LESSONS 1

THEME: Clinical Pharmacology of Antianginal Drugs.

Clinical Pharmacology of Antiarrhythmic Drugs Clinical Pharmacology of Antihypertensive  and Antihypotensive Drugs. Clinical Pharmacology of Cardiac Glycosides. Clinical Pharmacology of Diuretics

 

Clinical pharmacology of antianginal drugs

 Angina pectoris is a clinical syndrome characterized by episodes of chest pain. It occurs when there is a deficit in myocardial oxygen supply (myocardial ischemia) in relation to myocardial oxygen demand. It is most often caused by atherosclerotic plaque in the coronary arteries but may also be caused by coronary vasospasm. The development and progression of atherosclerotic plaque is called coronary artery disease (CAD). Atherosclerotic plaque narrows the lumen, decreases elasticity, and impairs dilation of coronary arteries. The result is impaired blood flow to the myocardium, especially with exercise or other factors that increase the cardiac workload and need for oxygen. The continuum of CAD progresses from angina to myocardial infarction. There are three main types of angina: classic angina, variant angina, and unstable angina. The Canadian Cardiovascular Society classifies clients with angina according to the amount of physical activity they can tolerate before anginal pain occurs. These categories can assist in clinical assessment and evaluation of therapy.

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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.

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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 Prinzmetals 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.

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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, Prinzmetals 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.

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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.

Table2 Beneficial and Deleterious Effects of Nitrates in the Treatment of Angina.

 

Effect

Result

Potential beneficial effects 

 

  Decreased ventricular volume

Decreased myocardial oxygen requirement

  Decreased arterial pressure

  Decreased ejection time

  Vasodilation of epicardial coronary arteries

Relief of coronary artery spasm

  Increased collateral flow

Improved perfusion to ischemic myocardium

  Decreased left ventricular diastolic pressure

Improved subendocardial perfusion

Potential deleterious effects 

 

  Reflex tachycardia

Increased myocardial oxygen requirement

  Reflex increase in contractility

 

  Decreased diastolic perfusion time due to tachycardia

Decreased coronary perfusion

 

Table 3 Nitrate and Nitrite Drugs Used in the Treatment of Angina.

 

Drug

Dose

Duration of Action

Short-acting 

 

 

  Nitroglycerin, sublingual

0.151.2 mg

1030 minutes

  Isosorbide dinitrate, sublingual

2.55 mg

1060 minutes

  Amyl nitrite, inhalant

0.180.3 mL

35 minutes

Long-acting 

 

 

  Nitroglycerin, oral sustained-action

6.513 mg per 68 hours

68 hours

  Nitroglycerin, 2% ointment, transdermal

11.5 inches per 4 hours

36 hours

  Nitroglycerin, slow-release, buccal

12 mg per 4 hours

36 hours

  Nitroglycerin, slow-release patch, transdermal

1025 mg per 24 hours (one patch per day)

810 hours

  Isosorbide dinitrate, sublingual

2.510 mg per 2 hours

1.52 hours

  Isosorbide dinitrate, oral

1060 mg per 46 hours

46 hours

  Isosorbide dinitrate, chewable oral

510 mg per 24 hours

23 hours

  Isosorbide mononitrate, oral

20 mg per 12 hours

610 hours

Sympathetic stimulation of beta1 receptors in the heart increases heart rate and force of myocardial contraction, both of which increase myocardial oxygen demand and may precipitate acute anginal attacks. Beta-blocking drugs prevent or inhibit sympathetic stimulation. Thus, the drugs reduce heart rate and myocardial contractility, particularly when sympathetic output is increased during exercise. A slower heart rate may improve coronary blood flow to the ischemic area. Beta blockers also reduce blood pressure, which in turn decreases myocardial workload and oxygen demand. In angina pectoris, beta-adrenergic blocking agents are used in long-term management to decrease the frequency and severity of anginal attacks, decrease the need for sublingual nitroglycerin, and increase exercise tolerance. When a beta blocker is being discontinued after prolonged use, it should be tapered in dosage and gradually discontinued or rebound angina can occur.

These drugs should not be given to clients with known or suspected coronary artery spasms because they may intensify the frequency and severity of vasospasm. This probably results from unopposed stimulation of alpha-adrenergic receptors, which causes vasoconstriction, when beta-adrenergic receptors are blocked by the drugs. Clients who continue to smoke may have reduced efficacy with the use of beta blockers. Clients with asthma should be observed for bronchospasm from blockage of beta2 receptors in the lung. Beta blockers should be used with caution in clients with diabetes mellitus because they can conceal signs of hypoglycemia except for sweating).

The b-adrenergic blockers agents supress the activation of the heart by blocking b1 receptors. They also reduce the work of the heart by decreasing cardiac output and causing a slight decrease in blood pressure. Propranolol is the prototype of this class of compounds, but other b-blockers, such as metoprolol and atenolol are equally effective. Propranolol decreases the oxygen requirement of heart muscle and therefore is effective in reducing the chest pain on exertion that is common in angina. Propranolol is therefore useful in the chronic management of stable angina (not for acute treatment). Tolerance to moderate exercise is increased and this is noticeable by improvement in the electrocardiogram. Agents with intrinsic sympathomymetic activity (for example, pindolol and acebutolol) are less effective and should be avoided. The b-blockers reduce the frequency and severity oh angina attacks. These agents are particularly useful in the treatment of patients with myocardial infarction. The b-blockers can be used with nitrates to increase exercise duration and tolerance. They are, however, contraindicated in patients with diabetes, peripheral vascular disease, or chronic pulmonary disease.

Propranolol is well absorbed after oral administration. It is then metabolized extensively in the liver; a relatively small proportion of an oral dose (approximately 30%) reaches the systemic circulation. For this reason, oral doses of propranolol are much higher than IV doses. Onset of action is 30 minutes after oral administration and 1 to 2 minutes after IV injection. Because of variations in the degree of hepatic metabolism, clients vary widely in the dosages required to maintain a therapeutic response.

