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INDICATIONS

• See table below for specific FDA indications for each beta-blocker.
• With or without diabetes, treatment of HTN alone or in conjunction with other antihypertensive agents
• Management of angina pectoris
• Secondary prevention of post-MI
• Supraventricular arrhythmias
• Pheochromocytoma
• Essential tremor
• Prophylaxis for migraine headaches
• Symptomatic treatment of hypertrophic subaortic stenosis
• Mild-to-severe heart failure of ischemic or cardiomyopathic origin (carvedilol and metoprolol only)

MECHANISM

• Beta-blockers compete with adrenergic neurotransmitters (e.g. catecholamines) for binding at sympathetic receptor sites which results in a decreased heart rate, cardiac output, and both systolic and diastolic blood pressure.

USUAL ADULT DOSING

• JNC 7 recommended usual adult dose for the treatment of hypertension (see table below for dosing recommendations for other indications)
• Atenolol 25-100 mg once-daily
• Bisoprolol 2.5 to 10 mg once-daily
• Metoprolol 50-100 mg per day in one to two divided doses OR metoprolol XL 50-100 mg once daily.
• Nadolol 40-120 mg once-daily
• Propranolol 40-160 mg in two divided doses OR propranolol LA 60-180 mg once-daily.
• Timolol 20-40 mg in two divided doses.
• Carvedilol 12.5-50 mg in two divided doses.
• Labetalol 200-800 mg in two divided doses.

DOSING IN SPECIAL POPULATIONS

• Atenolol, bisoprolol, nadalol, and timolol (especially with concurrent hepatic impairment) need dose adjustment with renal failure.

• Metoprolol, propranolol, timolol, labetolol, and carvedilol need dose adjustment with hepatic insufficiency. Carvedilol should be avoided in severe hepatic impairment.

• Atenolol is pregnancy category D. All other beta-blockers are pregnancy category C, but many experts recommend avoiding in 2nd and 3rd trimester of pregnancy.

• Human and/or animal data suggest that all beta-blockers are excreted into breast milk. Atenolol should be avoided in breastfeeding patients. Bisoprolol and carvedilol should be used only if the benefit outweigh the risk. The American Academy of Pediatrics considers metoprolol, nadolol, propranolol, timolol, and labetolol to be compatible with breastfeeding.

ADVERSE DRUG REACTIONS

• Bronchospasm in patients with asthma and COPD
• Fatigue

• Sinus bradycardia (AV block)
• Hypotension
• Hyperglycemia
• GI (e.g diarrhea, nausea, vomiting)
• CNS side effects (e.g. dizziness, vertigo, fatigue)
• Exacerbation of peripheral vascular disease (avoid beta-blockers in patients with severe peripheral vascular disease).
• Slightly increased serum triglyceride and decrease HDL (may occur less commonly with carvediolol and labetalol)
• Depression, dreams, hallucinations (more common in elderly patients)

• CHF (especially in patients with preexisting left ventricular dysfunction)
• Agranulocytosis and thrombocytopenia
• Rash

DRUG INTERACTIONS

• The addition of other anti-hypertensive agents (e.g. ACE inhibitors, ARBs, Calcium Channel blockers, clonidine) may result in additive antihypertensive effect.
• Since beta-2 receptor blockade can decrease insulin secretion and worsen insulin sensitivity, non-selective beta-blockers (e.g propranolol, nadolol, timolol) may decrease the efficacy of sulfonylureas such as glyburide and glipizide.
• Insulin, sufonylureas: beta-blockers can 1) blunt the tachycardic response to hypoglycemia; 2) exaggerate the hypertensive response to hypoglycemia due to unopposed alpha adrenergic stimulation.
• Any agents that decreases AV nodal conduction (e.g. digoxin, disopyramide, class IC antiarrhythmics such as flecainide, propafenone) may result in additive AV nodal conduction with beta-blocker co-administration.
• CYP 2D6 inhibitors (e.g. ritonavir, amiodarone, quinidine, propafenone, nicardipine, citalopram, fluoxetine,) may increase serum concentrations of metoprolol, timolol, and propranolol. Use low dose metoprolol, timolol, and propanalol with slow tritration.
• CYP 2C9 inhibitors (e.g. etravirine, fluconazole, ketoconazole, gemfibrozil, nicardipine) may increase serum concentrations of carvedilol. Use low dose carvedilol with slow titration.
• CYP 3A4 inhibitors (e.g. protease inhibitors, azole antifungal, macrolides) may increase bisoprolol serum concentrations. Use low dose bisoprolol with slow titration.
• Rifampin may decrease serum concentrations of metoprolol, timolol, propranolol, carvedilol, and bisoprolol. May need to increase beta-blocker dose.

PHARMACOKINETIC

COMMENTS

• Beta blockers can mask symptoms of hypoglycemia (e.g. tremor, tachycardia, palpitations). Diaphoretic response to hypoglycemia is generally not masked.
• Incidence of hypoglycemia similar between captopril and atenolol (UKPDS 39), suggesting no adverse effect of beta blockers.
• Cardioselective betablockers  (e.g. atenolol, metoprolol) bind more selectively at B1 than B2 receptors. At lower doses, cardioselective beta-blockers may be preferred in patients with diabetes and peripheral vascular disease.
• Selective beta-blockers (e.g. atenolol, metoprolol) may also have less adverse effect on glycemic control.
• Although beta-blockers may have a mildly negative effect on glycemic control this can be easily overcome with anti-diabetic therapy, and reduction of cardiovascular disease and mortality benefit post-MI have been demonstrated in people with diabetes treated with beta-blockers.
• Beta-blockers vary in their pharmacokinetic and pharmacodynamic effects, but their anti-hypertensive effects are comparable.
• Beta-blockers with intrinsic sympathomimetic effects (e.g. acebutolol, pindolol, and penbutolol) are generally not recommended since they do not reduce cardiovascular events as well as other beta-blockers.
• Beta-blockers may be preferred for use in patients with history of recent myocardial infarction.
• May increase the risk of diabetes development up to 28% after six years (Gress).

REFERENCES

RELATED MODULES

• Cardiovascular Disease Screening and Management
• Peripheral Vascular Disease