Chapter 17 Cardiovascular Drugs

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Cardiology: An Integrated Approach >
Chapter 17: Cardiovascular Drugs

Maha M. Saber-Ayad
Learning Objectives
Learning Objectives
By the end of this chapter the student will be able to:
Recognize the main practical points regarding the pharmacokinetics, pharmacodynamics, mechanisms of action, clinical use, and adverse
e ects of the following drug groups:
Vasodilators
Antiadrenergic drugs
Inotropes and vasopressors
Antiarrhythmic drugs
Diuretics
Antithrombotic drugs
Antidyslipidemic drugs
Introduction
This chapter reviews the basic and clinical pharmacology of cardiovascular drugs; focusing on practical, relevant points related to their
pharmacokinetics, mechanisms of action, clinical use, and adverse e ects. Despite the large number of available drugs used in the treatment of
cardiovascular diseases, the most commonly used drugs are classified under a few categories of agents. The classification used in this chapter is
based on the main mechanism of action of the drug. It should be noted that a single class of drugs can be used in treating more than one
disease. As clarified in previous chapters, for managing a particular disease, there may be a number of drugs from di erent classes that can be
used either alternatively, in combination, or during a particular stage of a disease.
Vasodilators
Vasodilators are useful agents in the treatment of heart failure and hypertension. Several groups of drugs can lead to vasodilatation; including
those inhibiting the renin-angiotensin-aldosterone system (RAAS), direct-acting vasodilators, calcium channel blockers, organic nitrates, and α-
adrenergic blockers (discussed under “antiadrenergic agents” in this chapter).
Inhibitors of the Renin-Angiotensin-Aldosterone System
Angiotensin II is one of the most potent vasoconstrictor peptides in the body. Therefore, inhibitors of the renin-angiotensin-aldosterone system
(RAAS) are frequently used in the treatment of hypertension and heart failure. It plays an important role in preventing the remodeling of the le
ventricle following myocardial infarction. Figure 17.1 summarizes some actions of angiotensin II. Angiotensin-converting enzyme (ACE)
inhibitors suppress angiotensin II formation (Fig. 17.2), whereas angiotensin receptor antagonists directly block the receptors of angiotensin II
and minimize its e ect.
Figure 17.1
Angiotensin II receptor-mediated e ects that increase blood pressure.
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Figure 17.2
Formation of angiotensin II and e ects of angiotensin-converting enzyme inhibitors.
Angiotensin-Converting Enzyme Inhibitors
Captopril is the short-acting active prototype of this group. Enalapril is an oral prodrug that is converted by hydrolysis to an active compound,
enalaprilat, with e ects similar to those of captopril. Enalaprilat itself is available only for intravenous use, primarily for hypertensive
emergencies. Lisinopril is a lysine derivative of enalaprilat. Benazepril, fosinopril, moexipril, perindopril, quinapril, ramipril, and trandolapril are
other long-acting members of this class. All are prodrugs, like enalapril, and are converted to active agents by hydrolysis, primarily in the liver.
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CLINICAL CORRELATION 17.1
Afro-Caribbean patients respond less favorably than Caucasians to ACE inhibitors as anti hypertensive agents.
By blocking the synthesis of angiotensin II, ACE inhibitors decrease the systemic arterial pressure, facilitate natriuresis (by decreasing
aldosterone production and reducing Na+ reabsorption from the distal nephron), and reduce adverse ventricular remodeling. In addition, ACE
inhibitors decrease the degradation of the natural vasodilator bradykinin, which accumulates and contributes to the antihypertensive e ect,
most likely by stimulating the endothelial release of nitric oxide and the synthesis of vasodilating prostaglandins (eg, prostacyclin).
Main indications of ACE inhibitors
Hypertension: ACE inhibitors are e ective in the treatment of most hypertensive patients. Afro-Caribbean patients respond less favorably than
Caucasians. Renin-angiotensin activity has been demonstrated in the tissue outside the circulation, including the vessel walls, where ACE
inhibitors may exert a vasodilator e ect independent of the circulating renin levels.
Diabetic nephropathy: ACE inhibitors increase renal blood flow, without altering the glomerular filtration rate, because of the dilatation of both
the a erent and e erent glomerular arterioles. Used alone, ACE inhibitors show a similar antihypertensive e icacy as diuretics and β-blockers.
Diabetic nephropathy is a syndrome of progressive deterioration of renal function, proteinuria, and hypertension. ACE inhibitors are beneficial in
delaying the progress of diabetic nephropathy through favorable e ects on the intraglomerular pressure.
Heart failure: ACE inhibitors decrease the peripheral vascular resistance (decreased a erload), decrease cardiac filling pressures (decrease
preload), and increase cardiac output.
Main adverse e ects of ACE inhibitors
Hypotension: It is more likely to occur in heart failure patients, in whom intravascular volume depletion is the result of vigorous diuretic use. This
side e ect can be avoided by reducing the diuretics and starting ACE inhibitors at a low dose, to be gradually increased.
Hyperkalemia: Conditions that may result in significant hyperkalemia with concomitant use of ACE inhibitors include (1) renal impairment; (2)
diabetic nephropathy (due to hyporeninemic hypoaldosteronism, a common condition in elderly diabetics); and (3) potassium-sparing diuretics.
Renal impairment: Patients with intravascular volume depletion and who are receiving ACE inhibitors are likely to develop hypotension,
decreased renal perfusion, and azotemia. ACE inhibitor therapy is contraindicated in patients with bilateral renal artery stenosis because these
patients rely on high-e erent arteriolar pressure (which is greatly a ected by the level of angiotensin II) to maintain the glomerular filtration rate
(GFR). ACE inhibitor therapy will suddenly decrease e erent arteriolar tone and glomerular hydrostatic pressure with an abrupt decrease in GFR.
Cough: Approximately 20% of patients receiving ACE inhibitors su er from irritation of the upper airways, which results in a dry cough. Its
mechanism may be related to an increase in bradykinin concentration. This side e ect can last for weeks a er the drug is discontinued. The use
of nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce this adverse e ect.
Other adverse e ects: Very rare reactions to ACE inhibitors include angioedema and agranulocytosis. ACE inhibitors are contraindicated in
pregnancy due to their teratogenic e ects (renal agenesis).
ACE inhibitors are beneficial in delaying the progress of diabetic nephropathy by increasing the renal blood flow.
Cough and angioedema rarely occur with ARBs, much less frequently than with ACE inhibitors.
Angiotensin Receptor Blocking Agents
Losartan and valsartan were the first marketed blockers of the angiotensin II type 1 (AT1) receptors (ARBs). Other drugs in this class include
candesartan, eprosartan, irbesartan, telmisartan, and olmesartan. These are more selective blockers for angiotensin e ects than ACE inhibitors
that do not a ect the bradykinin metabolism. ARBs have the potential for more complete inhibition of angiotensin action compared with ACE
inhibitors (there are enzymes other than ACE inhibitors that are capable of generating angiotensin II, thus the action of ACE inhibitors do not
completely inhibit angiotensin II synthesis). Angiotensin receptor blockers provide benefits similar to those of ACE inhibitors in patients with
heart failure and chronic kidney disease. Adverse e ects are similar to those described for ACE inhibitors, including the hazard of use during
pregnancy. Cough and angioedema can occur but are much less frequent than with ACE inhibitors. ARBs are most commonly used in patients
who have had adverse reactions to ACE inhibitors.
Other Inhibitors of the Renin-Angiotensin-Aldosterone System
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In addition to ACE inhibitors and ARBs, other RAAS antagonists include aliskiren (a direct renin inhibitor); and spironolactone and eplerenone
(aldosterone receptor antagonists).
Drug-induced lupus is a recognized adverse e ect of hydralazine.
Direct-Acting Vasodilators
Oral vasodilators include hydralazine and minoxidil are used in the long-term treatment of hypertension; the parenteral vasodilators include
nitroprusside, diazoxide, and fenoldopam, which are used to treat hypertensive emergencies. Other vasodilators include the calcium channel
blockers, which are used in both circumstances; and the nitrates, which are used mainly in angina. All of the vasodilators that are e ective in the
treatment of hypertension also relax the smooth muscles of the arterioles. Sodium nitroprusside and the nitrates can also relax the veins.
Hydralazine
Hydralazine has low bioavailability due to its extensive first-pass metabolism. The rate depends on whether the patient displays fast or slow
hepatic acetylation of the drug. Slow acetylators show less hepatic degradation, higher bioavailability, and greater antihypertensive e ects than
fast acetylators. Hydralazine has a short plasma half-life (2-4 hours), but its e ect covers 12 hours because the drug has a high-binding capacity
to the vascular tissues.
Use of direct vasodilators is associated with salt and water retention. Diuretics should be added to achieve e ective antihypertensive action.
Hydralazine is a potent and direct arteriolar dilator. The mechanism of its e ect is likely related to the release of nitric oxide from the
endothelium. The fall of blood pressure following the use of hydralazine leads to an increase in the sympathetic outflow and cardiac stimulation
(reflex tachycardia), which is mediated through baroreceptors. β-blockers are usually used in combination with hydralazine to minimize this
e ect.
Adverse e ects of hydralazine include: (1) headache (cerebral vasodilatation); (2) palpitation (reflex tachycardia); (3) flushing (systemic
vasodilatation); and (4) drug-induced lupus, especially in slow acetylators (a syndrome that presents with arthralgia, myalgia, skin rash, and
fever).
Minoxidil
Minoxidil is a potent oral vasodilator. The e ect minoxidil sulfate and active metabolite results in the opening of the potassium channels in the
smooth muscle membranes. Increased potassium permeability causes smooth muscle cell hyperpolarization, which makes contraction less
likely. Like hydralazine, minoxidil dilates the arterioles but not the veins. Because of its greater antihypertensive e ect, minoxidil should replace
hydralazine when the response to the latter is below optimum, or in patients with renal failure and severe hypertension, who sometimes do not
respond well to hydralazine.
Even more than with hydralazine, the use of minoxidil is associated with reflex stimulation of both the sympathetic and renin-angiotensin-
aldosterone systems that results in sodium and water retention. Minoxidil must be used in combination with a β-blocker and a loop diuretic.
Adverse e ects include tachycardia, palpitations, angina, and edema. Headaches, sweating, and hypertrichosis (the latter is particularly
bothersome in women) are relatively common. Minoxidil is an example of how an adverse e ect can become a therapy. Topical minoxidil (such
as Rogaine) is used as a stimulant for hair growth to correct baldness.
Sodium Nitroprusside
Sodium nitroprusside is a potent vasodilator, administered by intravenous infusion. It is used to treat hypertensive emergencies as well as
severe heart failure. The drug is both an arterial and venous dilator that results in both reduced peripheral vascular resistance and venous
return. This action occurs by activating guanylyl cyclase, either via the release of nitric oxide or by direct stimulation of the enzyme and
increased intracellular cyclic guanosine monophosphate (cGMP).
In the absence of heart failure, the blood pressure decreases because of a decrease in vascular resistance, whereas the cardiac output does not
change or may decrease slightly. In patients with heart failure and low cardiac output, the output o en increases as a result of a reduction in the
a erload.
Nitroprusside is a complex of iron, cyanide groups, and a nitroso moiety. It is rapidly metabolized by uptake into the red blood cells with the
release of nitric oxide and cyanide. Cyanide, in turn, is metabolized by the mitochondrial enzyme rhodanese, in the presence of a sulfur donor, to
the less toxic thiocyanate. Thiocyanate is distributed in the extracellular fluid and is slowly eliminated by the kidneys.
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Nitroprusside rapidly lowers blood pressure; its e ects will disappear within 1 to 10 minutes a er discontinuation. The drug is administered by
intravenous infusion. Sodium nitroprusside in an aqueous solution is sensitive to light and must therefore be freshly prepared prior to each
administration and covered with opaque foil. High-infusion rates, if continued for more than an hour, can result in toxicity. The arterial blood
pressure should be continuously monitored during sodium nitroprusside therapy.
Adverse e ects of sodium nitroprusside include the following:
1. Toxicity, related to the accumulation of cyanide—metabolic acidosis, arrhythmias, excessive hypotension, and death. The administration of
sodium thiosulfate (a sulfur donor) facilitates the metabolism of cyanide. Hydroxocobalamin combines with cyanide to form the nontoxic
cyanocobalamin. Both can be used for prophylaxis or for the treatment of cyanide poisoning during nitroprusside infusion. Thiocyanate
toxicity includes weakness, disorientation, psychosis, muscle spasms, and convulsions, which are confirmed when serum concentrations
greater than 10 mg/dL are found.
2. Delayed hypothyroidism occurs as a result of thiocyanate inhibition of iodide uptake by the thyroid.
3. Methemoglobinemia during infusion of nitroprusside has also been reported.
Fenoldopam
Fenoldopam is a peripheral arteriolar dilator used for hypertensive emergencies and postoperative hypertension (the same indications as those
for nitroprusside). It acts primarily as an agonist of dopamine D1 receptors, which result in the dilation of the peripheral arteries and an increase
in sodium excretion in urine (natriuresis). As with other direct vasodilators, the major toxicities include reflex tachycardia, headache, and
flushing. Fenoldopam also increases intraocular pressure and should be avoided in patients with glaucoma. Unlike sodium nitroprusside,
fenoldopam does not lead to thiocyanate toxicity.
Dihydropyridine drugs (eg, nifedipine) are more selective as vasodilators and have a less negative inotropic e ect on the myocardium than
verapamil and diltiazem.
Calcium Channel Blockers
Calcium channel blockers (CCBs) include verapamil, diltiazem, and the dihydropyridine family (amlodipine, felodipine, isradipine, nicardipine,
nifedipine, and nisoldipine). Clevidipine is a newer member of this group, which is only formulated for intravenous use.
As mentioned in Chapter 4, there are 2 main types of voltage-gated Ca++ channels, L and T; the currently available drugs in this class block the L-
type. An increase in intracellular Ca++ concentration leads to increased contractions in both the heart and the smooth muscle cells of the blood
vessels. The use of CCBs will lead to a reduction in the amount of Ca++ available, which results in vasodilation and a negative inotropic e ect in
the myocardium.
Other organs that possess smooth muscle (including the gastrointestinal, uterine, and bronchiolar tissues) are also susceptible to this relaxing
e ect. As mentioned in Chapter 4, the pacemaker of the heart (eg, the SA and AV nodes) are the most dependent on the inward Ca++ current for
depolarization. Some CCBs can reduce sinus firing and AV nodal conduction. The e ect on cardiac conduction depends not only on whether the
specific CCB reduces the inward Ca++ current, but also on whether it delays the recovery of the Ca+ channel to its resting state. Verapamil and
diltiazem exert this e ect, whereas dihydropyridine CCBs (eg, nifedipine) do not.
Hemodynamic di erences among calcium channel blockers a ect the choice of a particular drug. Nifedipine and the other dihydropyridine
agents are more selective as vasodilators and have a less negative inotropic e ect on the myocardium than verapamil and diltiazem. Reflex
sympathetic activation with slight tachycardia maintains or increases cardiac output in most patients who are given dihydropyridines. Verapamil
