2017Pharmacology of Sedative-Hypnotics

dr.Datten Bangun,MSc,SpFK

Dept.Farmakologi & Terapetik

Fak.Kedokteran UHN
Medan
 Sedative & Hypnotics

Sedative : Drugs that calm 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 Chlordiazepoxide
Diazepam Flurazepam.
Quazepam Prazepam
Nitrazepam
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.
 Mechanism of Action (Con’d):

Benzodiazepine:
 facilitation of 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, and limbic system.
 PHARMACOKINETICS
1. most of them are well absorbed orally,

A. Rapid absorption:
e.g. triazolam & Alprazolam
diazepam & chlorazepate

B. 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 active
 elimination half life of the parent comp. 
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.----- hati-hati.....

“Young ladies.....never leave your drinks

unattended”
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  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
= 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.Anterograde amnesia--------
girls......never leave your drinks unattended
9. 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).
.
 Pharmacokinetics
(Cont’d)
• 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  circulatory collapse due to

medullary vasomotor depression  direct
vasodilatation.
 4. Enzyme induction.

Misalnya:estrogen,progesteron
=== hati-hati dg pengguna pil KB====kadarnya
akan turun=====pengguna bisa hamil

 Increase activity of hepatic gamma amino levulinic acid

synthetase ALA  synthesis of porphyrin (# porphyria).

 CYT P-450 microsomal enzymes inducers (Tolerance -

drug interaction).
 Uses :
1. Anticonvulsants: (Phenobarbitone)
tonic-clonic seizures, status epilepticus and febrile
convulsion.

2.Induction of anesthesia
(thiopental, methohexital).

3.Hypnotic (pentobarbital)

4. 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.
4.Hormon estrogen,progesteron====pil KB
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).
 Zolpidem (Ambien):

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.
 Zolpidem (Ambien) (cont’d)
 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.
 Zolpidem (Ambien) (cont’d)

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.

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

 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.
• Thank you for your attention