Tag: Medication

What is Flubromazolam?

Published on by Andrew Marshall3 Comments

Introduction

Flubromazolam (JYI-73) is a triazolobenzodiazepine (TBZD), which are benzodiazepine (BZD) derivatives.

Flubromazolam is reputed to be highly potent, and concerns have been raised that clonazolam and flubromazolam in particular may pose comparatively higher risks than other designer benzodiazepines, due to their ability to produce strong sedation and amnesia at oral doses of as little as 0.5 mg. Life-threatening adverse reactions have been observed at doses of only 3 mg of flubromazolam.

Sweden

Flubromazolam has been classified as an illegal substance in Sweden after seizures by customs and police, as well as indications from the EMCDDA of wider use as a recreational drug.

Switzerland

Flubromazolam is illegal in Switzerland as of December 2015.

United Kingdom

In the UK, flubromazolam has been classified as a Class C drug by the May 2017 amendment to The Misuse of Drugs Act 1971 along with several other designer benzodiazepine drugs.

What is Eszopiclone?

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Introduction

Eszopiclone, sold under the brand-name Lunesta among others, is a medication used in the treatment of insomnia.

Evidence supports slight to moderate benefit up to six months. It is taken orally. Common side effects include headache, dry mouth, nausea, and dizziness. Severe side effects may include suicidal thoughts, unhealthy non-medical use, hallucinations, and angioedema. Greater care is recommended in those with liver problems and older people. Rapid decreasing of the dose may result in withdrawal. Eszopiclone is classified as a nonbenzodiazepine sedative hypnotic and as a cyclopyrrolone. It is the S-stereoisomer of zopiclone. It works by interacting with the GABA receptors.

Approved for medical use in the United States in 2004, eszopiclone is available as generic medication. In 2017, it was the 214th most commonly prescribed medication in the United States, with more than two million prescriptions. Eszopiclone is not sold in the European Union, as in 2009 the EMA ruled that it was too similar to zopiclone to be considered a new patentable product.

Brief History

In a controversial 2009 article in the New England Journal of Medicine, “Lost in Transmission — FDA Drug Information That Never Reaches Clinicians”, it was reported that the largest of three Lunesta trials found that compared to placebo Lunesta “was superior to placebo” while it only shortened initial time falling asleep by 15 minutes on average. “Clinicians who are interested in the drug’s efficacy cannot find efficacy information in the label: it states only that Lunesta is superior to placebo. The FDA’s medical review provides efficacy data, albeit not until page 306 of the 403-page document. In the longest, largest phase 3 trial, patients in the Lunesta group reported falling asleep an average of 15 minutes faster and sleeping an average of 37 minutes longer than those in the placebo group. However, on average, Lunesta patients still met criteria for insomnia and reported no clinically meaningful improvement in next-day alertness or functioning.”

Availability in Europe

On 11 September 2007, Sepracor signed a marketing deal with British pharmaceutical company GlaxoSmithKline for the rights to sell eszopiclone (under the name Lunivia rather than Lunesta) in Europe. Sepracor was expected to receive approximately $155 million if the deal went through. In 2008 Sepracor submitted an application to the EMA (the European Union’s equivalent to the US FDA) for authorisation to market the drug in the EU, and initially received a favourable response. However, Sepracor withdrew its authorization application in 2009 after the EMA stated it would not be granting eszopiclone ‘new active substance’ status, as it was essentially pharmacologically and therapeutically too similar to zopiclone to be considered a new patentable product. Since the patent on zopiclone has expired, this ruling would have allowed rival companies to also legally produce cheaper generic versions of eszopiclone for the European market. As of November 2012, Sepracor has not resubmitted its authorisation application and eszopiclone is not available in Europe. The deal with GSK fell through, and GSK instead launched a $3.3 billion deal to market Actelion’s almorexant sleeping tablet, which entered phase 3 medical trials before development was abandoned due to side effects.

Medical Uses

A 2018 Cochrane review found that it produced moderate improvement in sleep onset and maintenance. The authors suggest that where preferred non-pharmacological treatment strategies have been exhausted, eszopiclone provides an efficient treatment for insomnia. In 2014, the USFDA asked that the starting dose be lowered from 2 milligrams to 1 milligram after it was observed in a study that even 8 hours after taking the drug at night, some people were not able to cope with their next-day activities like driving and other activities that require full alertness.

Eszopiclone is slightly effective in the treatment of insomnia where difficulty in falling asleep is the primary complaint. Kirsch et al. found the benefit over placebo to be of questionable clinical significance. Although the drug effect and the placebo response were rather small and of questionable clinical importance, the two together produce a reasonably large clinical response. It is not recommended for chronic use in the elderly.

Elderly

Sedative hypnotic drugs including eszopiclone are more commonly prescribed to the elderly than to younger patients despite benefits of medication being generally unimpressive. Care should be taken in choosing an appropriate hypnotic drug and if drug therapy is initiated it should be initiated at the lowest possible dose to minimise side effects.

In 2015, the American Geriatrics Society reviewed the safety information about eszopiclone and similar drugs and concluded that the “nonbenzodiazepine, benzodiazepine receptor agonist hypnotics (eszopiclone, zaleplon, zolpidem) are to be avoided without consideration of duration of use because of their association with harms balanced with their minimal efficacy in treating insomnia.”

The review made this determination both because of the relatively large dangers to elderly individuals from zolpidem and other “z-drugs” together with the fact the drugs have “minimal efficacy in treating insomnia.” This was a change from the 2012 AGS recommendation, which suggested limiting use to 90 days or less. The review stated: “the 90‐day‐use caveat [was] removed from nonbenzodiazepine, benzodiazepine receptor agonist hypnotics, resulting in an unambiguous ‘avoid’ statement (without caveats) because of the increase in the evidence of harm in this area since the 2012 update.”

An extensive review of the medical literature regarding the management of insomnia and the elderly found that there is considerable evidence of the effectiveness and durability of non-drug treatments for insomnia in adults of all ages and that these interventions are underutilized. Compared with the benzodiazepines, the nonbenzodiazepine sedative-hypnotics, including eszopiclone appeared to offer few, if any, significant clinical advantages in efficacy or tolerability in elderly persons. It was found that newer agents with novel mechanisms of action and improved safety profiles, such as the melatonin receptor agonists, hold promise for the management of chronic insomnia in elderly people. Long-term use of sedative-hypnotics for insomnia lacks an evidence base and has traditionally been discouraged for reasons that include concerns about such potential adverse drug effects as cognitive impairment (anterograde amnesia), daytime sedation, motor incoordination, and increased risk of motor vehicle accidents and falls. In addition, the effectiveness and safety of long-term use of these agents remain to be determined. It was concluded that more research is needed to evaluate the long-term effects of treatment and the most appropriate management strategy for elderly persons with chronic insomnia.

A 2009 meta-analysis found a higher rate of infections.

Adverse Effects

Sleeping pills, including eszopiclone, have been associated with an increased risk of death.

Hypersensitivity to eszopiclone is a contra-indication to its use. Some side effects are more common than others. Recommendations around use of eszopiclone may be altered by other health conditions. These conditions or circumstances may occur in people that have lowered metabolism and other conditions. The presence of liver impairment, lactation and activities requiring mental alertness (e.g. driving) may be considered when determining frequency and dosage.

  • Unpleasant taste.
  • Headache.
  • Peripheral oedema.
  • Chest pain.
  • Abnormal thinking.
  • Behaviour changes.
  • Depression.
  • Hallucinations.
  • Sleep driving and sleepwalking.
  • Dry mouth.
  • Rash.
  • Altered sleep patterns.
  • Impaired coordination.
  • Dizziness.
  • Daytime drowsiness.
  • Itching.
  • Painful or frequent urination.
  • Back pain.
  • Aggressive behaviour.
  • Confusion.
  • Agitation.
  • Suicidal thoughts.
  • Depersonalisation.
  • Amnesia.

