Trimecaine Synthesis Essay

Clinical data
Pronunciation
Trade namesLamictal, others[1]
AHFS/Drugs.comMonograph
MedlinePlusa695007
License data
Pregnancy
category
  • AU:D
  • US:C (Risk not ruled out)
Routes of
administration
By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability98%
Protein binding55%
MetabolismLiver (mostly UGT1A4-mediated)
Biological half-life29 hours
ExcretionUrine (65%), faeces (2%)
Identifiers

IUPAC name

  • 6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine
CAS Number
PubChemCID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
ECHA InfoCard100.074.432
Chemical and physical data
FormulaC9H7Cl2N5
Molar mass256.091 g/mol
3D model (JSmol)

SMILES

  • NC1=NC(N)=NN=C1C2=CC=CC(Cl)=C2Cl

InChI

  • InChI=1S/C9H7Cl2N5/c10-5-3-1-2-4(6(5)11)7-8(12)14-9(13)16-15-7/h1-3H,(H4,12,13,14,16) Y
  • Key:PYZRQGJRPPTADH-UHFFFAOYSA-N Y
 NY (what is this?)  (verify)

Lamotrigine, sold as the brandname Lamictal among others, is an anticonvulsant medication used to treat epilepsy and bipolar disorder.[2] For epilepsy, this includes focal seizures, tonic-clonic seizures, and seizures in Lennox-Gastaut syndrome.[2] In bipolar disorder, it is used to treat acute episodes of depression, rapid cycling in bipolar type II, and prevent recurrence in bipolar type I.[2]

Common side effects include sleepiness, headache, vomiting, trouble with coordination, and rash.[2] Serious side effects include lack of red blood cells, increased risk of suicide, Stevens-Johnson syndrome, and allergic reactions.[2] There are concerns that use during pregnancy or breastfeeding may result in harm.[3] Lamotrigine is a phenyltriazine, making it chemically different from other anticonvulsants.[2] How it works is not exactly clear.[2] It appears to increase the action of gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the central nervous system and decrease voltage-sensitive sodium channels.[4][2]

Lamotrigine was first marketed in the United Kingdom in 1991 and approved for use in the United States in 1994.[5][2] It is on the World Health Organization's List of Essential Medicines, the most effective and safest medicines needed in a health system.[6] The wholesale cost in the developing world is about 3.57 USD per month as of 2015.[7] In the United States, this amount has a wholesale cost of about 4.64 USD.[8]

Medical uses[edit]

Epilepsy[edit]

Lamotrigine used for the treatment of partial seizures.[9] It is considered a first-line drug for primary generalised tonic-clonic seizures (includes simple partial, complex partial and secondarily generalised seizures), and as an adjuvant therapy in partial seizures (focal onset tonic-clonic, atypical absence, myoclonic, and due to Lennox-Gastaut syndrome). It is also used as an alternative medication for absence seizure and atypical absence, myoclonic, and atonic seizures.[10][11]

It is also appropriate for the treatment of Lennox–Gastaut syndrome.[12] It is one of a small number of FDA-approved therapies for this severe form of epilepsy. Lamotrigine reduces the frequency of LGS seizures, and is one of two medications known to decrease the severity of drop attacks.[13] Combination with valproate is common, but this increases the risk of lamotrigine-induced rash, and necessitates reduced dosing due to the interaction of these drugs.[14]

Bipolar disorder[edit]

Lamotrigine is approved in the US for maintenance treatment of bipolar I disorder and bipolar II disorder.[15][16] While the anticonvulsants carbamazepine and valproate are predominantly antimanics, lamotrigine is most effective for preventing the recurrent depressive episodes of bipolar disorder. The drug seems ineffective in the treatment of current rapid-cycling, acute mania, or acute depression in bipolar disorder; however, it is effective at prevention of or delaying of manic, depressive, or rapid cycling episodes.[17] According to studies in 2007, lamotrigine may treat bipolar depression without triggering mania, hypomania, mixed states, or rapid-cycling.[18]

