BARBITURATES AND BENZODIAZIPINES

 Sedatives: These are drugs that subdue excitement and calms, relax the subject
without inducing sleep, though drowsiness may be produced. Sedation refers to
decreased responsiveness to stimulation; is associated with some decrease in alertness,
ideation and motor activity.

 Hypnotics: A drug that induces and/or maintains sleep, similar to normal arousable
sleep. This is not to be confused with ‘hypnosis’ meaning a trans-like state in which
the subject becomes passive and highly suggestible. The sedatives and hypnotics are
CNS depressants with somewhat differing time-action and dose-action relationships.
 Agents with quicker onset, shorter duration and steeper dose-response are
preferred as hypnotics, while more slowly acting drugs with flatter dose-response
are employed as sedatives.

 The sedatives reduce anxiety and induce calming effect with little or no effect on
motor and mental functions. Hypnotic drugs produce drowsiness and facilitate the
onset and maintenance of a state of sleep that as much as possible resembles
natural sleep.
 However, a hypnotic at lower dose may act as sedative. Thus, sedation, hypnosis
and general anaesthesia may be regarded as increasing grades of CNS depression.
Hypnotics given in high doses can produce general anaesthesia.
 Barbiturates
 Barbiturates are drugs that act as central nervous system depressants, and can therefore produce a
wide spectrum of activities from mild sedation to total anaesthesia, hypnotics and
anticonvulsants.
 Barbiturates have addiction potential both physical and psychological.

 Barbiturates were for a long time widely used as sedative-hypnotics, but they are now replaced by
benzodiazepines in routine medical practice such as treatment of anxiety and insomnia because
the benzodiazepines are less dangerous in overdose.
 Barbiturates have a low therapeutic index, i.e. relatively small overdose may endanger life, they
can also cause dependence and have been popular drugs of abuse.
Barbiturates

 Barbiturates produce CNS depression of varying degrees from mild sedation to

general anaesthesia.

 Based on their duration of action, the barbiturates are divided into;

 Long acting (Phenobarbitone and Barbitone).

 Intermediate acting (Amobarbitone, Aprobarbitone and Butabarbitone).

 Short acting (Penthobarbitone and Secobarbitone).

 Ultra short acting (Thiopentone sodium, Hexobarbitone and Methohexitone).

 Barbiturates

 Mechanism of action: Barbiturates inhibit and causes CNS depression. This is brought

about by stimulating the inhibitory neurotransmitter system in the brain called the GABA

system. The GABA channel is a chloride channel that has five cells at it gate.

 When they bind to the GABA channel, they prolong opening of the channel and letting in

chloride ions into the cells in the brain. This leads to increased negative charge and alters

the voltage in the brain.

 This change in voltage makes the brain cells resistant to nerve impulses and depresses them.
 Barbiturates

 Pharmacokinetics: Barbiturates are well absorbed from the gastrointestinal tract.

They are widely distributed in the body. The rate of entry into CNS is dependent
on lipid solubility. Highly-lipid soluble thiopentone has practically instantaneous
entry, while less lipid-soluble ones (pentobarbitone) take longer; phenobarbitone
enters very slowly. Barbiturates cross placenta and are secreted in milk; can
produce effects on the foetus and suckling infant. Three processes such as
redistribution, metabolism and excretion, are involved in termination of action of
barbiturates: the relative importance of each varies with the compound.
 Barbiturates

On intravenous injection, the highly lipid soluble compounds (thiopentone) enter the
CNS rapidly and produce anaesthesia in less than 1 min, and then diffuse back quickly
to redistribute to less vascular tissues (muscle, fat). Consciousness is regained in 6-10
min, but ultimate disposal occurs by metabolism (t½ 9 hours). Intermediate lipid
solubility barbiturates are primarily metabolized in the liver by oxidation, dealkylation
and conjugation. Their plasma t½ ranges between 12–36 hours. Barbiturates with low
lipid-solubility, in addition to being metabolized, are significantly excreted unchanged
in urine.
 Clinical uses of barbiturates

 Except for phenobarbitone in epilepsy and thiopentone/ methohexitone in

anaesthesia, no other barbiturate is commercially available or used now. As
hypnotic and anxiolytic. The barbiturates have been superseded by
benzodiazepines.
Adverse effects

 Hangover was common after the use of barbiturates as hypnotic.

