Propranolol (INN) is a non-selective beta blocker mainly used in the treatment of hypertension. It was the first successful beta blocker developed. It is the only drug proven effective for the prophylaxis of migraines in children. Propranolol is available in generic form as propranolol hydrochloride, as well as an AstraZeneca product under the trade names Inderal, Inderal LA, Avlocardyl, Avlocardyl, Deralin, Dociton, Inderalici, InnoPran XL, Sumial (depending on marketplace and release rate). It is also marketed by Wyeth.

History and development

Scottish scientist and St. Andrews graduate James W. Black successfully developed propranolol in the late 1950s. He was awarded the Nobel Prize in Medicine for this discovery in 1988. Black discovered it quite accidentally after doing research with topical antifungal ointments on rats. A similar drug, liasinol had been used for years as antifungal, and he found that all rats with the AB8 recessive gene for vascular constriction died when exposed to liasinol. In spring of 1959, Black discovered that, after twice phosphoralating it (thus, developing propranolol ) the rats with the AB8 gene survived. He used the new drug as an antifungal for several months before discovering its use as a beta blocker.

Propranolol 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.

Pharmacology

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 stabilizing activity (only at high blood concentrations, eg overdosage). Only L-propranolol is a powerful adrenoceptor antagonist, whereas D-propranolol is not. However, both have local anesthetic effect.

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 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.

Toxic levels are associated with plasma concentrations above 2000 ng/ml

Clinical use

Indications

Propranolol is indicated for the management of various conditions including:

• Hypertension
• Angina pectoris
• Tachyarrhythmias
• Myocardial infarction
• Control of tachycardia/tremor associated with anxiety and hyperthyroidism and lithium therapy
• Essential tremor
• Migraine prophylaxis
• Tetralogy of Fallot
• Phaeochromocytoma (along with α blocker)
• Post Traumatic Stress Disorder (experimental)

While once first-line treatment for hypertension, the role for beta-blockers was downgraded in June 2006 in the United Kingdom to fourth-line as they perform less well than 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 also used to lower portal vein pressure in portal hypertension and prevent oesophageal variceal bleeding.

Propranolol is often used by musicians and other performers to prevent stage fright.

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

Precautions/contraindications

Propranolol should be used with caution in patients with:

• Diabetes mellitus or hyperthyroidism, since signs and symptoms of hypoglycaemia may be masked. Also, propranolol may affect blood sugar levels
• 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

Propranolol is contraindicated in patients with:

Research into propranolol and epilepsy

Alexander Massey in the UK, is currently researching the theoretical use of propranolol as an anticonvulsant, and also the benefits of use against myoclonic and partial seizure brain activity is being explored.

Edited Version of an article resleased by A. Massey some months ago... The drug propranolol has, over the past few years, has been subject to many tests attempting to establish a use in treatment of post traumatic stress disorder. However one area that I believe has gone untested is the use in epilepsy. For those unfamiliar with the chemical make up of the drug, propranolol contains C16H21NO2. This key construction binds with beta receptors in the heart, slowing beat rate, but more importantly, propranolol blocks the β1- and β2-adrenergic receptors for epinephrine (formerly known as Adrenaline). We will return to the effects of epinephrine in a moment. - Propranolol also acts as Topical anaesthesia, or a local antithetic effect. This property, combined with adequate perfusion to the brain tissues, provides the basic ‘numbing’ of the overactive/oversensitive synapses that antiepileptic drugs achieve. But to fully understand the benefits and possible problems the propranolol could hold for epileptics we have to take a deeper look at one the key ‘ingredients’ – hydrochloride. The hydrochloric salt aids and is part of the freezer cells that prevent neurotransmitters in the brain from becoming too active, and likewise hydrochloride prevents the receptors from receiving the action potentials If the message has already been sent and received by the brain once before. An example of freezer cells in use would be to place your hand on the desk. You feel the initial impact but then your hand is pretty much sense free. Without freezer cells you would repeatedly feel your hand hitting the desk. We now look at the similarity to photo-sensitive epilepsy. A repeating pattern can trigger a seizure because the synapses do not slow the rate of neurotransmissions caused by a pattern, a high contrast white, or strobe light information in the brain. A use in epilepsy would therefore have to be considered BUT a problem exists. A moment ago we read the propranolol blocks epinephrine receptors. This could be a big problem in terms of seizure prevention. According to the research of Drs. V. A. Karlov and M. A. Gleiser at the Department of Nervous Diseases of the Medical Faculty, Moscow Medical Stomatological Institute: epinephrine repolarization is important to prevent low blood sugars and other related effects that cause seizures. Propranolol as we discussed, prevents epinephrine binding to sites in the brain and also so some extent the release of epinephrine. It would seem then that the drug’s positives and negatives would both cancel themselves out in terms of theoretical effects. But early tests reveal that this is not the case. Very simple UNOFFICIAL early tests cave been carried out and patients suffering with partial seizures with some secondary generalization have shown an improvement (shortening) in the frequency and length of the partial seizures, the secondary generalization rate also appeared to drop. It would seem that the combined effect of calming of the heart and presence of hydrochloride in the brain has beneficial effects for epileptics....

Research into propranolol, memory, conscience, and PTSD

Recent research suggests that propranolol has effects in the brain with regard to emotional processing. Some experiments suggest that emotional memories are recalled and restored every time they are relived, and that propranolol inhibits the restorage of bad memories and so can be used as a treatment for post-traumatic stress disorder (PTSD). There is also evidence that it inhibits the storing of emotional memories in the first place, so that propranolol administered before action in battle can prevent post traumatic stress. In a report in 2001, the President's Council on Bioethics warned that such use as a 'memory-blunter' could endanger society, because "blocking emotional memories risks falsifying our perception and understanding of the world. It risks making shameful acts seem less shameful, or terrible acts less terrible, than they really are"http://www.cognitiveliberty.org/neuro/memory_drugs_sd.html. This has implications for the many patients on beta blockers in society who are not warned that one side effect is an alteration in personality that might only be noticed by those around themhttp://www.unlvrebelyell.com/article.php?ID=10203.

Research into role against malaria

Propranolol along with a number of other membrane-acting drugs have been investigated for possible effects on P. falciparum and so the treatment of malaria. In vitro positive effects until recently had not been matched by useful in vivo anti-parasite activity against P. vinckei, or P. yoelii nigeriensis. However a single study from 2006 has suggested that propranolol may reduce the dosages required for existing drugs to be effective against P. falciparum by 5- to 10-fold, suggesting a role for combination therapies.

Media

• Propranolol as an experimental treatment for Post Traumatic Stress Disorder was a subject of the television show Boston Legal, Season 3, Episode 14, Selling Sickness.
• Propranolol was used by one of the criminals in the TV show CSI: NY episode titled "Some buried bones" , Season 3 Episode 15 (2004-02-17).
• Propranolol was referenced on the Late Show With David Letterman on May 4, 2007 in a mock-advertisement.
• Dr. Linguard committed suicide in the Season 18 premiere for Law & Order by overdosing on propranolol.

References

External links

• Historical Remarks about Propranolol and its inventor
• Scientific American Interview with James McGaugh
• CBS NEWS 60 Minutes: A Pill To Forget
• Therapeutic Forgetting: The Legal and Ethical Implications of Memory Dampening (Vanderbilt Law Review)