Sunday, November 29, 2009

Sedative- Hypnotics

Overview



Barbiturates belong in a class of drugs known as sedative-hypnotics, which are commonly described by their sleep-inducing and anxiety-decreasing effects. They were first used for medicinal purposes in the early 1900’s, but became a trend in the 60’s and 70’s for treating anxiety, insomnia, and seizure disorders. Barbiturate use and abuse has steadily decreased since the 1970’s due to the invention of safer sedative-hypnotic drugs, known as benzodiazepines. Today, barbiturates are primarily used to treat insomnia and as a means of preoperative sedation. They are also still used in the veterinary field for anesthesia and for the use in capital punishment by lethal injection.
There are 4 classes of barbiturates and they are classified according to their speed of onset and their duration of action:


1) Ultrashort-Acting Barbiturates- these have a very short duration of action and are generally used for anesthesia because they can be controlled with ease.
2) Short-Acting Barbiturates
3) Intermediate-Acting Barbiturates
4) Long-Acting Barbiturates

Barbiturates can be highly toxic because predicting the correct dosage can be difficult. They can be abused to reduce anxiety, decrease inhibitions, and to treat unwanted effects of illicit drugs.
Benzodiazepines are sedative hypnotic drugs which were discovered accidently in 1955 by Leo Sternbach while working at Hoffmann-La Roche. In 1957, a co-worker came across a left over compound named “chlordiazepoxide” which displayed resilient sedative, anticonvulsant, and muscle relaxant effects. Benzodiazepines became world wide in 1960. Soon, the production of benzodiazepines led to a decline in barbiturate usage.
Benzodiazepines are classified into 3 groups by their elimination half-lives:


1) Short-Acting Benzodiazepines- half-lives consist of 1-8 hours. Used to treat insomnia, have high abuse potential, and can cause severe withdrawal symptoms.
2) Intermediate-Acting Benzodiazepines- half-lives consist of 8-40 hours. Used for treating anxiety-related symptoms and for alchol detoxification.
3) Long-Acting Benzodiazepines- half-lives consist of 40-200 hours. Used primarly to treat seizures and have limited abuse and withdrawal effects.



How They Work





Benzodiazepines submit their effects by acting on GABA receptors, the GABAA receptor in particular. They bind to the receptor complex to enhance the efficiency of GABA; thus, the amount of GABA needed to open the channel is decreased. The GABAA receptor is composed of five subunits, and in each subunit there are many subtypes. GABAA receptors consist of many subtype subunit configurations which lead to many different effects. For example, benzodiazepines that highly activate the A1 receptor create greater hypnotic effects, whereas benzodiazepines that have higher affinity for GABAA receptors containing A2 and A3 subunits have larger anti-anxiety effects. Overall, benzodiazepines increase the release of GABA which suppresses the activity of other neurotransmitters.
Barbiturates contain high affinity for the GABAA receptor at the alpha subunit, which is private from where benzodiazepines bind. Here, barbiturates potentiate the effect of GABA. Similarly, barbiturates also block the AMPA receptor, which is a subtype of the glutamate receptor. Thus, barbiturates potentiate inhibitory GABAA receptors and inhibit excitatory AMPA receptors which create suppressing effects in the central nervous system. When induced in large quantities, barbiturates can inhibit Ca2+ release of neurotransmitters. They do so by enhancing the duration of the chloride ion channel opening at the GABAA receptor. Due to their level of control over the gating and opening of the chloride ion channel, their potential for toxicity is much higher than that of benzodiazepines.



Abuse





Benzodiazepines can cause tolerance, dependence, and withdrawal symptoms. There are two ways in which benzodiazepines can be metabolized. The first way is done by cytochrome P450 enzymes, which contain high potential for interactions with other drugs. The second way they can be metabolized is through glucuronidation, which inquires less drug interactions. There are certain drugs which can inhibit cytochrome enzymes in the liver which reduces the rate benzodiazepines are eliminated. This can lead to drug accumulation and the potential for greater side-effects. On the contrary, drugs that induce CYP450 enzymes increase the elimination of benzodiazepines and decrease their rate of action. Taking benzodiazepines with alcohol, opiates, or other CNS depressants will potentiate their effects. This can result in increased sedation, impaired motor coordination, suppressed breathing, and increased toxicity. Abuse can range from occasional binges with large doses, to chronic and compulsive abuse of high doses. The users who are most likely to abuse benzodiazepines are polly-drug users. After continuous use for three weeks or longer, withdrawal symptoms can already be observed. There is also potential for physical and psychological dependence. Another major issue of benzodiazepine misuse is when it is administered intravenously. This can cause abscesses, cellulitis, arterial puncture, hepatitis, or AIDS. Lastly, because benzodiazepines do not increase the release of dopamine in the mesolimbic system, the abuse of these drugs is probably due to the development of tolerance leading toward withdrawal.
Barbiturates create a feeling of intoxication which greatly resembles alcohol intoxication. Symptoms of barbiturate intoxication are respiratory depression, lowered blood pressure, fatigue, fever, unusual excitement, irritability, dizziness, poor concentration, sedation, confusion, impaired coordination, impaired judgment, or even respiratory arrest. Although the use of barbiturates has declined since the 1970’s, a recent high school survey suggests that abuse among teens has been increasing for the last ten years. A reason for this may be to counteract the symptoms of other drugs. For example, barbiturates would counteract the feelings of excitement produced by cocaine. At small doses of abuse, one may feel drowsy, disinhibited, and intoxicated. At high doses, one may lose coordination and stumble as if drunk, develop slurred speech, and become confused. At even higher doses, one may go into a coma and or stop breathing. The main reason why barbiturates are no longer prescribed compared to benzodiazepines is because they carry a narrow therapeutic-to-toxic range. This means that the smallest difference in dosage could bring about fatal effects.