A 2009 meta-analysis found a 44% higher rate of mild infections, such as pharyngitis or sinusitis, in people taking eszopiclone or other hypnotic drugs compared to those taking a placebo.

Dependence

In the United States eszopiclone is a schedule IV controlled substance under the Controlled Substances Act. Use of eszopiclone may lead to physical and psychological dependence. The risk of non-medical use and dependence increases with the dose and duration of usage and concomitant use of other psychoactive substances. The risk is also greater in patients with a history of alcohol use disorder or other substance use disorder or history of psychiatric disorders. Tolerance may develop after repeated use of benzodiazepines and benzodiazepine-like drugs for a few weeks.

A study funded and carried out by Sepracor, the manufacturer of eszopiclone, found no signs of tolerance or dependence in a group of patients followed for up to six months.

Non-Medical Use

A study of non-medical use potential of eszopiclone found that in persons with a known history of non-medical benzodiazepine use, eszopiclone at doses of 6 and 12 mg produced effects similar to those of diazepam 20 mg. The study found that at these doses which are two or more times greater than the maximum recommended doses, a dose-related increase in reports of amnesia, sedation, sleepiness, and hallucinations was observed for both eszopiclone (Lunesta) as well as for diazepam (Valium).

Overdose

According to the US Prescribing Information, overdoses of eszopiclone up to 90 times the recommended dose have been reported in which the patient fully recovered. According to the May 2014 edition of the official US Prescribing Information, fatalities have been reported only in cases in which eszopiclone was combined with other drugs or alcohol.

Poison control centres reported that between 2005 and 2006 there were 525 total eszopiclone overdoses recorded in the state of Texas, the majority of which were intentional suicide attempts.

If consumed within the last hour, eszopiclone overdose can be treated with the administration of activated charcoal or via gastric lavage.

Interactions

There is an increased risk of central nervous system depression when eszopiclone is taken together with other CNS depressant agents, including antipsychotics, sedative hypnotics (like barbiturates or benzodiazepines), antihistamines, opioids, phenothiazines, and some antidepressants. There is also increased risk of central nervous system depression with other medications that inhibit the metabolic activities of the CYP3A4 enzyme system of the liver. Medications that inhibit this enzyme system include nelfinavir, ritonavir, ketoconazole, itraconazole and clarithromycin. Alcohol also has an additive effect when used concurrently with eszopiclone. Eszopiclone is most effective if it is not taken after a heavy meal with high fat content.

Pharmacology

Eszopiclone acts on benzodiazepine binding site situated on GABAA neurons as a positive allosteric modulator. Eszopiclone is rapidly absorbed after oral administration, with serum levels peaking between .45 and 1.3 hours. The elimination half-life of eszopiclone is approximately 6 hours and it is extensively metabolized by oxidation and demethylation. Approximately 52% to 59% of a dose is weakly bound to plasma protein. Cytochrome P450 (CYP) isozymes CYP3A4 and CYP2E1 are involved in the biotransformation of eszopiclone; thus, drugs that induce or inhibit these CYP isozymes may affect the metabolism of eszopiclone. Less than 10% of the orally administered dose is excreted in the urine as racemic zopiclone. In terms of benzodiazepine receptor binding and relevant potency, 3 mg of eszopiclone is equivalent to 10 mg of diazepam.

What is Estazolam?

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Introduction

Estazolam, sold under the brand name Prosom among others, is a tranquiliser medication of the triazolobenzodiazepine (TBZD) class, which are benzodiazepines (BZDs) fused with a triazole ring.

It possesses anxiolytic, anticonvulsant, hypnotic, sedative and skeletal muscle relaxant properties. Estazolam is an intermediate-acting oral benzodiazepine. It is used for short-term treatment of insomnia.

It was patented in 1968 and came into medical use in 1975.

Medical Uses

Estazolam is prescribed for the short-term treatment of certain sleep disorders. It is an effective hypnotic drug showing efficacy in increasing the time spent asleep as well as reducing awakenings during the night. Combination with non-pharmacological options for sleep management results in long-term improvements in sleep quality after discontinuation of short-term estazolam therapy. Estazolam is also sometimes used as a preoperative sleep aid. It was found to be superior to triazolam in side effect profile in preoperative patients in a trial. Estazolam also has anxiolytic properties and due to its long half life can be an effective short-term treatment for insomnia associated with anxiety.

Side Effects

A hang-over effect commonly occurs with next day impairments of mental and physical performance. Other side effects of estazolam include somnolence, dizziness, hypokinesia, and abnormal coordination.

In September 2020, the US Food and Drug Administration (FDA) required the boxed warning be updated for all benzodiazepine medicines to describe the risks of abuse, misuse, addiction, physical dependence, and withdrawal reactions consistently across all the medicines in the class.

Tolerance and Dependence

The main safety concern of benzodiazepines such as estazolam is a benzodiazepine dependence and the subsequent benzodiazepine withdrawal syndrome which can occur upon discontinuation of the estazolam. A review of the literature found that long-term use of benzodiazepines such as estazolam is associated with drug tolerance, drug dependence, rebound insomnia and CNS related adverse effects. Estazolam should only be used short term and at the lowest effective dose to avoid complications related to long-term use. Non-pharmacological treatment options however, were found to have sustained improvements in sleep quality. The short-term benefits of benzodiazepines on sleep begin to reduce after a few days due to tolerance to the hypnotic effects of benzodiazepines in the elderly.

Contraindications and Special Caution

Benzodiazepines require special precaution if used in the elderly, during pregnancy, in children, alcohol or drug-dependent individuals and individuals with comorbid psychiatric disorders.

Elderly

An extensive review of the medical literature regarding the management of insomnia and the elderly found that there is considerable evidence of the effectiveness and durability of non-drug treatments for insomnia in adults of all ages and that these interventions are underutilized. Compared with the benzodiazepines including estazolam, the nonbenzodiazepine sedative-hypnotics appeared to offer few, if any, significant clinical advantages in efficacy or tolerability in elderly persons. It was found that newer agents with novel mechanisms of action and improved safety profiles, such as the melatonin agonists, hold promise for the management of chronic insomnia in elderly people. Long-term use of sedative-hypnotics for insomnia lacks an evidence base and has traditionally been discouraged for reasons that include concerns about such potential adverse drug effects as cognitive impairment (anterograde amnesia), daytime sedation, motor incoordination, and increased risk of motor vehicle accidents and falls. In addition, the effectiveness and safety of long-term use of these agents remain to be determined. It was concluded that more research is needed to evaluate the long-term effects of treatment and the most appropriate management strategy for elderly persons with chronic insomnia.

Pharmacology

Estazolam is classed as a “triazolo” benzodiazepine drug. Estazolam exerts its therapeutic effects via its benzodiazepines receptor agonist properties. Estazolam at high doses decreases histamine turnover via its action at the benzodiazepine-GABA receptor complex in mouse brains.

Pharmacokinetics

Peak plasma levels are achieved within 1-6 hours. Estazolam is an intermediate acting benzodiazepine. The elimination half life of estazolam is an average of 19 hours, with a range of 8-31 hours. The major metabolite of estazolam is 4-hydroxyestazolam. Other identified metabolites include 1-oxo-estazolam, 4′-hydroxy-estazolam, and benzophenone.

Interactions

Alcohol enhances the sedative hypnotic properties of estazolam. In package inserts, the manufacturer clearly warns about an interaction with Ritonavir, and although clinical interactions of Ritonavir with estazolam have not yet been described, the lack of clinical descriptions of the interactions does not negate the seriousness of the interaction.

EEG Effects in Rabbits

An animal study in rabbits demonstrated that estazolam induces a drowsy pattern of spontaneous EEG including high voltage slow waves and spindle bursts increase in the cortex and amygdala, while the hippocampal theta rhythm is desynchronised. Also low voltage fast waves occur particularly in the cortical EEG. The EEG arousal response to auditory stimulation and to electric stimulation of the mesencephalic reticular formation, posterior hypothalamus and centromedian thalamus is significantly suppressed. The photic driving response elicited by a flash light in the visual cortex is significantly suppressed by estazolam.

