THEME: Clinical Pharmacology of Antianginal
Drugs.
Clinical Pharmacology of Antiarrhythmic Drugs
Clinical Pharmacology of Antihypertensive and Antihypotensive Drugs.
Clinical Pharmacology of Cardiac Glycosides. Clinical Pharmacology of Diuretics
Clinical pharmacology of antianginal drugs
Angina
pectoris is a clinical syndrome characterized by episodes of chest pain. It
occurs when there is a deficit in myocardial oxygen supply (myocardial
ischemia) in relation to myocardial oxygen demand. It is most often caused by
atherosclerotic plaque in the coronary arteries but may also be caused by
coronary vasospasm. The development and progression of atherosclerotic plaque
is called coronary artery disease (CAD). Atherosclerotic plaque narrows the
lumen, decreases elasticity, and impairs dilation of coronary arteries. The
result is impaired blood flow to the myocardium, especially with exercise or
other factors that increase the cardiac workload and need for oxygen. The
continuum of CAD progresses from angina to myocardial infarction. There are
three main types of angina: classic angina, variant angina, and unstable
angina. The Canadian Cardiovascular Society classifies clients with angina according to the amount of physical activity they can
tolerate before anginal pain occurs. These categories can assist in clinical
assessment and evaluation of therapy.
Classic anginal pain is usually described as
substernal chest pain of a constricting, squeezing, or suffocating nature. It
may radiate to the jaw, neck, or shoulder, down the left or both arms, or to
the back. The discomfort is sometimes mistaken for arthritis, or for
indigestion, as the pain may be associated with nausea, vomiting, dizziness,
diaphoresis, shortness of breath, or fear of impending doom. The discomfort is
usually brief, typically lasting 5 minutes or less until the balance
of oxygen supply and demand is restored.
For clients at any stage of CAD development,
irrespective of symptoms of myocardial ischemia, optimal management involves
lifestyle changes and medications, if necessary, to control or reverse risk
factors for disease progression. Risk factors are frequently additive in nature
and are classified as nonmodifiable and modifiable. Nonmodifiable risk factors
include age, race, gender, and family history. The risk factors that can be
altered include smoking, hypertension, hyperlipidemia, obesity, sedentary
lifestyle, stress, and the use of drugs that increase cardiac workload (eg,
adrenergics, corticosteroids).
Thus, efforts are needed to assist clients
in reducing blood pressure, weight, and serum cholesterol levels, when
indicated, and developing an exercise program. For clients with diabetes
mellitus, glucose and blood pressure control can reduce the microvascular
changes associated with the condition. In addition, clients should avoid
circumstances known to precipitate acute attacks, and those who smoke should
stop. Smoking is harmful to clients because:
• Nicotine increases
catecholamines which, in turn, increase heart rate and blood pressure.
• Carboxyhemoglobin,
formed from the inhalation of carbon monoxide in smoke, decreases delivery of
blood and oxygen to the heart, decreases myocardial contractility, and increases the risks of
life-threatening cardiac dysrhythmias
(eg, ventricular fibrillation) during ischemic episodes.
• Both nicotine and
carbon monoxide increase platelet adhesiveness and aggregation, thereby
promoting thrombosis.
• Smoking increases
the risks for myocardial infarction, sudden cardiac death, cerebrovascular
disease (eg, stroke), peripheral vascular disease (eg, arterial insufficiency),
and hypertension. It also reduces high-density lipoprotein, the “good”
cholesterol.
Additional nonpharmacologic
management strategies include surgical revascularization (eg, coronary artery
bypass graft) and interventional procedures that reduce blockages (eg,
percutaneous transluminal coronary angioplasty [PTCA], intracoronary stents,
laser therapy, and rotoblators). However, most clients still require
antianginal and other cardiovascular medications to manage their disease.
ANTIANGINAL
DRUGS
Drugs used for
myocardial ischemia are the organic nitrates, the beta-adrenergic blocking
agents, and the calcium channel blocking agents. These drugs relieve anginal
pain by reducing myocardial oxygen demand or increasing blood supply to the
myocardium. Nitrates and beta blockers are described in the following sections
and dosage ranges are listed in Drugs at a Glance: Nitrates and Beta Blockers.
Calcium channel blockers are described in a following section; indications for
use and dosage ranges are listed in Drugs at a Glance: Calcium Channel
Blockers.
Organic nitrates (and nitrates) are
simple nitric and nitrous acid esters of alcohols. These compounds cause a
rapid reduction in myocardial oxygen demand followed by rapid relief of
symptoms. They are effective in stable and anstable angina, as well as
Prinzmetal’s or variant angina pectoris.
Nitrates, b-blockers,
and calcium channel-blockers are equally effective for relief of anginal
symptoms. However, for prompt relief of an ongoing attack of angina
precipitated by exercise or emotional stress, sublingual (or spray form) nitroglycerin (NITROSTAT) is the drug of choice.
Mechanisms
of action: The organic nitrates, such
as nitroglycerin, are thought to relax vascular smooth muscle by their
intracellular conversion to nitrite ions and then to nitric oxide (NO),
what leads to dephosphorylation of the
myosin light chain, resulting in vascular smooth muscle relaxation.
At therapeutic doses, nitroglycerin has
two major effects. First, it causes dilation of the large veins, resulting in
pooling blood in the veins. This
diminishes preload (venous return to the heart), and reduces the work of the
heart. Second, nitroglycerin dilates the coronary vasculature, providing
increased blood supply to the heart muscle. Nitroglycerin causes a decrease in
myocardial oxygen consumption because of decreased cardiac work.
Pharmacokinetics. The time to onset of
action varies from one minute for nitroglycerin to more than one hour for isosorbide mononitrate. Significant
first-pass metabolism of nitroglycerin occurs in the liver. Therefore, it
is common to give the drug either
sublingually or via a transdermal patch.
Adverse effects. The most common adverse effect of
nitroglycerin, as well as the other nitrates, is headache. 30 to 60 % of
patients receiving intermittent nitrate therapy with long-acting agents develop
headaches. High doses of organic nitrates can also cause postural hypotension,
facial flushing, and tachycardia.
Tolerance
to the actions of nitrates develops rapidly. It can be overcome by provision of
a daily “nitrate-free interval” to restore sensitivity to the drug. This
interval is typically 6 to 8, 10-12 hours, usually at night because there is
decreased demand on the heart at that time. Nitroglycerin patches are worn for
12 hours and removed for 12 hours. However, Prinzmetal’s or variant angina
worsens early in the morning, perhaps due to circardian catecholamine surges. These patients nitrate-free interval should
be late afternoon.
Nitroglycerin
Extended release Buccal Tablets (contain 1, 2, 2.5, 3, 5 mg of
nitroglycerin). When a buccal tablet is
placed under the lipp or in the buccal pouch, it adheres to the mucosa. As the
tablets gradually dissolves, it releases
nitroglycerin to the systemic circulation. Buccal nitroglycerin can be tried as
a means of aborting an acute anginal attack.
Nitroglycerin
tablets (NITROSTAT) – is a
stabilized sublingual formulation, which
contains 0,15, 0,3, 0,4,
0,6 mg of nitroglycerin. Nitroglycerin is rapidly absorbed
following sublingual administration. Its onset is approximately one to three
minutes. Significant pharmacologic effects are present for 30 to 60 minutes
following administration by the above route. Nitroglycerin is indicated for the
prophylaxis, treatment and management of patients with angina pectoris. One
tablet should be dissolved under the tongue or in the buccal pouch at the first
sign of an acute anginal attack. The
dose may be repeated approximately every
five minutes until relief is obtained. If the pain persists after a total of 3-tablets in a 15-minute period, drug
combination should be recommended.
Nitroglycerin (NITRO-BID)
2,5, 6,5, 9 mg capsules. Capsules must
be swollowed. Administer the
smallest effective dose two or three
times daily at 8 to 12 hours intervals. Contraindications: acute or recent myocardial infarction, severe
anemia, closed-angled glaucoma, postural hypotension, increased intracranial
pressure, and idiosyncrasy to the drug.
Nitroglycerin
injection – for intravenous use only. Must be diluted in
dextrose 5 % injection, or sodium chloride (0,9 %) injection.
Nitroglycerin should not be mixed with other drugs. The concentration of the infusion solution
should not exceed 400 mg/ml of nitroglycerin.
Indication and usage:
1.
Control of blood pressure in perioperative hypertension: hypertension associated with surgical
procedures, especially cardiovascular procedures, such as hypertension seen
during intratracheal intubation,
anesthesia, skin incision, sternotomy, cardiac bypass.
2.
Congestive heart failure associated with
acute myocardial infarction.
3.
Treatment of angina pectoris.
4.
Production of controlled hypotension during surgical procedures.
Nitroglycerin
2 % (NITRO-BID Ointment) (20-, 60-mg tubes) is indicated for the treatment and prevention of angina
pectoris due to coronary artery disease.
Controlled clinical trials have
demonstrated that this form of nitroglycerin is effective in improving exercise
tolerance in patients with exertional angina pectoris. Clinical trials have
shown significant improvement in exercise time until chest pain for up to six
hours after single aplication of various doses of nitroglycerin ointment (mean
doses ranged from 5 to 36 mg) to a 36-inch2 (150x150 mm) area of
trunk.
When applying the ointment, place the
dose-determining applicator supplied
with the package printed-side down and squeeze
the necessary amount of ointment from the tube onto the applicator. Then
place the applicator with the ointment-side down onto the desired area of skin,
usually the chest or back.. A suggested started
dose for NITRO-BID is 7,5 mg applied to a 1x3 inch area every 8 hours.
If angina pectoris occurs while the
ointment is in place, the dose should be increased, for example, to 1 inch on a 2x3 inch area. The frequency of dosing
may be also increased (eg, every 6 hours). An initiation of therapy or change of in dosage, blood
pressure (patient standing) should be monitored.
Isosorbide
dinitrate is an orally active nitrate. The drug is not readily
metabolized by the liver or smooth
muscle and has lower potency than nitroglycerin in relaxing vascular smooth
muscle.
Isosorbide dinitrate (Isordil, Sorbitrate) is used to reduce the frequency and severity of
acute anginal episodes. When given sublingually or in chewable tablets, it acts
in about 2 minutes, and its effects last 2 to 3 hours. When higher doses are
given orally, more drug escapes metabolism in the liver and produces systemic
effects in approximately 30 minutes. Therapeutic effects last about 4 hours
after oral administration. The effective oral dose is usually determined by
increasing the dose until headache occurs, indicating the maximum tolerable
dose. Sustained-release capsules also are available.
Isosorbide
mononitrate (Ismo, Imdur) is the
metabolite and active component of isosorbide dinitrate. It is well absorbed
after oral administration and almost 100% bioavailable. Unlike other oral
nitrates, this drug is not subject to first-pass hepatic metabolism. Onset of
action occurs within 1 hour, peak effects occur between 1 and 4 hours, and the
elimination half-life is approximately 5 hours. It is used only for prophylaxis
of angina; it does not act rapidly enough to relieve acute attacks.
The
beneficial and deleterious effects of nitrate-induced vasodilation are
summarized in Table 2.
Sympathetic
stimulation of beta1 receptors in the heart increases heart rate and force of
myocardial contraction, both of which increase myocardial oxygen demand and may
precipitate acute anginal attacks. Beta-blocking drugs prevent or inhibit
sympathetic stimulation. Thus, the drugs reduce heart rate and myocardial
contractility, particularly when sympathetic output is increased during
exercise. A slower heart rate may improve coronary blood flow to the ischemic
area. Beta blockers also reduce blood pressure, which in turn decreases
myocardial workload and oxygen demand. In angina pectoris, beta-adrenergic
blocking agents are used in long-term management to decrease the frequency and
severity of anginal attacks, decrease the need for sublingual nitroglycerin,
and increase exercise tolerance. When a beta blocker is being discontinued
after prolonged use, it should be tapered in dosage and gradually discontinued
or rebound angina can occur.
These drugs should not be given
to clients with known or suspected coronary artery spasms because they may
intensify the frequency and severity of vasospasm. This probably results from
unopposed stimulation of alpha-adrenergic receptors, which causes
vasoconstriction, when beta-adrenergic receptors are blocked by the drugs.
Clients who continue to smoke may have reduced efficacy with the use of beta
blockers. Clients with asthma should be observed for bronchospasm from blockage
of beta2 receptors in the lung. Beta blockers should be used with caution in
clients with diabetes mellitus because they can conceal signs of hypoglycemia
except for sweating).
The b-adrenergic blockers
agents supress the activation of the heart by blocking b1
receptors. They also reduce the work of the heart by decreasing cardiac output
and causing a slight decrease in blood pressure. Propranolol
is the prototype of this class of
compounds, but other b-blockers,
such as metoprolol and atenolol are equally effective.