There is less evidence of therapeutic benefit when lamotrigine is used to treat a current mood episode. It has not demonstrated effectiveness in treating acute mania,[19] and there is controversy regarding the drug’s effectiveness in treating acute bipolar depression.[20] While the 2002 American Psychiatric Association (APA) guidelines recommend lamotrigine as a first-line treatment for acute depression in Bipolar II disorder,[21] the APA’s website notes that the guidelines, being more than five years old, “can no longer be assumed to be current".[22] A paper written in 2008 by Nasser et al. reviewed evidence from trials that were unpublished and not referenced in the 2002 APA guidelines, and it concludes that lamotrigine has "very limited, if any, efficacy in the treatment of acute bipolar depression".[17] A 2008 paper by Calabrese et al. examined much of the same data, and found that in five placebo-controlled studies, lamotrigine did not significantly differ from placebo in the treatment of bipolar depression.[23] However, in a meta-analysis of these studies conducted in 2008, Calabrese found that lamotrigine was effective in individuals with bipolar depression, with a number needed to treat (NNT) of 11, or 7 in severe depression.[24]

A 2013 review about lamotrigine concluded that it is recommended in bipolar maintenance when depression is prominent and that more research is needed in regards to its role in the treatment of acute bipolar depression and unipolar depression. Furthermore, no information to recommend its use in other psychiatric disorders was found.[25]

Other uses[edit]

Off-label uses include the treatment of peripheral neuropathy, trigeminal neuralgia, cluster headaches, migraines, and reducing neuropathic pain.[26][27][28] Although a systematic review conducted in 2013 concluded that well-designed clinical trials have shown no benefit for lamotrigine in neuropathic pain.[29] Off-label psychiatric usage includes the treatment of treatment-resistant obsessive-compulsive disorder,[30]depersonalization disorder,[31]hallucinogen persisting perception disorder,[32]schizoaffective disorder,[33]borderline personality disorder,[34] and post-traumatic stress disorder.[35] In at least two cases, lamotrigine seemed efficacious for Kleine-Levin syndrome[36][37] but caused no improvement in at least one case.[38]

[edit]

Lamotrigine prescribing information has a black box warning about life-threatening skin reactions, including Stevens–Johnson syndrome (SJS), DRESS syndrome and toxic epidermal necrolysis (TEN).[39] The manufacturer states that nearly all cases appear in the first two to eight weeks of therapy,[39] or if the medication is suddenly stopped then resumed at the normal dosage.[citation needed] Patients should seek medical attention for any unexpected skin rash, as its presence is an indication of a possible serious or even deadly side-effect of the drug. Not all rashes that occur while taking lamotrigine progress to SJS or TEN. Between 5 and 10% of patients will develop a rash, but only one in a thousand patients will develop a serious rash. Rash and other skin reactions are more common in children, so this medication is often reserved for adults. For patients whose lamotrigine has been stopped after development of a rash, re-challenge with lamotrigine is also a viable option. However, it is not applicable for very serious cases.[40]

There is also an increased incidence of these eruptions in patients who are currently on, or recently discontinued a valproate-type anticonvulsant drug, as these medications interact in such a way that the clearance of both is decreased and the effective dose of lamotrigine is increased.[39]

Side-effects such as rash, fever, and fatigue are very serious, as they may indicate incipient Stevens–Johnson syndrome, toxic epidermal necrolysis, DRESS syndrome or aseptic meningitis.[41]

Other side-effects include loss of balance or coordination; double vision; crossed eyes; pupil constriction; blurred vision; dizziness and lack of coordination; drowsiness, insomnia; anxiety; vivid dreams or nightmares; dry mouth, mouth ulcers;[39]memory problems; mood changes; itchiness; runny nose; cough; nausea, indigestion, abdominal pain, weight loss; missed or painful menstrual periods; and vaginitis. The side-effect profile varies for different patient populations.[41] Overall adverse effects in treatment are similar between men, women, geriatric, pediatric and racial groups.[42]

Lamotrigine has been associated with a decrease in white blood cell count (leukopenia).[43] Lamotrigine does not prolong QT/QTc in TQT studies in healthy subjects.[44]

Cases of lamotrigine-induced neuroleptic malignant syndrome have been reported.[45][46]

Women[edit]

Women are more likely than men to have side-effects.[47] This is the opposite of most other anticonvulsants.

