Sedative & Hypnotics

Prof. Hanan Hagar

Pharmacology Department

Medical College

King Saud University

Sedative & Hypnotics

Anxiolytics : Drugs that clam the patient and

reduce anxiety without inducing normal sleep.

Hypnotics : 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 Nomenclature

End with suffix azolam or azepamAlprazolamEstazolamTriazolamLorazepamDiazepamOxazepam Temazepam Nitrazepam

Classification of benzodiazepines According to duration of action :

- Short acting: (3-5 hours).Triazolam

-  Intermediate: (6-24 hours) (LEOTAN). Lorazepam Estazolam

Oxazepam Temazepam AlprazolamNitrazepam

-  Long acting: ( 24-72 hours) Chlorazepate Chlordiazepoxide Diazepam Flurazepam Quazepam Prazepam

According to uses Anxiolytics Lorazepam Oxazepam Alprazolam Chlordiazepoxide Diazepam Prazepam Clonazepam

Hypnotics

short: Triazolam

Intermediate:

Lorazepam , Estazolam

Temazepam Nitrazepam

Long: Flurazepam, Quazepam

Preanesthetics

  Diazepam - Midazolam

    

Mechanism of Action

By binding to BZ receptors (BZ1 or BZ2).

Bzs facilitate GABA-induced chloride channels hyperpolarization = GABA-mediated inhibitory neurotansmission

Mechanism of Action

Benzodiazepines combine with BZ receptors increase GABA action on GABA receptors chloride channels opening

chloride influx to the cell cell membrane hyperpolarization inhibition of propagation of action potential inhibitory effect on different sites of the brain especially motor cortex & limbic system.

Pharmacokinetics of benzodiazepines Bzs are lipid soluble, well absorbed orally,

Rapid absorption

e.g. triazolam & diazepam & chlorazepate

(chlorazepate is prodrug converted by acid hydrolysis in stomach to form nordiazepam (desmethyldiazepam).

Slower absorption

e.g. lorazepam & oxazepam, temazepam (LOT)

Can be given parenterally

Chlordiazepoxide - Diazepam (IV only NOT IM)

Lorazepam - Midazolam (IV or IM) Bzs are widely distributed. Cross placental barrier during pregnancy

and are excreted in milk (Fetal & neonatal

depression). Redistribution from CNS to skeletal muscles,

adipose tissue) (termination of action).

All benzodiazepines are metabolized in the

liver to active compounds

EXCEPT No active metabolites are formed for

(LEO) Lorazepam, Estazolam, Oxazepam

Metabolism occurs in two phases

Phase I: ( liver microsomal system)

Phase II: glucouronide conjugation excreted in the urine.

Many of Phase I metabolites are active elimination half life of the parent comp. cumulative effect with multiple doses

Pharmacological Actions

Anxiolytic action. Depression of cognitive and psychomotor function. Sedative & hypnotic actions:

At higher dose, benzodiazepines change sleep pattern

Induction of normal sleep ( reduce latency of sleep). Increase non REM sleep (stage II). Decrease REM sleep & slow waves sleep (3,4 stages). 

Anterograde amnesia Some have anticonvulsant effect:

diazepam, lorazepam, clonazepam, clorazepate. Some have central skeletal muscle relaxant effect e. g. Diazepam (relax muscle spasticity by increasing presynaptic inhibition in the spinal cord). CVS and respiratory system: Minimal depressant effects in therapeutic doses & in normal patients.

Therapeutic Uses

Anxiety disorders:   short term relief of severe anxietyGeneral anxiety disorder major depressive disorders Obsessive compulsive disorderPanic attack with depression Alprazolam

since it has (antidepressant effect).

Sleep disorders (Insomnia)Triazolam: initiate sleep (tolerance & rebound insomnia)Estazolam - Lorazepam - temazepam:

(sustain sleep)Flurazepam – Quazepam (hangover).

Usage for 1-2 weeks tolerance to their effect on sleep patterns

Drug withdrawal anxiety, irritability, restlessness, increase in REM sleep, rebound insomnia

Treatment of epilepsy Diazepam – Lorazepam Clonazepam -Clorazepate Muscle relaxation: in spastic states (Diazepam)As cerebral palsy and multiple sclerosis.