has the greatest depressant e ect on the heart and can decrease the heart rate and cardiac output. Diltiazem has intermediate actions. Some
studies report an increase in the risk of myocardial infarction or mortality in patients receiving short-acting nifedipine for hypertension. It is
therefore recommended that only sustained-release calcium channel blockers with long half-lives be used for the treatment of chronic
hypertension. Intravenous nicardipine and clevidipine are available for the treatment of hypertension when oral therapy is not su icient;
parenteral verapamil and diltiazem can also be used for the same indication, or to treat arrhythmias. Side e ects includes first-degree
atrioventricular block and constipation; both are dose dependent. Peripheral edema is a common side e ect. Nifedipine and other
dihydropyridines may cause gingival hyperplasia.
Organic Nitrates
Nitroglycerin is the prototype of the organic nitrate group. Although nitroglycerin is used in the manufacture of dynamite, the systemic
formulations used in the medication are not explosive. Nitroglycerin sublingual tablets can lose their potency when stored as a result of
volatilization and adsorption to plastic surfaces. Therefore, the drug should be kept in tightly closed glass containers.
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Pharmacokinetic factors govern the choice of agent and mode of therapy when using nitrates.
It is important to allow a nitrate-free interval of several hours each day to avoid nitrate tolerance and maintain drug e icacy.
Pharmacokinetics
Oral bioavailability of the traditional organic nitrates (eg, nitroglycerin and isosorbide dinitrate) is low (<10%-20%), because the liver contains a
high-capacity organic nitrate reductase. Therefore, the sublingual route, which avoids the first-pass e ect, is preferred for achieving a
therapeutic blood level rapidly. Nitroglycerin and isosorbide dinitrate are both absorbed e iciently by this route and reach therapeutic blood
levels within a few minutes, but only have a short duration of action (15-30 minutes). Oral preparations contain an amount of drug su icient to
result in sustained systemic blood levels of the parent drug plus active metabolites. Pentaerythritol (PETN) is an oral “long-acting” nitrate (>6
hours). Sustained-release nitroglycerin, isosorbide dinitrate, and mononitrate have duration of action of 2 to 14 hours. Transdermal nitroglycerin
patches and paste applied to the skin can also deliver a sustained release. The e icacy of the long-acting preparations decreases because there
is a rapid development of drug tolerance with continuous use. Therefore, it is important that the dosing regimens allow for a drug-free interval
of several hours each day to maintain e icacy. Intravenous nitroglycerin is administered by continuous infusion, which is the most beneficial
treatment for hospitalized patients with unstable angina or acute myocardial infarction.
Amyl nitrite and related nitrites are highly volatile liquids. Amyl nitrite is available in fragile glass ampules packaged in a protective cloth
covering. The ampule can be crushed with the fingers, resulting in a rapid release of vapors that are inhalable through the cloth covering. The
inhalation route provides very rapid absorption and, like the sublingual route, avoids the hepatic first-pass e ect. Because of its unpleasant odor
and short duration of action, amyl nitrite is now obsolete for angina.
Excretion, primarily in the form of glucuronide derivatives of the denitrated metabolites, is largely accomplished by the kidneys.
Pharmacodynamics
Mechanism of Action in Smooth Muscle
Nitrates produce vascular smooth muscle relaxation. The drug is converted into nitric oxide (NO) at the plasma membrane of the vascular
smooth muscle cells. Nitric oxide activates guanylate cyclase to produce cGMP that leads to vasodilatation. At low doses, nitroglycerin produces
a greater dilation of veins than of the arterioles. This results in venous pooling, a decrease in the venous return, and a decrease in the right and
le ventricular filling. Systemic arterial resistance remains generally unchanged, but cardiac output can decline because of the diminished
preload, especially in patients with volume depletion. Arterial dilation occurs to some extent in the coronary arteries and can also occur in the
facial blood vessels (leading to flushing) and meningeal arterioles (leading to headaches).
At high doses, nitrates can result in widespread arteriolar dilatation and systemic hypotension with reflex tachycardia. It should be noted that
this e ect is not significant in patients with heart failure because the decreasing a erload in these patients usually improves the cardiac output
and reduces the sympathetic drive.
The major use of nitrates is in the treatment of angina pectoris to reduce the preload. The smaller le ventricular size lowers the ventricular wall
stress and myocardial oxygen consumption. Nitrates are useful in Prinzmetal variant angina for dilating the coronary arteries.
Nicorandil and several other antianginal agents combine the activity of nitric oxide release with a direct potassium channel-opening action, thus
providing an additional mechanism for causing vasodilation.
There is a gradient response in the vasodilator e ect of nitrates, with veins responding at the lowest concentrations, and arteries responding at
slightly higher ones. The epicardial coronary arteries are sensitive, but concentric atheromas can prevent significant dilation. On the other hand,
eccentric lesions allow the blood flow to increase when nitrates relax the smooth muscle on the side away from the plaque. Arterioles and
precapillary sphincters are dilated the least, partly because of reflex responses and partly because di erent vessels vary in their ability to release
nitric oxide from the drug.
Action on the Platelets
Nitrates increase cGMP in platelets, leading to an inhibition of platelet aggregation. Intravenous nitroglycerin can be of value in unstable angina,
in part for its action on the platelets.
Other E ects
Nitrite ion (not nitrate) reacts with hemoglobin (which contains ferrous iron) to produce methemoglobin (which contains ferric iron). Because
methemoglobin has a very low a inity for oxygen, large doses of nitrites can result in pseudocyanosis, tissue hypoxia, and death. The plasma
levels of nitrites that result from large doses of organic and inorganic nitrates are too low to cause significant methemoglobinemia in adults.
Nitrate Tolerance
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With continuous exposure to nitrates, isolated smooth muscle can develop complete tolerance (tachyphylaxis), and the intact human becomes
progressively more tolerant when long-acting preparations (oral, transdermal) or continuous intravenous infusions are used for more than a few
hours. The mechanisms by which tolerance develops are not completely understood. Supplementation of cysteine may partially reverse this
tolerance, suggesting that reduced availability of sulfhydryl donors may play a role. Systemic compensation also plays a role in tolerance in the
intact human. Initially, a significant sympathetic discharge occurs, and a er one or more days of therapy with long-acting nitrates, the retention
of salt and water can partially reverse the favorable hemodynamic changes normally caused by nitroglycerin.
In addition to their favorable vasodilator e ects in the treatment of ischemic heart disease, nitrates inhibit platelet aggregation.
Clinical Uses
Nitrates are mainly used in the treatment of angina pectoris. As mentioned in Chapter 6, venodilatation leads to a reduction of the le
ventricular preload and wall stress. This lowers oxygen consumption and restores the balance between oxygen demand and supply. Nitrates are
also used in patients with coronary spasm (Prinzmetal angina).
Other Nitro Vasodilators
Nicorandil is a nicotinamide nitrate ester that causes vasodilation of the normal coronary arteries but has more complex e ects in patients with
angina. Clinical studies suggest that it reduces both preload and a erload. It also provides myocardial protection via preconditioning by
activating the cardiac KATP channels. One large trial has shown a significant reduction in relative risk of fatal and nonfatal coronary events in
patients receiving the drug. Molsidomine is a prodrug that is converted to a nitric oxide-releasing metabolite. It is said to have an e icacy
comparable to that of the organic nitrates and is not subject to tolerance.
Natriuretic Peptides
Natriuretic peptides are secreted from the atrial and ventricular myocardium in patients with heart failure. These peptides cause vasodilatation
and sodium and water excretion. Nesiritide is a human recombinant β-type natriuretic peptide, available in intravenous form. Given to
hospitalized patients with decompensated heart failure, the drug increases cardiac output and reduces sympathetic and renin-angiotensin
system activation. It can also promote diuresis. However, the drug has not shown any improvement in the survival of patients with heart failure.
Phosphodiesterase-5 Inhibitor Sildenafil
This drug is used for the treatment of erectile dysfunction. It also decreases pulmonary vascular resistance and is used in patients with primary
pulmonary hypertension. When combined with nitrates, sildenafil may cause severe hypotension; therefore these drugs should not be used
concomitantly (an interval of at least 24 hours is required).
Endothelin Antagonists
Bosentan and tezosentan are orally active competitive inhibitors of endothelin that showed some benefits in experimental animal models with
heart failure, but results in human trials have been disappointing. Bosentan is used to treat pulmonary hypertension but has teratogenic and
hepatotoxic e ects.
An interval of at least 24 hours is required, if nitrates and sildenafil are to be used concomitantly.
Antiadrenergic Drugs
Drugs that inhibit the sympathetic nervous system can act on the central nervous system (CNS), postganglionic sympathetic nerve endings, and
peripheral α and β receptors. These drugs are used mainly for the treatment of systemic hypertension.
Blood pressure is controlled mainly via the sympathetic and renin-angiotensin-aldosterone system (Fig. 17.3). Antiadrenergic drugs can
overcome the sympathetic tone and decrease the blood pressure. In addition, long-term use of β-blockers suppresses renin release; thus
ultimately inhibiting angiotensin II synthesis.
Figure 17.3
A. Blood pressure control. B. Mechanism of action of antihypertensive agents.
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Central Adrenergic Inhibitors (CNS α2-Agonists)
Adrenergic receptors α2 are present in the presynaptic neurons of the CNS. When stimulated, they lead to a decrease in central sympathetic
outflow, thus reducing peripheral vascular resistance and cardiac stimulation, which leads to a reduction in the blood pressure. This group
includes clonidine, α-methyl dopa, guanabenz, and guanfacine. All are used infrequently as oral antihypertensive agents (because of the
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availability of better tolerated drugs). Clonidine is also available as a skin patch. Side e ects include sedation, dry mouth, bradycardia, and also
rebound hypertension, if the drug is stopped suddenly.
Sympathetic Nerve-Ending Antagonists
Reserpine inhibits the uptake of norepinephrine into the storage vesicles. The antihypertensive e ect is a result of a depletion of
catecholamines, which leads to a decrease in myocardial contractility and peripheral vascular resistance. Reserpine can lead to CNS toxicity in
the form of sedation and impaired concentration. The most serious e ect is psychic depression.
Peripheral α-Adrenergic Receptor Antagonists
These are divided into drugs acting on both α1 and α2-receptors and those that inhibit α1 alone. Note that α1-selective receptor blockers
(prazosin, terazosin, doxazosin) are infrequently prescribed as antihypertensive agents. Their selectivity provides an advantage of less reflex
tachycardia than the nonselective agents. Normally, drug-induced vasodilation activates baroreceptor-mediated sympathetic stimulation that
leads to undesired tachycardia. This e ect is augmented by drugs that block the presynaptic α2-receptors, because the feedback inhibition of
norepinephrine release is prevented. However α1-selective agents do not block the negative feedback on the α2-receptors.
Selective α1-receptor blockers (eg, prazosin) have the advantage of causing less reflex tachycardia.
Nowadays, terazosin and doxazosin are mainly used for the symptomatic treatment of benign prostatic hyperplasia, as they lead to a relaxation
of prostatic smooth muscle tone.
Phentolamine and phenoxybenzamine are nonselective α-blockers, used in the treatment of pheochromocytoma, a tumor of the adrenal
medulla (and other tissues) that abnormally secretes catecholamines in the circulation.
Terazosin and doxazosin are mainly used for symptomatic treatment of benign prostatic hyperplasia.
β-Adrenergic Receptor Antagonists
This class of drugs is used for a number of cardiovascular conditions, including ischemic heart disease, hypertension, heart failure, and
tachyarrhythmias. β-antagonists decrease inotropy, slow down the heart rate, and decrease conduction velocity. The e ect of these drugs is
most marked when there is an activation of the sympathetic nervous system (eg, during exercise). Drugs of this class can be classified according
to:
Relative a inity of the drug for β1- and β2-receptors (selectivity)
Whether partial β-agonist activity is present (intrinsic activity)
Whether the drug also has a vasodilator e ect
Di erences in pharmacokinetic properties
Selective β1-blockers act mainly on the myocardium, with less of an e ect on the bronchial or vascular smooth muscle tissues (where β2-
receptors are present), thus producing less adverse e ects, for example, bronchospasm and vasoconstriction in susceptible patients. Agents
with partial β-agonist e ects tend to slow the heart rate less than other β-blockers (an undesired e ect for anti-ischemic and antiarrhythmic
use).
Nonselective β-blockers may decrease cardiac output, due to a decrease in cardiac contractility, heart rate, and a slight increase in peripheral
resistance (through β2- blocking). β-blockers with partial agonistic activity (eg, pindolol) or those possessing some α-blocking activity (eg,
labetalol) can lower peripheral resistance. Table 17.1 shows the important properties of the most commonly used β-blockers.
Main therapeutic uses of β-blockers include:
Hypertension
Angina
Myocardial infarction
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Arrhythmias
Heart failure
Clinical Uses
Ischemic heart disease: These drugs reduce myocardial oxygen consumption. β-blockers improve survival following acute myocardial infarction.
Selective agents without intrinsic sympathomimetic activity should be used.
Hypertension: With initial use, these drugs decrease cardiac output. However, the main antihypertensive e ect is a result of a decrease in renin
secretion by the kidneys with chronic use.
Heart failure: A negative inotropic e ect of β-blockers is expected to worsen heart failure. However, clinical trials show survival benefits of
chronic β-blockers (carvedilol, metoprolol, bisoprolol) in heart failure. The mechanism is mainly related to blunting of the cardiotoxic e ect of
excessive circulating catecholamines.
Arrhythmias.
Adverse E ects
1. β2-blockades (with nonselective agents) can lead to bronchospasm in patients who are susceptible or have bronchial asthma or chronic
obstructive airway disease.
2. β2-blockades can precipitate vasoconstriction, which can lead to the exacerbation of Raynaud phenomenon or a worsening of peripheral
vascular disease.
3. Heart blocks (a ect the AV nodes).
4. Abrupt withdrawal of β-blockers leads to the precipitation of myocardial ischemia in patients with coronary artery disease.
5. An undesirable reduction of HDL cholesterol and an elevation in triglycerides can occur.
6. β2-blockades can impair recovery from hypoglycemia in diabetic patients su ering an insulin reaction. In addition, they can mask warning
sympathetic symptoms of hypoglycemia, for example, tachycardia.
7. Other adverse e ects include fatigue, insomnia, depression, and impotence. β-blockers should be used cautiously with non-dihydropyridine
calcium channel blockers (verapamil and diltiazem), as both classes of drugs decrease myocardial contractility and AV nodal conduction,
possibly precipitating heart failure and heart block.
Table 17.1
β-blockers
β Agonistic activity Selective β1 blockers Nonselective β-blockers
Present Acebutolol Pindolol