Tolerance/ Withdrawal


Tolerance to benzodiazepines sedative effects develop fast but their anxiolytic effects are slower. Benzodiazepine tolerance can rapidly develop due to decreased pharmacological effects such as sedative, hypnotic, anticonvulsant, and muscle relaxant actions.
The acute benzodiazepine withdrawal syndrome generally lasts five to twenty-eight days after withdrawal. Common symptoms are:
-Perceptual disturbance
-Depersonalization
-Distortion of body image
-Sensory hypersensitivity
-Confusion, delirium
-psychotic symptoms
NOTE: some of these symptoms can last up to six to twelve months. In some cases, a protracted phase may develop in which symptoms weaken but may return sporadically. Symptoms that are likely to be recurrent are:
-Anxiety
-Insomnia
-Cognitive impairment
-Depression
-Sensory and motor phenomena
-Gastrointestinal disturbances
Lastly, the benzodiazepine dose, its half-life, potency, treatment duration, rate of benzodiazepine withdrawal, and severity of underlying anxiety all attribute with the overall severity of withdrawal symptoms.


http://www.youtube.com/watch?v=uDbPnAQ-c1o&feature=related



Barbiturate abuse can lead to psychological and physical dependence, and tolerance. Physical dependence can be relieved with long-acting barbiturates due to their long half-lives. They can create numerous health-related problems when they are consumed over time. A couple examples are blood problems and liver disease.
Basic withdrawal symptoms due to barbiturate addiction:
-Sleepiness
-Irritability
-Restlessness
-Seizures
-Death


Treatment


Presently, benzodiazepines have many therapeutic uses. They can treat:
-Panic Disorder
-Generalized Anxiety Disorder
-Insomnia
-Seizures
-Alcohol Withdrawal
-Anxiety
Benzodiazepines can be used in intensive care units to sedate patients who are receiving mechanical ventilation, or those who are in extreme distress. They can also treat muscle spasms, psychiatric emergencies such as acute psychosis for those with schizophrenia or mania, and they can treat pre-operate anxiety.
On the other hand, when treating benzodiazepine withdrawal, it is important to remember that the slower the withdrawal rate, the less intense the withdrawal symptoms are. The first step of benzodiazepine treatment would be detoxification. Here, benzodiazepine dependency can be carried out by using an equal dose of either valium or chlordiazepoxide, and by reducing their amounts every to two to four weeks. It is highly paramount to administer an accurate reduction of doses because if they are not equivalent, severe withdrawal effects can occur. Other factors contributing to the withdrawal treatment can be cognitive behaviour therapy, the type of benzodiazepine the user used, their lifestyle, personality, what kind of social support they have, and what kinds of environmental stressors they will have around them. In conclusion, CBT and a dosage reduction program are very effective tools to treat ones benzodiazepine withdrawal.
When treating barbiturate withdrawal, it is important that the user is admitted to a hospital setting. Prolonged therapy is key to avoid dangerous symptoms of withdrawal. Abusers who are addicted face the same treatment as benzodiazepines addicts, which is a dose reduction treatment program until they are drug free. Psychiatric therapy can also be used as a method of therapy.



References


Ashton, C Heather. (2004). Protracted withdrawal symptoms from benzodiazepines. Comprehension Handbook of Drug and Alcohol Addiction.

Barbiturates. (2009, November 24) In Wikipedia: the free encyclopedia. Retrieved November 28, 2009, from http://en.wikipedia.org/wiki/Barbiturates


Benzodiazepines. (2009, November 22) In Wikipedia: the free encyclopedia. Retrieved November 28, 2009, from http://en.wikipedia.org/wiki/Benzodiazapines


EMedicineHealth. Barbiturate Abuse. Retrieved November 22, 2009, from, http://www.emedicinehealth.com/barbiturate_abuse/article_em.htm


Lingford-Hughs, Anne. (2003). Neurobiology of addiction and implications fortreatment. The British Journal of Psychiatry,182, 197-100.


Onyett, Steve R. (1989). The benzodiazepine withdrawal syndrome and its management. Journal of the Royal College of General Practitioners, 39, 160-63.


Recovery Connection. Retrieved November 28, 2009, from http://www.recoveryconnection.org/drug_index/barbiturates.php


Seevers, M.H. (1968). Psychopharmacological elements of drug dependence. JAMA, 206, 1263-66.


Susman, Jeffrey & Klee, Brian. (2005). The role of high-potency benzodiazepines in the treatment of panic disorder. Prim Care Companion J Clin Psychiatry, 7(1), 5-11.


Zwanzger, Peter & Rupprecht, Rainer. (2005). Selective GABAergic treatment for panic? Investigations and experimental panic induction and panic disorder. Psychiatry Neuroscience, 30 (3), 167-73.



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