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
Prof. Hanan Hagar
King Saud University
Anxiolytics : Drugs that clam the patient and reduce anxiety without inducing normal sleep.
Hypnotics : Drugs that initiate and maintain
the normal sleep.
1. Benzodiazepines ( BDZ )
3. Miscellaneous ( non BDZ non barbiturate drugs).
End with suffix azolam or azepam
According to duration of action :
- Short acting: (3-5 hours).
- Intermediate: (6-24 hours) (LEOTAN).
- Long acting: ( 24-72 hours)
According to uses
Lorazepam Oxazepam Alprazolam
Chlordiazepoxide Diazepam Prazepam
Lorazepam , Estazolam
Long: Flurazepam, Quazepam
Diazepam - Midazolam
By binding to BZ receptors (BZ1 or BZ2).
Bzs facilitate GABA-induced chloride channels hyperpolarization = GABA-mediated inhibitory neurotansmission
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.
Bzs are lipid soluble, well absorbed orally,
e.g. triazolam & diazepam & chlorazepate
(chlorazepate is prodrug converted by acid hydrolysis in stomach to form nordiazepam (desmethyldiazepam).
e.g. lorazepam & oxazepam, temazepam (LOT)
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
Redistribution from CNS to skeletal muscles,
adipose tissue) (termination of action).
liver to active compounds
EXCEPTNo active metabolites are formed for
(LEO) Lorazepam, Estazolam, Oxazepam
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
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).
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.
short term relief of severe anxiety
General anxiety disorder
major depressive disorders
Obsessive compulsive disorder
Panic attack with depression Alprazolam
since it has (antidepressant effect).
Triazolam: initiate sleep
(tolerance & rebound insomnia)
Estazolam - Lorazepam - temazepam:
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
Diazepam – Lorazepam
Muscle relaxation: in spastic states (Diazepam)
As cerebral palsy and multiple sclerosis.
To control withdrawal symptoms of alcohols
Preanesthetic medication e.g. diazepam
Induction of balanced anesthesia (Midazolam)
Adjunct therapy during minor surgery
(endoscopy, bronchoscopy, dental surgery).
Ataxia (motor incoordination),
Hangover: Sleep tendency, drowsiness,
confusion especially in long acting drugs.
Dependence: Physical and Psychological
Skin rash and teratogenic effect.
Respiratory & cardiovascular depression
Rebound insomnia, anorexia, anxiety, agitation, tremors and convulsion.
Not for pregnant women or breast-feeding.
Not for people over 65.
Used for limited time (2 weeks)
a selective competitive antagonist of BZD
Blocks action of benzodiazepines, zolpidem, & zaleplon but not other sedative/hypnotics.
Blocks psychomotor, cognitive and memory
impairment of BZs.
Has short duration of action T 1 /2 = 1 hour
Undergoes extensive first pass metabolism
NO active metabolites
Should be used IV
(Repeated doses are necessary).
1. Acute BZD toxicity (comatose patients).
2. Reversal of BZD sedation after endoscopy,
Precipitate withdrawal symptoms.
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 anticonvulsant effect.
Minimal psychomotor dysfunction
Minimal tolerance & dependence.
Minimal rebound insomnia.
Its efficacy is similar to benzodiazepines.
Minor effect on sleep pattern, but high
Respiratory depression occur at high doses in
combination with other CNS depressant as
a hypnotic drug for short term treatment of insomnia.
Rifampicin, phenytoin, carbamazepine
Binds to BZs receptors and facilitate GABA
Short onset of action
Short duration of action (1 hr)
Metabolized by liver microsomal enzymes CYP3A4
Metabolism is inhibited by cimetidine.
Little effect on sleep pattern
Potentiates action of other CNS depressants (alcohol).
Dose reduction as before.
Used as hypnotic drug
Less impairment of pyschomotor and cognitive functions than BZs or zolpidem.
are second choice as sedative - hypnotic
Mechanism 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).
Long acting( 24-28 h): Phenobarbitone
Intermediate (8-24h): Amylobarbitone
Ultrashort acting (25 minutes): thiopental
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.
Excreted in the urine. Alkalinization increases
excretion ( NaHCO3 ).
Cross the placenta ( # pregnancy).
1. CNS depression : a dose-dependent fashion.
Sedative & hypnotic
anesthesia in large dose
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
Hypovolemic states, CHF, normal doses
may cause cardiovascular collapse.
Large dose circulatory collapse due to
medullary vasomotor depression direct
CYT P-450 microsomal enzymes inducers (Tolerance - drug interaction).
Increase activity of hepatic gamma amino
levulinic acid synthetase (ALA) synthesis of
porphyrin (# porphyria).
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).
Hyperbilirubinemia and kernicterus in the neonates (increase glucouronyl transferase activity).
1. Respiratory depression.
2. Hangover: residual sedation after awakening.
4. Withdrawal symptoms
5. Precipitation of acute attack of porphyria.
6. Many drug interactions.
7. Allergic reaction: urticaria and skin rash.
Respiratory depression, cardiovascular collapse, comaand death.
1.Acute intermittent porphria.
3.Liver & kidney diseases.
5.Old people (mental confusion).
7.Hypersensitivity to barbiturates.
1. Other CNS depressants: Ethanol
2. MAOI: potentiate CNS depression
3. Phenytoin, warfarin, and dicumarol: their
metabolism is increased.
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.