Anxiolytic Sedative and Hypnotic Drugs lecture

Anxiolytic , sedative and hypnotic Drugs-1

SEDATIVE
Drugs that have an inhibitory effect on the CNS to the degree that they reduce:
Nervousness
Excitability
Irritability without causing sleep
HYPNOTICS
Calm or soothe the CNS to the point that they cause sleep A hypnotic drug should produce drowsiness and encourage the onset and maintenance of a state of sleep resembles the natural sleep state.

Anxiolytics: reduce anxiety sedatives: decrease activity, calming effect

Hypnotics: induce sleep some drugs have anxiolytic and sedative / hypnotic effects.
Anxiolytic, Sedative and Hypnotic Drugs
 Most anxiolytic and sedative –hypnotic drugs produce dose – depended depression of the central nervous system function
CNS Depression
Sedation
Hypnosis
General Anesthesia
Poisoning
Death
The ideal anxiolytic drug should calm the patient without causing too much day time sedation and drowsiness and without producing physical or psychological dependence


Summary of anxiolytic and hypnotic drugs
 Barbiturates.
 Benzodiazepines.
 Other anxiolytic drugs: buspirone, hydroxyzine, antidepressants.
 Other hypnotic agents: antihistamine, chloral hydrate, ethanol, ramelteon, zolpidem

Barbiturates

They have been largely replaced by the benzodiazepines, because Barbiturates:
 Induce tolerance
 Induce drug-metabolizing enzymes
 Physical dependence and
 Very severe withdrawal symptoms
 Narrow therapeutic index
Certain barbiturates, such as the very short-acting thiopental, are still used to induce anesthesia
Barbiturates are classified according to their duration of action into:
 Ultra-short acting :thiopental (20 minutes)
 Short acting: pentobarbital, secobarbital, amobarbital (3-8)hours
 Long acting : phenobarbital (1- 2 ) days

Mechanism of action of barbiturates

 The sedative-hypnotic action of the barbiturates is due to their interaction with GABA receptors, which enhances GABAergic transmission. The binding site is distinct from that of the benzodiazepines. Barbiturates potentiate GABA action on chloride entry into the neuron by prolonging the duration of the chloride channel openings.
 In addition, barbiturates can block excitatory glutamate receptors.
 Anesthetic concentrations of pentobarbital also block highfrequency sodium channels. All of these lead to decreased neuronal activity.


Actions of barbiturates:
 Depression of CNS: At low doses, the barbiturates produce sedation (calming effect, reducing excitement). At higher doses, the drugs cause hypnosis, followed by anesthesia (loss of feeling or sensation), and finally, coma and death.
Thus, any degree of depression of the CNS is possible, depending on the dose.
Barbiturates have no analgesic properties.

Respiratory depression : over dosage cause respiratory depression and death.

 Circulatory collaps (by toxic dose)
 Enzyme induction: Barbiturates induce P450 microsomal enzymes in the liver.
Therefore, chronic barbiturate administration diminishes the action of many drugs that are dependent on p450 metabolism example (phenytoin , nticoagulants)
Therapeutic uses of barbiturates:
 Anesthesia: The ultra short-acting barbiturates, such as thiopental, are used intravenously to induce anesthesia.
 Anticonvulsant: Phenobarbital is used in long-term management of tonic-clonic seizures, status epilepticus, Phenobarbital has been regarded as the drug of choice for treatment of young children with recurrent febrile seizures.
 Anxiety: Barbiturates have been used as mild sedatives to relieve anxiety, nervous tension, and insomnia.
When used as hypnotics, they suppress REM sleep more than other stages.
However, most have been replaced by the benzodiazepines.

 Pharmacokinetics of barbiturates

 Barbiturates are absorbed orally and distributed widely throughout the body.
Barbiturates are metabolized in the liver, and inactive metabolites are excreted in the urine.
 They readily cross the placenta and can depress the fetus.
Adverse effect of barbiturates
1. CNS: Barbiturates cause drowsiness, impaired concentration, The CNS depressant effects of barbiturates synergize with those of ethanol.
2. Drug hangover: Hypnotic doses of barbiturates produce a feeling of tiredness well after the patient wakes.
This drug hangover may lead to impaired ability to function normally for many hours after waking. Occasionally, nausea and dizziness occur.
3. Induce the P450 system and may decrease the duration of action of drugs that are metabolized by these hepatic enzymes.
4. Increase porphyrin synthesis, and they are contraindicated in patients with acute intermittent porphyria.
5. Physical dependence: Abrupt withdrawal from barbiturates may cause tremors, anxiety, weakness, nausea and vomiting, seizures, delirium, and cardiac arrest.
6. Poisoning: death resulting from drug overdoses because of severe depression of respiration and cardiovascular depression.


 Note: No specific barbiturate antagonist is available

Treatment of patient with barbiturates poisoning

 artificial respiration
 purging the stomach of its contents if the drug has been recently taken
 Hemodialysis may be necessary if large quantities have been taken.
 Alkalinization of the urine often aids in the elimination of phenobarbital .

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