Cardiovascular

Agents
The cardiovascular system includes the heart, blood
vessels (arteries and veins), and blood flow. Blood
that is abundant in oxygen (O2), nutrients, and
hormones moves through vessels called arteries,
which narrow to arterioles and then capillaries.
Capillaries transport nourished blood to body cells
and absorb waste products, such as carbon dioxide
(CO2), urea, creatinine, and ammonia. The
deoxygenated blood returns to the circulation by
small venules and larger veins to be eliminated by the
lungs and kidneys with other waste products
 HEART

The heart is composed of four chambers including

the right and left atria and the right and left
ventricles . The right atrium receives
deoxygenated blood from the circulation, and the
right ventricle pumps blood through the pulmonary
artery to the lungs for gas exchange (carbon
dioxide for oxygen). The left atrium receives
oxygenated blood, and the left ventricle pumps the
blood into the aorta for systemic circulation.
 CONDUCTION OF ELECTRICAL
IMPULSES
The myocardium is capable of generating and
conducting its own electrical impulses. The cardiac
impulse normally originates in the sinoatrial (SA) node
located in the posterior wall of the right atrium. The
SA node is frequently called the pacemaker, because
it regulates the heartbeat (firing of cardiac impulses),
which is approximately 60 to 80 beats/min in the
normal adult.
The AV node is called the pacemaker, having an adult
rate of 40 to 60 beats/min. If the SA node fails, the AV
node takes over, thus causing a slower heart rate.
 CIRCULATION

◈There are two types of circulation—pulmonary and

systemic. With pulmonary circulation, the heart pumps
deoxygenated blood from the right ventricle through the
pulmonary artery to the lungs. The pulmonary artery carries
blood that has a high concentration of carbon dioxide.
Oxygenated blood returns to the left atrium by the
pulmonary vein. With systemic circulation, also called
peripheral circulation, the heart pumps blood from the left
ventricle to the aorta and into the general circulation.
Arteries and arterioles carry the blood to capillary beds.
Nutrients in the capillary blood are transferred to cells in
exchange for waste products. Blood returns to the heart
through venules and veins.
 BLOOD

Blood is composed of plasma, red blood cells (erythrocytes),

white blood cells (leukocytes), and platelets. Plasma, made up of 90%
water and 10% solutes, constitutes 55% of the total blood volume. The
solutes in plasma include glucose, protein, lipids, amino acids,
electrolytes, minerals, lactic and pyruvic acids, hormones, enzymes,
oxygen, and carbon dioxide.

The major function of blood is to provide nutrients, including

oxygen, to body cells. Most of the oxygen is carried on the hemoglobin
of red blood cells (RBCs). White blood cells (WBCs) are the major
defense mechanism of the body and act by engulfing microorganisms.
They also produce antibodies. The platelets are large cells that cause
blood to coagulate. RBCs have a life span of approximately 120 days,
whereas the life span of a WBC is only 2 to 24 hours.
 Cardiac Glycosides

Also called digitalis glycosides, this group of drugs inhibits the sodium-
potassium pump, resulting in an increase in intracellular sodium. This
increase leads to an influx of calcium, causing the cardiac muscle fibers
to contract more efficiently. Digitalis preparations have three effects on
heart muscle: (1) positive inotropic action (increases myocardial
contraction stroke volume), (2) negative chronotropic action (decreases
heart rate), and (3) negative dromotropic action (decreases conduction
of heart cells). The increase in myocardial contractility strengthens
cardiac, peripheral, and kidney function by enhancing cardiac output,
decreasing preload, improving blood flow to the periphery and kidneys,
decreasing edema, and promoting fluid excretion. As a result, fluid
retention in the lung and extremities is decreased. Digoxin does not
prolong life. It acts by increasing the force and velocity of myocardial
systolic contraction.

