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.
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
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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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.
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.
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.
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.
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.
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.
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.
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.
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.
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 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.
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.
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.
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.
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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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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