Metoprolol (Lopressor): Drug Whys
By Mike McEvoy
Generic Name: Metoprolol (multiple manufacturers)
Common Brand Name: Lopressor (Novartis Pharmaceuticals – U.S.)
Popularity: 16th most commonly prescribed drug between 2002 – 2008 (U.S.)
Classes: Beta-adrenergic blocker, antianginal, antiarrhythmic, antihypertensive, antimigraine.
Treatment Uses — Angina pectoris, heart failure, mild to moderate high blood pressure, and to improve survival after heart attacks. Also effective in treating arrhythmias, pheochrocytoma, essential tremor and neuroleptic drug induced movement disorders, preventing migraine headaches, reducing eye pressures in glaucoma, and reducing the frequency of vasovagal syncopal episodes.
May have a role in treatment of aggressive behavior, panic attacks, and reducing atherosclerosis. Widely used (off-label) by performers to reduce symptoms of stage fright. Intravenous (IV) metoprolol has been useful for reducing infusion site related pain associated with propofol injection. There is considerable evidence that preoperative treatment with metoprolol (or other beta-blocker) is associated with a significant reduction in adverse cardiac events during and after surgical procedures. Many hospitals routinely administer beta-blockers preoperatively as a risk reduction strategy.
Dosing and Administration — Recommended oral starting dose of metoprolol for treatment of hypertension in adults is 25 to 100 milligrams once daily, titrated upwards at one to two week intervals to achieve optimal antihypertensive effects. Maintenance doses usually range from 100-400 mg per day, preferably using extended-release oral tablets.
Smaller doses are used to treat arrhythmias or angina, and the smallest doses initiated for heart failure therapy. Initial intravenous dosing to treat acute myocardial infarct (AMI) or unstable angina is three IV boluses of 5 mg (each injected over 1 minute) at 2 minute intervals, usually followed by oral dosing of 50 milligrams every 6 hours for 48 hours or 25 milligrams every 6 hours for 48 hours if unable to tolerate the full initial IV regimen.
Following AMI, oral dosing should be continued for at least three years. Safety in children under 6 years of age has not been established but for treatment of hypertension in children age 6 and older, initial oral dosing is recommended at 1 milligram per kilogram given once daily (maximum initial dose of 50 milligrams), titrated to clinical response. Some pediatric studies have safely used higher initial dosing regimens.
Peak drug levels are highest when oral metoprolol is taken with meals; taking the drug with or immediately following meals is recommended to avoid fluctuations in drug concentrations.
Dosage adjustments are not needed for patients with renal failure but are required in patients with liver disease due to extensive metabolism of metoprolol in the liver. Maintenance doses of metoprolol should be taken after hemodialysis. Dose adjustments do not appear necessary in elderly patients.
Overdoses of metoprolol can lead to death. Signs and symptoms include bradycardia, hypotension, bronchospasm, and cardiovascular failure. Treatment is supportive. Gastric lavage may be helpful if performed early. Atropine should be administered and if ineffective, isoproterenol may help to increase heart rate.
Intravenous glucagon is the drug of choice for its ability to improve heart rate and pump function independently of beta-receptors. Doses up to 10 mg may be needed, followed by a continuous infusion. For IV doses above 2 mg, discard the (cadiotoxic) phenol diluent supplied and dilute with sterile water instead (newer preparations no longer use phenol diluents).
Catecholamine infusions and pressors may be helpful, particularly when glucagon is ineffective, but will often require five to 15 times normal dosing to overcome beta receptor blockade. Fluids are often ineffective or contraindicated due to heart failure caused by beta blockade. Beta-2 stimulants such as theophylline can be used to reverse bronchospasm. Hemodialysis does remove metoprolol.
Pharmacology/Pharmacokinetics/Stability — Following oral administration, beta blocking effects occur within 1 hour and have a dose related duration of between 3-6 hours. Extended (sustained) release tablets take longer to reach peak plasma levels and have longer dose durations than immediate release forms.
When given IV, effects are faster, with maximum beta blocking effect seen at 20 minutes, then tapering off from 5 to 8 hours, dependent on the total dose given (5 to 15 mg). Five mg of intravenous metoprolol is approximately equivalent to 12.5 mg given orally.
Distressing rebound effects from abrupt discontinuation of long-term metoprolol therapy warrants tapering doses downward over a two-week period. Metoprolol contains a Black Box Warning from the FDA (the highest alert possible) against abrupt discontinuation of the drug, which has been reported to exacerbate angina and occasionally lead to myocardial infarction.
The liver eliminates the majority of metoprolol from the body. Kidneys excrete the remaining 3-10 percent of the drug.