Propranolol decreases the oxygen
requirement of heart muscle and therefore is effective in reducing the chest
pain on exertion that is common in angina. Propranolol is therefore useful in
the chronic management of stable angina (not for acute treatment). Tolerance to
moderate exercise is increased and this is noticeable by improvement in the
electrocardiogram. Agents with intrinsic sympathomymetic activity (for example,
pindolol and acebutolol) are less effective and should be avoided. The b-blockers reduce the frequency and severity oh angina
attacks. These agents are particularly useful in the treatment of patients with
myocardial infarction. The b-blockers can
be used with nitrates to increase exercise duration and tolerance. They are, however, contraindicated
in patients with diabetes, peripheral vascular disease, or chronic pulmonary
disease.
Propranolol is well absorbed after
oral administration. It is then metabolized extensively in the liver; a
relatively small proportion of an oral
dose (approximately 30%) reaches the systemic circulation. For this reason,
oral doses of propranolol are much higher than IV doses. Onset of action is 30
minutes after oral administration and 1 to 2 minutes after IV injection.
Because of variations in the degree of hepatic metabolism, clients vary widely
in the dosages required to maintain a therapeutic response.
Atenolol,
metoprolol, and nadolol have the same actions, uses, and adverse effects as
propranolol, but they have long half-lives and can be given once daily. They
are excreted by the kidneys, and dosage must be reduced in clients with renal
impairment.
Calcium
Channel Blocking Agents
Calcium channel
blockers act on contractile and conductive tissues of the heart and on vascular
smooth muscle. For these cells to function normally, the concentration of
intracellular calcium must be increased. This is usually accomplished by
movement of extracellular calcium ions into the cell (through calcium channels
in the cell membrane) and release of bound calcium from the sarcoplasmic
reticulum in the cell. Thus, calcium plays an important role in maintaining
vasomotor tone, myocardial contractility, and conduction. Calcium channel
blocking agents prevent the movement of extracellular calcium into the cell. As
a result, coronary and peripheral arteries are dilated, myocardial
contractility is decreased, and the conduction system is depressed in relation
to impulse formation (automaticity) and conduction velocity.
In angina pectoris, the drugs
improve the blood supply to the myocardium by dilating coronary arteries and
decrease the workload of the heart by dilating peripheral arteries. In variant
angina, calcium channe l blockers reduce coronary artery vasospasm. In atrial
fibrillation or flutter and other supraventricular tachydysrhythmias, diltiazem
and verapamil slow the rate of ventricular response. In hypertension, the drugs lower
blood pressure primarily by dilating peripheral arteries.
Calcium channel blockers are
well absorbed after oral administration but undergo extensive first-pass
metabolism in the liver. Most of the drugs are more than 90% protein bound and
reach peak plasma levels within 1 to 2 hours (6 hours or longer for
sustained-release forms). Most also have short elimination half-lives (<5
hours), so doses must be given three or four times daily unless
sustained-release formulations are used. Amlodipine (30 to 50 hours), bepridil
(24 hours), and felodipine (11 to 16 hours) have long elimination half-lives
and therefore can be given once daily. The drugs are metabolized in the liver, and
dosage should be reduced in clients with severe liver disease. Dosage
reductions are not required with renal disease. The calcium channel blockers
approved for use in the
The drugs also vary in
clinical indications for use; most are used for angina or hypertension, and
only diltiazem and verapamil are used to manage supraventricular
tachydysrhythmias. In clients with CAD, the drugs are effective as monotherapy
but are commonly prescribed in combination with beta blockers. In addition,
nimodipine is approved for use only in subarachnoid hemorrhage, in which it
decreases spasm in cerebral blood vessels and limits the extent of brain
damage. In animal studies, nimodipine exerted greater effects on cerebral
arteries than on other arteries, probably because it is highly lipid soluble
and penetrates the blood–brain barrier. Contraindications
include second- or third-degree heart block, cardiogenic shock, and severe
bradycardia, heart failure, or hypotension. The drugs should be used cautiously
with milder bradycardia, heart failure, or hypotension and with renal or
hepatic impairment.
The calcium channel blockers inhibit the entrance of calcium into
cardiac and smooth muscle cells of the coronary and systemic arterial beds. All
calcium channel blockers are therefore vasodilators that cause a decrease in
smooth muscle tone and vascular resistance. At clinical doses, these agents
affect primarily the resistance of vascular smooth muscle and the myocardium.
[Note: Verapamil mainly affects the
myocardium, whereas nifedipine
exertrs a greater effect on smooth muscle in the peripheral vasculature. Diltiazem is intermediate inits
actions].
Nifedipine (adalat) –
10, 20 mg capsules – functions mainly as
an arteriolar vasodilator. This drug has minimal effect on cardiac conduction
or heart rate. Nifedipine is
administered orally and has a short life (about 4 hours) requiring multiple
dosing. The vasodilation effect of nifedipine
is useful in the treatment of variant angina caused by spontaneous coronary
spasm.
Therapy should be initiated with 19 mg
capsule. The starting dose is one 10 mg calsule, swallowed whole, 3
times/day. The usual effective dose range is 10 20 mg three times daily.
Doses of 20-30 mg three or four times daily may be effective in patients with
evidence of coronary artery spasm. More
than 180 mg per day is not recommended. Nifedipine titration should proceed
over a 7-14 day period. A single dose should rarely exceed 30 mg.
Nifedipine
can cause
flushing, headeache, hypotension, and peripheral edema as side effects of its
vasodilation activity. The drug may cause reflex tachycardia if peripheral
vasodilation is marked resulting in a substantial decrease in blood pressure.
Verapamil slows cardiac
conduction directly and thus decreases heart rate and oxygen demand. Verapamil causes greater negative
inotropic effects than does nifedipine, but it is a weaker vasodilator. Verapamil is contraindicated
in patients with preexisting depressed cardiac function or AV condunction
abnormalities. It is also causes constipation. Verapamil should be used with caution in digitalized patients,
since it increases digoxin levels.
Diltiazem
has cardiovascular effects thah are
similar to those of verapamil. It reducws the heart rate, although to a lesser
extent than verapamil, and also decreases blood pressure. In addition, diltiazem can relieve coronary artery
spasm and is therefore particularly useful in patients with variant angina. The
incidence of adverse side effects is low.
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Adjunctive Antianginal Drugs
In addition to antianginal drugs,
several other drugs may be used to control risk factors and prevent progression
of myocardial ischemia to myocardial infarction and sudden cardiac death. These
may include:
• Aspirin. This drug has become the standard of care because of its
antiplatelet (ie, antithrombotic) effects. Recommended doses vary from 81 mg
daily to 325 mg daily or every other day; apparently all doses are beneficial
in reducing the possibility of myocardial reinfarction, stroke, and death.
Clopidogrel, 75 mg/day,
is an acceptable alternative for individuals with
aspirin allergy.
• Antilipemics. These drugs may be needed by clients who are unable to
lower serum cholesterol levels sufficiently with a low-fat diet. Lovastatin or
a related “statin” is often used. The goal is usually to reduce the serum
cholesterol level below 200 mg/dL and lowdensity lipoprotein cholesterol to
below 130 mg/dL.
• Antihypertensives. These drugs may
be needed for clients with hypertension. Because beta blockers and calcium
channel blockers are used to manage hypertension as well as angina, one of
these drugs may be effective for both disorders.
PRINCIPLES
OF THERAPY
Goals of Therapy
The goals of drug therapy are to
relieve acute anginal pain; reduce the number and severity of acute anginal
attacks; improve exercise tolerance and quality of life; delay progression of
CAD; prevent myocardial infarction; and prevent sudden cardiac death.
Choice
of Drug and Dosage Form
For relief of
acute angina and prophylaxis before events that cause acute angina,
nitroglycerin (sublingual tablets or translingual spray) is usually the primary
drug of choice. Sublingual or chewable tablets of isosorbide dinitrate also may
be used. For long-term prevention or management of recurrent angina, oral or
topical nitrates, beta-adrenergic blocking agents, or calcium channel blocking
agents are used.
Combination
drug therapy with a nitrate and one of the other drugs is common and effective.
Clients taking one or more long-acting antianginal drugs should carry a
short-acting drug as well, to be used for acute attacks.
Titration of Dosage
Dosage of all antianginal drugs should be
individualized to achieve optimal benefit and minimal adverse effects. This is
usually accomplished by starting with relatively small doses and increasing
them at appropriate intervals as necessary. Doses may vary widely among
individuals.
Tolerance to
Long-Acting Nitrates
Clients who take long-acting dosage
forms of nitrates on a regular schedule develop tolerance to the vasodilating
(antianginal) effects of the drug. The clients more likely to develop tolerance
are those on high-dose, uninterrupted therapy. Although tolerance decreases the
adverse effects of hypotension, dizziness, and headache, therapeutic effects
also may be decreased. As a result, episodes of chest pain may occur more often
or be more severe than expected. In addition, shortacting nitrates may be less
effective in relieving acute pain. Opinions seem divided about the best way to
prevent or manage nitrate tolerance. Some authorities recommend using short-acting
nitrates when needed and avoiding the long-acting forms. Others recommend using
the long-acting forms for 12 to 16 hours daily during active periods and
omitting them during inactive periods or sleep.
Thus, a dose of an oral nitrate or
topical ointment would be given every 6 hours for three doses daily, allowing a
rest period of 6 hours without a dose. Transdermal discs should be removed at
bedtime. If anginal symptoms occur during sleeping hours, short-acting nitrates
may be beneficial in relieving the symptoms. All nitrates should be
administered at the lowest effective dosage.
Use in Children
The safety and effectiveness of
antianginal drugs have not been established for children. Nitroglycerin has
been given IV for heart failure and intraoperative control of blood pressure,
with the initial dose adjusted for weight and later doses titrated to response.
Use in Older Adults
Antianginal drugs are often used
because cardiovascular disease and myocardial ischemia are common problems in
older adults. Adverse drug effects, such as hypotension and syncope, are likely
to occur, and they may be more severe than in younger adults. Blood pressure
and ability to ambulate safely should be closely monitored, especially when
drug therapy is started or dosages are increased. Ambulatory clients also
should be monitored for their ability to take the drugs correctly.
With calcium channel blockers, older
adults may have higher plasma concentrations of verapamil, diltiazem,
nifedipine, and amlodipine. This is attributed to decreased hepatic metabolism
of the drugs, probably because of decreased hepatic blood flow. In addition,
older adults may experience more hypotension with verapamil, nifedipine, and
felodipine than younger clients. Blood pressure should be monitored with these
drugs.
Use in Renal
Impairment
Little information is available
about the use of antianginal drugs in clients with impaired renal function. A
few studies indicate that advanced renal failure may alter the pharmacokinetics
of calcium channel blockers. Although the pharmacokinetics of diltiazem and
verapamil are quite similar in clients with normal and impaired renal function,
caution is still advised. With verapamil, about 70% of a dose is excreted as
metabolites in urine.
Dosage
reductions are considered unnecessary with verapamil and diltiazem but may be
needed with nifedipine and several other dihydropyridine derivatives. With
nifedipine, protein binding is decreased and the elimination half-life is
prolonged with renal impairment. In a few clients, reversible elevations in
blood urea nitrogen and serum creatinine have occurred. With nicardipine,
plasma concentrations are higher in clients with renal impairment, and dosage
should be reduced. Bepridil should be used with caution because its metabolites
are excreted mainly in urine.
Use in Hepatic
Impairment
Nitrates, beta blockers, and
calcium channel blockers are metabolized in the liver, and all should be used
with caution in clients with significant impairment of hepatic function from reduced
blood flow or disease processes.
With oral nitrates, it is difficult
to predict effects. On the one hand, first-pass metabolism is reduced, which
increases bioavailability (amount of active drug) of a given dose. On the other
hand, the nitrate reductase enzymes that normally deactivate the drug may
increase if large doses are given. In this case, more enzymes are available and
the drug is metabolized more rapidly, possibly reducing therapeutic effects of
a given dose. Relatively large doses of oral nitrates are sometimes given to
counteract the drug tolerance (reduced hemodynamic effects) associated with
chronic use. In addition, metabolism of nitroglycerin and isosorbide dinitrate
normally produces active metabolites. Thus, if metabolism is reduced by liver
impairment, drug effects may be decreased and shorter in duration.
With calcium channel blockers,
impairment of liver function has profound effects on the pharmacokinetics and
pharmacodynamics of most of these drugs. Thus, the drugs should be used with
caution, dosages should be substantially reduced, and clients should be closely
monitored for drug effects (including periodic measurements of liver enzymes).
These recommendations stem from the following effects:
• An
impaired liver produces fewer drug-binding plasma proteins such as albumin.
