High Blood pressure

Description: Metoprolol is a competitive, œA-selective adrenergic antagonist, similar to atenolol. In contrast to pindolol, metoprolol does not have intrinsic sympathomimetic activity and does not exhibit membrane-stabilizing activities as both pindolol and propranolol possess. Metoprolol is more lipid soluble than atenolol, but less than propranolol and betaxolol, which affects its route of elimination and, theoretically, its potential for CNS side effects. Furthermore, metoprolol has the shortest plasma half-life of the cardioselective œ-blockers. Metoprolol was approved by the FDA in 1978. (Continued below video)

Mechanism of Action: Like other œ-adrenergic antagonists, metoprolol competes with adrenergic neurotransmitters (e.g., catecholamines) for binding at sympathetic receptor sites. Similar to betaxolol and atenolol, metoprolol, in low doses, selectively blocks œA-adrenergic receptors in the heart and vascular smooth muscle. Pharmacodynamic consequences of œA-receptor blockade include a decrease in both resting and exercise heart rate and cardiac output, and a decrease in both systolic and diastolic blood pressure. Metoprolol may reduce reflex orthostatic hypotension. As with all "selective" adrenergic antagonists, selectivity for the œA-receptor is lost at higher doses. Atdoses > 400 mg/day, metoprolol also can competitively block œA-adrenergic receptors in the bronchial and vascular smooth muscles, potentially causing bronchospasm.

Actions that make metoprolol useful in treating hypertension include a negative chronotropic effect that decreases heart rate at rest and after exercise; a negative inotropic effect that decreases cardiac output; reduction of sympathetic outflow from the CNS; and suppression of renin release from the kidneys. Thus, metoprolol, like other œ-blockers, affects blood pressure via multiple mechanisms.

Actions that make metoprolol useful in treating hypertension also apply to the management of chronic stable angina. The reduction in myocardial oxygen demand induced by metoprolol decreases the frequency of anginal attacks and the requirements for nitrate, and increases exercise tolerance.

Metoprolol has been used in the management of hereditary or familial essential tremor. œ-blockade controls the involuntary, rhythmic and oscillatory movements of essential tremor. Tremor amplitude is reduced, but not the frequency of tremor. The mechanism of action is unclear, but the antitremor effect may be mediated by blockade of peripheral œA receptor mechanisms.

Pharmacokinetics: After oral administration, metoprolol is quickly and almost completely absorbed from the GI tract, but only 50% of an oral dose reaches systemic circulation as unchanged drug because of first-pass metabolism in the liver. Food increases the amount of drug absorbed. Hypotensive effects begin within 60 minutes of an oral dose of the immediate-release product, and the maximal therapeutic effect occurs within the first week of treatment. Following administration of extended-release tablets, peak metoprolol serum concentrations are approximately one-third of those attained with conventional-release tablets, with the peak concentration occurring about 7 hours following dosing. After IV administration, the maximal hypotensive response occurs within 20 minutes. The plasma concentrations attained following IV administration are 2-2.5 times those reached with the conventional oral tablet.

Metoprolol is widely distributed throughout the body, crosses the blood-brain barrier and the placenta, and is concentrated in breast milk. Although the drug is not extensively bound to plasma proteins, the hypotensive effects of metoprolol can last up to 1 month after discontinuation of the drug, possibly because of extensive tissue binding.

Metabolism of metoprolol occurs primarily in the liver. The rate of metabolism is dependent partly on the genetic polymorph that determines the rate of hepatic hydroxylation. In most subjects, hydroxylation occurs relatively rapidly, and the half-life of metoprolol is about 3-4 hours; in slow hydroxylators, the half-life is prolonged to about 7 hours. The drug is excreted mainly via the kidney as metabolites, with 95% of an oral dose excreted renally, primarily via glomerular filtration, within 72 hours.

CONTRAINDICATIONS/PRECAUTIONS: Abrupt discontinuation of any œ-adrenergic-blocking agent, including metoprolol, can result in the development of myocardial ischemia, infarction, ventricular arrhythmias, or severe hypertension, particulary in patients with preexisting cardiac disease.

Metoprolol should be used with caution in patients with hyperthyroidism or thyrotoxicosis because the drug can mask the tachycardia that occurs in this condition. Abrupt withdrawal of metoprolol in a patient with hyperthyroidism can precipitate a thyroid storm. Note, however, that œ-blockers are, in general, useful in the treatment of hyperthyroid-related states.

