SEDATIVES,

HYPNOTICS,
ANXIOLYTICS
Sedatives are drugs used to calm anxious
and restless patients thus allowing sleep
without actually producing it while
hypnotics are drugs used to induce
drowsiness and sleep. Small doses of
hypnotics can be used as sedatives.
 CLASSES OF ANXIOLYTIC AND HYPNOTIC
DRUGS
• Benzodiazepines: the most important class, used for
treating both anxiety states and insomnia
• 5-HT1A-receptor agonists: recently introduced, show
anxiolytic activity with little sedation.
• Barbiturates: now largely obsolete as anxiolytic/sedative
agents, though amobarbital is still occasionally
prescribed.
• β-adrenoceptor antagonists: used mainly to reduce
physical symptoms of anxiety (tremor, palpitations, etc.);
no effect on affective component.
• Miscellaneous other agents are still used occasionally to
treat insomnia (eg chloral hydrate)
Dose-response curves for two hypothetical sedative-hypnotics

5
 BENZODIAZEPINES
• BENZODIAZEPINES now the most
commonly used drugs in this class and have
largely replaced barbiturates.
• Benzodiazepines, at low doses are useful
anxiolytics and at high doses produce a
hypnotic effect.
• They produce fewer and less serious side-
effects than barbiturates.
• Dependence liability is lower.
CLASSIFICATION OF BENZODIAZEPINES

Classification is based on the duration of action

• Short acting (t1/2 < 5hr) eg. Midazolam and

Triazolam
2. Intermediate acting (t1/2 = 5-24hr) eg.
Alprazolam, Clonazepam, Oxazepam, Lorazepam
3. Long acting (t1/2 > 24hr) eg Chlordiazepoxide,
clorazepate, diazepam, flurazepam
MECHANISM OF ACTION

Benzodiazepines enhance GABA-mediated

inhibition of neuronal activity. This they do by
binding to specific benzodiazepine receptor sites
that are part of but distinct from the GABAA
receptor-chloride channel complex. As a result the
ability of GABA to open chloride channels is
increased. Activity of the benzodiazepines requires
the presence of GABA. They act on polysynaptic
pathways throughout CNS.
Schematic diagram of benzodiazepine-GABA-chloride ion channel complex.
 PHARMACOKINETICS
• Benzodiazepines are administered orally when
used as sedatives and hypnotics. The rate of
absorption is variable and some are rapidly
redistributed from the brain to the peripheral
tissues. This redistribution is important for
terminating the action of the highly soluble
benzodiazepines.
• Benzodiazepines bind to a variable extent to
plasma proteins (3-4% Flurazepam 99%
Diazepam) to a variable extent.
 PHARMACOKINETICS

• Benzodiazepines are metabolized mostly in the

liver by microsomal oxidation and
glucuronidation. Some metabolites are
pharmacologically active.

• Benzodiazepines have only weak effects on

hepatic drug-metabolizing enzymes.
PHARMACOLOGICAL ACTIONS
It is assumed that all benzodiazepines produce
qualitatively similar actions and that virtually all
their effects result from actions on CNS. These
include:

• sedation
• hypnosis
• decreased anxiety
• muscle relaxation
• anticonvulsant
 OTHER ACTIONS
• Benzodiazepines have very slight effects on
respiration, cardiovascular system and the
gastrointestinal tract.
• They potentiate the effect of ethanol
• Large doses of benzodiazepines taken before
labour may cause hypothermia, hypotonia and
mild respiratory depression in the neonate.
Heavy use (or abuse) by pregnant mother may
produce withdrawal syndrome in newborn.
 THERAPEUTIC USES

1. Anxiety states
2. Insomnia
3. Seizures
4. Pre-anaesthetic medication
5. Muscle relaxation – spontaneous spasms
6. Withdrawal from CNS depressants
ADVERSE EFFECTS

2. May cause rebound insomnia

3. Ataxia
4. Daytime drowsiness
5. Confusion in the elderly
6. Blurred vision
7. Hypotension and constipation
TOLERANCE AND DEPENDENCE

• Tolerance develops to sedative and

hypnotic but not anxiolytic effects of the
benzodiazepines. Benzodiazepines confer
cross-tolerance to barbiturates and ethanol.

• Withdrawal syndrome depends on

benzodiazepine of abuse and can be severe.
 BARBITURATES
These are classified according to t
duration of action
3. Ultra-short acting barbiturates suc
thiop
2. Short acting barbiturates suc
pentobarbital, secobarbital and amoba
3. Long acting barbiturates suc
Phenoba
 MECHANISM OF ACTION

Block conduction in reticular activating

system. Interact with binding sites on GABA
receptor-chloride channel complex that is
separate from the benzodiazepine binding
site. Barbiturates increase chloride channel
activation. They can act independently of
GABA. Affect mono- and polysynaptic
pathways.
PHARMACOLOGICAL ACTIONS

