2. SEDATIVES
• A drug that subdues excitement and calms the subject without
inducing sleep, though drowsiness may be produced
– refers to decreased responsiveness to any level of
stimulation; is associated with some decrease in motor activity and
ideation
– depression of awareness to the environment and reduction
of responsiveness to external stimulation.
• Newer sedative agents should reduce anxiety and exert a calming
effect with little or no effect on motor or mental functions.
3. HYPNOTICS
A drug that induces and/or maintains sleep, similar to
normal sleep which can be aroused.
Should not be confused with ―Trans like state‖ – hypnosis.
4. ANXIOLYTICS
• Drugs that relieve anxiety
• Site of action is on the
limbic system which
regulates thought and
mental function.
AMNIASAC
• Drugs that cause the loss
of memory.
• Site of action is on the
midbrain and ascending
RAS which maintain
wakefulness.
5. • The same drug can cause different effects based on dose.
– Low dose - sedatives—relieve anxiety and promote
relaxation
– Higher doses - hypnotics—can cause drowsiness and
promote sleep
– Even higher doses - anesthetics—can cause anesthesia and
are used for patient management during surgery
8. GABAA RECEPTOR
• The pentapeptide structure of
the GABAA receptor has
binding sites for
Benzodiazepines and for other
drugs, including Barbiturates
and Ethanol.
• GABA—inhibitory transmitter
in brain regions
–Limbic system (alter
mood)
– RAS (cause drowsiness)
– Motor cortex (relax
muscles)
9. • Most S-H drugs facilitate the actions of GABA, a major
inhibitory neurotransmitter in the CNS.
• GABAA receptor activation leads to increased Cl-ion
influx.
• GABAB receptor activation causes increased efflux of K+
• Both mechanisms result in membrane hyperpolarization.
10. BENZODIAZEPINES
• Chemically: all BZS contain a
carboxamide group in the 7-
membered heterocyclic ring
structure
• A substituent in the 7
position, such as a halogen or
a nitro group, is required for
sedative- hypnotic activity
11. CLASSIFICATION
Long Acting
1-3 days
Intermediate Acting
Up to 16 hrs
Short Acting
3-8 hrs
Diazepam Alprazolam Oxazepam
Flurazepam Estazolam Triazolam
Clorazepate Lorazepam
Chlordiazepoxide Temazepam
Quzepam
12. MECHANISM of ACTION
• Benzodiazepines acts on GABAA-receptors at α+/γ2 subunit
• BZs potentiate GABA → increase frequency of Cl-ion channel
opening (no change in conductance) → causes hyperpolarization→
raise firing threshold→ and thus inhibits the formation of action
potential
• Inhibitory effect on different sites of the brain especially motor
cortex, and limbic system.
• GABA—inhibitory transmitter in brain regions
– Limbic system (alter mood)
– RAS (cause drowsiness)
– Motor cortex (relax muscles)
13.
14. PHARMACOLOGICAL EFFECTS
1. Reduction of anxiety and aggression: affects the
hippocampus and nucleus amygdalae.
2. Sedation and induction of sleep:
a: the latency of sleep onset is decreased
b: the duration of stage 2 NREM sleep is increased
c: the duration of slow-wave sleep is decreased
15. 3. Anticonvulsant and anti-seizure: They are highly
effective against chemically induced convulsions caused by
leptazol, bicuculline and similar drugs & so effective against
electrically induced convulsions.
• They enhance GABA-mediated synaptic systems and
inhibit excitatory transmission.
16. 4. Muscle relaxation: relax contracted muscle in joint disease
or muscle spasm.
5. Other effects
– Lead to temporary amnesia
– Decrease the dosage of anesthetic
– Depress respiratory and cardiovascular function.
17. PHARMACOKINETICS
• Most of them are well absorbed orally.
• BZs are lipid soluble and widely distributed.
Redistribution from CNS to skeletal muscles & adipose
tissue.
• Crosses placental barrier during pregnancy and are
excreted in milk (Fetal & neonatal depression).
• Highly bound to plasma protein.
18. • All BZs are metabolized in the liver
• Phase I: liver microsomal system
• Phase II: glucouronide conjugation and excreted in the
urine.
• Many of Phase I metabolites are active: Increase
elimination half life of the parent compound , cumulative
effect with multiple doses.
• No active metabolites are formed for Lorazepam,
Estazolam, Oxazepam.
19. CLINICAL USES
1. As Hypnotic: Not all are useful as hypnotic agents,
although all have sedative or calming effects
2. As anxiolytic and for day time sedation
3. Anterograde amnesia: short acting BZs used in
premedication for endoscopy, bronchoscopy &
angioplasty.
4. In anesthesia :
Pre-anesthetic medication - Diazepam
Induction of balanced anesthesia - Midazolam
20. 5. As Muscle relaxant: muscle spasms in multiple sclerosis
and cerebral palsy.
6. Anticonvulsant:
Status epilepticus - Diazepam, Lorazepam
Absence & myoclonic seizure – Clonazepam,
Clorazepate
7. Alcohol & other sedative hypnotic withdrawal symptoms:
chlordiazepoxide, chlorazepate, diazepam &
oxazepam
21. ADVERSE EFFECTS
1. Dizziness, vertigo, ataxia, disorientation
2. Amnesia, impairment of psychomotor skills.
3. Hangover may be seen on large dose.
4. Weakness, blurring of vision, dry mouth and urinary
incontinence.
5. Paradoxical stimulation, irritability and sweating
(Flurazepam).
6. Pregnancy– flaccidity and respiratory depression in
neonate
22. TOLERANCE
• Reduction in drug effect requiring an increase in dosage to
maintain the same response.
• Chronic use leads to tolerance (cross with other S-H
drugs), possibly via down regulation of BZ receptors.
• The antianxiety effects of the BZ are less subject to
tolerance than sedative and hypnotic effects.
23. DEPENDANCE
• Physiological dependence: removal of the drug evokes
unpleasant symptoms, usually the opposite of the drugs
effects
• Psychological dependence: the drug taker feels compelled
to use the drug & suffers anxiety when separated from
drug.
24. BZ ANTAGONIST
FLUMAZENIL
• It is a BZ analogue which competes with BZ agonists for the
receptor and reverses their depressant effects.
• Abolishes the hypnogenic, psychomotor and cognitive effects
of BZs.
• KINETICS: Absorbed orally; bioavailability is -16%.
• On i.v. injection, action of flumazenil starts in seconds and
lasts for 1-2 hr; elimination tl/2 is 1 hr, due to rapid metabolism.
• USES:
1. To reverse BZ anaesthesia: An i.v. injection of 0.3- 1 mg
of flumazenil.
2. BZ overdose: 0.2 mg/min may be injected i.v.
till the patient regains consciousness.
25. WITHDRAWAL SYMPTOMS
• Abrupt discontinuation, particularly if high doses used for
prolong period.
1. Anxiety / panic attacks
2. Agitation
3. Confusion
4. Delirium
5. Depression
6. Grand Mal seizures
7. Insomnia
8. Muscle spasm
