CLINICAL
PHARMACOLOGY OF ANTIANGINAL DRUGS. CLINICAL PHARMACOLOGY OF ANTIHYPERLIPIDEMIC
DRUGS. TREATMENT OF MYOCARDIAL
INFARCTION. CLINICAL PHARMACOLOGY OF
ANTIARRHYTHMIC DRUGS
Clinical pharmacology of antianginal
drugs
Ischemic heart disease is the
most common cardiovascular disease in developed countries, and angina pectoris
is the most common condition involving tissue ischemia in which vasodilator
drugs are used. The name denotes chest pain caused by accumulation of
metabolites resulting from myocardial ischemia. The organic nitrates, eg, nitroglycerin,
are the mainstay of therapy for the immediate relief of angina. Another group
of vasodilators, the calcium channel blockers, is also important,
especially for prophylaxis, and beta-blockers, which are not
vasodilators, are also useful in prophylaxis. Several newer groups of drugs are
under investigation, including drugs that alter myocardial metabolism and
selective cardiac rate inhibitors.
Angina pectoris is a clinical
syndrome characterized by episodes of chest pain. It occurs when there is a
deficit in myocardial oxygen supply (myocardial ischemia) in relation to
myocardial oxygen demand. It is most often caused by atherosclerotic plaque in
the coronary arteries but may also be caused by coronary vasospasm. The
development and progression of atherosclerotic plaque is called coronary artery
disease (CAD). Atherosclerotic plaque narrows the lumen, decreases elasticity,
and impairs dilation of coronary arteries. The result is impaired blood flow to
the myocardium, especially with exercise or other factors that increase the
cardiac workload and need for oxygen. The continuum of CAD progresses from
angina to myocardial infarction. There are three main types of angina: classic
angina, variant angina, and unstable angina. The Canadian Cardiovascular
Society classifies clients with angina according to the amount of physical
activity they can tolerate before anginal pain occurs. These categories can
assist in clinical assessment and evaluation of therapy.
Classic
anginal pain is usually described as substernal chest pain of a constricting,
squeezing, or suffocating nature. It may radiate to the jaw, neck, or shoulder,
down the left or both arms, or to the back. The discomfort is sometimes mistaken
for arthritis, or for indigestion, as the pain may be associated with nausea,
vomiting, dizziness, diaphoresis, shortness of breath, or fear of impending
doom. The discomfort is usually brief, typically lasting 5 minutes or less
until the balance
of oxygen supply and
demand is restored.
For clients
at any stage of CAD development, irrespective of symptoms of myocardial
ischemia, optimal management involves lifestyle changes and medications, if
necessary, to control or reverse risk factors for disease progression. Risk
factors are frequently additive in nature and are classified as nonmodifiable
and modifiable. Nonmodifiable risk factors include age, race, gender, and
family history. The risk factors that can be altered include smoking,
hypertension, hyperlipidemia, obesity, sedentary lifestyle, stress, and the use
of drugs that increase cardiac workload (eg, adrenergics, corticosteroids).
Thus,
efforts are needed to assist clients in reducing blood pressure, weight, and
serum cholesterol levels, when indicated, and developing an exercise program.
For clients with diabetes mellitus, glucose and blood pressure control can
reduce the microvascular changes associated with the condition. In addition,
clients should avoid circumstances known to precipitate acute attacks, and
those who smoke should stop. Smoking is harmful to clients because:
• Nicotine increases
catecholamines which, in turn, increase heart rate and blood pressure.
• Carboxyhemoglobin,
formed from the inhalation of carbon monoxide in smoke, decreases delivery of
blood and oxygen to the heart, decreases myocardial contractility, and increases the risks of
life-threatening cardiac dysrhythmias
(eg, ventricular
fibrillation) during ischemic episodes.
• Both nicotine and carbon
monoxide increase platelet adhesiveness and aggregation, thereby promoting
thrombosis.
• Smoking increases the
risks for myocardial infarction, sudden cardiac death, cerebrovascular disease
(eg, stroke), peripheral vascular disease (eg, arterial insufficiency), and
hypertension. It also reduces high-density lipoprotein, the “good” cholesterol.
Additional
nonpharmacologic management strategies include surgical revascularization (eg,
coronary artery bypass graft) and interventional procedures that reduce
blockages (eg, percutaneous transluminal coronary angioplasty [PTCA],
intracoronary stents, laser therapy, and rotoblators). However, most clients
still require antianginal and other cardiovascular medications to manage their
disease.
ANTIANGINAL DRUGS
Drugs used for myocardial ischemia are the organic nitrates, the
beta-adrenergic blocking agents, and the calcium channel blocking agents. These
drugs relieve anginal pain by reducing myocardial oxygen demand or increasing
blood supply to the myocardium. Nitrates and beta blockers are described in the
following sections and dosage ranges are listed in Drugs at a Glance: Nitrates
and Beta Blockers. Calcium channel blockers are described in a following
section; indications for use and dosage ranges are listed in Drugs at a Glance:
Calcium Channel Blockers.
Organic nitrates (and nitrates) are simple nitric and nitrous
acid esters of alcohols. These compounds cause a rapid reduction in myocardial
oxygen demand followed by rapid relief of symptoms. They are effective in
stable and anstable angina, as well as Prinzmetal’s or variant angina pectoris.
Nitrates,
b-blockers, and
calcium channel-blockers are equally effective for relief of anginal symptoms.
However, for prompt relief of an ongoing attack of angina precipitated by
exercise or emotional stress, sublingual (or spray form) nitroglycerin (NITROSTAT) is the drug of choice.
Mechanisms of action: The organic nitrates, such as nitroglycerin, are thought
to relax vascular smooth muscle by their intracellular conversion to nitrite
ions and then to nitric oxide (NO), what
leads to dephosphorylation of the myosin light chain, resulting in
vascular smooth muscle relaxation.
At
therapeutic doses, nitroglycerin has two major effects. First, it causes dilation
of the large veins, resulting in pooling blood in the veins. This diminishes preload (venous
return to the heart), and reduces the work of the heart. Second, nitroglycerin
dilates the coronary vasculature, providing increased blood supply to the heart
muscle. Nitroglycerin causes a decrease in myocardial oxygen consumption
because of decreased cardiac work.
Pharmacokinetics.
The time to onset of action varies from one minute for nitroglycerin to more
than one hour for isosorbide
mononitrate. Significant first-pass metabolism of nitroglycerin occurs in the
liver. Therefore, it is common to give
the drug either sublingually or via a transdermal patch.
Adverse effects. The most common adverse
effect of nitroglycerin, as well as the other nitrates, is headache. 30 to
60 % of patients receiving intermittent nitrate therapy with long-acting
agents develop headaches. High doses of organic nitrates can also cause
postural hypotension, facial flushing, and tachycardia.
Tolerance to the actions of
nitrates develops rapidly. It can be overcome by provision of a daily
“nitrate-free interval” to restore sensitivity to the drug. This interval is
typically 6 to 8, 10-12 hours, usually at night because there is decreased
demand on the heart at that time. Nitroglycerin patches are worn for 12 hours
and removed for 12 hours. However, Prinzmetal’s or variant angina worsens early
in the morning, perhaps due to circardian catecholamine surges. These patients nitrate-free interval should
be late afternoon.
Nitroglycerin Extended release Buccal
Tablets (contain 1, 2, 2.5, 3, 5 mg of nitroglycerin). When a buccal tablet is placed under the lipp or
in the buccal pouch, it adheres to the mucosa. As the tablets gradually
dissolves, it releases nitroglycerin to
the systemic circulation. Buccal nitroglycerin can be tried as a means of
aborting an acute anginal attack.
Nitroglycerin tablets (NITROSTAT) – is a stabilized sublingual formulation, which contains 0,15, 0,3, 0,4,
0,6 mg of nitroglycerin.
Nitroglycerin is rapidly absorbed following sublingual administration. Its
onset is approximately one to three minutes. Significant pharmacologic effects
are present for 30 to 60 minutes following administration by the above route.
Nitroglycerin is indicated for the prophylaxis, treatment and management of
patients with angina pectoris. One tablet should be dissolved under the tongue
or in the buccal pouch at the first sign of an acute anginal attack. The dose may be repeated approximately every five minutes until relief is obtained.
If the pain persists after a total of
3-tablets in a 15-minute period,
drug combination should be
recommended.
Nitroglycerin (NITRO-BID) 2,5, 6,5, 9 mg capsules. Capsules must be swollowed. Administer the smallest
effective dose two or three times daily at 8 to 12 hours intervals. Contraindications: acute or recent myocardial infarction, severe
anemia, closed-angled glaucoma, postural hypotension, increased intracranial
pressure, and idiosyncrasy to the drug.
Nitroglycerin injection – for intravenous use only. Must be diluted in
dextrose 5 % injection, or sodium chloride (0,9 %) injection.
Nitroglycerin should not be mixed with other drugs. The concentration of the infusion solution should
not exceed 400 mg/ml of nitroglycerin.
Indication
and usage:
1. Control of blood pressure in perioperative
hypertension: hypertension associated
with surgical procedures, especially cardiovascular procedures, such as
hypertension seen during intratracheal
intubation, anesthesia, skin incision, sternotomy, cardiac bypass.
2. Congestive heart failure associated with acute myocardial infarction.
3. Treatment of angina pectoris.
4. Production of controlled hypotension during
surgical procedures.
Nitroglycerin 2 % (NITRO-BID
Ointment) (20-, 60-mg tubes) is indicated for
the treatment and prevention of angina pectoris due to coronary artery
disease. Controlled clinical trials have demonstrated that this form of
nitroglycerin is effective in improving exercise tolerance in patients with
exertional angina pectoris. Clinical trials have shown significant improvement
in exercise time until chest pain for up to six hours after single aplication
of various doses of nitroglycerin ointment (mean doses ranged from 5 to 36 mg)
to a 36-inch2 (150x150 mm) area of trunk.
When
applying the ointment, place the dose-determining applicator supplied with the package printed-side down
and squeeze the necessary amount of
ointment from the tube onto the applicator. Then place the applicator with the
ointment-side down onto the desired area of skin, usually the chest or back.. A
suggested started dose for NITRO-BID is
7,5 mg applied to a 1x3 inch area every 8 hours. If angina pectoris occurs while the ointment is in place, the
dose should be increased, for example, to 1 inch on a 2x3 inch area. The frequency of dosing
may be also increased (eg, every 6 hours). An initiation of therapy or change of in dosage, blood
pressure (patient standing) should be monitored.
Isosorbide dinitrate is an
orally active nitrate. The drug is not readily metabolized by the liver or smooth muscle and has lower
potency than nitroglycerin in relaxing vascular smooth muscle.
Isosorbide dinitrate (Isordil, Sorbitrate) is
used to reduce the frequency and severity of acute anginal episodes. When given
sublingually or in chewable tablets, it acts in about 2 minutes, and its
effects last 2 to 3 hours. When higher doses are given orally, more drug
escapes metabolism in the liver and produces systemic effects in approximately
30 minutes. Therapeutic effects last about 4 hours after oral administration.
