Barbiturates and Benzodiazepines PDF

BARBITURATES AND BENZODIAZIPINES Sedatives: These are drugs that subdue excitement and calms, relax the subject without inducing sleep, though drowsiness may be produced. Sedation refers to decreased responsiveness to stimulation; is associated with some decrease in alertness, ideation and motor ac...

BARBITURATES AND BENZODIAZIPINES Sedatives: These are drugs that subdue excitement and calms, relax the subject without inducing sleep, though drowsiness may be produced. Sedation refers to decreased responsiveness to stimulation; is associated with some decrease in alertness, ideation and motor activity. Hypnotics: A drug that induces and/or maintains sleep, similar to normal arousable sleep. This is not to be confused with ‘hypnosis’ meaning a trans-like state in which the subject becomes passive and highly suggestible. The sedatives and hypnotics are CNS depressants with somewhat differing time-action and dose-action relationships. Agents with quicker onset, shorter duration and steeper dose-response are preferred as hypnotics, while more slowly acting drugs with flatter dose-response are employed as sedatives. The sedatives reduce anxiety and induce calming effect with little or no effect on motor and mental functions. Hypnotic drugs produce drowsiness and facilitate the onset and maintenance of a state of sleep that as much as possible resembles natural sleep. However, a hypnotic at lower dose may act as sedative. Thus, sedation, hypnosis and general anaesthesia may be regarded as increasing grades of CNS depression. Hypnotics given in high doses can produce general anaesthesia.  Barbiturates Barbiturates are drugs that act as central nervous system depressants, and can therefore produce a wide spectrum of activities from mild sedation to total anaesthesia, hypnotics and anticonvulsants. Barbiturates have addiction potential both physical and psychological. Barbiturates were for a long time widely used as sedative-hypnotics, but they are now replaced by benzodiazepines in routine medical practice such as treatment of anxiety and insomnia because the benzodiazepines are less dangerous in overdose. Barbiturates have a low therapeutic index, i.e. relatively small overdose may endanger life, they can also cause dependence and have been popular drugs of abuse. Barbiturates Barbiturates produce CNS depression of varying degrees from mild sedation to general anaesthesia. Based on their duration of action, the barbiturates are divided into; Long acting (Phenobarbitone and Barbitone). Intermediate acting (Amobarbitone, Aprobarbitone and Butabarbitone). Short acting (Penthobarbitone and Secobarbitone). Ultra short acting (Thiopentone sodium, Hexobarbitone and Methohexitone).  Barbiturates Mechanism of action: Barbiturates inhibit and causes CNS depression. This is brought about by stimulating the inhibitory neurotransmitter system in the brain called the GABA system. The GABA channel is a chloride channel that has five cells at it gate. When they bind to the GABA channel, they prolong opening of the channel and letting in chloride ions into the cells in the brain. This leads to increased negative charge and alters the voltage in the brain. This change in voltage makes the brain cells resistant to nerve impulses and depresses them.  Barbiturates Pharmacokinetics: Barbiturates are well absorbed from the gastrointestinal tract. They are widely distributed in the body. The rate of entry into CNS is dependent on lipid solubility. Highly-lipid soluble thiopentone has practically instantaneous entry, while less lipid-soluble ones (pentobarbitone) take longer; phenobarbitone enters very slowly. Barbiturates cross placenta and are secreted in milk; can produce effects on the foetus and suckling infant. Three processes such as redistribution, metabolism and excretion, are involved in termination of action of barbiturates: the relative importance of each varies with the compound.  