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Propranolol

Propranolol

Overview

Propranolol is a sympatholytic non-selective beta blocker
Beta blocker
Beta blockers or beta-adrenergic blocking agents, beta-adrenergic antagonists, beta-adrenoreceptor antagonists or beta antagonists, are a class of drugs used for various indications. They are particularly for the management of cardiac arrhythmias, cardioprotection after myocardial infarction ,...

. Sympatholytics are used to treat hypertension, anxiety and panic. It was the first successful beta blocker developed. Propranolol is available in generic form as propranolol hydrochloride, as well as an AstraZeneca
AstraZeneca
AstraZeneca plc is a global pharmaceutical and biologics company headquartered in London, United Kingdom. It is the world's seventh-largest pharmaceutical company measured by revenues and has operations in over 100 countries...

 and Wyeth
Wyeth
Wyeth, formerly one of the companies owned by American Home Products Corporation , was a pharmaceutical company. The company was based in Madison, New Jersey, USA...

 product under the brand names Inderal, Inderal LA, Avlocardyl (also available in prolonged absorption form named "Avlocardyl Retard"), Deralin, Dociton, Inderalici, InnoPran XL, Sumial, Anaprilinum (depending on marketplace and release rate), Bedranol SR (Sandoz
Sandoz
Founded in 2003, Sandoz presently is the generic drug subsidiary of Novartis, a multinational pharmaceutical company. The company develops, manufactures and markets generic drugs as well as pharmaceutical and biotechnological active ingredients....

).

Propranolol is one of the banned substances in the Olympics
Olympic Games
The Olympic Games is a major international event featuring summer and winter sports, in which thousands of athletes participate in a variety of competitions. The Olympic Games have come to be regarded as the world’s foremost sports competition where more than 200 nations participate...

, presumably for its use in controlling social anxiety (stage fright
Stage fright
Stage fright or performance anxiety is the anxiety, fear, or persistent phobia which may be aroused in an individual by the requirement to perform in front of an audience, whether actually or potentially . In the context of public speaking, this fear is termed glossophobia, one of the most common...

) and tremors.

Scottish
Scotland
Scotland is a country that is part of the United Kingdom. Occupying the northern third of the island of Great Britain, it shares a border with England to the south and is bounded by the North Sea to the east, the Atlantic Ocean to the north and west, and the North Channel and Irish Sea to the...

 scientist James W. Black
James W. Black
Sir James Whyte Black, OM, FRS, FRSE, FRCP was a Scottish doctor and pharmacologist. He spent his career both as researcher and as an academic at several universities. Black established the physiology department at the University of Glasgow, where he became interested in the effects of adrenaline...

 successfully developed propranolol in the 1960s.
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Encyclopedia

Propranolol is a sympatholytic non-selective beta blocker
Beta blocker
Beta blockers or beta-adrenergic blocking agents, beta-adrenergic antagonists, beta-adrenoreceptor antagonists or beta antagonists, are a class of drugs used for various indications. They are particularly for the management of cardiac arrhythmias, cardioprotection after myocardial infarction ,...

. Sympatholytics are used to treat hypertension, anxiety and panic. It was the first successful beta blocker developed. Propranolol is available in generic form as propranolol hydrochloride, as well as an AstraZeneca
AstraZeneca
AstraZeneca plc is a global pharmaceutical and biologics company headquartered in London, United Kingdom. It is the world's seventh-largest pharmaceutical company measured by revenues and has operations in over 100 countries...

 and Wyeth
Wyeth
Wyeth, formerly one of the companies owned by American Home Products Corporation , was a pharmaceutical company. The company was based in Madison, New Jersey, USA...

 product under the brand names Inderal, Inderal LA, Avlocardyl (also available in prolonged absorption form named "Avlocardyl Retard"), Deralin, Dociton, Inderalici, InnoPran XL, Sumial, Anaprilinum (depending on marketplace and release rate), Bedranol SR (Sandoz
Sandoz
Founded in 2003, Sandoz presently is the generic drug subsidiary of Novartis, a multinational pharmaceutical company. The company develops, manufactures and markets generic drugs as well as pharmaceutical and biotechnological active ingredients....

