Hypnotics & Antianxiety Agents

Hypnosis is the induction of a state of drowsiness and facilitation of the onset and maintenance of sleep from which the patient can be aroused (sedation≫hypnosis≫anesthesia≫coma≫death).

General drug effects: Barbituates and alcohol strongly depress sleep latency REM sleep. Benzos strongly depress non-REM sleep (stages 3 & 4) as well as REM sleep and latency When hypnotics are discontinued, many patients experience a rebound insomnia (longer-acting benzos produce less of this, but do produce daytime sedation). Anxiolytics have little effect on the peripheral autonomic nervous system but do depress spinal reflexes and convulsions.

GABA-A receptor: At high concentrations, barbiturates may substitute for GABA (GABAmimetic). Benzodiazepine antagonsists (flumazenil) have no intrinsic activity but will block the effects of agonists and inverse agonists.

Barbituates: Weak acids (pKa 7-8). Phenobarbital is useful as an anticonvulsant as compared to others where marked CNS depression accompanies anticonvulsant effects. Long acting (Phenobarbital), intermediate- to short-acting (amobarbital, pentobarbital, secobarbital), ultra short-acting (thiopental). Alkalosis causes ionization of the drug in the plasma and a shift from tissues to plasma. Acidosis causes more drug to enter the CNS. Physical redistribution (thiopental) allows for rapid onset and recovery. Alkalinization of the urine can shorten the duration of action of barbiturates. Metabolized by hepatic microsomal enzymes. Renally excreted as glucuronide conjugates (Phenobarbital excreted 50% unchanged).

• CNS effects: GABAmimetic. At high concentrations, barbiturates raise neuronal thresholds for excitation and decrease repetitive activity. Respiratory depression is usually the cause of death in overdose. The cough reflex is not suppressed, except at toxic doses, so laryngospasm is one of the chief complications during anesthesia.

• Liver: Induce microsoma enzymes, thereby stimulating metabolism of many drugs (including barbiturates). Barbs stimulate -ALA synthetase and are contraindicated in patients with acute intermittent porphyria.

• Treatment of overdose: Alkalinize urine, maintain airway, consider lavage, NO CNS STIMULANTS.

• Therapeutic applications: Anticonvulsant, suppression of abstinence syndromes, induction of bilirubin conjugation in congenital jaundice of the newborn.

Benzodiazepines: Have largely replaced the barbs for clinical use in producing hypnosis. Tolerance can develop more rapidly to the hypnotic effects of short-acting benzos (triazolam). The absence of rebound in the case of flurazepam is probably related to metabolites with long half-lives. Longer-acting benzos act thru metabolites. Short-acting benzos should be administered to elederly patients because of decreased ability to metabolize drugs. Choice of hypnotics represents a trade-off betweem cumulative effects leading to psychomotor impairment (long-acting) and rebound effects leading to worsening of insomnia and anxiety (short-acting). Benzos do not induce liver enzymes and do not interact significantly with other medications.

• Clinical uses: Anxiety disorders, depression with anxiety (alprazolam has specific antidepressant activity), panic disorders (alprazolam), spastic musculoskeletal diseases, seizures (diazepam is DOC for status epilepticus), alcohol withdrawal syndrome, premedication (diazepam has amnesic action), sleep disorders, anxiety reaction to psychedelic drugs, adjunct in GI and CV disorders, adjunct in treatment of schizophrenia.

• Advantages: Higher therapeutic index, lower tolerance, less addictive, fewer drug interactions.

• Adverse effects: Excessive sedation and drowsiness, ataxia; more apparent in elderly; show synergism with other CNS depressants; high therapeutic index (impossible to OD on benzos).; contraindicated in 1st trimester; alprazolam shows significant depedence problems.

Flumazenil – Benzo antagonist; no intrinsic activity; reverses the sedative and depressant effects of benzodiazepines. However, it is ineffective for most other sedatives (e.g., barbiturates).

Zolpidem – Not a BDZ; good hypnotic with less effects of stages of sleep (improves overall sleep time; synergistic effect with other CNS depressants.

Chloral hydrate – Prodrug that must be metabolized to trichlorethanol; similar to barbiturates but does not induce p450 enzymes.

Buspirone – Atypical anxiolytic; NOT A HYPNOTIC; acts at 5-HT1A and DA-2 receptors; does not produce tolerance and physical dependence.

Baclofen – Skeletal muscle relaxant; targets the presynaptic GABA-B receptor; site of therapeutic action is primarily the spinal cord; used in treatment of MS and spinal injury; few side effects.

Dantrolene – Produces muscle relaxation by interfering with calcium release in skeletal muscle; used in treatment malignant hyperthermia; occasional hepatitis that can be fatal.

Category: Pharmacology Notes