.
Digoxin is a secondary drug for HF. First-line drugs used to treat acute HF
include intravenous inotropic agents (dopamine and dobutamine) and
phosphodiesterase inhibitors, such as milrinone
 DIGOXIN

Pharmacokinetics :The absorption rate of digoxin in oral tablet form is 70%. The
rate is 90% in liquid and capsule form. The proteinbinding power for digoxin is
30%. The half-life is 30 to 40 hours. Because of its long half-life, drug
accumulation can occur. Side effects should be closely monitored to detect
digitalis toxicity

Pharmacodynamics: In patients with a failing heart, cardiac glycosides increase

myocardial contraction, which increases cardiac output and improves circulation
and tissue perfusion. Because these drugs decrease conduction through the AV
node, the heart rate decreases. The onset and peak actions of oral and
intravenous (IV) digoxin vary.
 Antianginal drugs

Are used to treat angina pectoris. This is a condition of acute cardiac pain
caused by inadequate blood flow to the myocardium due to either plaque
occlusions within or spasms of the coronary arteries. With decreased blood flow,
there is a decrease in oxygen to the myocardium, which results in pain. Anginal
pain is frequently described by the patient as tightness, pressure in the center of
the chest, and pain radiating down the left arm. Referred pain felt in the neck
and left arm commonly occurs with severe angina pectoris. Anginal attacks may
lead to MI (heart attack). Anginal pain usually lasts for only a few minutes.
Stress tests, echocardiogram, cardiac profile laboratory tests, and cardiac
catheterization may be needed to determine the degree of blockage in the
coronary arteries and then also to treat the condition.
 ANTIDYSRHYTHMIC DRUGS

◈A cardiac dysrhythmia (arrhythmia) is defined as any deviation from the normal

rate or pattern of the heartbeat. This includes heart rates that are too slow
(bradycardia), too fast (tachycardia), or irregular. The terms dysrhythmia
(disturbed heart rhythm) and arrhythmia (absence of heart rhythm) are used
interchangeably, despite the slight difference in meaning.
Diuretics
 Diuretics

◈Diuretics are used for two main purposes: to decrease hypertension (lower
blood pressure) and to decrease edema (peripheral and pulmonary) in heart
failure (HF) and renal or liver disorders. Hypertension is an elevated blood
pressure. Diuretics discussed in this chapter are used either alone or in
combination to decrease blood pressure and edema.
 THIAZIDES AND THIAZIDE-LIKE DIURETICS

◈Thiazide diuretics are used primarily for patients with normal renal function. If
the patient has a renal disorder and creatinine clearance is less than 30
mL/min, the effectiveness of the thiazide diuretic is greatly decreased.
Thiazides cause a loss of sodium, potassium, and magnesium, but they
promote calcium reabsorption. Hypercalcemia (calcium excess) may result, and
the condition can be hazardous to the patient who is digitalized or has cancer
that causes hypercalcemia. Thiazides affect glucose tolerance, so
hyperglycemia can also occur.Thiazidesshould be used cautiously in patients
with diabetes mellitus. Laboratory test results (e.g., electrolytes, glucose) need
to be monitored.
 THIAZIDES AND THIAZIDE-LIKE DIURETICS

◈Pharmacokinetics Thiazides are well absorbed from the gastrointestinal (GI)

tract. Hydrochlorothiazide has moderate protein-binding power. The half-life of
the thiazide drugs is longer than that of the loop diuretics. For this reason,
thiazides should be administered in the morning to avoid nocturia (nighttime
urination) and sleep interruption.
◈Pharmacodynamics Thiazides act directly on arterioles to cause vasodilation,
which can lower blood pressure. Other action includes the promotion of sodium
chloride and water excretion, resulting in a decrease in vascular fluid volume and
a concomitant decrease in cardiac output and blood pressure. The onset of
action of hydrochlorothiazide occurs within 2 hours. Peak concentration times
are long (3 to 6 hours). Thiazides are divided into three groups, according to their
duration of action: short-acting (duration less than 12 hours), intermediate-acting
(duration 12 to 24 hours), and long-acting (duration more than 24 hours).
 Side Effects and Adverse Reactions.