Abuse

Refer to Benzodiazepine Use Disorder.

A primate study found that estazolam has abuse potential. Estazolam is a drug with the potential for misuse. Two types of drug misuse can occur; recreational misuse, where the drug is taken to achieve a high or when the drug is continued long term against medical advice. Estazolam became notorious in 1998 when a large amount of an ‘herbal sleeping mix’ called Sleeping Buddha was recalled from the shelves after the FDA discovered that it contained estazolam. In 2007, a Canadian product called Sleepees was recalled after it was found to contain undeclared estazolam.

What is Triazolobenzodiazepine?

Published on by Andrew Marshall7 Comments

Introduction

Triazolobenzodiazepines (TBZD) are a class of benzodiazepine (BZD) derivative pharmaceutical drugs. Chemically, they differ from other benzodiazepines by having an additional fused triazole ring.

Examples include:

  • Adinazolam.
  • Alprazolam.
  • Bromazolam.
  • Clonazolam.
  • Estazolam.
  • Flualprazolam.
  • Flubromazolam.
  • Flunitrazolam.
  • Nitrazolam.
  • Pyrazolam.
  • Triazolam.
  • Zapizolam.

Synthesis

Synthesis of 1-methyltriazolobenzodiazepines (alprazolam type) is possible by heating 1,4-benzodiazepin-2-thiones with hydrazine and acetic acid in n-butanol under reflux.

What is the WHO Model List of Essential Medicines?

Published on by Andrew Marshall13 Comments

Introduction

The WHO Model List of Essential Medicines (aka Essential Medicines List or EML), published by the World Health Organisation (WHO), contains the medications considered to be most effective and safe to meet the most important needs in a health system.

The list is frequently used by countries to help develop their own local lists of essential medicines. As of 2016, more than 155 countries have created national lists of essential medicines based on the WHO’s model list. This includes countries in both the developed and developing world.

40 years of the WHO Model List of Essential Medicines was celebrated in 2017.

The list is divided into core items and complementary items. The core items are deemed to be the most cost-effective options for key health problems and are usable with little additional health care resources. The complementary items either require additional infrastructure such as specially trained health care providers or diagnostic equipment or have a lower cost–benefit ratio. About 25% of items are in the complementary list. Some medications are listed as both core and complementary. While most medications on the list are available as generic products, being under patent does not preclude inclusion.

The first list was published in 1977 and included 208 medications. The WHO updates the list every two years. The 14th list was published in 2005 and contained 306 medications. In 2015, the 19th edition of the list was published and contains around 410 medications. The 20th edition was published in 2017, and contains 433 medications. The 21st list was published in 2019 and contains 460 medications. The 22nd list was published in 2021 and contains 479 medications. Various national lists contain between 334 and 580 medications.

A separate list for children up to 12 years of age, known as the WHO Model List of Essential Medicines for Children (EMLc), was created in 2007 and is in its 8th edition. It was created to make sure that the needs of children were systematically considered such as availability of proper formulations. Everything in the children’s list is also included in the main list. The list and notes are based on the 19th to 22nd edition of the main list. An α indicates a medicine is only on the complementary list. Therapeutic alternatives with similar clinical performance are listed for some medicines and they may be considered for national essential medicines lists.

Anaesthetics, Preoperative Medicines and Medical Gases

  • General anaesthetics and oxygen:
    • Inhalational medicines.
      • Halothane.
      • Isoflurane.
      • Nitrous oxide.
      • Oxygen.
    • Injectable medicines.
      • Ketamine.
      • Propofol.
  • Local anaesthetics:
    • Bupivacaine.
    • Lidocaine.
    • Lidocaine/epinephrine (lidocaine + epinephrine).
    • Ephedrineα.
  • Preoperative medication and sedation for short-term procedures:
    • Atropine
    • Midazolam
    • Morphine
  • Medical gases:
    • Oxygen.

Medicines for Pain and Palliative Care

  • Non-opioids and non-steroidal anti-inflammatory medicines (NSAIMs):
    • Acetylsalicylic acid (aspirin).
    • Ibuprofen.
    • Paracetamol.
  • Opioid analgesics:
    • Codeine.
    • Fentanyl.
    • Morphine.
    • Methadoneα.
  • Medicines for other common symptoms in palliative care:
    • Amitriptyline.
    • Cyclizine.
    • Dexamethasone.
    • Diazepam.
    • Docusate sodium.
    • Fluoxetine.
    • Haloperidol.
    • Hyoscine butylbromide.
    • Hyoscine hydrobromide.
    • Lactulose.
    • Loperamide.
    • Metoclopramide.
    • Midazolam.
    • Ondansetron.
    • Senna.

Antiallergics and Medicines used in Anaphylaxis

  • Dexamethasone.
  • Epinephrine (adrenaline).
  • Hydrocortisone.
  • Loratadine.
  • Prednisolone.

Antidotes and Other Substances used in Poisonings

  • Non-specific:
    • Charcoal, activated.
  • Specific.
    • Acetylcysteine.
    • Atropine.
    • Calcium gluconate.
    • Methylthioninium chloride (methylene blue).
    • Naloxone.
    • Penicillamine.
    • Prussian blue.
    • Sodium nitrite.
    • Sodium thiosulfate.
    • Deferoxamineα.
    • Dimercaprolα.
    • Fomepizoleα.
    • Sodium calcium edetateα.
    • Succimerα.