There is evidence showing interactions between lamotrigine and female hormones, which can be of particular concern for women on estrogen-containing hormonal contraceptives. Ethinylestradiol, the ingredient of such contraceptives, has been shown to decrease serum levels of lamotrigine.[48] Women starting an estrogen-containing oral contraceptive may need to increase the dosage of lamotrigine to maintain its level of efficacy. Likewise, women may experience an increase in lamotrigine side-effects upon discontinuation of the pill. This may include the "pill-free" week where lamotrigine serum levels have been shown to increase twofold.[39]

Pregnancy and breastfeeding[edit]

Many studies have found no association between lamotrigine exposure in utero and birth defects, while those that have found an association have found only slight associations with minor malformations like cleft palates.[49] Review studies have found that overall rates of congenital malformations in infants exposed to lamotrigine in utero are relatively low (1-4%), which is similar to the rate of malformations in the general population.[50][51] It is known that lamotrigine is a weak inhibitor of human dihydrofolate reductase (DHFR) and other, more powerful, human DHFR inhibitors like methotrexate are known to be teratogenic.[49]

Lamotrigine is expressed in breast milk; the manufacturer does not recommend breastfeeding during treatment. In "Medications and Mothers' Milk," a frequently updated review of scientific literature, lamotrigine is rated as L3: moderately safe.[52]

Other types of effects[edit]

Lamotrigine binds to melanin-containing tissues such as the iris of the eye. The long-term consequences of this are unknown.[53]

Some patients have reported experiencing a loss of concentration, even with very small doses. Lamotrigine has been implicated in the apoptoticneurodegeneration of the developing brain.[54]GlaxoSmithKline investigated lamotrigine for the treatment of ADHD with inconclusive results. No detrimental effects on cognitive function were observed; however, the only statistical improvement in core ADHD symptoms was an improvement on a Paced Auditory Serial Addition Test (PASAT) that measures auditory processing speed and calculation ability.[55] Another study reported that lamotrigine might be a safe and effective treatment option for adult ADHD comorbid with bipolar and recurrent depression.[56]

Lamotrigine is known to affect sleep. Studies with small numbers (10–15) of patients reported that lamotrigine increases sleep stability (increases the duration of REM sleep, decreases the number of phase shifts and decreases the duration of slow-wave sleep),[57] and that there was no effect on vigilance,[58] and daytime somnolence and cognitive function.[59] However, a retrospective study of 109 patients' medical records found that 6.7% of patients experienced an "alerting effect" resulting in intolerable insomnia, for which the treatment had to be discontinued.[60]

Lamotrigine can induce a type of seizure known as a myoclonic jerk, which tends to happen soon after the use of the medication.[61] When used in the treatment of myoclonic epilepsies such as juvenile myoclonic epilepsy, lower doses (and lower plasma levels) are usually needed, as even moderate doses of this drug can induce seizures, including tonic-clonic seizures, which can develop into status epilepticus, which is a medical emergency. It can also cause myoclonic status epilepticus.[42]

In overdose, lamotrigine can cause uncontrolled seizures in most people. Reported results in overdoses involving up to 15 g include increased seizures, coma and death.[42]

Pharmacology[edit]

Mechanism of action[edit]

Lamotrigine is a member of the sodium channel blocking class of antiepileptic drugs.[62] This may suppress the release of glutamate and aspartate, two of the dominant excitatory neurotransmitters in the CNS.[63] It is generally accepted to be a member of the sodium channel blocking class of antiepileptic drugs,[64] but it could have additional actions since it has a broader spectrum of action than other sodium channel antiepileptic drugs such as phenytoin and is effective in the treatment of the depressed phase of bipolar disorder, whereas other sodium channel blocking antiepileptic drugs are not, possibly on account of its sigma receptor activity. In addition, lamotrigine shares few side-effects with other, unrelated anticonvulsants known to inhibit sodium channels, which further emphasises its unique properties.[65] Lamotrigine is inactivated by glucuronidation in the liver.[66]

