Hypnotics and sedatives

General consideration

• A sedative drug decrease activity , moderates excitement ,and calms the recipient .

• A hypnotic drug produces drowsiness and facilitates the outset and maintenance of a state of sleep that resembles natural sleep in its electroencephalographic characteristics and from which the recipient can be aroused easily.

• The nonbenzodiazepine sedative-hypnotic drugs belong to a group of agents that depress the CNS in relatively nonselective , dose-dependent fashion ,producing progressively calming or drowsiness, sleep( pharmacological hypnosis), unconsciousness ,coma, surgical anesthesia, and fatal depression of respiration and cardiovascular regulation.

• Benzodiazepine : – Although coma may occur at very high

doses, neither surgical anesthesia nor fatal intoxication are produced by benzodiazepine without the presence of other drugs with CNS depressant actions.

– Benzodiazepines displaced older agents for the treatment of insomnia and anxiety.

History

• Since antiquity, alcohol beverages and potions containing laudanum and various herbals have been used to induce sleep.

• The first agent to be introduced specifically as a sedative and soon thereafter as a hypnotic bromide in the middle of 19th century.

• Phenobarbital led to search for agents with more selective effects on the function of the CNS.

• The introduction of chlordiazepoxide into clinical medicine in 1961 ushered in the era of benzodiazepines; more than 3000 have been synthesized, over 120 have been tested for biological activity, and about 35 are in clinical use in various parts of the world.

• Benzodiazepines have displaced the barbiturates as sedative-hypnotic agents.

Benzodiazepines

• Absorption : – all of the benzodiazepines essentially are co

mpletely absorbed, with the exception of clorazepate ( it is rapidly decarboxylated in gastric juice to N-desmethyl –diazepam, which subsequently is absorbed completely.). some benzodiazepines (flurazepam, prazepam) reach the systemic circulation only in the form of active metabolites.

– Drugs active at the benzodiazepines receptor may be to divided into four categories based on their elimination half life time:• Ultra-short-acting benzodiazepines • Short-acting agents, with T1/2 less than 6h, includin

g triazolam, the nonbenzodiazepines zolpidem.• Intermediate-acting agents, with T1/2 6~24hs,includ

ing estazolam and temazepam• Long-acting agents, with T1/2 greater than 24hs, inc

luding flurazepam and quazepam.

• Distribution– The benzodiazepines and their active metabo

lites bind to plasma proteins. The extent of binding correlates strongly with lipid solubility and ranges from about 70% for alprazolam to nearly 99% for diazepam. The concentration in the cerebrospinal fluid(CSF) is approximately equal to the concentration of free drug in plasma.

Blood-brain barrier• Protecting the brain

from "foreign substances" (such as viruses and bacteria) in the blood that could injure the brain

• Shielding the brain from hormones and neurotransmitters in the rest of the body

• Maintaining a constant environment (homeostasis) for the brain

– There is rapid uptake of benzodiazepines into the brain and other highly perfused organs after intravenous administration (or oral administration of a rapidly absorbed compound), rapid uptake is followed by a phase of redistribution into tissues that are less well perfused, especially muscle and fat.

– These drugs cross the placental barrier and secreted into breast milk.

Biotransformation

Pharmacological uses and clinical uses

• Benzodiazepines may produce antianxiety , sedation, hypnosis, anticonvulsion and respiratory depression with the increase of dose.

• Antianxiety

– All sedative-hypnotic drugs are capable of relieving anxiety at sedative doses, but benzodiazepines exert antianxiety action at the lowest effective doses that do not cause sedation.

• Benzodiazepines are used for the relieving of anxiety states, including restlessness, worry, stress and phobia state.

• Chlordiazepoxide and diazepam are often used in antianxiety.

• Sedation :– Benzodiazepines are used prior to general an

esthesia to relieve the stress of patients. Diazepam can cause temporary loss of memory after an intravenous administration. it is used for patients undergoing tracheoscopy and electric defibrillation before the treatment or examination.

• Hypnosis – Benzodiazepines

reduce awaking times during sleep, prolong sleep time and short sleep latency. Insomnia , especially insomnia with anxiety, is treated with benzodiazepines.

• Most benzodiazepines decrease sleep latency, especially when first used, and diminish the number of awakenings and the time in stage 0 (a stage of wakefulness). Time in stage 1(descending drowsiness) usually is decreased , and there is a prominent decrease in the time spent in slow-wave sleep ( stage3,4).

• Most benzodiazepines increase the time from onset of spindle sleep to the first burst of REM sleep , and the time spent in REM sleep usually is shortened.

• Despite the shortening of stage4 and REM sleep, the net effect of administration of benzodiazepines typically is an increase in total sleep time, largely because of an increase in time spent in stage 2.

• Anticonvulsant effects– benzodiazepines inhibit the development a

nd spread of epileptiform activity in the CNS and are useful in the treatment of convulsion and status epileticus.

