Pharmacology

Pharmacodynamics[edit]

Propranolol[37]
Site Ki (nM) Species Ref
5-HT1A 55–272 Human [38][39]
5-HT1B 56–85 Rat [40][41]
5-HT1D 4,070 Pig [42]
5-HT2A 4,280 Human [43]
5-HT2B 457–513 (+)
166–316 ()
Human [44]
5-HT2C 61,700 (+)
5,010 ()
736–2,457
Human
Human
Rodent
[44]
[44]
[45][39]
5-HT3 >10,000 Human [46]
α1 ND ND ND
α2 1,297–2,789 Rat [47]
β1 0.02–2.69 Human [48][49]
β2 0.01–0.61 Human [48][49]
β3 450 Mouse [50]
D1 >10,000 Human [39]
D2 >10,000 Human [39]
H1 >10,000 Human [51]
SERT 3,700 Rat [52]
NET 5,000 (IC50) Rat [53]
DAT 29,000 (IC50) Rat [53]
VDCC >10,000 Rat [54]
Values are Ki (nM), unless otherwise noted. The smaller the value, the more strongly the drug binds to the site.

Propranolol is classified as a competitive non-cardioselective sympatholytic beta blocker that crosses the blood–brain barrier. It is lipid soluble and also has sodium channel blocking effects. Propranolol is a non-selective β-adrenergic receptor antagonist, or beta blocker;[55] that is, it blocks the action of epinephrine (adrenaline) and norepinephrine (noradrenaline) at 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. overdose).[56] Propranolol is able to cross the blood–brain barrier and exert effects in the central nervous system in addition to its peripheral activity.[21]

In addition to blockade of adrenergic receptors, propranolol has very weak inhibitory effects on the norepinephrine transporter and/or weakly stimulates norepinephrine release (i.e., the concentration of norepinephrine is increased in the synapse).[57][53] Since propranolol blocks β-adrenoceptors, the increase in synaptic norepinephrine only results in α-adrenoceptor activation, with the α1-adrenoceptor being particularly important for effects observed in animal models.[57][53] Therefore, it can be looked upon as a weak indirect α1-adrenoceptor agonist in addition to potent β-adrenoceptor antagonist.[57][53] In addition to its effects on the adrenergic system, there is evidence that indicates that propranolol may act as a weak antagonist of certain serotonin receptors, namely the 5-HT1A5-HT1B, and 5-HT2B receptors.[58][59][44] The latter may be involved in the effectiveness of propranolol in the treatment of migraine at high doses.[44]

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.[60][61][62]

Mechanism of action[edit]

Propranolol is a competitive antagonist of beta-1-adrenergic receptors in the heart.[63] It competes with sympathomimetic neurotransmitters for binding to receptors, which inhibits sympathetic stimulation of the heart. Blockage of neurotransmitter binding to beta 1 receptors on cardiac myocytes inhibits activation of adenylate cyclase, which in turn inhibits cAMP synthesis leading to reduced PKA 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.[64]

Pharmacokinetics[edit]

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.[64] Coadministration with food appears to enhance bioavailability.[65] Despite complete absorption, propranolol has a variable bioavailability due to extensive first-pass metabolismHepatic 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. Most of the metabolites are excreted in the urine.[64]

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).[66] Effective plasma concentrations are between 10 and 100 mg/l.[citation needed] Toxic levels are associated with plasma concentrations above 2000 mg/l.[citation needed]

History[edit]

British scientist James W. Black developed propranolol in the 1960s.[67] It was the first beta-blocker effectively used in the treatment of coronary artery disease and hypertension.[68] In 1988, Black was awarded the Nobel Prize in Medicine for this discovery. Propranolol was inspired by the early β-adrenergic antagonists dichloroisoprenaline and pronethalol. The key difference, which was carried through to essentially all subsequent beta blockers, was the inclusion of an oxymethylene group (-O-CH2-) between the aryl and ethanolamine moieties of pronethalol, 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 bisoprololnebivololcarvedilol, or metoprolol) are now used preferentially in the treatment of hypertension.[68]

Society and culture[edit]

In a 1987 study by the International Conference of Symphony and Opera Musicians, it was shown that 27% of interviewed members admitted to using beta blockers such as propranolol for musical performances.[69] For about 10–16% of performers, their degree of stage fright is considered pathological.[69][70] Propranolol is used by musicians, actors, and public speakers for its ability to treat anxiety symptoms activated by the sympathetic nervous system.[71] It has also been used as a performance-enhancing drug in sports where high accuracy is required, including archeryshootinggolf[72] and snooker.[72] In the 2008 Summer Olympics50-metre pistol silver medalist and 10-metre air pistol bronze medalist Kim Jong-su tested positive for propranolol and was stripped of his medals.[73]

Brand names[edit]

Original propranolol was marketed in 1965, under the brand name Inderal and manufactured by ICI Pharmaceuticals (now AstraZeneca). Propranolol is also marketed under brand names Avlocardyl, Deralin, Dociton, Inderalici, InnoPran XL, 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.[74]