2016 Pharmacology of

ANXIOLYTIC and SEDATIVE- HYPNOTIC DRUGS

Dr.Datten Bangun MSc,SpFK

Dept.Farmakologi & Therapeutik
Fak.Kedokteran UHN
MEDAN
 BASIC PHARMACOLOGY OF SEDATIVE-
HYPNOTICS

• An effective sedative (anxiolytic) agent should reduce

anxiety and exert a calming effect with little or no
effect on motor or mental functions.

• A hypnotic drug should produce drowsiness and

encourage the onset and maintenance of a state of
sleep that as far as possible resembles the natural
sleep state.
 BASIC PHARMACOLOGY OF SEDATIVE-
HYPNOTICS

• Hypnotic effects involve more pronounced depression

of the central nervous system than sedation, and this
can be achieved with most sedative drugs simply by
increasing the dose.

• Graded dose-dependent depression of central nervous

system function is a characteristic of sedative-
hypnotics.
 Normal sleep
Normal sleep consists of distinct stages,based on
three physiologic measures:
1.the electroencephalogram,
2.the electromyogram, and
3.the electronystagmogram.

Non-rapid eye movement(NREM) sleep: 70%-75%

Stage 1,2
Stage 3,4:slow wave sleep, SWS
Rapid eye movement(REM) sleep
 CHEMICAL CLASSIFICATION
1. Benzodiazepines: not to lead general anesthesia,
rarely death.
2. Barbiturates: the older sedative-hypnotics, general
depression of central nervous system.
-With such drugs, an increase in dose above that
needed for hypnosis may lead to a state of general
anesthesia.
-At still higher doses, it may depress respiratory
and vasomotor centers in the medulla, leading to
coma and death.
3. Other classes of drugs: chloral hydrate, buspirone,
et al.
 Ⅰ.Benzodiazepines
• The first benzodiazepine, chlordiazepoxide,
was synthesised by accident in 1961.
 PHARMACOLOGICAL EFFECTS

1. Reduction of anxiety and aggression :

affects the hippocampus and nucleus
amygdalae

2. Sedation and induction of sleep:

(1) the latency of sleep onset is decreased;
(2) the duration of stage 2 NREM sleep is
increased;
(3) the duration of slow-wave sleep is
decreased.
 PHARMACOLOGICAL EFFECTS

Reasons for their extensive clinical use:

(1) great margin of safety;
(2) little effect on REM sleep;
(3) little hepatic microsomal drug-
metabolizing enzymes;
(4) slight physiologic and psychologic
dependence and withdrawal syndrome;
(5) less adverse effects such as residual
drowsiness and incoordination movement.
3. Anticonvulsant and antiseizure
They are highly effective against chemically
induced convulsions caused by leptazol,
bicuculline and similar drugs but less so
against electrically induced convulsions.

The can enhance GABA-mediated synaptic

systems and inhibit excitatory transmission.
4. Muscle relaxation
relax contracted muscle in joint diease or muscle
pasm.

5. Other effects
lead to temporary amnesia
decrease the dosage of anesthetic;
depress respiratory and cardiovascular fuction.
 MECHANISM OF ACTION
• Benzodiazepines act very selectively on GABAA-
receptors, which mediate the fast inhibitory
synaptic response produced by activity in GABA-
ergic neurons.

• The effect of benzodiazepines is to enhance the

response to GABA, by facilitating the opening of
GABA-activated chloride channels (an increase
in the frequency of channel opening, but no
change in the conductance or mean open time).
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.
 PHARMACOKINETIC ASPECTS
• Well absorbed when given orally;
• They bind strongly to plasma protein, and
their high lipid solubility cause many of
them to accumulate gradually in body fat.
Distribution volumes is big.
• Metabolic transformation in the
microsomal drug-metabolizing enzyme
systems of the liver, eventually excreted as
glucuronide conjugates in the urine.
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
• They vary greatly in duration of action, and
can be roughly divided into
– Short-acting compounds: triazolam,
oxazepam(15-30min, t1/2 2-3 h)
– Medium-acting compounds: estazolam,
nitrazepam (40min, t1/2 5-8 h)
– Long-acting compounds: diazepam,
flurazepam(50h)
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).
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).
 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.
 ADVERSE DRUG REACTION
• Acute toxicity: Benzodiazepines in acute
overdose are considerably less dangerous
than other sedative-hypnotic drugs.
• Cause prolonged sleep,without serious
depression of respiration or cardiovascular.
• The availability of an effective antagonist,
flumazenil.
 ADVERSE DRUG REACTION
• Side-effects during therapeutic use:
drowsiness, confusion, amnesia, impaired
coordination. Main disadvantages are
interaction with alcohol, long-lasting
hangover and the development of
dependence.
• Tolerance and dependence: induction
of hepatic drug-metabolising enzymes; a
change at the receptor level;
 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
 Ⅱ.BARBITURATES
Classification
(1) Ultra-short-acting barbiturates: act within seconds,
and their duration of action is 30min. Therapeutic
use of Thiopental: anesthesia
(2) Short-acting barbiturates: have a duration of action
of about 2h. The principal use of Secobarbital : sleep-
inducing hypnotics.
 Ⅱ.BARBITURATES (cont’d)
Classification