Metoprolol is a beta-1 selective adrenergic receptor antagonist capable of inhibiting heart rate response to norepinephrine, isoproterenol, and epinephrine (in decreasing order of degree). It is cardioselective, blocking primarily receptors in cardiac tissue, but this selectivity is dose related, decreasing as doses increase.
At high doses, cardioselective beta-blockers may antagonize peripheral beta-2 receptors (found in blood vessels). Metoprolol has incredibly beneficial effects on heart failure patients for reasons not well understood. It is theorized that the combined reduction of renin-angiotensin system activation, lowered heart rate, and resultant remodeling of the left ventricle collectively account for the significant mortality reduction reported in heart failure patients.
Metoprolol is compatible with most commonly used IV solutions (D5W, NS, LR). Both oral and intravenous forms are light sensitive, and tablets are also moisture sensitive (requiring tightly sealed, light resistant pill containers). Extended release tablets may be split in half but should not be chewed or crushed. Tablets should be stored at room temperature (54-86 F) and IV metoprolol stored below 86 F. A compounding pharmacy can prepare an oral suspension of metoprolol (10 milligrams per milliliter) stable for 60 days under refrigeration.
Cautions and Warnings — Do not give metoprolol to patients with heart rates below 45/min, second or third degree heart blocks, first degree blocks with P-R Intervals of 0.24 sec or greater, systolic blood pressure less than 100 mmHg, or significant heart failure.
As it is metabolized in the liver, be careful using metoprolol in patients with impaired liver function. In pheocromocytoma and cocaine toxicity, administration of any beta-blocking agent can lead to paradoxical elevations in blood pressure from unopposed alpha stimulation. An alpha-blocker agent should be administered prior to using a beta-blocker in these situations. Likewise, in patients being treated with both metoprolol and an alpha-blocking agent (such as clonidine), metoprolol should be discontinued several days before stopping the alpha-blocker to avoid marked rebound hypertension.
Metoprolol crosses the placenta and studies in animals have demonstrated adverse effects on the fetus. There are no well controlled studies in humans. Potential benefits to pregnant women may outweigh the risks of using metoprolol during pregnancy. The American Academy of Pediatrics rates metoprolol, "usually compatible with breastfeeding." While metoprolol is concentrated in breast milk, these levels are not typically pharmacologically significant. There have been no reports of adverse effects to infants drinking breast milk from mothers taking metoprolol.
Multiple instances of confusing intravenous norepinephrine for metoprolol have occurred. Two factors seem to promote this (usually lethal) drug error: look alike packaging and names that are alphabetically close (Lopressor and Levophed). Keep this safety point in mind whenever you use metoprolol.
Important Side Effects and Interactions — Although widely used, metoprolol can be a dangerous drug. Its most common side effects include tiredness, dizziness, depression, diarrhea, itching, and rash (all with reported incidences ranging from 5-10 percent of patients). Beta blocking effects of metoprolol occasionally exacerbate reactive airway disease, allergic reactions, or claudication associated with peripheral vascular disease.
Impotence or sexual dysfunction rarely occurs due to its cardioselectivity. Blood pressure and heart rate should be monitored; significant reductions are an adverse effect. Beta blockers can mask symptoms of hypoglycemia in persons with diabetes (such as tachycardia and diaphoresis) but the risks of altering glucose control are minimal and benefits of beta-blockers (when indicated) in this population outweigh risks. A slight increase in serum potassium levels usually accompanies initiation of beta-blocker therapy although total body potassium does not change.
There are currently 176 medications reported to interact with metoprolol. Two drug interactions are important for EMS providers: beta-blockers and amiodarone. Response to metoprolol is dose dependent and this requires extra caution when administering metoprolol to patients already taking beta-blockers.
Amiodarone has beta blocking properties with numerous reports of hypotension, bradycardia, and cardiac arrest when combined with metoprolol. Look carefully for evidence of AV blocks or sick sinus syndrome before giving metoprolol to people taking amiodarone.
Average Costs — U.S.
• 5 mg/5 ml ampule for injection (generic)
ALS Service cost: $4.56 each
Large Hospital cost: $2.40 each
• 50 mg tablet/100 mg tablet (generic)*
Patient cost: $0.60/0.74 each
Large Hospital cost: $0.02/0.08 each
*Wal Mart and Target both include this med in their $4/month programs
1. MICROMEDEX® Healthcare Series: Thomson Micromedex, Greenwood Village, Colorado (accessed June, 2010).
2. Albany Medical Center Pharmacy, Albany, New York.