Atenolol, metoprolol, and nadolol have the same actions, uses, and adverse effects as propranolol, but they have long half-lives and can be given once daily. They are excreted by the kidneys, and dosage must be reduced in clients with renal

impairment.

Calcium Channel Blocking Agents

Calcium channel blockers act on contractile and conductive tissues of the heart and on vascular smooth muscle. For these cells to function normally, the concentration of intracellular calcium must be increased. This is usually accomplished by movement of extracellular calcium ions into the cell (through calcium channels in the cell membrane) and release of bound calcium from the sarcoplasmic reticulum in the cell. Thus, calcium plays an important role in maintaining vasomotor tone, myocardial contractility, and conduction. Calcium channel blocking agents prevent the movement of extracellular calcium into the cell. As a result, coronary and peripheral arteries are dilated, myocardial contractility is decreased, and the conduction system is depressed in relation to impulse formation (automaticity) and conduction velocity.

In angina pectoris, the drugs improve the blood supply to the myocardium by dilating coronary arteries and decrease the workload of the heart by dilating peripheral arteries. In variant angina, calcium channe l blockers reduce coronary artery vasospasm. In atrial fibrillation or flutter and other supraventricular tachydysrhythmias, diltiazem and verapamil slow the rate of ventricular response. In hypertension, the drugs lower blood pressure primarily by dilating peripheral arteries.

Calcium channel blockers are well absorbed after oral administration but undergo extensive first-pass metabolism in the liver. Most of the drugs are more than 90% protein bound and reach peak plasma levels within 1 to 2 hours (6 hours or longer for sustained-release forms). Most also have short elimination half-lives (<5 hours), so doses must be given three or four times daily unless sustained-release formulations are used. Amlodipine (30 to 50 hours), bepridil (24 hours), and felodipine (11 to 16 hours) have long elimination half-lives and therefore can be given once daily. The drugs are metabolized in the liver, and dosage should be reduced in clients with severe liver disease. Dosage reductions are not required with renal disease. The calcium channel blockers approved for use in the 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 bloodbrain 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.

Clinical Pharmacology of Some Calcium Channel-Blocking Drugs

 

Drug

Oral Bioavailability (%)

Half-life (hours)

Indication

Dosage

Dihydropyridines 

 

 

 

 

  Amlodipine

6590

3050

Angina, hypertension

510 mg orally once daily

  Felodipine

1520

1116

Hypertension, Raynaud's phenomenon

510 mg orally once daily

  Isradipine

1525

8

Hypertension

2.510 mg orally twice daily

  Nicardipine

35

24

Angina, hypertension

2040 mg orally every 8 hours

  Nifedipine

4570

4

Angina, hypertension, Raynaud's phenomenon

310 mcg/kg IV; 2040 mg orally every 8 hours

  Nimodipine

13

12

Subarachnoid hemorrhage

40 mg orally every 4 hours

  Nisoldipine

< 10

612

Hypertension

2040 mg orally once daily

  Nitrendipine

1030

512

Investigational

20 mg orally once or twice daily

Miscellaneous 

 

 

 

 

  Diltiazem

4065

34

Angina, hypertension, Raynaud's phenomenon

75150 mcg/kg IV; 3080 mg orally every 6 hours

  Verapamil

2035

6

Angina, hypertension, arrhythmias, migraine

75150 mcg/kg IV; 80160 mg orally every 8 hours

 

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 drugsand in particular the fact that they can precipitate lethal arrhythmias in some patientshas 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 hearts abil-ity to pump sufficient blood to body tissues). The normal heart can 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 BezoldJarisch) 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 (5060 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 HisPurkinje system.

The resulting rhythm is slow (1540 b.p.m.) and relatively unreliable. Dizziness and blackouts (StokesAdams attacks) often occur. In the elderly, it is usually caused by degenerative fibrosis and calcification of the distal conduction system (Levs disease). In younger individuals, a proximal progressive cardiac conduction disease due to the inflammatory process is known as Lenegres 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 cardioverterdefibrillator (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 quinidines 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 postmyocardial 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 postmyocardial 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.

Clinical pharmacology of antihypertensive drugs

HYPERTENSION

Hypertension is persistently high blood pressure that results from abnormalities in regulatory mechanisms. It is usually defined as a systolic pressure above 140 mm Hg or a diastolic pressure above 90 mm Hg on multiple blood pressure measurements.

 

Primary or essential hypertension (that for which no cause can be found) makes up 90% to 95% of known cases. Secondary hypertension may result from renal, endocrine, or central nervous system disorders and from drugs that stimulate the SNS or cause retention of sodium and water. Primary hypertension can be controlled with appropriate therapy; secondary hypertension can sometimes be cured by surgical therapy.

The Sixth Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure, published in 1997, classified blood pressures in adults (in mm of Hg), as follows:

Normal systolic 130 or below; diastolic 85 or below

High normal systolic 130 to 139; diastolic 85 to 89

Stage 1 hypertension (mild) systolic 140 to 159; diastolic

90 to 99

Stage 2 hypertension (moderate) systolic 160 to 179;

diastolic 100 to 109

Stage 3 hypertension (severe) systolic 180 to 209; diastolic

110 to 119

Stage 4 hypertension (very severe) systolic 210 or above; diastolic 120 or above

A systolic pressure of 140 or above with a diastolic pressure below 90 is called isolated systolic hypertension and is more common in the elderly.

Hypertension profoundly alters cardiovascular function by increasing the workload of the heart and causing thickening and sclerosis of arterial walls. As a result of increased cardiac workload, the myocardium hypertrophies as a compensatory mechanism and heart failure eventually occurs. As a result of endothelial dysfunction and arterial changes (vascular remodeling), the arterial lumen is narrowed, blood supply to tissues is decreased, and risks of thrombosis are increased. In addition, necrotic areas may develop in arteries, and these may rupture with sustained high blood pressure. The areas of most serious damage are the heart, brain, kidneys, and eyes. These are often called target organs.

