Downers Flashcards
What are downers?
‘Downers’ are compounds that depress CNS activity, usually interpreted as hypnotics and sedatives.
Hypnotics produce drowsiness
Sedatives calm anxious/restless patients - improves compliance
Depressants are drugs that lower the level of arousal.
Inorganic bromides
KBr, based on a reputation for diminishing libido, was recommended for the treatment of epilepsy.
The recommended dose was 3-5 grams/day, which is quite a high concentration. Some hospitals reported to use tons/year.
It has nearly complete bioavailability and a half-life of 12 days. Dose adjustment is problematic due to the long half-life - 1 mg/mL is a toxic dose.
Bromide became a synonym for a dullard in the early 20th Century. It was allegedly dispensed to squaddies in the British Army to curb sexual desire, but this is likely an urban myth
It was available until 1975 in the US as an OTC sedative/headache remedy
MMoA is probably replacement of CNS chloride resulting in neuronal depression.
Chloral hydrate
Described in 1869 by Oscar Liebreich
Easy to manufacture and widely consumed.
Unclear MMoA for sedative effects, but likely related to GABA. Also a cardiac K+ channel inhibitor leading to dysrhythmias.
Administered frequently in asylums to increase compliance
Had a reputation for being added covertly to spirits as it did not have an obvious taste - reduces alcohol metabolism, having synergistic effects. It causes a rapid loss of consciousness and is associated with sexual assault.
Paraldehyde
Paraldehyde is a cyclic trimer of acetaldehyde.
Synthesised in 1830-1850s Germany.
Used to calm alcohol withdrawal in asylums from the 1880s.
Limited abuse due to bad taste and smell
Barbiturates
Barbituric acid was first prepared in 1863. Only its substituents, like barbitone (1903), are psychoactive.
Over 2500 chemical variants have been described
There are 50 marketed barbiturates, used as sleeping aids, anxiolytics and anticonvulsants.
Sodium thiopental is ultra-short acting. IV administration causes a loss in consciousness in 30 seconds, and respiratory failure can occur within 10 minutes in overdose. It is used in pet euthanasia (UK) and the lethal injection (US).
Repeated administration of barbiturates leads to CYP450 induction and tolerance.
Psychological and physical dependence occurs. Withdrawal is associated with nausea and vomiting, visual disturbances, convulsions and occasionally death.
They are CNS depressants, acting as GABA-A PAMs, leading to Cl- influx and hyperpolarisation.
Low doses often cause an initial euphoria, possibly due to disinhibition. This is closely followed by dissociation and occlusion of the senses.
In WW2 Pacific US military personnel offered ‘goofballs’ to help them tolerate the climate.
The 1950s became associated with abuse and suicides.
Barbiturates have a more pronounced depressive effect on the central nervous system, leading to slowed breathing and heart rate, alongside muscle relaxation.
Benzodiazepines can therefore be considered safer.
Benzodiazepines
Benzodiazepines (BDZ) are GABA-A PAMs. There are 13 in clinical use, including diazepam (valium, 1963) and nitrazepam (mogadon, 1972).
Chlordiazepoxide was discovered by accident in 1957 and then licensed in 1960.
It is a hypnotic, sedative, muscle relaxant, anticonvulsant, amnesic and anxiolytic.
- Excess GABA signalling can interfere with memory and GABA in the cortex relieves anxiety.
Tolerance and dependence are observed and fatality can occur in overdose.
Flunitrazepam (Rohypnol, 1974) is also known as ‘roofie’. It causes impairment of cognitive function and confusion, which are magnified by alcohol consumption, so it is associated with sexual assaults.
Active metabolites remain in the system for >24h - trace amounts can be identified in the body long after dosage, which can help with conviction.
It is used clinically to treat severe insomnia and assist anaesthesia.
Roche added a blue dye & reduced the dose to try to combat this
Withdrawn in most European countries in 2010s, never marketed in US
Long term BDZ consumption is often linked to consumption of other drugs, such as alcohol and opioids - there is an attempt to mediate the effects of these with benzodiazepines, but these have their own issues. Subjectively, there may be synergy or the second drug reduces the comedown.
Acute withdrawal is associated with anxiety, increased heart rate and blood pressure, shaking, insomnia and photosensitivity or hyperacusis.
Seizure and death may occur following withdrawal.
There has been an increase in the number of deaths associated with BDZ in the last 20 years, but many of these individuals were actually consuming multiple drugs at the same time.
Bemzodiazepine molecular target and brain regions
GABA-A receptors are pentameric ligand-gated chloride channels that mediate fast inhibitory signalling.
Two GABA molecules bind a channel. If benzodiazepine also binds, there is increased Cl- influx.
In the (α1)2(β2)2𝛾2 GABA-A receptor, GABA binds at the α1/β2 interface and BDZs bind at the α1/𝛾2 interface.
Human GABA-A receptor subunits are encoded by 19 paralogous genes that can, in theory, give rise to 495,235 receptor types. We do not know how different subunit combinations affect signalling.