It is a triazine derivate that inhibits voltage-sensitivesodium channels, leading to stabilization of neuronal membranes. It also blocks L-, N-, and P-type calcium channels and has weak 5-hydroxytryptamine-3 (5-HT3) receptor inhibition. These actions are thought to inhibit release of glutamate at cortical projections in the ventral striatumlimbic areas,[67] and its neuroprotective and antiglutamatergic effects have been pointed out as promising contributors to its mood stabilizing activity.[68] Observations that lamotrigine reduced γ-aminobutyric acid (GABA) A receptor-mediated neurotransmission in rat amygdala,[69] suggest that a GABAergic mechanism may also be involved, although this concept is controversial.[70]

Lamotrigine does not have pronounced effects on any of the usual neurotransmitter receptors (adrenergic, dopamineD1 and D2, muscarinic, GABA, histaminergicH1, serotonin5-HT2, and N-methyl-D-asparate). Inhibitory effects on 5-HT, norepinephrine, and dopamine transporters are weak.[71] Lamotrigine is a weak inhibitor of dihydrofolate reductase,[72] but whether this effect is sufficient to contribute to a mechanism of action or increases risk to the fetus during pregnancy is not known. Early studies of lamotrigine's mechanism of action examined its effects on the release of endogenous amino acids from rat cerebral cortex slices in vitro. As is the case for antiepileptic drugs that act on voltage-dependent sodium channels, lamotrigine inhibited the release of glutamate and aspartate evoked by the sodium-channel activator veratrine and was less effective in the inhibition of acetylcholine or GABA release. At high concentrations, it had no effect on spontaneous or potassium evoked amino acid release.[47]

These studies suggested that lamotrigine acts presynaptically on voltage-gated sodium channels to decrease glutamate release. Several electrophysiological studies have investigated the effects of lamotrigine on voltage-dependent sodium channels. For example, lamotrigine blocked sustained repetitive firing in cultured mouse spinal cord neurons in a concentration-dependent manner, at concentrations that are therapeutically relevant in the treatment of human seizures. In cultured hippocampal neurons, lamotrigine reduced sodium currents in a voltage-dependent manner, and at depolarised potentials showed a small frequency-dependent inhibition. These and a variety of other results indicate that the antiepileptic effect of lamotrigine, like that of phenytoin and carbamazepine, is at least in part due to use- and voltage-dependent modulation of fast voltage-dependent sodium currents. However, lamotrigine has a broader clinical spectrum of activity than phenytoin and carbamazepine and is recognised to be protective against generalised absence epilepsy and other generalised epilepsy syndromes, including primary generalised tonic–clonic seizures, juvenile myoclonic epilepsy, and Lennox-Gastaut syndrome.

The basis for this broader spectrum of activity of lamotrigine is unknown, but could relate to actions of the drug on voltage-activated calcium channels. Lamotrigine blocks T-type calcium channels weakly, if at all. However, it does inhibit native and recombinant high-voltage–activated calcium channels (N- and P/Q/R-types) at therapeutic concentrations. Whether this activity on calcium channels accounts for lamotrigine's broader clinical spectrum of activity in comparison with phenytoin and carbamazepine remains to be determined.

It antagonises the following receptors with the following IC50 values:[72]

  • 5-HT3, IC50=18μM
  • σ receptors, IC50=145μM

Pharmacokinetics[edit]

The pharmacokinetics of lamotrigine follow first-order kinetics, with a half-life of 29 hours and volume of distribution of 1.36 L/kg.[73] Lamotrigine is rapidly and completely absorbed after oral administration. Its absolute bioavailability is 98% and its plasma Cmax occurs from 1.4 to 4.8 hours. Available data indicate that its bioavailability is not affected by food. Estimate of the mean apparent volume of distribution of lamotrigine following oral administration ranges from 0.9 to 1.3 L/kg. This is independent of dose and is similar following single and multiple doses in both patients with epilepsy and in healthy volunteers.[74]

Lamotrigine is metabolized predominantly by glucuronic acidconjugation. Its major metabolite is an inactive 2-n-glucuronide conjugate.[75] Lamotrigine has fewer drug interactions than many anticonvulsant drugs, although pharmacokinetic interactions with carbamazepine, phenytoin and other hepatic enzyme inducing medications may shorten half-life.[76] Dose adjustments should be made on clinical response, but monitoring may be of benefit in assessing compliance.[47]