Carteolol
Absent Atenolol Carvedilola

Betaxolol
Labetalola
Bisoprolol
Propranolol
Metoprolol
Nadolol
Nebivololb Timolol
a
Has a vasodilating e ect by blocking α1 receptors.
b
Has a vasodilating e ect, likely mediated by nitric oxide.
Inotropic Drugs and Vasopressor Agents
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Inotropic agents are the drugs that increase the ventricular contraction and improve the systolic function of a failing heart. This group includes
cardiac glycosides, sympathomimetic agents, and phosphodiesterase inhibitors. All these drugs increase calcium in the cardiac myocyte and
enhance actin and myosin interaction, thus improving myocardial contractility. They cause a shi in the ventricular contraction curve (Frank-
Starling curve) in an upward direction (ie, it improves the stroke volume and cardiac output for a given filling pressure).
Digitalis
Digitalis is not the first drug and never the only drug to be used in the treatment of heart failure. The drug is used when heart failure is not
controlled by vasodilator and diuretic therapy. Digitalis is the genus name for the family of plants that provide most of the medically useful
cardiac glycoside, digoxin. These plants have been known for thousands of years but were only used sporadically until 1785, when William
Withering, an English physician and botanist, described the clinical e ects of an extract of the purple foxglove plant (Digitalis purpurea, a major
source of these agents). Digoxin is currently the most commonly used drug from this group.
Pharmacokinetics
A er oral administration, only 65% to 80% of digoxin is absorbed. Once present in the blood, all cardiac glycosides are widely distributed to the
tissues, including the central nervous system. More than 60% of digoxin is excreted and unchanged by the kidneys. Its renal clearance is
proportional to creatinine clearance, and the half-life is 36 to 40 hours in patients with normal renal function. Dose adjustment is required in
patients with renal impairment.
Pharmacodynamics
Digoxin has multiple direct and indirect cardiovascular e ects, with both therapeutic and toxic consequences. In addition, it has undesirable
e ects on the CNS and gut.
Molecular Mechanism of Action
At the molecular level, digoxin inhibits Na+/K+-ATPase, the membrane-bound transporter o en called the sodium pump (Fig. 17.4). This action is
responsible for the positive inotropic action of digoxin, and also for the toxicity of the drug. Other molecular-level e ects of digitalis have been
studied in the heart and are discussed below. Receptors for cardiac glycosides that exist on the sodium pump have led to the assumption that an
endogenous digitalis-like steroid, possibly ouabain or marinobufagenin, must exist. In addition, more functions of Na+/K+-ATPase have been
postulated, involving apoptosis, cell growth, and di erentiation, immunity, and carbohydrate metabolism.
A. Cardiac E ects
1. Mechanical e ects
Digoxin increases contraction of the cardiac sarcomere by increasing the free calcium concentration in the cardiomyocyte during systole.
The increase in calcium concentration is the result of a 2-step process: first, an increase of intracellular sodium concentration because of
Na+/K+-ATPase inhibition; and second, a relative reduction of calcium expulsion from the cells by the sodium-calcium exchanger (NCX in
Fig. 17.4) caused by an increase in intracellular sodium. The increased cytoplasmic calcium is sequestered by sarcoplasmic reticulum
Ca2+-ATPase (SERCA) in the sarcoplasmic reticulum (SR) for later release.
2. Electrical e ects
The e ects of digitalis on the electrical properties of the heart are a mixture of direct and autonomic actions (Table 17.2). Direct actions
on the membranes of cardiac cells follow a well-defined progression: an early, brief prolongation of the action potential (as a result of an
increase in potassium conductance that is caused by an increase in intracellular calcium), followed by a shortening (especially the
plateau phase). These e ects are observed at therapeutic concentrations of digoxin.
At higher concentrations, the resting membrane potential is reduced (made less negative) as a result of inhibition of the sodium pump
and reduced intracellular potassium. As toxicity progresses, a erpotentials or delayed a erdepolarizations (DADs) appear. If it occurs
regularly in the Purkinje system and reaches the threshold, bigeminy will occur (Fig. 17.5). With further intoxication, each a erpotential-
evoked action potential will itself elicit a suprathreshold a erpotential, and a self-sustaining tachycardia will be established. If allowed to
progress, such a tachycardia can deteriorate into fibrillation; in the case of ventricular fibrillation, the arrhythmia will be rapidly fatal
unless corrected.
Autonomic actions of cardiac glycosides on the heart involve both the parasympathetic and the sympathetic systems. At low therapeutic
doses, parasympathomimetic e ects predominate, and lead to ECG changes because of the early e ects of digitalis at therapeutic levels
(Table 17.3). This action involves sensitization of the baroreceptors, central vagal stimulation, and facilitation of the muscarinic
transmission at the cardiac muscle cell. Cholinergic innervation is much richer in the atria, so these actions a ect atrial and
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atrioventricular nodal function more than the ventricles. At toxic levels, sympathetic outflow is increased by digitalis. This e ect is not
essential for typical digitalis toxicity but sensitizes the myocardium and exaggerates all of the toxic e ects of the drug.
B. E ects on Other Organs
Cardiac glycosides a ect all excitable tissues, including smooth muscle and the CNS. Outside of the heart, the gastrointestinal tract is the
most common site of digitalis toxicity. The e ects include anorexia, nausea, vomiting, and diarrhea. This toxicity is caused in part by direct
e ects on the gastrointestinal tract and in part by CNS actions.
CNS e ects include vagal and chemoreceptor trigger zone stimulation. Less o en, disorientation and hallucinations—especially in the
elderly—and visual disturbances are noted. The latter e ect may include aberrations of color perception. Gynecomastia is a rare e ect
reported in men taking digitalis.
C. Interactions with Potassium, Calcium, and Magnesium
Potassium and digitalis interact in 2 ways. First, they inhibit each other’s binding to Na+/K+-ATPase; therefore hyperkalemia decreases the
inhibitory actions of cardiac glycosides on the pump, whereas hypokalemia facilitates these actions. Second, abnormal cardiac automaticity
is inhibited by hyperkalemia. Thus, a moderate increase of K+ reduces the toxic e ects of digitalis.
Hypercalcemia increases the risk of a digitalis-induced arrhythmia by accelerating an overload of intracellular calcium stores that appears to
be responsible for digitalis-induced abnormal automaticity. The e ects of magnesium ions are opposite to those of calcium. Therefore,
serum electrolytes should be carefully monitored in patients on digoxin therapy.
Figure 17.4
Mechanism of action of cardiac glycosides. (Reproduced, with permission, from Toy EC, Loose DS, Tischkau SA, Pillai AS. Case Files:
Pharmacology. 3rd ed. New York, NY: McGraw-Hill; 2014.)
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Table 17.2
E ects of digoxin on electrical properties of cardiac tissues
Tissue or variable E ects at therapeutic dosage E ects at toxic dosage
Sinus node ↓ Rate ↓ Rate
Atrial muscle ↓ Refractory period ↓ Refractory period, arrhythmias
Atrioventricular node ↓ Conduction velocity, ↑ refractory period ↓ Refractory period, arrhythmias
Purkinje system, ventricular muscle Slight ↓ refractory period Extrasystole, tachycardia, fibrillation
Electrocardiogram ↑ PR interval, ↓ QT interval Tachycardia, fibrillation, arrest at extremely high dosage
Source: Katzung BG, Trevor AJ. Basic and Clinical Pharmacology. 13th ed. New York, NY: McGraw-Hill; 2015.
Figure 17.5
Electrocardiographic record showing digitalis-induced bigeminy.
Table 17.3
Comparison of the e ects of sympathomimetic agents on di erent adrenergic receptors
Drug Receptor stimulation
α1 (Vasoconstriction) β1 (Cardiac stimulation) β2 (Vasodilation) D1 (Increase renal perfusion)
Dopamine +++ (at high dose) +++ (at moderate and high dose) ++ +++ (at low dose)
Dobutamine + +++ + No e ect
Norepinephrine +++ +++ No e ect No e ect
Epinephrine +++ +++ + No e ect
Isoproterenol No e ect +++ +++ No e ect
Clinical Use
Digoxin is reserved for treatment in patients with congestive heart failure with atrial fibrillation as it has the benefit of ventricular rate control in
this case. It is also used as an add-on drug in patients who are only partially controlled by ACE inhibitors, β- blockers, and diuretics. Digoxin can
be used as an antiarrhythmic agent to treat atrial fibrillation, flutter, and reentrant supraventricular tachycardia (SVT). However, its use is
currently less frequent due to the availability of more e ective agents (eg, CCBs, β- blockers, and amiodarone).
Digitalis Toxicity
The risk of digitalis toxicity is significant because of the narrow therapeutic index. Although many side e ects are minor, fatal arrhythmias can
occur. Extracardiac signs of acute digitalis toxicity involve the gastrointestinal tract (nausea, anorexia, vomiting), which is usually because of
digoxin’s e ect on the area postrema of the brain stem. The most common cardiac manifestations of digitalis toxicity include atrioventricular
junctional rhythm, premature ventricular depolarizations, bigeminal rhythm, ventricular tachycardia, and second-degree atrioventricular
blockade. However, it has been claimed that digitalis can cause virtually any arrhythmia.
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Many factors can precipitate digitalis toxicity; the most common is hypokalemia as a result of the concurrent use of diuretics in heart failure.
Hypomagnesemia and hypercalcemia can also promote digitalis toxicity. Concomitant amiodarone use can lead to a reduced clearance of
digoxin.
Treatment of digitalis-induced tachyarrhythmias includes correction of hypokalemia and intravenous lidocaine. A high-degree AV block can
require a temporary pacemaker. In patients with severe intoxication, the administration of digoxin-specific antibodies can be life-saving.
Digoxin should never be used as a first line of treatment for congestive heart failure in the absence of atrial fibrillation.
Digitalis-induced tachyarrhythmias should be managed by correcting electrolyte disturbance (mainly hypokalemia) and intravenous lidocaine
(Class Ib antiarrhythmic drugs).
Other Positive Inotropic Drugs Used in Heart Failure
Major e orts are underway to find safer, positive inotropic agents because cardiac glycosides have an extremely narrow therapeutic index and
may not decrease mortality in chronic heart failure.
Bipyridines
Milrinone inhibits phosphodiesterase isozyme 3 (PDE-3). It is only available in parenteral form. It has an elimination half-life of 3 to 6 hours, with
10% to 40% being excreted by the kidneys. Inamrinone is an older congener.
Milrinone increases myocardial contractility by increasing inward calcium flux in the heart. It can also alter the intracellular movement of
calcium by influencing the sarcoplasmic reticulum. In addition, it can cause vasodilatation. The e ect of milrinone results in an increase in cAMP
and an increase in contractility and vasodilation.
The toxicity of inamrinone includes nausea and vomiting, arrhythmias, thrombocytopenia, and elevated liver enzymes. Milrinone is less likely to
cause bone marrow and liver toxicity, but it can cause arrhythmias. Milrinone is now used only intravenously and only for acute heart failure or
severe exacerbation of chronic heart failure.
Bipyridines are used only for short-term therapy of refractory congestive heart failure.
Sympathomimetic Amines
These drugs exert inotropic e ects by binding to β1-receptors; they increase the activity of adenylate cyclase and, thus, increase cAMP. Increased
cAMP activates protein kinases, which promote intracellular calcium by phosphorylating L-type calcium channels. The increase in calcium entry
triggers a rise in calcium release from the sarcoplasmic reticulum. This results in an increase in contractility of the myocardium. Both
intravenous dopamine and dobutamine are used frequently in the treatment of acute heart failure. Norepinephrine, epinephrine, and
isoproterenol are used in special circumstances. Table 17.3 shows a comparison between di erent sympathomimetic amines.
Dopamine e ects on various adrenergic receptors mainly depend on the infusion rate of the drug.
Dopamine is an endogenous catecholamine and a precursor of norepinephrine. This combination of e ects is due to its action on di erent
adrenergic receptors. It is used in treatment of heart failure associated with hypotension and impaired renal perfusion. At low doses (<2
μg/kg/min), dopamine activates mainly dopaminergic receptors in the renal and mesenteric vasculature; thus vasodilatation occurs with
increased renal blood flow and glomerular filtration with the facilitation of diuresis.
Dobutamine is only useful for short duration of treatment, as the downregulation of adrenergic receptors leads to less e ects with prolonged
use.
Medium doses (2-10 μg/kg/min) have an inotropic action by stimulating cardiac β1-receptors and indirectly promoting norepinephrine release
from the sympathetic nerve terminals. This e ect increases the heart rate, myocardial contractility, and stroke volume, thus increasing the
cardiac output.
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At high doses (>10 μg/kg/min), dopamine also stimulates α-receptors, thus inducing vasoconstriction and increasing systemic vascular
resistance. High doses of dopamine may be indicated in hypotensive states; for example, shock. However, these doses should not be used in
most patients with heart failure because increased peripheral vascular resistance increases the a erload, with further impairment of cardiac
contractility and output.
Major dopamine toxicity occurs in patients who are treated with high doses, in the form of tachyarrhythmias.
Dobutamine is a synthetic analog of dopamine that stimulates β1-, β2-, and α-receptors. It increases cardiac contractility with its e ect on β1, but
does not increase peripheral vascular resistance, because of the balance between α and β2 e ects on the blood vessels. The drug is beneficial in
the treatment of heart failure not accompanied by hypotension. Unlike dopamine, dobutamine does not stimulate dopaminergic receptors. The
drug is e ective for short duration of treatment (<1 week), as a downregulation of the adrenergic receptors leads to less e ects of dobutamine
with prolonged use. The major adverse e ect is tachyarrhythmias, although less severe than with dopamine.
Norepinephrine is an endogenous catecholamine, synthesized from dopamine in adrenergic postganglionic nerves and in the adrenal medulla.
Through its stimulatory e ect on β1-receptors, the drug has positive inotropic e ects. It acts on peripheral α-receptors causing marked
vasoconstriction. The increase in peripheral vascular resistance increases the mean arterial blood pressure.
With this combined e ect, norepinephrine is beneficial in patients with “warm shock,” in which heart failure is associated with hypotension due
to vasodilatation. It should be noted that vasoconstriction induced by norepinephrine is marked and can lead to further impairment in cardiac
contractility, and close hemodynamic monitoring is needed to adjust the dose and duration of therapy. Major adverse e ects include
precipitation of myocardial ischemia (due to an increase in cardiac contractility and a erload), and tachyarrhythmias.
Epinephrine is the major catecholamine released by the adrenal medulla. It is formed by the decarboxylation of norepinephrine. The drug is an
agonist of α-, β1-, and β2-receptors. Low-dose intravenous infusion of epinephrine stimulates β1-receptors with a positive inotropic e ect and
increase in heart rate, thus the stroke volume and cardiac output are increased. The stimulation of β2-receptors leads to vasodilatation, which
decreases the total peripheral resistance and blood pressure.
At higher doses, epinephrine is a potent vasopressor, as its α-stimulatory e ects predominate. In this case, the inotropic and chronotropic
e ects as well as the vasoconstrictor e ects contribute to an increase in the arterial blood pressure.
Epinephrine is used most frequently in managing cardiac arrest, when both inotropic and chronotropic e ects are required. The most common
toxic e ect is tachyarrhythmias. Epinephrine is contraindicated in patients receiving β-blockers, because the unopposed α-vasoconstrictor e ect
can produce severe hypertension.
Isoproterenol is a synthetic epinephrine analog. The drug is a pure β-agonist with no e ect on α-receptors. Isoproterenol has positive inotropic
and chronotropic e ects by increasing cardiac output. Stimulation of the β2-receptors leads to peripheral vasodilation and a decrease in
peripheral resistance. The drug is sometimes used in emergency settings to increase the heart rate in patients with bradyarrhythmias, as a
bridge to pacemaker implantation. It can be useful in patients with systolic dysfunction and slow heart rate with high peripheral vascular
resistance (in the case of postcardiac surgery in patients on previous β-blocker therapy). Isoproterenol is contraindicated in patients with
ischemic heart disease, as cardiac stimulation leads to an increase in myocardial oxygen consumption.
Table 17.3 compares the e ects of sympathomimetic agents on di erent adrenergic receptors.
Isoproterenol can be used in emergency settings to increase the heart rate in patients with bradyarrhythmias, as a bridge to pacemaker
implantation.
Vasopressin
Vasopressin is an endogenous antidiuretic hormone secreted by the posterior pituitary. Its main function is to maintain water balance.
Vasopressin acts as a potent vasoconstrictor when administered at higher than physiological doses. It directly stimulates vascular smooth
muscle V1 receptors. It is useful to maintain blood pressure in patients with vasodilatory shock, for example, in septic shock. Vasopressin can be
used in cardiac arrest as a part of advanced life support. The drug increases coronary perfusion pressure and increases the blood flow to vital
organs.
Investigational Positive Inotropic Drugs
Istaroxime is an investigational steroid derivative. It exerts a positive inotropic e ect by inhibiting Na+/K+-ATPase (like cardiac glycosides). In
addition, it facilitates the sequestration of Ca2+ by the sarcoplasmic reticulum. The latter action is likely to render the drug less arrhythmogenic
than digitalis.
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Levosimendan is a drug that sensitizes the troponin system to calcium; thus increasing myocardial contractility. It also inhibits
phosphodiesterase and causes vasodilation. Some clinical trials suggest that this drug may be e ective in patients with heart failure.
Omecamtiv mecarbil is an investigational parenteral agent that activates cardiac myosin and prolongs systole without increasing oxygen
consumption of the heart. It has been shown to reduce signs of heart failure in animal models. A larger trial in patients with acute heart failure
was disappointing, but another trial in those with chronic failure is underway.
Antiarrhythmic Drugs
Pharmacological treatment of cardiac arrhythmias, especially tachyarrhythmias, is a common approach. It should be noted that antiarrhythmic
agents are among the most dangerous drugs because of their potential serious adverse e ects. Understanding their mechanisms of action,
indications, and toxicities is very important.
Di erent classes of antiarrhythmic drugs have been described. The Vaughan Williams classification appeared in 1970. The classification depends
on the mechanism of drug action, and is still one of the most widely used classification systems for antiarrhythmic drugs (Table 17.4).
Table 17.4
Vaughan Williams classification of antiarrhythmic agents
Class rank Mechanism of action Examples
Class I Na+ channel blockers
Class Ia Decrease conduction velocity and increase APD Quinidine

