propranolol

Propranolol
Systematic (IUPAC) name
(RS)-1-(isopropylamino)-3-(1-naphthyloxy)propan-2-ol
Identifiers
CAS number	525-66-6
ATC code	C07AA05
PubChem	4946
DrugBank	APRD00194
ChemSpider	4777
Chemical data
Formula	C16H21NO2
Mol. mass	259.34 g/mol
SMILES	eMolecules & PubChem
Pharmacokinetic data
Bioavailability	26%
Metabolism	hepatic (extensive)
Half life	4-5 hours
Excretion	renal <1%
Therapeutic considerations
Licence data	US FDA:link
Pregnancy cat.	C(AU) C(US)
Legal status	Prescription Only (S4)(AU) POM(UK) ℞-only(US)
Routes	oral, iv
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Propranolol (INN) is a non-selective beta blocker mainly used in the treatment of hypertension. It was the first successful beta blocker developed. It is the only drug proven effective for the prophylaxis of migraines in children. Propranolol is available in generic form as propranolol hydrochloride, as well as an AstraZeneca and Wyeth product under the trade names Inderal, Inderal LA, Avlocardyl (also available in prolonged absorption form named "Avlocardyl Retard"), Deralin, Dociton, Inderalici, InnoPran XL, Sumial, Anaprilinum (depending on marketplace and release rate).

History and development

Scottish scientist and St. Andrews graduate James W. Black successfully developed propranolol in the late 1950s. In 1988, he was awarded the Nobel Prize in Medicine for this discovery. Propranolol was derived 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 a methoxy 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.

Newer, more selective beta-blockers (such as nebivolol) are now used in the treatment of hypertension.

Indications

An 80 mg capsule of Propranolol.

Propranolol is indicated for the management of various conditions including:

• Hypertension
• Angina pectoris
• Tachyarrhythmias
• Myocardial infarction
• Control of tachycardia/tremor associated with anxiety, hyperthyroidism or lithium therapy.
• Essential tremor
• Migraine prophylaxis
• Cluster headaches prophylaxis
• Tension headache (Off the label use)

• There has been some experimentation in psychiatric areas:^[1]
  • Treating the excessive drinking of fluids in psychogenic polydipsia,^[2][3]
  • Antipsychotic-induced akathisia,^[4]
  • Aggressive behavior of patients with brain injuries^[5]
  • Post-traumatic stress disorder
• Glaucoma

While 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 evidence is increasing that the most frequently used beta-blockers at usual doses carry an unacceptable risk of provoking type 2 diabetes. ^[6]

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

Off-label and investigational use

Propranolol is often used by musicians and other performers to prevent stage fright. It has been taken by surgeons to reduce their own inate hand tremors during surgery.^[7]

Propranolol is currently being investigated as a potential treatment for post-traumatic stress disorder. ^[8][9][10]. Propranolol works to inhibit the actions of norepinephrine, a neurotransmitter that enhances memory consolidation. Studies have shown that individuals given propranolol immediately after a traumatic experience show less severe symptoms of PTSD compared to their respective control groups that did not receive the drug (Vaiva et al., 2003). However, results remain inconclusive as to the success of propranolol in treatment of PTSD.

Recent evidence (June 2008) suggests that propranolol can be used to treat severe hemangiomas^[11]. This treatment may prove superior to corticosteroids, as propranolol has far less side effects.

Propranolol along with a number of other membrane-acting drugs have been investigated for possible effects on P. falciparum and so the treatment of malaria. In vitro positive effects until recently had not been matched by useful in vivo anti-parasite activity against P. vinckei,^[12] or P. yoelii nigeriensis.^[13] However a single study from 2006 has suggested that propranolol may reduce the dosages required for existing drugs to be effective against P. falciparum by 5- to 10-fold, suggesting a role for combination therapies.^[14]

Precautions and contradications

Propranolol should be used with caution in patients with:^[15]

• Diabetes mellitus or hyperthyroidism, since signs and symptoms of hypoglycaemia may be masked. Also, propranolol may affect blood sugar levels
• 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

Propranolol is contraindicated in patients with:^[15]

• Reversible airways disease, particularly asthma or chronic obstructive pulmonary disease (COPD)
• Bradycardia (<60 beats/minute)
• Sick sinus syndrome
• Atrioventricular block (second or third degree)
• Shock
• Severe hypotension
• Uncontrolled congestive heart failure
• Cocaine toxicity [per American Heart Association guidelines, 2005]

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 hypoglycemia and bradycardia.^{[citation needed]}

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.^{[citation needed]}

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 and may be up to 12 hours, if the single dose is high enough (e.g., 80 mg). Effective plasma concentrations are between 10–100 ng/mL.

Toxic levels are associated with plasma concentrations above 2000 ng/ml.

Mechanism of action

Propranolol is a non-selective beta blocker, that is, it blocks the action of epinephrine and norepinephrine on both β₁- and β₂-adrenergic receptors. It has little intrinsic sympathomimetic activity (ISA) but has strong membrane stabilizing activity (only at high blood concentrations, eg overdosage). Research has also shown that propranolol has inhibitory effects on the norepinephrine transporter and/or stimulates norepinephrine release (present experiments have shown that the concentration of norepinephrine is increased in the synapse but do not have the ability to discern which effect is taking place).^[16] Since propranolol blocks β-adrenoceptors, the increase in synaptic norepinephrine only results in α-adrenergic activation, with the α1-adrenoceptor being particularly important for effects observed in animal models. Therefore, some have suggested that it be looked upon as an indirect α1 agonist as well as a β antagonist. Probably owing to the effect at the α1-adrenoceptor, the racemate and the individual enantiomers of propranolol have been shown to substitute for cocaine in rats, with the most potent enantiomer being S-(-)-propranolol. Both enantiomers of the drug have a local anesthetic (topical) effect. In addition, some evidence suggests that propranolol may function as a partial agonist at one or more serotonin receptors (possibly 5-HT_1B).

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:^[15]

• verapamil
• epinephrine
• β₂-adrenergic receptor agonists
• clonidine
• ergot alkaloids
• isoprenaline
• non-steroidal anti-inflammatory drugs
• quinidine
• cimetidine
• lidocaine
• phenobarbital
• rifampicin
• Fluvoxamine slows down the metabolism of propranolol significantly leading to increased blood levels of propranolol.^[17]

Dosage

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

• Hypertension, angina, essential tremor
  • 120–320 mg daily in divided doses
  • Sustained-release formulations are available in some markets.

• Migraine Prophylaxis
  • The initial dose is 80 mg Inderal daily in divided doses. The usual effective dose range is 160 mg to 240 mg per day.
    • The dosage may be increased gradually to achieve optimum migraine prophylaxis. If a satisfactory response is not obtained within four to six weeks after reaching the maximum dose, Inderal therapy should be discontinued.

• Tachyarrhythmia, anxiety (GAD), hyperthyroidism
  • 10–40 mg 3–4 times daily

• Performance anxiety
  • 5–10 mg 30min or 1.5hrs before and after performance, optionally 5–10 mg night before. Up to 40 mg if necessary, but side-effects may present. ^[18]

Intravenous (IV) propranolol may be used in acute arrhythmia or thyrotoxic crisis.^[19]

References

External links

• Historical Remarks about Propranolol and its inventor
• Scientific American Interview with James McGaugh
• CBS NEWS 60 Minutes: A Pill To Forget
• Therapeutic Forgetting: The Legal and Ethical Implications of Memory Dampening (Vanderbilt Law Review)