Side Effects of Benzodiazepines:
Drowsiness, confusion, amnesia and impaired motor coordination, which considerably impairs manual skills such as driving performance. An interaction with alcohol is often claimed, whereby a low plasma concentration of benzodiazepines can enhance the depressant effect of alcohol. The long and unpredictable duration of action of many benzodiazepines is important in relation to side effects. Drugs such as nitrazepam that are used as hypnotics have been shown to produce a substantial day-after impairment of job performance and driving skill.
Acute Toxicity of Benzodiazepines:
Benzodiazepines in acute overdose are considerably less dangerous than other anxiolytic/hypnotic drugs. The effect of an overdose is to cause prolonged sleep, without serious depression of respiration or cardiovascular function. However, in the presence of other CNS depressants, particularly alcohol, benzodiazepines can cause severe, even life-threatening, respiratory depression. The availability of an effective antagonist, flumazenil, means that the effects of an acute overdose can be counteracted, which is not possible for most CNS depressants.
Tolerance; Dependence of Benzodiazepines:
Tolerance, a decrease in responsiveness to a drug following continuous exposure, is a common feature of sedative-hypnotic use. The changes in responsiveness of the central nervous system (pharmacodynamic tolerance) may explain tolerance to benzodiazepines.
The consequences of abuse of these agents can be defined in both psychologic and physiologic terms. When the pattern of sedative-hypnotic use becomes compulsive, more serious complications develop, including physical dependence and tolerance.
Physical dependence can be described as an altered physiologic state that requires continuous drug administration to prevent the appearance of an abstinence or withdrawal syndrome. This syndrome is characterized by states of increased anxiety, insomnia, and CNS excitability that may progress to convulsions.
All sedative-hypnotics are capable of causing physical dependence when used on a chronic basis. However, the severity of withdrawal symptoms differs between individual drugs and depends also on the magnitude of the dose used immediately prior to cessation of use.
Differences in the severity of withdrawal symptoms between individual sedative-hypnotics relate in part to half-life, since drugs with long half-lives are eliminated slowly enough to accomplish gradual withdrawal with few physical symptoms. Therefore, benzidiazepines produces less intense withdrawal symptoms after stopping of therapy due to the long plasma half-life and their active metabolites.
Drug Interactions of Benzodiazepine:
They potentiate the CNS depressant effect of alcohol as well as the other CNS depressant drugs.
Concurrent administration of benzodiazepines with liver microsomal enzyme inhibitors such as cimetidine would lead to excessive sedation and drowsiness due to the increase in benzodiazepine’s plasma levels. Lorazepam, temazepam and oxazepam are metabolized by a different metabolic pathway involving glucuronidation which is not affected by cimetidine.
Benzodiazepine Antagonists:
Flumazenil:
Flumazenil is one of several 1,4-benzodiazepine derivatives with high affinity to Benzodiazepines receptors that act as competitive antagonists. It blocks many of the actions of benzodiazepines but does not antagonize the CNS effects of other sedative-hypnotics, ethanol, opioids, or general anesthetics.
Flumazenil is used in reversing the CNS depressant effects of benzodiazepines overdose and following use of these drugs in anesthetic and diagnostic procedures.
When given intravenously, flumazenil acts rapidly but has a short half-life (0.7-1.3 hours) due to rapid hepatic clearance. Adverse effects of flumazenil include agitation, confusion, dizziness, and nausea.
Barbiturates:
Pharmacodynamics of Barbiturates:
Barbiturates facilitate the actions of GABA at multiple sites in the CNS, but in contrast to benzodiazepines they appear to increase the duration of the GABA-gated channel openings. At high concentrations, barbiturates may directly activate chloride channels. These effects involve a binding site or sites distinct from the benzodiazepines binding site.
Barbiturates are less selective in their actions than benzodiazepines, since they also depress the actions of excitatory neurotransmitters and exert non-synaptic membrane effects in parallel with their effects on GABA neurotransmission. This multiplicity of sites of action of barbiturates may be the basis for their ability to induce full surgical anesthesia and for their more pronounced central depressant effects compared to benzodiazepines. 
Pharmacological Effects of Barbiturates:
CNS depressant Effect:
q Sedation: drowsiness, mental confusion.
q Hypnosis: abnormal sleep and hangover. Barbiturates inhibit the REM sleep however, after stopping administration, a rebound increase in REM sleep with nightmares may occur.
q Amnesia.
q Anesthesia:
Certain sedative-hypnotics in high doses will depress the central nervous system to the point known as stage III or general anesthesia thiopental is very lipid-soluble, penetrating brain tissue rapidly following intravenous administration.
Rapid tissue redistribution accounts for the short duration of action of these drugs, which are therefore useful in anesthesia practice.
q Anticonvulsant effects:
Phenobarbital is effective in the treatment of grand mal and jacksonian epilepsy.
q Respiratory and circulatory depression:
High doses of barbiturates depress the respiratory and vasomotor centers leading to death.
Gastrointestinal effects:
They inhibit gut motility and secretion.
Kidney:
They cause the release of antidiuretic hormone causing oliguria and anuria.