The capacity of available tests to detect potentially adverse consequences of melanin binding is unknown. Clinical trials excluded subtle effects and optimal duration of treatment. There are no specific recommendations for periodic ophthalmological monitoring. Lamotrigine binds to the eye and melanin-containing tissues which can accumulate over time and may cause toxicity. Prescribers should be aware of the possibility of long-term ophthalmologic effects and base treatment on clinical response. Patient compliance should be periodically reassessed with lab and medical testing of liver and kidney function to monitor progress or side effects.[47]

History[edit]

  • December 1994 — Lamotrigine was approved for the treatment of partial seizures.[9]
  • August 1998 — for use as adjunctive treatment of Lennox-Gastaut syndrome in pediatric and adult patients, new dosage form: chewable dispersible tablets.
  • December 1998 — for use as monotherapy for treatment of partial seizures in adult patients when converting from a single enzyme-inducing anticonvulsant drug.
  • January 2003 — for use as adjunctive therapy for partial seizures in pediatric patients as young as two years of age.
  • June 2003 — approved for maintenance treatment of Bipolar II disorder; the first such medication since lithium.[15]
  • January 2004 — for use as monotherapy for treatment of partial seizures in adult patients when converting from the anti-epileptic drug valproate [including valproic acid (Depakene); sodium valproate (Epilim) and divalproex sodium (Depakote)].

Trade names[edit]

Lamotrigine was originally brought to market by GlaxoSmithKline, trademarked as Lamictal; it also available in generic form under many brand names worldwide.[1][77]

References[edit]