To control withdrawal symptoms of alcohols diazepam- chlordiazepoxide

In anesthesia Preanesthetic medication e.g. diazepam Induction of balanced anesthesia (Midazolam) Adjunct therapy during minor surgery

(endoscopy, bronchoscopy, dental surgery).

 

ADVERSE EFFECTS

• Ataxia (motor incoordination), • Cognitive impairment.• Hangover: Sleep tendency, drowsiness, confusion especially in long acting drugs.• Tolerance • Dependence: Physical and Psychological • Skin rash and teratogenic effect.• Respiratory & cardiovascular depression (Toxic effects).

Withdrawal symptoms:

Rebound insomnia, anorexia, anxiety, agitation, tremors and convulsion.

Drug Interactions

Examples

CNS depressants CNS depressants, alcohol & Antihistaminics of

effect of benzodiazepines

Cytochrome P450 (CYT P450) inhibitors

Cimetidine & Erythromycin

t ½ of benzodiazepines

CYT P450 inducers Phenytoin & Rifampicin

t 1/2 of benzodiazepines

Dose should be reduced in

o Liver diseaseo Old people.

Precautions

• Not for pregnant women or breast-feeding.• Not for people over 65. • Used for limited time (2 weeks)

FLUMAZENIL

a selective competitive antagonist of BZD

receptors.

Blocks action of benzodiazepines, zolpidem,

& zaleplon 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 Uses1.  Acute BZD toxicity (comatose patients).

2. Reversal of BZD sedation after endoscopy,

dentistry.

Side Effects   Nausea Dizziness Precipitate withdrawal symptoms.

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).

has no muscle relaxant effect.

 has no anticonvulsant effect.

  Minimal psychomotor dysfunction

Minimal tolerance & dependence.

 Minimal rebound insomnia.

 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.

Adverse Effects Dizziness

GIT upset

Drowsiness

Uses

a hypnotic drug for short term treatment of insomnia.

Drug Interactions

Inducers

Rifampicin, phenytoin, carbamazepine

Inhibitors

Cimetidine, erythromycin

Zaleplon Binds to BZs receptors and facilitate GABA

actions. Rapid absorption Short onset of actionShort duration of action (1 hr) Metabolized by liver microsomal enzymes CYP3A4

Metabolism is inhibited by cimetidine.

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 and cognitive functions than BZs or zolpidem.

Barbiturates

are second choice as sedative - hypnoticMechanism of Action are less selective in action than BZD. 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). depress excitatory neurotransmitters action. Interfere with Na & K transport across cell membranes (reticular activating system inhibition).

Classification of barbiturates:

Long acting( 24-28 h): Phenobarbitone Intermediate (8-24h): Amylobarbitone Short-acting(3-8h):

• Pentobarbitone

• Secobarbitone

• Amobarbital Ultrashort acting (25 minutes): thiopental

Pharmacokinetics All barbiturates are weak acids Are absorbed orally. Distribute throughout the body depending on lipid solubility e.g. thiobarbiturates are very lipid soluble with high rate of entry into CNS. Redistribute in the body from the brain to

skeletal muscles - adipose tissues.

Metabolized in the liver to inactive

metabolites

Excreted in the urine. Alkalinization increases

excretion ( NaHCO3 ).

Cross the placenta ( # pregnancy).

Pharmacological actions

1. CNS depression : 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 circulatory collapse due to

medullary vasomotor depression direct

vasodilatation.

4. Enzyme induction.

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

       Increase activity of hepatic gamma amino

levulinic acid synthetase (ALA) synthesis of

porphyrin (# porphyria).

Uses : Anticonvulsants: (Phenobarbitone)

• Phenobarbital is indicated in the treatment of all types of seizures except absence seizures.

• Tonic-clonic seizures, status epilepticus

• Eclampsia 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.

ToxicityRespiratory depression, cardiovascular collapse, coma and death.

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 interactions1. Other CNS depressants: Ethanol2. MAOI: potentiate CNS depression3. Phenytoin, warfarin, and dicumarol: their metabolism is increased.

Advantages of BZD over barbiturates1. 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.