What is Melitracen?

Introduction

Melitracen (brand names Melixeran) is a tricyclic antidepressant (TCA), for the treatment of depression and anxiety.

Refer to Flupentixol/Melitracen.

Background

In addition to single drug preparations, it is also available as Deanxit, marketed by Lundbeck, a combination product containing both melitracen and flupentixol.

The pharmacology of melitracen has not been properly investigated and is largely unknown, but it is likely to act in a similar manner to other TCAs. Indeed, melitracen is reported to have imipramine and amitriptyline-like effects and efficacy against depression and anxiety, though with improved tolerability and a somewhat faster onset of action.

What is Flupentixol?

Introduction

Flupentixol (INN), also known as flupenthixol (former BAN), marketed under brand names such as Depixol and Fluanxol is a typical antipsychotic drug of the thioxanthene class.

It was introduced in 1965 by Lundbeck. In addition to single drug preparations, it is also available as flupentixol/melitracen – a combination product containing both melitracen (a tricyclic antidepressant) and flupentixol. Flupentixol is not approved for use in the United States. It is, however, approved for use in the UK, Australia, Canada, Russian Federation, South Africa, New Zealand, Philippines and various other countries.

Brief History

In March 1963 the Danish pharmaceutical company Lundbeck began research into further agents for schizophrenia, having already developed the thioxanthene derivatives clopenthixol and chlorprothixene. By 1965 the promising agent flupenthixol had been developed and trialled in two hospitals in Vienna by Austrian psychiatrist Heinrich Gross. The long-acting decanoate preparation was synthesised in 1967 and introduced into hospital practice in Sweden in 1968, with a reduction in relapses among patients who were put on the depot.

Medical Uses

Flupentixol’s main use is as a long-acting injection given once in every two or three weeks to individuals with schizophrenia who have poor compliance with medication and suffer frequent relapses of illness, though it is also commonly given as a tablet. There is little formal evidence to support its use for this indication but it has been in use for over fifty years.

Flupentixol is also used in low doses as an antidepressant. There is tentative evidence that it reduces the rate of deliberate self-harm, among those who self-harm repeatedly.

Adverse Effects

Common (>1% incidence) adverse effects include:

  • Extrapyramidal side effects such as (which usually become apparent soon after therapy is begun or soon after an increase in dose is made):
    • Muscle rigidity.
    • Hypokinesia.
    • Hyperkinesia.
    • Parkinsonism.
    • Tremor.
    • Akathisia.
    • Dystonia.
  • Dry mouth.
  • Constipation.
  • Hypersalivation – excessive salivation.
  • Blurred vision.
  • Diaphoresis – excessive sweating.
  • Nausea.
  • Dizziness.
  • Somnolence.
  • Restlessness.
  • Insomnia.
  • Overactivity.
  • Headache.
  • Nervousness.
  • Fatigue.
  • Myalgia.
  • Hyperprolactinemia and its complications such as: (acutely).
    • Sexual dysfunction.
    • Amenorrhea – cessation of menstrual cycles.
    • Gynecomastia – enlargement of breast tissue in males.
    • Galactorrhea – the expulsion of breast milk that’s not related to breastfeeding or pregnancy
      and if the hyperprolactinemia persists chronically, the following adverse effects may be seen:
    • Reduced bone mineral density leading to osteoporosis (brittle bones).
    • Infertility.
  • Dyspepsia – indigestion.
  • Abdominal pain.
  • Flatulence.
  • Nasal congestion.
  • Polyuria – passing more urine than usual.

Uncommon (0.1-1% incidence) adverse effects include:

  • Fainting.
  • Palpitations.

Rare (<0.1% incidence) adverse effects include:

  • Blood dyscrasias (abnormalities in the cell composition of blood), such as:
    • Agranulocytosis – a drop in white blood cell counts that leaves one open to potentially life-threatening infections.
    • Neutropenia – a drop in the number of neutrophils (white blood cells that specifically fight bacteria) in one’s blood.
    • Leucopenia – a less severe drop in white blood cell counts than agranulocytosis.
    • Thrombocytopenia – a drop in the number of platelets in the blood. Platelets are responsible for blood clotting and hence this leads to an increased risk of bruising and other bleeds.
  • Neuroleptic malignant syndrome – a potentially fatal condition that appear to result from central D2 receptor blockade. The symptoms include:
    • Hyperthermia
    • Muscle rigidity
    • Rhabdomyolysis
    • Autonomic instability (e.g. tachycardia, diarrhoea, diaphoresis, etc.).
    • Mental status changes (e.g. coma, agitation, anxiety, confusion, etc.).

Unknown incidence adverse effects include:

  • Jaundice.
  • Abnormal liver function test results.
  • Tardive dyskinesia – an often incurable movement disorder that usually results from years of continuous treatment with antipsychotic drugs, especially typical antipsychotics like flupenthixol. It presents with repetitive, involuntary, purposeless and slow movements; TD can be triggered by a fast dose reduction in any antipsychotic.
  • Hypotension.
  • Confusional state.
  • Seizures.
  • Mania.
  • Hypomania.
  • Depression.
  • Hot flush.
  • Anergia.
  • Appetite changes.
  • Weight changes.
  • Hyperglycaemia – high blood glucose (sugar) levels.
  • Abnormal glucose tolerance.
  • Pruritus – itchiness.
  • Rash.
  • Dermatitis.
  • Photosensitivity – sensitivity to light.
  • Oculogyric crisis.
  • Accommodation disorder.
  • Sleep disorder.
  • Impaired concentration.
  • Tachycardia.
  • QTc interval prolongation – an abnormality in the electrical activity of the heart that can lead to potentially fatal changes in heart rhythm (only in overdose or <10 ms increases in QTc).
  • Torsades de pointes.
  • Miosis – constriction of the pupil of the eye.
  • Paralytic ileus – paralysis of the bowel muscles leading to severe constipation, inability to pass wind, etc.
  • Mydriasis.
  • Glaucoma.

