pattern of episodic angina that

occurs at rest and is due to coronary artery spasm.

oSymptoms are caused by decreased blood flow to the heart muscle due to spasm of the coronary artery

oGenerally responds promptly to coronary vasodilators, such as nitroglycerin and calcium channel blockers

Basic Pharmacology of Drugs used to treat Angina

• The three drug groups traditionally used in angina (organic nitrates, calcium channel blockers and beta blockers) decrease myocardial oxygen requirement by decreasing the determinants of oxygen demand (heart rate, ventricular volume, blood pressure and contractility).

Basic Pharmacology of Drugs used to treat Angina

• In some patients, the nitrates and the calcium channel blockers may cause a redistribution of coronary flow and increase oxygen delivery to ischemic tissue.

• In variant angina, these two drug groups also increase myocardial oxygen delivery by reversing coronary artery spasm.

Organic NitratesOrganic nitrates (and nitrites) used in

the treatment of angina pectoris are simple nitric and nitrous acid esters of glycerol.

These compounds cause a rapid reduction in myocardial oxygen demand, followed by relief of symptoms.

Organic NitratesNitroglycerin (Glyceryl Nitrate), Isosorbide Mononitrate, Isosorbide DinitrateMOA: Decrease coronary vasoconstriction or spasm and increase perfusion of the myocardium by relaxing coronary arteries. In addition they relax veins, decreasing preload and myocardial oxygen consumption.

Administered Nitrates

Increased Nitric Oxide

Increased cGMP

Increased Dephosphorylation of Myosin Light Chain

Reduced Ca2+ concentration in the cytosol

Vascular Smooth Muscle Relaxation

Organic NitratesTherapeutic Use: For prompt relief of an ongoing attack of angina precipitated by exercise or emotional stress, sublingual nitroglycerin is the drug of choice.Pharmacokinetics and Dosage: The time to onset of action varies from 1 minute for nitroglycerin to more than 1 hour for isosorbide mononitrate. Significant first pass metabolism of nitroglycerin occurs in the liver. Therefore, it is common to take the drug either sublingually or via a transdermal patch.

Organic NitratesToxicity/side effects: • Throbbing headache• postural hypotension

Sildenafil + nitrates = “dangerous hypotension”

Rarely, transdermal nitroglycerin patches have ignited when external defibrillator was applied to the chest of patients in ventricular fibrillation. Such patches should be removed before use of external defibrillator to prevent superficial burns.

• facial flushing• tachycardia.

Organic NitratesContraindication: Elevated intracranial pressureTolerance: 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 is typically 10 to 12 hours. Nitroglycerine patches are worn for 12 hours then removed for 12 hours usually in the afternoon to counteract the circadian catecholamine surges in cases of variant angina.

Other Nitro-VasodilatorsNicorandil• Is a nicotinamide nitrate ester that has

vasodilating properties in normal coronary arteries.

Therapeutic Use: Treatment of chronic stable angina pectorisDosing: 10-20 mg twice a dayToxicity/side effects: Headache, abdominal pain, flush

Beta-adrenergic BlockersThe beneficial effects of β-blocking

agents are related to their hemodynamic effects – decreased heart rate, blood pressure, and contractility – which decrease myocardial oxygen requirements at rest and during exercise.

Lower heart rate is also associated with an increase in diastolic perfusion time that may increase coronary perfusion.

Beta-adrenergic BlockersHowever, reduction of heart

rate and blood pressure, and consequently decreased myocardial oxygen consumption, appear to be the most important mechanisms for relief of angina and improved exercise tolerance.

Beta-adrenergic BlockersMetoprolol, AtenololMOA: Suppress the activation of the heart by blocking the β1 receptors and reduce the work of the heart by decreasing heart rate, contractility, cardiac output and blood pressure. (NOTE: Agent with intrinsic sympathomimetic activity i.e. pindolol are less effective and should be avoided in angina).

Beta-adrenergic BlockersTherapeutic Use: Treatment of patients with myocardial infarction. (Note: It is important not to discontinue β-blocker therapy abruptly. The dose should be gradually tapered off over to 5 to 10 days to avoid rebound angina or hypertension). Pharmacokinetics and Dosage: Metoprolol is extensively metabolized and has short half-life of 4 to 6 hrs. Atenolol is not extensively metabolized with a half-life of 6 hrs.

