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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

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Sedative hypnotics

Sedative & Hypnotics

Prof. Hanan Hagar

Pharmacology Department

Medical College

King Saud University


Sedative hypnotics1

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


BenzodiazepinesNomenclature

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 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

EXCEPTNo 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

Withdrawal symptoms:

Rebound insomnia, anorexia, anxiety, agitation, tremors and convulsion.



Dose should be reduced in

Liver disease

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

dosessuppress 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

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, comaand 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.


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