Interactions

It should not be used concomitantly with medications known to prolong the QTc interval (e.g. 5-HT3 antagonists, tricyclic antidepressants, citalopram, etc.) as this may lead to an increased risk of QTc interval prolongation. Neither should it be given concurrently with lithium (medication) as it may increase the risk of lithium toxicity and neuroleptic malignant syndrome. It should not be given concurrently with other antipsychotics due to the potential for this to increase the risk of side effects, especially neurological side effects such as neuroleptic malignant syndrome. It should be avoided in patients on CNS depressants such as opioids, alcohol and barbiturates.

Contraindications

It should not be given in the following disease states:

  • Pheochromocytoma.
  • Prolactin-dependent tumours such as pituitary prolactinomas and breast cancer.
  • Long QT syndrome.
  • Coma.
  • Circulatory collapse.
  • Subcortical brain damage.
  • Blood dyscrasia.
  • Parkinson’s disease.
  • Dementia with Lewy bodies.

What is Flupentixol/Melitracen?

Introduction

Flupentixol/melitracen (trade name Frenxit, Placida, Deanxit, Anxidreg, Danxipress) is a combination of two psychoactive agents flupentixol (a typical antipsychotic drug of the thioxanthene class) and melitracen, a tricyclic antidepressant (TCA) which has antidepressant properties.

It is designed for short term usage only. It is produced by Lundbeck.

Other Brand Names

  • Pentoxol.m (scotmann pharmaceuticals Pakistan).
  • Sensit (Eskayef Bangladesh Ltd.).
  • Renxit (Renata Ltd.).
  • Melixol (Square Pharmaceuticals Ltd.).
  • Melanxit (Organic Health Care Ltd.).
  • Benzit (Bio-Pharma Ltd.).
  • Leanxit (ACME Laboratories Ltd.).
  • Danxipress (Vickmans Lab Ltd.).
  • Amilax (Amico Lab Ltd).

What is Barbiturate Overdose?

Introduction

Barbiturate overdose is poisoning due to excessive doses of barbiturates.

Refer to Barbiturate Dependence.

Background

Symptoms typically include difficulty thinking, poor coordination, decreased level of consciousness, and a decreased effort to breathe (respiratory depression). Complications of overdose can include noncardiogenic pulmonary oedema. If death occurs this is typically due to a lack of breathing.

Barbiturate overdose may occur by accident or purposefully in an attempt to cause death. The toxic effects are additive to those of alcohol and benzodiazepines. The lethal dose varies with a person’s tolerance and how the drug is taken. The effects of barbiturates occur via the GABA neurotransmitter. Exposure may be verified by testing the urine or blood.

Treatment involves supporting a person’s breathing and blood pressure. While there is no antidote, activated charcoal may be useful. Multiple doses of charcoal may be required. Haemodialysis may occasionally be considered. Urine alkalinisation has not been found to be useful. While once a common cause of overdose, barbiturates are now a rare cause.

Mechanism of Action

Barbiturates increase the time that the chloride pore of the GABAA receptor is opened, thereby increasing the efficacy of GABA. In contrast, benzodiazepines increase the frequency with which the chloride pore is opened, thereby increasing GABA’s potency.

Treatment

Treatment involves supporting a person’s breathing and blood pressure. While there is no antidote, activated charcoal may be useful. Multiple doses of charcoal may be required. Haemodialysis may occasionally be considered. Urine alkalinisation has not been found to be useful.

If a person is drowsy but awake and can swallow and breathe without difficulty, the treatment can be as simple as monitoring the person closely. If the person is not breathing, it may involve mechanical ventilation until the drug has worn off. Psychiatric consult is generally recommended.

Notable Cases

People who are known to have committed suicide by barbiturate overdose include, Gillian Bennett, Charles Boyer, Ruan Lingyu, Dalida, Jeannine “The Singing Nun” Deckers, Felix Hausdorff, Abbie Hoffman, Phyllis Hyman, C. P. Ramanujam, George Sanders, Jean Seberg, Lupe Vélez and the members of Heaven’s Gate cult. Others who have died as a result of barbiturate overdose include Pier Angeli, Brian Epstein, Judy Garland, Jimi Hendrix, Marilyn Monroe, Inger Stevens, Dinah Washington, Ellen Wilkinson, and Alan Wilson; in some cases these have been speculated to be suicides as well. Those who died of a combination of barbiturates and other drugs include Rainer Werner Fassbinder, Dorothy Kilgallen, Malcolm Lowry, Edie Sedgwick and Kenneth Williams. Dorothy Dandridge died of either an overdose or an unrelated embolism. Ingeborg Bachmann may have died of the consequences of barbiturate withdrawal (she was hospitalised with burns, the doctors treating her not being aware of her barbiturate addiction). Maurice Chevalier unsuccessfully attempted suicide in March 1971 by swallowing a large amount of barbiturates and slitting his wrists; however, he suffered severe organ damage as a result and died from multiple organ failure nine months later.

Differential Diagnosis

The differential diagnosis should include intoxication by other substances with sedative effects, such as benzodiazepines, anticonvulsants (carbamazepine), alcohols (ethanol, ethylene glycol, methanol), opioids, carbon monoxide, sleep aids, and gamma-Hydroxybutyric acid (GHB – a known date rape drug). Natural disease that can result in disorientation may be in the differential, including hypoglycaemia and myxoedema coma. In the right setting, hypothermia should be ruled out.

What is Barbiturate Dependence?

Introduction

Barbiturate dependence develops with regular use of barbiturates. This in turn may lead to a need for increasing doses of the drug to get the original desired pharmacological or therapeutic effect.

Refer to Barbiturate Overdose.

