Sedatives & Hypnotics

What is a sedative?

The drug which reduces anxiety & exert a calming effect in the patient is a sedative / anxiolytic.

Sedatives show therapeutic efficacy with minimum depression of CNS.

What is a hypnotic?

The drug which encourages the onset & maintenance of a state of sleep.

Hypnotics show therapeutic efficacy with more pronounced depression of CNS than sedative.

Classification

1.Benzodiazepines---

Diazepam

Oxazepam

Lorazepam

Nitrazepam

Midazolum

2.Barbiturates---- (less commonly used)

Secobarbital

Phenobarbital

Pentobarbital

3.Newer hypnotics----

Zolpidem

Zaleplon

Zopiclone

Eszopiclone
Melatonin receptor agonist → Ramelteon, Tasimelteon

Orexin antagonist → Suvorexant

4.Buspirone (anxiolytic agent)

5.Older agents (rarely used now a days)---

Glutethimide

Meprobamate

Chloral hydrate

Ethanol
BENZODIAZEPINES

Classification (according to duration of action)

Ultrashort (˂ 6 hr)

Midazolam

Triazolam

Short (12 – 18 hr)

Lorazepam

Oxazepam

Temazepam

Medium (24 hr)

Alprazolam

Nitrazepam

Long (24 – 48 hr)

Diazepam

Clonazepam

Flurazepam

Chlordiazepoxide
Mechanism of action

1)Benzodiazepine binds with benzodiazepine receptor ( which is a molecular component of

GABA receptor chloride ion channel macromolecular complex ).

2)Enhance GABA′s effects & there is an increase in the frequency of chloride (Cl-) channel
opening ( i.e. benzodiazepine enhance GABA′s effects allosterically).

3)Increased chloride ion entry inside the neuronal cells causing hyperpolarization & reduced
excitability leading to sedation & hypnosis.

Benzodiazepine binding site ligands

3 types of ligand – benzodiazepine receptor interactions have been reported →

i)Agonist –

Benzodiazepines

Zolpidem

Zaleplon

Zopiclone

Eszopiclone

ii)Antagonist –

Flumazenil

iii)Inverse agonist –

β – carbolines ( binds with benzodiazepine receptor & produce anxiety & seizure / convulsion )
Pharmacological effects

Sedation & Amnesia

*Calming effect with reduction of anxiety

*Anterograde amnesia – inability to remember events occurring during the drug′s duration of
action.

*Long acting drugs in relatively low doses used as anxiolytic

Hypnosis

*Rapid onset of sleep

*Prolongation of stage 2 NREM sleep

*Decrease the time of waking during the night

*Short acting drugs mainly used as hypnotic

Anesthesia

*Highly lipid soluble drugs in high doses cause general anesthesia e.g. midazolam in I/V route.

Anticonvulsant effect

*Clonazepam has more anticonvulsant effect.

*Diazepam used intravenously in status epilepticus

Skeletal muscle relaxation

*Exert inhibitory effects on polysynaptic reflexes & useful for relaxing contracted voluntary
muscle in muscle spasm.
Effect on respiration & cardiovascular function

*Significant cardio-respiratory depression in patients with –

Pulmonary disease

Heart failure

Hypovolemic states

Other diseases that impair cardiovascular function

*Depression of the medullary respiratory centre is the cause of death due to overdose.

*Respiratory & cardiovascular effects are more marked when sedative-hypnotics given
intravenously.

Tolerance & Dependence

*Tolerance – Repeated administration of some drugs ( e.g. benzodiazepines for ≥ 3 weeks ) may
lead to gradual reduction of response / effect by those drugs, which is known as tolerance.

When tolerance exist, it becomes necessary to increase the dose of a drug to get an effect
previously obtained with a smaller dose.

*Dependence – Repetitive use of some drugs ( e.g. benzodiazepines ) result in tolerance to the
effect of those drugs & appearance of withdrawal / abstinence syndrome when drug use is
abruptly discontinued, is known as dependence.

Withdrawal / abstinence syndrome of benzodiazepines

Irritability

Insomnia

Phonophobia

Photophobia

Depression

Muscle cramps

Convulsion
Treatment of dependence of sedatives & hypnotics

Long acting drugs e.g. chlordiazepoxide or diazepam is adminietered in progressively

decreasing doses to patients during withdrawal from dependence to sedatives – hypnotics /
alcohol.

Withdrawal of benzodiazepines should be gradual, about 1/8th of the dose every 2 weeks, aiming
to complete it in 6 – 12 weeks.

Clinical uses

1)For relief of anxiety

2)For insomnia

3)Pre anesthetic medication

4)For treatment of epilepsy & seizure disorders (febrile convulsion in children diazepam given
per rectally)

5)As a component of balanced anesthesia (intravenously)

6)For control of alcohol or other sedative – hypnotic withdrawal states

7)For skeletal muscle relaxation in specific neuromuscular disorders (e.g. mucle spasticity in
spinal injury, cerebral palsy, multiple sclerosis, stroke)

8)Treatmentment in psychiatry –

Initial management of mania

Control of drug induced hyperexcitability states

ADR

Unwanted effects occurring during normal therapeutic use

Drowsiness

Confusion (depressed cognitive function)

Amnesia

Impaired Psychomotor function

Hangover effect

Toxic effects resulting from acute overdose

*Significant cardio-respiratory depression in patients with –

Pulmonary disease

Heart failure

Hypovolemic states

Other diseases that impair cardiovascular function

*Depression of the medullary respiratory centre is the cause of death due to overdose.

*Flumazenil is the effective anagonist for the treatment in benzodiazepine ovrdose.

Tolerance & dependence in chronic use

BARBITURATES

Classification (Name & use)

Long acting → Phenobarbital (Epilepsy)

Shot acting → Pentobarbital (sedative & hypnotic – rarely used)

Ultra short acting → Thiopental sodium (General anesthesia – for induction)

Mechanism of action (drug of low therapeutic index)

1)Act by enhancing the action of GABA.

2)In overdose acts as GABA – mimetic & directly open the Cl - ion channel, leading to severe
cardiorespiratory depression (drug of low therapeutic index)

Difference between benzodiazepines & barbiturates / advantages of benzodiazepines

1)High therapeutic index / Low therapeutic index

2)Availability of Flumazenil for treatment of overdose / No such antidote available

3)Does not cause enzyme induction / Causes enzyme induction – so more chance of drug
interaction

4)Less tolerance & dependence / More tolerance & dependence.

Drug interactions of benzodiazepines

Benzodiazepines + Alcohol / opioids / anticonvulsants / phenothiazines / antihistamines /

tricyclic antidepressants → additive CNS depression
BUSPIRONE

*Partial agonist at 5HT1A receptor ( inhibitory autoreceptor ) & reduce the release of 5HT.

*Disadvantages –

Slow onset of action ( takes 3-4 weeks to produce antianxiety effect ).

Not effective in acute anxiety state

No hypnotic, anticonvulsant, muscle relaxant effect.

*Advantages –

No drowsiness

No tolerance & dependence in chronic use

Less psychomotor impairment

Suitable for elderly patient

Other classes of drugs that exert sedative effects →

Quetiapin (antipsychotic) – resistant insomnia as a part of another psychiatric disorder.

Many antidepressant drugs – currently used widely in management of chronic anxiety disorders.

Antihistamines --- Hydroxyzine, Promethazine, Diphenhydramine, Doxylamine – are available

in over the counter sleep aids ( also as a hypnotic agent in children )