The effective oral dose is usually determined by increasing the dose until
headache occurs, indicating the maximum tolerable dose. Sustained-release
capsules also are available.
Isosorbide mononitrate (Ismo, Imdur) is the
metabolite and active component of isosorbide dinitrate. It is well absorbed
after oral administration and almost 100% bioavailable. Unlike other oral
nitrates, this drug is not subject to first-pass hepatic metabolism. Onset of
action occurs within 1 hour, peak effects occur between 1 and 4 hours, and the
elimination half-life is approximately 5 hours. It is used only for prophylaxis
of angina; it does not act rapidly enough to relieve acute attacks.
The
beneficial and deleterious effects of nitrate-induced vasodilation are
summarized in Table 2.
Sympathetic stimulation of beta1 receptors in the heart increases heart
rate and force of myocardial contraction, both of which increase myocardial
oxygen demand and may precipitate acute anginal attacks. Beta-blocking drugs
prevent or inhibit sympathetic stimulation. Thus, the drugs reduce heart rate
and myocardial contractility, particularly when sympathetic output is increased
during exercise. A slower heart rate may improve coronary blood flow to the
ischemic area. Beta blockers also reduce blood pressure, which in turn
decreases myocardial workload and oxygen demand. In angina pectoris,
beta-adrenergic blocking agents are used in long-term management to decrease
the frequency and severity of anginal attacks, decrease the need for sublingual
nitroglycerin, and increase exercise tolerance. When a beta blocker is being
discontinued after prolonged use, it should be tapered in dosage and gradually
discontinued or rebound angina can occur.
These drugs
should not be given to clients with known or suspected coronary artery spasms
because they may intensify the frequency and severity of vasospasm. This
probably results from unopposed stimulation of alpha-adrenergic receptors,
which causes vasoconstriction, when beta-adrenergic receptors are blocked by
the drugs. Clients who continue to smoke may have reduced efficacy with the use
of beta blockers. Clients with asthma should be observed for bronchospasm from
blockage of beta2 receptors in the lung. Beta blockers should be used with
caution in clients with diabetes mellitus because they can conceal signs of
hypoglycemia except for sweating).
The
b-adrenergic
blockers agents supress the
activation of the heart by blocking b1 receptors. They also reduce the work of the heart by decreasing cardiac
output and causing a slight decrease in blood pressure. Propranolol
is the prototype of this class of
compounds, but other b-blockers, such as metoprolol and atenolol
are equally effective. Propranolol decreases
the oxygen requirement of heart muscle and therefore is effective in
reducing the chest pain on exertion that is common in angina. Propranolol is
therefore useful in the chronic management of stable angina (not for acute
treatment). Tolerance to moderate exercise is increased and this is noticeable
by improvement in the electrocardiogram. Agents with intrinsic sympathomymetic
activity (for example, pindolol and acebutolol) are less effective and
should be avoided. The b-blockers
reduce the frequency and severity oh angina attacks. These agents are
particularly useful in the treatment of patients with myocardial infarction.
The b-blockers can be used with nitrates to increase
exercise duration and tolerance. They
are, however, contraindicated in patients with diabetes, peripheral vascular
disease, or chronic pulmonary disease.
Propranolol
is well absorbed after oral administration. It is then metabolized extensively
in the liver; a relatively small
proportion of an oral dose (approximately 30%) reaches the systemic
circulation. For this reason, oral doses of propranolol are much higher than IV
doses. Onset of action is 30 minutes after oral administration and 1 to 2
minutes after IV injection. Because of variations in the degree of hepatic
metabolism, clients vary widely in the dosages required to maintain a
therapeutic response.
Atenolol, metoprolol, and nadolol have the same actions, uses, and adverse effects as
propranolol, but they have long half-lives and can be given once daily. They
are excreted by the kidneys, and dosage must be reduced in clients with renal
impairment.
Atenolol
BRAND
NAME: Tenormin
DRUG CLASS AND MECHANISM: Atenolol is a beta-adrenergic blocking agent that
blocks the effects of adrenergic drugs, for example, adrenaline or epinephrine,
on nerves of the sympathetic nervous system. One of the important functions of beta-adrenergic
stimulation is to stimulate the heart to beat more rapidly. By blocking the
stimulation of these nerves, atenolol reduces the heart rate and is useful in
treating abnormally
rapid heart rhythms.
Atenolol also reduces the force of contraction of heart muscle and lowers blood
pressure. By reducing the heart rate, the force of muscle contraction, and the
blood pressure against which the heart must pump, atenolol reduces the work of
heart muscle and the need of the muscle for oxygen. Since angina occurs when oxygen demand of the heart muscle
exceeds the supply, atenolol is helpful in treating angina. Atenolol was
approved by the FDA in August 1981.
Metoprolol
BRAND NAMES: Lopressor, Toprol XL
DRUG CLASS AND MECHANISM: Metoprolol is a beta-adrenergic blocking agent that
is used for treating high
blood pressure,
heart pain, abnormal
rhythms of the heart,
and some neurologic conditions. Examples of beta-adrenergic blockers include
propanolol (Inderal), atenolol (Tenormin), and timolol (Blocadren). Metoprolol blocks the action of
the sympathetic nervous system, a portion of the involuntary nervous system, by
blocking beta receptors on sympathetic nerves. Since the sympathetic nervous system
is responsible for increasing the rate with which the heart beats, by blocking
the action of these nerves metoprolol reduces the heart rate and is useful in
treating abnormally rapid heart rhythms.
Metoprolol also reduces the force of contraction of
heart muscle and thereby lowers blood pressure. By reducing the heart rate and
the force of muscle contraction, metoprolol reduces the need for oxygen by
heart muscle. Since heart pain (angina
pectoris) occurs when
oxygen demand of the heart muscle exceeds the supply of oxygen, metoprolol, by
reducing the demand for oxygen, is helpful in treating heart pain. The FDA
approved metoprolol in August 1978.
PREPARATIONS: Tablets: 25, 50, and 100 mg. Tablets (extended
release): 25, 50, 100, and 200 mg. Injection: 1 mg/ml
PRESCRIBED FOR: Metoprolol is prescribed for patients with high blood
pressure (hypertension). It is also used to treat chest
pain (angina
pectoris) related to coronary artery disease. Metoprolol is also useful in
slowing and regulating certain types of abnormally
rapid heart rates
(tachycardias). Other uses for metoprolol include the prevention of migraine
headache and the
treatment of certain types of tremors (familial or hereditary essential tremors).
DOSING: Metoprolol should be taken before meals or at bedtime. The dose for
treating hypertension is 100-450 mg daily in single or divided doses. Angina is
treated with 100-400 mg daily in two divided doses. Acute myocardial infarction
is treated with three 5 mg injections administered 2 minutes apart followed by
treatment with 50 mg oral metoprolol every 6 hours for 48 hours. After 48
hours, patients should receive 100 mg orally twice daily for at least 3 months.
DRUG INTERACTIONS: Calcium
channel blockers and
digoxin (Lanoxin) can lower of blood pressure and heart
rate to dangerous levels when administered together with metoprolol.
Metoprolol can mask the early warning symptoms of low
blood sugar (hypoglycemia) and should be used with caution in patients
receiving treatment for diabetes.
PREGNANCY: Safe use of metoprolol during pregnancy has not been established.
NURSING MOTHERS: Small quantities of metoprolol are excreted in breast
milk and may potentially
cause adverse effects in the infant.
SIDE EFFECTS: Metoprolol is generally well tolerated. Side effects
include abdominal cramps, diarrhea, constipation, fatigue, insomnia, nausea, depression, dreaming, memory
loss, fever, impotence, lightheadedness, slow heart rate, low
blood pressure,
cold extremities, sore
throat, and shortness
of breath or wheezing.
Metoprolol can aggravate breathing difficulties in patients with asthma, chronic
bronchitis, or
emphysema.
CLINICAL PHARMACOLOGY
CORGARD (nadolol) is a nonselective beta-adrenergic
receptor blocking agent. Clinical pharmacology studies have demonstrated
beta-blocking activity by showing (1) reduction in heart rate and cardiac
output at rest and on exercise, (2) reduction of systolic and diastolic blood
pressure at rest and on exercise, (3) inhibition of isoproterenol-induced
tachycardia, and (4) reduction of reflex orthostatic tachycardia.
CORGARD (nadolol) specifically competes with
beta-adrenergic receptor agonists for available beta receptor sites; it
inhibits both the beta1 receptors located chiefly in
cardiac muscle and the beta2 receptors located chiefly
in the bronchial and vascular musculature, inhibiting the chronotropic,
inotropic, and vasodilator responses to beta-adrenergic stimulation
proportionately. CORGARD has no intrinsic sympathomimetic activity and, unlike
some other beta-adrenergic blocking agents, nadolol has little direct
myocardial depressant activity and does not have an anesthetic-like membrane
stabilizing action. Animal and human studies show that CORGARD slows the
sinus rate and depresses AV conduction. In dogs, only minimal amounts of
nadolol were detected in the brain relative to amounts in blood and other
organs and tissues. CORGARD has low lipophilicity as determined by
octanol/water partition coefficient, a characteristic of certain beta-blocking
agents that has been correlated with the limited extent to which these agents
cross the blood-brain barrier, their low concentration in the brain, and low
incidence of CNS-related side effects.
In controlled clinical studies, CORGARD
(nadolol) at doses of 40 to 320 mg/day has been shown to decrease both
standing and supine blood pressure, the effect persisting for approximately 24
hours after dosing.
The mechanism of the antihypertensive effects of
beta-adrenergic receptor blocking agents has not been established; however,
factors that may be involved include (1) competitive antagonism of
catecholamines at peripheral (non-CNS) adrenergic neuron sites (especially
cardiac) leading to decreased cardiac output, (2) a central effect leading to
reduced tonic-sympathetic nerve outflow to the periphery, and (3) suppression
of renin secretion by blockade of the beta-adrenergic receptors responsible for
renin release from the kidneys.
While cardiac output and arterial pressure are reduced
by nadolol therapy, renal hemodynamics are stable, with preservation of renal
blood flow and glomerular filtration rate.
By blocking catecholamine-induced increases in heart
rate, velocity and extent of myocardial contraction, and blood pressure,
CORGARD (nadolol) generally reduces the oxygen requirements of the heart at any
given level of effort, making it useful for many patients in the long-term
management of angina pectoris. On the other hand, nadolol can increase oxygen
requirements by increasing left ventricular fiber length and end diastolic
pressure, particularly in patients with heart failure.
Although beta-adrenergic receptor blockade is useful
in treatment of angina and hypertension, there are also situations in which sympathetic
stimulation is vital. For example, in patients with severely damaged hearts,
adequate ventricular function may depend on sympathetic drive. Beta-adrenergic
blockade may worsen AV block by preventing the necessary facilitating effects
of sympathetic activity on conduction. Beta2-adrenergic
blockade results in passive bronchial constriction by interfering with
endogenous adrenergic bronchodilator activity in patients subject to
bronchospasm and may also interfere with exogenous bronchodilators in such
patients.
