Inderal(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 long-acting 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]
Common side effects include nausea, abdominal pain, and constipation.[1] It should not be used in those with an already slow heart rate and most of those with heart failure.[1] Quickly stopping the medication in those with coronary artery disease may worsen symptoms.[1] It may worsen the symptoms of asthma.[1] Caution is recommended in those with liver or kidney problems.[1] Propranolol may cause harmful effects in the baby if taken during pregnancy.[5] Its use during breastfeeding is probably safe, but the baby should be monitored for side effects.[6] It is a non-selective beta blocker which works by blocking β-adrenergic receptors.[1]
Propranolol was patented in 1962 and approved for medical use in 1964.[7] It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system.[8] Propranolol is available as a generic medication.[1] The wholesale cost in the developing world is between US$0.24 and US$2.16 per month as of 2014.[9] In the United States it costs about $15 per month at a typical dose.[1] In 2016 it was the 43rd most prescribed medication in the United States with more than 18 million prescriptions.[10]
Medical uses
Propranolol is used for treating various conditions, including:
Cardiovascular
§ Hypertension
§ Angina pectoris (with the exception of variant angina)
§ Myocardial infarction
§ Tachycardia (and other sympathetic nervous system symptoms, such as muscle tremor) associated with various conditions, including anxiety, panic, hyperthyroidism, and lithium therapy
§ Portal hypertension, to lower portal vein pressure
§ Prevention of esophageal variceal bleeding and ascites
§ Anxiety
§ Hypertrophic cardiomyopathy
While once a first-line treatment for hypertension, the role for beta blockers was downgraded in June 2006 in the United Kingdom to fourth-line, as they do not perform as well as 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.[11]
Propranolol is not recommended for the treatment of hypertension 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.[12]
Psychiatric
Propranolol is occasionally used to treat performance anxiety.[2] Evidence to support its use in other anxiety disorders is poor.[13] Some experimentation has been conducted in other psychiatric areas:[14]
§ Post-traumatic stress disorder (PTSD) and specific phobias (see subsection below)
§ Aggressive behavior of patients with brain injuries[15]
§ Treating the excessive drinking of fluids in psychogenic polydipsia[16][17]
PTSD and phobias
Propranolol is being investigated as a potential treatment for PTSD.[18][19] Propranolol works to inhibit the actions of norepinephrine, a neurotransmitter that enhances memory consolidation. In one small study individuals given propranolol immediately after trauma experienced fewer stress-related symptoms and lower rates of PTSD than respective control groups who did not receive the drug.[20] Due to the fact that memories and their emotional content are reconsolidated in the hours after they are recalled/re-experienced, propranolol can also diminish the emotional impact of already formed memories; for this reason, it is also being studied in the treatment of specific phobias, such as arachnophobia, dental fear, and social phobia.[21]
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.[22] 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."[23]
Others
§ Essential tremor. Evidence for use for akathisia however is insufficient[24]
§ Migraine and cluster headache prevention[25][26] and in primary exertional headache[27]
§ Hyperhidrosis (excessive sweating)
§ Proliferating infantile hemangioma
§ Glaucoma
§ Thyrotoxicosis by deiodinase inhibition
Propranolol may be used to treat severe infantile hemangiomas (IHs). This treatment shows promise as being superior to corticosteroids when treating IHs. Extensive clinical case evidence and a small controlled trial support its efficacy.[28]
Contraindications
Propranolol may be contraindicated in people with:[29]
§ Reversible airways 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
§ Cocaine toxicity [per American Heart Association guidelines, 2005]
Adverse effects
Propranolol should be used with caution in people with:[29]
§ 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, which may be worsened
§ Other drugs with bradycardic effects
Pregnancy and lactation
Propranolol, like other beta blockers, is classified as pregnancy category C in the United States and ADEC category C in Australia. β-blocking agents in general reduce perfusion of the placenta, which may lead to adverse outcomes for the neonate, including lung or heart complications, or premature birth. The newborn may experience additional adverse effects such as low blood sugar and a slower than normal heart rate.[30]
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.[31] 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".[30][31][32][33]
Due to the high penetration across the blood–brain barrier, lipophilic beta blockers such as propranolol and metoprolol are more likely than other less lipophilic beta blockers to cause sleep disturbances such as insomnia and vivid dreams, and nightmares.[34] Dreaming (rapid eye movement sleep, REM) was reduced and increased awakening.[35][needs update]
Adverse drug reactions associated with propranolol therapy are similar to other lipophilic beta blockers.
Overdose
In overdose propranolol is associated with seizures.[36] Cardiac arrest may occur in propranolol overdose due to sudden ventricular arrhythmias, or cardiogenic shock which may ultimately culminate in bradycardic PEA.[37] Propranolol should be used with extreme caution in depressed or atypically depressed patients with possible suicidal ideation.[citation needed]
Mechanism of action
Propranolol is a competitive antagonist of beta-1-adrenergic receptors in the heart.[65] 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 production. 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.[66]
