Propranolol - Wikipedia PDF

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Summary

Lecture about propanolol pharmacology ...

Description

Propranolol Propranolol, sold under the brand name Inderal among others, is a medication of the beta blocker class.[1] It is used to treat high blood pressure, a number of types of irregular heart rate, thyrotoxicosis, capillary hemangiomas, performance anxiety, and essential tremors.[1][2][3] It is used to prevent migraine headaches, and to prevent further heart problems in those with

angina or previous heart attacks.[1] It can be taken by mouth or by injection into a vein.[1] The formulation that is taken by mouth comes in short-acting and longacting versions.[1] Propranolol appears in the blood after 30 minutes and has a maximum effect between 60 and 90 minutes when taken by mouth.[1][4]

Propranolol

Clinical data Pronunciation

prəʊˈpranəlɒl

Trade names

Inderal, others

AHFS/Drugs.com

Monograph

License data

EUEMA:by INN USDailyMed:Propranolol USFDA:Propranolol

Pregnancy category

AU: C

US: C (Risk not ruled Routes of administration ATC code

out) By mouth, rectal, intravenous C07AA05 (WHO ) Legal status

Legal status

AU: S4 (Prescription only) CA: ℞-only UK: POM (Prescription only) US: ℞-only

Pharmacokinetic data Bioavailability

26%

Protein binding

90%

Metabolism

Liver (extensive) 1A2, 2D6; minor: 2C19, 3A4

Metabolites

Ndesisopropylpropranolol, 4'-hydroxypropanolol

Elimination half-life

4–5 hours

Excretion

Kidney (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

[54]

5-HT 2B

457–513 (+) 166–316 (–) 61,700 (+)

5-HT 2C 5,010 (–)

Rat

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 βadrenergic 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 βadrenoceptor 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-HT1A, 5-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 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

…

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 metabolism. Hepatic impairment therefore increases its bioavailability. The main metabolite 4hydroxypropranolol, 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. Toxic levels are associated with plasma concentrations above 2000mg/l.

History 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 (-OCH2-) 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 bisoprolol, nebivolol, carvedilol, or metoprolol) are now used preferentially in the treatment of hypertension.[68]

Society and culture 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 performanceenhancing drug in sports where high accuracy is required, including archery, shooting, golf[72] and snooker.[72] 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.[73]

Brand names

…

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]

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