Absorption of nadolol after oral dosing is variable,
averaging about 30 percent. Peak serum concentrations of nadolol usually occur
in three to four hours after oral administration and the presence of
food in the gastrointestinal tract does not affect the rate or extent of
nadolol absorption. Approximately 30 percent of the nadolol present in
serum is reversibly bound to plasma protein.
Unlike many other beta-adrenergic blocking agents,
nadolol is not metabolized by the liver and is excreted unchanged, principally
by the kidneys.
The half-life of therapeutic doses of nadolol is about
20 to 24 hours, permitting once-daily dosage. Because nadolol is excreted
predominantly in the urine, its half-life increases in renal failure.
Steady-state serum concentrations of nadolol are attained in six
to nine days with once daily dosage in persons with normal renal function.
Because of variable absorption and different individual responsiveness, the
proper dosage must be determined by titration.
Exacerbation of angina and, in some cases, myocardial
infarction and ventricular dysrhythmias have been reported after abrupt
discontinuation of therapy with beta-adrenergic blocking agents in patients
with coronary artery disease. Abrupt withdrawal of these agents in patients
without coronary artery disease has resulted in transient symptoms, including
tremulousness, sweating, palpitation, headache, and malaise. Several mechanisms
have been proposed to explain these phenomena, among them increased sensitivity
to catecholamines because of increased numbers of beta receptors.
INDICATIONS AND USAGE
Angina Pectoris
Nadolol is indicated for the long-term management of
patients with angina pectoris.
Hypertension
Nadolol is indicated in the management of
hypertension; it may be used alone or in combination with other
antihypertensive agents, especially thiazide-type diuretics.
CONTRAINDICATIONS
Nadolol is contraindicated in bronchial asthma, sinus
bradycardia and greater than first-degree conduction block, cardiogenic shock,
and overt cardiac failure
WARNINGS
Cardiac Failure
Sympathetic stimulation may be a vital component
supporting circulatory function in patients with congestive heart failure, and
its inhibition by beta-blockade may precipitate more severe failure. Although
beta-blockers should be avoided in overt congestive heart failure, if
necessary, they can be used with caution in patients with a history of failure
who are well compensated, usually with digitalis and diuretics. Beta-adrenergic
blocking agents do not abolish the inotropic action of digitalis on heart
muscle.
IN PATIENTS WITHOUT A HISTORY OF HEART FAILURE,
continued use of beta-blockers can, in some cases, lead to cardiac failure.
Therefore, at the first sign or symptom of heart failure, the patient should be
digitalized and/or treated with diuretics, and the response observed closely,
or nadolol should be discontinued (gradually, if possible).
Exacerbation of Ischemic Heart Disease Following Abrupt Withdrawal
Hypersensitivity to catecholamines has been observed
in patients withdrawn from beta-blocker therapy; exacerbation of angina and, in
some cases, myocardial infarction have occurred after abrupt
discontinuation of such therapy. When discontinuing chronically administered
nadolol, particularly in patients with ischemic heart disease, the dosage
should be gradually reduced over a period of one to two weeks and the patient
should be carefully monitored. If angina markedly worsens or acute coronary
insufficiency develops, nadolol administration should be reinstituted promptly,
at least temporarily, and other measures appropriate for the management of
unstable angina should be taken. Patients should be warned against interruption
or discontinuation of therapy without the physician's advice. Because coronary
artery disease is common and may be unrecognized, it may be prudent not to
discontinue nadolol therapy abruptly even in patients treated only for
hypertension.
Nonallergic Bronchospasm (e.g., chronic bronchitis, emphysema)
PATIENTS WITH BRONCHOSPASTIC DISEASES SHOULD IN
GENERAL NOT RECEIVE BETA-BLOCKERS. Nadolol should be administered with caution
since it may block bronchodilation produced by endogenous or exogenous
catecholamine stimulation of beta2 receptors.
Major Surgery
Because beta-blockade impairs the ability of the heart
to respond to reflex stimuli and may increase the risks of general anesthesia
and surgical procedures, resulting in protracted hypotension or low cardiac
output, it has generally been suggested that such therapy should be withdrawn
several days prior to surgery. Recognition of the increased sensitivity to
catecholamines of patients recently withdrawn from beta-blocker therapy,
however, has made this recommendation controversial. If possible, beta-blockers
should be withdrawn well before surgery takes place. In the event of emergency
surgery, the anesthesiologist should be informed that the patient is on
beta-blocker therapy. The effects of nadolol can be reversed by administration
of beta-receptor agonists such as isoproterenol, dopamine, dobutamine, or
levarterenol. Difficulty in restarting and maintaining the heart beat has also
been reported with beta-adrenergic receptor blocking agents.
Diabetes and Hypoglycemia
Beta-adrenergic blockade may prevent the appearance of
premonitory signs and symptoms (e.g., tachycardia and blood pressure changes)
of acute hypoglycemia. This is especially important with labile diabetics.
Beta-blockade also reduces the release of insulin in response to hyperglycemia;
therefore, it may be necessary to adjust the dose of antidiabetic drugs.
Thyrotoxicosis
Beta-adrenergic blockade may mask certain clinical
signs (e.g., tachycardia) of hyperthyroidism. Patients suspected of developing
thyrotoxicosis should be managed carefully to avoid abrupt withdrawal of
beta-adrenergic blockade which might precipitate a thyroid storm.
PRECAUTIONS
Impaired Renal Function
Nadolol should be used with caution in patients with
impaired renal function. (See
Drug Interactions
When administered concurrently, the following drugs
may interact with beta-adrenergic receptor blocking agents:
Anesthetics, general: Exaggeration of the hypotension induced by
general anesthetics
Antidiabetic drugs (oral agents and insulin): Hypoglycemia or hyperglycemia; adjust dosage of
antidiabetic drug accordingly Catecholamine-depleting
drugs (e.g.,reserpine): Additive effect; monitor closely for evidence of
hypotension and/or excessive bradycardia (e.g., vertigo, syncope, postural
hypotension).
Response to Treatment for Anaphylactic Reaction
While taking beta-blockers, patients with a history of
severe anaphylactic reaction to a variety of allergens may be more reactive to
repeated challenge, either accidental, diagnostic, or therapeutic. Such
patients may be unresponsive to the usual doses of epinephrine used to treat
allergic reaction.
Carcinogenesis, Mutagenesis, Impairment of Fertility
In chronic oral toxicologic studies (one to two
years) in mice, rats, and dogs, nadolol did not produce any significant toxic
effects. In two- year oral carcinogenic studies in rats and mice, nadolol
did not produce any neoplastic, preneoplastic, or non-neoplastic pathologic
lesions. In fertility and general reproductive performance studies in rats,
nadolol caused no adverse effects.
Pregnancy Category
In animal reproduction studies with nadolol, evidence
of embryo- and fetotoxicity was found in rabbits, but not in rats or hamsters,
at doses 5 to 10 times greater (on a mg/kg basis) than the maximum
indicated human dose. No teratogenic potential was observed in any of these
species.
There are no adequate and well-controlled studies in
pregnant women. Nadolol should be used during pregnancy only if the potential
benefit justifies the potential risk to the fetus. Neonates whose mothers are
receiving nadolol at parturition have exhibited bradycardia, hypoglycemia, and
associated symptoms.
Nursing Mothers
Nadolol is excreted in human milk. Because of the
potential for adverse effects in nursing infants, a decision should be made
whether to discontinue nursing or to discontinue therapy taking into account
the importance of CORGARD (nadolol) to the mother.
Pediatric Use
Safety and effectiveness in pediatric patients have
not been established.
ADVERSE REACTIONS
Most adverse effects have been mild and transient and
have rarely required withdrawal of therapy.
Cardiovascular: Bradycardia with heart rates of less than 60 beats
per minute occurs commonly, and heart rates below 40 beats per minute and/or
symptomatic bradycardia were seen in about 2 of 100 patients. Symptoms of
peripheral vascular insufficiency, usually of the Raynaud type, have occurred
in approximately 2 of 100 patients. Cardiac failure, hypotension, and
rhythm/conduction disturbances have each occurred in about 1 of 100 patients.
Single instances of first degree and third degree heart block have been
reported; intensification of AV block is a known effect of beta-blockers
Central Nervous System: Dizziness or fatigue has been reported in
approximately 2 of 100 patients; paresthesias, sedation, and change in behavior
have each been reported in approximately 6 of 1000 patients.
Respiratory: Bronchospasm has been reported in approximately 1 of
1000 patients
Gastrointestinal: Nausea, diarrhea, abdominal discomfort, constipation,
vomiting, indigestion, anorexia, bloating, and flatulence have been reported in
1 to 5 of 1000 patients.
Miscellaneous: Each of the following has been reported in 1 to 5 of
1000 patients: rash; pruritus; headache; dry mouth, eyes, or skin; impotence or
decreased libido; facial swelling; weight gain; slurred speech; cough; nasal
stuffiness; sweating; tinnitus; blurred vision. Reversible alopecia has been
reported infrequently.
The following adverse reactions have been reported in
patients taking nadolol and/or other beta-adrenergic blocking agents, but no
causal relationship to nadolol has been established.
Central Nervous System: Reversible mental depression progressing to
catatonia; visual disturbances; hallucinations; an acute reversible syndrome
characterized by disorientation for time and place, short-term memory loss,
emotional lability with slightly clouded sensorium, and decreased performance
on neuropsychometrics.
Gastrointestinal: Mesenteric arterial thrombosis; ischemic colitis;
elevated liver enzymes.
Hematologic: Agranulocytosis; thrombocytopenic or
nonthrombocytopenic purpura.
Allergic: Fever combined with aching and sore throat;
laryngospasm; respiratory distress.
Miscellaneous: Pemphigoid rash; hypertensive reaction in patients
with pheochromocytoma; sleep disturbances; Peyronie's disease.
The oculomucocutaneous syndrome associated with the
beta-blocker practolol has not been reported with nadolol.
OVERDOSAGE
Nadolol can be removed from the general circulation by
hemodialysis.
In addition to gastric lavage, the following measures
should be employed, as appropriate. In determining the duration of corrective
therapy, note must be taken of the long duration of the effect of nadolol.
Excessive Bradycardia
Administer atropine (0.25 to 1.0 mg). If there is no
response to vagal blockade, administer isoproterenol cautiously.
Cardiac Failure
Administer a digitalis glycoside and diuretic. It has
been reported that glucagon may also be useful in this situation.
Hypotension
Administer vasopressors, e.g., epinephrine or
levarterenol. (There is evidence that epinephrine may be the drug of choice.)
Bronchospasm
Administer a beta2-stimulating
agent and/or a theophylline derivative.
DOSAGE AND ADMINISTRATION
Dosage must be individualized. Nadolol may be
administered without regard to meals.