This means that a greater proportion of a given dose is unbound and therefore
active.
• In
clients with cirrhosis, bioavailability of oral drugs is greatly increased and
metabolism (of both oral and parenteral drugs) is greatly decreased. Both of
these effects increase plasma levels of drug from a given dose (essentially an
overdose). The effects result from shunting of blood around the liver so that
drug molecules circulating in the bloodstream do not come in contact with
drug-metabolizing enzymes and therefore are not metabolized. For example, the
bioavailability of verapamil, nifedipine, felodipine, and nisoldipine is
approximately double and their clearance is approximately one third that of
clients without cirrhosis.
• Although
hepatotoxicity is uncommon, clinical symptoms of hepatitis, cholestasis, or
jaundice and elevated liver enzymes (eg, alkaline phosphatase, creatine kinase
[CK], lactate dehydrogenase [LDH], aspartate aminotransferase [AST], alanine
aminotransferase [ALT]) have occurred, mainly with diltiazem, nifedipine, and
verapamil. These changes resolve if the causative drug is stopped.
Use in Critical
Illness
Antianginal drugs have multiple
cardiovascular effects and may be used alone or in combination with other
cardiovascular drugs in clients with critical illness. They are probably used
most often to manage severe angina, severe hypertension, or serious cardiac
dysrhythmias. For example, IV nitroglycerin may be used for angina and
hypertension; an IV beta blocker or calcium channel blocker may be used to
improve cardiovascular function with angina, hypertens ion, or supraventricular
tachydysrhythmias. With any of these drugs, dosage must be carefully titrated
and clients must be closely monitored for hypotension and other drug effects.
In addition, absorption of oral
drugs or topical forms of nitroglycerin may be impaired in clients with
extensive edema, heart failure, hypotension, or other conditions that impair
blood flow to the gastrointestinal tract or skin.
CARDIAC DYSRHYTHMIAS
Cardiac
arrhythmias are a common problem in clinical practice, occurring in up to 25%
of patients treated with digitalis, 50% of anesthetized patients, and over 80%
of patients with acute myocardial infarction. Arrhythmias may require treatment
because rhythms that are too rapid, too slow, or asynchronous can reduce
cardiac output. Some arrhythmias can precipitate more serious or even lethal
rhythm disturbances; for example, early premature ventricular depolarizations
can precipitate ventricular fibrillation. In such patients, antiarrhythmic
drugs may be precipitate ventricular fibrillation. In such patients,
antiarrhythmic drugs may be lifesaving. On the other hand, the hazards of
antiarrhythmic drugs—and in particular the fact that they can precipitate
lethal arrhythmias in some patients—has led to a reevaluation of their relative
risks and benefits. In general, treatment of asymptomatic or minimally
symptomatic arrhythmias should be avoided for this reason.
Cardiac dysrhythmias can
originate in any part of the conduction system or from atrial or ventricular
muscle. They result from disturbances in electrical impulse formation
(automaticity), conduction (conductivity), or both. The characteristic of
automaticity allows myocardial cells other than the SA node to depolarize and
initiate the electrical impulse that culminates in atrial and ventricular
contraction. This may occur when the SA node fails to initiate an impulse or
does so too slowly. When the electrical impulse arises anywhere other than the
SA node, it is an abnormal or ectopic focus. If the ectopic focus depolarizes
at a rate faster than the SA node, the ectopic focus becomes the dominant
pacemaker. Ectopic pacemakers may arise in the atria, AV node, Purkinje fibers,
or ventricular muscle. They may be activated by hypoxia, ischemia, or
hypokalemia. Ectopic foci indicate myocardial irritability (increased
responsiveness to stimuli) and potentially serious impairment of cardiac
function.
A common mechanism by which
abnormal conduction causes dysrhythmias is called reentry excitation. During normal conduction, the electrical
impulse moves freely down the conduction system until it reaches recently
excited tissue that is refractory to stimulation. This causes the impulse to be
extinguished. The SA node then recovers, fires spontaneously, and the
conduction process starts over again. Reentry excitation means that an impulse
continues to reenter an area of the heart rather than becoming extinguished.
For this to occur, the impulse must encounter an obstacle in the normal
conducting pathway. The obstacle is usually an area of damage, such as
myocardial infarction. The damaged area allows conduction in only one direction
and causes a circular movement of the impulse.
Dysrhythmias may be mild or severe,
acute or chronic, episodic or relatively continuous. They are clinically
significant if they interfere with cardiac function (ie, the heart’s abil-ity
to pump sufficient blood to body tissues). The normal heartcan maintain an
adequate cardiac output with ventricular rates ranging from 40 to 180 beats per
minute. The diseased heart, however, may not be able to maintain an adequate
cardiac output with heart rates below 60 or above 120. Dysrhythmias are usually
categorized by rate, location, or patterns of conduction.
BRADYCARDIAS
AND HEART BLOCK
Bradycardias
may be due to failure of impulse formation (sinus bradycardia) or failure of
impulse conduction from the atria to the ventricles (atrioventricular block).
Bradycardia
Sinus bradycardia
Sinus
bradycardia is due to extrinsic factors influencing a relatively normal sinus
node or due to intrinsic sinus node disease. The mechanism can be acute and
reversible or chronic and degenerative. Common causes of sinus bradycardia
include:
Extrinsic causes
■ hypothermia,
hypothyroidism, cholestatic jaundice and raised intracranial pressure
■ drug therapy with
beta-blockers, digitalis and other antiarrhythmic drugs
■ neurally mediated
syndromes.
Intrinsic causes
■ acute ischaemia and
infarction of the sinus node (as a complication of acute myocardial infarction)
■ chronic degenerative
changes such as fibrosis of the atrium and sinus node (sick sinus syndrome).
Sick sinus syndrome or
sinoatrial disease is usually caused by idiopathic fibrosis of the sinus node.
Other causes of fibrosis such as ischaemic heart disease, cardiomyopathy or
myocarditis can also cause the syndrome. Patients develop episodes of sinus
bradycardia or sinus arrest and commonly, owing to diffuse atrial disease,
experience paroxysmal atrial tachyarrhythmias (tachy-bradysyndrome).
Neurally mediated
syndromes
Neurally
mediated syndromes are due to a reflex (called Bezold–Jarisch) that may result
in both bradycardia (sinus bradycardia, sinus arrest and AV block) and reflex
peripheral vasodilatation. These syndromes usually present as syncope or
pre-syncope (dizzy spells).
Carotid sinus
syndrome occurs in the elderly and mainly results in bradycardia. Syncope
occurs.
Neurocardiogenic
(vasovagal) syncope (syndrome) usually presents in young adults but may present
for the first time in elderly patients. It results from a variety of situations
(physical and emotional) that affect the autonomic nervous system. The efferent
output may be predominantly bradycardic, predominantly vasodilatory or mixed.
Postural
orthostatic tachycardia syndrome (POTS) is a sudden and significant increase in
heart rate associated with normal or mildly reduced blood pressure produced by
standing.
The underlying
mechanism is a failure of the peripheral vasculature to appropriately constrict
in response to orthostatic stress, which is compensated by an excessive
increase in heart rate.
Many
medications, such as antihypertensives, tricyclic antidepressants and
neuroleptics can be the cause of syncope, particularly in the elderly. Careful
dose titration and avoidance of combining two agents with potential to cause
syncope help to prevent iatrogenic syncope.
Treatment
The management
of sinus bradycardia is first to identify and if possible remove any extrinsic
causes. Temporary pacing may be employed in patients with reversible causes
until a normal sinus rate is restored and in patients with chronic degenerative
conditions until a permanent pacemaker is implanted.
Chronic
symptomatic sick sinus syndrome requires permanent pacing (DDD), with
additional antiarrhythmic drugs (or ablation therapy) to manage any tachycardia
element. Thromboembolism is common in tachy-brady syndrome and patients should
be anticoagulated unless there is a contraindication. Patients with carotid
sinus hypersensitivity (asystole > 3 s), especially if symptoms are
reproduced by carotid sinus massage, and in whom life-threatening causes of
syncope have been excluded, benefit from pacemaker implantation. Treatment options
in vasovagal attacks include avoidance, if possible, of situations known to
cause syncope in a particular patient. Increased salt intake, compression of
the lower legs with hose and drugs such as beta-blockers, alpha-agonists or
myocardial negative inotropes (such as disopyramide) may be helpful. In
selected patients with ‘malignant’ neurocardiogenic syncope (syncope associated
with injuries) permanent pacemaker therapy is helpful. These patients benefit
from dual chamber pacemakers with a feature called ‘rate drop response’ which,
once activated, paces the heart at a fast rate for a set period of time in
order to prevent syncope.
Heart
block
Heart block or
conduction block may occur at any level in the conducting system. Block in
either the AV node or the His bundle results in AV block, whereas block lower
in the conduction system produces bundle branch block.
Atrioventricular
block
There are three
forms:
First-degree AV block
This is simple prolongation of
the PR interval to more than 0.22 s. Every atrial depolarization is followed by
conduction to the ventricles but with delay (Fig.).
An ECG showing
first-degree atrioventricular block with a prolonged PR interval. In this trace
coincidental ST depression is also present.
Three varieties of seconddegree
atrioventricular (AV) block. (a) Wenckebach (Mobitz type I) AV block. The PR interval gradually
prolongs until the P wave does not conduct to the ventricles (arrows). (b)
Mobitz type II AV block. The P waves that do not conduct to the ventricles
(arrows) are not preceded by gradual PR interval prolongation. (c) Two P
waves to each QRS complex. The PR interval prior to the dropped P wave is
always the same. It is not possible to define this type of AV block as type I
or type II Mobitz block and it is, therefore, a third variety of second-degree
AV block (arrows show P waves).
Two examples of complete heart
block. (a)
Congenital complete heart block. The QRS complex is narrow (0.08 s) and the
QRS rate is relatively rapid (52 b.p.m.). (b) Acquired complete heart block.
The QRS complex is broad (0.13 s) and the QRS rate is relatively slow (38
b.p.m.).
Second-degree AV
block
This occurs when some P waves
conduct and others do not.
There are several forms (Fig.):
■ Mobitz I block
(Wenckebach block phenomenon) is progressive PR interval prolongation until a P
wave fails to conduct. The PR interval before the blocked P wave is much longer
than the PR interval after the blocked P wave.
■ Mobitz II block occurs
when a dropped QRS complex is not preceded by progressive PR interval
prolongation. Usually the QRS complex is wide (> 0.12 s). Usually the QRS
complex is wide (> 0.12 s).
■ 2 : 1 or 3 : 1
(advanced) block occurs when every second or third P wave conducts to the
ventricles. This form of second-degree block is neither Mobitz I nor II.
Wenckebach AV block in general is due to block in the AV node, whereas Mobitz
II block signifies block at an infranodal level such as the His bundle. The
risk of progression to complete heart block is greater and the reliability of
the resultant escape rhythm is less with Mobitz II block. Therefore pacing is
usually indicated in Mobitz II block, whereas patients with Wenckebach AV block
are usually monitored. Acute myocardial infarction may produce second-degree
heart block. In inferior myocardial infarction, close monitoring and
transcutaneous temporary back-up pacing are all that is required. In anterior
myocardial infarction, second-degree heart block is associated with a high risk
of progression to complete heart block, and temporary pacing followed by
permanent pacemaker implantation is usually indicated. 2 : 1 Heart block may
either be due to block in the AV node or at an infra-nodal level. Management
depends on the clinical setting in which it occurs.
Third-degree
(complete) AV block
Complete heart
block occurs when all atrial activity fails to conduct to the ventricles
(Fig.). In patients with complete heart block the aetiology needs to be
established. In this situation life is maintained by a spontaneous escape
rhythm.
Narrow complex escape rhythm
(< 0.12 s QRS complex) implies that it originates in the His bundle and
therefore that the region of block lies more proximally in the AV node. The
escape rhythm occurs with an adequate rate (50–60 b.p.m.) and is relatively reliable.
Treatment depends on the aetiology. Recent-onset
narrow-complex AV block due to transient causes may respond to intravenous
atropine, but temporary pacing facilities should be available for the
management of these patients. Chronic narrow-complex AV block requires
permanent pacing (dual chamber) if it is symptomatic or associated with heart
disease. Pacing is also advocated for isolated,
congenital AV block, even if
asymptomatic. Broad complex escape rhythm (> 0.12 s) implies that the escape
rhythm originates below the His bundle and therefore that the region of block
lies more distally in the His–Purkinje system.
The resulting
rhythm is slow (15–40 b.p.m.) and relatively unreliable. Dizziness and
blackouts (Stokes–Adams attacks) often occur. In the elderly, it is usually
caused by degenerative fibrosis and calcification of the distal conduction
system (Lev’s disease). In younger individuals, a proximal progressive cardiac
conduction disease due to the inflammatory process is known as Lenegre’s
syndrome. Sodium channel abnormalities have been identified in both syndromes.