◈Side effects and adverse reactions of thiazides include electrolyte imbalances

(hypokalemia, hypercalcemia, hypomagnesemia, and bicarbonate loss),
hyperglycemia (elevated blood sugar), hyperuricemia (elevated serum uric acid
level), and hyperlipidemia (elevated blood lipid level).
 Contraindications.

◈Thiazides are contraindicated for use in renal failure. Symptoms of severe

kidney impairment or shutdown include oliguria (marked decrease in urine
output), elevated blood urea nitrogen (BUN), and elevated serum creatinine.
◈Drug Interactions. Of the numerous thiazide drug interactions, the most serious
occurs with digoxin. Thiazides can cause hypokalemia, which enhances the
action of digoxin, and digitalis toxicity can occur. Potassium supplements are
frequently prescribed, and serum potassium levels are monitored. Thiazides also
induce hypercalcemia, which enhances the action of digoxin, resulting in
possible digitalis toxicity.
 LOOP (HIGH CEILING) DIURETICS

◈The loop, or high-ceiling, diuretics act on the thick ascending loop of Henle to
inhibit chloride transport of sodium into the circulation (inhibit passive
reabsorption of sodium). Sodium and water are lost, together with potassium,
calcium, and magnesium. Loop diuretics can affect blood sugar and increase uric
acid levels. Drugs in this group are extremely potent and cause marked depletion
of water and electrolytes.
 LOOP (HIGH CEILING) DIURETICS

◈Pharmacokinetics Loop diuretics are rapidly absorbed by the GI tract. These

drugs are highly protein bound with half-lives that vary from 30 minutes to 1.5
hours. Loop diuretics compete for proteinbinding sites with other highly protein-
bound drugs.
◈Pharmacodynamics Loop diuretics have a great saluretic (sodiumchloride–
losing) or natriuretic (sodium-losing) effect and can cause rapid diuresis,
decreasing vascular fluid volume and causing a decrease in cardiac output and
blood pressure. Because furosemide is a more potent diuretic than thiazide
diuretics, it causes a vasodilatory effect; thus renal blood flow increases before
diuresis. Furosemide is used when other conservative measures, such as
sodium restriction and use of less potent diuretics, fail. The oral dose of
furosemide is usually twice that of an intravenous (IV) dose. The onset of action
of loop diuretics occurs within 30 to 60 minutes. The onset of action for IV
furosemide is 5 minutes. Duration of action is shorter than that of the thiazides.
 Side Effects and Adverse Reactions.

◈The most common side effects of loop diuretics are fluid and electrolyte
imbalances such as hypokalemia, hyponatremia, hypocalcemia,
hypomagnesemia, and hypochloremia. Hypochloremic metabolic alkalosis may
result, which can worsen hypokalemia. Orthostatic hypotension can occur.
Thrombocytopenia, skin disturbances, and transient deafness are rarely seen.
Table 43-3 lists the physiologic and laboratory changes associated with loop
diuretics.
 Drug Interactions.

◈The major drug interaction is with digitalis preparations. If the patient takes
digoxin with a loop diuretic, digitalis toxicity can result. Hypokalemia enhances
the action of digoxin and increases the risk for digitalis toxicity. The patient
needs potassium replacement with food or supplements. Serum potassium
levels should be closely monitored, especially when the patient is taking high
dosages of loop diuretics. Table 43-4 lists the data for the four loop diuretics.
ANTIHYPERTENSIVE
DRUG
 Hypertension

◈Hypertension is an increase in blood pressure such that the systolic pressure is

greater than 140 mm Hg and the diastolic pressure is greater than 90 mm Hg.
Essential hypertension is the most common type, affecting 90% of persons with
high blood pressure.
 Sympatholytics (Sympathetic Depressants)

◈The sympatholytics comprise five groups of drugs: (1) betaadrenergic blockers,

(2) centrally acting alpha2 agonists, (3) alpha-adrenergic blockers, (4)
adrenergic neuron blockers (peripherally acting sympatholytics), and (5) alpha1-
and beta1-adrenergic blockers. Beta-adrenergic blockers block the beta
receptors, and alpha-adrenergic blockers block the alpha receptors.
 Beta-Adrenergic Blockers