).

Propranolol is one of the banned substances in the Olympics
Olympic Games
The Olympic Games is a major international event featuring summer and winter sports, in which thousands of athletes participate in a variety of competitions. The Olympic Games have come to be regarded as the world’s foremost sports competition where more than 200 nations participate...

, presumably for its use in controlling social anxiety (stage fright
Stage fright
Stage fright or performance anxiety is the anxiety, fear, or persistent phobia which may be aroused in an individual by the requirement to perform in front of an audience, whether actually or potentially . In the context of public speaking, this fear is termed glossophobia, one of the most common...

) and tremors.

History and development


Scottish
Scotland
Scotland is a country that is part of the United Kingdom. Occupying the northern third of the island of Great Britain, it shares a border with England to the south and is bounded by the North Sea to the east, the Atlantic Ocean to the north and west, and the North Channel and Irish Sea to the...

 scientist James W. Black
James W. Black
Sir James Whyte Black, OM, FRS, FRSE, FRCP was a Scottish doctor and pharmacologist. He spent his career both as researcher and as an academic at several universities. Black established the physiology department at the University of Glasgow, where he became interested in the effects of adrenaline...

 successfully developed propranolol in the 1960s. In 1988, he was awarded the Nobel Prize in Medicine for this discovery. Propranolol was derived from the early β-adrenergic antagonists dichloroisoprenaline
Dichloroisoprenaline
Dichloroisoprenaline , also known as dichlorosisoproterenol, was the first beta blocker ever to be developed. It is non-selective for the β1-adrenergic and β2-adrenergic receptors...

 and pronethalol
Pronethalol
Pronethalol was an early non-selective beta blocker clinical candidate. It was never used clinically due to carcinogenicity in mice, which was thought to result from formation of a carcinogenic naphthalene epoxide metabolite....

. The key structural modification, which was carried through to essentially all subsequent beta blockers, was the insertion of a aryloxy bridge into the aryl
Aryl
In the context of organic molecules, aryl refers to any functional group or substituent derived from an aromatic ring, be it phenyl, naphthyl, thienyl, indolyl, etc....

ethanolamine
Ethanolamine
Ethanolamine, also called 2-aminoethanol or monoethanolamine , is an organic chemical compound that is both a primary amine and a primary alcohol . Like other amines, monoethanolamine acts as a weak base...

 structure of pronethalol thus greatly increasing the potency of the compound. This also apparently eliminated the carcinogenicity found with pronethalol in animal models.

Newer, more selective beta-blockers (such as nebivolol
Nebivolol
Nebivolol is a β1 receptor blocker with nitric oxide-potentiating vasodilatory effect used in treatment of hypertension and, in Europe, also for left ventricular failure...

, carvedilol
Carvedilol
Carvedilol is a non-selective beta blocker/alpha-1 blocker indicated in the treatment of mild to moderate congestive heart failure . It is marketed under various trade names including Carvil , Coreg , Dilatrend , Eucardic , and Carloc as a generic drug ., and as a...

, or metoprolol
Metoprolol
Metoprolol is a selective β1 receptor blocker used in treatment of several diseases of the cardiovascular system, especially hypertension. The active substance metoprolol is employed either as metoprolol succinate or metoprolol tartrate...

) are now used in the treatment of hypertension
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...

.

Indications


Propranolol is indicated for the management of various conditions including:
  • Hypertension
    Hypertension
    Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...

  • Angina pectoris
  • Tachyarrhythmias
  • Myocardial infarction
    Myocardial infarction
    Myocardial infarction or acute myocardial infarction , commonly known as a heart attack, results from the interruption of blood supply to a part of the heart, causing heart cells to die...

  • Control of tachycardia
    Tachycardia
    Tachycardia comes from the Greek words tachys and kardia . Tachycardia typically refers to a heart rate that exceeds the normal range for a resting heart rate...