• Relaxation of muscle– Benzodiazepines exert inhibitory effects on

polysynaptic reflexes and internuncial transmission in CNS , leading to muscle relaxation. They are useful for relaxing muscle spasm induced by cerebral palsy.

mechanisms

Mechanism of action

Adverse reaction

• Dizziness, asthesia, drowsiness may be produced in the continous administration of therapeutic dose of benzodiazepines.

• Lightheadedness , motor incoordination , impairment of mental and motor function, confusion etc. interaction with ethanol may be especially serious.

• Tolerance , dependence , and addiction may appear in long –term administration– Withdrawal symptoms may include temporar

y intensification of the problems that originally prompted their use. Dysphoria, irritability, unpleasant dreams, faintness also may occur. And very few manifest compulsive drug-seeking behavior upon discontinuation of benzodiazepines.

Barbiturates

• Classification – Ultra-short-acting: duration of action is 30m

in. Thiopental– Short-acting: duration of action is 2~3h, sec

obarbital – Intermediate-acting : is 3~6h, phentobarbita

l and amobarbital– Long-acting: duration of action is 6~8h, phe

nobarbital

• Pharmacokinetics – Absortion :

• For sedative –hypnotic use, the barbiturates usually are administered orally. Such doses are rapidly and probably completely absorbed. The onset of action varies from 10 to 60min, depending on the agent and the formulation, and is delayed by the presence of food in the stomach. The intravenous route is usually reserved for management of status epilepticus (phenobarbital sodium) or for the induction and /or maintenance of general anesthesia.

– Distribution • Barbiturates are distributed widely and

readily across the placenta. the highly lipid-soluble barbiturates, led by those used to induce anesthesia, undergo redistribution after intravenous injection.

– Biotransformation and excretion• Nearly complete metabolism and /or

conjugation of barbiturates in the liver precedes their renal excretion.

Mechanism of action

– Barbiturates enlarge GABA-induced chloride currents by prolonging periods during which bursts of channel opening occur, rather than by increasing the frequency of these bursts, as benzodiazepines do .

• Barbiturates also enhance the binding of GABA to GABAA receptors in a chloride-dependent and picrotoxin-sensitive fashion, they promote (rather than displace ) the binding of benzodiazepines

Pharmacological effects

• Barbiturates depress CNS at all levels in a dose-dependent fashion. As dose of barbiturates used increases, they produce sedative, hypnosis , anticonvulsion of vasomotor center.

• Barbiturates augment action of other CNS depressants.

• As hypnotics , Barbiturates increase the total sleep time and alter the stages of sleep in a dose-dependent manner. Like the benzodiazepines, these drugs decrease sleep latency, the number of awakening , and the durations of REM and slow –wave sleep.

• Most barbiturates, especially phenobarbital ,can induce hepatic microsomal drug-metabolizing enzyme.– The activation of the enzymes results in incre

ase degradation of the barbiturates, ultimately leading to barbiturates tolerance.

– It also causes increased inactivation and decreased action of other compounds in drug interaction.

Clinical uses

• Sedation and hypnosisInsomnia: the perfect hypnotic would alow sleep to occur, with normal sleep architecture , rather than produce a pharmacologically altered sleep pattern. It would not cause next-day effects, either of rebound anxiety or continued sedation.

• Anticonvulsion– Barbiturates are still employed in the emerg

ency treatment of convulsions, such as occur in tetanus, eclampsia ,status epilepticus ,cerebral hemorrhage .

• Antiepileptism: phenobarbital is often used for epileptism in infant and child.

• Intravenous anesthetics or intravenous adjunct to surgical anesthetics

• The Barbiturates are employed as diagnostic and therapeutic aids in psychiatry ; these uses sometimes are referred to as narcoanalysis and narcotherapy, respectively.

• Anesthetic doses of barbiturates attenuate cerebral edema resulting from surgery ,head injury, or cerebral ischemia, and they may decrease infarct size and increase survival.

• Phenobarbital has been successfully used to treat hyperbilirubinemia and kernicterus in the neonate.

Adverse reaction

• After-effects– Drowsiness may last

for only a few hours after a hypnotic dose of barbiturates, but residual depression of the CNS sometimes is evident the following day.

• Rebound phenomenon

• Dependence – Physiological and psychological

dependence can occur– Withdrawal of barbiturates may result in

severe tremors, vivid hallucinations ,and psychoses.

• Barbiturates poisoning– Coma, severe respiratory depression,

cardiovascular collapse and renal failure.

• Treatment of acute overdosage– Supporting respiration and circulation

• Constant attention must be given to the maintenance of a patent airway and adequate ventilation and to the prevention of pneumonia; oxygen should be administered. Gastric lavage should be considered if fewer than 24h have elapsed since ingestion.

• Alkalizing the gastric juice , the body fluids and the urine, and promoting diuresis.