Procainamide
Disopyramide
Class Ib Minimal change in conduction velocity and a slight decrease in action potential duration Lidocaine
Mixelitene
Class Ic Marked prolongation of CV Flecainide

Propafenone
Class II β blockers Propranolol

Metoprolol
Class III K+ channel blockers; prolong APD—used in atrial and ventricular arrhythmias Amiodarone
Sotalol
Ibutilide
Dofetilide
Class IV Ca2+ channel blockers (non-dihydropyridines) Virapamil

Diltiazem
Others Adenosine
Mechanisms of Action
Arrhythmias are caused by abnormal pacemaker activity or abnormal impulse propagation. Thus, the aim of therapy of the arrhythmias is to
reduce ectopic pacemaker activity and modify conduction or refractoriness in reentry circuits to stop arrhythmia. The major pharmacologic
mechanisms currently available for accomplishing these goals include (1) sodium-channel blockade, (2) blockade of the sympathetic autonomic
e ects in the heart, (3) prolongation of the e ective refractory period, and (4) calcium channel blockade.
Drugs with use-dependent properties preferentially block electrical activity when there is a fast tachycardia or when there is a significant loss of
resting potential, with less of an e ect on normal tissue.
E ect on Automaticity
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Antiarrhythmic drugs decrease the automaticity of ectopic pacemakers more than that of the SA node. They also reduce conduction and
excitability and increase the refractory period in depolarized tissue more than in normally polarized tissue. This is a result of the selective
blocking of the sodium or calcium channels of depolarized cells. The drugs bind readily to activate channels (ie, during phase 0) or inactivated
channels (ie, during phase 2) but bind poorly or not at all to rested channels. Therefore, these drugs block electrical activity when there is a fast
tachycardia (frequent channel activations and inactivation per unit time) or when there is a significant loss of resting potential (many inactivated
channels during rest). This type of drug action is o en described as use-dependent or state-dependent; that is, channels that are being used
frequently, or are in an inactivated state, are more susceptible to a block. The phenomenon of use-dependency applies to some of the Class I
sodium-channel blockers (Fig. 17.6).
Figure 17.6
A schematic representation of Na+ channels cycling through di erent conformational states during the cardiac action potential. Transitions
between rested, activated, and inactivated states are dependent on membrane potential and time. The activation gate is shown as m and the
inactivation gate as h. Potentials typical for each state are shown under each channel schematic as a function of time. The dashed line indicates
that part of the action potential during which most Na+ channels are completely or partially inactivated and unavailable for reactivation.
(Reproduced, with permission, from Katzung BG, Trevor AJ, eds. Basic & Clinical Pharmacology. 13th ed. New York, NY: McGraw-Hill; 2015.)
In cells with abnormal automaticity, most of these drugs reduce the phase 4 slope by blocking either sodium or calcium channels, thereby
reducing the ratio of sodium (or calcium) permeability to potassium permeability. As a result, the membrane potential during phase 4 stabilizes
closer to the potassium equilibrium potential. In addition, some agents may increase the threshold (making it more positive). β-adrenoceptor-
blocking drugs indirectly reduce the phase 4 slope by blocking the positive chronotropic action of norepinephrine in the heart.
E ect on Reentry
In reentry arrhythmias (Fig. 17.7), which depend on critically depressed conduction, most antiarrhythmic agents slow conduction further by 1 or
both of 2 mechanisms: (1) steady-state reduction in the number of available unblocked channels, which reduces the excitatory currents to a
level below that required for propagation; and (2) prolongation of recovery time of the channels still able to reach the rested and available state,
which increases the e ective refractory period. As a result, early extrasystoles are unable to propagate at all; later impulses propagate more
slowly and are subject to a bidirectional conduction block.
Figure 17.7
E ects of Class I antiarrhythmic drugs on the duration of the ventricular action potential.
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Proarrhythmogenic E ects
Antiarrhythmic drugs can suppress ectopic automaticity and abnormal conduction that occurs in depolarized cells, while minimally a ecting
the electrical activity in normally polarized parts of the heart. As the dosage is increased, these agents also depress conduction in normal tissue,
eventually resulting in drug-induced arrhythmias. Furthermore, a drug concentration that is therapeutic (antiarrhythmic) under the initial
circumstances of treatment may become “proarrhythmic” (arrhythmogenic) during fast heart rates (more development of the block), acidosis
(slower recovery from the block for most drugs), hyperkalemia, or ischemia.
Class IA Antiarrhythmics
Class IA prolongs action potential duration (APD) and the e ective refractory period (ERP). Class IB shortens APD and ERP. Class IC neither
changes APD nor ERP (Fig. 17.7).
E ects on Reentrant Arrhythmias
These drugs produce a moderate blockade of sodium channels, thus slowing the rate of phase 0 depolarization and reducing the conduction
velocity of the myocardial cells. If markedly impaired within the reentrant circuit, the impulse will decay and the arrhythmia will stop. In
addition, Class IA prolongs the action potential and the refractory period (via blocking potassium channels responsible for repolarization). This
helps to stop the impulse propagation.
E ects on Arrhythmias Caused by Increased Automaticity
Class IA drugs raise the threshold value and can inhibit pacemaker channels. In this way, they depress the slope of phase 4 depolarization in
pacemaker tissues. These e ects are most pronounced in the Purkinje fibers and abnormal ectopic pacemakers.
E ects on ECGs
Prolongation of QRS and QT intervals (due to a prolonged action potential duration)
At higher doses, significant QT prolongation can lead to a er-depolarization with provocation of an arrhythmia
Indications
These are used for the treatment of reentrant and ectopic supraventricular and ventricular tachycardias. However, their use is infrequent, due to
the availability of more e ective and safer drugs.
Specific Class IA Drugs
Quinidine
In addition to the properties of Class IA, quinidine also has an anticholinergic e ect that can increase conduction at the AV node, thus
antagonizing its direct depressant e ect. Quinidine is metabolized mainly in the liver, so the dose should be reduced in patients with liver
disease.
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Noncardiac and cardiac adverse e ects occur frequently with quinidine. The most common one is gastrointestinal upset. Cinchonism refers to
the CNS toxicity by quinidine that includes tinnitus, confusion, hearing loss, and visual disturbance. Quinidine can lead to marked QT
prolongation and life-threatening ventricular tachyarrhythmia (torsades de pointes).
Procainamide is similar to quinidine in its electrophysiological e ect, but QT prolongation is less marked. Procainamide, on the other hand, has
a mild ganglionic blocking e ect and can lead to peripheral vasodilatation and negative inotropic e ects.
Procainamide is available both in oral and parenteral forms. More than 50% of the drug is excreted and unchanged by the kidneys; the
remainder is acetylated by the liver into an active metabolite that is excreted in the urine.
Noncardiac adverse e ects of procainamide include fever and rash. About 30% of patients develop a lupus-like syndrome a er 6 months of
therapy, manifested as arthralgia, rash, and connective tissue inflammation (drug-induced lupus). This e ect occurs o en in slow acetylators
and is reversible on stopping the drug. Procainamide should be given only for short-term therapy.
Disopyramide
Disopyramide has electrophysiologic e ects similar to procainamide, but has higher anticholinergic e ects. Thus, constipation, urinary
retention, and exacerbation of glaucoma are common adverse e ects. It also has a more pronounced negative inotropic e ect and should be
used cautiously, if at all, in patients with le ventricular failure. The drug is particularly e ective in patients with hypertrophic cardiomyopathy
with dynamic outflow tract obstruction because of its negative inotropic e ect.
Disopyramide is administered orally. It is excreted mainly by the kidneys. In patients with renal failure, the drug accumulates and can lead to QT
prolongation and ventricular arrhythmias.
Class IB Antiarrhythmics
These drugs inhibit the fast sodium channels, but di er from Class IA, as they shorten the duration of the action potential. This is due to blocking
small sodium currents that normally continue through the phase 2 of action potential. At therapeutic levels, Class IB drugs do not alter the
electrical activity of normal tissue, but act mainly on the diseased or ischemic cells. Class IB drugs decrease the slope of phase 0 depolarization
in the ischemic tissues, thus inhibiting the reentrant arrhythmias. The automaticity of ectopic foci is also inhibited by decreasing phase 4
spontaneous depolarization and raising the threshold potential. Intravenous lidocaine suppresses delayed a erdepolarizations.
This class is most commonly used to treat ventricular arrhythmias, especially if associated with ischemia or digoxin toxicity. QT interval is not
prolonged with Class IB drugs.
Specific Class IB Drugs
Lidocaine
The drug is administered only by intravenous routes, as oral absorption is unpredictable. For this reason, the drug is used to treat ventricular
arrhythmias in hospitalized patients. The drug undergoes hepatic metabolism and the half-life is markedly a ected by the rate of hepatic blood
flow.
The most common adverse e ects are related to the CNS, including confusion, dizziness, and seizures. These e ects are dose-related and can be
prevented by monitoring the serum level, in particular, for patients with impaired liver function.
Mexiletine is similar to lidocaine in its chemical structure, pharmacological actions, and adverse e ects. The drug can be administered orally.
Class IC Antiarrhythmics
These are the most potent sodium-channel blockers. Class IC drugs decrease the upstroke of the action potential and the conduction velocity in
the atria, ventricles, and conduction system. They significantly prolong the refractory period in the AV node and accessory pathways.
This group was developed as a treatment for ventricular arrhythmias, but studies have shown that they increase mortality if used in patients
with ventricular ectopies a er myocardial infarction or those who have survived cardiac arrest. In patients with underlying le ventricular
dysfunction, Class IC can precipitate heart failure. This class of drugs can be used in the treatment of supraventricular arrhythmias in patients
with otherwise normal hearts.
Flecainide is well absorbed orally. About 40% is excreted unchanged in urine; the remainder is metabolized in the liver into inactive metabolites.
The drug may aggravate ventricular arrhythmias or precipitate heart failure in susceptible patients. Other adverse e ects include confusion,
dizziness, and blurred vision (CNS).
Propafenone is similar to flecainide with respect to its electrophysiologic properties, but it also exhibits a β-adrenergic-blocking e ect.
Metabolism of the drug is variable, according to genetic variations of the metabolizing enzymes.
Class II Antiarrhythmics
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The drugs of this class are β-blockers that are used in the treatment of both supraventricular and ventricular arrhythmias. Most of their
antiarrhythmic properties are attributed to decreasing sympathetic activity of the myocardium. Additional actions including a membrane
stabilizing e ect, which does not contribute significantly to their antiarrhythmic e ect. β-blockers decrease the upslope of phase 4
depolarization and decrease firing of the SA node and Purkinje fibers. In addition, they prevent a erdepolarizations that are mainly caused by
excessive catecholamines, thus preventing triggered arrhythmias caused by this mechanism. β-blockers also prolong the refractory period of
the AV node (Fig. 17.8).
Figure 17.8
E ects of Class II antiarrhythmic drugs (β-blockers) on the action potential.
β-blockers decrease the oxygen demands of the myocardium, thus reducing myocardial ischemia. They have also been shown to reduce
mortality a er myocardial infarction.
ECG E ects
Prolonged PR interval (due to slowing AV conduction)
QRS and QT intervals are not a ected
Clinical Uses
Treatment of tachyarrhythmias related to excessive catecholamines (eg, exercise or emotion-induced)
Treatment of atrial flutter and fibrillation (rate control; slowing the ventricular rate)
Termination of reentrant supraventricular tachycardia (in which the AV node constitutes one limb of the reentry circuit)
Suppressing ventricular premature beats and other ventricular arrhythmias induced by exercise
Treatment of ventricular arrhythmias caused by QT prolongation
Class III Antiarrhythmics
These drugs are heterogeneous in chemical structure. The most important common property of this class is the significant prolongation of the
Purkinje fiber action potential, mainly by blocking the potassium outward current of phase 3 repolarization. They have little e ect on phase 0
depolarization and conduction velocity (Fig. 17.9).
Figure 17.9
E ects of Class III antiarrhythmic drugs (K+ channel blockers) on the action potential.
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Amiodarone is an important antiarrhythmic drug with many adverse e ects. The main mechanism of action is the prolongation of action
potential. In addition, the drug shares actions with each of the other antiarrhythmic classes. The slope of phase 0 depolarization may be
reduced through the sodium-channel blocking e ect (Class I e ect). Amiodarone also has a β-blocking e ect (Class II e ect) and a weak calcium
channel-blocking e ect (Class IV e ect).
Pharmacokinetics:
The drug is absorbed slowly from the gastrointestinal tract. It reaches a peak plasma concentration in 5 to 6 hours. It is highly lipophilic and
extensively bound to tissues. It undergoes slow hepatic metabolism. The plasma half-life is long and variable (25-60 days). The dose needs no
adjustment in patients with renal impairment.
E ects on ECG:
Prolongation of PR interval
Prolongation of QT interval
Amiodarone is also a vasodilator (α-receptor and calcium channel blocker) and negative inotrope (β-blocker and CCB). Vasodilatation is more
pronounced than the negative inotropic e ect; thus cardiac output is not a ected in patients treated by amiodarone.
Clinical Uses
Ventricular arrhythmias: ventricular tachycardia, ventricular flutter
Supraventricular arrhythmias, atrial fibrillation, atrial flutter
Emergency treatment of ventricular arrhythmias during cardiac resuscitation
Treatment of arrhythmias in patients with le ventricular dysfunction; the drug causes less proarrhythmogenic e ects than other
antiarrhythmics
Low doses of amiodarone are used for long-term suppression of atrial fibrillation and flutter
Adverse E ects
Pulmonary fibrosis is the most serious adverse e ect. It may represent a hypersensitivity reaction. If recognized early, it is reversible with
cessation of the drug.
Amiodarone can cause cardiac toxicity including bradycardia and aggravation of ventricular arrhythmias (in 2% of patients). In patients treated
with amiodarone, QT interval prolongation is modest. On the other hand, bradycardia and slowing of AV conduction may be significant.
Intravenous administration can lead to hypotension.
Abnormal thyroid function: The drug contains a significant iodine load. In addition, it inhibits peripheral conversion of T4 to T3. During the initial
phase of treatment, it is common to observe transient abnormalities in thyroid function tests without clinical findings. Over time, some patients
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develop hypothyroidism (due to the antithyroid e ect of iodine) or hyperthyroidism (due to the iodine e ect in iodine-deficient areas, or a direct
thyroid inflammatory e ect induced by amiodarone in susceptible patients).
Gastrointestinal e ects: nausea, anorexia
Elevation of liver enzymes
Neurological e ects: proximal muscle weakness, peripheral neuropathy, ataxia, tremors, and sleep disturbance
Corneal microdeposits may be detected, but rarely a ects vision
Cardiac output is not a ected in patients treated by amiodarone.
Monitoring of Adverse E ects
ECG, thyroid, and liver function tests, chest x-ray, and sometimes pulmonary function tests are required in patients on long-term amiodarone
therapy.
Dronedarone is a noniodinated analog of amiodarone. While it is not as potent an antiarrhythmic drug, it lacks pulmonary, liver and thyroid
adverse e ects. Dronedarone acts on several ion channels, including blocking IKr, IKs, ICa, and INa. It also has β-adrenergic-blocking action. On
oral administration, it reaches a plasma steady-state concentration in 4 to 8 days. The major adverse e ects are gastrointestinal; nausea,
vomiting, and diarrhea. The drug is contraindicated in patients with advanced or decompensated heart failure, as studies have shown an
increase in mortality.
Sotalol is a nonselective β-blocker. In practice, it is used as an oral antiarrhythmic with Class III properties. It prolongs action potential duration
and increases the refractory period of the atria and ventricles. It inhibits conduction in accessory pathways. The drug is used in the treatment of
supraventricular and ventricular arrhythmias. Sotalol is mainly eliminated by renal excretion. The dose needs to be adjusted in renal
impairment. Adverse e ects are similar to that of other β-blockers. Torsades de pointes may occur in 2% of patients receiving sotalol,
particularly in female patients and those with a history of heart failure.
Dofetilide is another oral Class III antiarrhythmic used in the management of atrial fibrillation and flutter. The drug can exhibit prolonged QT
interval and may lead to torsades de pointes. The drug is mainly excreted in urine and dose adjustment is required in patients with renal
impairment.
Dronedarone is a non-iodinated analog of amiodarone, which lacks pulmonary, hepatic, and thyroid adverse e ects.
Ibutilide is another Class III antiarrhythmic agent, but its major mechanism of action is related to the activation of a slow inward sodium current
that prolongs the plateau (phase 2) of the action potential. The drug is used in the treatment of atrial flutter and fibrillation (for conversion to
normal sinus rhythm; rhythm control). The drug can prolong QT interval. Careful ECG monitoring is necessary for several hours a er drug
administration.
Class IV Antiarrhythmics