    /tremor associated with anxiety
    Anxiety
    Anxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...

    , hyperthyroidism
    Hyperthyroidism
    Hyperthyroidism is the term for overactive tissue within the thyroid gland causing an overproduction of thyroid hormones . Hyperthyroidism is thus a cause of thyrotoxicosis, the clinical condition of increased thyroid hormones in the blood. Hyperthyroidism and thyrotoxicosis are not synonymous...

     or lithium therapy
    Lithium pharmacology
    Lithium pharmacology refers to use of the lithium ion, Li+, as a drug. A number of chemical salts of lithium are used medically as a mood stabilizing drug, primarily in the treatment of bipolar disorder, where they have a role in the treatment of depression and particularly of mania, both acutely...

    .
  • Essential tremor
    Essential tremor
    Essential tremor is a slowly progressive neurological disorder whose most recognizable feature is a tremor of the arms that is apparent during voluntary movements such as eating and writing...

  • Migraine
    Migraine
    Migraine is a chronic neurological disorder characterized by moderate to severe headaches, and nausea...

     prophylaxis
  • Cluster headaches prophylaxis
  • Tension headache
    Tension headache
    A tension headache is the most common type of primary headache. The pain can radiate from the neck, back, eyes, or other muscle groups in the body. Tension-type headaches account for nearly 90% of all headaches...

     (Off the label use)
  • Shaky hands

  • There has been some experimentation in psychiatric areas:
    • Treating the excessive drinking of fluids in psychogenic polydipsia
      Psychogenic polydipsia
      Primary polydipsia or psychogenic polydipsia is a special form of polydipsia. It is usually associated with a patient's increasing fluid intake due to the sensation of having a dry mouth....

      ,
    • Antipsychotic
      Antipsychotic
      An antipsychotic is a tranquilizing psychiatric medication primarily used to manage psychosis , particularly in schizophrenia and bipolar disorder. A first generation of antipsychotics, known as typical antipsychotics, was discovered in the 1950s...

      -induced akathisia
      Akathisia
      Akathisia, or acathisia, is a syndrome characterized by unpleasant sensations of inner restlessness that manifests itself with an inability to sit still or remain motionless...

      ,
    • Aggressive behavior of patients with brain injuries
      Acquired brain injury
      An acquired brain injury is brain damage caused by events after birth, rather than as part of a genetic or congenital disorder such as fetal alcohol syndrome, perinatal illness or perinatal hypoxia. ABI can result in cognitive, physical, emotional, or behavioural impairments that lead to permanent...

    • Post-traumatic stress disorder
      Post-traumatic stress disorder
      Posttraumaticstress disorder is a severe anxiety disorder that can develop after exposure to any event that results in psychological trauma. This event may involve the threat of death to oneself or to someone else, or to one's own or someone else's physical, sexual, or psychological integrity,...

  • Glaucoma
    Glaucoma
    Glaucoma is an eye disorder in which the optic nerve suffers damage, permanently damaging vision in the affected eye and progressing to complete blindness if untreated. It is often, but not always, associated with increased pressure of the fluid in the eye...

  • Primary exertional headache


While once first-line treatment for hypertension
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...

, the role for beta-blockers was downgraded in June 2006 in the United Kingdom
United Kingdom
The United Kingdom of Great Britain and Northern IrelandIn the United Kingdom and Dependencies, other languages have been officially recognised as legitimate autochthonous languages under the European Charter for Regional or Minority Languages...

 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
Diabetes mellitus type 2
Diabetes mellitus type 2formerly non-insulin-dependent diabetes mellitus or adult-onset diabetesis a metabolic disorder that is characterized by high blood glucose in the context of insulin resistance and relative insulin deficiency. Diabetes is often initially managed by increasing exercise and...

.

