Cardio- General Considerations

A. Goal of antianginal therapy 
 • Decrease oxygen demand of myocardial tissue or

increase oxygen supply (Fig. 14-1). 


B. Antianginal drugs 
 1. Used to treat angina pectoris caused by myocardial

ischemia (Box 14-1). 
 2. Vasodilator action on the coronary, cerebral, and
peripheral vascular beds 


C. Coronary blood flow 


1. Depends on:
 a. Aortic diastolic pressure
 b. Duration of diastole
 c. Resistance of

the coronary vascular bed

D. Metabolic modulators

1. Myocardium generates energy from metabolism of fatty acids. 


2. Use of pFOX inhibitors (e.g., trimetazidine) shifts metabolism to glucose metabolism,


 which is more efficient in generating adenosine triphosphate (ATP) in the
ischemic heart. 


3. Ranolazine initially assigned to pFOX inhibitor group; now believed to block a late

 sodium current that facilitates calcium entry via the sodium-calcium exchanger.



II. Antianginal Drugs
 A. Nitrites and nitrates

1. Pharmacokinetics
 • Classification is primarily based on duration of action.

a. Rapid-acting agents
 (1) Amyl nitrite (inhalation)
 (2) Nitroglycerin

(intravenous, sublingual) 


b. Long-acting agents
 (1) Isosorbide dinitrate (regular oral, sustained-release

oral, sublingual) (2) Nitroglycerin (transdermal, ointment, sustained-release
 oral)
 (3) Isosorbide dinitrate (regular oral, sustained-release oral) 


2. Mechanism of action

a. Vasorelaxation mechanism

. (1) Release of the nitrite ion 


. (2) Nitrite metabolized to nitric oxide (NO) 


. (3) NO activates guanylyl cyclase 
 • Increases cyclic guanosine

monophosphate (cGMP) levels 


. (4) cGMP relaxes vascular smooth muscle 


b. Nitrates do not increase total coronary blood flow in patients with ischemia
 (1)
But, they redistribute blood to ischemic areas by dilating large supply
epicardial 
 arteries
 (2) Thus, correcting the myocardial oxygen
imbalance (see Fig. 14-1). 


c. Effects of nitrate-induced vasodilation

. (1) Increases venous capacitance (reducing preload) 


. (2) Decreases arteriole resistance (decreases afterload) 


. (3) Preload is affected more greatly (decreased return of blood to right

heart) than 
 afterload. 


. (4) Reduction of preload and afterload lowers oxygen demand. 


Objective of antianginal therapy: to balance O2 demand with O2 supply in myocardial tissue.

Ischemic heart preferentially uses fatty acid oxidation rather than glucose oxidation to generate ATP.

Both sodium nitroprusside and organic nitrates increase cGMP levels via a nitric oxide- dependent mechanism.

Nitrate-induced vasodilation results in

Nitrates redistribute blood to ischemic areas but do not increase overall coronary blood flow.

Nitrates reduce preload more than afterload because they dilate large veins.

113

OXYGEN SUPPLY

Regional flow distribution

Flow to ischemic subendocardial tissue improved by nitrates, CCBs, and -blockers

OXYGEN DEMAND

Heart Cardiac

Coronary blood flow

Increased by nitrates and CCBs

Oxygen extraction

rate

contractility

Myocardial wall tension

Decreased by -blockers and some CCBs

14-1: Effects of nitrates, calcium channel blockers (CCBs), and beta blockers on myocardial oxygen supply
and demand.

Preload decreased by nitrates

Afterload decreased by CCBs

BOX 14-1 ANTIANGINAL DRUGS

Nitrites and Nitrates

Amyl nitrite
 Isosorbide dinitrate Isosorbide mononitrate Nitroglycerin

b-Adrenergic Receptor Antagonists Atenolol
 Metoprolol
 Propranolol

Calcium Channel Blockers

Amlodipine Diltiazem Nifedipine Verapamil

Metabolic Modulators

Ranolazine

ED drugs inhibit phosphodiesterase; hence increasing cGMP.

Don’t use sildenafil type ED drugs with organic nitrates.

“Monday disease”: Industrial workers had severe headaches on Monday from organic nitrates in the
workplace; each day the headache was less due to tolerance. The tolerance was reversed over the weekend and
the cycle started again on Monday.

3.

4.

5.

d. Drugs used to treat erectile dysfunction (ED)

. (1) Discussed with the nitrates because: 
 (a) Nitrates increase the formation of
cGMP
 (b) ED drugs, selectively inhibit the breakdown of cGMP 
 Inhibit
phosphodiesterase type 5 (PDE-5) in the corpus cavernosum 


. (2) Drugs include: 
 (a) Sildenafil; duration 2 to 4 hours (b) Tadalafil; duration up to
36 hours (c) Vardenafil; duration 2 to 6 hours 


. (3) Should not be given concomitantly with other vasodilators, including nitrates 


. (4) Should stop taking these drugs with either vision or hearing loss 


. (5) Sildenafil is also used to treat pulmonary arterial hypertension 


Uses of nitrates
 a. Treatment of acute angina pectoris

b. Prophylaxis of angina attacks
 c. Treatment of heart failure (with hydralazine)

d. Treatment of hypertensive emergencies, control of perioperative hypertension Adverse

effects

a. Headaches (usually transient)

b. Dizziness 


c. Hypotension 


d. Flushing 


e. Reflex tachycardia 


f. Methemoglobinemia (nitrites)
 (1) Methemoglobin contains oxidized iron (ferric) (2)

Methemoglobin cannot bind to oxygen 


Tolerance
 a. Develops and disappears rapidly (2–3 days)

• Headaches disappear as tolerance develops
 b. Limits the usefulness of nitrates in

continuous prophylaxis

• To counter tolerance, patches are usually removed between 10 PM and 6 AM.