◈Beta-adrenergic blockers, frequently called beta blockers, are used as

antihypertensive drugs or in combination with a diuretic. Beta blockers are also
used as antianginals and antidysrhythmics

◈Beta (β+ and β−)-adrenergic blockers reduce cardiac output by diminishing the
sympathetic nervous system response to decrease basal sympathetic tone. With
continued use of beta blockers, vascular resistance is diminished, and blood
pressure is lowered. Beta blockers reduce heart rate, contractility, and renin
release. There is a greater hypotensive response in patients with higher renin
levels.
 Beta-Adrenergic Blockers

◈Pharmacokinetics Metoprolol is well absorbed from the gastrointestinal tract. Its

half-life is short and its protein-binding power is low.

◈Pharmacodynamics Cardioselective beta-adrenergic blockers block beta1

receptors, thereby decreasing heart rate and blood pressure. The nonselective
beta blockers block beta1 and beta2 receptors, which can result in bronchial
constriction. Beta blockers cross the placental barrier and are excreted in breast
milk. The onset of action of oral beta blockers is usually 30 minutes or less, and
the duration of action is 6 to 12 hours. When beta blockers are administered
intravenously, the onset of action is immediate, peak time is 20 minutes
(compared with 1.5 hours orally), and duration of action is 4 to 10 hours
 Side Effects and Adverse Reactions.

◈Side effects and adverse reactions include decreased pulse rate, markedly
decreased blood pressure, and (with noncardioselective beta1 and beta2
blockers) bronchospasm. Beta blockers should not be abruptly discontinued,
because rebound hypertension, angina, dysrhythmias, and myocardial infarction
can result. Beta blockers can cause dizziness, insomnia, depression, fatigue,
nightmares, and sexual dysfunction.
 Centrally Acting Alpha2 Agonists

◈Centrally acting alpha2 agonists decrease the sympathetic response from the
brainstem to the peripheral vessels. They stimulate the alpha2 receptors, which
in turn decreases sympathetic activity; increases vagus activity; decreases
cardiac output; and decreases serum epinephrine, norepinephrine, and renin
release. All of these actions result in reduced peripheral vascular resistance and
increased vasodilation.
 Side Effects and Adverse Reactions.

◈Side effects and adverse reactions of alpha2 agonists include drowsiness, dry
mouth, dizziness, and slow heart rate (bradycardia)
◈Alpha-Adrenergic Blockers This group of drugs blocks the alpha-adrenergic
receptors (alpha blockers), resulting in vasodilation and decreased blood
pressure. They help maintain the renal blood flow rate. Alpha blockers are
useful in treating hypertension in patients with lipid abnormalities. They
decrease the very-low-density lipoproteins (VLDL) and the low-density
lipoproteins (LDL) that are responsible for the buildup of fatty plaques in the
arteries (atherosclerosis). In addition, they increase highdensity lipoprotein
(HDL) levels. Alpha blockers are safe for patients with diabetes, because they
do not affect glucose metabolism. They also do not affect respiratory function
◈Pharmacokinetics Prazosin is absorbed through the GI tract, but a large
portion of prazosin is lost during hepatic first-pass metabolism. The half-life is
short, so the drug should be administered twice a day. Prazosin is highly
protein-bound, and when it is given with other highly protein-bound drugs, the
patient should be assessed for adverse reactions. Pharmacodynamics
Selective alpha-adrenergic blockers dilate the arterioles and venules,
decreasing peripheral resistance and lowering blood pressure. With prazosin,
the heart rate is only slightly increased, whereas with nonselective alpha
blockers such as phentolamine, the blood pressure is greatly reduced, and
reflex tachycardia can occur. Nonselective alpha blockers are more effective for
acute hypertension; selective alpha blockers are more useful for long-term
essential hypertension. The onset of action of prazosin occurs between 30
minutes and 2 hours. The duration of action of prazosin is 10 hours
◈Side Effects and Adverse Reactions. Side effects of prazosin, doxazosin, and
terazosin include orthostatic hypotension (dizziness, faintness,
lightheadedness, and increased heart rate, which may occur with first dose),
nausea, headache, drowsiness, nasal congestion caused by vasodilation,
edema, and weight gain. Side effects of phentolamine include hypotension,
reflex tachycardia caused by the severe decrease in blood pressure, nasal
congestion caused by vasodilation, and GI disturbances.
◈Drug Interactions. Drug interactions occur when alphaadrenergic blockers
are taken with antiinflammatory drugs and nitrates (e.g., nitroglycerin for
angina). Peripheral edema is intensified when prazosin and an
antiinflammatory drug are taken daily. Nitroglycerin taken for angina lowers
blood pressure. If prazosin is taken with nitroglycerin, syncope (faintness)
caused by a decrease in blood pressure can occur.
◈Adrenergic Neuron Blockers (Peripherally Acting Sympatholytics) Adrenergic
neuron blockers are potent antihypertensive drugs that block norepinephrine
release from the sympathetic nerve endings, causing a decrease in
norepinephrine release that results in a lowering of blood pressure. There is a
decrease in both cardiac output and peripheral vascular resistance.Reserpine
(the most potent drug)is used to control severe hypertension. Orthostatic
hypotension is a common side effect,so the patient should be advised to rise
slowly from a reclining or sitting position. The adrenergic neuron blockers are
considered the last choices for treatment of chronic hypertension, because
these drugs can cause orthostatic hypotension. Use of reserpine may cause
vivid dreams, nightmares, and suicidal ideation. The drugs in this group can
cause sodium and water retention. These drugs can be taken alone or with a
diuretic to decrease peripheral edema.
◈Alpha1- and Beta1-Adrenergic Blockers

