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)

ClassificationsAccording 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.

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 activePhase 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: Minimaldepressant 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 disease2. 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.

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.

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.

Advantages of BZD over barbiturates1. 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.

Usesa hypnotic drug for short term treatment of insomnia

Dose should be reduced in hepatic or old patients.

Adverse Effects GIT upsetDrowsiness Dizziness

Drug interactionsRifampicin (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.