Initially and perhaps for years, primary hypertension may produce no symptoms. If symptoms occur, they are usually vague and nonspecific. Hypertension may go undetected, undetected, or it may be incidentally discovered when blood pressure measurements are taken as part of a routine physical examination, screening test, or assessment of other disorders. Eventually, symptoms reflect target organ damage.

Hypertension is often discovered after a person experiences angina pectoris, myocardial infarction, heart failure, stroke, or renal disease. Hypertensive emergencies are episodes of severely elevated blood pressure that may be an extension of malignant (rapidly progressive) hypertension or caused by cerebral hemorrhage, dissecting aortic aneurysm, renal disease, pheochromocytoma, or eclampsia. These require immediate management, usually intravenous (IV) antihypertensive drugs, to lower blood pressure. Symptoms include severe headache, nausea, vomiting, visual disturbances, neurologic disturbances, disorientation, and decreased level of consciousness (drowsiness, stupor, coma). Hypertensive urgencies are episodes of less severe hypertension and are often managed with oral drugs. The goal of management is to lower blood pressure within 24 hours. In most instances, it is better to lower blood pressure gradually and to avoid wide fluctuations in blood pressure.

 

Mild hypertension can often be controlled with a single drug. More severe hypertension may require treatment with several drugs that are selected to minimize adverse effects of the combined regimen. Treatment is initiated with any of four drugs depending on the individual patient: a diuretic, a b-blocker, an ACE inhibitor, or a calcium channel blocker. If blood pressure is inadequately controlled, a second drug is added. A b-blocker is usually added if the initial drug was a diuretic, or a diuretic is added if the first drug was a b-blocker. A vasodilator can be added as a third step for those patients who still fail to respond.

Certain subsets of the hypertensive population respond better to one class of drug than another. For example, black patients respond well to diuretics and calcium channel blockers, but therapy with b-blockers or ACE inhibitors is often less effective. Similarly, calcium channel blockers, ACE inhibitors, and diuretics are favored for treatment of hypertension in the elderly, whereas b-blockers and a-antagonists are less well tolerated. Furthermore, hypertension may coexist with other diseases that can be aggravated by some of the antihypertensive drugs.

 

ANTIHYPERTENSIVE DRUGS

Drugs used in the management of primary hypertension belong to several different groups, including angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), also called angiotensin II receptor antagonists (AIIRAs), antiadrenergics, calcium channel blockers, diuretics, and direct vasodilators. In general, these drugs act to decrease blood pressure by decreasing cardiac output or peripheral vascular resistance.

 

 

 

I. DIURETICS

Bumetanide, furosemide, hydrochlorthiazide, spironolactone, triamterene

II. b-BLOCKERS

Atenolol, labetalol, metoprolol, propranolol, timolol

III. ACE INHIBITORS

Captopril, benazepril, enalapril, fosinopril, lisinopril, moexipril, quinapril, ramipril

IV. ANGIOTENSIN II ANTAGONIST

Losartan

V. Ca++CHANNEL BLOCKERS

Amlodipine, diltiazem, felodipine, isradipine, nicardipine, nifedipine, nisoldipine, verapamil

VI. a-BLOCKERS

Doxazosin, prazosin, terazosin

VII. OTHER

Clonidine, diazoxide, hydralazine, a-methyldopa, minoxidil, sodium nitroprusside

 

 

Treatment of hypertension in patients with concomitant diseases

 

CONCOMITANT DISEASE

DRUGS COMMONLY USED IN TREATING HYPERTENSION

Angina pectoris

 

 

 

 

Commonly used drugs

 

b-Blockers

 

Ca++ Channel blockers

Alternative drugs

diuretics

 

ACE inhibitors

 

Diabetes (insulin-dependent)

 

 

 

Commonly used drugs

 

 

ACE inhibitors

Ca++ Channel blockers

 

Alternative drugs

 

 

 

 

Hyperlipidemia

 

 

 

 

Commonly used drugs

 

 

ACE inhibitors

Ca++ Channel blockers

 

Alternative drugs

 

 

 

 

Congestive heart failure

 

 

 

Commonly used drugs

diuretics

 

ACE inhibitors

 

Alternative drugs

 

 

 

Avoid verapamil

Previous myocardial infarction

 

 

 

Commonly used drugs

 

b-Blockers

ACE inhibitors

 

Alternative drugs

diuretics

 

 

Ca++ Channel blockers

Chronic renal disease

 

 

 

Commonly used drugs

diuretics

 

 

Ca++ Channel blockers

Alternative drugs

 

b-Blockers

ACE inhibitors

 

Asthma, chronic pulmonary disease

 

 

 

Commonly used drugs

diuretics

 

 

Ca++ Channel blockers

Alternative drugs

 

 

ACE inhibitors

 

 

DIURETICS and/or b-Blockers are currently recommended as the first-line drug therapy for hypertension. Low-dose diuretic therapy is safe and effective in preventing stroke, myocardial infarction, congestive heart failure and total mortality. Recent data suggest that diuretics are superior to b-Blockers in older adults.

 

 

 

 Antihypertensive effects of diuretics are usually attributed to sodium and water depletion. In fact, diuretics usually produce the same effects as severe dietary sodium restriction. In many cases of hypertension, diuretic therapy alone may lower blood pressure. When diuretic therapy is begun, blood volume and cardiac output decrease. With long-term administration of a diuretic, cardiac output returns to normal, but there is a persistent decrease in peripheral vascular resistance. This has been attributed to a persistent small reduction in extracellular water and plasma volume, decreased receptor sensitivity to vasopressor substances such as angiotensin, direct arteriolar vasodilation, and arteriolar vasodilation secondary to electrolyte depletion in the vessel wall.

In moderate or severe hypertension that does not respond to a diuretic alone, the diuretic may be continued and another antihypertensive drug added, or monotherapy with a different type of antihypertensive drug may be tried.