◈This group of drugs blocks both the alpha1 and beta1 receptors.
Labetalol (Normodyne) is an example of an alpha/beta blocker.
Blocking the alpha1 receptor causes vasodilation, decreasing
resistance to blood flow. The effect on the alpha receptor is stronger
than the effect on the beta receptor; therefore blood pressure is
lowered and pulse rate is moderately decreased. By blocking the
cardiac beta1 receptor, both heart rate and atrioventricular (AV)
contractility are decreased. Large doses of alpha/beta blockers could
block beta2-adrenergic receptors, thus increasing airway resistance.
Patients who have severe asthma should not take large doses of
labetalol.
◈Losartan (Cozaar), valsartan (Diovan), irbesartan
(Avapro), candesartan cilexetil (Atacand),
eprosartan (Teveten), olmesartan medoxomil
(Benicar), and telmisartan (Micardis) are examples
of ARBs. These agents block the vasoconstrictor
effects of angiotensin II at the receptor site. The
combination of losartan potassium and
hydrochlorothiazide tablets and valsartan and
hydrochlorothiazide tablets and others should not
cause serum potassium excess or loss. ARBs may
be used as a first-line treatment for hypertension.
Anticoagulants,
Antiplatelets, and
Thrombolytics
 PATHOPHYSIOLOGY: THROMBUS FORMATION

◈Thrombosis is the formation of a clot in an arterial or venous vessel. The

formation of an arterial thrombus could be caused by blood stasis (decreased
circulation), platelet aggregation on the blood vessel wall, or blood coagulation
 ANTICOAGULANTS

◈Anticoagulants are used to inhibit clot formation. Unlike

thrombolytics, they do not dissolve clots that have already
formed, but rather act prophylactically to prevent new clots
from forming. Anticoagulants are used in patients with
venous and arterial disorders that put them at high risk for
clot formation.Venous problems include deep vein
thrombosis (DVT) and pulmonary embolism, and arterial
problems include coronary thrombosis, or myocardial
infarction; presence of artificial heart valves; and
cerebrovascular accidents (CVAs, or stroke).
 Heparin

