sedative & hypnotics prof. hanan hagar pharmacology department medical college king saud...
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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).
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.
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.