Propranolol

Indications

• FDA-approved for hypertension, angina, atrial fibrillation, post-myocardial infarction protection, essential tremor, and migraine prophylaxis.
• FDA-approved for pheochromocytoma as an adjunct to alpha blockade and for hypertrophic subaortic stenosis; Hemangeol treats infantile hemangioma.
• Used off-label for performance or situational anxiety, where a single dose before a speech, audition, or examination blunts tremor and palpitations.
• Used off-label for antipsychotic-induced akathisia, where a Cochrane review supports central beta-blockers despite small and older trials.
• Used off-label for lithium-induced postural tremor, typically at low divided doses that do not compromise blood pressure.
• Used off-label for aggression and agitation after traumatic brain injury, where higher divided doses have modest supportive evidence.

Mechanism of action

• Nonselective competitive antagonist at beta-1 and beta-2 adrenergic receptors, reducing heart rate, contractility, and peripheral tremor.
• Blocking peripheral beta receptors removes the somatic feedback of anxiety, including tachycardia, tremor, and voice quivering.
• High lipophilicity gives good central nervous system penetration, which is thought to underlie its benefit in akathisia and aggression.
• It does not treat the cognitive or worry component of anxiety, so it complements rather than replaces psychotherapy or serotonergic agents.
• Beta-2 blockade in bronchial smooth muscle causes the bronchoconstriction that makes it dangerous in asthma.

Pharmacokinetics

• Almost completely absorbed but heavily first-pass metabolized, so oral bioavailability is only about 25 percent and varies widely.
• Immediate-release half-life is 3-6 hours, while long-acting capsules provide 8-11 hours of exposure and once-daily dosing.
• Metabolized by CYP2D6, CYP1A2, and CYP2C19, so both CYP2D6 poor metabolizer status and enzyme inhibitors raise concentrations.
• Highly protein bound at about 90 percent and highly lipophilic, giving rapid brain penetration and central effects.
• Hepatic impairment markedly increases exposure and requires lower doses, while renal impairment has little effect on clearance.

Dosing

• Performance anxiety off-label: 10-40 mg PO taken 30 to 60 minutes before the event, with a test dose at home before first real use.
• Akathisia off-label: 10-20 mg PO two to four times daily, usually 30-80 mg/day, titrated against pulse and blood pressure.
• Lithium-induced tremor off-label: 10-40 mg/day PO in divided doses, or as needed before situations where tremor matters most.
• Essential tremor on label: start 40 mg PO twice daily and titrate to 120-320 mg/day divided, using the long-acting form for adherence.
• Reduce the dose in hepatic impairment and in known CYP2D6 poor metabolizers, who show substantially higher plasma concentrations.
• Taper over 1 to 2 weeks when stopping chronic therapy, since abrupt withdrawal can precipitate angina, arrhythmia, or myocardial infarction.

Adverse effects

• Fatigue, bradycardia, hypotension, dizziness, and cold extremities are the common dose-related effects across all indications.
• Bronchospasm can be severe or fatal in asthma and in significant chronic obstructive pulmonary disease, which are effective contraindications.
• It masks the adrenergic warning signs of hypoglycemia except sweating and can delay glucose recovery in insulin-treated diabetes.
• Sleep disturbance, vivid dreams, and fatigue are reported, while the historical association with depression is weak and inconsistent.
• Abrupt discontinuation after chronic use can cause rebound tachycardia, hypertension, angina, and myocardial infarction.
• Sexual dysfunction, exercise intolerance, and worsening peripheral vascular symptoms are common reasons patients stop the drug.

Monitoring

• Check heart rate and blood pressure before starting and after each dose increase; hold or reduce the dose for pulse below 55 beats per minute.
• Screen specifically for asthma, chronic obstructive pulmonary disease, decompensated heart failure, and high-degree atrioventricular block.
• In diabetes, review glucose monitoring practice, since the usual adrenergic hypoglycemia warning signs will be blunted.
• For akathisia, measure response with the Barnes Akathisia Rating Scale and reassess the offending antipsychotic dose at the same time.
• Confirm that as-needed users know a single dose is for a discrete event and that daily escalation is not the intended pattern.

Interactions

• CYP2D6 inhibitors such as fluoxetine, paroxetine, bupropion, and quinidine substantially raise propranolol levels and adverse effects.
• CYP1A2 inhibitors including fluvoxamine, ciprofloxacin, and viloxazine also increase exposure, while smoking cessation raises levels further.
• Additive bradycardia and atrioventricular block with verapamil, diltiazem, digoxin, amiodarone, and cholinesterase inhibitors.
• Propranolol raises thioridazine and chlorpromazine concentrations and can potentiate hypotension with antipsychotics.
• Blunts the effect of beta-agonist rescue inhalers and can antagonize epinephrine used for anaphylaxis, complicating emergency treatment.

Special populations

• Pregnancy: crosses the placenta and may cause fetal growth restriction, bradycardia, and neonatal hypoglycemia; use when clearly indicated.
• Lactation: relative infant dose is low and propranolol is generally considered compatible with breastfeeding with routine infant monitoring.
• Pediatric: Hemangeol is labeled for infantile hemangioma, and off-label psychiatric use in children requires cardiac screening first.
• Geriatric: start low because of bradycardia, orthostatic hypotension, fall risk, and reduced hepatic clearance with age.
• Hepatic impairment requires dose reduction, while renal impairment generally does not because metabolism is hepatic.

Clinical pearls

• It treats the body of anxiety, not the worry; pair it with therapy rather than using it daily.
• Asthma is a hard stop, and in diabetes it hides every hypoglycemia cue except sweating.
• Never stop chronic beta-blockade abruptly; taper over 1 to 2 weeks to avoid rebound ischemia.