Propranolol

Propranolol (INN) is a non-selective beta blocker mainly used in the treatment of hypertension. It was the first successful beta blocker developed. Propranolol is commonly marketed by Wyeth under the trade name Inderal.

History and development

Scottish scientist James W. Black successfully developed propranolol in the late 1950s. He was awarded the Nobel Prize in Medicine for this discovery in 1988.

Propranolol was developed from the early β-adrenergic antagonists dichloroisoprenaline and pronethalol. The key structural modification, which was carried through to essentially all subsequent beta blockers, was the insertion of an oxymethylene bridge into the arylethanolamine structure of pronethalol thus greatly increasing the potency of the compound. This also apparently eliminated the carcinogenicity found with pronethalol in animal models.

Pharmacology

Propranolol is a non-selective beta blocker, that is, it blocks the action of epinephrine on both β1- and β2-adrenergic receptors. It has little intrinsic sympathomimetic activity (ISA) but has strong membrane stabilising activity.

Pharmacokinetics

Propranolol is rapidly and completely absorbed, with peak plasma levels achieved approximately 1–3 hours after ingestion. Co-administration with food appears to enhance bioavailability. Despite complete absorption, propranolol has a variable bioavailability due to extensive first-pass metabolism. Hepatic impairment will therefore increase its bioavailability. The main metabolite 4-hydroxypropranolol, with a longer half-life (5.2–7.5 hours) than the parent compound (3–4 hours), is also pharmacologically active.

Propranolol is a highly lipophilic drug achieving high concentrations in the brain. The duration of action of a single oral dose is longer than the half-life indicates and may be up to 12 hours, if the single dose is high enough (eg. 80 mg). Effective plasma concentrations are between 10–100 ng/mL.

Clinical use

Indications

Propranolol is indicated for the management of various conditions including (Rossi, 2006):

  • Hypertension
  • Angina
  • Tachyarrhythmias
  • Myocardial infarction
  • Control of tachycardia/tremor associated with anxiety and hyperthyroidism
  • Essential tremor
  • Migraine prophylaxis
  • Tetralogy of Fallot
  • Phaeochromocytoma (along with α blocker)

    Whilst once first-line treatment for hypertension, the role for beta-blockers was downgraded in June 2006 in the United Kingdom to fourth-line as they perform less well than other drugs, particularly in the elderly, and there is increasing evidence that the most frequently used beta-blockers at usual doses carry an unacceptable risk of provoking type 2 diabetes.

    It is also used to lower portal vein pressure in portal hypertension and prevent oesophageal variceal bleeding.

    Propranolol is currently being investigated as a potential treatment for post-traumatic stress disorder.

    Precautions/contraindications

    Propranolol should be used with caution in patients with:

  • Diabetes mellitus or hyperthyroidism, since signs and symptoms of hypoglycaemia may be masked
  • Peripheral vascular disease and Raynaud's syndrome, which may be exacerbated
  • Phaeochromocytoma, as hypertension may be aggravated without prior alpha blocker therapy
  • Myasthenia gravis, may be worsened
  • Other drugs with bradycardic effects

    (Rossi, 2006)

    Propranolol is contraindicated in patients with:

  • Reversible airways disease, particularly asthma or chronic obstructive pulmonary disease (COPD)
  • Bradycardia (<50 beats/minute)
  • Sick sinus syndrome
  • Atrioventricular block (second or third degree)
  • Shock
  • Severe hypotension
  • Uncontrolled congestive heart failure

    (Rossi, 2006)

    Adverse effects

    Adverse drug reactions (ADRs) associated with propranolol therapy are similar to other lipophilic beta blockers (see beta blocker).

    Pregnancy and Lactation

    Propranolol, like other beta blockers, is classified as Pregnancy category C in the United States and ADEC Category C in Australia. Beta-blocking agents in general reduce perfusion of the placenta which may lead to adverse outcomes for the neonate, including pulmonary or cardiac complications, or premature birth. The newborn may experience additional adverse effects such as hypoglycaemia and bradycardia.

    Most beta-blocking agents appear in the milk of lactating women. This is especially the case for a lipophilic drug like propranolol. Breastfeeding is not recommended in patients receiving propranolol therapy.

    Interactions

    Beta blockers, including propranolol, have an additive effect with other drugs which decrease blood pressure, or which decrease cardiac contractility or conductivity. Clinically-significant interactions particularly occur with verapamil, epinephrine, β2-adrenergic receptor agonists, clonidine, ergot alkaloids, isoprenaline, non-steroidal anti-inflammatory drugs, quinidine, cimetidine, lidocaine, phenobarbital and rifampicin. (Rossi, 2006)

    Dosage

    The usual maintenance dose ranges for oral propranolol therapy vary by indication.

  • Hypertension, angina, essential tremoro 120–320 mg daily in divided doses.o Sustained-release formulations are available in some markets.
  • Tachyarrhythmia, anxiety, hyperthyroidismo 10–40 mg 3–4 times daily

    Intravenous (IV) propranolol may be used in acute arrhythmia or thyrotoxic crisis (Joint Formulary Committee, 2004).

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