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Lesson B.2 Notes

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Queen's University
Pharmacology and Toxicology
PHAR 100
Bill Racz

Lesson B.3 - Sedative-hypnotics and Anxiolytics Introduction The sedative-hypnotic agents are central nervous system (CNS) depressants. These drugs produce dose-dependent CNS depression ranging from: antianxiety effect → sedation → hypnosis (sleep) → general anesthesia. The magnitude of CNS depression produced by a drug at a particular dose determines whether the agent is considered as an antianxiety agent, a sedative, or a hypnotic at that dose. History • The first agents to be introduced into clinical medicine as sedatives and hypnotics were bromides, in the mid 19 century • Prior, ethyl alcohol and herbal preparations were the only drugs available • Unfortunately, bromide accumulates in the body due to slow elimination rate o produced a condition known as bromism, characterized by mental and neurological aberrations, skin rash and gastrointestinal disturbance o Chloral hydrate and paraldehyde were introduced shortly after (safer) • 1912, the introduction of phenobarbital heralded the age of the barbiturates • 1950's, meprobamate and glutethimide were introduced • 1961, chlordiazepoxide was introduced and ushered in the era of the benzodiazepines Therapeutic Uses (a) Antianxiety relief: The benzodiazepines are the drugs of choice. (b) Sedative (reduce sensory-motor function, reduce tension): The wide margin of safety of the benzodiazepines allows these drugs to be used in clinical situations where sedation is required. (c) Hypnotic (sleep): The short-acting benzodiazepines are the drugs most widely used as hypnotics. (d) Anticonvulsant agent for certain types of epilepsy: Phenobarbital has been used to control generalized tonic-clonic and partial seizures. Some of the benzodiazepines are useful in absence seizures and status epilepticus. (e) Treatment of skeletal muscle spasm: Benzodiazepines reduce elevated skeletal muscle tone and are useful in neuromuscular disorders, e.g. cerebral palsy. Lesson B.3 - Sedative-hypnotics and Anxiolytics (f) Treatment of alcohol withdrawal syndrome: Most of the benzodiazepines are useful in the treatment of alcohol withdrawal. There is cross-dependence on the two agents, diazepam substituting for alcohol. Diazepam is the drug of choice. Benzodiazepines (Drug of First Choice) Mechanisms of SNAAction In 1977, specific receptors for the benzodiazepines were discovered in the nervous system. These receptors are highest in density in the cerebral cortex, cerebellum and limbic system. These drugs: (a) Increase synaptic inhibition and thus dampen neuronal responses. (b) By activating the benzodiazepine receptor, they enhance the action of gamma- aminobutyric acid (GABA), the major inhibitory neurotransmitter in the CNS. The sites of action include the cerebellum, cerebral cortex, limbic system, reticular activating system, and the spinal cord. They act on the same structure as GABA, but not on the GABA receptor. Pharmacological Properties • Very high therapeutic index • Anxiety relief • Decrease aggression • Produce sedation and amnesia • Some members of this group are effective hypnotics • Minimal suppression of REM-type sleep with regular dose • Skeletal muscle relaxation • Anticonvulsant action Pharmacokinetics: • pharmacological property for which there are appreciable differences among the various benzodiazepines • different durations of action which is determined by rate of liver metabolism and formation or lack of pharmacologically active metabolites Lesson B.3 - Sedative-hypnotics and Anxiolytics • The individual benzodiazepines have similar pharmacological profiles, but are used for different purposes: o Diazepam is used as an anxiolytic and anticonvulsant o Flurazepam is used as a hypnotic o Alprazolam is the drug of choice for panic disorders Routes of administration: benzodiazepines usually capsule or tablet (sometimes intravenous) Effects of short termlow/moderate doses: • CNS; the desirable effects o relief from anxiety and tension, relaxation and calmness • Other effects may include mild to moderate impairment of motor coordination, drowsiness, lethargy, fatigue, and impairment of thinking and memory • Rapid Intravenous administration o Respiratory depression • Gastrointestinal o nausea, constipation, dry mouth and abdominal discomfort • moderate dose o impair motor coordination and impair driving Effects of short termhigher dosage: • drowsiness, over-sedation and sleep • Prior to sleep, patient resembles in an intoxicated state o blurred vision, poor coordination, slow reflexes, and impaired thought Lesson B.3 - Sedative-hypnotics and Anxiolytics • very high dosage o coma (can also occur at low dosage if taken with other CNS depressants, ex. alcohol) Effects of Long term use: • varies between individuals • Some take large amounts for long periods of time without any major evidence of intoxication • others will demonstrate the symptoms of chronic sedative-hypnotic intoxication o impaired thinking, poor memory and judgment, disorientation, slurred speech, poor coordination, and weak muscles Lethality • benzodiazepine - very common in overdose • fortunately, wide safety margin prevents many overdoses Tolerance • develops to the sedative and impairment of coordination effects • tolerance to anxiolytic effect is less common Physical Dependence/Withdrawal • not much of an issue unless using drug for over a year • severity of withdrawal depends on o the individual benzodiazepine used o amount and duration o abruptness of ceasing to use Psychological dependence (addiction) Lesson B.3 - Sedative-hypnotics and Anxiolytics • may develop in some users, but by no means all. There is a persistent craving for the drug, even when it no longer produces an effect Patterns of use • The benzodiazepines are among the most widely prescribed drugs in the world • 10% Canadians use it at least once a year for medical reasons • Diazepam and lorazepam are the preferred drugs and are often used in combination with alcohol to enhance the effect of alcohol. o Interestingly, 30-76% of alcohol abusers use benzodiazepines Potential for Abuse • Low abuse liability • Inherent harmfulness is low Barbiturates The barbiturates are potent CNS depressants. At low doses, they induce a state of relaxation and tranquillity and will mildly impair cognitive (thinking) and motor function. At moderate doses, they can induce sleep, but prior to inducing sleep, they can impair motor and cognitive functions. This moderately impaired state can be pleasurable. At higher doses still, they induce anesthesia, i.e. a state of unconsciousness where powerful or painful stimuli are not experienced. As the dose increases, they cause greater and greater depression of the respiratory centre in the brain. Death results from respiratory failure. The clinical uses for the barbiturates are limited. The short-acting ones are used to induce anesthesia, and phenobarbital (a long-acting agent) is used as an antiepileptic. They have been replaced for the most part by newer and safer drugs. Common street names are barbs, downers and goofballs. Other street names are based on the colour of the capsule, e.g. red devils for Seconal. Mechanism of Action The action of the barbiturates is less selective than that of the benzodiazepines on the CNS. They potentiate the effect of GABA at its receptor, enhancing the inhibitory effect of GABA, but they do not bind to the benzodiazepine receptor but have their own
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