Class IV antiarrhythmic agents exert electrophysiological e ects by selective L-type calcium channel blockade. They include non-
dihydropyridine calcium channel blockers (verapamil and diltiazem). They are most e ective in tissues that depend on a calcium current for
their action potential; that is, the SA and AV nodes. This results in slowing down the heart rate, slowing the conduction in the AV node, and
terminating reentrant arrhythmias traveling through the AV node (Fig. 17.10).
Figure 17.10
E ects of Class IV antiarrhythmic drugs (Ca++ channel blockers) on the action potential.
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Clinical Uses
Mainly reentry supraventricular tachycardia (eg, AV node reentrant tachycardia); verapamil is the second choice (adenosine is the first)
Pharmacology and toxicity
Therapeutic use of calcium channel blockers include:
Hypertension
(systemic and pulmonary)
Angina
Arrhythmias
Other Antiarrhythmic Drugs
Adenosine
Adenosine is an endogenous nucleoside with a very short plasma half-life of only 10 seconds. It is used in the treatment of supraventricular
reentrant tachycardia and given by intravenous infusion. The drug binds to adenosine receptors in the SA and AV nodes, leading to the activation
of potassium channels and increasing the outward potassium current and membrane hyperpolarization. This suppresses spontaneous
depolarization of the SA node and slows the AV nodal conduction. Adenosine also inhibits adenylate cyclase and decreases intracellular cAMP.
This results in a decrease in the inward pacemaker current (If) and the inward calcium current. This further adds to its e ect on the SA and AV
nodes. Adenosine causes a transient AV block, so that it terminates the reentrant pathway (the AV node is a part of the circuit). As the drug half-
life is very short, there may only be transient adverse e ects. These include headache, chest pain, flushing, and bronchospasm. Ca eine and
theophylline competitively antagonize the action of adenosine, so higher doses of the drug are required in patients who drink co ee or tea
excessively. On the other hand, dipyridamole inhibits the breakdown of adenosine and augments its e ects.
Adenosine is used in the treatment of supraventricular reentrant tachycardia and given by intravenous infusion.
Diuretics
These drugs increase urine volume and sodium excretion by interfering with sodium, chloride, and water transport across the renal tubular cell
membranes (Fig. 17.11). To understand the mechanisms of action of diuretics, the main points on physiology of tubular reabsorption will be
revised.
Figure 17.11
Sites of action of diuretics on the renal tubules.
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Tubular Reabsorption
Only about 1% of the glomerular filtrate actually leaves the body because the rest (the other 99%) is reabsorbed into the blood while it passes
through the renal tubules and ducts.
1. In the Proximal Convoluted Tubules: Most of the volume of the filtrate solution is reabsorbed in the proximal convoluted tubule. This
includes some water and most/all of the glucose (except in patients with diabetes mellitus). Most of the energy consumed by the kidneys is
used in the reabsorption of sodium ions (Na+).
2. In the Loop of Henle: The 2 limbs of the loop of Henle have di erent permeabilities.
a. Descending Limb of the Loop of Henle: The epithelial lining of the descending limb of Henle is relatively permeable to water—but much
less permeable to Na+, Cl-, and urea. Therefore, water gradually moves from the descending limb and into the interstitium.
b. Thick Ascending Limb of the Loop of Henle: The thick ascending limb of Henle reabsorbs NaCl via a di erent transport process from that
of the thin ascending limb of Henle.
3. In the Distal Convoluted Tubules: The distal convoluted tubules react to the amount of antidiuretic hormones in the blood: The presence of
antidiuretic hormones in the blood causes the cells in the distal convoluted tubules to become more permeable to water.
a. Only 10% of the filtered NaCl is reabsorbed in the distal convoluted tubules.
b. Calcium is actively reabsorbed via an apical Ca+2 channel and basolateral Na+/Ca+2 exchanger. This process is regulated by the
parathyroid hormone.
Thiazides are the preferred diuretic for the treatment of hypertension. Loop diuretics have a higher diuretic e ect, but their e ect is antagonized
by stimulating the renin-angiotensin-aldosterone system to counter any fall in blood pressure. Potassium-sparing diuretics are the weakest
diuretics and their use is not associated with potassium loss. They can be used in refractory edema, usually in combination with loop diuretics to
avoid hypokalemia. There is a role for the aldosterone antagonists: spironolactone and eplerenone, in the treatment of heart failure.
Main Indications of Diuretics
Congestive heart failure
Nephrotic syndrome
Hepatic failure with ascites
Hypertension: the antihypertensive e ect is not directly related to diuresis, but to a subtle alteration of the contractile responses in the vascular
smooth muscle
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Indapamide is unique among the thiazides as it has a predominantly vasodilating e ect.
Thiazide Diuretics (Chlorthalidone, Indapamide, Metolazone)
Thiazides are well-absorbed orally and usually well-tolerated. They are less potent than loop diuretics and their sustained action makes them
e ective in chronic conditions such as hypertension and mild congestive heart failure (CHF).
Thiazides act at the distal tubule, where they inhibit the reabsorption of approximately 3% to 5% of the filtered sodium, by inhibiting a Na+-Cl-
carrier mechanism at the luminal membrane. Indapamide is unique among the thiazides in that it has a predominantly vasodilating e ect.
Thiazides have a poor diuretic e ect in the case of impaired renal function, except for metolazone. Thiazides are not e ective when the
glomerular filtration rate is <25 mL/min.
Thiazides are not e ective when the glomerular filtration rate is low.
Adverse e ects include: (1) hypokalemia and metabolic alkalosis, as a result of increased Na+ delivery to the distal tubule, where an exchange
for K+ and H+ takes place, and from volume depletion and secondary hyperaldosteronism; (2) hyponatremia (especially with chronic use), due to
increased Na+ excretion; (3) hyperuricemia (and possible precipitation of gout) due to decreased excretion of uric acid; (4) hyperglycemia, due to
impaired pancreatic insulin release; (5) increased low density lipoprotein (LDL) cholesterol and triglycerides; (6) hypercalcemia; and (7)
weakness, fatigability, and paresthesias.
Loop Diuretics (Furosemide, Bumetanide, Torsemide, Ethacrynic Acid)
These drugs act mainly on the thick ascending limp of the loop of Henle. They are potent diuretics, which result in the excretion of 20% to 25% of
the filtered Na+ through inhibition of the Na+-2Cl−K+ cotransport system. As a result, there is a loss of the hypertonic interstitium and the
gradient for passive water movement out of the collecting ducts, which is diminished and thus, diuresis occurs.
Loop diuretics are indicated in the treatment of: (1) acute pulmonary edema and (2) chronic heart failure. Loop diuretics are e ective in the case
of renal impairment (in contrast to thiazide diuretics). These agents cause vasodilation through generating prostaglandins and nitric oxide from
endothelial cells, which act to relax vascular smooth muscle cells, thus decreasing the venous return to the heart.
Adverse e ects include: (1) intravascular volume depletion. (2) Hypokalemia due to impairment of Na+ reabsorption in the loop of Henle that
leads to an increase in the amount of Na+ delivered to the distal tubule, which leads to a greater exchange for K+ than usual. In addition, volume
depletion that results from use of loop diuretics leads to activation of the renin-angiotensin-aldosterone system that promotes additional Na+-
K+ exchange. (3) Metabolic alkalosis that results from (a) increased H+ secretion into the distal tubule due to secondary hyperaldosteronism and
(b) contraction alkalosis, in which volume depletion promotes increased sodium bicarbonate reabsorption by the proximal tubule. (4)
Hypomagnesemia because magnesium reabsorption depends on the NaCl transport in the thick ascending limb of the loop of Henle, the action
is blocked by loop diuretics. (5) Ototoxicity can develop due to electrolyte disturbances of the endolymphic system, because of Na+-2Cl−K+
cotransport inhibition by the diuretic at that site.
Bumetanide is similar to furosemide but has greater potency and bioavailability.
Furosemide is the most commonly used loop diuretic with a short duration of action (2-4 hours). Bumetanide is similar to furosemide but has
greater potency and bioavailability. It has a lower incidence of ototoxicity than other loop diuretics. Torsemide is similar to furosemide with
more complete bioavailability. Ethacrynic acid is the only nonsulfonamide loop diuretic, so it can be prescribed to patients with sulfonamide
hypersensitivity, but it has a higher incidence of ototoxicity that limits its use.
Potassium-Sparing Diuretics (Spironolactone, Eplerenone, Triamterene, Amiloride)
These are weak diuretics that antagonize Na+ reabsorption at the distal convoluted tubule and cortical collecting tubule. Unlike other diuretics,
hypokalemia is not a side e ect. Potassium-sparing diuretics are used to maintain the serum potassium level in states of primary and secondary
hyperaldosteronism. Two mechanisms of action can lead to potassium-sparing diuresis: (1) aldosterone antagonism (spironolactone,
eplerenone) and (2) direct inhibition of Na+ permeability in the collecting duct, independently of aldosterone (triamterene, amiloride).
Spironolactone is a synthetic steroid that competes for the cytoplasmic aldosterone receptor, thereby inhibiting the Na+ channel in the kidney.
This leads to the diminishment of the lumen negative potential that should drive K+ and H+ ion excretion at the distal nephron; thus the K+ and
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H+ ions are retained in the circulation. Spironolactone also exerts cardiac antiremodeling e ects in patients with heart failure by improving
symptoms and reducing mortality (Chapter 11).
Adverse e ects include: (1) hyperkalemia, thus K+ supplements and ACE inhibitors or ARBs should be used cautiously and (2) antiandrogenic
activity may produce gynecomastia in men and menstrual disturbance in women.
Eplerenone is a specific inhibitor of aldosterone receptors, but lacks the antiandrogenic e ects of spironolactone.
Triamterene and amiloride have a related structure to spironolactone, but act independently of aldosterone. They inhibit the reabsorption of
Na+ and lead to the diminished excretion of K+ and H+. Triamterene is metabolized by the liver, and its active product is secreted into the
proximal tubule by the organic cation transport system. Amiloride is secreted directly into the proximal tubule and appears unchanged in urine.
Table 17.5 compares changes in urinary electrolyte patterns and blood pH in response to di erent diuretic agents.
Table 17.5
Changes in urinary electrolyte patterns and blood pH in response to diuretic drugs
Urinary electrolytes
Group NaCl NaHCO3 K+ Blood pH
Carbonic anhydrase inhibitors + +++ + Acidosis
Loop agents ++++ 0 + Alkalosis
Thiazides ++ + + Alkalosis
Loop agents plus thiazides +++++ + ++ Alkalosis
K+-sparing agents + (+) – Acidosis
+, Increase; –, decrease; 0, no change.
Source: Katzung BG, Trevor AJ. Basic and Clinical Pharmacology. 13th ed. New York, NY: McGraw-Hill; 2015:fig 15-2.
Antithrombotic Drugs
This group of drugs includes platelet inhibitors (antiplatelet agents) and anticoagulants. These agents act to prevent the formation of
thrombi/clots in the blood and do not a ect the already formed thrombus. This is in contrast to fibrinolytic (thrombolytic) agents; for example,
streptokinase and alteplase.
Platelet Inhibitors
Platelets are an important component of the hemostatic system. To fulfill this function, platelets perform 3 main functions: (1) adhesion to the
injured site, (2) activation and release of mediators, and (3) aggregation. Certain mediators, for example, ADP and thromboxane A2 stimulate
platelet aggregation and form the primary hemostatic plug. During the process of platelet plug formation, the platelet membrane IIb/IIIa
receptors undergo conformational change, which allow the GP IIb/IIIa receptors to bind to the fibrinogen molecules that tightly link the
platelets. The platelet plug is stabilized and binds to the site of injury by the mesh of fibrin, which is produced by the simultaneous activation of
the coagulation factors.
Platelet activation is regulated by the release of stored Ca++ from the platelet tubular system. This results in increased cytosolic calcium
concentration that activates protein kinase and phosphorylation of platelet regulatory proteins, which finally results in the synthesis of
mediators of platelet aggregation.
Calcium release is modulated by several factors. Thrombin and other agonists generate intermediaries that stimulate calcium release from the
dense tubules. TXA2 increases the intracellular Ca++ by binding to its platelet receptors, which inhibit adenylate cyclase activity and decrease
cAMP formation. Endothelial-derived prostacyclins (PGIs) stimulate adenylate cyclase activity and increase platelet cAMP concentration, which
inhibits Ca++ release from the platelets (Fig. 17.12).
Figure 17.12
Mechanism of action of antiplatelet drugs.
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Antiplatelet drugs interfere with platelet function at various points along the sequence of activation and aggregation. The most commonly used
antiplatelet drug is aspirin, but there are a number of antiplatelet agents that are becoming more commonly used.
Aspirin
Aspirin inhibits platelet aggregation by irreversible acetylation and blockade of the cyclooxygenase 1 enzyme that is essential for the production
of TXA2. As previously mentioned, TXA2 is also important for plug formation. It should be noted that the antiplatelet e ect is not a property of
COX II inhibitors.
The prostaglandin PGI2 is a major antagonist of TXA2 that is produced by the endothelium. The synthesis of PGI2 also depends on
cyclooxygenase. Aspirin at high doses inhibits the synthesis of PGI2, but unlike platelets, endothelial cells are still able to generate. Thus when
used at low doses, aspirin significantly inhibits TXA2 synthesis with little e ect on PGI2.
Aspirin has many proven clinical benefits in patients with cardiovascular diseases, in particular for patients with unstable angina and for
secondary prevention a er myocardial infarction. The role of aspirin is less clear for primary prevention. To achieve an antiplatelet e ect, aspirin
should be administered at a daily dose of 75 to 325 mg. Aspirin cannot replace warfarin to prevent stroke in patients with atrial fibrillation.
Main Adverse E ects
Gastrointestinal upset is the most common adverse e ect (can be minimized by using low-dose and enteric-coated tablets)
Gastrointestinal bleeding
Hemorrhagic stroke
Asthma exacerbation in patients with aspirin-induced asthma
Aspirin may exacerbate gout, as it competes with uric acid for renal tubular excretion
Thienopyridines (Clopidogrel, Ticlopidine, Prasugrel)
This group of drugs inhibit ADP-mediated platelet activation. Normally, extracellular ADP activated platelets by binding to 2 types of receptors.
The first is P2Y1, which acts through phospholipase C to increase the calcium in the platelets and promotes platelet activation. The second
receptor is P2Y2, which is linked to inhibitory G protein that decreases cAMP, thus raising the platelet calcium. ADP-induced platelet aggregation
requires that both receptors are activated at the same time. Thienopyridine is converted into active metabolites in the liver that inhibit P2Y12
irreversibly, thus inhibiting platelet aggregation. The combination of aspirin and clopidogrel is indicated in patients a er percutaneous
angioplasty, unstable angina, NSTEMI, and STEMI for secondary prophylaxis.
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Thienopyridine-active metabolites irreversibly inhibit P2Y12, thus inhibiting platelet aggregation.
Concomitant use of omeprazole and clopidogrel may interfere with the action of CYP2C19, with less activation of clopidogrel.
Adverse E ects
Bleeding, dyspepsia, diarrhea
Ticlopidine may cause neutropenia (0.8-2.5%), thrombotic thrombocytopenic purpura (0.02%); these hematologic e ects are much rarer with
clopidogrel
Clopidogrel is a prodrug that needs to be converted by the cytochrome P450 enzyme to active metabolites. This contributes to the delayed
action of clopidogrel. Patients with common polymorphism of cytochrome P450 2C19 isoenzyme demonstrate weak platelet inhibition and less
clinical benefits from clopidogrel. The use of omeprazole may interfere with the action of CYP2C19 with less activation of clopidogrel. Prasugrel
is more potent than clopidogrel.
Glycoprotein IIb/IIIa Inhibitors (Abciximab, Eptifibatide, Tirofiban)
This class of drugs represents the most potent antiplatelet agents. These drugs reversibly inhibit the final common pathway of platelet
aggregation; the binding of activated platelet GP IIb/IIIa receptors to fibrinogen, and von Willebrand factor, thus impairing the formation of the
platelet plug. There are 3 types of GP IIb/IIIa receptor blockers: (1) monoclonal antibodies (eg, abciximab, which is the Fab fragment of chimeric
human-mouse monoclonal antibodies), (2) synthetic peptide antagonists (eg, eptifibatide), and (3) synthetic nonpeptide antagonists (eg,
tirofiban). These drugs markedly improve the outcome of percutaneous angioplasty, and also patients with acute coronary syndrome.
The major adverse e ects include bleeding (1%-10%) and thrombocytopenia (2% with abciximab, and less with other agents). Abciximab
adverse e ects are transient, as the drug half-life is short (30 minutes).
Dipyridamole
This drug is infrequently prescribed nowadays; only to patients who cannot tolerate aspirin, but it is not that e ective. The action of the drug is
related, in part, to increasing cAMP, mainly by inhibiting phosphodiesterase enzymes. Dipyridamole has no clear cardiovascular benefits.
Glycoprotein IIb/IIIa inhibitors are indicated for the treatment of acute coronary syndrome and as an adjunctive for percutaneous coronary
intervention.
Anticoagulant Drugs
This group of drugs interferes with the coagulation cascade and prevents secondary thrombus formation. Both intrinsic and extrinsic
coagulation cascades end by the formation of a fibrin clot by action of the thrombin. Thus, major functions of anticoagulant drugs are to inhibit
the activation of thrombin by factor Xa (heparin and fondaparinux), to inhibit thrombin itself (unfractionated heparin and direct thrombin
inhibitors), or to decrease the production of functional coagulation factors (warfarin).
Heparin
Unfractionated Heparin (UFH)

