Sedative & Hypnotics

By Prof. Dr. Hanan Hagar

Sedative & Hypnotics

Sedative : Drugs that clam the patient and reduce anxiety without inducing normal sleep. Hypnotic : Drugs that initiate and maintain the normal sleep.

Classification of Hypnotic Drugs 1. Benzodiazepines ( BDZ ) 2. Barbiturates 3. Miscellaneous ( non BDZ non barbiturate drugs).  Zolpidem  Zaleplon

BENZODIAZEPINES (BDZ)

Classifications
According to Duration of Action : - Short acting: (3-5 hours). Triazolam - Intermediate: (6-24 hours). Alprazolam Lorazepam (ALEOT) Estazolam Oxazepam Temazepam

Long acting: ( 24-72 hours)

Chlorazepate Diazepam Quazepam Nitrazepam Chlordiazepoxide Flurazepam. Prazepam

According to uses
Sedative (Anxiolytics) Alprazolam Chlordiazepoxide Diazepam Prazepam Hypnotics Triazolam Lorazepam Estazolam Temazepam Flurazepam Nitrazepam Quazepam Preanesthetics Diazepam - Midazolam

Mechanism of Action Bzs binding to BZ receptors (BZ1 or BZ2) to facilitate GABA-induced chloride channels hyperpolarization = GABA-mediated inhibitory neurotransmission.

Bzs p facilitation of GABA action on GABA receptors p chloride channels opening p o chloride influx to the cell p cell membrane hyperpolarization p inhibition of propagation of action potential p inhibitory effect on different sites of the brain especially motor cortex, and limbic system.

PHARMACOKINETICS

1. most of them are well absorbed orally, Rapid absorption e.g. triazolam & Alprazolam diazepam & chlorazepate Slow absorption e.g. lorazepam & oxazepam, temazepam (LOT)

2. Chlorazepate is a prodrug converted by acid hydrolysis in stomach to form nordiazepam (desmethyldiazepam). 3. Can be given parenterally

Diazepam-Chlordiazepoxide (IV only NOT IM) Midazolam Lorazepam (IV or IM)

4. Bzs are lipid soluble and widely distributed 5. Redistribution from CNS to skeletal muscles, adipose tissue) (termination of action). 6. Cross placental barrier during pregnancy and are excreted in milk (Fetal & neonatal depression).

7. Highly bound to plasma protein. 8. ALL Bzs are metabolized in the liver Phase I: ( liver microsomal system) Phase II: glucouronide conjugation and excreted in the urine.

9. Many of Phase I metabolites are activep active o elimination half life of the parent comp. p cumulative effect with multiple doses EXCEPT No active metabolites are formed for (LEO) Lorazepam, Estazolam, Oxazepam

Pharmacological Actions 1. Anxiolytic action. 2. Depression of cognitive and psychomotor function. 3.Anterograde amnesia.

4. Hypnotic actions at higher dose, BDZs change sleep pattern  Induction of normal sleep (latency of sleep is reduced).  Increase non REM sleep (stage II).  Decrease REM sleep & slow waves sleep (3,4 stages).  Usage for more than 2 weeks p tolerance to their effect on sleep patterns

4. Anticonvulsant effect: especially diazepam, lorazepam, clorazepate, clonazepam, nitrazepam. 5. Central skeletal muscle relaxant effect e.g. Diazepam relaxes muscle spasticity by presynaptic inhibition in the spinal cord.

6. CVS and respiratory system: Minimal depressant effects in therapeutic doses & in normal patients.

Therapeutic Uses Anxiety disorders: alprazolam General anxiety disorders Panic attack - major depressive disorders

Sleep disorders (Insomnia). Triazolam: initiate sleep ???? Estazolam - Lorazepam - temazepam: sustain sleep???? Flurazepam - Quazepam Long acting drugs can cause hangover.

To control withdrawal symptoms of alcohols diazepam- chlordiazepoxide. Treatment of epilepsy Diazepam Lorazepam: Status epilepticus Clonazepam-Clorazepate: absence , myoclonic seizures. Muscle relaxation: in spastic states (Diazepam)

In anesthesia  Preanesthetic medication diazepam  Induction of balanced anesthesia (Midazolam)  Adjunct therapy during minor surgery (endoscopy, bronchoscopy, dental surgery).

ADVERSE EFFECTS 1.Ataxia (motor incoordination), cognitive impairment. 2.Hangover Sleep tendency, drowsiness, confusion especially in long acting drugs. 3. Tolerance 4. Physical and Psychological dependence 5. withdrawal symptoms Rebound Insomnia, anorexia, anxiety, agitation, tremors and convulsion.

6. Drug Interaction   Synergistic effect with other CNS depressants Enzyme Modulators. Rifampicin (decreases half life) Cimetidine (increases half life)

7. Skin rash 8. Teratogenic effect.

Dose reduction in 1. Liver disease 2. Old people. Contraindication to be combined with Alcohol and other CNS depressants, antihistaminics.

FLUMAZENIL  a selective competitive antagonist of BZD receptors (Bz1).  Blocks action of benzodiazepines, zaleplon and zolpidem but not other sedative /hypnotics.  Blocks psychomotor, cognitive and memory impairment of BZs.

PHARMACOKINETICS  Has short duration of action T 1 /2 = 1 hour  Absorbed orally  Undergoes extensive first pass metabolism  NO active metabolites  Should be used IV  (Repeated doses are necessary).