Broad-complex AV block may also be caused by ischaemic heart disease,
myocarditis or cardiomyopathy. Permanent pacemaker implantation is indicated,
as pacing considerably reduces the mortality. Because ventricular arrhythmias
are not uncommon, an implantable cardioverter–defibrillator (ICD) may be
indicated in those with severe left ventricular dysfunction (> 0.30 s).
Antiarrhythmic agents
Antidysrhythmic agents are diverse drugs used for
prevention and management of cardiac dysrhythmias. Dysrhythmias, also called
arrhythmias, are abnormalities in heart rate or rhythm. They become significant
when they interfere with cardiac function and ability to perfuse body tissues.
To aid in understanding of dysrhythmias and antidysrhythmic drug therapy, the
physiology of cardiac conduction and contractility is reviewed.
Effects of drugs on automaticity: Most of antiarrhythmic agents suppress
automaticity (1) by decreasing the slope of diastolic depolarization and/or by raising the threshold of discharge to a less negative
voltage. Such drugs cause the frequency of discharge to decrease, an effect
that is more pronounced in cells with
ectopic pacemaker activity than in normal cells.
Indications for Use
Antidysrhythmic drug therapy commonly is indicated
in the following conditions:
1. To convert atrial fibrillation (AF) or flutter
to normalsinus rhythm (NSR)
2. To maintain NSR after conversion from AF or
flutter
3. When the ventricular rate is so fast or
irregular that cardiac output is impaired. Decreased cardiac output leads to
symptoms of decreased systemic, cerebral, and coronary circulation.
4. When dangerous dysrhythmias occur and may be
fatal if not quickly terminated. For example, ventricular tachycardia may cause
cardiac arrest.
Effects
of drugs on conduction abnormalities: Antiarrhythmic agents prevent reentry
by slowing conduction and/or increasing
the refractory period to convent a unidirectional block into a bidirectional
block.
As noted above, the antiarrhythmic
drugs can modify impulse generation and conduction. More than
a dozen such drugs that are patentially usefull in treating arrhythmias are currently available. However, only a limited number of these
agents are clinically beneficial in the treatment of selected
arrhythmias. For example, the acute termination
of ventricular tachycardia by lidocaine
or supraventricular tachycardia by adenosine or verapamil
are examples in which antiarrhythmic
therapy results in decreased morbidity. In contrast, many of the antiarrhythmic
agents are now known to have lethal proarrhythmic actions, that is, to cause
arrhythmias.
The antiarrhythmic drugs can be
classified according to their
predominant effects on the action potential. Although this classification is convenient,
it is not entirely clear-cut, because many of the drugs have actions relating
to more than one class or they have active metabolites with a different class
of action.
Classification of antiarrhythmic drugs
|
CLASS |
Mechanism
of Action |
Drug
name |
|
IA |
Na+Channel
blocker |
Disopyramide,
procainamide, quinidine |
|
IB |
Na+Channel
blocker |
Lidocaine,
mexiletine, tocainide |
|
IC |
Na+Channel
blocker |
Flecainide,
propafenone |
|
II |
b
Adrenoreceptor blocker |
Esmolol,
metoprolol, pindolol, propranolol |
|
III |
K+Channel
blocker |
Amiodarone,
bretylium, sotalol |
|
IV |
Ca++
Channel blocker |
Diltiazem,
verapamil |
|
Other
antiarrhythmic drugs |
Adenosine,
digoxin |
|
Class
I drugs have been subdivided into three groups according to
their effect on the duration of the action potential.
Quinidine (200, 300 mg)
is the prototype
Procainamide (500 mg) –
this Class IA drug, a derivative of the local anesthetic procaine, shows
actions similar to those of quinidine. Adverse effects:
With chronic use procainamide causes a high incidence of side effects,
including a reversible lupus erythematosus-like syndrome that develops in 25 to
30 % of patients. Toxic concentrations of procainamide may cause asystole
or induction of ventricular arrhythmias. Central nervous system side effects
include depression, hallucination and psychosis. With this drug,
gastrointestinal intolreance is less
frequent than with quinidine.
Disopyramide (caps. 100, 150
mg) produces a negative inotropic effect that is greater than
the weak effect exerted by quinidine and procainamide, and unlike the latter
drugs, disopyramide causes peripheral
vasoconstriction. The drug may produce a clinically important decrease in myocardial contractility in
patients with preexisting impairment of left ventricular function. Disopyramide
is used for treatment of ventricular arrhythmias as an alternative to procainamide or quinidine. Adverse
effects: Disopyramide shows
effects of anticholinergic activity, for ex., dry mouth, urinary retention,
blurred vision, and constipation.
Lidocaine (amp. 1 % 10,
20 ml [10 mg/ml]; 2 % 2, 10 ml[20 mg/ml]) is a Class
IB drug. The IB agents rapidly associate
and dissociate from sodium channels.
Class IB drugs are particularly useful in treating ventricular arrhythmias. Lidocaine is the drug of choice for
emergency treatment of cardiac arrhythmias. Unlike quinidine, which suppresses arrhythmias caused by increased normal
automaticity, lidocaine suppresses
arrhythmias caused by abnormal automaticity. Lidocaine, like quinidine, abolishes
ventricular reentry. Lidocaine is
useful in treating ventricular arrhythmias arising during myocardial ischemia,
such as that experienced during a myocardial infarction. The drug does not
markedly slow conduction and thus has little effect on atrial or AV junction
arrhythmias. Lidocaine is given
intravenously because of extensive first-pass transformation by the liver,
which precludes oral administration. Lidocaine
has fairly wode toxic-to-therapeutic ratio; it shows little impairment of left
ventricular function, and has no negative inotropic effect. The CNS effects include drowsiness, slurred
speech, paresthesia, agitation, confusion, and convulsions; cardiac arrhythmias
may also occur.
Mexiletine (caps. 150, 200, 250 mg) and tocainide (tab. 400 mg) are Class IB drugs with actions similar to those of lidocaine. These agents can be administered orally. Tocainide
has pulmonary toxicity, which may lead to pulmonary fibrosis.
Flecainide (tab. 50, 100, 150
mg) is a Class IC drug.
These drugs are approved only for
refractory ventricular arrhythmias. It is particularly useful in suppressing
premature ventricular contraction. Flecainide has a negative
inotropic effect and can aggravate congestive heart failure. Flecainide is absorbed orally and has a
half-life of 16 to 20 hours. Flecainide
can cause dizziness, blured vision,
headache, and nausea. Like other Class IC drugs, flecainide can aggravate preexisting arrhythmias or induce life-threatening ventricular tachycardia that is resistant to
treatment.
Propafenone
(tab. 150, 300 mg) is Class IC drug shows actions similar to those of flecainide.
The
Class II agents
include the b-adrenergic
antagonists. These drugs diminish Phase 4 depolarisation, thus depressing
automaticity, prolonging AV conduction,
and decreasing heart rate and contractility.
These agents
exert antidysrhythmic effects by blocking sympathetic nervous system
stimulation of beta receptors in the heart and decreasing risks of ventricular
fibrillation. Blockage of receptors in the SA node and ectopic pacemakers
decreases automaticity, and blockage of receptors in the AV node increases the
refractory period. The drugs are effective for management of supraventricular
dysrhythmias and those resulting from excessive sympathetic activity. Thus,
they are most often used to slow the ventricular rate of contraction in
supraventricular tachydysrhythmias (eg, AF, atrial flutter, paroxysmal
supraventricular tachycardia [PSVT]).
As a class, beta blockers
are being used more extensively because of their effectiveness and their
ability to reduce mortality in a variety
of clinical settings, including post–myocardial
infarction and heart failure. Reduced mortality may result from the drugs’ ability to prevent ventricular
fibrillation.Only four of the beta blockers marketed in the United States are
approved by the Food and Drug Administration (FDA) for management of
dysrhythmias.
Class II
agents are useful in treating tachyarrhythmias caused by increased sympathetic activity. They are also used for
atrial flutter and fibrillation, and for AV nodal reentrant tachycardia.
Propranolol
(tab. 10, 20, 40, 60, 80 mg) (a nonselective b-antagonist)
reduces the incidence of sudden arrhythmic death after myocardial infarction (the most common
cause of death in this group of
patients). Propranolol diminishes cardiac output, having both
negative inotropic and chronotropic effects. It directly depresses
sino-auricular and atrioventricular
activity. The b-blockers
are effective in attenuating supraventricular cardiac arrhythmias but are
generally not effective against ventricular arrhythmias. Propranolol has a serious
and potentially lethal side effect when
administered to an asthmatic. An immediate contraction of the bronchiolar
smooth muscle prevents air from entering the lungs. Therefore, propranolol must never be used in
treating any individual with obstructive pulmonary disease. Treatment with the b-blockers
must never be stopped quickly because of the risk of precipitating cardiac arrhythmias, which may be severe. The b-blockers
must be tapered off gradually for 1 week.
Long-term treatment with a b-antagonists
leads to up-regulation of the b-receptor.
Some men do complain of impaired sexual activity. Fasting hypoglycemia may occur. Drugs that interfere with the metabolism of
propranolol, such as cimetidine, furosemide, and chlorpromazine. May potentiate
its antihypertensive effects.
Drugs that preferentially block the b1
receptors have been developed to eliminate the unwanted bronchoconstrictor
effect (b2)
of propranolol seen among asthmatic patients. Cardioselective b-blockers,
such as metoprolol (tab. 50, 100 mg,
amp. 5 ml), esmolol (amp. 10 ml (2.5
g) 250 mg/ml), antagonize b1
receptors at doses 50 to 100 times less than those required to block b2
receptors. This cardioselectivity is
thus most pronounced at low doses and is lost at high drug doses. Esmolol is a very short-acting b
blocker used for intravenous administration in acute arrhythmias occurring
during surgery or emergency situations.
Class
III agents block potassium channels and thus diminish the
outward potassium current during repolarization of cardiac cells. They prolong
the effective refractory period. All Class III drugs have the potential to induce arrhythmias.
Although the drugs share a common mechanism of
action, they are very different drugs. As with beta blockers, clinical use of
class III agents is increasing because they are associated with less
ventricular fibrillation and decreased mortality compared with class I drugs.
Sotalol (tab.
80, 160 mg), although a class III antiarrhythmic agent,
also has potent b-blocker activity. Sotalol blocks a rapid outward potassium
current, known as the delayed
rectifier. b-blockers
are used for long-term therapy to decrease the rate of sudden death following an acute myocardial
infarction. They have strong
antifibrillary effects, particularly in the ischemic myocardium.
Sotalol was more effective
in preventing arrhythmia recurrence and
in decreasing mortality than imipramine, mexiletine, procainamide, propafenone
and quinidine in patients with sustained ventricular tachycardia. As with all
drugs that prolong the QT interval, the syndrome of
torside de pointes is a serious
potential effect, typically seen in 3 to 4 % of patients.
Bretylium (amp. 10 ml - 500
mg) is
reserved for the life-treatening
ventricular arrhythmias, especially recurrent ventricular fibrillation or
tachycardia. Bretylium initially
increases release of catecholamines and therefore increases heart rate, blood
pressure, and myocardial contractility. This is followed in a few minutes by a
decrease in vascular resistance, blood pressure, and heart rate. It is used
primarily in critical care settings for acute control of recurrent ventricular
fibrillation, especially in clients with recent myocardial infarction. It is
given by IV infusion, with a loading dose followed by a maintenance dose, or in
repeated IV injections. Because it is excreted almost entirely by the kidney,
drug half-life is prolonged with renal impairment and dosage must be reduced.
Adverse effects include hypotension and dysrhythmias.
Amiodarone
(tab. 200 mg) is effective in the treatment of severe refractory supraventricular avd
ventricular tachyarrhythmia. Its dominant effect is prolongation of the action
potential duration and the refractory period. Amiodarone has antianginal as well as antiarrhythmic activity. But its clinical usefulness is limited by its toxicity. Amiodarone is incompletely absorbed
after oral administration. The drug is
unusual in having a prolonged half-life of several weeks. Full clinical effects may not be achieved
until 6 weeks after of treatment.
Although
classified as a potassium channel blocker, amiodarone
also has electrophysiologic characteristics of sodium channel blockers,
beta blockers, and calcium channel blockers. Thus, it has vasodilating effects
and decreases systemicvascular resistance; it prolongs conduction in all
cardiac tissues and decreases heart rate; and it decreases contractility of the
left ventricle. Intravenous and oral amiodarone differ in their
electrophysiologic effects. When given IV, the major effect is slowing
conduction through the AV node and prolonging the effective refractory period.