Angina Pectoris
The usual initial dose is 40 mg CORGARD (nadolol) once
daily. Dosage may be gradually increased in 40 to 80 mg increments at 3 to 7
day intervals until optimum clinical response is obtained or there is
pronounced slowing of the heart rate. The usual maintenance dose is 40 or 80 mg
administered once daily. Doses up to 160 or 240 mg administered once daily may
be needed.
The usefulness and safety in angina pectoris of
dosages exceeding 240 mg per day have not been established. If treatment is to
be discontinued, reduce the dosage gradually over a period of one to two
weeks.
Hypertension
The usual initial dose is 40 mg CORGARD (nadolol) once
daily, whether it is used alone or in addition to diuretic therapy. Dosage may
be gradually increased in 40 to 80 mg increments until optimum blood pressure
reduction is achieved. The usual maintenance dose is 40 or 80 mg administered
once daily. Doses up to 240 or 320 mg administered once daily may be needed.
Dosage Adjustment in Renal Failure
Absorbed nadolol is excreted principally by the
kidneys and, although nonrenal elimination does occur, dosage adjustments are
necessary in patients with renal impairment. The following dose
intervals are recommended:
|
Creatinine |
Dosage |
|
>
50 |
24 |
|
31 -
50 |
24 -
36 |
|
10 -
30 |
24 -
48 |
|
<
10 |
40 -
60 |
Calcium Channel Blocking Agents
Calcium channel blockers act on contractile and conductive tissues of the
heart and on vascular smooth muscle. For these cells to function normally, the
concentration of intracellular calcium must be increased. This is usually
accomplished by movement of extracellular calcium ions into the cell (through
calcium channels in the cell membrane) and release of bound calcium from the
sarcoplasmic reticulum in the cell. Thus, calcium plays an important role in
maintaining vasomotor tone, myocardial contractility, and conduction. Calcium
channel blocking agents prevent the movement of extracellular calcium into the
cell. As a result, coronary and peripheral arteries are dilated, myocardial
contractility is decreased, and the conduction system is depressed in relation
to impulse formation (automaticity) and conduction velocity.
In angina
pectoris, the drugs improve the blood supply to the myocardium by dilating
coronary arteries and decrease the workload of the heart by dilating peripheral
arteries. In variant angina, calcium channe l blockers reduce coronary artery
vasospasm. In atrial fibrillation or flutter and other supraventricular
tachydysrhythmias, diltiazem and verapamil
slow the rate of ventricular response. In hypertension, the drugs lower
blood pressure primarily by dilating peripheral arteries.
Calcium
channel blockers are well absorbed after oral administration but undergo
extensive first-pass metabolism in the liver. Most of the drugs are more than
90% protein bound and reach peak plasma levels within 1 to 2 hours (6 hours or
longer for sustained-release forms). Most also have short elimination
half-lives (<5 hours), so doses must be given three or four times daily
unless sustained-release formulations are used. Amlodipine (30 to 50 hours),
bepridil (24 hours), and felodipine (11 to 16 hours) have long elimination
half-lives and therefore can be given once daily. The drugs are metabolized in
the liver, and dosage should be reduced in clients with severe liver disease.
Dosage reductions are not required with renal disease. The calcium channel
blockers approved for use in the United States vary in their chemical
structures and effects on body tissues. Seven of these are chemically
dihydropyridines, of which nifedipine is the prototype. Bepridil, diltiazem,
and verapamil differ chemically from the dihydropyridines and each other.
Nifedipine and related drugs act mainly on vascular smooth muscle to produce
vasodilation, whereas verapamil and diltiazem have greater effects on the
cardiac conduction system.
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.
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Adjunctive
Antianginal Drugs
In
addition to antianginal drugs, several other drugs may be used to control risk
factors and prevent progression of myocardial ischemia to myocardial infarction
and sudden cardiac death. These may include:
• Aspirin. This drug has become the standard of care because of its
antiplatelet (ie, antithrombotic) effects. Recommended doses vary from 81 mg
daily to 325 mg daily or every other day; apparently all doses are beneficial
in reducing the possibility of myocardial reinfarction, stroke, and death.
Clopidogrel, 75 mg/day,
is an acceptable alternative
for individuals with aspirin allergy.
• Antilipemics. These drugs may be needed by clients who are unable
to lower serum cholesterol levels sufficiently with a low-fat diet. Lovastatin
or a related “statin” is often used. The goal is usually to reduce the serum
cholesterol level below 200 mg/dL and lowdensity lipoprotein cholesterol to
below 130 mg/dL.
• Antihypertensives. These drugs
may be needed for clients with hypertension. Because beta blockers and
calcium channel blockers are used to manage hypertension as well as angina, one
of these drugs may be effective for both disorders.
PRINCIPLES OF THERAPY
Goals
of Therapy
The goals
of drug therapy are to relieve acute anginal pain; reduce the number and
severity of acute anginal attacks; improve exercise tolerance and quality of
life; delay progression of CAD; prevent myocardial infarction; and prevent
sudden cardiac death.
Choice of Drug and Dosage Form
For relief of acute angina and prophylaxis before events that cause acute
angina, nitroglycerin (sublingual tablets or translingual spray) is usually the
primary drug of choice. Sublingual or chewable tablets of isosorbide dinitrate
also may be used. For long-term prevention or management of recurrent angina,
oral or topical nitrates, beta-adrenergic blocking agents, or calcium channel
blocking agents are used.
Combination drug therapy with a nitrate and one
of the other drugs is common and effective. Clients taking one or more
long-acting antianginal drugs should carry a short-acting drug as well, to be
used for acute attacks.
Titration
of Dosage
Dosage of all antianginal
drugs should be individualized to achieve optimal benefit and minimal adverse
effects. This is usually accomplished by starting with relatively small doses
and increasing them at appropriate intervals as necessary. Doses may vary
widely among individuals.
Tolerance
to Long-Acting Nitrates
Clients
who take long-acting dosage forms of nitrates on a regular schedule develop
tolerance to the vasodilating (antianginal) effects of the drug. The clients
more likely to develop tolerance are those on high-dose, uninterrupted therapy.
Although tolerance decreases the adverse effects of hypotension, dizziness, and
headache, therapeutic effects also may be decreased. As a result, episodes of chest
pain may occur more often or be more severe than expected. In addition,
shortacting nitrates may be less effective in relieving acute pain. Opinions
seem divided about the best way to prevent or manage nitrate tolerance. Some
authorities recommend using short-acting nitrates when needed and avoiding the
long-acting forms. Others recommend using the long-acting forms for 12 to 16
hours daily during active periods and omitting them during inactive periods or
sleep.
Thus,
a dose of an oral nitrate or topical ointment would be given every 6 hours for
three doses daily, allowing a rest period of 6 hours without a dose.
Transdermal discs should be removed at bedtime. If anginal symptoms occur
during sleeping hours, short-acting nitrates may be beneficial in relieving the
symptoms. All nitrates should be administered at the lowest effective dosage.
Use
in Children
The safety
and effectiveness of antianginal drugs have not been established for children.
Nitroglycerin has been given IV for heart failure and intraoperative control of
blood pressure, with the initial dose adjusted for weight and later doses
titrated to response.
Use
in Older Adults
Antianginal
drugs are often used because cardiovascular disease and myocardial ischemia are
common problems in older adults. Adverse drug effects, such as hypotension and
syncope, are likely to occur, and they may be more severe than in younger
adults. Blood pressure and ability to ambulate safely should be closely
monitored, especially when drug therapy is started or dosages are increased.
Ambulatory clients also should be monitored for their ability to take the drugs
correctly.
With
calcium channel blockers, older adults may have higher plasma concentrations of
verapamil, diltiazem, nifedipine, and amlodipine. This is attributed to
decreased hepatic metabolism of the drugs, probably because of decreased
hepatic blood flow. In addition, older adults may experience more hypotension
with verapamil, nifedipine, and felodipine than younger clients. Blood pressure
should be monitored with these drugs.
Use
in Renal Impairment
Little
information is available about the use of antianginal drugs in clients with
impaired renal function. A few studies indicate that advanced renal failure may
alter the pharmacokinetics of calcium channel blockers. Although the
pharmacokinetics of diltiazem and verapamil are quite similar in clients with
normal and impaired renal function, caution is still advised. With verapamil,
about 70% of a dose is excreted as metabolites in urine.
Dosage reductions are considered unnecessary with verapamil and diltiazem
but may be needed with nifedipine and several other dihydropyridine
derivatives. With nifedipine, protein binding is decreased and the elimination
half-life is prolonged with renal impairment. In a few clients, reversible
elevations in blood urea nitrogen and serum creatinine have occurred. With
nicardipine, plasma concentrations are higher in clients with renal impairment,
and dosage should be reduced. Bepridil should be used with caution because its
metabolites are excreted mainly in urine.
Use
in Hepatic Impairment
Nitrates,
beta blockers, and calcium channel blockers are metabolized in the liver, and
all should be used with caution in clients with significant impairment of
hepatic function from reduced blood flow or disease processes.
With
oral nitrates, it is difficult to predict effects. On the one hand, first-pass
metabolism is reduced, which increases bioavailability (amount of active drug)
of a given dose. On the other hand, the nitrate reductase enzymes that normally
deactivate the drug may increase if large doses are given. In this case, more
enzymes are available and the drug is metabolized more rapidly, possibly
reducing therapeutic effects of a given dose. Relatively large doses of oral
nitrates are sometimes given to counteract the drug tolerance (reduced
hemodynamic effects) associated with chronic use. In addition, metabolism of
nitroglycerin and isosorbide dinitrate normally produces active metabolites.
Thus, if metabolism is reduced by liver impairment, drug effects may be
decreased and shorter in duration.
With
calcium channel blockers, impairment of liver function has profound effects on
the pharmacokinetics and pharmacodynamics of most of these drugs. Thus, the
drugs should be used with caution, dosages should be substantially reduced, and
clients should be closely monitored for drug effects (including periodic
measurements of liver enzymes). These recommendations stem from the following
effects:
• An impaired liver
produces fewer drug-binding plasma proteins such as albumin. This means that a
greater proportion of a given dose is unbound and therefore active.
• In clients with
cirrhosis, bioavailability of oral drugs is greatly increased and metabolism
(of both oral and parenteral drugs) is greatly decreased. Both of these effects
increase plasma levels of drug from a given dose (essentially an overdose). The
effects result from shunting of blood around the liver so that drug molecules
circulating in the bloodstream do not come in contact with drug-metabolizing
enzymes and therefore are not metabolized. For example, the bioavailability of
verapamil, nifedipine, felodipine, and nisoldipine is approximately double and
their clearance is approximately one third that of clients without cirrhosis.
• Although hepatotoxicity
is uncommon, clinical symptoms of hepatitis, cholestasis, or jaundice and
elevated liver enzymes (eg, alkaline phosphatase, creatine kinase [CK], lactate
dehydrogenase [LDH], aspartate aminotransferase [AST], alanine aminotransferase
[ALT]) have occurred, mainly with diltiazem, nifedipine, and verapamil. These
changes resolve if the causative drug is stopped.