Anticonvulsants/Antiepileptics

Anti-Infective Medicines

  • Anthelminthics:
    • Intestinal anthelminthics.
      • Albendazole.
      • Ivermectin.
      • Levamisole.
      • Mebendazole.
      • Niclosamide.
      • Praziquantel.
      • Pyrantel.
    • Antifilarials.
      • Albendazole.
      • Diethylcarbamazine.
      • Ivermectin.
    • Antischistosomals and other antinematode medicines.
      • Praziquantel.
      • Triclabendazole.
      • Oxamniquineα.
    • Cysticidal medicines.
      • Albendazoleα.
      • Mebendazoleα.
      • Praziquantelα.
  • Antibacterials:
    • Access group antibiotics.
      • Amikacin
      • Amoxicillin.
      • Amoxicillin/clavulanic acid (amoxicillin + clavulanic acid).
      • Ampicillin.
      • Benzathine benzylpenicillin.
      • Benzylpenicillin.
      • Cefalexin.
      • Cefazolin.
      • Chloramphenicol.
      • Clindamycin.
      • Cloxacillin.
      • Doxycycline.
      • Gentamicin.
      • Metronidazole.
      • Nitrofurantoin.
      • Phenoxymethylpenicillin (penicillin V).
      • Procaine benzylpenicillin.
      • Spectinomycin.
      • Sulfamethoxazole/trimethoprim (sulfamethoxazole + trimethoprim).
      • Trimethoprim.
    • Watch group antibiotics.
      • Azithromycin.
      • Cefixime.
      • Cefotaxime.
      • Ceftriaxone.
      • Cefuroxime.
      • Ciprofloxacin.
      • Clarithromycin.
      • Piperacillin/tazobactam (piperacillin + tazobactam).
      • Vancomycin.
      • Ceftazidimeα.
      • Meropenemα.
      • Vancomycinα.
    • Reserve group antibiotics.
      • Cefiderocolα.
      • Ceftazidime/avibactam (ceftazidime + avibactam)α.
      • Colistinα.
      • Fosfomycinα.
      • Linezolidα.
      • Meropenem/vaborbactam (meropenem + vaborbactam)α.
      • Plazomicinα.
      • Polymyxin Bα.
    • Antileprosy medicines.
      • Clofazimine.
      • Dapsone.
      • Rifampicin.
    • Antituberculosis medicines.
      • Ethambutol.
      • Ethambutol/isoniazid/pyrazinamide/rifampicin (ethambutol + isoniazid + pyrazinamide + rifampicin).
      • Ethambutol/isoniazid/rifampicin (ethambutol + isoniazid + rifampicin).
      • Isoniazid.
      • Isoniazid/pyrazinamide/rifampicin (isoniazid + pyrazinamide + rifampicin).
      • Isoniazid/rifampicin (isoniazid + rifampicin).
      • Isoniazid/rifapentine (isoniazid + rifapentine).
      • Moxifloxacin.
      • Pyrazinamide.
      • Rifabutin.
      • Rifampicin.
      • Rifapentine.
      • Amikacinα.
      • Amoxicillin/clavulanic acid (amoxicillin + clavulanic acid)α.
      • Bedaquilineα.
      • Clofazimineα.
      • Cycloserineα.
      • Delamanidα.
      • Ethionamideα.
      • Levofloxacinα.
      • Linezolidα.
      • Meropenemα.
      • Moxifloxacinα.
      • P-aminosalicylic acidα.
      • Streptomycinα.
  • Antifungal medicines.
    • Amphotericin B.
    • Clotrimazole.
    • Fluconazole.
    • Flucytosine.
    • Griseofulvin.
    • Itraconazole.
    • Nystatin.
    • Voriconazole.
    • Micafunginα.
    • Potassium iodideα.
  • Antiviral medicines
    • Antiherpes medicines.
      • Aciclovir.
    • Antiretrovirals.
    • Nucleoside/nucleotide reverse transcriptase inhibitors.
      • Abacavir.
      • Lamivudine.
      • Tenofovir disoproxil fumarate.
      • Zidovudine.
    • Non-nucleoside reverse transcriptase inhibitors.
      • Efavirenz.
      • [[Nevirapine].
    • Protease inhibitors.
      • Atazanavir/ritonavir (atazanavir + ritonavir).
      • Darunavir.
      • Lopinavir/ritonavir (lopinavir + ritonavir).
      • Ritonavir.
    • Integrase inhibitors.
      • Dolutegravir.
      • Raltegravir.
    • Fixed-dose combinations of antiretroviral medicines.
      • Abacavir/lamivudine (abacavir + lamivudine).
      • Dolutegravir/lamivudine/tenofovir (dolutegravir + lamivudine + tenofovir.
      • Efavirenz/emtricitabine/tenofovir.
      • Efavirenz/lamivudine/tenofovir (efavirenz + lamivudine + tenofovir).
      • Emtricitabine/tenofovir (emtricitabine + tenofovir).
      • Lamivudine/zidovudine (lamivudine + zidovudine).
    • Medicines for prevention of HIV-related opportunistic infections.
      • Isoniazid/pyridoxine/sulfamethoxazole/trimethoprim (isoniazid + pyridoxine + sulfamethoxazole + trimethoprim).
    • Other antivirals.
      • Ribavirin.
      • Valganciclovir.
      • Oseltamivirα.
      • Valganciclovirα.
    • Antihepatitis medicines.
    • Medicines for hepatitis B.
    • Nucleoside/Nucleotide reverse transcriptase inhibitors.
      • Entecavir.
      • Tenofovir disoproxil fumarate.
    • Medicines for hepatitis C.
    • Pangenotypic direct-acting antiviral combinations
      • Daclatasvir.
      • Daclatasvir/sofosbuvir (daclatasvir + sofosbuvir).
      • Glecaprevir/pibrentasvir (glecaprevir + pibrentasvir).
      • Sofosbuvir.
      • Sofosbuvir/velpatasvir (sofosbuvir + velpatasvir).
    • Non-pangenotypic direct-acting antiviral combinations
      • Dasabuvir.
      • Ledipasvir/sofosbuvir (ledipasvir + sofosbuvir).
      • Ombitasvir/paritaprevir/ritonavir (ombitasvir + paritaprevir + ritonavir).
    • Other antivirals for hepatitis C.
      • Ribavirin.
      • Pegylated interferon-alpha-2a or pegylated interferon-alpha-2bα.
  • Antiprotozoal medicines:
    • Antiamoebic and antigiardiasis medicines
      • Diloxanide.
      • Metronidazole.
    • Antileishmaniasis medicines
      • Amphotericin B.
      • Miltefosine.
      • Paromomycin.
      • Sodium stibogluconate or meglumine antimoniate.
    • Antimalarial medicines.
    • For curative treatment.
      • Amodiaquine.
      • Artemether.
      • Artemether/lumefantrine (artemether + lumefantrine).
      • Artesunate.
      • Artesunate/amodiaquine (artesunate + amodiaquine).
      • Artesunate/mefloquine (artesunate + mefloquine).
      • Artesunate/pyronaridine tetraphosphate (artesunate + pyronaridine tetraphosphate).
      • Chloroquine.
      • Dihydroartemisinin/piperaquine phosphate (dihydroartemisinin + piperaquine phosphate).
      • Doxycycline.
      • Mefloquine.
      • Primaquine.
      • Quinine.
      • Sulfadoxine/pyrimethamine (sulfadoxine + pyrimethamine).
    • For chemoprevention.
      • Amodiaquine + sulfadoxine/pyrimethamine (Co-packaged).
      • Chloroquine.
      • Doxycycline.
      • Mefloquine.
      • Proguanil.
      • Sulfadoxine/pyrimethamine (sulfadoxine + pyrimethamine).
    • Antipneumocystosis and antitoxoplasmosis medicines.
      • Pyrimethamine.
      • Sulfadiazine.
      • Sulfamethoxazole/trimethoprim (sulfamethoxazole + trimethoprim).
      • Pentamidineα.
    • Antitrypanosomal medicines.
    • African trypanosomiasis.
      • Fexinidazole.
    • Medicines for the treatment of 1st stage African trypanosomiasis.
      • Pentamidine.
      • Suramin sodium.
    • Medicines for the treatment of 2nd stage African trypanosomiasis.
      • Eflornithine.
      • Melarsoprol.
      • Nifurtimox.
      • Melarsoprolα.
    • American trypanosomiasis.
      • Benznidazole.
      • Nifurtimox.
  • Medicines for ectoparasitic infections.
    • Ivermectin.

Antimigraine Medicines

  • For treatment of acute attack:
    • Acetylsalicylic acid (aspirin).
    • Ibuprofen.
    • Paracetamol (acetaminophen).
    • Sumatriptan.
  • For prophylaxis:
    • Propranolol.

Immunomodulators and Antineoplastics

  • Immunomodulators for non-malignant disease:
    • Adalimumabα.
    • Azathioprineα.
    • Ciclosporinα.
    • Tacrolimusα.
  • Antineoplastics and supportive medicines:
    • Cytotoxic medicines.
      • Arsenic trioxideα.
      • Asparaginaseα.
      • Bendamustineα.
      • Bleomycinα.
      • Calcium folinateα.
      • Capecitabineα.
      • Carboplatinα.
      • Chlorambucilα.
      • Cisplatinα.
      • Cyclophosphamideα.
      • Cytarabineα.
      • Dacarbazineα.
      • Dactinomycinα.
      • Daunorubicinα.
      • Docetaxelα.
      • Doxorubicinα.
      • Etoposideα.
      • Fludarabineα.
      • Fluorouracilα.
      • Gemcitabineα.
      • Hydroxycarbamideα.
      • Ifosfamideα.
      • Irinotecanα.
      • Melphalanα.
      • Mercaptopurineα.
      • Methotrexateα.
      • Oxaliplatinα.
      • Paclitaxelα.
      • Pegaspargaseα.
      • Procarbazineα.
      • Realgar Indigo naturalis formulationα.
      • Tioguanineα.
      • Vinblastineα.
      • Vincristineα.
      • Vinorelbineα.
    • Targeted therapies.
      • All-trans retinoic acid (tretinoin) (ATRA)α.
      • Bortezomibα.
      • Dasatinibα.
      • Erlotinibα.
      • Everolimusα.
      • Ibrutinibα.
      • Imatinibα.
      • Nilotinibα.
      • Rituximabα.
      • Trastuzumabα.
    • Immunomodulators.
      • Filgrastimα.
      • Lenalidomideα.
      • Nivolumabα.
      • Thalidomideα.
    • Hormones and antihormones.
      • Abirateroneα.
      • Anastrozoleα.
      • Bicalutamideα.
      • Dexamethasoneα.
      • Hydrocortisoneα.
      • Leuprorelinα.
      • Methylprednisoloneα.
      • Prednisoloneα.
      • Tamoxifenα.
    • Supportive medicines.
      • Allopurinolα.
      • Mesnaα.
      • Rasburicaseα.
      • Zoledronic acidα.