Background

Barbiturate use can lead to both addiction and physical dependence, and as such they have a high potential for excess or non-medical use, however, it does not affect all users. Management of barbiturate dependence involves considering the affected person’s age, comorbidity and the pharmacological pathways of barbiturates.

Psychological addiction to barbiturates can develop quickly. The patients will then have a strong desire to take any barbiturate-like drug. The chronic use of barbiturates leads to moderate degradation of the personality with narrowing of interests, passivity and loss of volition. The somatic signs include hypomimia, problems articulating, weakening of reflexes, and ataxia.

The GABAA receptor, one of barbiturates’ main sites of action, is thought to play a pivotal role in the development of tolerance to and dependence on barbiturates, as well as the euphoric “high” that results from their use. The mechanism by which barbiturate tolerance develops is believed to be different from that of ethanol or benzodiazepines, even though these drugs have been shown to exhibit cross-tolerance with each other and poly drug administration of barbiturates and alcohol used to be common.

The management of a physical dependence on barbiturates is stabilisation on the long-acting barbiturate phenobarbital followed by a gradual titration down of dose. People who use barbiturates tend to prefer rapid-acting barbiturates (amobarbital, pentobarbital, secobarbital) rather than long-acting barbiturates (barbital, phenobarbital). The slowly eliminated phenobarbital lessens the severity of the withdrawal syndrome and reduces the chances of serious barbiturate withdrawal effects such as seizures. A cold turkey withdrawal can in some cases lead to death. Antipsychotics are not recommended for barbiturate withdrawal (or other CNS depressant withdrawal states) especially clozapine, olanzapine or low potency phenothiazines e.g. chlorpromazine as they lower the seizure threshold and can worsen withdrawal effects; if used extreme caution is required. The withdrawal symptoms after ending barbiturate consumption are quite severe and last from 4 to 7 days.

What is a Psycholeptic?

Introduction

In pharmacology, a psycholeptic is a medication which produces a calming effect upon a person.

Refer to Analeptic.

Background

Such medications include barbiturates, benzodiazepines, nonbenzodiazepines, phenothiazines, opiates/opioids, carbamates, ethanol, 2-methyl-2-butanol, cannabinoids (in some classifications), some antidepressants, neuroleptics, and some anticonvulsants.

Many herbal medicines may also be classified as psycholeptics (e.g. kava).

Psycholeptics are classified under N05 in the Anatomical Therapeutic Chemical Classification System.

What is a Barbiturate?

Introduction

A barbiturate is a drug that acts as a central nervous system depressant.

Barbiturates are effective as anxiolytics, hypnotics, and anticonvulsants, but have physical and psychological addiction potential as well as overdose potential among other possible adverse effects. They have largely been replaced by benzodiazepines and nonbenzodiazepines (“Z-drugs”) in routine medical practice, particularly in the treatment of anxiety and insomnia, due to the significantly lower risk of addiction and overdose and the lack of an antidote for barbiturate overdose. Despite this, barbiturates are still in use for various purposes: in general anaesthesia, epilepsy, treatment of acute migraines or cluster headaches, acute tension headaches, euthanasia, capital punishment, and assisted suicide.

The name barbiturate originates from the fact that they are all chemical derivatives of barbituric acid.

Refer to Psycholeptic.

Brief History

Barbituric acid was first synthesized 27 November 1864, by German chemist Adolf von Baeyer. This was done by condensing urea with diethyl malonate. There are several stories about how the substance got its name. The most likely story is that Baeyer and his colleagues went to celebrate their discovery in a tavern where the town’s artillery garrison were also celebrating the feast of Saint Barbara – the patron saint of artillerymen. An artillery officer is said to have christened the new substance by amalgamating Barbara with urea. Another story was barbiturate was invented on the feast day of St. Barbara. Another story holds that Baeyer synthesized the substance from the collected urine of a Munich waitress named Barbara. No substance of medical value was discovered, however, until 1903 when two German scientists working at Bayer, Emil Fischer and Joseph von Mering, discovered that barbital was very effective in putting dogs to sleep. Barbital was then marketed by Bayer under the trade name Veronal. It is said that Mering proposed this name because the most peaceful place he knew was the Italian city of Verona.

It was not until the 1950s that the behavioural disturbances and physical dependence potential of barbiturates became recognised.

Barbituric acid itself does not have any direct effect on the central nervous system and chemists have derived over 2,500 compounds from it that possess pharmacologically active qualities. The broad class of barbiturates is further broken down and classified according to speed of onset and duration of action. Ultrashort-acting barbiturates are commonly used for anaesthesia because their extremely short duration of action allows for greater control. These properties allow doctors to rapidly put a patient “under” in emergency surgery situations. Doctors can also bring a patient out of anaesthesia just as quickly, should complications arise during surgery. The middle two classes of barbiturates are often combined under the title “short/intermediate-acting.” These barbiturates are also employed for anaesthetic purposes, and are also sometimes prescribed for anxiety or insomnia. This is not a common practice anymore, however, owing to the dangers of long-term use of barbiturates; they have been replaced by the benzodiazepines and Z-drugs such as zolpidem, zaleplon and eszopiclone for sleep. The final class of barbiturates are known as long-acting barbiturates (the most notable one being phenobarbital, which has a half-life of roughly 92 hours). This class of barbiturates is used almost exclusively as anticonvulsants, although on rare occasions they are prescribed for daytime sedation. Barbiturates in this class are not used for insomnia, because, owing to their extremely long half-life, patients would awake with a residual “hang-over” effect and feel groggy.

Barbiturates can in most cases be used either as the free acid or as salts of sodium, calcium, potassium, magnesium, lithium, etc. Codeine- and Dionine-based salts of barbituric acid have been developed. In 1912, Bayer introduced another barbituric acid derivative, phenobarbital, under the trade name Luminal, as a sedative-hypnotic.