◈Anticoagulants are administered orally or parenterally

(subcutaneously [subQ] and intravenously [IV]). Heparin,
introduced in 1938, is a natural substance in the liver that
prevents clot formation. It was first used in blood
transfusions to prevent clotting
◈Heparin combines with antithrombin III, which accelerates
the anticoagulant cascade of reactions that prevents
thrombosis formation
◈Heparin is poorly absorbed through the gastrointestinal (GI)
mucosa, and much is destroyed by heparinase, a liver
enzyme. Because heparin is poorly absorbed orally, it is
given subQ for prophylaxis or IV to treat acute thrombosis. It
can be administered as an IV bolus or in IV fluid for
continuous infusion. Heparin prolongs clotting time
 Oral Anticoagulants

◈Warfarin (Coumadin) is an oral

anticoagulant from the coumarin drug family.
Dicumarol, a coumarin drug, and anisindione
from the indanedione group, have been
discontinued because of their many side
effects. Warfarin is synthesized from
dicumarol. Before warfarin was available for
human use, it was used in rodenticides to kill
rats by causing hemorrhage.
 ANTIPLATELET DRUGS

◈Antiplatelets are used to prevent thrombosis in

the arteries by suppressing platelet aggregation.
Heparin and warfarin prevent thrombosis in the
veins.
◈Long-term, low-dose aspirin therapy has been
found to be both an effective and inexpensive
treatment for suppressing platelet aggregation.
Aspirin inhibits cyclooxygenase, an enzyme
needed by platelets to synthesize thromboxane A2
(TxA2)
 THROMBOLYTICS

◈Thromboembolism (occlusion of an artery or vein

caused by a thrombus or embolus) results in
ischemia (deficient blood flow) that causes necrosis
(death) of the tissue distal to the obstructed area. It
takes approximately 1 to 2 weeks for the blood clot
to disintegrate by natural fibrinolytic mechanisms. If
a new thrombus or embolus can be dissolved more
quickly, tissue necrosis is minimized, and blood
flow to the area is reestablished faster. This is the
basis for thrombolytic therapy
Antihyperlipidemics and
Peripheral Vasodilators
 LIPOPROTEINS

◈Lipids (cholesterol, triglycerides, and

phospholipids) are bound in the inner shell of
protein, which is a carrier that transports lipids in
the bloodstream. When there is an excess of one
or more lipids in the blood, the condition is known
as hyperlipidemia or hyperlipoproteinemia
 APOLIPOPROTEINS

◈Apolipoproteins are within the lipoprotein shell

and contain apolipoprotein (apo) A-1, apoB, and
apoE. The major component of apoA1 is HDL. The
major component of apoB is LDL, which exists in
two forms, apoB-100 and apoB-48. ApoB-100 has
VLDL as well as LDL and is a better indicator of
risk for coronary artery disease (CAD) than LDL
alone.
 ANTIHYPERLIPIDEMI

◈CS Drugs that lower lipid levels include bile-acid

sequestrants, fibrates (fibric acid), nicotinic acid,
cholesterol absorption inhibitor, and hepatic 3-
hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA)
reductase inhibitors (statins). The statins have
fewer adverse effects and are well tolerated.
 Statins

◈The statin drugs inhibit the enzyme HMG CoA reductase

in cholesterol biosynthesis; thus the statins are called HMG
CoA reductase inhibitors. By inhibiting cholesterol
synthesis in the liver, this group of antihyperlipidemics
decreases the concentration of cholesterol, decreases LDL,
and slightly increases HDL cholesterol. Reduction of LDL
cholesterol may be seen as early as 2 weeks after initiating
therapy. The statin group has been useful in decreasing
CAD and reducing mortality rates.
 PERIPHERAL VASODILATORS

◈A common problem in older adults is peripheral arterial

(vascular) disease (PAD, PVD). It is characterized by
numbness and coolness of the extremities, intermittent
claudication (pain and weakness of limb when walking but
no symptoms at rest), and possible leg ulcers. The primary
cause is arteriosclerosis and hyperlipidemia, resulting in
atherosclerosis. The arteries become occluded.
 Pentoxifylline

◈Pentoxifylline (Trental), classified as a

hemorrheologic agent, improves microcirculation
and tissue perfusion by decreasing blood viscosity
and improving the flexibility of erythrocytes, thus
increasing tissue oxygenation.