 

  Thiazide diuretics. All oral diuretics are effective in the treatment of hypertension, but the thiazides have the most widespread use. Thiazides, such as hydochlorothiazide, lower blood pressure , initially by increasing sodium and water excretion. This causes a decrease in extracellular volume , resulting in a decrease in cardiac output and renal blood flow. With long term treatment, plasma volume approaches a normal value, but peripheral resistance decreases. Spironolactone, a potassium-sparing diuretic, is often used with thiazides.

Thiazide diuretics are usefull in combination therapy with a variety of other antihypertensive agents including b-blockers and ACE inhibitors. Thiazides are particularly useful in the treatment of black or elderly patients, and in those with chronic renal disease. Thiazides are not effective in patients with inadequate kidney function (creatinine clearance less than 50 mls/min). Loop diretics may be required in these patients.

Adverse effects: Thiazide diuretics induce hypokalemia and hyperuricemia in 70 % of patients, and hyperglycemia in 10 % of patients. Serum potassium levels should be monitored closely on patients who are predisposed to cardiac arrhythmias (with left ventricular hypertrophy, ischemic heart disease, or chronic congestive heart failure) (to prevent development of fatigue, cramps, and arrhythmias) and who are concurrently being treated with both thiazide diuretics and digitalis glycosides. Diuretics should be avoided in the treatment of hypertensive diabetics or patients with hyperlipidemia.

 

     The loop diuretics act promptly, even in patients who have poor renal function or who have not responded to thiazides or other diuretics.

b-ADRENOCEPTOR BLOCKING AGENTS reduce blood pressure primarily by decreasing cardiac output. They may also decrease sympathetic outflow from the CNS and inhibit the release of renin from the kidneys. The prototype b-blocker is propranolol, which acts at both b1 and b2 receptors. Newer agents, such as atenolol, metoprolol, bisoprolol, are selective for b1 receptors. These agents are commonly used in disease states such as asthma, in which propranolol is contraindicated.

 

The b-blockers are more effective for treating hypertension in white young patients. They are useful in treating conditions that may coexist with hypertension, such as supraventricular tachyarrhythmia, previous myocardial infarction, angina pectoris, glaucoma, and migraine headache.

The b-blockers are orally active. The b-blockers may take several weeks to develop their full effects.

Adverse effects. The b-blockers may cause CNS side effects such as fatigue, lethargy, insomnia, hypotension, and hallucinations; they may decrease libido and cause impotence; drug-induced sexual dysfunction can severly reduce patient compliance. The b-blockers may disturb lipid metabolism, decreasing high-density lipoproteins and increasing plasma triacylglycerol.

Drug withdrawal: Abrupt withdrawal may cause rebound hypertension, probably as a result of up-regulation on b-receptors. Patients should be taped off of b-blocker therapy in order to avoid precipitation of arrhythmias. The b-blockers should be avoided in treating patients with asthma, congestive heart failure, and peripheral vascular disease.

ACE-INHIBITORS.

Angiotensin-converting enzyme (also called kininase) is mainly located in the endothelial lining of blood vessels, which is the site of production of most angiotensin II. This same enzyme also metabolizes bradykinin, an endogenous substance with strong vasodilating properties. ACE inhibitors block the enzyme that normally converts angiotensin I to the potent vasoconstrictor angiotensin II. By blocking production of angiotensin II, the drugs decrease vasoconstriction (having a vasodilating effect) and decrease aldosterone production (reducing retention of sodium and water). In addition to inhibiting formation of angiotensin II, the drugs also inhibit the breakdown of bradykinin, prolonging its vasodilating effects. These effects and possibly others help to prevent or reverse the remodeling of heart muscle and blood vessel walls that impairs cardiovascular function and exacerbates cardiovascular disease processes. Because of their effectiveness

in hypertension and beneficial effects on the heart, blood vessels, and kidneys, these drugs are increasing in importance, number, and use. Widely used to treat heart failure and hypertension, the drugs may also decrease morbidity and mortality in other cardiovascular disorders. They improve postmyocardial infarction survival when added to standard therapy of aspirin, a beta blocker, and a thrombolytic.

 

ACE inhibitors may be used alone or in combination with other antihypertensive agents, such as thiazide diuretics. Although the drugs can cause or aggravate proteinuria and renal damage in nondiabetic people, they decrease proteinuria and slow the development of nephropathy in diabetic clients.

Most ACE inhibitors (captopril, enalapril, fosinopril, lisinopril, ramipril, and quinapril) also are used in the management of heart failure because they decrease peripheral vascular resistance, cardiac workload, and ventricular remodeling. Captopril and other ACE inhibitors are recommended as first-line agents for treating hypertension in diabetic clients, particularly those with type 1 diabetes and/or diabetic nephropathy, because they reduce proteinuria and slow progression of renal impairment.

ACE inhibitors are well absorbed with oral administration, produce effects within 1 hour that last approximately 24 hours, have prolonged serum half-lives with impaired renal function, and most are metabolized to active metabolites that are excreted in urine and feces. These drugs are well tolerated, with a low incidence of serious adverse effects (eg, neutropenia, agranulocytosis, proteinuria, glomerulonephritis, and angioedema). However, a persistent cough develops in approximately 10% to 20% of clients and may lead to stopping the drug. Also, acute hypotension may occur when an ACE inhibitor is started, especially in clients with fluid volume deficit. This reaction may be prevented by starting with a low dose, taken at bedtime, or by stopping diuretics and reducing dosage of other antihypertensive drugs temporarily. Hyperkalemia may develop in clients who have diabetes mellitus or renal impairment or who are taking nonsteroidal anti-inflammatory drugs, potassium supplements, or potassium-sparing diuretics.

These drugs are contraindicated during pregnancy because serious illnesses, including renal failure, have occurred in neonates whose mothers took an ACE inhibitor during the second and third trimesters.

 

The angiotensin-converting enzyme (ACE) inhibitors (captopril, enalapril, lisinopril) are recommended when the preferred first-line agents (diuretics or b-blockers) are contraindicated or ineffective. Despite their wide-spread use, it is not clear if antihypertensive therapy with ACE inhibitors increases the risk of other major diseases.