Uses

Medicine

Barbiturates such as phenobarbital were long used as anxiolytics and hypnotics. Intermediate-acting barbiturates reduce time to fall asleep, increase total sleep time, and reduce REM sleep time. Today they have been largely replaced by benzodiazepines for these purposes because the latter are less toxic in drug overdose. However, barbiturates are still used as anticonvulsants (e.g. phenobarbital and primidone) and general anaesthetics (e.g. sodium thiopental).

Barbiturates in high doses are used for medical aid in dying, and in combination with a muscle relaxant for euthanasia and for capital punishment by lethal injection. Barbiturates are frequently employed as euthanising agents in small-animal veterinary medicine.

Interrogation

Sodium thiopental is an ultra-short-acting barbiturate that is marketed under the name Sodium Pentothal. It is often mistaken for “truth serum”, or sodium amytal, an intermediate-acting barbiturate that is used for sedation and to treat insomnia, but was also used in so-called sodium amytal “interviews” where the person being questioned would be much more likely to provide the truth whilst under the influence of this drug. When dissolved in water, sodium amytal can be swallowed, or it can be administered by intravenous injection. The drug does not itself force people to tell the truth, but is thought to decrease inhibitions and slow creative thinking, making subjects more likely to be caught off guard when questioned, and increasing the possibility of the subject revealing information through emotional outbursts. Lying is somewhat more complex than telling the truth, especially under the influence of a sedative-hypnotic drug.

The memory-impairing effects and cognitive impairments induced by sodium thiopental are thought to reduce a subject’s ability to invent and remember lies. This practice is no longer considered legally admissible in court due to findings that subjects undergoing such interrogations may form false memories, putting the reliability of all information obtained through such methods into question. Nonetheless, it is still employed in certain circumstances by defence and law enforcement agencies as a “humane” alternative to torture interrogation when the subject is believed to have information critical to the security of the state or agency employing the tactic.

Chemistry

In 1988, the synthesis and binding studies of an artificial receptor binding barbiturates by six complementary hydrogen bonds was published. Since this first article, different kind of receptors were designed, as well as different barbiturates and cyanurates, not for their efficiencies as drugs but for applications in supramolecular chemistry, in the conception of materials and molecular devices.

Sodium barbital and barbital have also been used as pH buffers for biological research, e.g. in immuno-electrophoresis or in fixative solutions.

Side Effects

There are special risks to consider for older adults, and women who are pregnant. When a person ages, the body becomes less able to rid itself of barbiturates. As a result, people over the age of sixty-five are at higher risk of experiencing the harmful effects of barbiturates, including drug dependence and accidental overdose. When barbiturates are taken during pregnancy, the drug passes through the placenta to the foetus. After the baby is born, it may experience withdrawal symptoms and have trouble breathing. In addition, nursing mothers who take barbiturates may transmit the drug to their babies through breast milk. A rare adverse reaction to barbiturates is Stevens-Johnson syndrome, which primarily affects the mucous membranes.

Tolerance and Dependence

Refer to Barbiturate Dependence.

With regular use, tolerance to the effects of barbiturates develops. Research shows tolerance can develop with even one administration of a barbiturate. As with all GABAergic drugs, barbiturate withdrawal produces potentially fatal effects such as seizures, in a manner reminiscent of delirium tremens and benzodiazepine withdrawal although its more direct mechanism of GABA agonism makes barbiturate withdrawal even more severe than that of alcohol or benzodiazepines (subsequently making it one of the most dangerous withdrawals of any known addictive substance). Similarly to benzodiazepines, the longer acting barbiturates produce a less severe withdrawal syndrome than short acting and ultra-short acting barbiturates. Withdrawal symptoms are dose-dependent with heavier users being more affected than lower-dose addicts.

The pharmacological treatment of barbiturate withdrawal is an extended process often consisting of converting the patient to a long-acting benzodiazepine (i.e. Valium), followed by slowly tapering off the benzodiazepine. Mental cravings for barbiturates can last for months or years in some cases and counselling/support groups are highly encouraged by addiction specialists. Patients should never try to tackle the task of discontinuing barbiturates without consulting a doctor, due to the high lethality and relatively sudden onset of the withdrawal. Attempting to quit “cold turkey” may result in serious neurological damage, severe physical injuries received during convulsions, and even death via glutamatergic excitotoxicity.

Overdose

Refer to Barbiturate Overdose.

Some symptoms of an overdose typically include sluggishness, incoordination, difficulty in thinking, slowness of speech, faulty judgement, drowsiness, shallow breathing, staggering, and, in severe cases, coma or death. The lethal dosage of barbiturates varies greatly with tolerance and from one individual to another. The lethal dose is highly variable among different members of the class, with superpotent barbiturates such as pentobarbital being potentially fatal in considerably lower doses than the low-potency barbiturates such as butalbital. Even in inpatient settings, the development of tolerance is still a problem, as dangerous and unpleasant withdrawal symptoms can result when the drug is stopped after dependence has developed. Tolerance to the anxiolytic and sedative effects of barbiturates tends to develop faster than tolerance to their effects on smooth muscle, respiration, and heart rate, making them generally unsuitable for a long time psychiatric use. Tolerance to the anticonvulsant effects tends to correlate more with tolerance to physiological effects, however, meaning that they are still a viable option for long-term epilepsy treatment.

Barbiturates in overdose with other CNS (central nervous system) depressants (e.g. alcohol, opiates, benzodiazepines) are even more dangerous due to additive CNS and respiratory depressant effects. In the case of benzodiazepines, not only do they have additive effects, barbiturates also increase the binding affinity of the benzodiazepine binding site, leading to exaggerated benzodiazepine effects. (e.g. If a benzodiazepine increases the frequency of channel opening by 300%, and a barbiturate increases the duration of their opening by 300%, then the combined effects of the drugs increases the channels’ overall function by 900%, not 600%).