Antiparkinsonism Medicines

  • Biperiden.
  • Levodopa/carbidopa (levodopa + carbidopa).

Medicines Affecting the Blood

  • Antianaemia medicines:
    • Ferrous salt.
    • Ferrous salt/folic acid (ferrous salt + folic acid).
    • Folic acid.
    • Hydroxocobalamin.
    • Erythropoiesis-stimulating agentsα.
  • Medicines affecting coagulation:
    • Dabigatran.
    • Enoxaparin.
    • Heparin sodium.
    • Phytomenadione.
    • Protamine sulfate.
    • Tranexamic acid.
    • Warfarin.
    • Desmopressinα.
    • Heparin sodiumα.
    • Protamine sulfateα.
    • Warfarinα.
  • Other medicines for haemoglobinopathies:
    • Deferoxamineα.
    • Hydroxycarbamideα.

Blood Products of Human Origin and Plasma Substitutes

  • Blood and blood components:
    • Fresh frozen plasma.
    • Platelets.
    • Red blood cells.
    • Whole blood.
  • Plasma-derived medicines:
    • Human immunoglobulins.
      • Rho(D) immune globulin (anti-D immunoglobulin).
      • Anti-rabies immunoglobulin.
      • Anti-tetanus immunoglobulin.
      • Normal immunoglobulinα.
    • Blood coagulation factors.
      • Coagulation factor VIIIα.
      • Coagulation factor IXα.
    • Plasma substitutes.
      • Dextran 70.

Cardiovascular Medicines

  • Antianginal medicines:
    • Bisoprolol.
    • Glyceryl trinitrate.
    • Isosorbide dinitrate.
    • Verapamil.
  • Antiarrhythmic medicines:
    • Bisoprolol.
    • Digoxin.
    • Epinephrine (adrenaline).
    • Lidocaine.
    • Verapamil.
    • Amiodaroneα.
  • Antihypertensive medicines:
    • Amlodipine.
    • Bisoprolol.
    • Enalapril.
    • Hydralazine.
    • Hydrochlorothiazide.
    • Lisinopril/amlodipine (lisinopril + amlodipine).
    • Lisinopril/hydrochlorothiazide (lisinopril + hydrochlorothiazide).
    • Losartan.
    • Methyldopa.
    • Telmisartan/amlodipine (telmisartan + amlodipine).
    • Telmisartan/hydrochlorothiazide (telmisartan + hydrochlorothiazide).
    • Sodium nitroprussideα.
  • Medicines used in heart failure:
    • Bisoprolol.
    • Digoxin.
    • Enalapril.
    • Furosemide.
    • Hydrochlorothiazide.
    • Losartan.
    • Spironolactone.
    • Dopamineα.
  • Antithrombotic medicines:
    • Anti-platelet medicines.
      • Acetylsalicylic acid (aspirin).
      • Clopidogrel.
    • Thrombolytic medicines.
      • Alteplaseα.
      • Streptokinaseα.
    • Lipid-lowering agents.
      • Simvastatin.

Dermatological Medicines (Topical)

  • Antifungal medicines:
    • Miconazole.
    • Selenium sulfide.
    • Sodium thiosulfate.
    • Terbinafine.
  • Anti-infective medicines:
    • Mupirocin.
    • Potassium permanganate.
    • Silver sulfadiazine.
  • Anti-inflammatory and antipruritic medicines:
    • Betamethasone.
    • Calamine.
    • Hydrocortisone.
  • Medicines affecting skin differentiation and proliferation:
    • Benzoyl peroxide.
    • Calcipotriol.
    • Coal tar.
    • Fluorouracil.
    • Podophyllum resin.
    • Salicylic acid.
    • Urea.
  • Scabicides and pediculicides:
    • Benzyl benzoate.
    • Permethrin.

Diagnostic Agents

  • Ophthalmic medicines:
    • Fluorescein.
    • Tropicamide.
  • Radiocontrast media:
    • Amidotrizoate.
    • Barium sulfate.
    • Iohexol.
    • Barium sulfateα.
    • Meglumine iotroxateα.

Antiseptics and Disinfectants

  • Antiseptics:
    • Chlorhexidine.
    • Ethanol.
    • Povidone iodine.
  • Disinfectants:
    • Alcohol based hand rub.
    • Chlorine base compound.
    • Chloroxylenol.
    • Glutaral.

Diuretics

  • Amiloride.
  • Furosemide.
  • Hydrochlorothiazide.
  • Mannitol.
  • Spironolactone.
  • Hydrochlorothiazideα.
  • Mannitolα.
  • Spironolactoneα.

Gastrointestinal Medicines

  • Pancreatic enzymesα.
  • Antiulcer medicines:
    • Omeprazole.
    • Ranitidine.
  • Antiemetic medicines:
    • Dexamethasone.
    • Metoclopramide.
    • Ondansetron.
    • Aprepitantα.
  • Anti-inflammatory medicines:
    • Sulfasalazine.
    • Hydrocortisoneα.
    • Prednisoloneα.
  • Laxatives:
    • Senna.
  • Medicines used in diarrhoea:
    • Oral rehydration salts + zinc sulfate (Co-packaged).
    • Oral rehydration.
      • Oral rehydration salts.
    • Medicines for diarrhoea.
      • Zinc sulfate.

Medicines for Endocrine Disorders

  • Adrenal hormones and synthetic substitutes:
    • Fludrocortisone.
    • Hydrocortisone.
  • Androgens:
    • Testosteroneα.
  • Estrogens:
    • No listings in this section.
  • Progestogens:
    • Medroxyprogesterone acetate.
  • Medicines for diabetes:
    • Insulins.
      • Insulin injection (soluble).
      • Intermediate-acting insulin.
      • Long-acting insulin analogues.
    • Oral hypoglycaemic agents.
      • Empagliflozin.
      • Gliclazide.
      • Metformin.
      • Metforminα.
    • Medicines for hypoglycaemia.
      • Glucagon.
      • Diazoxideα.
  • Thyroid hormones and antithyroid medicines:
    • Levothyroxine.
    • Potassium iodide.
    • Methimazole.
    • Propylthiouracil.
    • Lugol’s solutionα.
    • Methimazoleα.
    • Potassium iodideα.
    • Propylthiouracilα.

Immunologicals

  • Diagnostic agents:
    • Tuberculin, purified protein derivative (PPD).
  • Sera, immunoglobulins and monoclonal antibodies:
    • Anti-rabies virus monoclonal antibodies.
    • Antivenom immunoglobulin.
    • Diphtheria antitoxin.
    • Equine rabies immunoglobulin.
  • Vaccines:
    • Recommendations for all.
      • BCG vaccine.
      • Diphtheria vaccine.
      • Haemophilus influenzae type b vaccine.
      • Hepatitis B vaccine.
      • Human papilloma virus (HPV) vaccine.
      • Measles vaccine.
      • Pertussis vaccine.
      • Pneumococcal vaccine.
      • Poliomyelitis vaccine.
      • Rotavirus vaccine.
      • Rubella vaccine.
      • Tetanus vaccine.
    • Recommendations for certain regions.
      • Japanese encephalitis vaccine.
      • Tick-borne encephalitis vaccine.
      • Yellow fever vaccine.
      • Recommendations for some high-risk populations.
      • Cholera vaccine.
      • Dengue vaccine.
      • Hepatitis A vaccine.
      • Meningococcal meningitis vaccine.
      • Rabies vaccine.
      • Typhoid vaccine.
    • Recommendations for immunisation programmes with certain characteristics.
      • Influenza vaccine (seasonal).
      • Mumps vaccine.
      • Varicella vaccine.