 

 

Actions. The ACE inhibitors lower blood pressure by reducing peripheral vascular resistance without reflexly increasing cardiac output, rate, or contractility. These drugs block the angiotensin converting enzyme that cleaves angiotensin I to form the potent vasoconstrictor, angiotensin II. Vasodilation occurs as a result of the combined effects of lower vasoconstriction caused by diminished levels of angiotensin II and the potent vasodilating effect of increased bradykinin. By reducing circulating angiotensin II levels, ACE inhibitors also decreas the secretion of aldosterone, resulting in decreased sodium and water retention.

Like b-blockers, ACE inhibitors are most effective in hypertensive patients who are white and young. However, when used in combination with a diuretic, the effectiveness of ACE inhibitors is similar in white and black hypertensive patients. Unlike b-blockers, ACE inhibitors are effective in the management of patients with chronic congestive heart failure. ACE inhibitors are now a standard in the care of a patient following a myocardial infarction. Therapy is started 24 hours after the end of the infarction.

 

Adverse effects. Common side effects include dry cough, rashes, fever, altered taste, hypotension, and hyperkalemia. Potassium levels must be monitored, and potassium supplements or spironolactone are contraindicated. Because of the risk of angioedema and first dose syncope, ACE inhibitors are first administered in the physicians office with close observation. Reversible renal failure can occur in patients with severe renal artery stenosis. ACE inhibitors are fetotoxic and should not be used in pregnant women.

ANGIOTENSIN II ANTAGONISTS.

 

Angiotensin II receptor blockers (ARBs) were developed to block the strong blood pressureraising effects of angiotensin II. Instead of decreasing production of angiotensin II, as the ACE inhibitors do, these drugs compete with angiotensin II for tissue binding sites and prevent angiotensin II from combining with its receptors in body tissues. Although multiple types of receptors have been identified, the AT1 receptors located in brain, renal, myocardial, vascular, and adrenal tissue determine most of the effects of angiotensin II on cardiovascular and renal functions. ARBs block the angiotensin II AT1 receptors and decrease arterial blood pressure by decreasing systemic vascular resistance .

These drugs are similar to ACE inhibitors in their effects on blood pressure and hemodynamics and are as effective as ACE inhibitors in the management of hypertension and probably heart failure. They are less likely to cause hyperkalemia than ACE inhibitors, and the occurrence of a persistent cough is rare. Overall, the drugs are well tolerated, and the incidence of most adverse effects is similar to that of placebo.

Losartan, the first ARB, is readily absorbed and rapidly metabolized by the cytochrome P450 liver enzymes to an active metabolite. Both losartan and the metabolite are highly bound to plasma albumin, and losartan has a shorter duration of action than its metabolite. When losartan therapy is started, maximal effects on blood pressure usually occur within 3 to weeks. If losartan alone does not control blood pressure, a low dose of a diuretic may be added. A combination product of losartan and hydrochlorothiazide is available.

 

The nanopeptide losartan, a highly selective angiotensin II receptor blocker, has recently been approved for antihypertensive therapy. Its pharmacologic effects are similar to ACE inhibitors in that it produces vasodilation and blocks aldosterone secretion. Its adverse effects is improved over the ACE inhibitors, although it is fetotoxic.

CALCIUM CHANNEL BLOCKERS.

Most of the available drugs are approved for use in hypertension. Nifedipine, a short-acting calcium channel blocker, has been used to treat hypertensive emergencies or urgencies, often by puncturing the capsule and squeezing the contents under the tongue or having the client bite and swallow the capsule. Such use is no longer recommended, because this practice is associated with an increased risk of adverse cardiovascular events precipitated by rapid and severe decrease in blood pressure.

As a group, the calcium channel blockers are well absorbed from the gastrointestinal tract following oral administration and are highly bound to protein. The drugs are metabolized in the liver and excreted in urine.

Calcium channel blockers are recommended when the preferred first-line agents are contraindicated or ineffective. Despite their wide-spread use, it is not clear what effects antihypertensive therapy with these drugs has on major disease. In hypertensive patients use of short-acting calcium channel blockers, especially in high doses, is associated with an increased risk of myocardial infarction.

The calcium channel blockers are divided into three chemical classes, each with different pharmacokinetic properties and clinical indications.

1.     Diphenylalkylamines. Verapamil is the least selective of any calcium channel blocker, and has significant effects on both cardiac and smooth-muscle cells. It is used to treat angina, supraventricular tachyarrhythmias, and migrane headache.

2.     Benzothiazepines. Diltiazem affects both cardiac and vascular smooth-muscle cells; however, it has a less pronounced negative inotropic effect on the heart than does verapamil.

3.     Dihydropyridines. This rapidly expanding class of calcium channel blockers includes the first-generation nifedipine, and new agents foe treating cardiovascular disease: amlodipine, felodipine, isradipine, nicardipine and nisoldipine. All the dihydropyridines have a much greater affinity for vascular calcium channels than for calcium channels in the heart. They are therefore particularly attractive in treating hypertension.

 

Calcium channel antagonists block the inward movement of calcium by binding to L-tipe calcium channels in the heart and in the smooth-muscle of the coronary and peripheral vasculature. This causes vascular smooth muscle to relax, dilating mainly arterioles.

Calcium channel blockers have an intrinsic natriuretic ; therefore, they do not usually require the addition of a diuretic. These agents are useful in the treatment of hypertensive patients who also have asthma, diabetes, angina, and/or peripheral vascular disease.

Adverse effects. Although infrequent, side effects include constipation in 10 % of patients, dizziness, headache, and a feeling of fatigue caused by a decrease in blood pressure. Verapamil should be avoid in treating patients with congestive heart failure due to its negative inotropic effects.

 

a-ADRENERGIC BLOCKING AGENTS.