BDZs binding can be hard to identify as these drugs can also bind mitochondria, not just GABA receptors.
We can use displacement of tagged 11C-flumazenil to identify BDZ binding to GABA channels over time.
Distribution of GABA sites is virtually ubiquitous in the brain. Probably 40% of neurons use GABA.
GABA analogues
GABA can activate both GABA-A and GABA-B channels. It is a relatively simple molecule, so analogues were synthesised.
Gabapentin was synthesised with the intention of creating a GABA analogue, as was pregabalin. However, they are not very good at activating GABA receptors and modulate Ca2+ channels instead. They change excitability and are useful clinically, but not through the expected mechanism of action.
GHB
GHB is a metabolite of GABA, while GBL is a prodrug of GHB. GHB is also known as ‘liquid ecstasy’.
GHB has depressant and euphoria-inducing effects. It was first used as an anaesthetic in the 1960s.
These have subjective similarities to alcohol. Some people become louder and more social while others withdraw, and there is a later impairment of focus.
GHB is steeply dose-dependent, causing confusion, vomiting, respiratory depression, coma and death at higher concentrations.
It is also associated with sexual assaults, used as a date rape drug due to its sedative effects which are especially potent when combined with alcohol. It is also used in club settings as it is reported to enhance the experience of the music.
Sleep disturbances and dependency occur with repeated use.
Causes severe withdrawal symptoms including tremors, insomnia, and anxiety.
Narrow therapeutic index. As GHB is often injected with alcohol or other drugs of abuse, the TI is further reduced.
It is classified as a Schedule 1 drug in the United States, but some formulations including Xyrem have been approved by the FDA as clinical treatments for narcolepsy or severe alcoholism.
GHB is illicitly used for a variety of purposes including relaxation, improved sleep, and enhanced sexual stimulation (Chemsex), and as a means of coming down from a stimulant-fuelled drug binge.
Methaqualone
Marketed as a safer alternative to barbiturates for insomnia in the 1960s, methaqualone gained popularity for its sedative and euphoric effects.
Effects resemble barbiturates and other downers as it exerts its effects through modulation of GABAA receptors, similarly to these drugs. It binds at the transmembrane β+/α− subunit interface, at the same site as GABA.
Marketed under various brand names like “Quaalude”.
It was misused, leading to dependence and overdoses.
By 1971, sales of methaqualone had reached over 91 million doses and increased to over 116 million the next year.
In 1972, shipment of 20,000 methaqualone pills arrived at Vassar College and were sold for $0.35-1 each. Enrolment was just over 2000 students, yet all the pills were used within 3 weeks. The resulted in many students needing medical attention.
Methaqualone was used by many high school students as it had a reputation for its potential aphrodisiac qualities. It has also been noted that methaqualone was used as a date-rape drug when it was still legal in the 1970s.
Methaqualone eventually lost popularity; by 1985 emergency room mentions of its use decreased 83% from 1980 in the United States.
This loss of popularity was in large part due to actions of the US government resulting in strict regulations and punishments, as it was classified as a schedule I substance.
Overdose can result in neurological, sensorimotor, and musculoskeletal adverse effects.
Kava
Kava, or Piper methysticum, is a plant from the Pacific islands with psychoactive properties stemming from its kavalactone content.
Traditionally consumed as a beverage prepared from macerated roots for ceremonial purposes.
Kavalactone content ranges from 4-17%.
Kava consumption leads to various psychoactive effects, including anxiolysis, muscle relaxation, and a sense of well-being.
Kava gained popularity in Europe and other parts of the world in the late 20th century but faced bans and regulations due to concerns about liver damage.
Kava is marketed as a natural alternative to alcohol, with kava bars emerging in the USA, Europe and Asia.
Unlike alcohol, kava does not typically cause anger or irritation.
Kavalactones readily cross the blood-brain barrier and impact neurotransmitter systems, reducing neuronal excitability and excitatory amino acids in the hippocampus and striatum. Sedative and anxiolytic effects may occur by reducing the release of excitatory neurotransmitters in limbic structures.
Kavalactones may reduce neuronal excitability by inhibiting Na+ and Ca2+ channels on presynaptic nerve endings.
Some studies suggest that kava has a mild, positive modulator activity on GABA-A receptors. Sedative effects correlate with increased GABA receptor binding.
The relaxing and euphoric effects of kava may be linked to the activation of mesolimbic dopaminergic neurons. Low doses of kavain decrease, while higher doses increase, dopamine levels in the nucleus accumbens.
Anxiolytic effects due to AChE inhibition and therefore increased parasympathetic ACh signalling.
Other receptor systems may also be affected.
Kavalactones may boost neuroprotection by activating the P38/nuclear factor-κB/cyclooxygenase 2 (COX-2) signalling pathway.
Kava shows promise as a treatment for anxiety and addiction, and its neuroprotective properties may have therapeutic potential for neurodegenerative diseases.