• sedation
• hypnosis
• decreased anxiety
• anticonvulsant
 OTHER ACTIONS
• Barbiturates can have marked respiratory
depressant action.
• Barbiturates also depress transmission in
sympathetic ganglia - may account for fall in
blood pressure.
• Barbiturates greatly induce DME systems.
Therefore are responsible for many adverse
drug interactions.
• They enhance porphyrin synthesis and so are
absolutely contraindicated in porphyria - can be
fatal.
THERAPEUTIC USES

2. Anaesthesia
3. Seizures
4. Anxiety
5. Sleep disorders
 ADVERSE EFFECTS
• Drowsiness, tiredness, impaired judgement
• Enzyme induction – cause of many drug
interactions
• Addiction – withdrawal symptoms
Barbiturate poisoning – severe respiratory and
cardiovascular depression results in shock-like
state. Treatment includes gastric lavage,
haemodialysis, artificial respiration and
alkalinization of the urine.
HT-51A agonists as anxiolytic drugs
• Buspirone is an azapirone derivative (others
include ipsapirone and gepirone). It is a partia
agonist at inhibitory presynaptic 5-HT1A
receptors and reduces 5-HT neurotransmission
It has no hypnotic properties. It has no action on
GABA-benzodiazepine receptor complex and canno
be used to treat benzodiazepine withdrawal syndrome
Anxiolytic effects take days or weeks to develop
• Side effects include dizziness, nervousness and
headache
 ZOLPIDEM AND ZOPICLONE
• These are non-benzodiazepine hypnotics
but act through a subset of the
benzodiazepine receptors.
• They are rapidly acting but with a short duration
(approximately 2hrs) of action. They are therefore used
for sleep-onset insomnia
• They produce minimal hangover effect.

• They have no anticonvulsant action and do not relax

skeletal muscles.
β-ADRENOCEPTOR ANTAGONISTS

These are used to reduce heart rate and

other manifestations of anxiety related to
hyperactivity of the sympathetic nervous
system.
 ETHANOL
Ethanol acts as a general CNS depressant,
similar to volatile anaesthetic agents. The
exact mechanism of action is not known but
several cellular mechanisms have been
postulated. These include:

6. inhibition of calcium channel opening

7. enhancement of GABA action and
8. inhibition of NMDA-type glutamate receptors.
 PHARMACOKINETICS
• Ethanol is absorbed throughout the gastrointestinal
tract. It is subject to significant first pass in the
stomach and liver. It is quickly distributed to other
parts of the body at a rate determined by blood flow
to that organ. It is eventually distributed throughout
the body water. High concentrations in the brain are
rapidly reached because of the high blood flow to the
brain.
• Ethanol is metabolized in the liver by alcohol dehydrogenase
to yield acetaldehyde which in turn is converted into acetate
by aldehyde dehydrogenase. Acetate is oxidized into carbon
dioxide and water. Excretion is via the lungs, urine milk and
sweat.
PHARMACOLOGICAL ACTIONS
Acute effects
- Low-moderate doses: general CNS depression
– disinhibition of inhibitory CNS pathways
leading to impaired judgement, euphoria, ataxia
- Moderate-toxic doses – further CNS depression
– sedative effect with further decrease in mental
acuity and motor function
- Toxic dose – CNS depression resulting in
anaesthesia with profound respiratory
depression
PHARMACOLOGICAL ACTIONS

Acute effects
- Cutaneous vasodilation – action on
vasomotor center as well as a direct action
on vascular smooth muscle
- Diuresis – increase in fluid volume and
decreased release of ADH
- Relaxation of uterine smooth muscle
- Reduced cardiac contractility
 CONSEQUENCES OF CHRONIC
ETHANOL USAGE
1. Cirrhosis of the liver
2. Fetal alcohol syndrome – retarded
growth, congenital heart abnormalities
3. Pancreatitis and Gastritis (increased
secretions)
4. Increased gastrointestinal bleeding and
incidence of peptic ulcer
5. Cardiomyopathy
6. Cancer of upper gastrointestinal tract and
liver
 Ethanol is used:

3. topically to reduce body temperature and also as

an antiseptic agent
4. by injection to produce irreversible nerve block
5. by inhalation to reduce foaming in pulmonary
oedema
6. orally for sedative effect
7. orally to increase appetite
8. to treat methanol and ethylene glycol poisoning.
 Effective plasma concentration:

• Threshold effects: about 40 mg/100 ml

(5mmol/l)

• Severe intoxication: about 150 mg/100 ml

• Death from respiratory failure: about 500

mg /100 ml
 Chloral Hydrate
• This is similar to ethanol in its mechanism of action.
It has a rapid onset and short duration of action.
It is metabolized in the liver into trichloroethanol
which is the active form. Trichloroethanol is highly
bound to plasma proteins. It is used to treat
insomnia in children and the elderly. Tolerance
develops to the hypnotic effect of chloral hydrate.

• Chloral hydrate has an unpleasant taste and odor

(bad breath). It also causes gastric irritation and
occassionally, cardiac arrhythmias