Muscle Relaxants (Peripherally-Acting) and Cholinesterase Inhibitors

  • Atracurium.
  • Neostigmine.
  • Suxamethonium.
  • Vecuronium.
  • Pyridostigmineα.
  • Vecuroniumα.

Ophthalmological Preparations

  • Anti-infective agents:
    • Aciclovir.
    • Azithromycin.
    • Erythromycin.
    • Gentamicin.
    • Natamycin.
    • Ofloxacin.
    • Tetracycline.
  • Anti-inflammatory agents:
    • Prednisolone.
  • Local anaesthetics:
    • Tetracaine.
  • Miotics and antiglaucoma medicines:
    • Acetazolamide.
    • Latanoprost.
    • Pilocarpine.
    • Timolol.
  • Mydriatics:
    • Atropine.
    • Epinephrine (adrenaline)α.
  • Anti-vascular endothelial growth factor (VEGF):
    • Bevacizumabα.

Medicines for Reproductive Health and Perinatal Care

  • Contraceptives:
    • Oral hormonal contraceptives.
      • Ethinylestradiol/levonorgestrel (ethinylestradiol + levonorgestrel).
      • Ethinylestradiol/norethisterone (ethinylestradiol + norethisterone).
      • Levonorgestrel.
      • Ulipristal.
    • Injectable hormonal contraceptives.
      • Estradiol cypionate/medroxyprogesterone acetate (estradiol cypionate + medroxyprogesterone acetate).
      • Medroxyprogesterone acetate.
      • Norethisterone enantate.
    • Intrauterine devices.
      • IUD with copper.
      • IUD with progestogen.
    • Barrier methods.
      • Condoms.
      • Diaphragms.
    • Implantable contraceptives.
      • Etonogestrel-releasing implant.
      • Levonorgestrel-releasing implant.
    • Intravaginal contraceptives.
      • Ethinylestradiol/etonogestrel (ethinylestradiol + etonogestrel).
      • Progesterone vaginal ring.
  • Ovulation inducers:
    • Clomifeneα.
  • Uterotonics:
    • Carbetocin.
    • Ergometrine.
    • Mifepristone + misoprostol (Co-packaged).
    • Misoprostol.
    • Oxytocin.
  • Antioxytocics (tocolytics):
    • Nifedipine.
  • Medicines administered to the mother:
    • Dexamethasone.
    • Multiple micronutrient supplement.
    • Tranexamic acid.
  • Medicines administered to the neonate:
    • Caffeine citrate.
    • Chlorhexidine.
    • Ibuprofenα.
    • Prostaglandin E1α.
    • Surfactantα.

Peritoneal Dialysis Solution

  • Intraperitoneal dialysis solution (of appropriate composition)α.

Medicines for Mental and Behavioural Disorders

  • Medicines used in psychotic disorders:
  • Medicines used in mood disorders:
    • Medicines used in depressive disorders.
    • Medicines used in bipolar disorders.
      • Carbamazepine.
      • Lithium carbonate.
      • Valproic acid (sodium valproate).
  • Medicines for anxiety disorders:
  • Medicines used for obsessive compulsive disorders:
    • Clomipramine.
  • Medicines for disorders due to psychoactive substance use:
    • Bupropion.
    • Nicotine replacement therapy.
    • Varenicline.
    • Methadoneα.

Medicines Acting on the Respiratory Tract

  • Antiasthmatics and medicines for chronic obstructive pulmonary disease:
    • Budesonide.
    • Budesonide/formoterol (budesonide + formoterol).
    • Epinephrine (adrenaline).
    • Ipratropium bromide.
    • Salbutamol.
    • Tiotropium.

Solutions Correcting Water, Electrolyte and Acid-Base Disturbances

  • Oral:
    • Oral rehydration salts.
    • Potassium chloride.
  • Parenteral:
    • Glucose.
    • Glucose with sodium chloride.
    • Potassium chloride.
    • Sodium chloride.
    • Sodium hydrogen carbonate.
    • Sodium lactate, compound solution.
  • Miscellaneous:
    • Water for injection.

Vitamins and Minerals

  • Ascorbic acid.
  • Calcium.
  • Colecalciferol.
  • Ergocalciferol.
  • Iodine.
  • Multiple micronutrient powder.
  • Nicotinamide.
  • Pyridoxine.
  • Retinol.
  • Riboflavin.
  • Thiamine.
  • Calcium gluconateα.

Ear, Nose and Throat Medicines

  • Acetic acid.
  • Budesonide.
  • Ciprofloxacin.
  • Xylometazoline.

Medicines for Diseases of Joints

  • Medicines used to treat gout:
    • Allopurinol.
  • Disease-modifying agents used in rheumatoid disorders (DMARDs):
    • Chloroquine.
    • Azathioprineα.
    • Hydroxychloroquineα.
    • Methotrexateα.
    • Penicillamineα.
    • Sulfasalazineα.
  • Juvenile joint diseases:
    • Acetylsalicylic acid (aspirin).
  • Dental preparations:
    • Fluoride.
    • Glass ionomer cement.
    • Silver diamine fluoride.

What is Troparil?

Published on by Andrew MarshallLeave a comment

Introduction

Troparil (also known as (–)-2β-Carbomethoxy-3β-phenyltropane, WIN 35,065-2, or β-CPT) is a stimulant drug used in scientific research.

Troparil is a phenyltropane-based dopamine reuptake inhibitor (DRI) that is derived from methylecgonidine. Troparil is a few times more potent than cocaine as a dopamine reuptake inhibitor, but is less potent as a serotonin reuptake inhibitor, and has a duration spanning a few times longer, since the phenyl ring is directly connected to the tropane ring through a non-hydrolysable carbon-carbon bond. The lack of an ester linkage removes the local anaesthetic action from the drug, so troparil is a pure stimulant. This change in activity also makes troparil slightly less cardiotoxic than cocaine. The most commonly used form of troparil is the tartrate salt, but the hydrochloride and naphthalenedisulfonate salts are also available, as well as the free base.

Background

The first known published synthesis of troparil and the related compound WIN 35428 is by Clarke and co-workers during the 1970s. Apparently, it was their intention to separate the stimulant actions of cocaine from its toxicity and dependence liability. Troparil is the only regular phenyltropane having a NET (Norepinephrine transporter) affinity that exceeds the DAT (dopamine transporter) affinity.

Application

Phenyltropanes are likely to have less abuse and dependency compared with cocaine.

Troparil is used in scientific research into the dopamine reuptake transporter. 3H-radiolabelled forms of troparil have been used in humans and animals to map the distribution of dopamine transporters in the brain. It is also used for animal research into stimulant drugs as an alternative to cocaine which produces similar effects, but avoids the stringent licensing requirements for the use of cocaine itself.

Troparil has similar effects to cocaine in animal studies, but recreational use of this compound to date has proven extremely rare. Despite being easily made by the reaction of methylecgonidine with phenylmagnesium bromide, the relative scarcity of methylecgonidine and the demanding reaction conditions required for the synthesis put production of this compound beyond the capacity of most illicit drug manufacturers, and legitimate supplies of troparil are available only in very small quantities for a very high price.

Legality

The legal status of troparil is unclear, but it may be considered a controlled substance analogue of cocaine in the United States on the grounds of its related chemical structure. The legal status of troparil and many other cocaine analogues in Canada, is dependent on if ecgonine, coca, or cocaine were derivatives of the compound, according to the wording on the entry of coca in Schedule 1 of the Controlled Drugs and Substances Act.

What is RTI-353?