Thus, it is given IV mainly for acute suppression of refractory,
hemodynamically destabilizing ventricular tachycardia and ventricular
fibrillation. It is given orally to treat recurrent ventricular tachycardia or
ventricular
fibrillation and to maintain a NSR after conversion of
AF and flutter. Low doses (100 to 200 mg/day) may preventrecurrence of AF with
less toxicity than higher doses of amiodarone or usual doses of other agents,
including quinidine.
Amiodarone
shows a variety of toxic effects. After long-term use, more than one half of the
patients receiving the drug show side effects sufficiently severe to prompt its
discontinuation. Some of the more common effects include interstial pulmonary fibrosis,
gastrointestinal tract intolerance, tremor, ataxia, dizziness, hyper- or
hypothyroidism, liver toxicity, photosensitivity, neuropathy, muscle weakness, and blue skin
discoloration caused by iodine accumulation in the skin. Recent clinical trials have shown that amiodarone did not reduce incidence of sudden death or prolong survival in patients with
congestive heart failure. Adverse
effects include hypothyroidism, hyperthyroidism, pulmonary fibrosis, myocardial
depression, hypotension, bradycardia, hepatic dysfunction, central nervous
system (CNS) disturbances (depression, insomnia, nightmares, hallucinations),
peripheral neuropathy and muscle weakness,
bluish discoloration of skin and corneal deposits that may cause
photosensitivity, appearance of colored halos around lights, and reduced visual
acuity. Most adverse effects
areconsidered dose dependent and reversible.
Ibutilide
is indicated for management of
recent onset of AF or atrial flutter, in which the goal is conversion to NSR.
The drug enhances the efficacy of cardioversion. Ibutilide is structurally
similar to sotalol but lacks clinically significant beta-blocking activity.
Ibutilide is widely distributed and has an elimination half-life of about 6
hours. Most of a dose is metabolized, and the metabolites are excreted in urine
and feces. Adverse effects include supraventricular and ventricular
dysrhythmias (particularly torsades de pointes) and hypotension. Ibutilide
should be administered in a setting with personnel and equipment available for
emergency use.
Dofetilide
is indicated for the maintenance
of normal sinus rhythm in symptomatic clients who are in AF of more than
one-week duration. Adverse effects increase with decreasing creatinine
clearance levels so renal function must be assessed and initial dosage is
dependent on creatinine clearance levels. High dosages in clients with renal
dysfunction result in drug accumulation and prodysrhythmia (torsades de
pointes). The drug has an elimination half-life of approximately 8 hours with
the kidneys being the major route of elimination. The drug should initially be
administered in a setting with personnel and equipment available for emergency
use.
The
Class IV drugs are calcium channel blockers. They decrease
the inward current carried by calcium and slowed
conduction in tissues dependent on calcium currents, such as the AV
node.
Verapamil
and diltiazem.
Verapamil (tab. 40, 80, 120, 240 mg)
shows greater action on the heart than
on vascular smooth muscle, whereas nifedipine,
a calcium channel-blocker used to treat hypertension exerts a stronger effect on vascular smooth muscle than on the
heart. Diltiazem (tab. 30, 60, 90, 120 mg) is intermediate in its actions. Verapamil and diltiazem bind
only to open, depolarized channels, thus
preventing repolarization until the drug
dissociates from the channel. These
drugs are therefore use-dependent, that
is, they block most effectively when the
heart beating rapidly, since in a normally paced heart, the calcium channels
have time to repolarize, and the bound
drug dissociates from the channel before
the next conduction pulse.
Verapamil and diltiazem are more effective against atrial than ventricular dysrhythmias.
They are useful in treating reentrant
supraventricular tachycardia and reducing ventricular rate
in atrial flutter and fibrillation. Verapamil and diltiazem are absorbed after
oral administration. Verapamil is extensively metabolized by the
liver; thus, care should be taken in administration of this drug to patients
with hepatic dysfunction.
Verapamil and diltiazem have negative inotropic properties
and therefore may be contraindicated
in patients with preexisting depressed cardiac function.
Both drugs can also cause a decrease in
blood pressure caused by peripheral vasodilation.
Other antiarrhythmic drugs:
Digoxin (tab. 0.125, 0.25, 0.5 mg, amp. 1, 2 ml
0.025 %) shortens the refractory period in atrial
and ventricular myocardial
cells while prolonging the effective refractory period
and diminishing conduction velocity in
Purkinje fibers. Digoxin is used to control the ventricular response rate in atrial fibrillation and
flutter. At toxic concentrations, digoxin causes ectopic ventricular
beats that may result in ventricular tachycardia and fibrillation. [This
arrhythmia is usually treated with lidocaine or phenytoin].
Adenosine
is a naturally occurring nucleoside, but
at high doses the drug decreases conduction velocity, prolongs the
refractory period, and decreases
automaticity in the AV node. Intravenous
adenosine is the drug of choice for abolishing acute supraventricular tachycardia. It has
low toxicity, but causes flushing, chest pain and hypotension. Adenosine has an extremely short duration of action (about 15 seconds).
Magnesium
sulfate is given IV in the management of
several dysrhythmias, including prevention of recurrent episodes of torsades de
pointes and management of digitalis-induced dysrhythmias. Its antidysrhythmic
effects may derive from imbalances of magnesium, potassium, and calcium.
Hypomagnesemia increases myocardial irritability and is a risk factor for both
atrial and ventricular dysrhythmias. Thus, serum magnesium levels should be
monitored in clients at risk
and replacement therapy instituted when indicated.
However, in some instances, the drug seems to have antidysrhythmic effects even
when serum magnesium levels are normal.
Therapeutic indications
for some commonly encountered arrhythmias
|
Type of arrhythmia |
Class I |
Class II |
Class III |
Class IV |
Other |
|
ATRIAL ARRHYTHMIAS |
|||||
|
Atrial flutter |
|
|
|
|
|
|
Commonly used drugs |
|
Propranolol |
|
Verapamil |
|
|
Alternative drugs |
Quinidine |
|
|
|
Digoxin |
|
Atrial fibrillation |
|
|
|
|
|
|
Commonly used drugs |
|
Propranolol |
|
|
Anticoagulant therapy |
|
Alternative drugs |
Quinidine |
|
Amiodarone |
|
|
|
SUPRAVENTRICULAR TACHYCARDIAS |
|||||
|
AV nodal reentry |
|
|
|
|
|
|
Commonly used drugs |
|
Propranolol |
|
Verapamil |
|
|
Alternative drugs |
|
|
|
|
Digoxin |
|
Acute
supraventricular tachycardia |
|
|
|
|
|
|
Commonly used drugs |
|
|
|
|
Adenosine |
|
Alternative drugs |
|
|
|
Verapamil |
|
|
VENTRICULAR TACHYCARDIAS |
|||||
|
Acute
ventricular tachycardia |
|
|
|
|
|
|
Commonly used drugs |
Lidocaine |
|
|
|
|
|
Alternative drugs |
|
|
Sotalol, amiodarone |
|
|
|
Ventricular
fibrillation (not responding to electrical defibrillation) |
|
|
|
|
|
|
Commonly used drugs |
|
|
|
|
Epinephrine |
|
Alternative drugs |
Lidocaine |
|
Bretylium, amiodarone |
|
|
Pharmacologic Management of
Dysrhythmias
Rational drug therapy for
cardiac dysrhythmias requires accurate identification of the dysrhythmia,
understanding of the basic mechanisms causing the dysrhythmia, observation of
the hemodynamic and ECG effects of the dysrhythmia, knowledge of the
pharmacologic actions of specific antidysrhythmic drugs, and the expectation
that therapeutic effects will outweigh potential adverse effects. Even when
these criteria are met, antidysrhythmic drug therapy is somewhat empiric.
Although some dysrhythmias usually respond to particulardrugs, different drugs
or combinations of drugs are often required.
General trends and guidelines for
drug therapy of supraventricular and ventricular dysrhythmias are described in
the following sections.
General
Trends
1.
There is a relative consensus of opinion among clinicians about appropriate
management for acute, symptomatic dysrhythmias, in which the goals are to
abolish the abnormal rhythm, restore NSR, and prevent recurrence of the
dysrhythmia. There is less agreement about long-term use of the drugs, which is
probably indicated only for clients who experience recurrent symptomatic
episodes.
2. Class I agents do not prolong survival in any
group of clients and their use is declining. For example, quinidine is no
longer recommended to slow heart rate or prevent recurrence of AF. Some
clinicians recommend restricting this class to clients without structural heart
disease, who are less likely to experience increased
mortality than others.
3. Class II and class III drugs are being used
increasingly, because of demonstrated benefits in relieving symptoms and
decreasing mortality rates in clients with heart disease.
Supraventricular Tachydysrhythmias
1. Propranolol
and other beta blockers are being increasingly used for tachydysrhythmias,
especially in clients with myocardial infarction, heart failure, or
exerciseinduced dysrhythmias. In addition to controlling dysrhythmias, the
drugs decrease the mortality rate in these clients. Also, a beta blocker is the
management of choice if a rapid heart rate is causing angina or other symptoms
in a client with known coronary artery disease.
2. Atrial
fibrillation is the most common dysrhythmia. Management may involve
conversion to NSR by electrical or
pharmacologic means or long-term drug therapy to slow the rate of ventricular
response. Advantages of conversion to NSR include improvement of symptoms and
decreased risks of heart failure or thromboembolic problems. If pharmacologic conversion
is chosen, IV adenosine, dofetilide,
ibutilide, verapamil, or diltiazem may
be used. Once converted to NSR, clients usually require long-term drug therapy.
Low-dose amiodarone seems to be
emerging as the drug of choice for preventing recurrent AF after electrical or
pharmacologic conversion. The low doses cause fewer adverse effects than the
higher ones used for life-threatening ventricular dysrhythmias. When clients
are not converted to NSR, drugs are given to slow the heart rate. This strategy
is used for clients who:
a. Have chronic AF but are asymptomatic
b. Have had AF for longer than 1 year
c. Are elderly
d. Have not responded to multiple drugs
In addition to amiodarone, other drugs used to slow the
heart rate include a beta blocker,
digoxin, verapamil, or diltiazem. In
most clients, a beta blocker, verapamil, or diltiazem may be preferred. In
clients with heart failure, digoxin may be preferred. In addition, the class IC
agents flecainide or propafenone may be
used to suppress paroxysmal atrial flutter and
fibrillation in clients with minimal or no heart disease.
3. IV adenosine,
ibutilide, verapamil, or diltiazem may
be used to convert PSVT to a NSR. These drugs block conduction across the AV
node.
Ventricular
Dysrhythmias
1. Treatment of asymptomatic PVCs and nonsustained
ventricular tachycardia (formerly standard practice with lidocaine in clients
post–myocardial infarction) is not recommended.
2. A beta
blocker may be preferred as a first-line drug for symptomatic ventricular
dysrhythmias. Amiodarone, bretylium,
flecainide, propafenone, and sotalol
are also used in the management of life-threatening ventricular
dysrhythmias, such as sustained ventricular tachycardia. Class I agents (eg, lidocaine, mexiletine, tocainide) may
be used in clients with structurally normal hearts. Lidocaine may also be used
for treating digoxin-induced ventricular dysrhythmias.
3. Amiodarone,
sotalol, or a beta blocker may
be used to prevent recurrence of ventricular tachycardia or fibrillation in
clients resuscitated from cardiac arrest.
4. Moricizine
is infrequently used in the
Use in Children
Antidysrhythmic drugs are less
often needed in children than in adults, and their use has decreased with
increased use of catheter ablative techniques. Catheter ablation uses radio
waves to destroy dysrhythmia-producing foci in cardiac tissue
and reportedly causes fewer adverse effects and
complications than long-term antidysrhythmic drug therapy.
Antidysrhythmic drug therapy is
also less clear-cut in children. The only antidysrhythmic drug that is FDA approved
for use in children is digoxin. However, pediatric cardiologists have used
various drugs and developed guidelines for their use, especially dosages. As
with adults, the drugs should be used only when clearly indicated, and children
should be monitored closely because all of the drugs can cause adverse effects,
including hypotension and new or worsened dysrhythmias.
Supraventricular
tachydysrhythmias are the most common sustained dysrhythmias in children. IV adenosine, digoxin, procainamide, or propranolol can be used acutely to
terminate supraventricular tachydysrhythmias. IV verapamil, which is often used
in adults to terminate supraventricular tachydysrhythmias, is contraindicated
in infants and small children. Although it can be used cautiously in older
children, some clinicians recommend that IV verapamil be avoided in the
pediatric population. Digoxin or a beta blocker may be used for longterm
management of supraventricular tachydysrhythmias.
