Antianginal Drugs`````

Dr. Everton McIntosh October 13, 2011

Learning Objectives

Define angina pectoris Attain a basic understanding of the pathophysiology of angina Learn the different classes of drugs used to treat angina Learn the rational use of these drugs in treating angina

Definition of terms
Angina Pectoris is the principal symptoms of patient with ischemic heart disease. Manifested by sudden, severe, pressing substernal pain that often radiates to the left shoulder and along the flexor surface of the left arm. Usually precipitated by exercise, excitement or a heavy meal.

Determinant of Myocardial Oxygen Supply 1. Coronary blood flow

Determined by: perfusion pressure duration of diastole coronary bed resistance
2.

Arterio-venous oxygen difference

Determinant of Myocardial Oxygen demand Major Determinants 1. Wall stress

intraventricular pressure ventricular volume wall thickness
2. 3.

Heart rate Contractility

Determinants of Vascular Tone Relaxation of vascular smooth muscle by: 1. Increase cGMP 2. Decrease intracellular calcium 3. Increase cAMP 4. Stabilizing or preventing depolarization of the vascular smooth muscle cell membrane

Summary Myocardial Oxygen Supply-Demand Ballance

Types of Angina
Typical Angina ( Classical Angina ) pain is commonly induced by exercise, excitement or a heavy meal secondary to advanced atherosclerosis of the coronary vessels associated with ST-segment depression on ECG

Variant Angina ( Prinzmetal Angina) pain is induced while at rest associated with ST-segment elevation on ECG secondary to vasospasm of the coronary vessels Unstable angina may involve coronary spasm and may also have the component of atherosclerosis the duration of manifestation is longer than the first two and has the manifestation of Myocardial infarction

Treatment Plan:
A. decrease the risk factor like atherosclerosis, hypertension, smoking B. increase oxygen supply C. decrease oxygen demand

ANTIANGINAL DRUGS
I. AGENTS WHICH O2 DEMAND & O2 SUPPLY A. NITRATES B. CALCIUM CHANNEL BLOCKERS II. AGENTS WHICH O2 DEMAND C. BETA BLOCKERS

NITRATES AND NITRITES Classification of nitrates: 1. Rapidly acting nitrates

* used to terminate acute attack of angina * e.g.- Nitroglycerin and Amyl nitrate * usually administered sublingually
2.

Long acting nitrates

* used to prevent an attack of angina * e.g. -Erythrytyl tetranitrate, Isosorbide dinitrate, Pentaerythrytol tetranitrate * administered orally or topically

Nitrates

Glyceryl trinitrate (GTN)

Isosorbide (di)nitrate

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Nitric Oxide and Vasodilation

After receptor stimulation, L-argininedependent metabolic pathway produces nitric oxide (NO) or thiol derivative (R-NO). NO causes increase in cyclic guanosine monophosphate (cGMP), which causes relaxation of vascular smooth muscle. EDRF=endothelium-derived relaxing factor.
From: Inhaled Nitric Oxide Therapy ROBERT J. LUNN, M.D. From the Department of Anesthesiology, Mayo Clinic Rochester, Rochester, Minnesota.

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GTN

Vascular Smooth Muscle Cell

R-SH OrganicNitrate Ester Reductase

NO2- R-SHNO

See : Nitrates, Digoxin and Calcium Channel Blockers Dr. Paul Forrest Royal Prince Alfred Hospital

Nitrosot hiols (RSNO) + Guanylate Cyclase

cGMP GTP

RELAXATION

Protein Kinase G
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Nitrates
Coronary artery dilatation Decrease coronary bed resistance
(Relieved coronary vasospasm)

Increase coronary blood flow Increase oxygen supply

Nitrates
Reduction on peripheral resistance
(Secondary to dilatation of aorta)

Decrease blood pressure Decrease after load

Decrease workload
Decrease oxygen consumption

Nitrates
Reduced venous return
(Due to dilatation of the veins)

Decrease left ventricular volume Decrease preload Decrease workload Decrease oxygen consumption

Effects
1.
2.

3.

Coronary artery dilatation Reduction of peripheral arterial resistance decrease after load Reduce venous return decrease preload

Potential Beneficial Effects of Nitrates.

Beneficial effects Decrease Ventricular vol. Decrease arterial pressure Decrease ejection time Vasodilatation of epicardial coronary art. Increase collateral flow due to venodilatation Decrease left ventricular pressure > decrease preload due to dilatation of the vein > decrease after load due to dilatation of the arteries Relief of coranary artery spasm Increase perfusion to ischemic myocardium Improved subendocardial perfusion Results Decrease myocardial oxygen requirement

Potential Deleterious Effects

Deleterious Effects Reflex tachycardia
Reflex increase in contractility Decrease diastolic perfusion Decrease myocardial perfusion

Results Increase myocardial oxygen requirement

ROUTES OF ADMINISTRATION
1. Sublingual route rational and effective for the treatment of acute attacks of angina pectoris. Half-life depend only on the rate at which they are delivered to the liver. 2. Oral route to provide convenient and prolonged prophylaxis against attacks of angina 3. Intravenous Route useful in the treatment of coronary vasospasm and acute ischemic syndrome. 4. Topical route used to provide gradual absorption of the drug for prolonged prophylactic purpose.

C. Pharmacokinetics

The time to onset of action varies from 1 minute for sublingual nitroglycerin to more than 1 hour for oral 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, thereby avoiding this route of elimination. Isosorbide mononitrate owes its improved bioavailability and long duration of action to its stability against hepatic breakdown. Oral isosorbide dinitrate undergoes denitration to two mononitrates, both of which possess antianginal activity.

