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A class of drugs that act as central nervous system depressants, and can therefore produce a wide spectrum of effects, from mild sedation to total anesthesia. They are also effective as anxiolytics, hypnotics, and anticonvulsants. Barbiturates also have weak analgesic effects. They have addiction potential, both physical and psychological. Barbiturates have now largely been replaced by benzodiazepines in routine medical practice mainly because benzodiazepines are significantly less dangerous in overdose. Barbiturates bind to the GABA-α receptor at the beta subunit, 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 GABA-ergic effect, barbiturates block the AMPA receptor, a subtype of glutamate receptor. Glutamate is the principal excitatory neurotransmitter in the mammalian CNS. Taken together, the findings that barbiturates potentiate inhibitory GABA-α receptors and inhibit excitatory AMPA receptors can explain the CNS-depressant effects of these agents. At higher concentration, they inhibit the Ca2+-dependent release of neurotransmitters. Barbiturates produce their pharmacological effects by increasing the duration of chloride ion channel opening at the GABA-α receptor whereas benzodiazepines increase the frequency of the chloride ion channel opening at the GABA-α receptor The direct gating or opening of the chloride ion channel is the reason for the increased toxicity of barbiturates compared to benzodiazepines in overdose.
1. Allobarbital, allobarbitone, Cibalgine, Dial-Ciba
Allobarbital is a barbiturate derivative used primarily as an anticonvulsant although it has now largely been replaced by newer drugs with improved safety profiles. Other uses for allobarbital included treatment of insomnia and anxiety and as an adjutant to boost the activity of analgesic drugs. Allobarbital was never particularly widely used compared to better known barbiturates such as phenobarbital and secobarbital, although it saw more use in some European countries such as Bulgaria and Slovakia and is still used in Poland, but only as compound. Wikipedia.
2. Amobarbital sodium (formerly known as amylobarbitone or sodium amytal)
Amobarbital sodium is a barbiturate derivative. It has sedative-hypnotic properties. If amobarbital is taken for extended periods of time, physical and psychological dependence can develop. Amobarbital dependence mimics delirium tremens and may be life-threatening. It depresses the sensory cortex; decreases motor activity; alters cerebellar function and produces drowsiness, sedation, and hypnosis.
3. Barbital, Barbitone, Veronal, Medinal
Barbital (diethylmalonyl urea or diethylbarbituric acid) was used as a sleeping aid (hypnotic) from 1903 until the mid-1950s. The sodium salt (known as medinal) is known also as sodium diethylbarbiturate. It had few side effects. Its therapeutic dose was far below the toxic dose. However, prolonged usage resulted in tolerance to the drug, requiring higher doses to reach the desired effect. Fatal overdoses of this slow acting hypnotic were not uncommon. It is no longer prescribed. Drugs.com
Phenobarbital is a long-acting barbiturate and the most widely used anticonvulsant worldwide, and the oldest still commonly used. It also has sedative and hypnotic properties, but as with other barbiturates, it has been superseded by the benzodiazepines for these indications. The World Health Organization recommends its use as first-line for partial and generalized tonic–clonic seizures (those formerly known as grand mal) in developing countries. It is no longer recommended as a first- or second-line choice anticonvulsant for most seizure types, though it is still commonly used to treat neonatal seizures and can be used in emergency situations. Drugs.com.
Benzodiazepines enhance the effect of the neurotransmitter gamma-aminobutyric acid (GABA) at the GABA-α receptor, resulting in sedative, hypnotic (sleep-inducing), anxiolytic (anti-anxiety), anticonvulsant, and muscle relaxant properties, and amnesic-dissociative actions. These properties make benzodiazepines useful in treating anxiety, insomnia, agitation, seizures, muscle spasms, alcohol withdrawal, and as a premedication for medical or dental procedures. Benzodiazepines are categorized as either short-, intermediate- or long-acting. Short- and intermediate-acting benzodiazepines are preferred for the treatment of insomnia; longer-acting benzodiazepines are recommended for the treatment of anxiety. In general, benzodiazepines are safe and effective in the short term, although cognitive impairments and paradoxical effects such as aggression or behavioral disinhibition occasionally occur.
Long-term use of benzodiazepines is controversial due to concerns about adverse psychological and physical effects. Benzodiazepines are prone to cause tolerance, physical dependence, and, upon cessation after long term use, a withdrawal syndrome. Benzodiazepines have a fast onset of action, high effectivity rate, and low toxicity in overdose; however, as with most medications, it may have drawbacks due to adverse or paradoxical effects.