Propranolol is also used to lower portal vein
Hepatic portal vein
The hepatic portal vein is not a true vein, because it does not conduct blood directly to the heart. It is a vessel in the abdominal cavity that drains blood from the gastrointestinal tract and spleen to capillary beds in the liver...

 pressure in portal hypertension
Portal hypertension
In medicine, portal hypertension is hypertension in the portal vein and its tributaries.It is often defined as a portal pressure gradient of 10 mmHg or greater.-Causes:Causes can be divided into prehepatic, intrahepatic, and posthepatic...

 and prevent esophageal variceal
Esophageal varices
In medicine , esophageal varices are extremely dilated sub-mucosal veins in the lower esophagus...

 bleeding.

Off-label and investigational use


Propranolol is often used by musicians and other performers to prevent stage fright
Stage fright
Stage fright or performance anxiety is the anxiety, fear, or persistent phobia which may be aroused in an individual by the requirement to perform in front of an audience, whether actually or potentially . In the context of public speaking, this fear is termed glossophobia, one of the most common...

. It has been taken by surgeons to reduce their own innate hand tremors
Tremor
A tremor is an involuntary, somewhat rhythmic, muscle contraction and relaxation involving to-and-fro movements of one or more body parts. It is the most common of all involuntary movements and can affect the hands, arms, eyes, face, head, vocal folds, trunk, and legs. Most tremors occur in the...

 during surgery.

Propranolol 80mg daily should be used post discharge in STEMI patients.

Propranolol is currently being investigated as a potential treatment for post-traumatic stress disorder
Post-traumatic stress disorder
Posttraumaticstress disorder is a severe anxiety disorder that can develop after exposure to any event that results in psychological trauma. This event may involve the threat of death to oneself or to someone else, or to one's own or someone else's physical, sexual, or psychological integrity,...

. Propranolol works to inhibit the actions of norepinephrine, a neurotransmitter that enhances memory consolidation. Studies have shown that individuals given propranolol immediately after a traumatic experience show less severe symptoms of PTSD compared to their respective control groups that did not receive the drug (Vaiva et al., 2003). Propranolol reduces the effects of nightmare
Nightmare
A nightmare is an unpleasant dream that can cause a strong negative emotional response from the mind, typically fear or horror, but also despair, anxiety and great sadness. The dream may contain situations of danger, discomfort, psychological or physical terror...

-related cardiac activity by keeping sinus rhythm
Sinus rhythm
In medicine, sinus rhythm is the normal beating of the heart, as measured by an electrocardiogram . It has certain generic features that serve as hallmarks for comparison with normal ECGs.- ECG structure :...

 low during nightmares, as a higher pulse and increased adrenaline are associated with severe nightmares. However, results remain inconclusive as to the success of propranolol in treatment of PTSD, including nightmares experienced by those with PTSD. There are also many ethical and legal questions surrounding the use of Propranolol-based medications for use as a "memory dampener," including: altering (memory-recalled) evidence during an investigation, modifying behavioral response to past (albeit traumatic) experiences, the regulation of these drugs, and others.

Propranolol in combination with etodolac is currently being investigated in a Phase 3 trial of 400 colorectal cancer patients as a potential treatment for prevention of colorectal cancer recurrence. The aim of this study is to assess the use of perioperative medical intervention using a combination of a propranolol and etodolac in order to attenuate the surgically induced immunosuppression and other physiological perturbations, aiming to reduce the rate of tumor recurrence and distant metastatic disease.

Recent evidence (June 2008) suggests that propranolol can be used to treat severe infantile hemangiomas (IHs). This treatment has proven superior to corticosteroids, as propranolol has fewer side effects and is more effective when treating IHs.

Propranolol was investigated for possible effects on resting energy expenditure and muscle catabolism in patients with severe burns. In children with burns, treatment with propranolol during hospitalization attenuated hypermetabolism and reversed muscle wasting.

Propranolol along with a number of other membrane-acting drugs have been investigated for possible effects on Plasmodium falciparum
Plasmodium falciparum
Plasmodium falciparum is a protozoan parasite, one of the species of Plasmodium that cause malaria in humans. It is transmitted by the female Anopheles mosquito. Malaria caused by this species is the most dangerous form of malaria, with the highest rates of complications and mortality...

and so the treatment of malaria
Malaria
Malaria is a mosquito-borne infectious disease of humans and other animals caused by eukaryotic protists of the genus Plasmodium. The disease results from the multiplication of Plasmodium parasites within red blood cells, causing symptoms that typically include fever and headache, in severe cases...

