Propranolol

Not to be confused with Profadol, Propanol, or Propofol.

Propranolol (INN)

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Systematic (IUPAC) name
(RS)-1-(1-methylethylamino)-3-(1-naphthyloxy)propan-2-ol
Clinical data
Trade names	Inderal
AHFS/Drugs.com	monograph
Licence data	US FDA:link
Pregnancy category	AU: C US: C (Risk not ruled out)
Legal status	AU: S4 (Prescription only) CA: ℞-only UK: POM (Prescription only) US: ℞-only
Routes of administration	Oral, rectal, IV
Pharmacokinetic data
Bioavailability	26%
Metabolism	hepatic (extensive) 1A2, 2D6; minor: 2C19, 3A4
Biological half-life	4–5 hours
Excretion	renal <1%
Identifiers
CAS Number	525-66-6 Y
ATC code	C07AA05 (WHO)
PubChem	CID: 4946
IUPHAR/BPS	564
DrugBank	DB00571 Y
ChemSpider	4777 Y
UNII	9Y8NXQ24VQ Y
KEGG	D08443 Y
ChEBI	CHEBI:8499 Y
ChEMBL	CHEMBL27 Y
Chemical data
Formula	C16H21NO2
Molecular mass	259.34 g/mol
SMILES CC(NCC(O)COC1=C(C=CC=C2)C2=CC=C1)C
InChI InChI=1S/C16H21NO2/c1-12(2)17-10-14(18)11-19-16-9-5-7-13-6-3-4-8-15(13)16/h3-9,12,14,17-18H,10-11H2,1-2H3 Y Key:AQHHHDLHHXJYJD-UHFFFAOYSA-N Y
(verify)

Propranolol is a sympatholytic nonselective beta blocker. It is used to treat high blood pressure, a number of heart dysrhythmias, thyrotoxicosis, and essential tremors. It is used to prevent migraine headaches, and to prevent further heart problems in those with angina or previous heart attacks. It comes in both oral and intravenous forms.

It should not be used in those with an already slow heart rate and most of those with heart failure. Quickly stopping the medication in those with coronary artery disease may worsen symptoms. It may worsen the symptoms of asthma. Common side effects include nausea, abdominal pain, and constipation. Greater care is recommended in those with liver or kidney problems. It may possibly cause harmful effects to the infant if taken during pregnancy.

It was the first successful beta blocker developed. It is on the World Health Organization's List of Essential Medicines, a list of the most important medications needed in a basic health system. Propranolol is available in generic form.

Medical uses

An 80 mg capsule of extended-release propranolol

A mixture of 20 mg and 10 mg propranolol tablets

Propranolol is indicated for the management of various conditions, including:

• Hypertension
• Angina pectoris (with the exception of variant angina)
• Tachyarrhythmias
• Myocardial infarction
• Control of tachycardia/tremor associated with anxiety, panic, hyperthyroidism, or lithium therapy
• Essential tremor
• Migraine prevention
• Cluster headache prevention
• Hyperhidrosis
• Proliferating infantile hemangioma
• Some experimentation has been conducted in psychiatric areas:
  • Treating the excessive drinking of fluids in psychogenic polydipsia
  • Antipsychotic-induced akathisia
  • Aggressive behavior of patients with brain injuries
  • Post-traumatic stress disorder
  • Calming down individuals with phobias by sedative effects
  • Performance anxiety
  • Facial blushing
• Glaucoma
• Thyrotoxicosis by deiodinase inhibition
• Primary exertional headache

While once a first-line treatment for hypertension, the role for beta blockers was downgraded in June 2006 in the United Kingdom to fourth-line, as they do not perform as well as 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.

Propranolol is not recommended for the treatment of hypertension by the Eighth Joint National Committee (JNC 8) because a higher rate of the primary composite outcome of cardiovascular death, myocardial infarction, or stroke compared to an angiotensin receptor blocker was noted in one study.

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

Other uses

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

Propranolol is being investigated as a potential treatment for post-traumatic stress disorder(PTSD). Propranolol works to inhibit the actions of norepinephrine, a neurotransmitter that enhances memory consolidation. Individuals given propranolol immediately after trauma experienced fewer stress-related symptoms and lower rates of PTSD than respective control groups who did not receive the drug. Propranolol reduces the effects of nightmare-related cardiac activity by keeping sinus rhythm low during nightmares, as a higher pulse and increased adrenaline are associated with severe nightmares. However, results remain inconclusive as to the success of propranolol in treatment of PTSD, including nightmares experienced by those with PTSD.

Ethical and legal questions have been raised surrounding the use of propranolol-based medications for use as a "memory damper", including: altering memory-recalled evidence during an investigation, modifying behavioral response to past (albeit traumatic) experiences, the regulation of these drugs, and others. However, Hall and Carter have argued that many such objections are "based on wildly exaggerated and unrealistic scenarios that ignore the limited action of propranolol in affecting memory, underplay the debilitating impact that PTSD has on those who suffer from it, and fail to acknowledge the extent to which drugs like alcohol are already used for this purpose."

