Sedative & Hypnotics

Dr. M. Masoom Akhtar

Anxiolytic and Hypnotic Drugs
 Sedative & Hypnotics
• Anxiety: Unpleasant emotional state consisting
of apprehension, tension and feeling of danger
without real or logical cause.
• Physical Symptoms: Tachycardia, sweating, tachypnea, trembling and weakness

 Anxiolytics : Drugs that clam the patient and reduce

anxiety without inducing normal sleep.

 Hypnotics : Drugs that initiate and maintain

the normal sleep.
 Definitions….
• Tolerance
A decreasing response to repetitive drug
doses. Higher doses are needed to produce
the same effect.

• Cross tolerance:means that individuals

tolerant to one drug will be tolerant to other
drugs in the same class or other classes
• physical dependence (physiological
dependence) in which the drug is used to
prevent WITHDRAWAL SYMPTOMS

• psychological dependence in which the

drug is used to obtain relief from tension or
emotional discomfort; called also emotional
dependence.
Classification of Sedative and Hypnotic drugs
1. Benzodiazepines ( BDZ )
2. Barbiturates
3. Miscellaneous ( non BDZ & non barbiturate
drugs).
 Zolpidem
 Zaleplon
 New Drugs
 Eszopiclone
 Ramelteon
Benzodiazepines Nomenclature
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
 modulate action of GABA on GABA
receptors  increase frequency of chloride
channels opening that  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 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.
 Drug Interactions
Examples
CNS depressants CNS depressants, alcohol &
Antihistaminics of
effect of benzodiazepines
Cytochrome P450 (CYT Cimetidine & Erythromycin
P450) inhibitors
t ½ of benzodiazepines

CYT P450 inducers Phenytoin & Rifampicin

t 1/2 of benzodiazepines
Dose should be reduced in

o Liver disease
o 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
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.
 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.
 5HT1A agonists
Buspirone

• acts as agonist at brain 5HT1A receptors

• rapidly absorbed orally.
• Slow onset of action (delayed effect)
• T½ : (2 – 4 h).
• liver dysfunction   its clearance.
• Drug Interactions with CYT P450 inducers
and inhibitors.
 Uses of buspirone
•As anxiolytic in mild anxiety & generalized
anxiety disorders.

•Not effective in severe anxiety/panic disorder.

 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, 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 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.
 Eszopiclone
• Eszopiclone [es-ZOE-pi-clone] is an oral non-
benzodiazepine hypnotic that also acts on the BZ1
receptor.
• It has been shown to be effective for insomnia for up to 6
months.
• Eszopiclone is rapidly absorbed (time to peak, 1 hour),
extensively metabolized by oxidation and demethylation
via the CYP450 system, and mainly excreted in urine.
Elimination half-life is approximately 6 hours.
• Adverse events with eszopiclone include anxiety, dry
mouth, headache, peripheral edema, somnolence, and
unpleasant taste.
 Ramelteon
• Ramelteon [ram-EL-tee-on] is a selective agonist at the MT
subtypes of melatonin receptors. Melatonin is a hormone secreted by
• the pineal gland that helps to maintain the circadian rhythm
underlying the normal sleep–wake cycle.
• Stimulation of MT1 and MT2 receptors by ramelteon is thought to
induce and promote sleep.
• Ramelteon is indicated for the treatment of insomnia characterized
• By difficulty falling asleep (increased sleep latency).
• It has minimal potential for abuse, and no evidence of dependence or
withdrawal effects has been observed. Therefore, ramelteon can be
administered long term.
• Common adverse effects of ramelteon include dizziness, fatigue,
• And somnolence.
• Ramelteon may also increase prolactin levels.