 Mental confusion, impaired performance and traffic accidents may occur.

• Tolerance and dependence Both cellular and pharmacokinetic (due to enzyme induction)
tolerance develops on repeated use. However, fatal dose is not markedly increased:
addicts may present with acute barbiturate intoxication. There is partial cross tolerance
with other CNS depressants. Addiction and dependence occurs, and barbiturates have
considerable abuse liability. This is one of the major disadvantages. Withdrawal
symptoms are—excitement, hallucinations, delirium, convulsions; deaths have occurred.
Contraindication

 Contraindications of barbiturates include;

 Severe liver and kidney dysfunction

 Impaired myocardial function in pregnant and lactating women

 Known hypersensitivity to barbiturates

 Severe intoxication with other CNS depressants such as alcohol, hypnotics and
narcotics.
 Barbiturate poisoning

 Acute barbiturate poisoning may arise from unintentional or intentional overdose or after a
therapeutic dose has been taken in association with alcohol.

 However, it is infrequently encountered currently due to unavailability of barbiturates.

Moreover, the principles of treatment apply to any CNS depressant poisoning.

 Manifestations are due to excessive CNS depression— patient is flabby and comatose with
shallow and failing respiration, fall in BP and cardiovascular collapse, renal shut down,
pulmonary complications, bullous eruptions. Death may result from paralysis of the respiratory
and vasomotor centres from bronchopneumonia occurring as a result of prolonged coma.
Treatment of barbiturate poisoning

 Treatment of barbiturate poisoning consists in measures designed to restore

respiration and circulation.

 Gastric lavage can be performed if the duration of the drug intake has not exceeded
one hour. This procedure is ineffective in later stage of acute poisoning. The next step
is to eliminate poison already absorbed by diuresis or dialysis.

 Diuresis is used in mild form of acute poisoning. Intravenous fluid such as isotonic
solution of sodium chloride with 100 mg-200mg of manitol in 5-10% solution.
Treatment of barbiturate poisoning
 Loop diuretics such as furosemide may be used.

 Artificial respiration is used in respiratory disorder

 Oxygen therapy is used for treatment of hypoxia

 Secretions are removed from upper respiratory tract

 Vasoconstriction agents such as norepinephrine or epinephrine is used for hypotension.

 Fluid replacement, blood transfusion and vasoconstricting agents are used in the
treatment of shock that occur occasionally in acute poisoning
Benzodiazepines

 Benzodiazepines are selective CNS depressants which produce sedation, relieve

anxiety, facilitate sleep, suppress seizure and reduce muscle tone.

 Anxiety disorders are among the most common of all CNS disorders afflicting
humans, with the painful experience of tension and apprehension.

 Symptoms of anxiety are commonly associated with depression, panic, social

phobias, for example; fear of meeting people, obsessive-compulsive disorder and
many personality disorders.
Benzodiazepines

 Based on their duration of action, the benzodiazepines are divided into;

 Long acting (diazepam, clonazepam, chlordiazepoxide, clorazepate etc).

 Intermediate acting (alprazolam, lorazepam, temazapam, estazolam etc)

 Short acting (triazolam, halazepam, flurazepam, midazolam etc)

Benzodiazepines

 Mechanism of action: Benzodiazepine bind to specific binding sites in the

GABAA receptor-chloride complex in the brain, and increases the frequency

of chloride channel opening in the presence of GABA; this increases

hyperpolarization-induced neuronal inhibition

Benzodiazepines
 Pharmacokinetics: There are marked pharmacokinetic differences among BZDs,
because they differ in lipid solubility by more than 50 fold. These differences are
important factors governing their choice for different uses. Oral absorption of some is
rapid while that of others is slow. Plasma protein binding also varies strongly (triazolam
10% to diazepam 99%). BZDs are widely distributed in the body. Benzodiazepines are
metabolized in liver mainly by CYP3A4 and CYP2C19 to dealkylated and hydroxylated
metabolites and excreted in urine.
Therapeutic uses
 As anxiolytic

 As sedative/hypnotic

 As anticonvulsant, especially emergency control of status epilepticus, febrile

convulsions, tetanus, etc.