1. Bromazepam, Lectopam, Lexotan, Lexilium, Lexaurin, Brazepam, Rekotnil, Bromaze, Somalium, Lexotanil (too many to list brand names)
Bromazepam has mainly an anti-anxiety agent with similar side effects to diazepam. In addition to being used to treat anxiety or panic states, bromazepam may be used as a premedicant prior to minor surgery. Bromazepam typically comes in doses of 3 mg and 6 mg tablets. Bromazepam is contraindicated and should be used with caution in women who are pregnant, the elderly, patients with a history of alcohol or other substance abuse disorders, and children. Prolonged use of bromazepam causes tolerance and may lead to both physical and psychological dependence on the drug. Drugs.com.
2. Clonazepam, Klonopin, Rivotril, Ravotril, Rivatril, Iktorivil, Clonex, Paxam, Petril, Naze, Kriadex, Linotril, Clonotril
Clonazepam has anxiolytic, anticonvulsant, muscle relaxant, amnestic, sedative, and hypnotic properties and an unusually long elimination half-life of 18–50 hours, making it generally considered to be among the longest-acting benzodiazepines. It has an intermediate onset of action, with a peak blood level occurring one to four hours after oral administration. Long-term effects include tolerance, dependence, and withdrawal syndrome, which occurs in one third of patients treated with clonazepam for longer than four weeks. Drugs.com
1. Westblom Ulf: Stiff-man syndrome and clonazepam. JAMA 1977, 237:1930. Link to article
3. Tranxene, Chlorazepate, Novo-Clopate
Clorazepate dipotassium is a benzodiazepine that possesses anxiolytic, anticonvulsant, sedative, hypnotic, and skeletal muscle relaxant properties. Clorazepate is a prodrug for desmethyldiazepam, which is rapidly produced as an active metabolite and a partial agonist of the GABA-α receptor . Clorazepate has a half life of 20 to 179 hours; a small amount of desmethyldiazepam is further metabolised into oxazepam. Clorazepate exerts its pharmacological properties via increasing the opening frequency of the chloride ion channel of GABA-α receptors. This effect of benzodiazepines requires the presence of the neurotransmitter GABA and results in enhanced inhibitory effects of the neurotransmitter GABA acting on GABA-α receptors. Peak plasma levels of the active metabolite desmethyl-diazepam are seen between 30 minutes and 2 hours after oral administration. Clorazepate is completely metabolised to desmethyl-diazepam in the gastrointestinal tract. Drugs.com.
4. Librium, Chlordiazepoxide, Angirex, Elenium, Klopoxid, Libotryp, Librax, Libritabs, Mesural, Multum, Novapam, Risolid, Silibrin, Sonimen, Tropium
Lirbium was the first benzodiazepine to be synthesized. It has a medium to long half-life. Its active metabolite has a very long half-life. The drug has amnestic, anticonvulsant, anxiolytic, hypnotic, and skeletal muscle relaxant properties. It should be avoided in patients with myasthenia gravis and ataxia. Drugs.com.
5. Diazepam, Valium
Diazepam is the first line treatment for stiff-person syndrome. Response of spasms to Valium is a diagnostic marker for SPS. Diazepam possesses anxiolytic, anticonvulsant, hypnotic, sedative, skeletal muscle relaxant, and amnestic properties. It enhances the effect of the neurotransmitter GABA by binding to the benzodiazepine site on the GABA-α receptor (via the constituent chlorine atom) leading to central nervous system depression. Adverse effects of diazepam include anterograde amnesia (especially at higher doses) and sedation, as well as paradoxical effects such as excitement, rage, or worsening of seizures in epileptics. It can cause or worsen depression, particularly after extended periods of use.