Prazosin, doxazosin and terazosin produce a competitive block of a1 adrenoreceptors. They decrease peripheral vascular resistance and lower arterial blood pressure by causing the relaxation of both arterial and venous smooth muscle. These drugs cause only minimal changes in cardiac output, renal blood flow, and glomerular filtration rate. Postural hypotension may occur in some individuals. Prazosin is used to treat mild to moderate hypertension and is prescribed in combination with propranolol or a diuretic for additive effects.

CENTRALLY-ACTING ADRENERGIC DRUGS

Clonidine a2-agonist diminishes central adrenergic outflow. Clonidine does not decrease renal blood flow or glomerular filtration and therefore is useful in the treatment of hypertension complicated by renal disease. Because it causes sodium and water retention, clonidine is usually administered in combination witj diuretic. Adverse effects are generally mild, but the drug can produce sedation and drying of nasal mucosa. Rebound hypertension occurs following abrupt withdrawal of clonidine. The drug therefore should be withdrawal slowly if the clinician wishes to change agents.

a-Methyldopa. This a2-agonist is converted to methylnorepinephrine centrally to diminish the adrenergic outflow from the CNS, leading to reduced total peripheral resistance and a decreased blood pressure. Because blood flow to the kidmey is not diminished by its use, a-methyldopa is especially valuable in treating hypertensive patients with renal insufficiency. The most common side effects of a-methyldopa are sedation and drowsiness.

VASODILATORS. The direct-acting smooth muscle relaxants, such as hydralazine and minoxidil, have traditionally not been used as primary drugs to treat hypertension. They act by producing relaxation of vascular smooth muscle, which decreases resistance and therefore decreases blood pressure. These agents produce reflex stimulation of the heart. They may prompt angina pectoris, myocardial infarction, or cardiac failure in predisposed individuals.

Hydralazine. This drug causes direct vasodilation, acting primarily on arteries and arterioles. Hydralazine is used to treat moderately severe hypertension. It is almost always administered in combination with a b-blocker such as propranolol (to balance the reflex tachycardia) and a diuretic (to decrease sodium retention). Adverse effects of hydralazine therapy include headache, nausea, sweating, arrhythmia, and precipitation of angina. A lupus-like syndrome can occur with high dosage, but it is reversible on discontinuation of the drug.

Minoxidil. This drug causes dilation of resistance vessels (arterioles) but not of capacitance vessels (venules). It is administered orally for treatment of severe to malignant hypertension that is refractory to other drugs. Reflex tachycardia may be severe and may require the concomitant use of a diuretic and a b-blocker. Minoxidil causes serious sodium and water retention, leading to volume overload, edema, and congestive heart failure.

 

MANAGEMENT OF HYPERTENSIVE EMERGENCY (intravenously)

 

HYPERTENSIVE EMERGENCY is a life-threatening situation in which the diastolic blood pressure is either over 150 mm Hg (with systolic blood pressure greater than 210 mm Hg) in an otherwise healthy person, or 130 mm Hg in an individual with preexisting complications, such as encephalopathy, cerebral hemorrhage, left ventricular failure, or aortic stenosis. The therapeutic goal is to rapidly reduce blood pressure.

Nitroprusside is administered intravenously, and causes prompt vasodilation, with reflex tachycardia. The drug has little effect outside the vascular system, acting equally on arterial and venous smooth muscle. It can reduce cardiac preload. Nitroprusside is metabolized rapidly and requires continuous infusion to maintain its hypotensive action. Nitroprusside is poisonous if given orally because of its hydrolysis to cyanide.

Diazoxide is a direct-acting arteriolar vasodilator. It has vascular effects like those of hydralazine. Foe patients with coronary insufficiency, diazoxide is administered intravenously with a b-blocker, which diminishes reflex activation of the heart. Diazoxide is useful in the treatment of hypertensive emergencies, hypertensive encephalopathy, and eclampsia. Excessive hypotension is the most serious toxicity.

Labetalol is the both an a- and b-blocker that has been successfully used on hypertensive emergencies. Labetalol does not cause the reflex tachycardia that may be associated with diazoxide. Labetalol carries the contraindications of a nonselective b-blocker.

SUMMARY: DRUGS USED IN HYPERTENSION

Drugs Used in Hypertension

 

Subclass

Mechanism of Action

Effects

Clinical Applications

Pharmacokinetics, Toxicities, Interactions

Diuretics 

  Thiazides: Hydrochlorothiazide

Block Na/Cl transporter in renal distal convoluted tubule

Reduce blood volume plus poorly understood vascular effects

Hypertension, mild heart failure

 

  Loop diuretics: Furosemide

Block Na/K/2Cl transporter in renal loop of Henle

Like thiazides greater efficacy

Severe hypertension, heart failure

See Chapter 15

  Spironolactone

Block aldosterone receptor in renal collecting tubule

Increase Na and decrease K excretion poorly understood reduction in heart failure mortality

Aldosteronism, heart failure, hypertension

 

  Eplerenone

Sympathoplegics, centrally acting 

  Clonidine, methyldopa

Activate 2 adrenoceptors
 

Reduce central sympathetic outflow reduce norepinephrine release from noradrenergic nerve endings

Hypertension  clonidine also used in withdrawal from abused drugs

Oral  clonidine also patch Toxicity: sedation  methyldopa hemolytic anemia

Sympathetic nerve terminal blockers 

  Reserpine

Blocks vesicular amine transporter in noradrenergic nerves and depletes transmitter stores

Reduce all sympathetic effects, especially cardiovascular, and reduce blood pressure

Hypertension but rarely used

Oral long duration (days) Toxicity: Reserpine: psychiatric depression, gastrointestinal disturbances  

  Guanethidine

Interferes with amine release and replaces norepinephrine in vesicles

Same as reserpine

Same as reserpine

Guanethidine: Severe orthostatic hypotension sexual dysfunction

Blockers 

 

 

 

 

  Prazosin

Selectively block 1 adrenoceptors
 

Prevent sympathetic vasoconstriction reduce prostatic smooth muscle tone

Hypertension benign prostatic hyperplasia

Oral Toxicity: Orthostatic hypotension 

  Terazosin

  Doxazosin

Blockers 

 