Barbiturates On intravenous injection, the highly lipid soluble compounds (thiopentone) enter the CNS rapidly and produce anaesthesia in less than 1 min, and then diffuse back quickly to redistribute to less vascular tissues (muscle, fat). Consciousness is regained in 6-10 min, but ultimate disposal occurs by metabolism (t½ 9 hours). Intermediate lipid solubility barbiturates are primarily metabolized in the liver by oxidation, dealkylation and conjugation. Their plasma t½ ranges between 12–36 hours. Barbiturates with low lipid-solubility, in addition to being metabolized, are significantly excreted unchanged in urine. Clinical uses of barbiturates Except for phenobarbitone in epilepsy and thiopentone/ methohexitone in anaesthesia, no other barbiturate is commercially available or used now. As hypnotic and anx i o l y t i c. T h e b a r b i t u r a t e s h a v e b e e n s u p e r s e d e d b y benzodiazepines. Adverse effects Hangover was common after the use of barbiturates as hypnotic. Mental confusion, impaired performance and traffic accidents may occur. Tolerance and dependence Both cellular and pharmacokinetic (due to enzyme induction) tolerance develops on repeated use. However, fatal dose is not markedly increased: addicts may present with acute barbiturate intoxication. There is partial cross tolerance with other CNS depressants. Addiction and dependence occurs, and barbiturates have considerable abuse liability. This is one of the major disadvantages. Withdrawal symptoms are—excitement, hallucinations, delirium, convulsions; deaths have occurred. Contraindication Contraindications of barbiturates include; Severe liver and kidney dysfunction Impaired myocardial function in pregnant and lactating women Known hypersensitivity to barbiturates Severe intoxication with other CNS depressants such as alcohol, hypnotics and narcotics. Barbiturate poisoning Acute barbiturate poisoning may arise from unintentional or intentional overdose or after a therapeutic dose has been taken in association with alcohol. However, it is infrequently encountered currently due to unavailability of barbiturates. Moreover, the principles of treatment apply to any CNS depressant poisoning. Manifestations are due to excessive CNS depression— patient is flabby and comatose with shallow and failing respiration, fall in BP and cardiovascular collapse, renal shut down, pulmonary complications, bullous eruptions. Death may result from paralysis of the respiratory and vasomotor centres from bronchopneumonia occurring as a result of prolonged coma. Treatment of barbiturate poisoning Treatment of barbiturate poisoning consists in measures designed to restore respiration and circulation. Gastric lavage can be performed if the duration of the drug intake has not exceeded one hour. This procedure is ineffective in later stage of acute poisoning. The next step is to eliminate poison already absorbed by diuresis or dialysis. Diuresis is used in mild form of acute poisoning. Intravenous fluid such as isotonic solution of sodium chloride with 100 mg-200mg of manitol in 5-10% solution. Treatment of barbiturate poisoning Loop diuretics such as furosemide may be used. Artificial respiration is used in respiratory disorder Oxygen therapy is used for treatment of hypoxia Secretions are removed from upper respiratory tract Vasoconstriction agents such as norepinephrine or epinephrine is used for hypotension. Fluid replacement, blood transfusion and vasoconstricting agents are used in the treatment of shock that occur occasionally in acute poisoning Benzodiazepines Benzodiazepines are selective CNS depressants which produce sedation, relieve anxiety, facilitate sleep, suppress seizure and reduce muscle tone. Anxiety disorders are among the most common of all CNS disorders afflicting humans, with the painful experience of tension and apprehension. Symptoms of anxiety are commonly associated with depression, panic, social phobias, for example; fear of meeting people, obsessive-compulsive disorder and many personality disorders. Benzodiazepines Based on their duration of action, the benzodiazepines are divided into; Long acting (diazepam, clonazepam, chlordiazepoxide, clorazepate etc). Intermediate acting (alprazolam, lorazepam, temazapam, estazolam etc) Short acting (triazolam, halazepam, flurazepam, midazolam etc) Benzodiazepines Mechanism of action: Benzodiazepine bind to specific binding sites in the GABAA receptor-chloride complex in the brain, and increases the frequency of chloride channel opening in the presence of GABA; this increases hyperpolarization-induced neuronal inhibition Benzodiazepines Pharmacokinetics: There are marked pharmacokinetic differences among BZDs, because they