Antianginal Drugs`````Antianginal Drugs`````

Dr. Everton McIntosh

October 13, 2011

Learning ObjectivesLearning Objectives

Define angina pectorisAttain a basic understanding of the

pathophysiology of anginaLearn the different classes of drugs used to

treat anginaLearn the rational use of these drugs in

treating angina

Definition of termsDefinition 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. Heart rate

3. 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 Summary Myocardial Oxygen Supply-Demand BallanceSupply-Demand Ballance

Types of AnginaTypes 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

vesselsUnstable 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 NITRITESClassification 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

IVMS 2004-2008 21

NitratesNitrates

Glyceryl trinitrate(GTN)

Isosorbide (di)nitrate

IVMS 2004-2008 22

Nitric Oxide and VasodilationNitric Oxide and Vasodilation

After receptor stimulation, L-arginine-dependent 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 TherapyROBERT J. LUNN, M.D.From the Department of Anesthesiology, Mayo Clinic Rochester, Rochester, Minnesota.

IVMS 2004-2008 23

GTN

NO2-

OrganicNitrate

Ester Reductase

R-SHR-SH

NO Nitrosothiols (R-

SNO)

Guanylate CyclaseGuanylate Cyclase+

GTPcGMP

Protein Kinase GProtein Kinase GRELAXATIONRELAXATION

Vascular Smooth Muscle Cell

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

NitratesNitrates

Coronary artery dilatation

Decrease coronary bed resistance (Relieved coronary vasospasm)

Increase coronary blood flow

Increase oxygen supply

NitratesNitrates

Reduction on peripheral resistance(Secondary to dilatation of aorta)

Decrease blood pressure

Decrease after load

Decrease workload

Decrease oxygen consumption

NitratesNitrates

Reduced venous return(Due to dilatation of the veins)

Decrease left ventricular volume

Decrease preload

Decrease workload

Decrease oxygen consumption

EffectsEffects

1. Coronary artery dilatation

2. Reduction of peripheral arterial resistance – decrease after load

3. Reduce venous return – decrease preload

Potential Beneficial Effects of Nitrates.

Beneficial effects Results

Decrease Ventricular vol. Decrease myocardial oxygen requirement

Decrease arterial pressure

Decrease ejection time

Vasodilatation of epicardial coronary art.

Relief of coranary artery spasm

Increase collateral flow due to venodilatation

Increase perfusion to ischemic myocardium

Decrease left ventricular pressure

> decrease preload due to dilatation of the vein

> decrease after load due to dilatation of the arteries

Improved subendocardial perfusion

Deleterious Effects Results

Reflex tachycardia Increase myocardial oxygen requirement

Reflex increase in contractility

Decrease diastolic perfusion

Decrease myocardial perfusion

Potential Deleterious EffectsPotential Deleterious Effects

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 angina3. 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. PharmacokineticsC. 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 Usual single dose Route of administration

Duration of action

Short acting

Nitroglycerin

0.15-1.2 mg sublingual 10 - 30 min

Isosorbide dinitrate 2.5-5 mg sublingual 10 – 60 min

Amyl nitrite 0.18 – 3 ml inhalation 3 – 5 min

Long acting

Nitroglycerin sustained action

6.5 – 13 mg q 6-8 hrs oral 6 – 8 hrs

Nitroglycerin 2% ointment

1 – 1.5 inches q hr topical 3 – 6 hrs

Niroglycerin slow released

1 –2 mg per 4 hrs Buccal mucosa 3 – 6 hrs

Nitroglycerin slow released

10 – 25 mg /24hrs (one patch/day}

transdermal 8 –10 hrs

Isosorbide dinitrate 2.5 – 10 mg per 2 hrs sublingual 1.5 – 2 hrs

Isosorbide dinitrate 10 –60 mg per 4-6 hrs oral 4 – 6 hrs

Isosorbide dinitrate chewable

5 – 10 mg per 2-4 hrs oral 2 – 3 hrs

Isosorbide mononitrate 20 mg per 12 hrs oral 6 –10 hrs

Adverse EffectsAdverse Effects

1. Throbbing headache

2. Flushing of the face

3. Dizziness – especially at the beginning of treatment

4. Postural Hypotension – due to pooling of blood in the dependent portion of the body

ContraindicationContraindication

1. Renal ischemia

2. Acute myocardial infarction

3. Patients receiving other antihypertensive agent

B-BlockersB-Blockers

Hemodynamics Effects

1.  Decrease heart rate

2. Reduced blood pressure and cardiac contractility without appreciable decrease in cardiac output

B-BlockersB-Blockers

Decrease heart rate & Contractility

Increase duration of diastole

Decrease workload

Increase coronary blood flow

Decrease O2 consumption

Increase oxygen supply

2. β-Adrenergic Blockers2. β-Adrenergic BlockersThe β-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 β1 receptors, and they reduce the work of the heart by decreasing heart rate, contractility, cardiac output, and blood pressure.

With β-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 β-blockers, such as metoprolol or atenolol, are preferred.

All β-blockers are nonselective at high doses and can inhibit β2 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 β-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 β-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 β-blocker therapy abruptly. The dose should be gradually tapered off over 5 to 10 days to avoid rebound angina or hypertension.

ContraindicationContraindication

1. Congestive heart failure

2. Asthma

3. Complete heart block

Ca - Channel BlockersCa - Channel Blockers

Effects1. Coronary artery dilatation

2. Reduction on peripheral arterial resistance – decrease after load

Ca Channel BlockersCa Channel Blockers

Coronary artery dilatation

Decrease coronary bed resistance (Relieved coronary vasospasm)

Increase coronary blood flow

Increase oxygen supply

Ca channel BlockersCa 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 Blockers1. Nifedipine2. Verafamil3. Diltiazem

Pharmacokineticss

Drugs Onset of action Peak of action Half-life

Nifedipine 20 minutes 1 hour 3-4 hours

Verafamil 1-2 hours 5 hours 8-10 hours

Diltiazem 15 minutes 30 minutes 3-4 hours

Nicardifine 20 minutes 45 minutes 2-4 hours

Felodipine 2-5 hours 6-7 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 Theraphy1. 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

Other Names Description Drug Therapy

STABLE Classic

Exertional

Fixed

Atherosclerotic

Obstruction coronary artery

Nitrates

CCB

B-blockers

VARIANT Prinzmetal’s

Vasospasmic

Vasospasm at any time

Nitrates

CCB

UNSTABLE Crescendo Combined effect

Pre= MI

Nitrates

CCB