Use
in Critical Illness
Antianginal
drugs have multiple cardiovascular effects and may be used alone or in combination
with other cardiovascular drugs in clients with critical illness. They are
probably used most often to manage severe angina, severe hypertension, or
serious cardiac dysrhythmias. For example, IV nitroglycerin may be used for
angina and hypertension; an IV beta blocker or calcium channel blocker may be
used to improve cardiovascular function with angina, hypertens ion, or
supraventricular tachydysrhythmias. With any of these drugs, dosage must be
carefully titrated and clients must be closely monitored for hypotension and
other drug effects.
In
addition, absorption of oral drugs or topical forms of nitroglycerin may be
impaired in clients with extensive edema, heart failure, hypotension, or other
conditions that impair blood flow to the gastrointestinal tract or skin.
CARDIAC DYSRHYTHMIAS
Cardiac
arrhythmias are a common problem in clinical practice, occurring in up to 25%
of patients treated with digitalis, 50% of anesthetized patients, and over 80%
of patients with acute myocardial infarction. Arrhythmias may require treatment
because rhythms that are too rapid, too slow, or asynchronous can reduce
cardiac output. Some arrhythmias can precipitate more serious or even lethal
rhythm disturbances; for example, early premature ventricular depolarizations
can precipitate ventricular fibrillation. In such patients, antiarrhythmic
drugs may be precipitate ventricular fibrillation. In such patients,
antiarrhythmic drugs may be lifesaving. On the other hand, the hazards of antiarrhythmic
drugs—and in particular the fact that they can precipitate lethal arrhythmias
in some patients—has led to a reevaluation of their relative risks and
benefits. In general, treatment of asymptomatic or minimally symptomatic
arrhythmias should be avoided for this reason.
Cardiac
dysrhythmias can originate in any part of the conduction system or from atrial
or ventricular muscle. They result from disturbances in electrical impulse
formation (automaticity), conduction (conductivity), or both. The characteristic
of automaticity allows myocardial cells other than the SA node to depolarize
and initiate the electrical impulse that culminates in atrial and ventricular
contraction. This may occur when the SA node fails to initiate an impulse or
does so too slowly. When the electrical impulse arises anywhere other than the
SA node, it is an abnormal or ectopic focus. If the ectopic focus depolarizes
at a rate faster than the SA node, the ectopic focus becomes the dominant
pacemaker. Ectopic pacemakers may arise in the atria, AV node, Purkinje fibers,
or ventricular muscle. They may be activated by hypoxia, ischemia, or
hypokalemia. Ectopic foci indicate myocardial irritability (increased
responsiveness to stimuli) and potentially serious impairment of cardiac function.
A common
mechanism by which abnormal conduction causes dysrhythmias is called reentry excitation. During normal
conduction, the electrical impulse moves freely down the conduction system
until it reaches recently excited tissue that is refractory to stimulation.
This causes the impulse to be extinguished. The SA node then recovers, fires
spontaneously, and the conduction process starts over again. Reentry excitation
means that an impulse continues to reenter an area of the heart rather than
becoming extinguished. For this to occur, the impulse must encounter an
obstacle in the normal conducting pathway. The obstacle is usually an area of
damage, such as myocardial infarction. The damaged area allows conduction in
only one direction and causes a circular movement of the impulse.
Dysrhythmias
may be mild or severe, acute or chronic, episodic or relatively continuous.
They are clinically significant if they interfere with cardiac function (ie,
the heart’s abil-ity to pump sufficient blood to body tissues). The normal
heartcan maintain an adequate cardiac output with ventricular rates ranging
from 40 to 180 beats per minute. The diseased heart, however, may not be able
to maintain an adequate cardiac output with heart rates below 60 or above 120.
Dysrhythmias are usually categorized by rate, location, or patterns of
conduction.
BRADYCARDIAS
AND HEART BLOCK
Bradycardias
may be due to failure of impulse formation (sinus bradycardia) or failure of
impulse conduction from the atria to the ventricles (atrioventricular block).
Bradycardia
Sinus bradycardia
Sinus
bradycardia is due to extrinsic factors influencing a relatively normal sinus
node or due to intrinsic sinus node disease. The mechanism can be acute and
reversible or chronic and degenerative. Common causes of sinus bradycardia
include:
Extrinsic causes
■ hypothermia,
hypothyroidism, cholestatic jaundice and raised intracranial pressure
■ drug therapy with
beta-blockers, digitalis and other antiarrhythmic drugs
■ neurally mediated
syndromes.
Intrinsic causes
■ acute ischaemia
and infarction of the sinus node (as a complication of acute myocardial
infarction)
■ chronic
degenerative changes such as fibrosis of the atrium and sinus node (sick sinus
syndrome).
Sick sinus syndrome or
sinoatrial disease is usually caused by idiopathic fibrosis of the sinus node.
Other causes of fibrosis such as ischaemic heart disease, cardiomyopathy or
myocarditis can also cause the syndrome. Patients develop episodes of sinus
bradycardia or sinus arrest and commonly, owing to diffuse atrial disease,
experience paroxysmal atrial tachyarrhythmias (tachy-bradysyndrome).
Neurally mediated
syndromes
Neurally
mediated syndromes are due to a reflex (called Bezold–Jarisch) that may result
in both bradycardia (sinus bradycardia, sinus arrest and AV block) and reflex
peripheral vasodilatation. These syndromes usually present as syncope or
pre-syncope (dizzy spells).
Carotid
sinus syndrome occurs in the elderly and mainly results in bradycardia. Syncope
occurs.
Neurocardiogenic
(vasovagal) syncope (syndrome) usually presents in young adults but may present
for the first time in elderly patients. It results from a variety of situations
(physical and emotional) that affect the autonomic nervous system. The efferent
output may be predominantly bradycardic, predominantly vasodilatory or mixed.
Postural
orthostatic tachycardia syndrome (POTS) is a sudden and significant increase in
heart rate associated with normal or mildly reduced blood pressure produced by
standing.
The
underlying mechanism is a failure of the peripheral vasculature to appropriately
constrict in response to orthostatic stress, which is compensated by an
excessive increase in heart rate.
Many
medications, such as antihypertensives, tricyclic antidepressants and
neuroleptics can be the cause of syncope, particularly in the elderly. Careful
dose titration and avoidance of combining two agents with potential to cause
syncope help to prevent iatrogenic syncope.
Treatment
The
management of sinus bradycardia is first to identify and if possible remove any
extrinsic causes. Temporary pacing may be employed in patients with reversible
causes until a normal sinus rate is restored and in patients with chronic
degenerative conditions until a permanent pacemaker is implanted.
Chronic
symptomatic sick sinus syndrome requires permanent pacing (DDD), with
additional antiarrhythmic drugs (or ablation therapy) to manage any tachycardia
element. Thromboembolism is common in tachy-brady syndrome and patients should
be anticoagulated unless there is a contraindication. Patients with carotid
sinus hypersensitivity (asystole > 3 s), especially if symptoms are
reproduced by carotid sinus massage, and in whom life-threatening causes of
syncope have been excluded, benefit from pacemaker implantation. Treatment
options in vasovagal attacks include avoidance, if possible, of situations
known to cause syncope in a particular patient. Increased salt intake,
compression of the lower legs with hose and drugs such as beta-blockers,
alpha-agonists or myocardial negative inotropes (such as disopyramide) may be
helpful. In selected patients with ‘malignant’ neurocardiogenic syncope
(syncope associated with injuries) permanent pacemaker therapy is helpful.
These patients benefit from dual chamber pacemakers with a feature called ‘rate
drop response’ which, once activated, paces the heart at a fast rate for a set
period of time in order to prevent syncope.
Heart block
Heart block
or conduction block may occur at any level in the conducting system. Block in
either the AV node or the His bundle results in AV block, whereas block lower
in the conduction system produces bundle branch block.
Atrioventricular block
There are
three forms:
First-degree AV block
This is simple
prolongation of the PR interval to more than 0.22 s. Every atrial
depolarization is followed by conduction to the ventricles but with delay
(Fig.).
An ECG
showing first-degree atrioventricular block with a prolonged PR interval. In
this trace coincidental ST depression is also present.
Three varieties of
seconddegree atrioventricular (AV) block. (a) Wenckebach (Mobitz type I) AV
block. The
PR interval gradually prolongs until the P wave does not conduct to the
ventricles (arrows). (b) Mobitz type II AV block. The P waves that do
not conduct to the ventricles (arrows) are not preceded by gradual PR interval
prolongation. (c) Two P waves to each QRS complex. The PR interval prior
to the dropped P wave is always the same. It is not possible to define this
type of AV block as type I or type II Mobitz block and it is, therefore, a
third variety of second-degree AV block (arrows show P waves).
Two examples of complete
heart block. (a) Congenital complete heart block. The QRS complex is narrow
(0.08 s) and the QRS rate is relatively rapid (52 b.p.m.). (b) Acquired
complete heart block. The QRS complex is broad (0.13 s) and the QRS rate is
relatively slow (38 b.p.m.).
Second-degree AV block
This occurs when some P
waves conduct and others do not.
There are several forms
(Fig.):
■ Mobitz I block
(Wenckebach block phenomenon) is progressive PR interval prolongation until a P
wave fails to conduct. The PR interval before the blocked P wave is much longer
than the PR interval after the blocked P wave.
■ Mobitz II block
occurs when a dropped QRS complex is not preceded by progressive PR interval
prolongation. Usually the QRS complex is wide (> 0.12 s). Usually the QRS
complex is wide (> 0.12 s).
■ 2 : 1 or 3 : 1
(advanced) block occurs when every second or third P wave conducts to the
ventricles. This form of second-degree block is neither Mobitz I nor II.
Wenckebach AV block in general is due to block in the AV node, whereas Mobitz
II block signifies block at an infranodal level such as the His bundle. The
risk of progression to complete heart block is greater and the reliability of
the resultant escape rhythm is less with Mobitz II block. Therefore pacing is
usually indicated in Mobitz II block, whereas patients with Wenckebach AV block
are usually monitored. Acute myocardial infarction may produce second-degree
heart block. In inferior myocardial infarction, close monitoring and
transcutaneous temporary back-up pacing are all that is required. In anterior
myocardial infarction, second-degree heart block is associated with a high risk
of progression to complete heart block, and temporary pacing followed by
permanent pacemaker implantation is usually indicated. 2 : 1 Heart block may
either be due to block in the AV node or at an infra-nodal level. Management
depends on the clinical setting in which it occurs.
Third-degree (complete) AV
block
Complete
heart block occurs when all atrial activity fails to conduct to the ventricles
(Fig.). In patients with complete heart block the aetiology needs to be
established. In this situation life is maintained by a spontaneous escape
rhythm.