 

 

 

  Metoprolol, others

Block 1 receptors; carvedilol also blocks receptors
 

Prevent sympathetic cardiac stimulation reduce renin secretion

Hypertension heart failure

See Chapter 10

  Carvedilol

  Propranolol: Nonselective prototypeblocker 

  Atenolol: Very widely used 1-selective blocker; claimed to have reduced central nervous system toxicity 

Vasodilators 

  Verapamil

Nonselective block of L-type calcium channels

Reduce cardiac rate and output reduce vascular resistance

Hypertension, angina, arrhythmias

See Chapter 12

  Diltiazem

  Nifedipine

Block vascular calcium channels > cardiac calcium channels

Reduce vascular resistance

Hypertension

See Chapter 12

  Amlodipine, other dihydropyridines

  Hydralazine

Causes nitric oxide release

Vasodilation reduce vascular resistance arterioles more sensitive than veins reflex tachycardia

Hypertension  minoxidil also used to treat hair loss

Oral Toxicity: Angina, tachycardia Hydralazine: Lupus-like syndrome 

  Minoxidil

Metabolite opens K channels in vascular smooth muscle

 

 

Minoxidil: Hypertrichosis

Parenteral agents 

  Nitroprusside

Releases nitric oxide

Powerful vasodilation

Hypertensive emergencies

Parenteral short duration Toxicity: Excessive hypotension, shock 

  Fenoldopam

Activates D1 receptors
 

  Diazoxide

Opens K channels

Angiotensin-converting enzyme (ACE) inhibitors 

  Captopril, many others

Inhibit angiotensin converting enzyme

Reduce angiotensin II levels reduce vasoconstriction and aldosterone secretion increase bradykinin

Hypertension heart failure, diabetes

Oral Toxicity: Cough, angioedema teratogenic

Angiotensin receptor blockers 

  Losartan, many others

Block AT1 angiotensin receptors
 

Same as ACE inhibitors but no increase in bradykinin

Hypertension heart failure

Oral Toxicity: Same as ACE inhibitors but no cough 

Renin inhibitor 

  Aliskiren

Inhibits enzyme activity of renin

Reduces angiotensin I and II and aldosterone

Hypertension

Oral Toxicity: Hyperkalemia, renal impairment potential teratogen

 

 

CLINICAL PHARMACOLOGY OF ANTIHYPOTENSIVE DRUGS

 

Shock is a clinical syndrome characterized by decreased blood supply to body tissues. Clinical symptoms depend on the degree of impaired perfusion of vital organs (eg, brain, heart, and kidneys). Common signs and symptoms include oliguria, heart failure, mental confusion, cool extremities, and coma. Most, but not all, people in shock are hypotensive.

In a previously hypertensive person, shock may be present if a drop in blood pressure of greater than 50 mm Hg has occurred, even if current blood pressure readings are normal. An additional consequence of inadequate blood flow to tissues is that cells change from aerobic (oxygen-based) to anaerobic metabolism. Lactic acid produced by anaerobic metabolism leads to generalized metabolic acidosis and eventually to organ failure and death if blood flow is not promptly restored.

 

Types of Shock

There are three general categories of shock that are based on the circulatory mechanisms involved. These mechanisms are intravascular volume, the ability of the heart to pump, and vascular tone.

Hypovolemic shock involves a loss of intravascular fluid volume that may be due to actual blood loss or relative loss from fluid shifts within the body.

Cardiogenic shock, also called pump failure, occurs when the myocardium has lost its ability to contract efficiently and maintain an adequate cardiac output.

Distributive or vasogenic shock is characterized by severe, generalized vasodilation, which results in severe hypotension and impairment of blood flow. Distributive shock is further divided into anaphylactic, neurogenic, and septic shock:

Anaphylactic shock results from a hypersensitivity (allergic) reaction to drugs or other substances.

Neurogenic shock results from inadequate sympathetic nervous system (SNS) stimulation. The SNS normally maintains sufficient vascular tone (ie, a small amount of vasoconstriction) to support adequate blood circulation. Neurogenic shock may occur with depression of the vasomotor center in the brain or decreased sympathetic outflow to blood vessels.

Septic shock can result from almost any organism that gains access to the bloodstream but is most often associated with gram-negative and gram-positive bacterial infections and fungi. It is important to know the etiology of shock because management varies among the types.

 

ANTISHOCK DRUGS

Drugs used in the management of shock are primarily the adrenergic drugs. In this chapter, the drugs are discussed only in relation to their use in hypotension and shock. In these conditions, drugs with alpha-adrenergic activity (eg, norepinephrine, phenylephrine) are used to increase peripheral vascular resistance and raise blood pressure. Drugs with beta-adrenergic activity (eg, dobutamine, isoproterenol) are used to increase myocardial contractility and heart rate, which in turn raises blood pressure. Some drugs have both alpha- and beta-adrenergic activity (eg, dopamine, epinephrine). In many cases, a combination of drugs is used, depending on the type of shock and the clients response to treatment. In an emergency, the drugs may be used to maintain adequate perfusion of vital organs until sufficient fluid volume is replaced and circulation is restored.

Adrenergic drugs with beta activity may be relatively contraindicated in shock states precipitated or complicated by cardiac dysrhythmias. Beta-stimulating drugs also should be used cautiously in cardiogenic shock after myocardial infarction because increased contractility and heart rate will increase myocardial oxygen consumption and extend the area of infarction. Individual drugs are described in the following section; indications for use and dosage ranges are listed in Drugs at a Glance: Drugs Used for Hypotension and Shock.

