Propranolol

Propranolol

Clinical data
Pronunciation	/proʊˈprænəˌlɑːl/
Trade names	Inderal, others
AHFS/Drugs.com	Monograph
License data	US DailyMed: Propranolol
Pregnancy category	AU: C
Routes of administration	Oral, rectal, intravenous
ATC code	C07AA05 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) CA: ℞-only UK: POM (Prescription only) US: WARNING[1]Rx-only EU: Rx-only
Pharmacokinetic data
Bioavailability	26%
Protein binding	90%
Metabolism	Liver (extensive) CYP1A2, CYP2D6; minor: CYP2C19, CYP3A4
Metabolites	N-desisopropylpropranolol, 4'-hydroxypropanolol
Elimination half-life	4–5 hours
Excretion	Kidney (<1%)
Identifiers
IUPAC name (RS)-1-(1-methylethylamino)-3-(1-naphthyloxy)propan-2-ol
JSmol)	Interactive image
Chirality	Racemic mixture
Melting point	96 °C (205 °F)
SMILES OC(COC1=C2C=CC=CC2=CC=C1)CNC(C)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
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Propranolol, sold under the brand name Inderal among others, is a medication of the

Propranolol is used for treating various conditions, including:

Cardiovascular

• Hypertension
• variant angina
  )
• Myocardial infarction
• lithium therapy
• portal vein
  pressure
• Prevention of esophageal variceal bleeding and ascites
• Anxiety
• Hypertrophic cardiomyopathy

While once a first-line treatment for

Propranolol is not recommended for the treatment of high blood pressure 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.[13]

Psychiatric

Propranolol is occasionally used to treat

• Post-traumatic stress disorder (PTSD) and specific phobias
• Aggressive behavior of patients with brain injuries^[17]
• Treating the excessive drinking of fluids in
  psychogenic polydipsia^[18][19]

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.[26] 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".^[27]

Other uses

• Essential tremor. Evidence for use for akathisia however is insufficient^[28]
• Migraine and cluster headache prevention^[29][30] and in primary exertional headache^[2][31]
• Hyperhidrosis (excessive sweating)^{[citation needed]}
• Infantile hemangioma Propranolol showed a higher rate of complete response than atenolol.^[32]
• Glaucoma^{[citation needed]}
• Thyrotoxicosis by deiodinase inhibition^{[citation needed}
  ]

Propranolol may be contraindicated in people with:^[34]

• Reversible airway diseases, particularly asthma or chronic obstructive pulmonary disease (COPD)
• Slow heart rate (bradycardia) (<60 beats/minute)
• Sick sinus syndrome
• Atrioventricular block (second- or third-degree)
• Shock
• Severe low blood pressure

Adverse effects

Propranolol should be used with caution in people with:^[34]

• hypoglycaemia
  may be masked
• 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

Pregnancy and lactation

Propranolol, like other beta blockers, is classified as

Most β-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.^[36] 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".^{[35][36][37][38]}

Overdose

In overdose propranolol is associated with

Since beta blockers are known to relax the cardiac muscle and to constrict the smooth muscle, 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:[34]

• Verapamil
• Epinephrine
  (adrenaline)
• β₂-adrenergic receptor agonists
  • Salbutamol, levosalbutamol, formoterol, salmeterol, clenbuterol etc.
• Clonidine
• Ergot alkaloids
• Isoprenaline (isoproterenol)
• Nonsteroidal anti-inflammatory drugs (NSAIDs)
• Quinidine
• Cimetidine
• Lidocaine
• Phenobarbital
• Rifampicin
• Fluvoxamine (slows down the metabolism of propranolol significantly, leading to increased blood levels of propranolol)^[41]

Pharmacology

Pharmacodynamics

Propranolol is classified as a competitive non-cardioselective sympatholytic

Both enantiomers of propranolol have a local anesthetic (topical) effect, which is normally mediated by blockade of voltage-gated sodium channels. 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.^[65][66][67]

Mechanism of action

Propranolol is a non-selective beta receptor antagonist.^[60] This means that it does not have preference to β₁ or β₂ receptors. It competes with sympathomimetic neurotransmitters for binding to receptors, which inhibits sympathetic stimulation of the heart. Blockage of neurotransmitter binding to β₁ receptors on cardiac myocytes inhibits activation of adenylate cyclase, which in turn inhibits cAMP synthesis leading to reduced PKA (Protein Kinase A) activation. This results in less calcium influx to cardiac myocytes through voltage gated L-type calcium channels meaning there is a decreased sympathetic effect on cardiac cells, resulting in antihypertensive effects including reduced heart rate and lower arterial blood pressure.^[68] Blockage of neurotransmitter binding to β₂ receptors on smooth muscle cells will increase contraction, which will increase hypertension.

Pharmacokinetics

Propranolol is rapidly and completely absorbed, with peak plasma levels achieved about 1–3 hours after ingestion. More than 90% of the drug is found bound to plasma protein in the blood.

Newer, more cardio-selective beta blockers (such as bisoprolol, nebivolol, carvedilol, or metoprolol) are now used preferentially in the treatment of hypertension.^[72]

Society and culture

In a 1987 study by the International Conference of Symphony and Opera Musicians, it was reported that 27% of interviewed members said they used beta blockers such as propranolol for musical performances.^[73] For about 10–16% of performers, their degree of stage fright is considered pathological.^[73][74] Propranolol is used by musicians, actors, and public speakers for its ability to treat anxiety symptoms activated by the sympathetic nervous system.^[75] It has also been used as a performance-enhancing drug in sports where high accuracy is required, including archery, shooting, golf,^[76] and snooker.^[76] In the 2008 Summer Olympics, 50-metre pistol silver medalist and 10-metre air pistol bronze medalist Kim Jong-su tested positive for propranolol and was stripped of his medals.^[77]

Brand names

Propranolol was first marketed under the brand name Inderal, manufactured by ICI Pharmaceuticals (now AstraZeneca), in 1965. "Inderal" is a quasi-anagram of "Alderlin", the trade name of pronethalol (which propranolol replaced); both names are an homage to Alderley Park, the ICI headquarters where the drugs were first developed.^[78]

Propranolol is also marketed under brand names Avlocardyl, Deralin, Dociton, Inderalici, InnoPran XL, Indoblok,^[79] Sumial, Anaprilin, and Bedranol SR (Sandoz). In India it is marketed under brand names such as Ciplar and Ciplar LA by Cipla. Hemangeol, a 4.28 mg/mL solution of propranolol, is indicated for the treatment of proliferating infantile hemangioma.^[80]

References