Narrow complex escape
rhythm (< 0.12 s QRS complex) implies that it originates in the His bundle
and therefore that the region of block lies more proximally in the AV node. The
escape rhythm occurs with an adequate rate (50–60 b.p.m.) and is relatively
reliable.
Treatment depends on the aetiology.
Recent-onset narrow-complex AV block due to transient causes may respond to
intravenous atropine, but temporary pacing facilities should be available for
the management of these patients. Chronic narrow-complex AV block requires
permanent pacing (dual chamber) if it is symptomatic or associated with heart
disease. Pacing is also advocated for isolated,
congenital AV block, even
if asymptomatic. Broad complex escape rhythm (> 0.12 s) implies that the
escape rhythm originates below the His bundle and therefore that the region of
block lies more distally in the His–Purkinje system.
The
resulting rhythm is slow (15–40 b.p.m.) and relatively unreliable. Dizziness
and blackouts (Stokes–Adams attacks) often occur. In the elderly, it is usually
caused by degenerative fibrosis and calcification of the distal conduction
system (Lev’s disease). In younger individuals, a proximal progressive cardiac
conduction disease due to the inflammatory process is known as Lenegre’s
syndrome. Sodium channel abnormalities have been identified in both syndromes.
Broad-complex AV block may also be caused by ischaemic heart disease,
myocarditis or cardiomyopathy. Permanent pacemaker implantation is indicated,
as pacing considerably reduces the mortality. Because ventricular arrhythmias
are not uncommon, an implantable cardioverter–defibrillator (ICD) may be
indicated in those with severe left ventricular dysfunction (> 0.30 s).
Antiarrhythmic agents
Antidysrhythmic agents are diverse drugs used for prevention and
management of cardiac dysrhythmias. Dysrhythmias, also called arrhythmias, are
abnormalities in heart rate or rhythm. They become significant when they
interfere with cardiac function and ability to perfuse body tissues. To aid in
understanding of dysrhythmias and antidysrhythmic drug therapy, the physiology
of cardiac conduction and contractility is reviewed.
Effects
of drugs on automaticity: Most of antiarrhythmic agents suppress
automaticity (1) by decreasing the slope of diastolic depolarization and/or by raising the threshold of discharge to a less negative
voltage. Such drugs cause the frequency of discharge to decrease, an effect
that is more pronounced in cells with
ectopic pacemaker activity than in normal cells.
Indications for Use
Antidysrhythmic drug
therapy commonly is indicated in the following conditions:
1. To convert atrial
fibrillation (AF) or flutter to normalsinus rhythm (NSR)
2. To maintain NSR after
conversion from AF or flutter
3. When the ventricular
rate is so fast or irregular that cardiac output is impaired. Decreased cardiac
output leads to symptoms of decreased systemic, cerebral, and coronary
circulation.
4. When dangerous
dysrhythmias occur and may be fatal if not quickly terminated. For example,
ventricular tachycardia may cause cardiac arrest.
Effects of drugs on conduction
abnormalities: Antiarrhythmic agents prevent reentry by slowing conduction
and/or increasing the refractory period
to convent a unidirectional block into a bidirectional block.
As
noted above, the antiarrhythmic drugs can
modify impulse generation and
conduction. More than a dozen such drugs
that are patentially usefull in
treating arrhythmias are currently
available. However, only a limited
number of these agents are
clinically beneficial in the treatment
of selected arrhythmias. For example, the acute termination of ventricular tachycardia by lidocaine or supraventricular
tachycardia by adenosine or verapamil
are examples in which antiarrhythmic
therapy results in decreased morbidity. In contrast, many of the antiarrhythmic
agents are now known to have lethal proarrhythmic actions, that is, to cause
arrhythmias.
The
antiarrhythmic drugs can be classified according to their predominant effects on the action
potential. Although this classification
is convenient, it is not entirely clear-cut, because many of the drugs have
actions relating to more than one class or they have active metabolites with a
different class of action.
Classification of antiarrhythmic drugs
|
CLASS |
Mechanism of Action |
Drug name |
|
IA |
Na+Channel blocker |
Disopyramide, procainamide, quinidine |
|
IB |
Na+Channel blocker |
Lidocaine, mexiletine, tocainide |
|
IC |
Na+Channel blocker |
Flecainide, propafenone |
|
II |
b
Adrenoreceptor blocker |
Esmolol, metoprolol, pindolol, propranolol |
|
III |
K+Channel blocker |
Amiodarone, bretylium, sotalol |
|
IV |
Ca++ Channel blocker |
Diltiazem, verapamil |
|
Other antiarrhythmic drugs |
Adenosine, digoxin |
|
Class I drugs have been subdivided into three groups according to
their effect on the duration of the action potential. Class IA agents slow the
rate of rise of the action potential, thus
slowing conduction, and prolong the action potential and increase the
ventricular effective refractory period. They have an intermediate speed of
association with activated/inactivated
sodium channels, and an intermediate rate of dissociation from resting channels. Class IB drugs have
little effect on the rate of depolarization, but rather they decrease the
duration of the action potential by
shortening repolarization. They rapidly
interact with sodium channels. Class IC
agents markedly depress the rate of rise
of the membrane action potential, and therfore they cause marked conduction
slowing but have little effect on the duration of the membrane action
potential or the ventricular effective refractory
period. They bind slowly to sodium channels.
Quinidine (200, 300 mg) is the prototype Class IA drug.
At high doses, it can actually
precipitate arrhythmias, which can lead
to fatal ventricular fibrillation. Because of quinidine’s toxic potential, calcium antagonists, such as verapamil,
are increasingly replacing this drug in clinical use. Quinidine is used in the treatment of a wide variety of
arrhythmias, including atrial, AV junctional, and ventricular
tachyarrhythmias. Quinidine is used to
maintain sinus rhythm after direct current cardioversion of atrial flutter or
fibrillation and to prevent frequent ventricular tachycardia. A potential adverse
effect of quinidine (or any
antiarrhythmic drug) is exacerbation of the arrhythmia. Quinidine may cause SA and AV block or asystole. At toxic levels, the drug may induce ventricular tachycardia. Cardiotoxic effects
are exacerbated by hyperkalemia. Quinidine can increase the steady state
concentration of digoxine by displacement
of digoxin from tissue binding sites.
Nauses, vomiting and diarrhea are commonly observed. Large doses may induce the symptoms
of conchonism, for ex., blurred vision, tinnitus, headache,
disorientation, and psychosis. The drug has a mild α-adrenergic blocking
action as well as an atropine-like effect.
Procainamide (500 mg) –
this Class IA drug, a derivative of the local anesthetic procaine, shows
actions similar to those of quinidine. Adverse effects: With chronic use
procainamide causes a high incidence of side effects, including a reversible
lupus erythematosus-like syndrome that develops in 25 to 30 % of patients.
Toxic concentrations of procainamide may cause asystole or induction of
ventricular arrhythmias. Central nervous system side effects include depression,
hallucination and psychosis. With this drug, gastrointestinal intolreance is
less frequent than with quinidine.
Disopyramide (caps. 100, 150 mg) produces a negative inotropic effect that is greater
than the weak effect exerted by quinidine
and procainamide, and unlike the
latter drugs, disopyramide causes
peripheral vasoconstriction. The drug may produce a clinically important decrease in myocardial contractility in
patients with preexisting impairment of left ventricular function. Disopyramide
is used for treatment of ventricular arrhythmias as an alternative to procainamide or quinidine. Adverse effects: Disopyramide shows effects of
anticholinergic activity, for ex., dry mouth, urinary retention, blurred
vision, and constipation.
Lidocaine (amp. 1 % 10, 20 ml [10 mg/ml]; 2 % 2, 10 ml[20
mg/ml]) is a Class IB
drug. The IB agents rapidly associate
and dissociate from sodium channels.
Class IB drugs are particularly useful in treating ventricular arrhythmias. Lidocaine is the drug of choice for
emergency treatment of cardiac arrhythmias. Unlike quinidine, which suppresses arrhythmias caused by increased normal
automaticity, lidocaine suppresses
arrhythmias caused by abnormal automaticity. Lidocaine, like quinidine, abolishes
ventricular reentry. Lidocaine is
useful in treating ventricular arrhythmias arising during myocardial ischemia,
such as that experienced during a myocardial infarction. The drug does not
markedly slow conduction and thus has little effect on atrial or AV junction
arrhythmias. Lidocaine is given
intravenously because of extensive first-pass transformation by the liver,
which precludes oral administration. Lidocaine
has fairly wode toxic-to-therapeutic ratio; it shows little impairment of left
ventricular function, and has no negative inotropic effect. The CNS effects include drowsiness, slurred
speech, paresthesia, agitation, confusion, and convulsions; cardiac arrhythmias
may also occur.
Mexiletine (caps. 150, 200, 250 mg) and tocainide (tab. 400 mg) are Class IB drugs with actions similar to those of lidocaine. These agents can be administered orally. Tocainide
has pulmonary toxicity, which may lead to pulmonary fibrosis.
Flecainide (tab. 50, 100, 150 mg) is a Class IC
drug. These drugs are approved only for
refractory ventricular arrhythmias. It is particularly useful in suppressing
premature ventricular contraction. Flecainide has a negative
inotropic effect and can aggravate congestive heart failure. Flecainide is absorbed orally and has a
half-life of 16 to 20 hours. Flecainide
can cause dizziness, blured vision,
headache, and nausea. Like other Class IC drugs, flecainide can aggravate preexisting arrhythmias or induce life-threatening ventricular tachycardia that is resistant to
treatment.
Propafenone (tab. 150, 300 mg) is Class IC drug shows actions similar to those of flecainide.
The Class II
agents include the b-adrenergic
antagonists. These drugs diminish Phase 4 depolarisation, thus depressing
automaticity, prolonging AV conduction,
and decreasing heart rate and contractility.
These
agents exert antidysrhythmic effects by
blocking sympathetic nervous system stimulation of beta receptors in the heart
and decreasing risks of ventricular fibrillation. Blockage of receptors in the
SA node and ectopic pacemakers decreases automaticity, and blockage of
receptors in the AV node increases the refractory period. The drugs are
effective for management of supraventricular dysrhythmias and those resulting
from excessive sympathetic activity. Thus, they are most often used to slow the
ventricular rate of contraction in supraventricular tachydysrhythmias (eg, AF,
atrial flutter, paroxysmal supraventricular tachycardia [PSVT]).
As a class, beta blockers are being used more extensively because of
their effectiveness and their ability to reduce mortality in a variety of clinical settings, including
post–myocardial infarction and heart
failure. Reduced mortality may result
from the drugs’ ability to prevent ventricular fibrillation.Only four of
the beta blockers marketed in the United States are approved by the Food and
Drug Administration (FDA) for management of dysrhythmias.
Class II agents are useful in treating
tachyarrhythmias caused by increased
sympathetic activity. They are also used for atrial flutter and
fibrillation, and for AV nodal reentrant tachycardia.