The longest-acting barbiturates have half-lives of a day or more, and subsequently result in bioaccumulation of the drug in the system. The therapeutic and recreational effects of long-acting barbiturates wear off significantly faster than the drug can be eliminated, allowing the drug to reach toxic concentrations in the blood following repeated administration (even when taken at the therapeutic or prescribed dose) despite the user feeling little or no effects from the plasma-bound concentrations of the drug. Users who consume alcohol or other sedatives after the drug’s effects have worn off, but before it has cleared the system, may experience a greatly exaggerated effect from the other sedatives which can be incapacitating or even fatal.

Barbiturates induce a number of hepatic CYP enzymes (most notably CYP2C9, CYP2C19, and CYP3A4), leading to exaggerated effects from many prodrugs and decreased effects from drugs which are metabolised by these enzymes to inactive metabolites. This can result in fatal overdoses from drugs such as codeine, tramadol, and carisoprodol, which become considerably more potent after being metabolised by CYP enzymes. Although all known members of the class possess relevant enzyme induction capabilities, the degree of induction overall as well as the impact on each specific enzyme span a broad range, with phenobarbital and secobarbital being the most potent enzyme inducers and butalbital and talbutal being among the weakest enzyme inducers in the class.

People who are known to have committed suicide by barbiturate overdose include Charles Boyer, Ruan Lingyu, Dalida, Jeannine “The Singing Nun” Deckers, Felix Hausdorff, Abbie Hoffman, Phyllis Hyman, C.P. Ramanujam, George Sanders, Jean Seberg, Lupe Vélez and the members of Heaven’s Gate cult. Others who have died as a result of barbiturate overdose include Pier Angeli, Brian Epstein, Judy Garland, Jimi Hendrix, Marilyn Monroe, Inger Stevens, Dinah Washington, Ellen Wilkinson, and Alan Wilson; in some cases these have been speculated to be suicides as well. Those who died of a combination of barbiturates and other drugs include Rainer Werner Fassbinder, Dorothy Kilgallen, Malcolm Lowry, Edie Sedgwick and Kenneth Williams. Dorothy Dandridge died of either an overdose or an unrelated embolism. Ingeborg Bachmann may have died of the consequences of barbiturate withdrawal (she was hospitalised with burns, the doctors treating her not being aware of her barbiturate addiction).

Mechanism of Action

Barbiturates act as positive allosteric modulators and, at higher doses, as agonists of GABAA receptors. GABA is the principal inhibitory neurotransmitter in the mammalian central nervous system (CNS). Barbiturates bind to the GABAA receptor at multiple homologous transmembrane pockets located at subunit interfaces,[19] which are binding sites distinct from GABA itself and also distinct from the benzodiazepine binding site. Like benzodiazepines, barbiturates potentiate the effect of GABA at this receptor. In addition to this GABAergic effect, barbiturates also block AMPA and kainate receptors, subtypes of ionotropic glutamate receptor. Glutamate is the principal excitatory neurotransmitter in the mammalian CNS. Taken together, the findings that barbiturates potentiate inhibitory GABAA receptors and inhibit excitatory AMPA receptors can explain the superior CNS-depressant effects of these agents to alternative GABA potentiating agents such as benzodiazepines and quinazolinones. At higher concentration, they inhibit the Ca2+-dependent release of neurotransmitters such as glutamate via an effect on P/Q-type voltage-dependent calcium channels. Barbiturates produce their pharmacological effects by increasing the duration of chloride ion channel opening at the GABAA receptor (pharmacodynamics: This increases the efficacy of GABA), whereas benzodiazepines increase the frequency of the chloride ion channel opening at the GABAA receptor (pharmacodynamics: This increases the potency of GABA). The direct gating or opening of the chloride ion channel is the reason for the increased toxicity of barbiturates compared to benzodiazepines in overdose.

Further, barbiturates are relatively non-selective compounds that bind to an entire superfamily of ligand-gated ion channels, of which the GABAA receptor channel is only one of several representatives. This Cys-loop receptor superfamily of ion channels includes the neuronal nACh receptor channel, the 5-HT3 receptor channel, and the glycine receptor channel. However, while GABAA receptor currents are increased by barbiturates (and other general anaesthetics), ligand-gated ion channels that are predominantly permeable for cationic ions are blocked by these compounds. For example, neuronal nAChR channels are blocked by clinically relevant anaesthetic concentrations of both thiopental and pentobarbital. Such findings implicate (non-GABA-ergic) ligand-gated ion channels, e.g. the neuronal nAChR channel, in mediating some of the (side) effects of barbiturates. This is the mechanism responsible for the (mild to moderate) anaesthetic effect of barbiturates in high doses when used in anaesthetic concentration.

Society and Culture

Legal Status

During World War II, military personnel in the Pacific region were given “goofballs” to allow them to tolerate the heat and humidity of daily working conditions. Goofballs were distributed to reduce the demand on the respiratory system, as well as maintaining blood pressure, to combat the extreme conditions. Many soldiers returned with addictions that required several months of rehabilitation before discharge. This led to growing dependency problems, often exacerbated by indifferent doctors prescribing high doses to unknowing patients through the 1950s and 1960s.

In the late 1950s and 1960s, an increasing number of published reports of barbiturate overdoses and dependence problems led physicians to reduce their prescription, particularly for spurious requests. This eventually led to the scheduling of barbiturates as controlled drugs.

In the Netherlands, the Opium Law classifies all barbiturates as List II drugs, with the exception of secobarbital, which is on List I.

There is a small group of List II drugs for which doctors have to write the prescriptions according to the same, tougher guidelines as those for List I drugs (writing the prescription in full in letters, listing the patients name, and have to contain the name and initials, address, city and telephone number of the licensed prescriber issuing the prescriptions, as well as the name and initials, address and city of the person the prescription is issued to). Among that group of drugs are the barbiturates amobarbital, butalbital, cyclobarbital, and pentobarbital.