Because these drugs depress conduction through the AV node, œ-blockers are contraindicated in patients with severe bradycardia or advanced AV block. In general, œ-blockers should not be used in patients with cardiogenic shock or systolic congestive heart failure, particularly in those with severely compromised left ventricular dysfunction, because the negative inotropic effect of these drugs can further depress cardiac output. In some patients with heart failure, however, œ-blockers given in low doses have been beneficial. Many œ-blockers are used in the treatment of hypertrophic cardiomyopathy. œ-blocker monotherapy should be used with caution in patients with a pheochromocytoma or vasospastic angina (Prinzmetal's angina) because of the risk of hypertension secondary to unopposed ›-receptor stimulation. In the treatment of myocardial infarction, œ-blockers are contraindicated in patients with hypotension (SBP < 100 mmHg).

Metoprolol should be used with caution in patients with diabetes mellitus because the drug can mask symptoms of hypoglycemia such as tachycardia, palpitations, blood pressure changes, tremor, and anxiety. However, metoprolol usually does not mask other symptoms of hypoglycemia (sweating and dizziness), nor does it, in usual doses, cause insulin-induced hypoglycemia. In addition, œ-blockers can precipitate hyperglycemia via inhibition of glycogenolysis. While œ-blockers probably should not be used in brittle diabetes, they may be used cautiously in more stable patients.

Although œA-adrenergic selective œ-blockers such as metoprolol are preferred over nonselective agents in patients with asthma or pulmonary conditions in which bronchospasm would put them at risk (e.g., COPD, emphysema, bronchitis), all œ-blockers should nevertheless be used with caution in these patients, particularly with high-dose therapy.

Patients receiving metoprolol before or during surgery involving general anesthetics that have negative inotropic effects (e.g., ether, cyclopropane, or trichlorethylene) should be monitored closely for signs of heart failure. Severe, protracted hypotension and difficulty in restarting the heart have been reported after surgery on patients receiving œ-blockers. If discontinuation of the drug is indicated, therapy should be stopped 2 days prior to surgery.

Metoprolol is relatively contraindicated in severe hepatic disease because of possible decreased clearance of the drug, since it is principally metabolized by the liver. Dosage adjustment may be necessary in such cases.

Metoprolol is classified as a pregnancy category C drug by the FDA, so appropriate consideration of risks/benefits of its use is prudent. Metoprolol is excreted into breast milk. The manufacturers do not recommend the use of metoprolol while breast-feeding because of the potential risk of potential toxicity in the nursing infant.

Metoprolol is relatively contraindicated in patients with Raynaud's disease or peripheral vascular disease because reduced cardiac output and the relative increase in › stimulation can exacerbate symptoms.

The actual relationship between depression and œ-blockers has not been definitively established. œ-blockers should be used with caution in patients with major depression.

œ-blockers may exacerbate conditions such as psoriasis.

œ-blockers may potentiate muscle weakness and double vision in patients with myasthenia gravis.

œ-blockers can be used safely in elderly patients, however these patients may have unpredictable responses to œ-blockers. They may be less sensitive to the antihypertensive effects of the drug, however, reduced excretion may increase the potency of œ-blockers in this population. The elderly have age-related peripheral vascular disease and the relative increase in › stimulation can exacerbate symptoms. Geriatric patients are at increased risk of œ-blocker-induced hypothermia.

Metoprolol is contraindicated in patients exhibiting hypersensitivity to the drug or any of its excipients.

DRUG INTERACTIONS: The antihypertensive effects of metoprolol are additive with other antihypertensive agents. This interaction is often used advantageously in treating hypertension; however, lower doses of each agent may be necessary. In general, metoprolol can be administered safely with most other antihypertensives. Hypotension can be potentiated when œ-blockers are coadministered with dihydroperidine-type calcium-channel blockers, most notably rapid-release nifedipine. It may be wise to avoid using metoprolol with guanethidine, reserpine, or other rauwolfia alkaloids that have a high incidence of orthostatic hypotension due to catecholamine depletion, since œ-blockers will interfere with reflex tachycardia, worsening the orthostasis.

While additive effects are possible with many other antiarrhythmics, particular attention should be given to using metoprolol in combination with other antiarrhythmic agents that exert significant effects on AV nodal conduction (e.g., amiodarone, cardiac glycosides, diltiazem, verapamil) which, when used with metoprolol or other œ-blockers, can cause complete AV block. Propafenone has been shown to increase the plasma concentrations and prolong the elimination half-life of metoprolol in 4 patients with cardiovascular disease.