. In vitro positive effects until recently had not been matched by useful in vivo anti-parasite activity against P. vinckei
Plasmodium vinckei
Plasmodium vinckei is a parasite of the genus Plasmodium subgenus Vinckeia.Like all Plasmodium species P. vinckei has both vertebrate and insect hosts. The vertebrate hosts for this parasite are rodents.- Description :...

, or P. yoelii nigeriensis
Plasmodium yoelii
Plasmodium yoelii is a parasite of the genus Plasmodium subgenus Vinckeia.Like all Plasmodium species P. yoelii has both vertebrate and insect hosts. The vertebrate hosts for this parasite are mammals.- Notes :...

. 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.

Precautions and contraindications


Propranolol should be used with caution in patients with:
  • Diabetes mellitus
    Diabetes mellitus
    Diabetes mellitus, often simply referred to as diabetes, is a group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced...

     or hyperthyroidism
    Hyperthyroidism
    Hyperthyroidism is the term for overactive tissue within the thyroid gland causing an overproduction of thyroid hormones . Hyperthyroidism is thus a cause of thyrotoxicosis, the clinical condition of increased thyroid hormones in the blood. Hyperthyroidism and thyrotoxicosis are not synonymous...

    , since signs and symptoms of hypoglycaemia may be masked.
  • Peripheral vascular disease and Raynaud's syndrome, which may be exacerbated
  • Phaeochromocytoma, as hypertension
    Hypertension
    Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...

     may be aggravated without prior alpha blocker
    Alpha blocker
    Alpha-1 blockers constitute a variety of drugs which block α1-adrenergic receptors in arteries and smooth muscles.-Pharmacology:...

     therapy
  • Myasthenia gravis
    Myasthenia gravis
    Myasthenia gravis is an autoimmune neuromuscular disease leading to fluctuating muscle weakness and fatiguability...

    , may be worsened
  • Other drugs with bradycardic
    Bradycardia
    Bradycardia , in the context of adult medicine, is the resting heart rate of under 60 beats per minute, though it is seldom symptomatic until the rate drops below 50 beat/min. It may cause cardiac arrest in some patients, because those with bradycardia may not be pumping enough oxygen to their heart...

     effects


Propranolol is contraindicated in patients with:
  • Reversible airways disease, particularly asthma
    Asthma
    Asthma is the common chronic inflammatory disease of the airways characterized by variable and recurring symptoms, reversible airflow obstruction, and bronchospasm. Symptoms include wheezing, coughing, chest tightness, and shortness of breath...

     or chronic obstructive pulmonary disease
    Chronic obstructive pulmonary disease
    Chronic obstructive pulmonary disease , also known as chronic obstructive lung disease , chronic obstructive airway disease , chronic airflow limitation and chronic obstructive respiratory disease , is the co-occurrence of chronic bronchitis and emphysema, a pair of commonly co-existing diseases...

     (COPD)
  • Bradycardia
    Bradycardia
    Bradycardia , in the context of adult medicine, is the resting heart rate of under 60 beats per minute, though it is seldom symptomatic until the rate drops below 50 beat/min. It may cause cardiac arrest in some patients, because those with bradycardia may not be pumping enough oxygen to their heart...

     (<60 beats/minute)
  • Sick sinus syndrome
    Sick sinus syndrome
    Sick sinus syndrome, also called sinus node dysfunction, is a group of abnormal heart rhythms presumably caused by a malfunction of the sinus node, the heart's primary pacemaker...

  • Atrioventricular block
    Atrioventricular block
    An atrioventricular block involves the impairment of the conduction between the atria and ventricles of the heart.The causes of pathological AV block are varied and include ischaemia, infarction, fibrosis or drugs. Certain AV blocks can also be found as normal variants, such as in athletes or...