Time to peak effect and duration of action for some common organic nitrate preparations

Drug
Short acting Nitroglycerin Isosorbide dinitrate Amyl nitrite Long acting Nitroglycerin sustained action Nitroglycerin 2% ointment Niroglycerin slow released

Usual single dose

0.15-1.2 mg 2.5-5 mg 0.18 3 ml 6.5 13 mg q 6-8 hrs 1 1.5 inches q hr 1 2 mg per 4 hrs

Route of administration
sublingual sublingual inhalation oral topical Buccal mucosa

Duration of action
10 - 30 min 10 60 min 3 5 min 6 8 hrs 3 6 hrs 3 6 hrs

Nitroglycerin released Isosorbide dinitrate

Isosorbide dinitrate Isosorbide dinitrate chewable

slow 10 25 mg /24hrs (one patch/day} 2.5 10 mg per 2 hrs

10 60 mg per 4-6 hrs 5 10 mg per 2-4 hrs

transdermal sublingual
oral oral

8 10 hrs 1.5 2 hrs

4 6 hrs 2 3 hrs

Isosorbide mononitrate

20 mg per 12 hrs

oral

6 10 hrs

Adverse Effects
1. 2. 3. 4.

Throbbing headache Flushing of the face Dizziness especially at the beginning of treatment Postural Hypotension due to pooling of blood in the dependent portion of the body

Contraindication
1.
2. 3.

Renal ischemia Acute myocardial infarction Patients receiving other antihypertensive agent

B-Blockers
Hemodynamics Effects 1. Decrease heart rate 2. Reduced blood pressure and cardiac contractility without appreciable decrease in cardiac output

B-Blockers
Decrease heart rate & Contractility
Increase duration of diastole Decrease workload

Increase coronary blood flow

Decrease O2 consumption Increase oxygen supply

2. -Adrenergic Blockers

The -adrenergic blocking agents decrease the oxygen demands of the myocardium by lowering both the rate and the force of contraction of the heart. They suppress the activation of the heart by blocking 1 receptors, and they reduce the work of the heart by decreasing heart rate, contractility, cardiac output, and blood pressure.

With -blockers, the demand for oxygen by the myocardium is reduced both during exertion and at rest. Propranolol is the prototype for this class of compounds, but it is not cardioselective. Thus, other blockers, such as metoprolol or atenolol, are preferred. All -blockers are nonselective at high doses and can inhibit 2 receptors. This is particularly important to remember in the case of asthmatics. Agents with intrinsic sympathomimetic activity (for example, pindolol) are less effective and should be avoided in angina. The -blockers reduce the frequency and severity of angina attacks. These agents are particularly useful in the treatment of patients with myocardial infarction and have been shown to prolong survival.

The -blockers can be used with nitrates to increase exercise duration and tolerance. They are, however, contraindicated in patients with asthma, diabetes, severe bradycardia, peripheral vascular disease, or chronic obstructive pulmonary disease. Note: It is important not to discontinue blocker therapy abruptly. The dose should be gradually tapered off over 5 to 10 days to avoid rebound angina or hypertension.

Contraindication
1. 2. 3.

Congestive heart failure Asthma Complete heart block

Ca - Channel Blockers
Effects
Coronary artery dilatation 2. Reduction on peripheral arterial resistance decrease after load
1.

Ca Channel Blockers
Coronary artery dilatation Decrease coronary bed resistance
(Relieved coronary vasospasm)

Increase coronary blood flow Increase oxygen supply

Ca channel Blockers
Reduction on peripheral resistance (Secondary to dilatation of aorta) Decrease blood pressure Decrease after load

Decrease workload
Decrease oxygen consumption

Most commonly used Ca Channel Blockers 1. Nifedipine 2. Verafamil 3. Diltiazem Pharmacokineticss

Drugs Nifedipine Verafamil Diltiazem Nicardifine Felodipine Onset of action 20 minutes 1-2 hours 15 minutes 20 minutes 2-5 hours Peak of action 1 hour 5 hours 30 minutes 45 minutes 6-7 hours Half-life 3-4 hours 8-10 hours 3-4 hours 2-4 hours 11-16 hour

Unwanted effect Nausea and vomiting Dizzyness Flushing of the face Tachycardia due to hypotension

Contraindications Cardiogenic shock Recent myocardial infarction Heart failure Atrio-ventricular block

Combination Theraphy 1. Nitrates and B-blockers

* The additive efficacy is primarily a result of one drug blocking the adverse effect of the other agent on net myocardial oxygen consumption * B-blockers blocks the reflex tachycardia associated with nitrates * Nitrates attenuate the increase in the left ventricular end diastolic volume associated with B-lockers by increasing venous capacitance

2.

Ca channel blockers and B-blockers

* useful in the treatment of exertional angina that is not controlled adequately with nitrates and B-blockers * B-blockers attenuate reflex tachycardia produce by nifedipine * These two drugs produce decrease blood pressure

3.

Ca channel blockers and Nitrates

* Useful in severe vasospastic or exertional angina (particularly in patient with exertional angina with congestive heart failure and sick sinus syndrome) * Nitrates reduce preload and after load * Ca channels reduces the after load * Net effect is on reduction of oxygen demand

4.

Triple drugs Nitrate + Ca channel blockers + B-blockers

*Useful in patients with exertional angina not controlled by the administration of two types of anti-anginal agent * Nifidipine decrease after load Nitrates decrease preload B-blockers decrease heart rate & myocardial contractility

Type of Angina
STABLE

Other Names
Classic Exertional Fixed Atherosclerotic

Description
Obstruction coronary artery

Drug Therapy
Nitrates CCB B-blockers

VARIANT

Prinzmetals Vasospasmic Crescendo

Vasospasm at any time Combined effect Pre= MI

Nitrates CCB Nitrates CCB

UNSTABLE