œ-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, œ-blockers may cause a pharmacodynamic interaction with antidiabetic agents. œ-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Also, œ-blockers can blunt the tachycardic response to and exaggerate the hypertensive response to hypoglycemia. Although no pharmacokinetic interaction has been observed between œ-blockers and antidiabetic agents, patients receiving œ-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective œ-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia.

Care must be taken when abruptly stopping clonidine to avoid the possibility of rebound hypertension, which can be augmented in patients currently receiving or simultaneously beginning therapy with metoprolol or another œ-blocker. Administration of œ-blockers during withdrawal of clonidine can precipitate severe blood pressure increases as a result of unopposed › stimulation. If metoprolol is to be substituted for clonidine, clonidine should be gradually tapered and metoprolol gradually increased over several days. It is possible to administer clonidine and metoprolol concurrently without sequelae, although hypotensive effects will be additive.

Concurrent use of œ-blocking agents with sympathomimetics can result in mutual antagonism of desired therapeutic effects of either agent (i.e., œA-and/or œA-agonism or antagonism), and/or can cause unopposed › pharmacodynamic effects. Despite its selectivity for œA-receptors, metoprolol should be expected to counteract the adrenergic agonists-even the ›-and œA-agonists-to some degree. Although œ-blocking agents are used to treat or reduce the signs and symptoms of cocaine intoxication and the subsequent cardiovascular manifestations of abuse of the drug, care must be exercised that unopposed › activity does not result and cause profound hypertension, bradycardia, or heart block.

Cimetidine has variable effects on metoprolol pharmacokinetics. Although cimetidine has been shown to increase metoprolol blood levels, another study showed no effect. Clinicians should be alert to exaggerated metoprolol effects if the drug is given with cimetidine.

Metoprolol interacts with diethyl ether and other general anesthetics that depress the myocardium and may increase the risk of developing hypotension and heart failure.

One report noted an interaction between fluoxetine and metoprolol. Bradycardia occurred in a patient receiving metoprolol after fluoxetine was added. The patient had not previously experienced this reaction while on either drug alone. The authors postulated that fluoxetine may have inhibited hepatic metabolism of metoprolol. A similar interaction was noted between metoprolol and fluvoxamine. It is suspected that fluvoxamine inhibits the hepatic metabolism of metoprolol.

NSAIDs can reduce the hypotensive effects of antihypertensives. Patients receiving œ-blockers for hypertension should be monitored for loss of antihypertensive effect if an NSAID is added.

Rifampin, a potent inducer of hepatic enzymes, has been shown to alter the pharmacokinetics of metoprolol. Although the clinical significance of this is uncertain, patients should be monitored for loss of metoprolol effects if rifampin is added.

ADVERSE REACTIONS: The adverse effects of metoprolol are generally mild and temporary; they usually occur at the onset of therapy and diminish over time.

Most adverse reactions of metoprolol are manifestations of its therapeutic effect. Sinus bradycardia and hypotension are rarely serious and can be reversed with IV atropine if necessary. AV block, secondary to depressed conduction at the AV node, can necessitate sympathomimetic and/or pressor therapy or use of a temporary pacemaker.

Congestive heart failure is more likely to occur in patients with preexisting left ventricular dysfunction and usually will respond to discontinuation of metoprolol therapy.

Adverse CNS effects include dizziness, fatigue, and depression. Although much less common with hydrophilic œ-blockers, CNS depression can occur, resulting in mental depression, fatigue, and, in some cases, vivid dreams.

Diarrhea and nausea/vomiting are the most common GI adverse effects during therapy with metoprolol.

Bronchospasm and dyspnea are more likely to occur if the dose of metoprolol is >400 mg/day because the beta selectivity of the drug is lost. Patients with preexisting bronchospastic disease are at greater risk.

Both hypoglycemia and hyperglycemia can occur during metoprolol therapy. Metoprolol can interfere with glycogenolysis to cause hyperglycemia, and it also can mask signs of hypoglycemia. Metoprolol should be used cautiously in brittle diabetics.

Hematologic adverse reactions, such as agranulocytosis, have been reported rarely during therapy with metoprolol.

œ-blockers have been shown to cause hypertriglyceridemia and decrease plasma HDLs during therapy. A recent meta-analysis suggested that these effects are less pronounced with cardioselective agents, such as metoprolol, particularly in diabetics. The clinical implications of these effects, in light of other cardiovascular advantages of œ-blocker therapy is not known. D

Myalgias and musculoskeletal pain can occur with metoprolol therapy.