In the United States, the Controlled Substances Act of 1970 classified most barbiturates as controlled substances – and they remain so as of September 2020. Barbital, methylphenobarbital (also known as mephobarbital), and phenobarbital are designated schedule IV drugs, and “Any substance which contains any quantity of a derivative of barbituric acid, or any salt of a derivative of barbituric acid” (all other barbiturates) were designated as being schedule III. Under the original CSA, no barbiturates were placed in schedule I, II, or V; however, amobarbital, pentobarbital, and secobarbital are schedule II controlled substances unless they are in a suppository dosage form.

In 1971, the Convention on Psychotropic Substances was signed in Vienna. Designed to regulate amphetamines, barbiturates, and other synthetics, the 34th version of the treaty, as of 25 January 2014, regulates secobarbital as schedule II, amobarbital, butalbital, cyclobarbital, and pentobarbital as schedule III, and allobarbital, barbital, butobarbital, mephobarbital, phenobarbital, butabarbital, and vinylbital as schedule IV on its “Green List”. The combination medication Fioricet, consisting of butalbital, caffeine, and paracetamol (acetaminophen), however, is specifically exempted from controlled substance status, while its sibling Fiorinal, which contains aspirin instead of paracetamol and may contain codeine phosphate, remains a schedule III drug.

Recreational Use

Recreational users report that a barbiturate high gives them feelings of relaxed contentment and euphoria. Physical and psychological dependence may also develop with repeated use. Chronic misuse of barbiturates is associated with significant morbidity. One study found that 11% of males and 23% of females with a sedative-hypnotic misuse die by suicide. Other effects of barbiturate intoxication include drowsiness, lateral and vertical nystagmus, slurred speech and ataxia, decreased anxiety, and loss of inhibitions. Barbiturates are also used to alleviate the adverse or withdrawal effects of illicit drug use, in a manner similar to long-acting benzodiazepines such as diazepam and clonazepam. Often polysubstance use occurs and barbiturates are consumed with or substituted by other available substances, most commonly alcohol.

People who use substances tend to prefer short-acting and intermediate-acting barbiturates. The most commonly used are amobarbital (Amytal), pentobarbital (Nembutal), and secobarbital (Seconal). A combination of amobarbital and secobarbital (called Tuinal) is also highly used. Short-acting and intermediate-acting barbiturates are usually prescribed as sedatives and sleeping pills. These pills begin acting fifteen to forty minutes after they are swallowed, and their effects last from five to six hours.

Slang terms for barbiturates include barbs, barbies, bluebirds, dolls, wallbangers, yellows, downers, goofballs, sleepers, ‘reds & blues’, and tooties.

What is the Rebound Effect?

Introduction

The rebound effect, or rebound phenomenon, is the emergence or re-emergence of symptoms that were either absent or controlled while taking a medication, but appear when that same medication is discontinued, or reduced in dosage.

In the case of re-emergence, the severity of the symptoms is often worse than pre-treatment levels.

Examples

Sedative Hypnotics

Rebound Insomnia

Rebound insomnia is insomnia that occurs following discontinuation of sedative substances taken to relieve primary insomnia. Regular use of these substances can cause a person to become dependent on its effects in order to fall asleep. Therefore, when a person has stopped taking the medication and is ‘rebounding’ from its effects, he or she may experience insomnia as a symptom of withdrawal. Occasionally, this insomnia may be worse than the insomnia the drug was intended to treat.

Common medicines known to cause this problem are eszopiclone, zolpidem, and anxiolytics such as benzodiazepines and which are prescribed to people having difficulties falling or staying asleep.

Rebound Depression

Depressive symptoms may appear to arise in patients previously free of such an illness.

Daytime Rebound

Rebound phenomena do not necessarily only occur on discontinuation of a prescribed dosage. For example, daytime rebound effects of anxiety, metallic taste, perceptual disturbances which are typical benzodiazepine withdrawal symptoms can occur the next day after a short-acting benzodiazepine hypnotic wears off. Another example is early morning rebound insomnia which may occur when a rapidly eliminated hypnotic wears off which leads to rebounding awakeness forcing the person to become wide awake before he or she has had a full night’s sleep. One drug which seems to be commonly associated with these problems is triazolam, due to its high potency and ultra short half life, but these effects can occur with other short-acting hypnotic drugs. Quazepam, due to its selectivity for type1 benzodiazepine receptors and long half-life, does not cause daytime anxiety rebound effects during treatment, showing that half-life is very important for determining whether a night-time hypnotic will cause next-day rebound withdrawal effects or not. Daytime rebound effects are not necessarily mild but can sometimes produce quite marked psychiatric and psychological disturbances.

Stimulants

Rebound effects from stimulants such as methylphenidate or dextroamphetamine include stimulant psychosis, depression and a return of ADHD symptoms but in a temporarily exaggerated form. Up to a third of ADHD children experience a rebound effect when methylphenidate is withdrawn.

Antidepressants

Many antidepressants, including SSRIs, can cause rebound depression, panic attacks, anxiety, and insomnia when discontinued.

Antipsychotics

Sudden and severe emergence or re-emergence of psychosis may appear when antipsychotics are switched or discontinued too rapidly.

Alpha-2 Adrenergic Agents

Rebound hypertension, above pre-treatment level, was observed after clonidine, and guanfacine discontinuation.

Others

Other Rebound Effects

An example is the use of highly potent corticosteroids, such as clobetasol for psoriasis. Abrupt withdrawal can cause a much more severe case of the psoriasis to develop. Therefore, withdrawal should be gradual, diluting the medication with lotion perhaps, until very little actual medication is being applied.

Another example of pharmaceutical rebound is a rebound headache from painkillers when the dose is lowered, the medication wears off, or the drug is abruptly discontinued.