Propranolol may be used to treat severe infantile hemangiomas (IHs). This treatment shows promise as being superior to corticosteroids when treating IHs. Extensive clinical case evidence and a small controlled trial support its efficacy.

Volunteers given the beta blocker propranolol scored lower on a range of psychological tests designed to reveal any racist attitudes than a group who took a placebo. The amygdala is involved in processing emotion, including fear, and has been shown to be inhibited by propranolol.

Adverse effects

See also: Beta_blocker § Adverse_effects

Due to the high penetration across the blood-brain barrier, lipophilic beta blockers such as propranolol and metoprolol are more likely than other less lipophilic beta blockers to cause sleep disturbances such as insomnia and vivid dreams and nightmares.

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

Precautions and contraindications

Propranolol should be used with caution in people 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, which may be worsened
• Other drugs with bradycardic effects

Propranolol is contraindicated in patients with:

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

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.

Most beta-blocking agents appear in the milk of lactating women. However, propranolol is highly bound to proteins in the bloodstream and is distributed into breast milk at very low levels. These low levels are not expected to pose any risk to the breastfeeding infant, and the American Academy of Pediatrics considers propranolol therapy "generally compatible with breastfeeding".

Interactions

Since beta blockers are known to relax the cardiac muscle and to constrict the smooth muscle, these beta adrenergic antagonists, 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
  • Salbutamol, levosalbutamol, formoterol, salmeterol, etc.
• clonidine
• ergot alkaloids
• isoprenaline
• nonsteroidal anti-inflammatory drugs
• quinidine
• cimetidine
• lidocaine
• phenobarbital
• rifampicin
• Fluvoxamine slows down the metabolism of propranolol significantly, leading to increased blood levels of propranolol.

Pharmacokinetics

Propranolol is rapidly and completely absorbed, with peak plasma levels achieved about 1–3 hours after ingestion. Coadministration with food appears to enhance bioavailability. Despite complete absorption, propranolol has a variable bioavailability due to extensive first-pass metabolism. Hepatic impairment therefore increases 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 and 100 mg/l. Toxic levels are associated with plasma concentrations above 2000 mg/l.

Mechanism of action

Propranolol is a nonselective 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, but has strong membrane stabilizing activity (only at high blood concentrations, e.g. overdosage). Propranolol has inhibitory effects on the norepinephrine transporter and/or stimulates norepinephrine release (the concentration of norepinephrine is increased in the synapse). 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, it can be looked upon as an indirect α1 agonist, as well as a β antagonist. Probably owing to the effect at the α1-adrenoceptor, the racemic and the individual enantiomers of propranolol have been shown to substitute for cocaine in rats, with the most potent enantiomer being S-(–)-propranolol. In addition, some evidence suggests propranolol may function as a partial agonist at one or more serotonin receptors (possibly 5-HT_1B).

Both enantiomers of the drug have a local anesthetic (topical) effect, which is normally mediated by blockade of voltage-gated sodium channels. Few studies have demonstrated propranolol's ability to block cardiac, neuronal, and skeletal voltage-gated sodium channels, accounting for its known "membrane stabilizing effect" and antiarrhythmic and other central nervous system effects.

History

Main article: Discovery and development of beta-adrenergic receptor antagonists (beta-blockers)

British scientist James W. Black developed propranolol in the 1960s. 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 an oxymethylene group into the aryl ethanolamine 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 cardio-selective beta blockers (such as nebivolol, carvedilol, or metoprolol) are now used in the treatment of hypertension.

Society and culture

In a 1987 study by the International Conference of Symphony and Opera Musicians, 27% of interviewed members admitted to using beta blockers such as propranolol for musical performances. For about 10-16% of performers, their degree of stage fright is considered pathological. Propranolol is used by musicians, actors, and public speakers for its ability to treat anxiety symptoms activated by the sympathetic nervous system. This can be seen as giving participating individuals an unfair advantage, especially in competitions, akin to the use of performance-enhancing drugs in athletes.

Brandnames

Propranolol is marketed in India under brand names such as Ciplar and Ciplar LA by Cipla, also other brands from AstraZeneca and Wyeth under brand names Inderal, Inderal LA, Avlocardyl, Deralin, Dociton, Inderalici, InnoPran XL, Sumial, Anaprilinum, and Bedranol SR (Sandoz). Hemangeol, a 4.28 mg/mL solution of propranolol, is indicated for the treatment of proliferating infantile hemangioma.

Research

In 2015, a trial in women with epithelial ovarian cancer showed that the intake of a nonselective β-blocker was associated with a longer survival compared to a β₁-selective β-blocker or no β-blocker. Currently, an interventional study is being conducted at the M.D. Anderson Cancer Center to access the feasibility of a nonselective β-blocker plus standard chemotherapy (paclitaxel and carboplatin or possibly docetaxel) to treat ovarian cancer.

See also

• Exaprolol
• Betaxolol
• Cetamolol

External links

• Scientific American Interview with James McGaugh
• U.S. National Library of Medicine: Drug Information Portal - Propranolol