Metoprolol has been associated with elevated hepatic enzymes. Sexual dysfunction, impotence, and libido decrease are less frequent adverse effects of beta-blocker therapy (<2%) than is generally perceived.

Dermatologic reactions with œ-blockers are usually mild and transient. Some of these reactions include pruritus, skin hyperpigmentation, reversible alopecia, xerosis, and exfoliative dermatitis.

PATIENT INFORMATION:

What do metoprolol tablets or extended-release tablets do?

Metoprolol (Lopressor^TM , Toprol XL) belongs to a group of medicines called beta-blockers. Beta-blockers reduce the workload on the heart and help it to beat more regularly. Metoprolol controls, but does not cure, high blood pressure (hypertension). Hypertension may not make you feel sick, but it can lead to serious heart problems. Metoprolol also relieves chest pain (angina) and can be helpful after a heart attack. Generic metoprolol tablets are available, but not extended-release tablets.

What should my doctor, dentist, or pharmacist know before I take metoprolol?

They need to know if you have any of these conditions:

• angina (chest pain)
• asthma, bronchitis or bronchospasm
• circulation problems, or blood vessel disease (such as Raynaud's disease)
• depression
• diabetes
• emphysema, or other lung disease
• history of heart attack or heart disease
• liver disease
• muscle weakness or disease
• pheochromocytoma
• psoriasis
• thyroid disease
• an unusual or allergic reaction to metoprolol, other beta-blockers, medicines, foods, dyes, or preservatives
• pregnant or trying to get pregnant
• breast-feeding

How should I take this medicine?

Take metoprolol tablets by mouth. Follow the directions on the prescription label. Swallow the tablets with a drink of water. Do not crush or chew extended-release tablets. Take tablets with or immediately after meals. Take your doses at regular intervals. Do not take your medicine more often than directed. Do not stop taking except on your doctor's advice.

Special precautions for use in children:

This medicine is not for children.

Elderly patients may have a stronger reaction to this medicine and need smaller doses.

What if I miss a dose?

If you miss a dose, take it as soon as you can. If it is almost time for your next dose, take only that dose. Do not take double or extra doses. There should be at least 4 hours between doses (or 8 hours if taking extended-release products).

What other medicines can interact with metoprolol?

• antiinflammatory drugs (NSAIDs, such as ibuprofen)
• cimetidine
• cocaine
• fluoxetine
• medicines for colds and breathing difficulties
• medicines for diabetes
• medicines for high blood pressure
• medicines to control heart rhythm
• rifampin
• water pills

Tell your doctor or pharmacist: about all other medicines you are taking, including non-prescription medicines; if you are a frequent user of drinks with caffeine or alcohol; if you smoke; or if you use illegal drugs. These may affect the way your medicine works. Check before stopping or starting any of your medicines.

What side effects may I notice from taking metoprolol?

Serious side effects with metoprolol include:

• anxiety
• cold, tingling, or numb hands or feet
• difficulty breathing, wheezing
• dizziness or fainting spells
• increase in the amount of urine passed
• increased thirst
• irregular heartbeat
• skin rash
• slow heart rate (fewer than recommended by your doctor)
• sweating
• swollen legs or ankles
• tremor, shakes
• weight loss

Call your doctor as soon as you can if you get any of these side effects.

Minor side effects with metoprolol include:

• diarrhea
• dry itching skin
• headache
• nausea, vomiting
• sexual difficulties, impotence
• unusual tiredness

Let your doctor know about these side effects if they do not go away or if they annoy you.

What do I need to watch for while I take metoprolol?

Check your heart rate and blood pressure regularly while you are taking metoprolol. Ask your doctor what your heart rate and blood pressure should be, and when you should contact him or her.

Do not stop taking this medicine suddenly. This could lead to serious heart-related side effects.

You may get drowsy or dizzy. Do not drive, use machinery, or do anything that needs mental alertness until you know how metoprolol affects you. To reduce the risk of dizzy or fainting spells, do not sit or stand up quickly, especially if you are an older patient. Alcohol can make you more drowsy, and increase flushing and rapid heartbeats. Avoid alcoholic drinks.

Metoprolol can affect blood sugar levels. If you are diabetic check with your doctor before you change your diet or the dose of your diabetic medicine.

If you are going to have surgery, tell your doctor or dentist that you are taking metoprolol.

Where can I keep my medicine?

Keep out of the reach of children in a container that small children cannot open.

Store at room temperature between 15 and 30C (59 and 86F). Protect from moisture. Throw away any unused medicine after the expiration date.

The P-I-E-N-O Parkinsn's List Drug Database Index

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