(3)Intermediate-acting barbiturates: have and effect

lasting 3-5h. The principal use of Amobarbital is as
hypnotics.
(4)Long-acting barbiturates: have a duration of action
greater than 6h. Such as Barbital and Phenobarbital.
Therapeutic uses: hypnotics and sedative, and
antiepileptic agents at low doses.
 BARBITURATES
• Barbiturates depress the CNS at all level
in a dose-dependent fashion.
• Now it mainly used in anaesthesia and
treatment of epilepsy;
• use as sedative-hypnotic agents is no
longer recommended.
 BARBITURATES

Reasons:
(1) have a narrow therapeutic-to-toxic dosage
range.
(2) suppress REM sleep.
(3) Tolerance develops relatively quickly.
(4) have a high potential for physical
dependence and abuse.
(5) potent inducers of hepatic drug-
metabolising enzymea.
 MECHANISM OF ACTION
(1) Barbiturates share with benzodiazepines the
ability to enhance the action of GABA, but
they bind a different site on the GABA-
receptor/chloride channel, and their action
seems to prolong the duration of the opening
of GABA-activated chloride channels.
(2) (2) At high doses, barbiturates can inhibit the
release of the Ca2+-dependent
neurotransmitter.
 Pharmacokinetics
• High lipid solubility allows rapid transport across
the blood-brain barrier and results in a short onset.
• Removal from the brain occurs via redistribution to
the other tissues results in short duration of action.
• Barbiturates and their metabolites the excretion via
the renal route. Alkalinization of the urine
expedites the excretion of barbiturates. Treatment
of acute overdosage: Sodium bicarbonate.
 Therapeutic uses

• Sedative-hypnotic agents
• Be used in the emergency treatment of
convulsions as in status epilepticus.
• Anesthetic (or be given before anesthetic)
• Combination with antipyretic-analgesic
• Treatment of hyperbilirubinemia and
kernicterus in the neonate.
 Adverse effects
• After effect: hangover---dizzy, drowsiness,
amnesia, impaired judgment, disorientation.

• Tolerance: decreased responsiveness to a drug

following repeated exposure because of down-
regulation of receptors and induction of
hepatic drug-metabolising enzymes.
 Adverse effects
• Dependence: including psychologic and
physiologic dependence. Withdrawal symptoms:
excitation, insomnia, tremor, anxiety,
hallucinations and sometimes convulsions.
• Depressant effect on respiration: can cross the
placental barrier during pregnancy and secrete
to breast milk.
• Others: Skin eruptions and porphyria
 Treatment of acute overdosage
• An overdose can result in coma, diminished reflexes,
severe respiratory depression, hypotension leading
to cardiovascular collapse, and renal failure.
• Treatment (A.B.C):
(1) supporting respiration and circulation.
(2) alkalinizing the urine and promoting diuresis.
(3) Hemodialysis or peritoneal dialysis.
Ⅲ.Nonbarbiturate sedative-hypnotics
Chloral hydrate
(1) relatively safe hypnotic, inducing sleep in a
half hour and lasting about 6h.
(2) used mainly in children and the elder, and
the patients when failed to other drug.
 Non benzodiazepines Anxiolytic:
Buspirone (Buspar)
• Different action to bzd.
• Not a CNS depressant.
• Partial agonist (stimulant) of dopaminergic &
serotoninergic receptors.
• No sedation, anti-convulsant or muscle relaxant
properties - just anxiolytic.
• Delayed action (1-2 weeks)
• Effect reduced if benzodiazepine used in last 3/12
 Comparison of benzodiazepine &
buspirone
Benzodiazepine
Rapid onset
Can cause sedation
May impair performance
Additive effects with alcohol
May cause dependence &
withdrawal
Pharmacokinetic change with
age
Associated with falls in elderly
(Keltner & Folks, 2001)
Buspirone
Delayed onset
(cannot be used PRN)
Does not cause sedation
Does not impair performance
No additive effect with alcohol
Non addictive
No pharmacokinetic change
with age
Does not cause falls in elderly
Expensive (Not on PBS)
 Buspirone: Agonist = Mimic

• Buspirone attaches to serotonin receptor mimicking

serotonin.
 Non benzo Hypnotic: Zopiclone
(Imovane)
• Similar action, side effects & contraindications
to benzo’s.
 Benzodiazepines key points
• Should not be used in patients with liver disease,
history of substance abuse, severe respiratory
distress, performing hazardous tasks
• Avoid during pregnancy/lactation if possible
• Assess for over sedation
• Cease slowly
• Monitor elderly (cognition, falls)
• Be aware they raise seizure threshold, and
• Potentiate CNS depressants (alcohol)
 Hypnotic key points

• Advise re rebound insomnia when

medications ceased
• Should not be used in sleep apnoea
• Avoid alcohol
• Hangover effect (impairing performance)
• Monitor in elderly (falls, double dosing)
Sleeping peacefully