4 CVS Lecture 4 - Antianginal Drugs
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Transcript of 4 CVS Lecture 4 - Antianginal Drugs
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