     (second or third degree)
  • Shock
  • Severe hypotension
    Hypotension
    In physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...

  • Cocaine toxicity [per American Heart Association guidelines, 2005]

Adverse effects



Adverse drug reaction
Adverse drug reaction
An adverse drug reaction is an expression that describes harm associated with the use of given medications at a normal dosage. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs...

s (ADRs) associated with propranolol therapy are similar to other lipophilic beta blockers (see beta blocker
Beta blocker
Beta blockers or beta-adrenergic blocking agents, beta-adrenergic antagonists, beta-adrenoreceptor antagonists or beta antagonists, are a class of drugs used for various indications. They are particularly for the management of cardiac arrhythmias, cardioprotection after myocardial infarction ,...

).

Pregnancy and lactation


Propranolol, like other beta blockers, is classified as Pregnancy category
Pregnancy category
The pregnancy category of a pharmaceutical agent is an assessment of the risk of fetal injury due to the pharmaceutical, if it is used as directed by the mother during pregnancy. It does not include any risks conferred by pharmaceutical agents or their metabolites that are present in breast...

 C in the United States and ADEC
Australian Drug Evaluation Committee
The Australian Drug Evaluation Committee or ADEC, was a committee that provided independent scientific advice to the Australian Government regarding therapeutic drugs. The committee was originally formed in 1963 and more recently authorised under the Therapeutic Goods Act 1989 as part of the...

 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
Human lung
The human lungs are the organs of respiration in humans. Humans have two lungs, with the left being divided into two lobes and the right into three lobes. Together, the lungs contain approximately of airways and 300 to 500 million alveoli, having a total surface area of about in...

 or cardiac
Human heart
The human heart is a muscular organ that provides a continuous blood circulation through the cardiac cycle and is one of the most vital organs in the human body...

 complications, or premature birth. The newborn may experience additional adverse effects such as hypoglycemia
Hypoglycemia
Hypoglycemia or hypoglycæmia is the medical term for a state produced by a lower than normal level of blood glucose. The term literally means "under-sweet blood"...

 and bradycardia
Bradycardia
Bradycardia , in the context of adult medicine, is the resting heart rate of under 60 beats per minute, though it is seldom symptomatic until the rate drops below 50 beat/min. It may cause cardiac arrest in some patients, because those with bradycardia may not be pumping enough oxygen to their heart...

.

Most beta-blocking agents appear in the milk of lactating
Lactation
Lactation describes the secretion of milk from the mammary glands and the period of time that a mother lactates to feed her young. The process occurs in all female mammals, however it predates mammals. In humans the process of feeding milk is called breastfeeding or nursing...

 women. This is especially the case for a lipophilic
Lipophilic
Lipophilicity, , refers to the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene. These non-polar solvents are themselves lipophilic — the axiom that like dissolves like generally holds true...

 drug like propranolol. Breastfeeding is not recommended in patients receiving propranolol therapy.

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
Bioavailability
In pharmacology, bioavailability is a subcategory of absorption and is used to describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. By definition, when a medication is administered...

. Despite complete absorption, propranolol has a variable bioavailability
Bioavailability
In pharmacology, bioavailability is a subcategory of absorption and is used to describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. By definition, when a medication is administered...

 due to extensive first-pass metabolism. Hepatic impairment will therefore increase its bioavailability. The main metabolite 4-hydroxypropranolol, with a longer half-life
Half-life
Half-life, abbreviated t½, is the period of time it takes for the amount of a substance undergoing decay to decrease by half. The name was originally used to describe a characteristic of unstable atoms , but it may apply to any quantity which follows a set-rate decay.The original term, dating to...

 (5.2–7.5 hours) than the parent compound (3–4 hours), is also pharmacologically active.

Propranolol is a highly lipophilic
Lipophilic
Lipophilicity, , refers to the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene. These non-polar solvents are themselves lipophilic — the axiom that like dissolves like generally holds true...

