Propranolol

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[[Image:{{{image\|Propranolol.png}}}\|{{{width\|220}}}px\|Propranolol chemical structure]] Propranolol
1-(isopropylamino)- 3-(naphthalen-1-yloxy)propan-2-ol IUPAC name
CAS number 525-66-6	}}}
PubChem 4946	DrugBank APRD00194
Chemical formula	C₁₆H₂₁NO₂
Molecular weight	259.34 g/mol
Bioavailability	30–70% (oral)
Metabolism	hepatic (extensive)
Elimination half-life	3–4 hours
Excretion	renal <1%
Pregnancy category	C (Australia) C (U.S.)
Legal status	Schedule 4 (Aust) POM (UK) Rx-only(U.S.)
Routes of administration	oral, IV

Propranolol (INN) (IPA: Template:IPA) is a non-selective beta blocker mainly used in the treatment of hypertension. It was the first successful beta blocker developed. Propranolol is commonly marketed by AstraZeneca under the trade name Inderal.

1 History and development
2 Pharmacology
3 Pharmacokinetics
4 Clinical use
5 References
6 External links

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History and development

Scottish scientist James W. Black successfully developed propranolol in the late 1950s. He was awarded the Nobel Prize in Medicine for this discovery in 1988.

Propranolol was developed 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 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.

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Pharmacology

Main article: Beta blocker

Propranolol is a non-selective beta blocker, that is, it blocks the action of epinephrine on both β₁- and β₂-adrenergic receptors. It has little intrinsic sympathomimetic activity (ISA) but has strong membrane stabilising activity.

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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 indicates 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.

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Clinical use

Main article: Beta blocker

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Indications

Propranolol is indicated for the management of various conditions including:

Hypertension
Angina
Tachyarrhythmias
Myocardial infarction
Control of tachycardia/tremor associated with anxiety and hyperthyroidism
Essential tremor
Migraine prophylaxis
Tetralogy of Fallot
Phaeochromocytoma (along with α blocker)

(Rossi, 2006)

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

Propranolol is currently being investigated as a potential treatment for post-traumatic stress disorder [1].

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Precautions/contraindications

Propranolol should be used with caution in patients 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, may be worsened
Other drugs with bradycardic effects

(Rossi, 2006)

Propranolol is contraindicated in patients with:

Reversible airways disease, particularly asthma or chronic obstructive pulmonary disease (COPD)
Bradycardia (<50 beats/minute)
Sick sinus syndrome
Atrioventricular block (second or third degree)
Shock
Severe hypotension
Uncontrolled congestive heart failure

(Rossi, 2006)

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Adverse effects

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

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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. This is especially the case for a lipophilic drug like propranolol. Breastfeeding is not recommended in patients receiving propranolol therapy.

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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 verapamil, epinephrine, β₂-adrenergic receptor agonists, clonidine, ergot alkaloids, isoprenaline, non-steroidal anti-inflammatory drugs, quinidine, cimetidine, lidocaine, phenobarbital and rifampicin. (Rossi, 2006)

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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.
Tachyarrhythmia, anxiety, hyperthyroidism
- 10–40 mg 3–4 times daily

Intravenous (IV) propranolol may be used in acute arrhythmia or thyrotoxic crisis (Joint Formulary Committee, 2004).

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References

Joint Formulary Committee. British National Formulary, 47th edition. London: British Medical Association and Royal Pharmaceutical Society of Great Britain; 2004.
Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006.

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