This is a group of glycosaminoglycans with di erent molecular weights. The drug action depends on its inhibitory e ects on antithrombin III in
the circulation. Antithrombin III (AT) is a protein that inhibits the action of thrombin and other clotting factors. When UFH binds to AT, the a inity
of AT for thrombin increases 1000-fold. This markedly reduces thrombin’s ability to convert fibrinogen into fibrin. In addition, a UFH-AT complex
also inhibits activated factor X. UFH has antiplatelet properties, because it blocks von Willebrand factor.
Unfractionated heparin therapy should be monitored by measuring the activated partial thromboplastin time to adjust the dose.
UFH is administered parenterally (intravenous/subcutaneous), because it is not absorbed from the gastrointestinal tract. For acute conditions,
an IV bolus is given followed by IV infusion. The bioavailability of UFH shows individual variations, because UFH is a heterogeneous group of
molecules with variable bindings to plasma proteins. Thus, monitoring by activated partial thromboplastin time is mandatory to adjust the
dose.
UFH is used in the following clinical settings: (1) unstable angina and NSTEMI, (2) acute myocardial infarction a er fibrinolytic therapy or if there
is an extensive regional wall motion abnormality, and (3) pulmonary embolism and deep venous thrombosis. In hospitalized bedridden patients,
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UFH is used subcutaneously in fixed low doses to prevent deep venous thrombosis.
The major adverse e ect of UFH is bleeding. An overdose of UFH should be treated with IV protamine sulfate (the antidote). The drug forms a
stable complex with UFH with immediate reversal of its action.
Heparin therapy should be stopped immediately in patients that develop heparin-induced thrombocytopenia type II and replaced with direct
thrombin inhibitors.
Heparin-induced thrombocytopenia (HIT) can occur in 2 forms. (1) The most common form is a result of direct heparin-induced platelet
aggregation. It occurs in 15% of patients and is usually asymptomatic, dose-dependent, and self-limited. This type rarely reduces the platelet
count significantly. (2) The less common and more serious form of HIT is immune-mediated. It a ects 3% of patients. It can lead to life-
threatening bleeding and paradoxically, to thrombosis. Thrombosis is caused by the formation of antibodies against heparin-platelet complexes
that result in platelet activation, aggregation, and clot formation. The platelet count can fall markedly and the condition is not dose-related.
Cessation of UFH is required and direct thrombin inhibitors are used instead to treat the original conditions.
Patients receiving UFH for long-term therapy are prone to osteoporosis.
Low Molecular Weight Heparin (Enoxaparin, Dalteparin, Tinzaparin)