 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.

Mechanism of action


Propranolol is a non-selective beta blocker
Beta blocker
Beta blockers or beta-adrenergic blocking agents, beta-adrenergic antagonists, beta-adrenoreceptor antagonists or beta antagonists, are a class of drugs used for various indications. They are particularly for the management of cardiac arrhythmias, cardioprotection after myocardial infarction ,...

, that is, it blocks the action of epinephrine
Epinephrine
Epinephrine is a hormone and a neurotransmitter. It increases heart rate, constricts blood vessels, dilates air passages and participates in the fight-or-flight response of the sympathetic nervous system. In chemical terms, adrenaline is one of a group of monoamines called the catecholamines...

 and norepinephrine
Norepinephrine
Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...

 on both β1- and β2-adrenergic receptor
Adrenergic receptor
The adrenergic receptors are a class of metabotropic G protein-coupled receptors that are targets of the catecholamines, especially noradrenaline and adrenaline ....

s. It has little intrinsic sympathomimetic activity (ISA) but has strong membrane stabilizing activity (only at high blood concentrations, e.g. overdosage). Research has also shown that propranolol has inhibitory effects on the norepinephrine transporter
Norepinephrine transporter
The norepinephrine transporter , also known as solute carrier family 6 member 2 , is a protein that in humans is encoded by the SLC6A2 gene....

 and/or stimulates norepinephrine release (present experiments have shown that the concentration of norepinephrine is increased in the synapse
Synapse
In the nervous system, a synapse is a structure that permits a neuron to pass an electrical or chemical signal to another cell...

 but do not have the ability to discern which effect is taking place). Since propranolol blocks β-adrenoceptors, the increase in synaptic norepinephrine only results in α-adrenergic activation, with the α1-adrenoceptor being particularly important for effects observed in animal models. Therefore, some have suggested that it be looked upon as an indirect α1 agonist as well as a β antagonist. Probably owing to the effect at the α1-adrenoceptor, the racemate and the individual enantiomers of propranolol have been shown to substitute for cocaine
Cocaine
Cocaine is a crystalline tropane alkaloid that is obtained from the leaves of the coca plant. The name comes from "coca" in addition to the alkaloid suffix -ine, forming cocaine. It is a stimulant of the central nervous system, an appetite suppressant, and a topical anesthetic...

 in rats, with the most potent enantiomer being S-(–)-propranolol. In addition, some evidence suggests that propranolol may function as a partial agonist at one or more serotonin receptors (possibly 5-HT1B).

Both enantiomers of the drug have a local anesthetic
Local anesthetic
A local anesthetic is a drug that causes reversible local anesthesia, generally for the aim of having local analgesic effect, that is, inducing absence of pain sensation, although other local senses are often affected as well...

 (topical) effect, which is normally mediated by blockade of voltage-gated sodium channels. Few studies have demonstrated propranolol's ability to block cardiac, neuronal, and skeletal voltage-gated sodium channels, accounting for its known “membrane stabilizing effect
Membrane stabilizing effect
Membrane stabilizing effects involve the inhibition or total abolishing of action potential from being propagated across the membrane. This phenomenon is common in nerve tissues as they are the carrier of impulses from the periphery to the central nervous system. Membrane stabilization is the...

” and anti-arrhythmic and other central nervous system effects.

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
    Verapamil
    Verapamil is an L-type calcium channel blocker of the phenylalkylamine class. It has been used in the treatment of hypertension, angina pectoris, cardiac arrhythmia, and most recently, cluster headaches. It is also an effective preventive medication for migraine...

  • epinephrine
    Epinephrine
    Epinephrine is a hormone and a neurotransmitter. It increases heart rate, constricts blood vessels, dilates air passages and participates in the fight-or-flight response of the sympathetic nervous system. In chemical terms, adrenaline is one of a group of monoamines called the catecholamines...

  • β2-adrenergic receptor agonists
    Beta2-adrenergic receptor agonist
    β2-adrenergic agonists, also known as β2-adrenergic receptor agonists, are a class of drugs used to treat asthma and other pulmonary disease states.-Uses:...