Long-term effects include tolerance, dependence, and withdrawal syndrome upon dose reduction. After cessation, cognitive deficits may persist for at least six months and longer than six months may be needed for recovery from some deficits. Diazepam also has physical dependence potential and can cause serious problems of physical dependence with long-term use. Compared to other benzodiazepines, though, physical withdrawal from diazepam following long-term use is usually far more mild due to its long elimination half-life. Drugs.com
6. Flurazepam, Dalmane, Dalmadorm
Flurazepam possesses anxiolytic, anticonvulsant, sedative, and skeletal muscle relaxant properties. It produces a metabolite with a very long half-life (40–250 hours), which may stay in the bloodstream for up to four days. It is unsuitable as a sleeping medication due to next-day sedation; however, this same effect may also provide next-day anxiety relief. For this reason it is sometimes utilized to treat anxiety-induced insomnia on the night before dental visits and other medical procedures. Flurazepam is associated with drug tolerance, drug dependence, rebound insomnia, and CNS related adverse effects. Flurazepam is best used for a short time period and at the lowest possible dose to avoid complications associated with long term use. Rebound effect or withdrawal syndrome may occur about four days after discontinuation of medication. Drugs.com
7. Lorazepam, Ativan, Orfidal
Lorazepam has all six intrinsic benzodiazepine effects: anxiolysis, anterograde amnesia, sedation/hypnosis, anti-seizure, anti-nausea/vomiting, and muscle relaxation. Lorazepam has a relatively high physical addiction potential. Lorazepam also has misuse potential for recreational purposes or continued use against medical advice. Its sedative-hypnotic and anterograde amnesic properties are sometimes used for criminal purposes in a manner similar to GHB. Withdrawal symptoms range from anxiety and insomnia to seizures and psychosis. Lorazepam is recommended for short-term use, up to two to four weeks only. Adverse effects, including anterograde amnesia, depression, and paradoxical effects such as excitement or worsening of seizures may occur. Children and the elderly are more sensitive. Lorazepam impairs body balance and standing steadiness and is associated with falls and hip fractures in the elderly. Drugs.com
8. Midazolam, Versed, Dormicum, Hypnovel
Versed is used for treatment of acute seizures, moderate to severe insomnia, and for inducing sedation and amnesia before medical procedures. It possesses profoundly potent anxiolytic, amnestic, hypnotic, anticonvulsant, skeletal muscle relaxant, and sedative properties, and has a fast recovery time. Gradual reduction after regular use can minimize withdrawal/rebound effects. Tolerance and the resultant withdrawal syndrome may be due to receptor down-regulation and GABA-α receptor alterations in gene expression which results in long-term changes in the function of the GABAergic neuronal system. If you take other benzodiazepines, it is important to coordinate your medications with any medical procedure performed under Versed. Drugs.com.
9. Nitrazepam, Alodorm, Arem, Insoma, Mogadon, Nitrados, Nitrazadon, Nitrosun, Ormodon, Paxadorm, Remnos, Somnite
Nitrazepam has sedative and motor-impairing properties, as well as amnestic, anticonvulsant, and skeletal muscle relaxant effects. Nitrazepam has an elimination half-life of 15 to 38 hours. Residual sleepiness, impaired psychomotor and cognitive functions may persist into the next day, which may impair the ability of users to drive safely and increases the risk of falls and hip fractures, and significant impairment of visual perception and sedative effects persisting into the next day typically occur. Impairment of psychomotor function may especially occur after repeated administration, with the elderly being more vulnerable to this adverse effect. Drugs.com.
10. Oxazepam, Serax, Alepam, Medopam, Murelax, Noripam, Opamox, Ox-Pam, Purata, Serax, Serepax, Vaben, Sobril, Oxascand, Oxapax, Alopam, Oxascan, Zaxpam, Praxiten, Seresta
It is used for the treatment of anxiety and insomnia and in the control of symptoms of alcohol withdrawal. It is a metabolite of diazepam, prazepam, and temazepam and has moderate amnesic, anxiolytic, anticonvulsant, hypnotic, sedative, and skeletal muscle relaxant properties. Drugs.com.
11. Xanax, Alprazolam
Xanax is the second most popular treatment for stiff-person syndrome. It has a fast onset of action and symptomatic relief. Ninety percent of peak effects are achieved within the first hour and full peak effects are achieved in 1.5 hours and has a short elimination half-life of approximately 11.2 hours. It causes a marked suppression of the HPA axis. The therapeutic properties include anxiolytic, anticonvulsant, muscle relaxant, hypnotic, and amnesic. It also elicits an increase in striatum dopamine concentrations. Patients on more than 4 mg per day have an increased potential for dependence. Abrupt withdrawal or rapid tapering in some cases causes seizures and rebound anxiety. Drugs.com.
References for benzodiazepine use:
1. Todman D. Stiff-Person Syndrome (Moersch-Woltman Syndrome. The Internet Journal of Neurology. 2006 Volume 7 Number 1. Link to article
2. Andreadou E, Kattoulas E, Sfagos C, Vassilopoulos D. Stiff person syndrome: avoiding misdiagnosis. Neurol Sci 2007;28:35. Link to article
3. Murinson B. Stiff-person syndrome. Johns Hopkins.School of Medicine. Link to article
4. Pétursson H. The Benzodiazepine Withdrawal Syndrome. Addiction. 1994 Nov;89(11):1455-9. Link to article
5. Cohen L. Stiff-man syndrome: two patients treated with diazepam. JAMA 1966, 195:160–162. Link to article
6. Finckle BS, McClosky KL, Goodman LS. Diazepam and drug-associated deaths: a survey in the United States and Canada. JAMA 1979;242:429-434. Link to article
7. Benzodiazepines: how they work and how to withdraw. Professor C Heather Ashton DM, FRCP. Revised August 2002. Link to article
8. Benzodiazepine Equivalence Table Link to article
Warning: Ethanol falls under this category and is especially dangerous when taken in combination with any of these medications and could result in overdose/toxicity.
GABA POSITIVE ALLOSTERIC MODULATORS