Propranolol (tab. 10, 20, 40, 60, 80 mg) (a nonselective b-antagonist) reduces the incidence
of sudden arrhythmic death after
myocardial infarction (the most common cause
of death in this group of patients). Propranolol diminishes cardiac output, having both
negative inotropic and chronotropic effects. It directly depresses
sino-auricular and atrioventricular
activity. The b-blockers are effective in attenuating
supraventricular cardiac arrhythmias but are generally not effective against
ventricular arrhythmias. Propranolol has
a serious and potentially lethal side effect when administered to an
asthmatic. An immediate contraction of the bronchiolar smooth muscle prevents
air from entering the lungs. Therefore, propranolol
must never be used in treating any individual with obstructive pulmonary
disease. Treatment with the b-blockers must
never be stopped quickly because of the risk of precipitating cardiac arrhythmias, which may be severe. The b-blockers must
be tapered off gradually for 1 week.
Long-term treatment with a b-antagonists
leads to up-regulation of the b-receptor. Some men do complain of impaired
sexual activity. Fasting hypoglycemia
may occur. Drugs that interfere with the
metabolism of propranolol, such as cimetidine, furosemide, and chlorpromazine.
May potentiate its antihypertensive effects.
Drugs that
preferentially block the b1 receptors have been developed to eliminate the unwanted
bronchoconstrictor effect (b2) of propranolol seen
among asthmatic patients.
Cardioselective b-blockers, such as metoprolol
(tab. 50, 100 mg, amp. 5 ml), esmolol
(amp. 10 ml (2.5 g) 250 mg/ml), antagonize b1 receptors at doses 50 to 100 times less than those required to block b2 receptors.
This cardioselectivity is thus most pronounced at low doses and is lost
at high drug doses. Esmolol is a very
short-acting b blocker used for intravenous administration in acute
arrhythmias occurring during surgery or emergency situations.
Class III agents block potassium channels and thus diminish the
outward potassium current during repolarization of cardiac cells. They prolong
the effective refractory period. All Class III drugs have the potential to induce arrhythmias.
Although
the drugs share a common mechanism of action, they are very different drugs. As
with beta blockers, clinical use of class III agents is increasing because they
are associated with less ventricular fibrillation and decreased mortality
compared with class I drugs.
Sotalol (tab. 80, 160 mg), although a class III antiarrhythmic agent, also has potent b-blocker
activity. Sotalol blocks a rapid outward potassium
current, known as the delayed
rectifier. b-blockers are used for long-term therapy to
decrease the rate of sudden death
following an acute myocardial infarction. They have strong antifibrillary effects, particularly in the
ischemic myocardium. Sotalol
was more effective in preventing
arrhythmia recurrence and in decreasing mortality than imipramine, mexiletine,
procainamide, propafenone and quinidine in patients with sustained ventricular
tachycardia. As with all drugs that prolong the QT interval, the syndrome of
torside de pointes is a serious
potential effect, typically seen in 3 to 4 % of patients.
Bretylium (amp. 10 ml - 500 mg) is
reserved for the life-treatening
ventricular arrhythmias, especially recurrent ventricular fibrillation or
tachycardia. Bretylium initially
increases release of catecholamines and therefore increases heart rate, blood
pressure, and myocardial contractility. This is followed in a few minutes by a
decrease in vascular resistance, blood pressure, and heart rate. It is used
primarily in critical care settings for acute control of recurrent ventricular
fibrillation, especially in clients with recent myocardial infarction. It is
given by IV infusion, with a loading dose followed by a maintenance dose, or in
repeated IV injections. Because it is excreted almost entirely by the kidney,
drug half-life is prolonged with renal impairment and dosage must be reduced.
Adverse effects include hypotension and dysrhythmias.
Amiodarone (tab. 200 mg) is effective in the treatment of severe refractory supraventricular avd
ventricular tachyarrhythmia. Its dominant effect is prolongation of the action potential
duration and the refractory period. Amiodarone
has antianginal as well as antiarrhythmic
activity. But its clinical
usefulness is limited by its toxicity. Amiodarone is incompletely absorbed after oral administration. The drug is unusual in
having a prolonged half-life of several weeks.
Full clinical effects may not be achieved until 6 weeks after of
treatment.
Although classified as a potassium channel
blocker, amiodarone also has
electrophysiologic characteristics of sodium channel blockers, beta blockers,
and calcium channel blockers. Thus, it has vasodilating effects and decreases
systemicvascular resistance; it prolongs conduction in all cardiac tissues and
decreases heart rate; and it decreases contractility of the left ventricle.
Intravenous and oral amiodarone differ in their electrophysiologic effects.
When given IV, the major effect is slowing conduction through the AV node and
prolonging the effective refractory period. Thus, it is given IV mainly for
acute suppression of refractory, hemodynamically destabilizing ventricular
tachycardia and ventricular fibrillation. It is given orally to treat recurrent
ventricular tachycardia or ventricular
fibrillation and to
maintain a NSR after conversion of AF and flutter. Low doses (100 to 200 mg/day)
may preventrecurrence of AF with less toxicity than higher doses of amiodarone
or usual doses of other agents, including quinidine.
Amiodarone
shows a variety of
toxic effects. After long-term use, more
than one half of the patients receiving the drug show side effects sufficiently
severe to prompt its discontinuation. Some of the more common effects include interstial pulmonary fibrosis,
gastrointestinal tract intolerance, tremor, ataxia, dizziness, hyper- or
hypothyroidism, liver toxicity, photosensitivity, neuropathy, muscle weakness, and blue skin
discoloration caused by iodine accumulation in the skin. Recent clinical trials have shown that amiodarone did not reduce incidence of sudden death or prolong survival in patients with
congestive heart failure. Adverse effects include hypothyroidism, hyperthyroidism,
pulmonary fibrosis, myocardial depression, hypotension, bradycardia, hepatic
dysfunction, central nervous system (CNS) disturbances (depression, insomnia,
nightmares, hallucinations), peripheral neuropathy and muscle weakness, bluish discoloration of skin and corneal
deposits that may cause photosensitivity, appearance of colored halos around
lights, and reduced visual acuity. Most adverse effects areconsidered dose
dependent and reversible.
Ibutilide is indicated for management of
recent onset of AF or atrial flutter, in which the goal is conversion to NSR.
The drug enhances the efficacy of cardioversion. Ibutilide is structurally
similar to sotalol but lacks clinically significant beta-blocking activity.
Ibutilide is widely distributed and has an elimination half-life of about 6
hours. Most of a dose is metabolized, and the metabolites are excreted in urine
and feces. Adverse effects include supraventricular and ventricular dysrhythmias
(particularly torsades de pointes) and hypotension. Ibutilide should be
administered in a setting with personnel and equipment available for emergency
use.
Dofetilide is indicated for the maintenance
of normal sinus rhythm in symptomatic clients who are in AF of more than
one-week duration. Adverse effects increase with decreasing creatinine
clearance levels so renal function must be assessed and initial dosage is
dependent on creatinine clearance levels. High dosages in clients with renal
dysfunction result in drug accumulation and prodysrhythmia (torsades de
pointes). The drug has an elimination half-life of approximately 8 hours with
the kidneys being the major route of elimination. The drug should initially be
administered in a setting with personnel and equipment available for emergency
use.
The Class IV drugs are calcium channel blockers. They decrease the inward current carried by calcium and slowed
conduction in tissues dependent on calcium currents, such as the AV
node.
Verapamil and diltiazem.
Verapamil (tab. 40, 80, 120, 240 mg)
shows greater action on the heart than
on vascular smooth muscle, whereas nifedipine,
a calcium channel-blocker used to treat hypertension exerts a stronger effect on vascular smooth muscle than on the
heart. Diltiazem (tab. 30, 60, 90, 120 mg) is intermediate in its actions. Verapamil and diltiazem bind
only to open, depolarized channels, thus
preventing repolarization until the drug
dissociates from the channel.
These drugs are therefore use-dependent,
that is, they block most effectively
when the heart beating rapidly, since in a normally paced heart, the calcium
channels have time to repolarize, and the
bound drug dissociates from the
channel before the next conduction pulse.
Verapamil and diltiazem are
more effective against atrial than
ventricular dysrhythmias. They are useful in treating reentrant supraventricular tachycardia and reducing
ventricular rate in atrial flutter and fibrillation. Verapamil and diltiazem are absorbed after oral administration. Verapamil is extensively metabolized by the liver; thus, care should be
taken in administration of this drug to patients with hepatic dysfunction.
Verapamil and diltiazem have
negative inotropic properties and therefore
may be contraindicated in patients
with preexisting depressed cardiac function. Both drugs can also cause a decrease in blood pressure caused by
peripheral vasodilation.
Other antiarrhythmic drugs:
Digoxin (tab. 0.125, 0.25, 0.5 mg, amp.
1, 2 ml 0.025 %) shortens the refractory period in atrial
and ventricular myocardial
cells while prolonging the effective refractory period
and diminishing conduction velocity in
Purkinje fibers. Digoxin is used to control the ventricular response rate in atrial fibrillation and
flutter. At toxic concentrations, digoxin causes ectopic ventricular
beats that may result in ventricular tachycardia and fibrillation. [This
arrhythmia is usually treated with lidocaine or phenytoin].
Adenosine is a naturally occurring
nucleoside, but at high doses the drug decreases conduction velocity, prolongs
the refractory period, and decreases
automaticity in the AV node. Intravenous
adenosine is the drug of choice for abolishing acute supraventricular tachycardia. It has
low toxicity, but causes flushing, chest pain and hypotension. Adenosine has an extremely short duration of action (about 15 seconds).
Magnesium
sulfate is
given IV in the management of several dysrhythmias, including prevention of
recurrent episodes of torsades de pointes and management of digitalis-induced
dysrhythmias. Its antidysrhythmic effects may derive from imbalances of
magnesium, potassium, and calcium. Hypomagnesemia increases myocardial
irritability and is a risk factor for both atrial and ventricular dysrhythmias.
Thus, serum magnesium levels should be monitored in clients at risk
and replacement therapy
instituted when indicated. However, in some instances, the drug seems to have
antidysrhythmic effects even when serum magnesium levels are normal.