Unlike UFH, the bioavailability of this group is more predictable. These drugs also interaction with AT, but preferentially inhibit factor Xa more
than thrombin, as direct thrombin inhibition requires molecules larger than low molecular weight heparin (LMWH). However, selective inhibition
of Xa leads to the prevention of downstream formation of thrombin.
Advantages of LMWHs over UFH
Inhibition of platelet-bound factor Xa, resulting in a more prominent anticoagulant e ect
Less binding to plasma proteins, with more predictable bioavailability
Fewer bleeding complications
A lower incidence of immune-mediated HIT
Practically, the major advantage of LMWH is its easy use, as it does not require monitoring. LMWH is administered once or twice daily
subcutaneously. In rare cases, when monitoring is required, for example, in patients with impaired renal function, factor Xa assays are used. In
patients with a history of HIT, LMWH should not be used, instead direct thrombin inhibitors are indicated.
Clinical Uses
Prophylaxis of DVT following hip, knee, or abdominal surgery
Treatment of DVT (with or without pulmonary embolism)
Management of acute coronary syndromes
Direct-Thrombin Inhibitors
The anticoagulant e ects of UFH and LMWH are limited, due to their link to AT, and they only inhibit circulating thrombin. The large heparin-AT
complex cannot inhibit thrombin that is bound to fibrin within a clot. In contrast, the direct thrombin inhibitors (lepirudin, bivalirudin,
argatroban) inhibit thrombin activity independent of AT and are e ective against both circulating and clot-bound thrombin. They do not cause
thrombocytopenia and are used to replace UFH in case of HIT. Bivalirudin is approved for use as an anticoagulant in patients with unstable
angina undergoing percutaneous coronary intervention. All direct thrombin inhibitors are potent anticoagulants and the major adverse e ect is
bleeding.
In contrast to heparin, fondaparinux does not inactivate formed thrombus, nor does it interfere with platelet action or cause HIT.
Fondaparinux
Fondaparinux is a synthetic polysaccharide that specifically inhibits factor Xa, thus, inhibiting thrombin activation. Like heparin, fondaparinux
binds to AT with high a inity, markedly increasing AT’s ability to inactivate factor Xa. In contrast, fondaparinux does not inactivate formed
thrombus, nor does it interfere with platelet action or cause HIT. It is administered by subcutaneous injection. It has a long half-life (17-21 hours),
so the drug can be prescribed in one daily dose. There are no known antidotes to fondaparinux.
The drug is approved for prevention of DVT a er certain surgical procedures and as a treatment for DVT and pulmonary embolism.
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Warfarin
Warfarin is the drug used for long-term anticoagulant therapy. It acts by antagonizing the enzyme epoxide reductase, which is necessary for
vitamin K metabolism. Under normal conditions, the reduced form of vitamin K enhances the carboxylation of a glutamic acid residue within
specific coagulation factors (factors II, VII, IX, and X), thus enhancing the binding of calcium to those factors, so they become functional.
Inhibiting carboxylation of the coagulation factors by warfarin renders them inactive. Natural coagulation inhibitors (protein C and S) are also
vitamin K dependent. Warfarin impairs their function as well, which counteracts the expected anticoagulant e ects of the drug.
Warfarin has a delayed onset of action (action starts within 2-7 days of the first dose). If immediate anticoagulation is required, UFH or LMWH
must be prescribed initially (anticoagulant “bridging”). The half-life of warfarin is 37 hours. The dosage should be individualized to achieve a
therapeutic target while minimizing the risk of bleeding.
If serious bleeding occurs during warfarin therapy, the e ect of the drug can be immediately reversed by transfusing with fresh frozen plasma.
The drug e ect should be monitored by measuring the prothrombin time, best reported as the International Normalized Ratio (INR).1 For
patients with uncomplicated atrial fibrillation, the target INR is usually 2 to 2.5. For patients with mechanical heart valves, the desired INR may
be higher (2.5-3.5).
Many factors can change the e ect of warfarin, so that dose modification is required. Liver disease and heart failure reduce warfarin
requirements. High-dietary ingestion of vitamin K-containing foods (eg, green leafy vegetables) increases the required dose. Many drugs can
interact with warfarin (Table 17.6). Using antiplatelet drugs in combination with warfarin markedly increases the risk of bleeding.
Table 17.6
Warfarin interactions with other drugs
Increased anticoagulant e ect Reduced anticoagulant e ect
Hepatic microsomal enzyme inhibitors Hepatic microsomal enzyme inducers

- Amiodarone - Rifampin
- Erythromycin - Carbamazepine
- Fluconazole - Nafcillin
- Ketoconazole
- Metronidazole
- Propafenone
Drugs displacing warfarin from plasma proteins Drug decreasing absorption

- Allopurinol - Cholestyramine
- Gemfibrozil - Sucralfate
- Phenytoin
Drugs altering vitamin K production by the gut flora