differ in lipid solubility by more than 50 fold. These differences are important factors governing their choice for different uses. Oral absorption of some is rapid while that of others is slow. Plasma protein binding also varies strongly (triazolam 10% to diazepam 99%). BZDs are widely distributed in the body. Benzodiazepines are metabolized in liver mainly by CYP3A4 and CYP2C19 to dealkylated and hydroxylated metabolites and excreted in urine. Therapeutic uses As anxiolytic As sedative/hypnotic As anticonvulsant, especially emergency control of status epilepticus, febrile convulsions, tetanus, etc. As centrally acting muscle relaxant for muscle spasms and spasticity. For pre-anaesthetic medication, intravenous anaesthesia and conscious sedation. Alcohol withdrawal in dependent subjects. Therapeutic uses Before ECT, electrical cardioversion of arrhythmias, cardiac catheterization, endoscopies, in obstetrics and many minor procedures— intravenous diazepam has gained popularity because of its calming-amnesic-analgesic and muscle relaxant properties and relative safety. In Psychosis, the potent benzodiazepines (injectable BZDs) are commonly employed, also adjunctively in short-term management of acute psychotic or manic patients. Adverse effects Toxic effects due to acute overdosage causes prolonged sleep. Other unwanted effects includes; drowsiness, confusion, amnesia and impaired motor coordination, dizziness, weakness, unsteadiness. Tolerance and dependence: Pharmacokinetic and tissue tolerance, can also cause physical dependence, i.e. stopping benzodiazepines treatment after weeks or months causes an increase in symptoms of anxiety. Interactions Benzodiazepines synergize with alcohol and other CNS depressants leading to excessive impairment. Concurrent use with sodium valproate has provoked psychotic symptoms. Drug interactions due to displacement from protein binding or microsomal enzyme induction are not significant. Since CYP 3A4 isoenzyme plays important role in metabolism of several BZDs, their action can be prolonged by CYP 3A4 inhibitors like ketoconazole, erythromycin and others. Cimetidine, isoniazid and oral contraceptives also retard BZD metabolism. Benzodiazepine anatagonist Flumazenil: This is a BZD analogue which has little intrinsic activity (practically no effect on normal subjects), but competes with BZD agonists as well as inverse agonists for the BZD receptor and reverses their depressant or stimulant effects respectively. Flumazenil abolishes the hypnogenic, psychomotor, cognitive and EEG effects of BZDs. Flumazenil is not used orally. This agent is given intravenously and its action starts in seconds and lasts for 1–2 hours. The elimination half-life (t½) is 1 hour, due to its rapid metabolism. Uses To reverse BZD anaesthesia: Patients anaesthetized/ sedated with a BZD wakeup, get oriented and regain motor control within 1 min of an intravenous injection of 0.3–1 mg of flumazenil. Resedation generally occurs within 1 hour (more with diazepam than with midazolam): supplemental doses of flumazenil may be given. This may allow early discharge of patients after diagnostic procedures and facilitates postanaesthetic management. Uses BZD overdose: Majority of patients of BZD overdose require only supportive measures like patent airway, maintenance of BP, cardiac and renal function (by fluid transfusion, etc.). In addition, flumazenil 0.2 mg/min may be injected i.v. till the patient regains consciousness. Practically all patients intoxicated with a BZD alone respond within 5 min (maximum total dose 1 mg). Uses However, reversal of respiratory depression is incomplete. Flumazenil blocks the hypnotic effect of zolpidem-like non-BZDs as well. In mixed CNS depressant poisoning, whatever sedation is not abolished by 5 mg of flumazenil should be taken to be due to a non-BZD/non-Zolpidem-like depressant. However, administration of flumazenil may be risky in mixed overdosage with a BZD plus a tricyclic antidepressant. It can also be hazardous in BZD-dependent subjects by precipitating severe withdrawal. Thus, the use of flumazenil in BZD overdosage requires great caution. Adverse effects Flumazenil is safe and well tolerated. Side effects noted during use of flumazenil as a BZD-antagonist are; agitation, discomfort, fearfulness, anxiety, coldness and withdrawal seizures.