Continuous usage of topical decongestants (nasal sprays) can lead to constant nasal congestion, known as rhinitis medicamentosa.

What is a Paradoxical Reaction?

Introduction

A paradoxical reaction or paradoxical effect is an effect of a chemical substance, typically a medical drug, that is opposite to what would usually be expected. An example of a paradoxical reaction is pain caused by a pain relief medication.

Paradoxical reactions are more commonly observed in people with attention deficit hyperactivity disorder (ADHD).

Substances

Amphetamines

Amphetamines are a class of psychoactive drugs that are stimulants. Paradoxical drowsiness can sometimes occur in adults.

Antibiotics

The paradoxical effect or Eagle effect (named after H. Eagle who first described it) refers to an observation of an increase in survivors, seen when testing the activity of an antimicrobial agent. Initially when an antibiotic agent is added to a culture media, the number of bacteria that survive drops, as one would expect. But after increasing the concentration beyond a certain point, the number of bacteria that survive, paradoxically, increases.

Antidepressants

In rare cases antidepressants can make users obsessively violent or have suicidal compulsions, which is in marked contrast to their intended effect. This can be regarded as a paradoxical reaction but, especially in the case of suicide, may in at least some cases be merely due to differing rates of effect with respect to different symptoms of depression: If generalised overinhibition of a patient’s actions enters remission before that patient’s dysphoria does and if the patient was already suicidal but too depressed to act on their inclinations, the patient may find themselves in the situation of being both still dysphoric enough to want to commit suicide but newly free of endogenous barriers against doing so. Children and adolescents are more sensitive to paradoxical reactions of self-harm and suicidal ideation while taking antidepressants but cases are still very rare.

Antipsychotics

Chlorpromazine, an antipsychotic and antiemetic drug, which is classed as a “major” tranquilizer may cause paradoxical effects such as agitation, excitement, insomnia, bizarre dreams, aggravation of psychotic symptoms and toxic confusional states.

Barbiturates

Phenobarbital can cause hyperactivity in children. This may follow after a small dose of 20 mg, on condition of no phenobarbital administered in previous days. Prerequisity for this reaction is a continued sense of tension. The mechanism of action is not known, but it may be started by the anxiolytic action of the phenobarbital.

Benzodiazepines

Benzodiazepines, a class of psychoactive drugs called the “minor” tranquilisers, have varying hypnotic, sedative, anxiolytic, anticonvulsant, and muscle relaxing properties, but they may create the exact opposite effects. Susceptible individuals may respond to benzodiazepine treatment with an increase in anxiety, aggressiveness, agitation, confusion, disinhibition, loss of impulse control, talkativeness, violent behaviour, and even convulsions. Paradoxical adverse effects may even lead to criminal behaviour. Severe behavioural changes resulting from benzodiazepines have been reported including mania, schizophrenia, anger, impulsivity, and hypomania.

Paradoxical rage reactions due to benzodiazepines occur as a result of an altered level of consciousness, which generates automatic behaviours, anterograde amnesia and uninhibited aggression. These aggressive reactions may be caused by a disinhibiting serotonergic mechanism.

Paradoxical effects of benzodiazepines appear to be dose related, that is, likelier to occur with higher doses.

In a letter to the British Medical Journal, it was reported that a high proportion of parents referred for actual or threatened child abuse were taking medication at the time, often a combination of benzodiazepines and tricyclic antidepressants. Many mothers described that instead of feeling less anxious or depressed, they became more hostile and openly aggressive towards the child as well as to other family members while consuming tranquilizers. The author warned that environmental or social stresses such as difficulty coping with a crying baby combined with the effects of tranquilisers may precipitate a child abuse event.

Self aggression has been reported and also demonstrated in laboratory conditions in a clinical study. Diazepam was found to increase people’s willingness to harm themselves.

Benzodiazepines can sometimes cause a paradoxical worsening of EEG readings in patients with seizure disorders.

Barbiturates such as pentobarbital have been shown to cause paradoxical hyperactivity in an estimated 1% of children, who display symptoms similar to the hyperactive-impulsive subtype of attention deficit hyperactivity disorder. Intravenous caffeine administration can return these patients’ behaviour to baseline levels.

Causes

The mechanism of a paradoxical reaction has as yet (2019) not been fully clarified, in no small part due to the fact that signal transfer of single neurons in subcortical areas of the human brain is usually not accessible.

There are, however, multiple indications that paradoxical reactions upon – for example – benzodiazepines, barbiturates, inhalational anaesthetics, propofol, neurosteroids, and alcohol are associated with structural deviations of GABAA receptors. The combination of the five subunits of the receptor (see image) can be altered in such a way that for example the receptor’s response to GABA remains unchanged but the response to one of the named substances is dramatically different from the normal one.

There are estimates that about 2-3% of the general population may suffer from serious emotional disorders due to such receptor deviations, with up to 20% suffering from moderate disorders of this kind. It is generally assumed that the receptor alterations are, at least partly, due to genetic and also epigenetic deviations. There are indication that the latter may be triggered by, among other factors, social stress or occupational burnout.

What are the Adverse Effects of Olanzpine?

Introduction

Below is a list of the adverse effects of the antipsychotic olanzapine, sorted by frequency of occurrence.