Published on by Andrew MarshallLeave a comment

Introduction

RTI(-4229)-353 is a phenyltropane derived drug which acts as an SSRI (Navarro et al., 2001).

Tamagnan et al. (2006) also made some phenyltropanes with high activity and selectivity for the SERT (pM affinity).

References

Navarro, H.A., Xu, H., Zhong, D., Blough, B.E., Ross, W.P., Kuhar, M.J. & Carroll, F.I. (2001) [(125)I]3beta-(4-ethyl-3-iodophenyl)nortropane-2beta-carboxylic acid methyl ester ([(125)I]EINT): a potent and selective radioligand for the brain serotonin transporter. Synapse: New York, N.Y. 41(3), pp.241-247.

Tamagnan, G., Alagille, D., Fu, X., Kula, N.S., Baldessarini, R.J., Innis, R.B. & Baldwin, R.M. (2006) Synthesis and monoamine transporter affinity of new 2beta-carbomethoxy-3beta-[aryl or heteroaryl]phenyltropanes. Bioorganic & Medicinal Chemistry Letters. 16(1), pp.217-220.

What is Phenacetin?

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Introduction

Phenacetin (acetophenetidin, N-(4-ethoxyphenyl)acetamide) is a pain-relieving and fever-reducing drug, which was widely used following its introduction in 1887.

It was withdrawn from medicinal use as dangerous from the 1970s (e.g. withdrawn in Canada in 1973, and by the US Food and Drug Administration (FDA) in 1983).

Brief History

Phenacetin was introduced in 1887 in Elberfeld, Germany by German company Bayer, and was used principally as an analgesic; it was one of the first synthetic fever reducers to go on the market. It is also known historically to be one of the first non-opioid analgesics without anti-inflammatory properties.

Prior to World War One, Britain imported phenacetin from Germany. During the war, a team including Jocelyn Field Thorpe and Martha Annie Whiteley developed a synthesis in Britain.

Known Mechanism of Action

Phenacetin’s analgesic effects are due to its actions on the sensory tracts of the spinal cord. In addition, phenacetin has a depressant action on the heart, where it acts as a negative inotrope. It is an antipyretic, acting on the brain to decrease the temperature set point. It is also used to treat rheumatoid arthritis (subacute type) and intercostal neuralgia.

In vivo, one of two reactions occur. Usually Phenacitin’s ether is cleaved to leave paracetamol (acetaminophen), which is the clinically relevant analgesic. A minority of the time the acetyl group is removed from the amine, producing carcinogenic P-Phenetidine. This reaction is quite rare, however, as evidenced by the fact that the drug was on the market for almost 100 years before a statistical link was established, when Canada, followed by the United States, withdrew it from the market.

Preparation

The first synthesis was reported in 1878 by Harmon Northrop Morse.

Phenacetin may be synthesized as an example of the Williamson ether synthesis: ethyl iodide, paracetamol, and anhydrous potassium carbonate are heated in 2-butanone to give the crude product, which is recrystallised from water.

Uses

Phenacetin was widely used until the third quarter of the twentieth century, often in the form of an A.P.C., or “aspirin-phenacetin-caffeine” compound analgesic, as a remedy for fever and pain. An early formulation (1919) was Vincent’s APC in Australia.

In the United States, the FDA ordered the withdrawal of drugs containing phenacetin in November 1983, due to its carcinogenic and kidney-damaging properties. It was also banned in India. As a result, some branded, and previously phenacetin-based, preparations continued to be sold, but with the phenacetin replaced by safer alternatives. A popular brand of phenacetin was Roche’s Saridon, which was reformulated in 1983 to contain propyphenazone, paracetamol and caffeine. Coricidin was also reformulated without phenacetin. Paracetamol is a metabolite of phenacetin with similar analgesic and antipyretic effects, but the new formulation has not been found to have phenacetin’s carcinogenicity.

Phenacetin has been used as a cutting agent to adulterate cocaine in the UK and Canada, due to the similar physical properties.

Due to its low cost, phenacetin is used for research into the physical and refractive properties of crystals. It is an ideal compound for this type of research.

In Canada phenacetin is used as a laboratory reagent, and in a few hair dye preparations (as a stabiliser for hydrogen peroxide). While it is considered a prescription drug, no marketed drugs contain phenacetin.

Safety

Phenacetin, and products containing phenacetin, have been shown in an animal model to have the side effect and after-effect of carcinogenesis. In humans, many case reports have implicated products containing phenacetin in urothelial neoplasms, especially urothelial carcinoma of the renal pelvis. Phenacetin is classified by the International Agency for Research on Cancer (IARC) as carcinogenic to humans. In one prospective series, phenacetin was associated with an increased risk of death due to urologic or renal diseases, death due to cancers, and death due to cardiovascular diseases. In addition, people with glucose-6-phosphate dehydrogenase deficiency may experience acute haemolysis, or dissolution of blood cells, while taking this drug. Acute haemolysis is possible in the case of patients who develop an IgM response to phenacetin leading to immune complexes that bind to erythrocytes in blood. The erythrocytes are then lysed when the complexes activate the complement system.

Chronic use of phenacetin is known to lead to analgesic nephropathy characterized by renal papillary necrosis. This is a condition which results in destruction of some or all of the renal papillae in the kidneys. It is believed that the metabolite p-phenetidine is at least partly responsible for these effects.

One notable death that can possibly be attributed to the use of this drug was that of the aviation pioneer Howard Hughes. He had been using phenacetin extensively for the treatment of chronic pain; it was stated during his autopsy that phenacetin use may have been the cause of his kidney failure.

What is Lormetazepam?

Published on by Andrew Marshall4 Comments

Introduction

Lormetazepam, sold under the brand name Noctamid among others, is a drug which is a short to intermediate acting 3-hydroxy benzodiazepine derivative and temazepam analogue. It possesses hypnotic, anxiolytic, anticonvulsant, sedative, and skeletal muscle relaxant properties.

It was patented in 1961 and came into medical use in 1980. Lormetazepam is not approved for sale in the United States or Canada. It is licensed in the UK as 0.5 and 1 mg tablets for short-term treatment (2-4 weeks) of moderately severe insomnia. It is licensed in the Netherlands as 1 and 2 mg tablets, under the brand names Loramet and Noctamid and as generic, available from several manufacturers. It is sold in Poland as Noctofer. A Dutch analysis stated that lormetazepam could be suitable to be included in drug prescribing formularies, although zolpidem, zopiclone, and temazepam appear better.

Medical Uses

Lormetazepam is considered a hypnotic benzodiazepine and is officially indicated for moderate to severe insomnia. Lormetazepam is a short-acting benzodiazepine and is sometimes used in patients who have difficulty in maintaining sleep or falling asleep. Hypnotics should only be used on a short-term basis or, in those with chronic insomnia, on an occasional basis.

Side Effects

Side effects of lormetazepam are similar to those of other hypnotic benzodiazepines and can for the most part be regarded as a class effect. In a sleep study, 1 mg lormetazepam increased total sleep time, reduced wakefulness, but did not alter REM sleep. However, at 2 mg doses, there were significant increases in stage 3 sleep and reductions in REM sleep. Rebound effects have been reported after chronic use including rebound REM. In one clinical trial with patients who had prior experience with older hypnotics temazepam and nitrazepam, most preferred lormetazepam due to less heavy sedation, amnesia, and residual effects. Some side effects, including drowsiness, amnesia, and respiratory depression, are increased when lormetazepam is combined with other drugs with similar effects, e.g. alcohol and nonbenzodiazepine drugs.

Although lormetazepam has been associated with adversely affecting immediate and delayed recall memory functions, studies have shown that lormetazepam’s amnesic properties may be lesser compared to other hypnotic benzodiazepines. For example, in a 1984 study comparing the amnesic effects of lormetazepam to temazepam and flurazepam showed that amnesia was smallest after lormetazepam and greatest after temazepam, which had produced greater amnesia than both lormetazepam and flurazepam by a significant margin.