 As centrally acting muscle relaxant for muscle spasms and spasticity.

 For pre-anaesthetic medication, intravenous anaesthesia and conscious sedation.

 Alcohol withdrawal in dependent subjects.

Therapeutic uses

 Before ECT, electrical cardioversion of arrhythmias, cardiac catheterization,

endoscopies, in obstetrics and many minor procedures— intravenous diazepam has

gained popularity because of its calming-amnesic-analgesic and muscle relaxant

properties and relative safety.

 In Psychosis, the potent benzodiazepines (injectable BZDs) are commonly

employed, also adjunctively in short-term management of acute psychotic or

manic patients.
Adverse effects

 Toxic effects due to acute overdosage causes prolonged sleep. Other unwanted
effects includes; drowsiness, confusion, amnesia and impaired motor
coordination, dizziness, weakness, unsteadiness.

 Tolerance and dependence: Pharmacokinetic and tissue tolerance, can also cause
physical dependence, i.e. stopping benzodiazepines treatment after weeks or
months causes an increase in symptoms of anxiety.
Interactions

 Benzodiazepines synergize with alcohol and other CNS depressants leading to

excessive impairment. Concurrent use with sodium valproate has provoked
psychotic symptoms. Drug interactions due to displacement from protein binding
or microsomal enzyme induction are not significant. Since CYP 3A4 isoenzyme
plays important role in metabolism of several BZDs, their action can be prolonged
by CYP 3A4 inhibitors like ketoconazole, erythromycin and others. Cimetidine,
isoniazid and oral contraceptives also retard BZD metabolism.
Benzodiazepine anatagonist

 Flumazenil: This is a BZD analogue which has little intrinsic activity (practically
no effect on normal subjects), but competes with BZD agonists as well as inverse
agonists for the BZD receptor and reverses their depressant or stimulant effects
respectively. Flumazenil abolishes the hypnogenic, psychomotor, cognitive and
EEG effects of BZDs. Flumazenil is not used orally. This agent is given
intravenously and its action starts in seconds and lasts for 1–2 hours. The
elimination half-life (t½) is 1 hour, due to its rapid metabolism.
Uses

 To reverse BZD anaesthesia: Patients anaesthetized/ sedated with a BZD

wakeup, get oriented and regain motor control within 1 min of an intravenous
injection of 0.3–1 mg of flumazenil. Resedation generally occurs within 1 hour
(more with diazepam than with midazolam): supplemental doses of flumazenil
may be given. This may allow early discharge of patients after diagnostic
procedures and facilitates postanaesthetic management.
Uses

 BZD overdose: Majority of patients of BZD overdose require only supportive

measures like patent airway, maintenance of BP, cardiac and renal function (by
fluid transfusion, etc.). In addition, flumazenil 0.2 mg/min may be injected i.v. till
the patient regains consciousness. Practically all patients intoxicated with a BZD
alone respond within 5 min (maximum total dose 1 mg).
Uses

 However, reversal of respiratory depression is incomplete. Flumazenil blocks the

hypnotic effect of zolpidem-like non-BZDs as well. In mixed CNS depressant
poisoning, whatever sedation is not abolished by 5 mg of flumazenil should be
taken to be due to a non-BZD/non-Zolpidem-like depressant. However,
administration of flumazenil may be risky in mixed overdosage with a BZD plus a
tricyclic antidepressant. It can also be hazardous in BZD-dependent subjects by
precipitating severe withdrawal. Thus, the use of flumazenil in BZD overdosage
requires great caution.
Adverse effects

 Flumazenil is safe and well tolerated. Side effects noted during use of flumazenil
as a BZD-antagonist are; agitation, discomfort, fearfulness, anxiety, coldness and
withdrawal seizures.