Very Common

Very common adverse effects of olanzapine, occurring more than 10%, include:

  • Weight gain (dose-dependent).
    • Weight gain of over 7% of a person’s initial body weight prior to treatment is in this category of very common too with some estimates of its incidence putting it at around 40.6%.
    • This adverse effect is most likely the result of its potent 5-HT2C receptor and H1 receptor blockade (or more specifically inverse agonism).
  • Somnolence (dose-dependent).
    • Tends to produce a moderate amount of sedation, less than clozapine and chlorpromazine but more than aripiprazole, amisulpride, paliperidone and sertindole and approximately that of quetiapine and risperidone.
  • Hyperprolactinemia elevated blood levels of the hormone, prolactin.
    • Prolactin is one of the hormones that plays a key role in lactation. Long-term uncontrolled hyperprolactinaemia can lead to bone demineralisation (osteoporosis) and an increased risk of fractures (breaks).
    • It tends to produce hyperlacticaemia less often than risperidone, paliperidone and the typical antipsychotics but more often than quetiapine and clozapine.
  • Hypertriglyceridaemia (elevated blood triglycerides).
  • Hypercholesterolaemia (elevated blood cholesterol levels).
  • Hyperglycaemia (elevated blood glucose levels).
    • This may be the result of olanzapine’s inhibitory effects on the M3 receptor which regulates the release of insulin from the pancreas.
  • Brain shrinkage (dose dependent).

Common

Common adverse effects of olanzapine, occurring from 1-10%, include:

  • Gynecomastia.
  • Extrapyramidal symptoms (EPS) (dose-dependent).
    • Tends to produce less extrapyramidal side effects than typical antipsychotics but more extrapyramidal side effects than sertindole, clozapine and quetiapine.
  • Mild and transient constipation and xerostomia (dry mouth).
  • Dizziness.
  • Weight gain of over 15% of one’s initial body weight.
    • Is reported to occur in approximately 7.1% of patients.
  • Glucosuria (glucose in the urine).
    • This is a consequence of hyperglycaemia.
  • Accidental injury.
  • Insomnia.
  • Orthostatic hypotension (a drop in blood pressure that occurs upon standing up).
  • Transient, asymptomatic elevations of hepatic aminotransferases (ALT, AST), especially in early treatment.
    • ALT & AST are liver enzymes which are often tested for as a measure of liver function.
  • Dyspepsia (indigestion).
  • Erectile dysfunction.
    • This is most likely the result of hyperprolactinaemia.
  • Decreased libido.
    • This is most likely the result of hyperprolactinaemia.
  • Rash.
  • Asthenia (weakness).
  • Fatigue.
  • Oedema the accumulation of fluid in the tissues of the body leading to swelling.
  • Akathisia an inner sense of restlessness that presents itself with the inability to stay still.
  • Parkinsonism tremor, muscle rigidity, reduced ability to move and being unstable on one’s feet.
  • Dyskinesia abnormal, involuntary, repetitive, and pointless movements.
  • Vomiting.
  • Coma.
  • Cardiac arrest.

Uncommon

Uncommon adverse effects of olanzapine, occurring from 0.1-1%, include:

  • Leukopenia a comparatively low white blood cell (the cells that defend the body from foreign invaders) count.
  • Neutropaenia a reduced neutrophil (the white blood cells that kill bacteria) count.
  • Bradycardia (low heart rate).
  • QTc interval prolongation (an abnormality in the electrical cycle of the heart).
  • Photosensitivity reaction.
  • Alopecia (hair loss).
  • Urinary incontinence.
  • Urinary retention, the inability to urinate.
  • Amenorrhea the cessation of menses (a woman’s menstrual cycles).
    • This is a complication of hyperprolactinaemia.
  • Breast enlargement (in either sex).
    • This is a complication of hyperprolactinaemia.
  • Galactorrhoea (expulsion of milk from the breasts that’s unrelated to pregnancy or lactation).
    • Most likely the result of hyperprolactinaemia.
  • High creatine phosphokinase (an abnormal laboratory finding).
  • Increased total bilirubin (a by product of the breakdown of haem – a part of blood cells that is used to carry oxygen).
    • In most people this is an indication of impaired liver function.
  • Abdominal pain.

Rare

Rare adverse effects of olanzapine, occurring from 0.01-0.1%, include:

  • Hepatitis.
  • Rash.
  • Seizures.
  • Glaucoma.
  • Blindness.

Very Rare (But Not Necessarily Causally Related)

Very rare adverse effects of olanzapine, occurring less than 0.01%, include:

  • Agranulocytosis, a potentially fatal drop in white blood cell count, basically an exaggerated form of leukopenia.
  • Thrombocytopaenia.
    • A drop in blood platelet counts which are involved in blood clotting.
  • Thromboembolism (blood clots; including pulmonary embolism and deep vein thrombosis).
  • Rhabdomyolysis (breakdown of muscle tissue leading to the release of myoglobin into the bloodstream which in turn damages the kidneys).
  • Alkaline phosphatase increased (an abnormal laboratory parameter).
  • Priapism (a painful and enduring erection).
  • Urinary hesitation.
  • Pancreatitis, swelling of the pancreas which supplies the body with insulin.
  • Neuroleptic malignant syndrome a potentially fatal complication of antipsychotic drug treatment.
    • Presents with hyperthermia, tremor, tachycardia (high heart rate), mental status change (e.g. confusion), etc.
  • Jaundice, which is basically when the body’s ability to clear a by product (called bilirubin) of the breakdown of an essential component of the blood called haem, is impaired leading to yellow discolouration of the skin, eyes and mucous membranes.
  • Diabetic coma.
  • Diabetic ketoacidosis.
    • Type II diabetes mellitus is basically where the body cannot effectively utilise sugars to produce energy due to the fact that its cells have become unresponsive to the hormone, insulin, which allows cells to utilise sugars for energy.
    • This in turn forces the body to burn fats for energy and fats require conversion to ketone bodies in order to be utilised by the cells of the body as an energy source.
    • The ketone bodies are acidic hence when the body is entirely reliant on these ketone bodies for energy the levels in the blood reaches a point where it overwhelms the body’s natural mechanisms to keep blood pH (a measure of acidity) within a safe range, leading to the blood becoming acidic which is potentially damaging to the tissues of the body due to the ability of acidic environments to denature the proteins of the body.
  • Anaphylactic reaction a potentially life-threatening allergic reaction.
  • Sudden cardiac death.