Antianginal Drugs

Antianginal Drugs Claro M. Isidro M.D.

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.

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

* Myocardial ischemia which produces angina results from imbalances in myocardial oxygen supply & demand relationship such as decreased oxygen supply and/or increased oxygen demand. Etiology Decrease oxygen supply Increase demand for oxygen

Determinant of Myocardial Oxygen Supply Coronary blood flow Determined by: perfusion pressure duration of diastole coronary bed resistance Arterio-venous oxygen difference

Determinant of Myocardial Oxygen demand Major Determinants Wall stress  intraventricular pressure ventricular volume wall thickness Heart rate Contractility

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

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 : Rapidly acting nitrates * used to terminate acute attack of angina * e.g.- Nitroglycerin and Amyl nitrate * usually administered sublingually Long acting nitrates * used to prevent an attack of angina * e.g. - Erythrytyl tetranitrate, Isosorbide dinitrate, Pentaerythrytol tetranitrate * administered orally or topically

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 Coronary artery dilatation Reduction of peripheral arterial resistance – decrease after load 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 Venodilatation 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

Potential Deleterious Effects Deleterious Effects Results Reflex tachycardia Increase myocardial oxygen requirement Reflex increase in contractility Decrease diastolic perfusion Decrease myocardial perfusion

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 .

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 Effects 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 Renal ischemia Acute myocardial infarction Patients receiving other antihypertensive agent

B-Blockers Hemodynamics Effects Decrease heart rate 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 O 2 consumption Increase oxygen supply

Contraindication Congestive heart failure Asthma Complete heart block

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

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 Nifedipine Verafamil 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 Theraphy 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

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

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

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

Antianginal Drugs

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Antianginal Drugs