 

INDIVIDUAL DRUGS

Dopamine is a naturally occurring catecholamine that functions as a neurotransmitter. Dopamine exerts its actions by stimulating alpha, beta, or dopaminergic receptors, depending on the dose being used. In addition, dopamine acts indirectly by releasing norepinephrine from sympathetic nerve endings and the adrenal glands. Peripheral dopamine receptors are located in splanchnic and renal vascular beds. At low doses (0.5 to 10 mcg/kg/min), dopamine selectively stimulatesdopaminergic receptors that may increase renal blood flow and glomerular filtration rate (GFR). It has long been accepted that stimulation of dopamine receptors by low doses of exogenous dopamine produces vasodilation in the renal circulation and increases urine output. More recent studies indicate that low-dose dopamine enhances renal function only when cardiac function is improved. At doses greater than 3 mcg/kg/min, dopamine binds to beta and alpha receptors and the selectivity of dopaminergic receptors is lost beyond 10 mcg/kg/min. At doses that stimulate beta receptors (3 to 20 mcg/kg/min), there is an increase in heart rate, myocardial contractility, and blood pressure. At the highest doses (20 to 50 mcg/kg/min), beta activity remains, but increasing alpha stimulation (vasoconstriction) may overcome its actions.

Dopamine is useful in hypovolemic and cardiogenic shock. Adequate fluid therapy is necessary for the maximal pressor effect of dopamine. Acidosis decreases the effectiveness of dopamine.

Dobutamine is a synthetic catecholamine developed to provide less vascular activity than dopamine. It acts mainly on beta1 receptors in the heart to increase the force of myocardial contraction with a minimal increase in heart rate. Dobutamine also may increase blood pressure with large doses. It is less likely to cause tachycardia, dysrhythmias, and increased myocardial oxygen demand than dopamine and isoproterenol. It is most useful in cases of shock that require increased cardiac output without the need for blood pressure support. It is recommended for short-term use only. It may be used with dopamine to augment the beta1 activity that is sometimes overridden by alpha effects when dopamine is used alone at doses greater than 10 mcg/kg/min.

Dobutamine has a short plasma half-life and therefore must be administered by continuous IV infusion. A loading dose is not required because the drug has a rapid onset of action and reaches steady state within approximately 10 minutes after the infusion is begun. It is rapidly metabolized to inactive metabolites.

Epinephrine is a naturally occurring catecholamine produced by the adrenal glands. At low doses, epinephrine stimulates beta receptors, which increases cardiac output by increasing the rate and force of myocardial contractility. It also causes bronchodilation. Larger doses act on alpha receptors to increase blood pressure.

Epinephrine is the drug of choice for management of anaphylactic shock because of its rapid onset of action and antiallergic effects. It prevents the release of histamine and other mediators that cause symptoms of anaphylaxis, thereby reversing vasodilation and bronchoconstriction. In early management of anaphylaxis, it may be given subcutaneously to produce therapeutic effects within 5 to 10 minutes, with peak activity in approximately 20 minutes.

Epinephrine is also used to manage other kinds of shock and is usually given by continuous IV infusion. However, bolus doses may be given in emergencies, such as cardiac arrest. It may produce excessive cardiac stimulation, ventricular dysrhythmias, and reduced renal blood flow. Epinephrine has an elimination half-life of about 2 minutes and is rapidly inactivated to metabolites, which are then excreted by the kidneys.

Isoproterenol is a synthetic catecholamine that acts exclusively on beta receptors to increase heart rate, myocardial contractility, and systolic blood pressure. However, it also stimulates vascular beta2 receptors, which causes vasodilation, and may decrease diastolic blood pressure. For this reason, isoproterenol has limited usefulness as a pressor agent. It also may increase myocardial oxygen consumption and decrease coronary artery blood flow, which in turn causes myocardial ischemia. Cardiac dysrhythmias may result from excessive beta stimulation. Because of these limitations, use of isoproterenol is limited to shock associated with slow heart rates and myocardial depression.

Metaraminol is used mainly for hypotension associated with spinal anesthesia. It acts indirectly by releasing norepinephrine from sympathetic nerve endings. Thus, its vasoconstrictive actions are similar to those of norepinephrine, except that metaraminol is less potent and has a longer duration of action.

Milrinone is used to manage cardiogenic shock in combination with other inotropic agents or vasopressors. It increases cardiac output and decreases systemic vascular resistance without significantly increasing heart rate or myocardial oxygen consumption. The increased cardiac output improves renal blood flow, which then leads to increased urine output, decreased circulating blood volume, and decreased cardiac workload.

Norepinephrine (Levophed) is a pharmaceutical preparation of the naturally occurring catecholamine norepinephrine. It stimulates alpha-adrenergic receptors and thus increases blood pressure primarily by vasoconstriction. It also stimulates beta1 receptors and therefore increases heart rate, force of myocardial contraction, and coronary artery blood flow. It is useful in cardiogenic and septic shock, but reduced renal blood flow limits its prolonged use. Norepinephrine is used mainly with clients who are unresponsive to dopamine or dobutamine. As with all drugs used to manage shock, blood pressure should be monitored frequently during infusion.

Phenylephrine (Neo-Synephrine) is an adrenergic drug that stimulates alpha-adrenergic receptors. As a result, it constricts arterioles and raises systolic and diastolic blood pressures. Phenylephrine resembles epinephrine but has fewer cardiac effects and a longer duration of action. Reduction of renal and mesenteric blood flow limit prolonged use.

 

Choice of Drug

The choice of drug depends primarily on the pathophysiology involved. For cardiogenic shock and decreased cardiac output, dopamine or dobutamine is given. With severe heart failure characterized by decreased cardiac output and high peripheral vascular resistance, vasodilator drugs (eg, nitroprusside, nitroglycerin) may be given along with the cardiotonic drug. The combination increases cardiac output and decreases cardiac workload by decreasing preload and afterload. However, vasodilators should not be used alone because of the risk of severe hypotension and further compromising tissue perfusion.

Milrinone may be given when other drugs fail. For distributive shock characterized by severe vasodilation and decreased peripheral vascular resistance, a vasoconstrictor or vasopressor drug, such as norepinephrine, is the drug of first choice. Drug dosage must be carefully titrated to avoid excessive vasoconstriction and hypertension, which causes impairment rather than improvement in tissue perfusion.

 

 

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