Therapeutic
indications for some commonly encountered arrhythmias
|
Type of arrhythmia |
Class I |
Class II |
Class III |
Class IV |
Other |
|
ATRIAL ARRHYTHMIAS |
|||||
|
Atrial flutter |
|
|
|
|
|
|
Commonly used drugs |
|
Propranolol |
|
Verapamil |
|
|
Alternative drugs |
Quinidine |
|
|
|
Digoxin |
|
Atrial fibrillation |
|
|
|
|
|
|
Commonly used drugs |
|
Propranolol |
|
|
Anticoagulant therapy |
|
Alternative drugs |
Quinidine |
|
Amiodarone |
|
|
|
SUPRAVENTRICULAR TACHYCARDIAS |
|||||
|
AV nodal reentry |
|
|
|
|
|
|
Commonly used drugs |
|
Propranolol |
|
Verapamil |
|
|
Alternative drugs |
|
|
|
|
Digoxin |
|
Acute
supraventricular tachycardia |
|
|
|
|
|
|
Commonly used drugs |
|
|
|
|
Adenosine |
|
Alternative drugs |
|
|
|
Verapamil |
|
|
VENTRICULAR TACHYCARDIAS |
|||||
|
Acute
ventricular tachycardia |
|
|
|
|
|
|
Commonly used drugs |
Lidocaine |
|
|
|
|
|
Alternative drugs |
|
|
Sotalol, amiodarone |
|
|
|
Ventricular
fibrillation (not responding to electrical defibrillation) |
|
|
|
|
|
|
Commonly used drugs |
|
|
|
|
Epinephrine |
|
Alternative drugs |
Lidocaine |
|
Bretylium, amiodarone |
|
|
Pharmacologic
Management of Dysrhythmias
Rational
drug therapy for cardiac dysrhythmias requires accurate identification of the
dysrhythmia, understanding of the basic mechanisms causing the dysrhythmia,
observation of the hemodynamic and ECG effects of the dysrhythmia, knowledge of
the pharmacologic actions of specific antidysrhythmic drugs, and the
expectation that therapeutic effects will outweigh potential adverse effects.
Even when these criteria are met, antidysrhythmic drug therapy is somewhat
empiric. Although some dysrhythmias usually respond to particulardrugs,
different drugs or combinations of drugs are often required.
General
trends and guidelines for drug therapy of supraventricular and ventricular
dysrhythmias are described in the following sections.
General Trends
1. There is a relative consensus of opinion
among clinicians about appropriate management for acute, symptomatic
dysrhythmias, in which the goals are to abolish the abnormal rhythm, restore
NSR, and prevent recurrence of the dysrhythmia. There is less agreement about
long-term use of the drugs, which is probably indicated only for clients who
experience recurrent symptomatic episodes.
2. Class I agents do not
prolong survival in any group of clients and their use is declining. For
example, quinidine is no longer recommended to slow heart rate or prevent
recurrence of AF. Some clinicians recommend restricting this class to clients
without structural heart disease, who are less likely to experience increased
mortality than others.
3. Class II and class III
drugs are being used increasingly, because of demonstrated benefits in
relieving symptoms and decreasing mortality rates in clients with heart
disease.
Supraventricular Tachydysrhythmias
1. Propranolol and other beta blockers are being increasingly used for
tachydysrhythmias, especially in clients with myocardial infarction, heart
failure, or exerciseinduced dysrhythmias. In addition to controlling
dysrhythmias, the drugs decrease the mortality rate in these clients. Also, a
beta blocker is the management of choice if a rapid heart rate is causing
angina or other symptoms in a client with known coronary artery disease.
2. Atrial fibrillation is the most common dysrhythmia. Management may
involve conversion to NSR by electrical or pharmacologic means or long-term
drug therapy to slow the rate of ventricular response. Advantages of conversion
to NSR include improvement of symptoms and decreased risks of heart failure or
thromboembolic problems. If pharmacologic conversion is chosen, IV adenosine, dofetilide, ibutilide,
verapamil, or diltiazem may be
used. Once converted to NSR, clients usually require long-term drug therapy.
Low-dose amiodarone seems to be
emerging as the drug of choice for preventing recurrent AF after electrical or
pharmacologic conversion. The low doses cause fewer adverse effects than the
higher ones used for life-threatening ventricular dysrhythmias. When clients
are not converted to NSR, drugs are given to slow the heart rate. This strategy
is used for clients who:
a. Have chronic AF but are
asymptomatic
b. Have had AF for longer
than 1 year
c. Are elderly
d. Have not responded to
multiple drugs
In addition to amiodarone,
other drugs used to slow the heart rate include a beta blocker, digoxin, verapamil, or diltiazem. In most clients, a beta blocker, verapamil, or diltiazem
may be preferred. In clients with heart failure, digoxin may be preferred. In
addition, the class IC agents flecainide
or propafenone may be
used to suppress
paroxysmal atrial flutter and fibrillation in clients with minimal or no heart
disease.
3. IV adenosine, ibutilide, verapamil, or diltiazem may be used to convert PSVT to a NSR. These drugs block
conduction across the AV node.
Ventricular Dysrhythmias
1. Treatment of
asymptomatic PVCs and nonsustained ventricular tachycardia (formerly standard
practice with lidocaine in clients post–myocardial infarction) is not
recommended.
2. A beta blocker may be preferred as a first-line drug for symptomatic
ventricular dysrhythmias. Amiodarone,
bretylium, flecainide, propafenone, and sotalol are also used in the management of life-threatening
ventricular dysrhythmias, such as sustained ventricular tachycardia. Class I
agents (eg, lidocaine, mexiletine,
tocainide) may be used in clients with structurally normal hearts.
Lidocaine may also be used for treating digoxin-induced ventricular
dysrhythmias.
3. Amiodarone, sotalol, or a
beta blocker may be used to prevent recurrence of ventricular tachycardia
or fibrillation in clients resuscitated from cardiac arrest.
4. Moricizine is infrequently used in the United States because of its
potential for causing undesirable cardiac events. It may be used to treat
life-threatening ventricular dysrhythmias (eg, sustained ventricular
tachycardia) that have not responded to safer drugs.
Use in Children
Antidysrhythmic
drugs are less often needed in children than in adults, and their use has
decreased with increased use of catheter ablative techniques. Catheter ablation
uses radio waves to destroy dysrhythmia-producing foci in cardiac tissue
and reportedly causes
fewer adverse effects and complications than long-term antidysrhythmic drug
therapy.
Antidysrhythmic
drug therapy is also less clear-cut in children. The only antidysrhythmic drug
that is FDA approved for use in children is digoxin. However, pediatric
cardiologists have used various drugs and developed guidelines for their use,
especially dosages. As with adults, the drugs should be used only when clearly
indicated, and children should be monitored closely because all of the drugs
can cause adverse effects, including hypotension and new or worsened
dysrhythmias.
Supraventricular tachydysrhythmias are the most common sustained
dysrhythmias in children. IV adenosine,
digoxin, procainamide, or propranolol
can be used acutely to terminate supraventricular tachydysrhythmias. IV
verapamil, which is often used in adults to terminate supraventricular
tachydysrhythmias, is contraindicated in infants and small children. Although
it can be used cautiously in older children, some clinicians recommend that IV
verapamil be avoided in the pediatric population. Digoxin or a beta blocker may
be used for longterm management of supraventricular tachydysrhythmias.
Propranolol is the beta blocker most
commonly used in children. It is one of the few antidysrhythmic drugs available
in a liquid solution. Propranolol has a shorter half-life (3 to 4 hours) in
infants than in children older than 1 to 2 years of age and adults (6 hours).
When given IV, antidysrhythmic effects are rapid, and clients require careful
monitoring for bradycardia and hypotension. E molol is being used more frequently to treat tachydysrhythmias in
children, especially those occurring after surgery.
Lidocaine may be used to treat ventricular
dysrhythmias precipitated by cardiac surgery or digitalis toxicity. Class I or
III drugs are usually started in a hospital setting, at lower dosage ranges,
because of prodysrhythmic effects. Prodysrhythmia is more common in children
with structural heart disease or significant dysrhythmias. In general, serum
levels should be monitored with class IA and IC drugs and IV lidocaine.
Flecainide is the class IC drug most commonly used in children. Class III drugs
are used in pediatrics mainly to treat life-threatening refractory tachydysrhythmias.
As in adults, most antidysrhythmic drugs and their metabolites are excreted
through the kidneys and may accumulate in children with impaired renal
function.
Use in Older Adults
Cardiac
dysrhythmias are common in older adults, but in general only those causing
symptoms of circulatory impairment should be treated with antidysrhythmic
drugs. Compared with younger adults, older adults are more likely to experience
serious adverse drug effects, including aggravation of existing dysrhythmias,
production of new dysrhythmias, hypotension, and heart failure. Cautious use is
required, and dosage usually needs to be reduced to compensate for heart
disease or impaired drug elimination processes.
Use in Critical Illness
Critically
ill clients often have multiple cardiovascular and other disorders that
increase their risks for development of acute, serious, and potentially
life-threatening dysrhythmias. They may also have refractory dysrhythmias that
require
strong, potentially toxic
antidysrhythmic drugs. Thus, antidysrhythmic drugs are often given IV in
critical care settings for rapid reversal of a fast rhythm. After reversal, IV
or oral drugs may be given to prevent recurrence of the dysrhythmia. Because
serious problems may stem from either dysrhythmias or their treatment, health
care providers should be adept in preventing, recognizing, and treating
conditions that predispose to the development of serious dysrhythmias (eg,
electrolyte imbalances, hypoxia). If dysrhythmias cannot be prevented, early
recognition and treatment are needed.
Overall,
any antidysrhythmic drug therapy in critically ill clients is preferably
performed or at least initiated in critical care units or other facilities with
appropriate equipment and personnel. For example, nurses who work in emergency
departments or critical care units must be certified in cardiopulmonary
resuscitation and advanced cardiac life support (ACLS). With ACLS, the American
Heart Association and others have developed algorithms to guide drug therapy of
dysrhythmias.
Use
in Renal Impairment
Antidysrhythmic
drug therapy in clients with renal impairment should be very cautious, with
close monitoring of drug effects (eg, plasma drug levels, ECG changes, symptoms
that may indicate drug toxicity). The kidneys excrete most antidysrhythmic
drugs and their metabolites. As a result, decreased renal perfusion or other
renal impairment can reduce drug elimination and lead to accumulation and
adverse effects if dosage is not reduced. As a general rule, dosage of bretylium,
digoxin, disopyramide, flecainide, lidocaine, moricizine, procainamide,
propafenone, quinidine, sotalol, and tocainide should be reduced in clients
with significant impairment of renal function. Dosage of adenosine, amiodarone,
ibutilide, and mexiletine does not require reduction.
Use in
Hepatic Impairment
As with
renal impairment, antidysrhythmic drug therapy in clients with hepatic
impairment should be very cautious, with close monitoring of drug effects (eg,
plasma drug levels, ECG changes, symptoms that may indicate drug toxicity).
Amiodarone
may be hepatotoxic and cause serious, sometimes fatal, liver disease. Hepatic
enzyme levels are often elevated without accompanying symptoms of liver
impairment. However, liver enzymes should be monitored regularly, especially in
clients receiving relatively high maintenance doses. If enzyme levels are above
three times the normal range or double in a client whose baseline levels were
elevated, dosage reduction or drug discontinuation should be considered.
Hepatic
impairment increases plasma half-life of several antidysrhythmic drugs, and
dosage usually should be reduced. These include disopyramide, flecainide,
lidocaine, mexiletine, moricizine, procainamide, propafenone, quinidine, and
tocainide. Dosages of adenosine and ibutilide are unlikely to need reductions
in clients with hepatic impairment.
PREPARATIONS
AVAILABLE
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