ملخص

Anxiolytic , Sedative and Hypnotic Drugs

SEDATIVE
HYPNOTICS
Anxiolytics
Drugs that have an inhibitory effect on the CNS to the degree that they reduce:
Nervousness
Excitability
Irritability without causing sleep

Calm or soothe the CNS to the point that they cause sleep

reduce anxiety

Some drugs have anxiolytic and sedative/hypnotic effects.

The ideal anxiolytic drug should calm the patient without causing too much day time sedation and drowsiness and without producing physical or psychological dependence

The ideal hypnotic drug should allow the patient to fall asleep quickly and should maintain sleep of sufficient quality and duration

largely replaced by the benzodiazepines, because Barbiturates:

Induce tolerance
Induce drug-metabolizing enzymes
Physical dependence and
Very severe withdrawal symptoms
Narrow therapeutic index
When used as hypnotics, they suppress REM sleep more than other stages.


Classification :
Ultra-short acting :thiopental
Short acting: pentobarbital,
Long acting: phenobarbital

Mechanism of action of barbiturates

1-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.
2- block excitatory glutamate receptors.
3-Anesthetic concentrations of pentobarbital also block high-frequency sodium channels.
All of these lead to decreased neuronal activity..
any degree of depression of the CNS is possible, depending on the dose.

Therapeutic uses of barbiturates:

1-Anesthesia: The ultra short-acting barbiturates, such as thiopental, are used intravenously to induce anesthesia.

2-Anticonvulsant: Phenobarbital is used in long-term management of tonic-clonic seizures, status epilepticus
the drug of choice for treatment of young children with recurrent febrile seizures.
3-Anxiety: Barbiturates have been used as mild sedatives to relieve anxiety

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.
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
5-Physical dependence: Abrupt withdrawal from barbiturates may cause tremors, anxiety, weakness, nausea and vomiting
6-. Poisoning: death resulting from drug overdoses because of severe depression of respiration and cardiovascular depression

Treatment of patient with barbiturates poisoning

1-artificial respiration
2-purging the stomach of its contents if the drug has been recently taken
3-Hemodialysis may be necessary if large quantities have been taken.
4-Alkalinization of the urine often aids in the elimination of Phenobarbital

Note: No specific barbiturate antagonist is available

Benzodiazepines

Benzodiazepines are the most widely used anxiolytic drugs. They have largely replaced barbiturates because:
The benzodiazepines are safer and more effective
Not cause drug – drug interaction
Produce tolerance and psychological dependence but physical dependence and withdrawal symptom are less marked
Benzodiazepines antagonist is available


Therapeutic uses
1- Anxiety disorders
2- The shorter-acting agents are used as premedication for anxiety-provoking and unpleasant procedures
3- Muscular disorders: Diazepam is useful in the treatment of skeletal muscle spasms
4- Midazolam is used for the induction of anesthesia
5- Seizures: Diazepam and lorazepam are the drugs of choice in terminating grand-mal epileptic seizures and status epilepticus.
6-Sleep disorders

The benzodiazepines have neither antipsychotic activity nor analgesic action

ANXIOLYTIC: diazepam, lorazepam
HYPNOTIC: Triazolam,

Mechanism of action:

Binding of GABA (the major inhibitory neurotransmitter in the central nervous system) to its receptor triggers an opening of a chloride channel, which leads to an increase in chloride conductance cause hyperpolrization and inhibit Action potential formation .

the duration of action may determine the therapeutic usefulness

All the benzodiazepines cross the placental barrier and may depress the CNS of the newborn if given before birth.
Nursing infants may also become exposed to the drugs in breast milk


Precautions:

Adverse effects

In treating patients with liver disease.
In patients with acute narrow-angle glaucoma.
Alcohol and other CNS depressants enhance the sedative-hypnotic effects of the benzodiazepines.

1- Drowsiness and confusion.

2- Psychological and physical dependence on benzodiazepines with high dose and prolong time
3- withdrawal symptoms, including confusion, anxiety, insomnia, tension, and rarely, seizures

Benzodiazepine Antagonist

Flumazenil (is a GABA-receptor antagonist) that can rapidly reverse the effects of benzodiazepines

rapid Onset of action with short duration , Frequent administration may be necessary to maintain reversal of a long-acting benzodiazepine
Side effects:
1.Dizziness, nausea, vomiting, and agitation
2.withdrawal in dependent patients
3. seizures
If a benzodiazepine is used to control seizure activity
If the patient ingests tricyclic antidepressants


Other anxiolytic drugs

Antidepressants

Hydroxyzine
Buspirone

1- managing the long-term symptoms of chronic anxiety disorders

2- considered as first-line agents, especially in patients with concerns for addiction

1- antihistamine with antiemetic activity.

2- used in patients with anxiety who have a history of drug abuse
3- Drowsiness is a possible adverse effect

1-treatment of generalized anxiety disorder

2-The actions of buspirone appear to be mediated by Serotonin and dopamine receptors
3-Undergoes metabolism by CYP3A4; thus, its half-life is shortened if taken with rifampin(an inducer of the enzyme)
Lengthened if taken with erythromycin(an inhibitor of the enzyme)
4-Adverse effects: Headaches, dizziness, nervousness

Other Hypnotic Agents

Zolpidem

Ramelteon

Chloral hydrate

Antihistamines: diphenhydramine

1-Zolpidem has no anticonvulsant or muscle-relaxing properties
2-shows few withdrawal effects
3-Zolpidem undergoes hepatic oxidation by the cytochrome P450
Drugs which induce this enzyme system, shorten the half-life of zolpidem,
Drugs that inhibit the enzyme may increase the half-life this drug.
4- Adverse effects of zolpidem include nightmares, agitation, headache, gastrointestinal upset

1-agonist of melatonin receptors

2-indicated for the treatment of insomnia
3- increase prolactin levels.
effective sedative and hypnotic
Induces sleep in about 30 minutes and the duration of sleep is about 6 hours.
It is irritating to the gastrointestinal tract
They are effective in treating mild types of insomnia.
They have numerous undesirable side effects