Transcript 01. Sedative _ Hypnotics

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 azepam
Alprazolam
Estazolam
Triazolam
Lorazepam
Diazepam
Oxazepam
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
Alprazolam
Nitrazepam
- Long acting: ( 24-72 hours)
Chlorazepate
Diazepam
Quazepam
Chlordiazepoxide
Flurazepam
Prazepam
According to uses
Anxiolytics
Lorazepam
Oxazepam
Chlordiazepoxide Diazepam
Clonazepam
Alprazolam
Prazepam
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 = GABAmediated 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 anxiety
General anxiety disorder
major depressive disorders
Obsessive compulsive disorder
Panic 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
CYT P450 inducers
Phenytoin & Rifampicin
t 1/2 of benzodiazepines
t ½ of benzodiazepines
Dose should be reduced in
o Liver disease
o 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 Uses
1. 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 action
Short 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 - 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).
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.
Toxicity
Respiratory 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 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.