Beta-adrenergic BlockersPharmacokinetics and Dosage: Metoprolol is given 100mg/day PO initially divided every 12 hours, may be increased at intervals of 1 week or longer; not to exceed 400mg/day. Atenolol is 50mg/day PO; after 1 week, may be increased to 100mg/day; some patients may require 200mg/day.

Beta-adrenergic BlockersToxicity/side effects: • Hypotension• Bradycardia• Fatigue

Contraindicated in patients with asthma, diabetes, severe bradycardia, peripheral vascular disease, or COPD.

Worsen intermittent claudication

• Insomnia• Sexual dysfunction

Calcium Channel BlockersCalcium is essential for muscular

contraction. Calcium influx is increased in ischemia because of the membrane depolarization that hypoxia produces. In turn, this promotes the activity of several adenosine triphosphate-consuming enzyme, thereby depleting energy stores and worsening the ischemia.

The calcium-channel blockers protect the tissue by inhibiting the entrance of calcium into cardiac and smooth cells of the coronary and systemic arterial beds.

Calcium Channel BlockersVerapamil mainly affects the myocardium,

whereas, nifedipine exerts a greater effect on smooth muscle in the peripheral vasculature. Diltiazem is intermediate in its actions.

Variant angina caused by spontaneous coronary spasm (either at work or at rest) rather than by increased myocardial oxygen requirement is controlled by organic nitrates or calcium-channel blockers; β-blockers are contraindicated.

Aggravate spams By blocking the vasoldilatory beta adrenergic B2 receptors, thereby allowing unopposed alpha adrenergic receptors

Calcium Channel BlockersNifedipineMOA: Functions mainly as arterioral vasodilator. Therapeutic Use: Treatment of variant angina caused by spontaneous coronary spasm.Pharmacokinetics and Dosage: It is administered orally, usually as extended-release tablets.

Calcium Channel BlockersToxicity/side effects:

• Flushing• Headache• Hypotension• Peripheral edema• Constipation• Reflex tachycardia.

Nicardepine – intracerebral and intravenous arterial infusion to prevent cerebral vasospasm with stroke

Calcium Channel Blockers

VerapamilMOA: Slows cardiac atrioventricular (AV) conduction directly, and decreases heart rate, contractility, blood pressure, and oxygen demand. It causes greater negative inotropic effects than nifedipine, but it is a weaker vasodilator.

Calcium Channel BlockersPharmacokinetics: This drug extensively metabolized by the liver; therefore, care must be taken to adjust the dose in patients with liver dysfunction. Toxicity/side effects: Constipation. Should be used with caution in patients taking digoxin, because verapamil increases digoxin levels.

Calcium Channel BlockersDiltiazemMOA: Slows AV conduction and decrease the rate of firing of the sinus node pacemaker.Therapeutic Use: Relieves coronary artery spasm and therefore is particularly useful in patients with variant anginaToxicity/side effects: Headache

Newer Antianginal DrugsRanolazine• Is a newer antianginal drug that appear

to act by reducing a late sodium current that facilitates calcium entry via the sodium-calcium exchanger.

• The resulting reduction in intracellular calcium concentration reduces cardiac contractility and work.

Newer Antianginal Drugs

Treatment of Peripheral Artery Disease (PAD) & Intermittent Claudication

Peripheral Artery Disease – a disease in which plaque builds up in the arteries

that carry blood to your head, organs, and limbs. – PAD usually affect the arteries in the legs.

Intermittent Claudication– main symptom of PAD– A tight or squeezing pain in the calf, foot, thigh, or

buttock that occurs during exercise, such as walking but relieved by rest.

Atherosclerosis can result. Plaque is made up of fat, cholesterol, calcium, fibrous tisssue and other substances in the blood

Treatment of Peripheral Artery Disease (PAD) & Intermittent Claudication

Two drugs are used almost exclusively for PAD:1. Pentoxifylline – is thought to act by

reducing the viscosity of blood, allowing it to flow more easily through partially obstructed areas.

2. Cilostazol – PDE3 inhibitor, may have antiplatelet and vasodilating effects.

*Both drugs have been shown to increase exercise tolerance in patients with severe claudication.

Surgical Intervention

Angioplasty

Options other than medications for treating angina include angioplasty and coronary bypass surgery.

Surgical Intervention