Propranolol is
the beta blocker most commonly used in children. It is one of the few
antidysrhythmic drugs available in a liquid solution. Propranolol has a shorter
half-life (3 to 4 hours) in infants than in children older than 1 to 2 years of
age and adults (6 hours). When given IV, antidysrhythmic effects are rapid, and
clients require careful monitoring for bradycardia and hypotension. E molol is being used more frequently
to treat tachydysrhythmias in children, especially those occurring after
surgery. 
Lidocaine may be used to
treat ventricular dysrhythmias precipitated by cardiac surgery or digitalis
toxicity. Class I or III drugs are usually started in a hospital setting, at
lower dosage ranges, because of prodysrhythmic effects. Prodysrhythmia is more
common in children with structural heart disease or significant dysrhythmias.
In general, serum levels should be monitored with class IA and IC drugs and IV
lidocaine. Flecainide is the class IC drug most commonly used in children.
Class III drugs are used in pediatrics mainly to treat life-threatening refractory
tachydysrhythmias. As in adults, most antidysrhythmic drugs and their
metabolites are excreted through the kidneys and may accumulate in children
with impaired renal function.
Use in Older Adults
Cardiac dysrhythmias are common
in older adults, but in general only those causing symptoms of circulatory
impairment should be treated with antidysrhythmic drugs. Compared with younger
adults, older adults are more likely to experience serious adverse drug
effects, including aggravation of existing dysrhythmias, production of new
dysrhythmias, hypotension, and heart failure. Cautious use is required, and
dosage usually needs to be reduced to compensate for heart disease or impaired
drug elimination processes.
Use in Critical Illness
Critically ill clients often
have multiple cardiovascular and other disorders that increase their risks for
development of acute, serious, and potentially life-threatening dysrhythmias.
They may also have refractory dysrhythmias that require
strong, potentially toxic antidysrhythmic drugs.
Thus, antidysrhythmic drugs are often given IV in critical care settings for
rapid reversal of a fast rhythm. After reversal, IV or oral drugs may be given
to prevent recurrence of the dysrhythmia. Because serious problems may stem
from either dysrhythmias or their treatment, health care providers should be
adept in preventing, recognizing, and treating conditions that predispose to
the development of serious dysrhythmias (eg, electrolyte imbalances, hypoxia).
If dysrhythmias cannot be prevented, early recognition and treatment are
needed.
Overall, any antidysrhythmic
drug therapy in critically ill clients is preferably performed or at least
initiated in critical care units or other facilities with appropriate equipment
and personnel. For example, nurses who work in emergency departments or
critical care units must be certified in cardiopulmonary resuscitation and
advanced cardiac life support (ACLS). With ACLS, the American Heart Association
and others have developed algorithms to guide drug therapy of dysrhythmias.
Use in Renal
Impairment
Antidysrhythmic drug therapy in
clients with renal impairment should be very cautious, with close monitoring of
drug effects (eg, plasma drug levels, ECG changes, symptoms that may indicate
drug toxicity). The kidneys excrete most antidysrhythmic drugs and their
metabolites. As a result, decreased renal perfusion or other renal impairment
can reduce drug elimination and lead to accumulation and adverse effects if
dosage is not reduced. As a general rule, dosage of bretylium, digoxin,
disopyramide, flecainide, lidocaine, moricizine, procainamide, propafenone,
quinidine, sotalol, and tocainide should be reduced in clients with significant
impairment of renal function. Dosage of adenosine, amiodarone, ibutilide, and
mexiletine does not require reduction.
Use
in Hepatic Impairment
As with renal impairment,
antidysrhythmic drug therapy in clients with hepatic impairment should be very
cautious, with close monitoring of drug
effects (eg, plasma drug levels, ECG changes, symptoms that may indicate drug
toxicity).
Amiodarone may be hepatotoxic and cause serious,
sometimes fatal, liver disease. Hepatic enzyme levels are often elevated
without accompanying symptoms of liver impairment. However, liver enzymes
should be monitored regularly, especially in clients receiving relatively high
maintenance doses. If enzyme levels are above three times the normal range or
double in a client whose baseline levels were elevated, dosage reduction or
drug discontinuation should be considered.
Hepatic impairment increases plasma half-life of
several antidysrhythmic drugs, and dosage usually should be reduced. These
include disopyramide, flecainide, lidocaine, mexiletine, moricizine,
procainamide, propafenone, quinidine, and tocainide. Dosages of adenosine and
ibutilide are unlikely to need reductions in clients with hepatic impairment.
Clinical
pharmacology of antihypertensive drugs
HYPERTENSION
Hypertension is persistently high blood pressure that results from
abnormalities in regulatory mechanisms. It is usually defined as a systolic
pressure above
Primary or essential hypertension (that for
which no cause can be found) makes up 90% to 95% of known cases. Secondary
hypertension may result from renal, endocrine, or central nervous system
disorders and from drugs that stimulate the SNS or cause retention of sodium
and water. Primary hypertension can be controlled with appropriate therapy;
secondary hypertension can sometimes be cured by surgical therapy.
The Sixth Report of the Joint National Committee on
Detection, Evaluation, and Treatment of High Blood Pressure, published in 1997,
classified blood pressures in adults (in mm of Hg), as follows:
• Normal = systolic 130 or below; diastolic
85 or below
• High normal = systolic 130 to 139; diastolic
85 to 89
• Stage 1 hypertension
(mild) = systolic 140 to 159;
diastolic
90 to 99
• Stage 2 hypertension
(moderate) = systolic 160 to 179;
diastolic 100 to 109
• Stage 3 hypertension
(severe) = systolic 180 to 209;
diastolic
110 to 119
• Stage 4 hypertension
(very severe) = systolic 210 or
above; diastolic 120 or above
A
systolic pressure of 140 or above with a diastolic pressure below 90 is called
isolated systolic hypertension and is more common in the elderly.
Hypertension
profoundly alters cardiovascular function by increasing the workload of the
heart and causing thickening and sclerosis of arterial walls. As a result of
increased cardiac workload, the myocardium hypertrophies as a compensatory
mechanism and heart failure eventually occurs. As a result of endothelial
dysfunction and arterial changes (vascular remodeling), the arterial lumen is
narrowed, blood supply to tissues is decreased, and risks of thrombosis are
increased. In addition, necrotic areas may develop in arteries, and these may
rupture with sustained high blood pressure. The areas of most serious damage
are the heart, brain, kidneys, and eyes. These are often called target organs.
Initially
and perhaps for years, primary hypertension may produce no symptoms. If
symptoms occur, they are usually vague and nonspecific. Hypertension may go
undetected, undetected,
or it may be incidentally discovered when blood pressure measurements are taken
as part of a routine physical examination, screening test, or assessment of
other disorders. Eventually, symptoms reflect target organ damage.
Hypertension is
often discovered after a person experiences angina pectoris, myocardial
infarction, heart failure, stroke, or renal disease. Hypertensive emergencies
are episodes of severely elevated blood pressure that may be an extension of
malignant (rapidly progressive) hypertension or caused by cerebral hemorrhage,
dissecting aortic aneurysm, renal disease, pheochromocytoma, or eclampsia.
These require immediate management, usually intravenous (IV) antihypertensive
drugs, to lower blood pressure. Symptoms include severe headache, nausea,
vomiting, visual disturbances, neurologic disturbances, disorientation, and
decreased level of consciousness (drowsiness, stupor, coma). Hypertensive
urgencies are episodes of less severe hypertension and are often managed with
oral drugs. The goal of management is to lower blood pressure within 24 hours.
In most instances, it is better to lower blood pressure gradually and to avoid
wide fluctuations in blood pressure.
Mild hypertension can often be
controlled with a single drug. More severe hypertension may require treatment
with several drugs that are selected to
minimize adverse effects of the combined
regimen. Treatment is initiated with any of four drugs depending on the
individual patient: a diuretic, a b-blocker, an ACE inhibitor, or a calcium channel
blocker. If blood pressure is
inadequately controlled, a second drug is added. A b-blocker is usually added if the initial drug was a
diuretic, or a diuretic is added if the first drug was a b-blocker. A vasodilator can be added as a third step
for those patients who still fail to respond.
Certain subsets of the hypertensive population
respond better to one class of drug than
another. For example, black patients respond well to diuretics and calcium
channel blockers, but therapy with b-blockers or ACE inhibitors is often less effective.
Similarly, calcium channel blockers, ACE inhibitors, and diuretics are favored
for treatment of hypertension in the elderly, whereas b-blockers and a-antagonists are less well tolerated. Furthermore,
hypertension may coexist with other
diseases that can be aggravated by some of the antihypertensive drugs.
ANTIHYPERTENSIVE DRUGS
Drugs used in the management of primary hypertension belong to several
different groups, including angiotensin-converting enzyme (ACE) inhibitors,
angiotensin II receptor blockers (ARBs), also called angiotensin II receptor
antagonists (AIIRAs), antiadrenergics, calcium channel blockers, diuretics, and
direct vasodilators. In general, these drugs act to decrease blood pressure by
decreasing cardiac output or peripheral vascular resistance.
I. DIURETICS
Bumetanide, furosemide,
hydrochlorthiazide, spironolactone, triamterene
II. b-BLOCKERS
Atenolol, labetalol,
metoprolol, propranolol, timolol
III. ACE
INHIBITORS
Captopril,
benazepril, enalapril, fosinopril, lisinopril, moexipril, quinapril, ramipril
IV. ANGIOTENSIN II ANTAGONIST
Losartan
V. Ca++CHANNEL BLOCKERS
Amlodipine, diltiazem,
felodipine, isradipine, nicardipine, nifedipine, nisoldipine, verapamil
VI. a-BLOCKERS
Doxazosin,
prazosin, terazosin
VII. OTHER
Clonidine,
diazoxide, hydralazine, a-methyldopa, minoxidil, sodium
nitroprusside
Treatment
of hypertension in patients with
concomitant diseases
|
CONCOMITANT DISEASE |
DRUGS COMMONLY USED IN TREATING HYPERTENSION |
|||
|
Angina pectoris |
|
|
|
|
|
Commonly used drugs |
|
b-Blockers |
|
Ca++ Channel blockers |
|
Alternative drugs |
diuretics |
|
ACE inhibitors |
|
|
Diabetes (insulin-dependent) |
|
|
|
|
|
Commonly used drugs |
|
|
ACE inhibitors |
Ca++ Channel blockers |
|
Alternative drugs |
|
|
|
|
|
Hyperlipidemia |
|
|
|
|
|
Commonly used drugs |
|
|
ACE inhibitors |
Ca++ Channel blockers |
|
Alternative drugs |
|
|
|
|
|
Congestive heart failure |
|
|
|
|
|
Commonly used drugs |
diuretics |
|
ACE inhibitors |
|
|
Alternative drugs |
|
|
|
Avoid verapamil |
|
Previous myocardial infarction |
|
|
|
|
|
Commonly used drugs |
|
b-Blockers |
ACE inhibitors |
|
|
Alternative drugs |
diuretics |
|
|
Ca++ Channel blockers |
|
Chronic
renal disease |
|
|
|
|
|
Commonly used drugs |
diuretics |
|
|
Ca++ Channel blockers |
|
Alternative drugs |
|
b-Blockers |
ACE inhibitors |
|
|
Asthma, chronic pulmonary
disease |
|
|
|
|
|
Commonly used drugs |
diuretics |
|
|
Ca++ Channel blockers |
|
Alternative drugs |
|
|
ACE inhibitors |
|
DIURETICS and/or b-Blockers
are currently recommended
as the first-line drug therapy for hypertension. Low-dose diuretic therapy is safe and effective in preventing stroke,
myocardial infarction, congestive heart failure and total mortality. Recent data suggest that diuretics are superior to b-Blockers in older adults.
Antihypertensive effects of diuretics are usually
attributed to sodium and water depletion. In fact, diuretics usually produce
the same effects as severe dietary sodium restriction. In many cases of
hypertension, diuretic therapy alone may lower blood pressure. When diuretic
therapy is begun, blood volume and cardiac output decrease. With long-term administration
of a diuretic, cardiac output returns to normal, but there is a persistent
decrease in peripheral vascular resistance. This has been attributed to a
persistent small reduction in extracellular water and plasma volume, decreased
receptor sensitivity to vasopressor substances such as angiotensin, direct
arteriolar vasodilation, and arteriolar vasodilation secondary to electrolyte
depletion in the vessel wall.
In
moderate or severe hypertension that does not respond to a diuretic alone, the
diuretic may be continued and another antihypertensive drug added, or
monotherapy with a different type of antihypertensive drug may be tried.