  1. ^ ab"Lamotrigine". Drugs.com. Retrieved 9 December 2017. 
  2. ^ abcdefghi"Lamotrigine". The American Society of Health-System Pharmacists. Retrieved 8 December 2017. 
  3. ^"Lamotrigine Use During Pregnancy | Drugs.com". Drugs.com. Retrieved 9 December 2017. 
  4. ^"Lamotrigine". PubChem Open Chemistry Database. US: National Institutes of Health. Retrieved December 13, 2016. 
  5. ^Shorvon, SD; Perucca, E; Engel, J (2015). The Treatment of Epilepsy (4th ed.). John Wiley & Sons, Incorporated. p. 1321. ISBN 9781118936993. 
  6. ^"WHO Model List of Essential Medicines (20th List)"(PDF). World Health Organization. March 2017. Retrieved 29 June 2017. 
  7. ^"Single Drug Information". International Medical Products Price Guide. Retrieved 9 December 2017. 
  8. ^"NADAC as of 2017-12-06". Centers for Medicare and Medicaid Services. Retrieved 9 December 2017. 
  9. ^ abanonymous (19 March 2004). "EFFICACY SUPPLEMENTS APPROVED IN CALENDAR YEAR 2003". FDA/Center for Drug Evaluation and Research. Retrieved 2008-04-09. 
  10. ^Kasper, D (2005). Fauci AS; Braunwald E; et al., eds. eds. Harrison’s Principles of Internal Medicine, 16th ed. McGraw-Hill. pp. 3–22. ISBN 9780071466332. 
  11. ^Tierny LM Jr (2006). McPhee SJ, Papadakis MA, eds. Current Medical Diagnosis and Treatment, 45th ed. McGraw-Hill. ISBN 0071454101. 
  12. ^Hancock EC, Cross JH (2013). "Treatment of Lennox-Gastaut syndrome". Cochrane Database of Systematic Reviews (2). doi:10.1002/14651858.CD003277.pub3. 
  13. ^French JA, Kanner AM, Bautista J, et al. (April 2004). "Efficacy and tolerability of the new antiepileptic drugs II: treatment of refractory epilepsy: report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society". Neurology. 62 (8): 1261–73. doi:10.1212/01.WNL.0000123695.22623.32. PMID 15111660. 
  14. ^Pellock JM (November 1999). "Managing pediatric epilepsy syndromes with new antiepileptic drugs". Pediatrics. 104 (5 Pt 1): 1106–16. doi:10.1542/peds.104.5.1106. PMID 10545555. 
  15. ^ abGlaxoSmithKline, 2003
  16. ^https://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/pediatricadvisorycommittee/ucm235547.pdf
  17. ^ abGhaemi, S.N.; Shirzadi, A.A.; Filkowski, M. (2008). "Publication Bias and the Pharmaceutical Industry: The Case of Lamotrigine in Bipolar Disorder". Medscape J Med. 10 (9): 211. PMC 2580079. PMID 19008973. 
  18. ^Goldberg JF, Calabrese JR, Saville BR, Frye MA, Ketter TA, Suppes T, Post RM, Goodwin FK (2009). "Mood stabilization and destabilization during acute and continuation phase treatment for bipolar I disorder with lamotrigine or placebo". Clinical Psychiatry. 70 (9): 1273–80. doi:10.4088/JCP.08m04381. PMID 19689918. 
  19. ^Goldsmith DR, Wagstaff AJ, Ibbotson T, Perry CM (2003). "Lamotrigine: a review of its use in bipolar disorder". Drugs. 63 (19): 2029–50. doi:10.2165/00003495-200363190-00009. PMID 12962521. 
  20. ^Geddes JR (May 2011). "Treatment of bipolar disorder". Lancet. 381 (9878): 1672–82. doi:10.1016/S0140-6736(13)60857-0. PMC 3876031. PMID 23663953. 
  21. ^"Acute Treatment — Formula and Implementation of a Treatment Plan". Practice Guideline for the Treatment of Patients With Bipolar Disorder Second Edition. American Psychiatric Association. Retrieved 15 August 2010. 
  22. ^"Main page". Practice Guideline for the Treatment of Patients With Bipolar Disorder Second Edition. American Psychiatric Association. Retrieved 15 August 2010. 
  23. ^Calabrese JR, Huffman RF, White RL, Edwards S, Thompson TR, Ascher JA, Monaghan ET, Leadbetter RA (2008). "Lamotrigine in the acute treatment of bipolar depression: results of five double-blind, placebo-controlled clinical trials". Bipolar Disorders. 10 (2): 323–333. doi:10.1111/j.1399-5618.2007.00500.x. PMID 18271912. 
  24. ^Calabrese JR, Geddes JR, Goodwin GM (2009). "Lamotrigine for treatment of bipolar depression: independent meta-analysis and meta-regression of individual patient data from five randomised trials". British Journal of Psychiatry. 194 (1): 4–9. doi:10.1192/bjp.bp.107.048504. PMID 19118318. 
  25. ^Reid, JG; Gitlin MJ; Altshuler LL (July 2013). "Lamotrigine in psychiatric disorders". J Clin Psychiatry. 74 (7): 675–84. doi:10.4088/JCP.12r08046. PMID 23945444. 
  26. ^Backonja M (June 2004). "Neuromodulating drugs for the symptomatic treatment of neuropathic pain". Curr Pain Headache Rep. 8 (3): 212–6. doi:10.1007/s11916-004-0054-4. PMID 15115640. 
  27. ^Jensen, T. S. (2002). "Anticonvulsants in neuropathic pain: Rationale and clinical evidence". European Journal of Pain. 6: 61–68. doi:10.1053/eujp.2001.0324. PMID 11888243. 
  28. ^Pappagallo M (October 2003). "Newer antiepileptic drugs: possible uses in the treatment of neuropathic pain and migraine". Clin Ther. 25 (10): 2506–38. doi:10.1016/S0149-2918(03)80314-4. PMID 14667954.
Lamotrigine, 150 mg tablet.

Not to be confused with Propanol.

beta blocker drug

Clinical data
Trade namesInderal, others
AHFS/Drugs.comMonograph
License data
Pregnancy
category
  • AU:C
  • US:C (Risk not ruled out)
Routes of
administration
By mouth, rectal, intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability26%
MetabolismLiver (extensive) 1A2, 2D6; minor: 2C19, 3A4
Biological half-life4–5 hours
ExcretionKidney (<1%)
Identifiers

IUPAC name

  • (RS)-1-(1-methylethylamino)-3-(1-naphthyloxy)propan-2-ol
CAS Number
PubChemCID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
ECHA InfoCard100.007.618
Chemical and physical data
FormulaC16H21NO2
Molar mass259.34 g/mol
3D model (JSmol)
ChiralityRacemic mixture