Pharmacokinetics of Barbiturates:
Lipid solubility plays a major role in determining the rate at which the particular drug enters into the brain.Thiopental in which the oxygen on C2 is replaced by sulfur, is very lipid-soluble, and a high rate of entry into the CNS contributes to the rapid onset of its central effects.
Redistribution of drug from the CNS to other tissues is an important feature of the biodisposition of sedative-hypnotics. Thiobarbiturates have shown that they are rapidly redistributed from the brain, first to highly perfused tissues such as skeletal muscle and subsequently to poorly perused adipose tissue. These processes contribute to the termination of their major CNS effects.
Redistribution to tissues other than the brain may be as important as biotransformation in terminating the CNS effects of many sedative-hypnotics. However, metabolic transformation to more water-soluble metabolites is necessary for clearance from the body of almost all drugs in this class. The microsomal drug-metabolizing enzyme systems of the liver are most important in this regard.
With the exception of phenobarbital, only insignificant quantities of the barbiturates are excreted unchanged. The major metabolic pathways involve oxidation by hepatic enzymes of chemical groups attached to C5, which are different for the individual barbiturates.
The elimination half-lives of secobarbital and pentobarbital range from 18 to 48 hours in different individuals. The elimination half-life of phenobarbital in humans is 4-5 days. Multiple dosing with these agents can lead to cumulative effects. Phenobarbital is excreted unchanged in the urine to a certain extent (20-30% in humans), and its elimination rate can be increased significantly by alkalinization of the urine.
Clinical Indications of Barbiturates:
q Sedatives and hypnotics e.g. pentobarbitone. They inhibit the REM sleep, however stopping of barbiturates may cause rebound increase in the REM sleep and nightmares.
q Anticonvulsants in treatment of epilepsy e.g. phenobarbitone.
q As preanaesthetic medication e.g. thiopental for either induction of anesthesia or as I.V. anesthetic for brief operations (15 mins).
q To counteract the CNS stimulant effect of CNS stimulant drugs.
Dosage of Barbiturate:
q Phenobarbital: 15-30mg 2-3 times daily.
q Pentobarbital: 100-200mg daily.
Side Effects of Barbiturates:
q Drowsiness, mental confusion, hangover.
q Hypersensitivity reactions.
Acute Toxicity of Barbiturates:
q Hypoxia, cyanosis, hypothermia.
q Respiratory, circulatory failure, coma, death.
Treatment of Toxicity:
q Emergency treatment by supporting respiration and circulation.
q Inhibiting further absorption by gastric lavage (if no coma) and promoting renal excretion by forced alkaline diuresis and hemodialysis.
q CNS stimulant drugs can be used such as analeptics.
Contra-indications of Barbiturates:
q In patients with acute porphyria due to the induction of delta-aminolevulinic acid synthase that cause a significant increase in porphyrin synthesis causing hematuria, neuropathy and muscle weakness.
q In liver and renal impairment.
q In respiratory disease as bronchial asthma.
Tolerance; Dependence of Barbiturates:
An increase in the rate of metabolic inactivation with chronic administration may be partly responsible (metabolic tolerance) for tolerance of barbiturates.
Drug dependence and withdrawal symptoms occur with barbiturates more severe compared to benzodiazepines.
Drug Interactions of Barbiturates:
Barbituartes would decrease the serum levels and the effect of concurrently administered drugs due to induction of liver microsomal enzymes.
Concurrent use of barbiturates and the other CNS depressant drugs may lead to respiratory depression.
Buspirone:
Benzodiazepines continue to be the agents of choice in the treatment of anxiety and insomnia however, their pharmacological effects include sedation and drowsiness, synergistic CNS depression with other drugs (especially alcohol), and dependence with continuous use are considered the main drawbacks. New anxiolytic drugs that act through non-GABAergic systems might have a reduced propensity for such actions.
Buspirone relieves anxiety without marked sedation. Unlike benzodiazepines, the drug has no hypnotic, anticonvulsant, or muscle relaxant properties.
Buspirone does not interact directly with GABAergic systems but appears to exert its anxiolytic effects by acting as a partial agonist at 5-HT1A receptors. It is not effective in blocking the withdrawal syndrome resulting from cessation of use of benzodiazepines or other sedative-hypnotics. Buspirone does not potentiate the CNS depressant effects of conventional sedative-hypnotic drugs.
Buspirone is rapidly absorbed from the gastrointestinal tract but undergoes extensive first-pass metabolism. Its elimination half-life is 4 hours, with virtually no free drug appearing in the urine. Liver enzymes metabolize buspirone via hydroxylation and N-dealkylation reactions, resulting in formation of several metabolites that may retain slight pharmacological activity.
Buspirone causes less psychomotor impairment than diazepam. Tachycardia, palpitations, headache, nervousness, gastrointestinal distress, and paresthesias may occur more frequently than with benzodiazepines. Its dose is 20mg daily, orally.
Zolpidem:
Zolpidem is an imidazopyridine derivative, structurally unrelated to benzodiazepines. The drug binds to benzodiazepines receptors and appears to have a similar mechanism of action to facilitate GABA-mediated inhibition. It is mainly used as a hypnotic. Zolpidem has an efficacy and side effect profile similar to that of triazolam.
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