Other Cardiovascular Drugs

Chapter 14 Other Cardiovascular Drugs



I. General Considerations

A. Goal of antianginal therapy

• Decrease oxygen demand of myocardial tissue or increase oxygen supply (Fig. 14-1).

image

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



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


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.


BOX 14-1 Antianginal Drugs



Nitrites and Nitrates


Amyl nitrite


Isosorbide dinitrate


Isosorbide mononitrate


Nitroglycerin



β-Adrenergic Receptor Antagonists


Atenolol


Metoprolol


Propranolol



Calcium Channel Blockers


Amlodipine


Diltiazem


Nifedipine


Verapamil



Metabolic Modulators


Ranolazine



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


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


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


(4) cGMP relaxes vascular smooth muscle


Nitrate-induced vasodilation results in lower cardiac oxygen demand.


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).


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


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.


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


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


ED drugs inhibit phosphodiesterase; hence increasing cGMP.


(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


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


3. 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

4. Adverse effects


a. Headaches (usually transient)

b. Dizziness

c. Hypotension

d. Flushing


“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.


e. Reflex tachycardia

f. Methemoglobinemia (nitrites)


(1) Methemoglobin contains oxidized iron (ferric)

(2) Methemoglobin cannot bind to oxygen

5. 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.

B. β-Adrenergic receptor antagonists (see Chapter 5)

1. Mechanism of action


a. β-Adrenergic receptor antagonists inhibit the reflex tachycardia produced by nitrates.

b. Myocardial oxygen requirements are reduced due to decreases in:


(1) Heart rate

(2) Myocardial contractility

(3) Blood pressure


Beta blockers reduce heart rate and blood pressure, leading to relief of angina and improved exercise tolerance in patients with severe angina.


2. Uses


a. Angina (in combination with other drugs, such as nitrates)


Beta blockers are not effective in treating Prinzmetal’s angina.


b. Other uses described in Chapter 5

C. Calcium channel blockers (see Chapter 12)

1. Mechanism of action


a. Block calcium movement into cells, inhibiting excitation-contraction coupling in myocardial and smooth muscle cells

b. Reduced:


(1) Heart rate

(2) Blood pressure

(3) Contractility

2. Uses


a. Ischemic coronary artery disease

b. Prinzmetal’s or variant angina


Calcium channel blockers are effective in the treatment of Prinzmetal’s angina.


c. Also, used to treat hypertension and arrhythmias

3. Adverse effects


a. Flushing

b. Edema

c. Dizziness

d. Constipation

D. Metabolic Modulator

• Ranolazine

1. Mechanism of action


a. Ranolazine was first reported as a pFOX inhibitor

b. Inhibits fatty acid oxidation shifting myocardial metabolism to glucose

c. Leads to more efficient production of ATP in ischemic tissue


pFOX inhibitor: inhibits fatty acid oxidation; shifts metabolism to glucose for energy.


d. Now believed to inhibit the late phase of the inward sodium channel (late INa) in ischemic cells during cardiac repolarization reducing intracellular sodium concentrations; this leads to:


(1) Reduced calcium influx via Na+/Ca2+ exchange

(2) Decreased intracellular calcium

(3) Reduced ventricular tension and myocardial oxygen consumption

2. Use

• Treatment of refractory chronic angina in combination with amlodipine, beta blockers, or nitrates

E. Therapeutic summary of selected drugs used to treat angina: (Table 14-1)

III. Drugs That Affect Cholesterol and Lipid Metabolism

A. General considerations

1. Hyperlipidemia is defined as high levels of serum lipids.


a. Primary hyperlipidemia is caused by genetic predisposition.

b. Secondary hyperlipidemia arises as a complication of disease states, such as:


(1) Diabetes

(2) Hypothyroidism

(3) Cushing’s disease

(4) Acromegaly

2. Atherosclerosis may result from the following contributing factors:


a. High levels of plasma lipids (particularly low density lipoprotein)

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Apr 8, 2017 | Posted by in PHARMACY | Comments Off on Other Cardiovascular Drugs

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