- Ciprofloxacin
- Piperacillin
If serious bleeding occurs during warfarin therapy, the e ect of the drug can be immediately reversed by transfusing with fresh frozen plasma.
The administration of vitamin K also reverses the drug e ects, but in a protracted fashion, taking a few hours. In patients with mechanical heart
valves, vitamin K should be avoided unless life-threatening bleeding occurs, for fear of the risk of vitamin K-induced valve thrombosis. Warfarin
is teratogenic (in particular for doses of ≥5 mg/day). The drug is should be avoided in the first trimester of prenancy, and replaced by UFH or
LMWH.
As there are many precautions with warfarin therapy, the current trend is toward using oral direct thrombin inhibitors and factor Xa antagonists
instead.
1
International Normalized Ratio
Fibrinolytic/Thrombolytic Drugs (Streptokinase, Alteplase, Urokinase)
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These drugs activate the conversion of plasminogen to plasmin, which is a serine protease that hydrolyzes fibrin, and subsequently dissolves
blood clots. Clot dissolution and reopening of the occluded blood vessel occurs more successfully if the fibrinolytic agent is given early a er the
clot formation, because clots become more resistant to the drug e ect with time.
Fibrinolytic agents were originally used for the treatment of deep venous thrombosis and pulmonary embolism with hemodynamic instability as
well as acute myocardial infarction and peripheral arterial thrombi. Currently, these drugs are used less frequently because of their adverse
e ects (mainly bleeding) and the development of new therapeutic modalities of the aforementioned diseases. They are still helpful in the
restoration of catheter and shunt patency, if occluded by thrombi. Fibrinolytic drugs are also used to treat acute small nonhemorrhagic strokes,
provided that patients present early to a specialized stroke unit.
The main adverse e ect of this group of drugs is hemorrhage. Thrombolytic agents do not di erentiate between the fibrin of an unwanted
thrombus and the fibrin of a beneficial physiological hemostatic clot. These drugs are contraindicated in pregnancy, in patients a er surgery or
big healing wounds, a history of hemorrhagic cerebrovascular stroke, brain tumors, head trauma, and metastatic cancer.
Alteplase (tissue plasminogen activator/tPA) has a low a inity for free plasminogen in the plasma and preferentially activates plasminogen that
is bound to fibrin in a thrombus or a hemostatic plug. The drug is synthesized by recombinant DNA technology. Alteplase is thus considered
“fibrin selective” at low doses. Alteplase is approved for the treatment of acute myocardial infarction, massive pulmonary embolism, and acute
ischemic stroke. Alteplase has a short half-life (5-10 minutes). It is given as a bolus (10%) and the rest is given by intravenous infusion over an
hour.
Streptokinase is an extracellular protein purified from cultures of group Cβ -hemolytic streptococci, thus the drug is highly antigenic. It forms a
complex with plasminogen, which then activates further molecules of plasminogen into plasmin. The complex also catalyzes degradation of
fibrinogen, clotting factors V and VII degradation. With the development of newer thrombolytic agents with fewer incidences of hypersensitivity
reactions, streptokinase is less frequently used.
Urokinase is naturally produced by the kidneys. As a drug, it is isolated from cultures of human renal cells. It has low antigenicity. It is only
approved for lysis of pulmonary emboli, although it is used in other conditions o -label, due to its relatively safe profile.
Lipid-Lowering Drugs
Drugs that control dyslipidemia are cardioprotective. They inhibit the progression of atherosclerosis and reduce mortality in high-risk patients.
Several mechanisms may underlie the pharmacodynamics of antidyslipidemic/lipid-regulating drugs (Fig. 17.13). Antidyslipidemic drugs have
unequal e ects regarding the lowering of various lipoproteins (Table 17.7).
Figure 17.13
Main sites of action of antidyslipidemic/lipid-regulating agents.
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Table 17.7
Comparison of antidyslipidemic drugs; showing their e ect on lowering di erent types of lipoproteins
Drug Statins Bile acid sequestrants Fibric acid derivatives Niacin
TC and LDL-C Reduction 20%–60% 10%–30% 5%–20% 5%–25%
TG Reduction 10%–30% 10%–15% 20%–50% 20%–50%
HDL Elevation 5%–15% 3%–5% 10%-20% 15%–35%
HMG CoA Reductase Inhibitors
These are the most e ective drugs for reducing LDL cholesterol. They are most commonly used because of their e ectiveness and tolerability.
This class of drugs includes fluvastatin, lovastatin, pravastatin, simvastatin, atorvastatin, and rosuvastatin (arranged from the least to the most
potent agent).
Mechanisms of Action: Statins act by inhibiting the enzyme HMG CoA reductase, a rate-limiting enzyme in cholesterol synthesis. They can
decrease LDL cholesterol in the blood by:
Reducing intrahepatic cholesterol content that induces increased expression of the LDL receptor gene, causing a greater number of LDL
receptors to appear on the surface of the hepatocyte, which facilitates the binding and clearance of LDL from the circulation.
Circulating LDL precursors (known as very low density lipoprotein [VLDL] remnants and intermediate-density lipoproteins) are cleared more
quickly from the blood, as they are recognized by the liver LDL receptors.
VLDL production from the liver decreases, because of the decreased intracellular cholesterol required for lipoprotein assembly.
Lowering VLDL production can also lead to a decrease in triglyceride levels. Lowering LDL reduces the lipid content of atherosclerotic lesions
and enhanced plaque stability, thus decreasing the probability of plaque rupture and thrombus formation. Statins also have potential
cardioprotective e ects, as they improve the endothelial function because of an increase in the synthesis of nitric oxide. They promote the
stability of plaque by inhibiting monocyte penetration into the arterial wall and reducing the macrophage secretion of metalloproteinase.
Statins also decrease lipoprotein oxidation, thus inhibiting the unregulated uptake of modified LDL cholesterol by macrophages. Finally, they
suppress inflammation, a key factor in atherosclerosis.
In addition to inhibition of HMG-CoA reductase, statins also decrease lipoprotein oxidation, thus inhibiting the unregulated uptake of modified
LDL cholesterol by macrophages.
Muscle aches are reported in 2% to 10% of patients receiving statin therapy, whereas severe myopathy is reported in only 0.5% of patients.
Adverse E ects
Mild gastrointestinal upset
Hepatotoxicity is dose-related and reversible. It occurs in less than 1% of patients. A ected patients may complain of fatigue, weight loss, and
anorexia, but most commonly they are asymptomatic with a transient elevation of transaminases (ALT, AST). Statin-induced hepatotoxicity is
higher with chronic excessive alcohol use.
Myopathy involves mainly the proximal leg and arm muscles. It ranges from vague aches to intense muscle pain and weakness. Rarely, it may
lead to rhabdomyolysis (muscle destruction) with myoglobinuria and acute tubular necrosis (acute renal failure). Muscle aches are reported in
2% to 10% of patients receiving statin therapy. Significant myositis is defined as more than a 10-fold elevation of creatine kinase and develops in
less than 0.5% of patients. However, the incidence of myopathy increases with concomitant use of certain drugs, for example, niacin and
fenofibrates. In addition, hepatic microsomal enzyme inhibitors (eg, erythromycin, clarithromycin, ketoconazole, and antiretroviral protease
inhibitors) inhibit the metabolizing enzyme P-450 3A4, which is responsible for statin metabolism.
Pravastatin, rosuvastatin, and fluvastatin are not significantly dependent on the cytochrome P-450 3A4 for their metabolism, thus they may be
less likely to cause myopathy if combined with enzyme inhibitors.
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Bile Acid-Binding Agents
These drugs include cholestyramine, colestipol, and colesevelam. They are large molecules, positively charged and bind bile acids (which are
negatively charged) in the intestine. They prevent the normal absorption of the bile acids through the enterohepatic circulation. To make up for
the loss, more hepatic cholesterol stores stimulate the production of LDL receptors. This leads to a reduction of the circulating lipoproteins
(similar to the action of statins). Unlike statins, new hepatic cholesterol production is also increased by decreased intrahepatic cholesterol
content. This may increase VLDL production with a rise of triglycerides.
Cholestyramine and colestipol are present in an unappealing gritty powder that should be mixed with fluid before intake. The potency of this
group is lower than that of statins. Thus, these agents are rarely used today, mainly as a second-line therapy for dyslipidemia, or in combination
with statins.
Bile acid-binding agents interfere with the absorption of fat-soluble vitamins and some drugs (eg, warfarin, digoxin, propranolol, and
levothyroxine). There should be an interval of 1 hour before or 3 to 4 hours if such drugs are to be given for the same patient. Bile acid
sequestrants are not absorbed into the blood, thus, they are unlikely to cause systemic adverse e ects.
Inhibitors of Cholesterol Absorption
Ezetimibe is the first member of this class. It inhibits the uptake of cholesterol at the brush border of the small intestinal epithelial cells. The
drug inhibits a specific transporter called Niemann-Pick type C1-like protein 1. Normally, a part of dietary and biliary cholesterol is uptaken by
these transporters and esterified into chylomicrons, which then enters the circulation to reach the liver. By inhibiting cholesterol uptake,
ezetimibe reduces the chylomicron level with a lesser amount delivered to the liver. This stimulates the compensatory production of LDL
receptors in the liver, thus increasing the clearance of circulating LDL.
When combined with statin therapy, a more potent LDL-lowering e ect results. The incidence of hepatic transaminase elevation is slightly higher
with this combination than with statin therapy alone. The combination does not increase the risk of statin-induced myopathy.
Niacin
Niacin is one of the oldest lipid-lowering drugs. It is the most e ective drug for raising HDL cholesterol (15%-35%). Unlike, most antidyslipidemic
agents, niacin reduces the level of lipoprotein (a), an LDL-like lipoprotein that carries an independent risk of cardiovascular disease.
Niacin a ects dyslipidemia by several mechanisms:
It inhibits the release of fatty acids from adipose tissue. Subsequently, liver production of triglycerides and VLDLs is reduced, and less LDL is
formed.
It enhances the clearance of triglycerides from the circulating VLDL by promoting the activity of lipoprotein lipase at the adipose and muscle
cells. The net e ect of these actions is a reduction in serum triglyceride and LDL levels.
It raises HDL by decreasing the hepatic uptake of its apoprotein; Apo AI, thus reducing the clearance of HDL by the liver. This mechanism does
not disturb the hepatic action of cholesterol.
Adverse e ects include transient cutaneous flushing in most patients (prostaglandin-mediated and can be relieved by using aspirin before the
niacin dose), gastrointestinal upset, exacerbation of peptic ulcer disease, and hepatotoxicity. Niacin should be used cautiously (if at all) in
diabetic patients due to the risk of insulin resistance and hyperglycemia. Niacin increases serum uric acid and may precipitate gout in
susceptible patients. Myopathy can rarely occur with niacin therapy (in particular if combined with statin therapy).
Fibrates
This group includes gemfibrozil and fenofibrates. They are the most potent drugs to reduce triglycerides (up to 50%). They also raise HDL
cholesterol.
Fibrates activate peroxisome proliferator-activated receptor α (PPAR-α), a nuclear receptor, which results in the activation of fatty acid oxidation
and an increase in the synthesis of lipoprotein lipase, thus decreasing triglycerides. Consequently, there is an increase in VLDL catabolism, which
can raise LDL cholesterol, especially in patients with baseline hypertriglyceridemia. Fibrates are believed to augment HDL cholesterol levels by
its action on PPAR-α receptors that increases the formation of apoprotein AI.
Fibrates are mainly used to decrease triglyceride levels and raise HDL. Adverse e ects include dyspepsia, gallstones, and myalgia. If combined
with statins, there is a higher risk of myopathy, thus monitoring creatine kinase is recommended when both are combined. Interaction with
warfarin results from displacing it from albumin-binding sites, thus increasing the free fraction of warfarin and augmenting its action.
Key Points
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This chapter covers the mechanisms of action, the clinical uses, and the adverse e ects of the following groups of drugs:
Vasodilators
Antiadrenergic drugs
Inotropes and vasopressors
Antiarrhythmic drugs
Diuretics
Antithrombotic drugs
Antidyslipidemic drugs
(PCSK9) inhibitors
Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are a new class of lipid-lowering medications that are administered as monthly
or bimonthly subcutaneous injections. PCSK9 is a binding protein that is expressed in hepatocytes. A er secretion, it binds to the LDL-R and
promotes their degradation. By blocking PCSK9, these drugs increase availability of LDL-R to remove LDL-C from the circulation. Loss-of-function
polymorphisms resulting in PCSK9 under-expression lead to lower low-density lipoprotein cholesterol (LDL-C) levels. Based on this observation,
PCSK9 inhibitors were developed as monoclonal antibodies to PCSK9. These drugs (eg, evolocumab and alirocumab) are indicated as an
adjunct to diet and maximally tolerated statin therapy to achieve the optimal LDL-C.
Case Studies
CASE 17.1 A 50-year-old patient with systolic dysfunction (ejection fraction of 37%) has permanent atrial fibrillation. His resting heart rate is
100/min and blood pressure is 120/80 mmHg; there is no lower limb edema or other evidence of sodium and water retention. His serum
creatinine is normal. He is already receiving appropriate doses of furosemide and enalapril. Which of the following would be the next therapy?
a. Amiodarone
b. Carvedilol
c. DC cardioversion
d. Digoxin
e. Metoprolol
The correct answer is b.
β-blockers have prognostic and symptomatic benefits in heart failure. Metoprolol, carvedilol, and bisoprolol are licensed for this use in most
countries. Digoxin can improve symptoms in severe heart failure. Digoxin can slow down the heart rate in at-rest patients with atrial fibrillation,
but it has less benefits on tachycardia related to exercise. This patient has permanent atrial fibrillation and as such DC cardioversion will not, by
definition, restore sinus rhythm.
CASE 17.2 A 35-year-old female patient with primary pulmonary hypertension is found to have a mean right atrial pressure of 20 mmHg and a
cardiac output of 1.5 L per min. The mean pulmonary artery pressure is 80 mmHg. There is no reactivity to vasodilators. She is already on
warfarin. Which is the most appropriate treatment at this stage?
a. ACE inhibitor
b. Oral calcium antagonist
c. Heart-lung transplantation
d. Prostacyclin treatment
e. β-blocker
The correct answer is d.
This patient has severe pulmonary hypertension with poor prognosis if untreated. Calcium antagonists should only be given to patients who
show reactivity to vasodilator challenge and have adequate cardiac output (>2.0 L/min). Patients with severe disease who fail to show
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vasoreactivity on provocation testing may benefit from prostacyclin treatment, so this is o ered to all such patients initially. Only those who do
not benefit from prostacyclin or continue to deteriorate are referred for heart-lung transplantation.
CASE 17.3 A 78-year-old man is admitted with atrial fibrillation and chest pain. He is given digoxin in the emergency department, which reduces
his rate to 90/min. His pain settles and his troponin I is negative. He has a previous history of myocardial infarction and heart failure. Which of
the following would be the optimal management subsequently?
a. Continue digoxin and add aspirin
b. DC cardiovert immediately
c. Start amiodarone, aspirin, and cardiovert a er 6 weeks
d. Continue digoxin and warfarinize
e. Start amiodarone, warfarin, and cardiovert a er 6 weeks
The correct answer is e.
A number of recent studies have suggested that restoration of sinus rhythm is not necessarily better than just controlling the heart rate.
However, this patient has impaired le ventricular function and would benefit from restoration of sinus rhythm. This is best achieved with
amiodarone. If this fails, DC cardioversion would be appropriate. Aspirin is insu icient in this situation to prevent thromboembolism, especially
if DC cardioversion is being considered.
Suggested Readings
Cattaneo M. New P2Y12 inhibitors. Circulation. 2010;121:171. [PubMed: 20048234]
Joy TR, Hegele RA. Narrative review: statin-related myopathy. Ann Intern Med. 2009;150:858. [PubMed: 19528564]
Katzung BG, Trevor AJ. Basic and Clinical Pharmacology. 13th ed. New York, NY: McGraw-Hill; 2015.
Martin F, Gonzalex-Conejero R, Capranzano P, et al. Pharmacogenetics in cardiovascular antithrombotic therapy. J Am Coll Cardiol.
2009;54:1041. [PubMed: 19744613]
Opie LH, Gersh BJ. Drugs for the Heart. 7th ed. Philadelphia, PA: WB Saunders; 2009.
Schulman S, Crowther MA. How I treat with anticoagulants in 2012: new and old anticoagulants, and when and how to switch. Blood.
2012;119(13):3016. [PubMed: 22302737]
Whalen K, Finkel R, Panavelil TA. Lippincott Illustrated Pharmacology. 6th ed. Philadelphia, PA: Wolter Kluwer; 2015.
McGraw Hill
Copyright © McGraw-Hill Global Education Holdings, LLC.
All rights reserved.
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Cardiology: An Integrated Approach >

Chapter 17: Cardiovascular Drugs

By the end of this chapter the student will be able to:

Inotropes and vasopressors

Inhibitors of the Renin-Angiotensin-Aldosterone System

Angiotensin-Converting Enzyme Inhibitors

CLINICAL CORRELATION 17.1

Main indications of ACE inhibitors

Main adverse e ects of ACE inhibitors

CLINICAL CORRELATION 17.2

CLINICAL CORRELATION 17.3

Angiotensin Receptor Blocking Agents

Other Inhibitors of the Renin-Angiotensin-Aldosterone System

CLINICAL CORRELATION 17.4

Drug-induced lupus is a recognized adverse e ect of hydralazine.

CLINICAL CORRELATION 17.5

Adverse e ects of sodium nitroprusside include the following:

3. Methemoglobinemia during infusion of nitroprusside has also been reported.

CLINICAL CORRELATION 17.6

Calcium Channel Blockers

CLINICAL CORRELATION 17.7

Action on the Platelets

CLINICAL CORRELATION 17.8

Other Nitro Vasodilators

Phosphodiesterase-5 Inhibitor Sildenafil

CLINICAL CORRELATION 17.9

Central Adrenergic Inhibitors (CNS α2-Agonists)

Sympathetic Nerve-Ending Antagonists

Peripheral α-Adrenergic Receptor Antagonists

CLINICAL CORRELATION 17.10

CLINICAL CORRELATION 17.11

β-Adrenergic Receptor Antagonists

Relative a inity of the drug for β1- and β2-receptors (selectivity)

Whether partial β-agonist activity is present (intrinsic activity)

Whether the drug also has a vasodilator e ect

Di erences in pharmacokinetic properties

CLINICAL CORRELATION 17.12

Main therapeutic uses of β-blockers include:

3. Heart blocks (a ect the AV nodes).

5. An undesirable reduction of HDL cholesterol and an elevation in triglycerides can occur.

β Agonistic activity Selective β1 blockers Nonselective β-blockers

Present Acebutolol Pindolol

Absent Atenolol Carvedilola

Inotropic Drugs and Vasopressor Agents

Molecular Mechanism of Action

B. E ects on Other Organs

C. Interactions with Potassium, Calcium, and Magnesium

Tissue or variable E ects at therapeutic dosage E ects at toxic dosage

Sinus node ↓ Rate ↓ Rate

Atrial muscle ↓ Refractory period ↓ Refractory period, arrhythmias

Atrioventricular node ↓ Conduction velocity, ↑ refractory period ↓ Refractory period, arrhythmias

Electrocardiogram ↑ PR interval, ↓ QT interval Tachycardia, fibrillation, arrest at extremely high dosage

Drug Receptor stimulation

α1 (Vasoconstriction) β1 (Cardiac stimulation) β2 (Vasodilation) D1 (Increase renal perfusion)

Dobutamine + +++ + No e ect

Norepinephrine +++ +++ No e ect No e ect

Epinephrine +++ +++ + No e ect

Isoproterenol No e ect +++ +++ No e ect

CLINICAL CORRELATION 17.13

CLINICAL CORRELATION 17.14

Other Positive Inotropic Drugs Used in Heart Failure

CLINICAL CORRELATION 17.15

CLINICAL CORRELATION 17.16