Therapeutic Uses 1. Acute BZD toxicity (comatose patients). 2. Reversal of BZD sedation after endoscopy, dentistry. Side Effects  Nausea  Dizziness  Precipitate withdrawal symptoms.

Barbiturates
are derivatives of barbituric acid second choice as sedative hypnotic Its members end with the suffix (barbital or barbitone) Thiobarbiturates are highly lipid soluble.

Classification :  Long acting( 24-28 h): Phenobarbitone  Intermediate (8-24h): Amylobarbitone  Short-acting(3-8h): Pentobarbitone Secobarbitone Amobarbital  Ultrashort acting (25 minutes): thiopental

Mechanism of Action 1. Facilitation of GABA action on the brain. increase the duration of the GABA gated channel opening but in large dose, they can directly activating chloride channels. (not through BZD receptors).

2. depress excitatory neurotransmitter actions 3. Interfere with Na & K transport across cell membranes (reticular activating system inhibition). 4. are less selective in action than BZD.

Pharmacokinetics 1. All barbiturates are weak acids 2. are lipid soluble 4. absorbed orally. 3. distribute throughout the body 5. Thiobarbiturates are very lipid soluble (high rate of entry into CNS- very brief onset of action).

6. Redistribute in the body from the brain to skeletal muscles- adipose tissues. 7. metabolized in the liver to inactive metabolites 8. Excreted in the urine. Alkalinization increases excretion (NaHCO3) 9. Cross the placenta ( # pregnancy).

Pharmacological actions 1. CNS depression: In a dose-dependent fashion. Sedative Hypnotic Anesthesia in large dose Anticonvulsant action Coma and death.

2. Respiratory depression: is dose related.  suppress hypoxic and chemoreceptor response to CO2  Large doses respiratory depression & death.

3. CVS depressions  Healthy patient: at low doses, they have insignificant effects.  Hypovolemic states, CHF, normal doses may cause cardiovascular collapse.  Large dose p circulatory collapse due to medullary vasomotor depression p direct vasodilatation.

4. Enzyme induction.  CYT P-450 microsomal enzymes inducers (Tolerance - drug interaction).

 Increase activity of hepatic gamma amino levulinic acid synthetase ALA p synthesis of porphyrin (# porphyria).

Uses : Anticonvulsants: (Phenobarbitone) tonic-clonic seizures, status epilepticus and febrile convulsion. Induction of anesthesia (thiopental, methohexital).

Hypnotic (pentobarbital) Hyperbilirubinemia and kernicterus in the neonates (increase glucouronyl transferase activity).

Adverse effects: 1. Respiratory depression. 2. Hangover: residual sedation after awakening. 3. Tolerance 4. Withdrawal symptoms 5. Precipitation of acute attack of porphyria. 6. Many drug interactions. 7. Allergic reaction: urticaria and skin rash.

Toxicity Respiratory depression, collapse, coma and death.

Cardiovascular

Contraindications 1. Acute intermittent porphria. 2. Respiratory obstruction. 3. Liver & kidney diseases. 4. Shock. 5. Old people ( mental confusion). 6. Pregnancy. 7. Hypersensitivity to barbiturates.

Contraindications 1. Acute intermittent porphria. 2. Respiratory obstruction. 3. Liver & kidney diseases. 4. Shock. 5. Old people ( mental confusion). 6. Pregnancy. 7. Hypersensitivity to barbiturates.

Drug interactions 1. Other CNS depressants: Ethanol 2. MAOI: potentiate CNS depression 3. Phenytoin, warfarin, and dicumarol: their metabolism is increased.

Advantages of BZD over barbiturates 1. Selective: minimal respiratory and cardiovascular depression. 2. High therapeutic index. 3. Less hangover. 4. Not enzyme inducer. 5. Less dependence with minimal withdrawal symptoms. 6. Has specific antagonist.

Zolpidem (Ambien)

 imidazopyridine derivative.

 acts on benzodiazepine receptors (BZ 1) & facilitate GABA mediated neuronal inhibition.  Its action is antagonized by flumazenil.  rapidly absorbed from GIT and metabolized to inactive metabolites via liver CYT P450.  Short duration of action ( 2- 4 h).

 Only hypnotic effect  Its efficacy is similar to benzodiazepines.  Minor effect on sleep pattern, but high doses suppress REM.  Respiratory depression occur at high doses in combination with other CNS depressant as ethanol.

 has no muscle relaxant effect.  has no anticonvulsant effect.  Minimal psychomotor dysfunction  Minimal tolerance & dependence.  Minimal rebound insomnia.

Uses a hypnotic drug for short term treatment of insomnia Dose should be reduced in hepatic or old patients.

Adverse Effects GIT upset Drowsiness Dizziness Drug interactions Rifampicin (decreases half life) Cimetidine (increases half life)

Zaleplon

 Binds to BZs receptors and facilitate GABA

actions.

Zaleplon

 Rapid absorption  rapid onset of action  Short duration of action (1 hr)  Metabolized by liver microsomal enzymes  metabolism is inhibited by cimetidine.

   

Only hypnotic effect decreases sleep latency Little effect on sleep pattern Potentiates action of other CNS depressants (alcohol).  Dose reduction as before.  Used as hypnotic drug  Advantages Less impairment of pyschomotor performance than BZs or zolpidem.