SMILES

  • CC(NCC(O)COC1=C(C=CC=C2)C2=CC=C1)C

InChI

  • InChI=1S/C16H21NO2/c1-12(2)17-10-14(18)11-19-16-9-5-7-13-6-3-4-8-15(13)16/h3-9,12,14,17-18H,10-11H2,1-2H3 Y
  • Key:AQHHHDLHHXJYJD-UHFFFAOYSA-N Y
  (verify)

Propranolol, sold under the brand name Inderal among others, is a medication of the beta blocker type.[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] Greater care 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 discovered in 1964.[7][8] It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system.[9] 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.[10] In the United States it costs about $15 per month at a typical dose.[1]

Medical uses[edit]

Propranolol is used for treating various conditions, including:

Cardiovascular[edit]

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[edit]

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]

PTSD and phobias[edit]

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. 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[edit]

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[edit]

See also: Beta blocker § Contraindications

Propranolol may be contraindicated in people with:[29]

Adverse effects[edit]

See also: Beta blocker § Adverse effects

Propranolol should be used with caution in people with:[29]

Pregnancy and lactation[edit]

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 pulmonary or cardiac complications, or premature birth. The newborn may experience additional adverse effects such as hypoglycemia and bradycardia.[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]

Adverse drug reactions associated with propranolol therapy are similar to other lipophilic beta blockers.

Overdose[edit]

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.

Interactions[edit]

Since beta blockers are known to relax the cardiac muscle and to constrict the smooth muscle, beta-adrenergic antagonists, 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:[29]

Pharmacology[edit]

Pharmacodynamics[edit]

SiteKi (nM)SpeciesRef
5-HT1A55–272Human[40][41]
5-HT1B56–85Rat[42][43]
5-HT1D4,070Pig[44]
5-HT2A4,280Human[45]
5-HT2B457–513 (+)
166–316 (–)
Human[46]
5-HT2C61,700 (+)
5,010 (–)
736–2,457
Human
Human
Rodent
[46]
[46]
[47][41]
5-HT3>10,000Human[48]
α1NDNDND
α21,297–2,789Rat[49]
β10.02–2.69Human[50][51]
β20.01–0.61Human[50][51]
β3450Mouse[52]
D1>10,000Human[41]
D2>10,000Human[41]
H1>10,000Human[53]
SERT3,700Rat[54]
NET5,000 (IC50)Rat[55]
DAT29,000 (IC50)Rat[55]
VDCC>10,000Rat[56]
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 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 beta blocker; 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).[57] 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).[58][55] 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.[58][55] Therefore, it can be looked upon as a weak indirect α1-adrenoceptor agonist in addition to potent β-adrenoceptor antagonist.[58][55] 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.[59][60][46] The latter may be involved in the effectiveness of propranolol in the treatment of migraine at high doses.[46]

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.[61][62][63]

Pharmacokinetics[edit]

Propranolol is rapidly and completely absorbed, with peak plasma levels achieved about 1–3 hours after ingestion. Coadministration with food appears to enhance bioavailability.[64] Despite complete absorption, propranolol has a variable bioavailability due to extensive first-pass metabolism. Hepatic impairment therefore increases 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 and 100 mg/l.[citation needed] Toxic levels are associated with plasma concentrations above 2000 mg/l.[citation needed]

History[edit]

Main article: Discovery and development of β-adrenergic receptor antagonists (beta-blockers)

British scientist James W. Black developed propranolol in the 1960s.[65] In 1988, he 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 (-O-CH2-) 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 in the treatment of hypertension.

Society and culture[edit]

In a 1987 study by the International Conference of Symphony and Opera Musicians, 27% of interviewed members admitted to using beta blockers such as propranolol for musical performances.[66] For about 10–16% of performers, their degree of stage fright is considered pathological.[66][67] Propranolol is used by musicians, actors, and public speakers for its ability to treat anxiety symptoms activated by the sympathetic nervous system.[68]

Brand names[edit]

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.[69]

Research[edit]

Clinical research has been conducted to learn if propranolol could be useful in the treatment of some cancers.[70]

References[edit]

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A mixture of 20 mg and 10 mg propranolol tablets

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