Thiazide
diuretics. All oral diuretics are
effective in the treatment of hypertension, but the thiazides have the most
widespread use. Thiazides, such as hydochlorothiazide,
lower blood pressure , initially by
increasing sodium and water excretion. This causes a decrease in extracellular volume , resulting in a decrease in cardiac output and
renal blood flow. With long term
treatment, plasma volume approaches a normal value, but peripheral resistance
decreases. Spironolactone, a potassium-sparing diuretic, is often used with
thiazides.
Thiazide diuretics are usefull
in combination therapy with a
variety of other antihypertensive agents
including b-blockers and ACE inhibitors. Thiazides are particularly useful in the
treatment of black or elderly patients,
and in those with chronic renal disease. Thiazides are not effective in
patients with inadequate kidney function (creatinine clearance less than 50
mls/min).
Adverse effects:
Thiazide diuretics induce hypokalemia and hyperuricemia in 70 % of
patients, and hyperglycemia in 10 % of patients. Serum potassium levels should be
monitored closely on patients who are
predisposed to cardiac arrhythmias (with left ventricular hypertrophy, ischemic
heart disease, or chronic congestive heart failure) (to prevent development of
fatigue, cramps, and arrhythmias) and who are concurrently being treated with
both thiazide diuretics and digitalis glycosides. Diuretics should be avoided in the treatment
of hypertensive diabetics or patients with hyperlipidemia.
The loop diuretics act
promptly, even in patients who have poor renal function or who have not
responded to thiazides or other diuretics.
b-ADRENOCEPTOR
BLOCKING AGENTS – reduce blood pressure
primarily by decreasing cardiac output.
They may also decrease sympathetic outflow from the CNS and inhibit the
release of renin from the kidneys. The
prototype b-blocker is propranolol, which acts at both b1 and b2 receptors. Newer agents, such as atenolol, metoprolol, bisoprolol, are
selective for b1 receptors. These agents are
commonly used in disease states such as asthma, in which propranolol is
contraindicated.
The b-blockers are more effective for treating hypertension
in white young patients. They are useful
in treating conditions that may coexist
with hypertension, such as supraventricular tachyarrhythmia, previous
myocardial infarction, angina pectoris, glaucoma, and migraine headache.
The b-blockers are orally active. The b-blockers may take several weeks to develop their full
effects.
Adverse
effects. The b-blockers may cause
CNS side effects such as fatigue, lethargy, insomnia, hypotension, and
hallucinations; they may decrease libido and cause impotence; drug-induced
sexual dysfunction can severly reduce
patient compliance. The b-blockers may disturb lipid metabolism, decreasing
high-density lipoproteins and increasing plasma triacylglycerol.
Drug withdrawal: Abrupt
withdrawal may cause rebound hypertension, probably as a result of
up-regulation on b-receptors. Patients should be
taped off of b-blocker therapy in order to
avoid precipitation of arrhythmias. The b-blockers should be avoided in treating patients with
asthma, congestive heart failure, and peripheral vascular disease.
ACE-INHIBITORS.
Angiotensin-converting
enzyme (also called kininase) is mainly located in the endothelial lining of
blood vessels, which is the site of production of most angiotensin II. This
same enzyme also metabolizes bradykinin, an endogenous substance with strong
vasodilating properties. ACE inhibitors block the enzyme that normally converts
angiotensin I to the potent vasoconstrictor angiotensin II. By blocking
production of angiotensin II, the drugs decrease vasoconstriction (having a
vasodilating effect) and decrease aldosterone production (reducing retention of
sodium and water). In addition to inhibiting formation of angiotensin II, the
drugs also inhibit the breakdown of bradykinin, prolonging its vasodilating
effects. These effects and possibly others help to prevent or reverse the
remodeling of heart muscle and blood vessel walls that impairs cardiovascular
function and exacerbates cardiovascular disease processes. Because of their
effectiveness
in hypertension and
beneficial effects on the heart, blood vessels, and kidneys, these drugs are increasing
in importance, number, and use. Widely used to treat heart failure and
hypertension, the drugs may also decrease morbidity and mortality in other
cardiovascular disorders. They improve post–myocardial infarction survival when
added to standard therapy of aspirin, a beta blocker, and a thrombolytic.
ACE inhibitors may be used alone or in combination with other
antihypertensive agents, such as thiazide diuretics. Although the drugs can
cause or aggravate proteinuria and renal damage in nondiabetic people, they
decrease proteinuria and slow the development of nephropathy in diabetic
clients.
Most ACE inhibitors (captopril, enalapril, fosinopril, lisinopril,
ramipril, and quinapril) also are used in the management of heart failure
because they decrease peripheral vascular resistance, cardiac workload, and
ventricular remodeling. Captopril and other ACE
inhibitors are recommended as first-line agents for treating hypertension in
diabetic clients, particularly those with type 1 diabetes and/or diabetic nephropathy,
because they reduce proteinuria and slow progression of renal impairment.
ACE
inhibitors are well absorbed with oral administration, produce effects within 1
hour that last approximately 24 hours, have prolonged serum half-lives with
impaired renal function, and most are metabolized to active metabolites that
are excreted in urine and feces. These drugs are well tolerated, with a low
incidence of serious adverse effects (eg, neutropenia, agranulocytosis, proteinuria,
glomerulonephritis, and angioedema). However, a persistent cough develops in
approximately 10% to 20% of clients and may lead to stopping the drug. Also,
acute hypotension may occur when an ACE inhibitor is started, especially in
clients with fluid volume deficit. This reaction may be prevented by starting
with a low dose, taken at bedtime, or by stopping diuretics and reducing dosage
of other antihypertensive drugs temporarily. Hyperkalemia may develop in
clients who have diabetes mellitus or renal impairment or who are taking nonsteroidal
anti-inflammatory drugs, potassium supplements, or potassium-sparing diuretics.
These
drugs are contraindicated during pregnancy because serious illnesses, including
renal failure, have occurred in neonates whose mothers took an ACE inhibitor
during the second and third trimesters.
The
angiotensin-converting enzyme (ACE) inhibitors (captopril, enalapril, lisinopril) are recommended when the preferred first-line agents (diuretics or
b-blockers) are contraindicated or
ineffective. Despite their wide-spread use, it is not clear if antihypertensive
therapy with ACE inhibitors increases the risk of other major diseases.
Actions.
The ACE inhibitors lower blood pressure by reducing peripheral vascular resistance without reflexly
increasing cardiac output, rate, or
contractility. These drugs block the
angiotensin converting enzyme that
cleaves angiotensin I to form the potent vasoconstrictor, angiotensin II.
Vasodilation occurs as a result of the combined effects of lower
vasoconstriction caused by diminished
levels of angiotensin II and the potent vasodilating effect of
increased bradykinin. By reducing
circulating angiotensin II levels, ACE inhibitors also decreas the secretion of aldosterone,
resulting in decreased sodium and water retention.
Like b-blockers, ACE inhibitors are most effective in
hypertensive patients who are white and
young. However, when used in combination with a diuretic, the effectiveness of
ACE inhibitors is similar in white and black hypertensive patients. Unlike b-blockers, ACE inhibitors are effective in the
management of patients with chronic congestive heart failure.
ACE inhibitors are now a standard in the care of a patient following a
myocardial infarction. Therapy is started
24 hours after the end of the infarction.
Adverse effects. Common side effects
include dry cough, rashes, fever, altered taste, hypotension, and hyperkalemia.
Potassium levels must be monitored, and potassium supplements or
spironolactone are contraindicated.
Because of the risk of angioedema and first dose syncope, ACE inhibitors are
first administered in the physician’s office with close observation.
Reversible renal failure can occur in
patients with severe renal artery stenosis. ACE inhibitors are fetotoxic and
should not be used in pregnant women.
ANGIOTENSIN II ANTAGONISTS.
Angiotensin II
receptor blockers (ARBs) were developed to block the strong blood
pressure–raising effects of angiotensin II. Instead of decreasing production of
angiotensin II, as the ACE inhibitors do, these drugs compete with angiotensin
II for tissue binding sites and prevent angiotensin II from combining with its
receptors in body tissues. Although multiple types of receptors have been
identified, the AT1 receptors located in brain, renal, myocardial, vascular,
and adrenal tissue determine most of the effects of angiotensin II on
cardiovascular and renal functions. ARBs block the angiotensin II AT1 receptors
and decrease arterial blood pressure by decreasing systemic vascular resistance
.
These drugs are similar to ACE inhibitors in their effects on blood
pressure and hemodynamics and are as effective as ACE inhibitors in the
management of hypertension and probably heart failure. They are less likely to
cause hyperkalemia than ACE inhibitors, and the occurrence of a persistent
cough is rare. Overall, the drugs are well tolerated, and the incidence of most
adverse effects is similar to that of placebo.
Losartan, the first ARB, is readily
absorbed and rapidly metabolized by the cytochrome P450 liver enzymes to an
active metabolite. Both losartan and the metabolite are highly bound to plasma
albumin, and losartan has a shorter duration of action than its metabolite.
When losartan therapy is started, maximal effects on blood pressure usually
occur within 3 to weeks. If losartan alone does not control blood pressure, a
low dose of a diuretic may be added. A combination product of losartan and
hydrochlorothiazide is available.
The
nanopeptide losartan, a highly
selective angiotensin II receptor blocker, has recently been approved for
antihypertensive therapy. Its
pharmacologic effects are similar to ACE inhibitors in that it produces
vasodilation and blocks aldosterone secretion. Its adverse effects is improved
over the ACE inhibitors, although it is
fetotoxic.
CALCIUM CHANNEL
BLOCKERS.
Most of the available drugs are approved for
use in hypertension. Nifedipine, a short-acting calcium channel blocker, has
been used to treat hypertensive emergencies or urgencies, often by puncturing
the capsule and squeezing the contents under the tongue or having the client
bite and swallow the capsule. Such use is no longer recommended, because this
practice is associated with an increased risk of adverse cardiovascular events
precipitated by rapid and severe decrease in blood pressure.
As a group, the
calcium channel blockers are well absorbed from the gastrointestinal tract
following oral administration and are highly bound to protein. The drugs are
metabolized in the liver and excreted in urine.
Calcium channel blockers are recommended when the preferred
first-line agents are contraindicated or ineffective. Despite their wide-spread
use, it is not clear what effects
antihypertensive therapy with these drugs has on major disease. In hypertensive patients use of short-acting
calcium channel blockers, especially in high doses, is associated with
an increased risk of myocardial
infarction.
The calcium channel blockers are divided into three
chemical classes, each with different pharmacokinetic
properties and clinical indications.
1.
Diphenylalkylamines. Verapamil is the least selective of any
calcium channel blocker, and has significant effects on both cardiac and smooth-muscle cells. It is used
to treat angina, supraventricular tachyarrhythmias, and migrane headache.
2.
Benzothiazepines. Diltiazem affects both cardiac and vascular smooth-muscle cells;
however, it has a less pronounced negative inotropic effect on the heart than
does verapamil.
3.
Dihydropyridines. This
rapidly expanding class of calcium channel blockers includes the
first-generation nifedipine, and new
agents foe treating cardiovascular
disease: amlodipine, felodipine,
isradipine, nicardipine and nisoldipine.
All the dihydropyridines have a much greater affinity for vascular calcium channels than for calcium channels in
the heart. They are therefore particularly attractive in treating hypertension.
Calcium channel antagonists block
the inward movement of calcium by
binding to L-tipe calcium channels in the heart and in the smooth-muscle of the
coronary and peripheral vasculature. This causes vascular smooth muscle to
relax, dilating mainly arterioles.
Calcium channel blockers have an
intrinsic natriuretic ; therefore, they do not usually require the addition of
a diuretic. These agents are useful in the treatment of hypertensive
patients who also have asthma, diabetes, angina, and/or peripheral vascular
disease.
Adverse
effects. Although infrequent, side effects include
constipation in 10 % of patients, dizziness, headache, and a feeling of
fatigue caused by a decrease in blood pressure. Verapamil should be avoid in
treating patients with congestive heart failure due to its negative inotropic
effects.
a-ADRENERGIC
BLOCKING AGENTS.
Prazosin, doxazosin and terazosin
produce a competitive block of a1 adrenoreceptors. They decrease peripheral vascular
resistance and lower arterial blood
pressure by causing the relaxation of
both arterial and venous smooth muscle. These drugs cause only minimal
changes in cardiac output, renal blood
flow, and glomerular filtration rate. Postural
hypotension may occur in some
individuals. Prazosin is
used to treat mild to moderate hypertension and is prescribed in combination with
propranolol or a diuretic for additive effects.
CENTRALLY-ACTING
ADRENERGIC DRUGS
Clonidine – a2-agonist – diminishes central adrenergic outflow.
Clonidine does not decrease renal blood flow or glomerular filtration and
therefore is useful in the treatment of
hypertension complicated by renal disease. Because it causes sodium and water
retention, clonidine is usually administered in combination witj diuretic.
