sedative & hypnotics by prof. dr. hanan hagar. sedative & hypnotics sedative : drugs that...
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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
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.
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.
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
Rapid absorption rapid onset of action Short duration of action (1 hr) Metabolized by liver microsomal enzymes metabolism is inhibited by cimetidine.