Side effects of lormetazepam include:

  • Somnolence.
  • Paradoxical increase in aggression.
  • Lightheadedness.
  • Confusion.
  • Muscle weakness.
  • Ataxia (particularly in the elderly).
  • Anterograde amnesia.
  • Headache.
  • Vertigo.
  • Hypotension.
  • Salivation changes.
  • Gastro-intestinal disturbances.
  • Visual disturbances.
  • Dysarthria.
  • Tremor.
  • Changes in libido.
  • Incontinence.
  • Urinary retention.
  • Blood disorders and jaundice.
  • Skin reactions.
  • Dependence and withdrawal reactions.

Residual “hangover” effects after nighttime administration of lormetazepam such as sleepiness, impaired psychomotor and cognitive functions may persist into the next day which may impair the ability of users to drive safely and increase risks of falls and hip fractures.

Benzodiazepines require special precaution if used during pregnancy, in children, in alcohol- or drug-dependent individuals and individuals with comorbid psychiatric disorders. Lormetazepam may be unsuitable for the elderly due to residual effects on memory and body sway which may result in falls. Lormetazepam causes impaired driving skills, thus caution is required in individuals who drive or operate machinery.

Tolerance, Dependence, and Withdrawal

The risks of tolerance, dependence, and withdrawal are very low when the drug is used for 2-4 weeks only, and lormetazepam is generally a safe and effective drug when used for no longer than 2-4 weeks. Some sleep disturbance in the form of rebound insomnia can, however, occur even after short-term usage of 7 days. Those with a history of addiction may be at increased risk of problems of tolerance and dependence especially those with a past history of dependency on sedative hypnotic drugs.

Lormetazepam as with other benzodiazepines is generally only recommended for short-term use (2-4 weeks) due to tolerance and loss of efficacy. Tolerance to and loss of the sedative effects of benzodiazepine hypnotics can occur within 14 days of regular use. Some studies however suggest such treatments retain their effectiveness in the long term – such a lack of consistency in the findings of many studies could be due to the variation of responses to benzodiazepine treatment.

Dependence is the medical term for addiction. Dependence can either be psychological and/or physical. Psychological dependence can manifest itself as a reliance on a drug to cope with everyday life or in the form of craving. Physical dependence occurs due to physiological adaptations occurring as the body attempts to overcome the drugs effects which is known as tolerance and the continuing need to take the drug to avoid or suppress withdrawal symptoms which can sometimes resemble the original condition being treated. When the dose or the drug is discontinued withdrawal symptoms typically occur. Lormetazepam as with all other benzodiazepines produces both physical and psychological dependence but the main problem of concern is physical dependence which appears in the form of the benzodiazepine withdrawal syndrome after the dosage is reduced or the drug is stopped completely. The dependence induced by lormetazepam is related to changes in the sensitivity of the GABA-BZD receptor complex.

Withdrawal symptoms which can occur from stopping benzodiazepines such as lormetazepam can include:

  • Rebound insomnia and nightmares.
  • Anxiety, panic attacks, and agoraphobia.
  • Clinical depression.
  • Malaise.
  • Lack of concentration.
  • Abdominal discomfort.
  • Depersonalisation and feelings of unreality.
  • Emotional lability.
  • Cognitive impairment.
  • Tinnitus.
  • Paraesthesiae, tingling, numbness, and pain.
  • Muscle pain, weakness, tension, painful tremor, shaking attacks, jerks, blepharospasm.
  • Excitability, jumpiness, and restlessness.
  • Stiffness.
  • Sweats.

Abrupt or over rapid withdrawal from high doses can provoke:

Withdrawal symptoms typically subside after 4-8 weeks but in approximately 10-15% of individuals symptoms can persist for many months and in rare cases years. Some “Withdrawal Symptoms” can emerge despite a constant dosage with the body needing extra dosage in order to feel normal. This is sometimes associated with dosage escalation.

Lormetazepam has a short to intermediate half-life of approximately 10-12 hours. Shorter acting benzodiazepine compounds are generally associated with a more intense and immediate withdrawal reaction compared to longer acting benzodiazepines. For this reason it is generally recommended to cross from lormetazepam to an equivalent dose of diazepam to gradually taper the dosage.

Pharmacology

The bioavailability of lormetazepam was found to be 80%.

Lormetazepam and other benzodiazepine drugs act as positive modulators at the GABAA benzodiazepine receptor complex. Lormetazepam binds to the benzodiazepine receptor which in turn enhances the effect of the GABAA receptor producing its therapeutic effects as well as adverse effects. When lormetazepam binds to the benzodiazepine receptor sites in sufficient quantities it produces sedation which is used clinically as a therapeutic treatment for insomnia. Lormetazepam alters the brain electrical activity which has been studied via EEG readings. Lormetazepam appears to be more selective in the type of benzodiazepine receptor it binds to showing a higher affinity for the omega 1 receptor which is responsible for sedation. Changes in EEG can therefore be used to measure the sedative sleep promoting properties of lormetazepam.

Trade Names

Trade names include Aldosomnil, Dilamet, Ergocalm, Loramet, Loretam, Metatop, Minias, Noctamid, Noctamide, Noctofer, Nocton, Pronoctan, Sedaben, and Stilaze.

Stereochemistry

Lormetazepam has a stereocenter and two enantiomers. Medications are racemates.

What is Fluphenazine?

Published on by Andrew Marshall1 Comment

Introduction

Fluphenazine, sold under the brand names Prolixin among others, is a high-potency typical antipsychotic medication.

It is used in the treatment of chronic psychoses such as schizophrenia, and appears to be about equal in effectiveness to low-potency antipsychotics like chlorpromazine. It is given by mouth, injection into a muscle, or just under the skin. There is also a long acting injectable version that may last for up to four weeks. Fluphenazine decanoate, the depot injection form of fluphenazine, should not be used by people with severe depression.

Common side effects include movement problems, sleepiness, depression and increased weight. Serious side effects may include neuroleptic malignant syndrome, low white blood cell levels, and the potentially permanent movement disorder tardive dyskinesia. In older people with psychosis as a result of dementia it may increase the risk of dying. It may also increase prolactin levels which may result in milk production, enlarged breasts in males, impotence, and the absence of menstrual periods. It is unclear if it is safe for use in pregnancy.

Fluphenazine is a typical antipsychotic of the phenothiazine class. Its mechanism of action is not entirely clear but believed to be related to its ability to block dopamine receptors. In up to 40% of those on long term phenothiazines, liver function tests become mildly abnormal.

Fluphenazine came into use in 1959. The injectable form is on the World Health Organisation’s List of Essential Medicines. It is available as a generic medication. It was discontinued in Australia around mid 2017.

Brief History

Fluphenazine came into use in 1959.

Medical Use

A 2018 Cochrane review found that fluphenazine was an imperfect treatment and other inexpensive drugs less associated with side effects may be an equally effective choice for people with schizophrenia.

Side Effects

Discontinuation

The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse. Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite. Other symptoms may include restlessness, increased sweating, and trouble sleeping. Less commonly there may be a feeling of the world spinning, numbness, or muscle pains. Symptoms generally resolve after a short period of time.

There is tentative evidence that discontinuation of antipsychotics can result in psychosis. It may also result in reoccurrence of the condition that is being treated. Rarely tardive dyskinesia can occur when the medication is stopped.

Pharmacology

Pharmacodynamics

Fluphenazine acts primarily by blocking post-synaptic D2 receptors in the basal ganglia, cortical and limbic system. It also blocks alpha-1 adrenergic receptors, muscarinic-1 receptors, and histamine-1 receptors.

Availability

The injectable form is on the World Health Organisation’s List of Essential Medicines, the safest and most effective medicines needed in a health system. It is available as a generic medication. It was discontinued in Australia around mid 2017.

Other Animals

In horses, it is sometimes given by injection as an anxiety-relieving medication, though there are many negative common side effects and it is forbidden by many equestrian competition organisations.