  • clonidine
    Clonidine
    Clonidine is a sympatholytic medication used to treat medical conditions, such as high blood pressure, some pain conditions, ADHD and anxiety/panic disorder...

  • ergot alkaloids
  • isoprenaline
  • non-steroidal anti-inflammatory drug
    Non-steroidal anti-inflammatory drug
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    s
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    Quinidine is a pharmaceutical agent that acts as a class I antiarrhythmic agent in the heart. It is a stereoisomer of quinine, originally derived from the bark of the cinchona tree.-Mechanism:...

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    Lidocaine , Xylocaine, or lignocaine is a common local anesthetic and antiarrhythmic drug. Lidocaine is used topically to relieve itching, burning and pain from skin inflammations, injected as a dental anesthetic or as a local anesthetic for minor surgery.- History :Lidocaine, the first amino...

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    Rifampicin
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     slows down the metabolism of propranolol significantly leading to increased blood levels of propranolol.

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.

  • Migraine Prophylaxis
    • The initial dose is 80 mg Inderal daily in divided doses. The usual effective dose range is 160 mg to 240 mg per day.
      • The dosage may be increased gradually to achieve optimum migraine prophylaxis. If a satisfactory response is not obtained within four to six weeks after reaching the maximum dose, Inderal therapy should be discontinued.

  • Tachyarrhythmia, anxiety (GAD), hyperthyroidism
    • 10-40 mg 3-4 times daily

  • Performance anxiety
    • 5-10 mg 30min or 1.5hrs before and after performance, optionally 5-10 mg night before. Up to 40 mg if necessary, but side-effects may present.


Intravenous (IV) propranolol may be used in acute arrhythmia or thyrotoxic crisis
Hyperthyroidism
Hyperthyroidism is the term for overactive tissue within the thyroid gland causing an overproduction of thyroid hormones . Hyperthyroidism is thus a cause of thyrotoxicosis, the clinical condition of increased thyroid hormones in the blood. Hyperthyroidism and thyrotoxicosis are not synonymous...

.

Chemistry


Propranolol, 1-(iso-propylamino)-3-(1-naphthyloxy)-2-propanol, is synthesized in two ways from the same initial substance. The first way consists of reacting 1-naphthol with epichlorohydrin
Epichlorohydrin
Epichlorohydrin is an organochlorine compound and an epoxide. This is a colorless liquid with a pungent, garlic-like odor, moderately soluble in water, but miscible with most polar organic solvents. Epichlorohydrin is a highly reactive compound and is used in the production of glycerol, plastics,...

. Opening of the epoxide
Epoxide
An epoxide is a cyclic ether with three ring atoms. This ring approximately defines an equilateral triangle, which makes it highly strained. The strained ring makes epoxides more reactive than other ethers. Simple epoxides are named from the parent compound ethylene oxide or oxirane, such as in...

 ring gives 1-chloro-3-(1-naphthyloxy)-2-propanol, which is reacted further with iso-propylamine, giving propranolol. The second method uses the same reagents in the presence of a base and consists of initially making 3-(1-naphthyloxy)propylenoxide, the subsequent reaction with isopropylamine
Isopropylamine
Isopropylamine, also called 2-aminopropane, 2-propanamine, monoisopropylamine, and MIPA, is an organic compound, an amine. It is a base, as typical for amines. It is a hygroscopic colorless liquid with ammonia-like odor. Its melting point is −95.2 °C and its boiling point is 32.4 °C. It is miscible...

which results in epoxide ring opening leading to the formation of propranolol.
  • A.F. Crowther, L.H. Smith, (1967).
  • A.F. Crowther, L.H. Smith, (1970).
  • A.F. Crowther, L.H. Smith, (1963).
  • A.F. Crowther, L.H. Smith, (1963).
  • A.F. Crowther, L.H. Smith, (1964).
  • A.F. Crowther, L.H. Smith, (1964).

External links