Adverse effects are generally mild, but the drug can produce sedation and
drying of nasal mucosa. Rebound hypertension occurs following abrupt withdrawal of clonidine. The drug
therefore should be withdrawal slowly if the clinician wishes to change agents.
a-Methyldopa. This a2-agonist is
converted to methylnorepinephrine centrally to diminish the adrenergic outflow
from the CNS, leading to reduced total peripheral resistance and a decreased blood pressure. Because blood
flow to the kidmey is not diminished by
its use, a-methyldopa
is especially valuable in treating
hypertensive patients with renal insufficiency. The most common side effects of
a-methyldopa
are sedation and drowsiness.
VASODILATORS. The
direct-acting smooth muscle relaxants, such as hydralazine and minoxidil,
have traditionally not been used as primary drugs to treat hypertension.
They act by producing relaxation of
vascular smooth muscle, which decreases
resistance and therefore decreases blood pressure. These agents produce reflex
stimulation of the heart. They may prompt
angina pectoris, myocardial infarction, or cardiac failure in predisposed individuals.
Hydralazine. This drug causes direct vasodilation, acting primarily on arteries and arterioles. Hydralazine
is used to treat moderately severe hypertension. It is almost always
administered in combination with a b-blocker such as propranolol (to balance the reflex
tachycardia) and a diuretic (to decrease sodium retention). Adverse effects
of hydralazine therapy include headache, nausea, sweating,
arrhythmia, and precipitation of angina. A lupus-like syndrome can occur with
high dosage, but it is reversible on discontinuation of the drug.
Minoxidil. This drug
causes dilation of resistance vessels (arterioles) but not of
capacitance vessels (venules). It is administered orally for treatment of
severe to malignant hypertension that is
refractory to other drugs. Reflex
tachycardia may be severe and may require the
concomitant use of a diuretic and a b-blocker. Minoxidil
causes serious sodium and water retention, leading to volume overload,
edema, and congestive heart failure.
MANAGEMENT OF HYPERTENSIVE EMERGENCY (intravenously)
HYPERTENSIVE
EMERGENCY – is a life-threatening
situation in which the diastolic blood pressure is either over
Nitroprusside is administered intravenously, and causes prompt vasodilation, with
reflex tachycardia. The drug has little
effect outside the vascular system,
acting equally on arterial and venous smooth muscle. It can reduce cardiac
preload. Nitroprusside is metabolized rapidly and requires continuous infusion to
maintain its hypotensive action. Nitroprusside is poisonous if given
orally because of its hydrolysis to cyanide.
Diazoxide is
a direct-acting arteriolar vasodilator. It has vascular effects like those of
hydralazine. Foe patients with coronary insufficiency, diazoxide is administered intravenously with a b-blocker, which
diminishes reflex activation of the heart. Diazoxide is useful in the treatment of hypertensive emergencies,
hypertensive encephalopathy, and eclampsia.
Excessive hypotension is the most serious toxicity.
Labetalol is
the both an a- and b-blocker that has been successfully used on
hypertensive emergencies. Labetalol
does not cause the reflex tachycardia that may be associated with diazoxide. Labetalol carries the contraindications
of a nonselective b-blocker.
SUMMARY:
DRUGS USED IN HYPERTENSION
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greater efficacy
CLINICAL PHARMACOLOGY OF ANTIHYPOTENSIVE DRUGS
Shock
is a clinical syndrome characterized by decreased blood supply to body tissues.
Clinical symptoms depend on the degree of impaired perfusion of vital organs
(eg, brain, heart, and kidneys). Common signs and symptoms include oliguria,
heart failure, mental confusion, cool extremities, and coma. Most, but not all,
people in shock are hypotensive.
In
a previously hypertensive person, shock may be present if a drop in blood
pressure of greater than
Types of Shock
There
are three general categories of shock that are based on the circulatory
mechanisms involved. These mechanisms are intravascular volume, the ability of
the heart to pump, and vascular tone.
Hypovolemic shock involves a loss of intravascular
fluid volume that may be due to actual blood loss or relative loss from fluid
shifts within the body.
Cardiogenic shock, also called pump failure, occurs when the myocardium has lost its ability to
contract efficiently and maintain an adequate cardiac output.
Distributive or vasogenic shock is characterized by severe, generalized
vasodilation, which results in severe hypotension and impairment of blood flow.
Distributive shock is further divided into anaphylactic, neurogenic, and septic
shock:
• Anaphylactic shock results from a hypersensitivity
(allergic) reaction to drugs or other substances.
• Neurogenic shock results from inadequate
sympathetic nervous system (SNS) stimulation. The SNS normally maintains
sufficient vascular tone (ie, a small amount of vasoconstriction) to support adequate
blood circulation. Neurogenic shock may occur with depression of the vasomotor
center in the brain or decreased sympathetic outflow to blood vessels.
• Septic shock can result from almost any
organism that gains access to the bloodstream but is most often associated with
gram-negative and gram-positive bacterial infections and fungi. It is important
to know the etiology of shock because management varies among the types.
ANTISHOCK DRUGS
Drugs used in the management of shock are primarily the adrenergic drugs.
In this chapter, the drugs are discussed only in relation to their use in
hypotension and shock. In these conditions, drugs with alpha-adrenergic
activity (eg, norepinephrine, phenylephrine) are used to increase peripheral
vascular resistance and raise blood pressure. Drugs with beta-adrenergic
activity (eg, dobutamine, isoproterenol) are used to increase myocardial
contractility and heart rate, which in turn raises blood pressure. Some drugs
have both alpha- and beta-adrenergic activity (eg, dopamine, epinephrine). In
many cases, a combination of drugs is used, depending on the type of shock and the client’s
response to treatment. In an emergency, the drugs may be used to maintain
adequate perfusion of vital organs until sufficient fluid volume is replaced
and circulation is restored.
Adrenergic
drugs with beta activity may be relatively contraindicated in shock states
precipitated or complicated by cardiac dysrhythmias. Beta-stimulating drugs
also should be used cautiously in cardiogenic shock after myocardial infarction
because increased contractility and heart rate will increase myocardial oxygen
consumption and extend the area of infarction. Individual drugs are described
in the following section; indications for use and dosage ranges are listed in
Drugs at a Glance: Drugs Used for Hypotension and Shock.
INDIVIDUAL DRUGS
Dopamine is a naturally occurring
catecholamine that functions as a neurotransmitter. Dopamine exerts its actions
by stimulating alpha, beta, or dopaminergic receptors, depending on the dose
being used. In addition, dopamine acts indirectly by releasing norepinephrine
from sympathetic nerve endings and the adrenal glands. Peripheral dopamine
receptors are located in splanchnic and renal vascular beds. At low doses (0.5
to 10 mcg/kg/min), dopamine selectively
stimulatesdopaminergic receptors that may increase renal blood flow and
glomerular filtration rate (GFR). It has long been accepted that stimulation of
dopamine receptors by low doses of exogenous dopamine produces vasodilation in
the renal circulation and increases urine output. More recent studies indicate
that low-dose dopamine enhances renal function only when cardiac function is
improved. At doses greater than 3 mcg/kg/min, dopamine binds to beta and alpha
receptors and the selectivity of dopaminergic receptors is lost beyond 10
mcg/kg/min. At doses that stimulate beta receptors (3 to 20 mcg/kg/min), there
is an increase in heart rate, myocardial contractility, and blood pressure. At
the highest doses (20 to 50 mcg/kg/min), beta activity remains, but increasing
alpha stimulation (vasoconstriction) may overcome its actions.
Dopamine is useful in hypovolemic and cardiogenic shock. Adequate fluid
therapy is necessary for the maximal pressor effect of dopamine. Acidosis decreases
the effectiveness of dopamine.
Dobutamine is a synthetic catecholamine
developed to provide less vascular activity than dopamine. It acts mainly on
beta1 receptors in the heart to increase the force of myocardial contraction
with a minimal increase in heart rate. Dobutamine also may increase blood
pressure with large doses. It is less likely to cause tachycardia,
dysrhythmias, and increased myocardial oxygen demand than dopamine and
isoproterenol. It is most useful in cases of shock that require increased
cardiac output without the need for blood pressure support. It is recommended
for short-term use only. It may be used with dopamine to augment the beta1
activity that is sometimes overridden by alpha effects when dopamine is used
alone at doses greater than 10 mcg/kg/min.
Dobutamine
has a short plasma half-life and therefore must be administered by continuous
IV infusion. A loading dose is not required because the drug has a rapid onset of action and
reaches steady state within approximately 10 minutes after the infusion is
begun. It is rapidly metabolized to inactive metabolites.
Epinephrine is a naturally occurring catecholamine produced by
the adrenal glands. At low doses, epinephrine stimulates beta receptors, which
increases cardiac output by increasing the rate and force of myocardial
contractility. It also causes bronchodilation. Larger doses act on alpha
receptors to increase blood pressure.
Epinephrine
is the drug of choice for management of anaphylactic shock because of its rapid
onset of action and antiallergic effects. It prevents the release of histamine
and other mediators that cause symptoms of anaphylaxis, thereby reversing
vasodilation and bronchoconstriction. In early management of anaphylaxis, it
may be given subcutaneously to produce therapeutic effects within 5 to 10
minutes, with peak activity in approximately 20 minutes.
Epinephrine is
also used to manage other kinds of shock and is usually given by continuous IV
infusion. However, bolus doses may be given in emergencies, such as cardiac
arrest. It may produce excessive cardiac stimulation, ventricular dysrhythmias,
and reduced renal blood flow. Epinephrine has an elimination half-life of about
2 minutes and is rapidly inactivated to metabolites, which are then excreted by
the kidneys.
Isoproterenol is a synthetic catecholamine that acts exclusively
on beta receptors to increase heart rate, myocardial contractility, and
systolic blood pressure. However, it also stimulates vascular beta2 receptors,
which causes vasodilation, and may decrease diastolic blood pressure. For this
reason, isoproterenol has limited usefulness as a pressor agent. It also may
increase myocardial oxygen consumption and decrease coronary artery blood flow,
which in turn causes myocardial ischemia. Cardiac dysrhythmias may result from
excessive beta stimulation. Because of these limitations, use of isoproterenol
is limited to shock associated with slow heart rates and myocardial depression.
Metaraminol is used mainly for hypotension associated with
spinal anesthesia. It acts indirectly by releasing norepinephrine from
sympathetic nerve endings. Thus, its vasoconstrictive actions are similar to
those of norepinephrine, except that metaraminol is less potent and has a
longer duration of action.
Milrinone is used to manage
cardiogenic shock in combination with other inotropic agents or vasopressors.
It increases cardiac output and decreases systemic vascular resistance without
significantly increasing heart rate or myocardial oxygen consumption. The
increased cardiac output improves renal blood flow, which then leads to
increased urine output, decreased circulating blood volume, and decreased
cardiac workload.
Norepinephrine (Levophed) is a pharmaceutical preparation of the
naturally occurring catecholamine norepinephrine. It stimulates
alpha-adrenergic receptors and thus increases blood pressure primarily by
vasoconstriction. It also stimulates beta1 receptors and therefore increases
heart rate, force of myocardial contraction, and coronary artery blood flow. It
is useful in cardiogenic and septic shock, but reduced renal blood flow limits
its prolonged use. Norepinephrine is used mainly with clients who are
unresponsive to dopamine or dobutamine. As with all drugs used to manage shock,
blood pressure should be monitored frequently during infusion.
Phenylephrine (Neo-Synephrine) is an adrenergic drug that
stimulates alpha-adrenergic receptors. As a result, it constricts arterioles
and raises systolic and diastolic blood pressures. Phenylephrine resembles
epinephrine but has fewer cardiac effects and a longer duration of action.
Reduction of renal and mesenteric blood flow limit prolonged use.
Choice of Drug
The
choice of drug depends primarily on the pathophysiology involved. For
cardiogenic shock and decreased cardiac output, dopamine or dobutamine is
given. With severe heart failure characterized by decreased cardiac output and
high peripheral vascular resistance, vasodilator drugs (eg, nitroprusside,
nitroglycerin) may be given along with the cardiotonic drug. The combination
increases cardiac output and decreases cardiac workload by decreasing preload
and afterload. However, vasodilators should not be used alone because of the
risk of severe hypotension and further compromising tissue perfusion.
Milrinone
may be given when other drugs fail. For distributive shock characterized by
severe vasodilation and decreased peripheral vascular resistance, a
vasoconstrictor or vasopressor drug, such as norepinephrine, is the drug of
first choice. Drug dosage must be carefully titrated to avoid excessive
vasoconstriction and hypertension, which causes impairment rather than
improvement in tissue perfusion.
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