Transcript Sedative _ Hypnotics - KSU Faculty Member websites

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  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,
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 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.
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
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  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)
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.