Chapter 5
• Barbiturates, General Anesthetics, and
Antiepileptic Drugs
Historical Background
• Alcohol is oldest of sedative-hypnotic agents
• Opium alkaloids (morphine) also used to induce
stupor and sleep
• In 1912, phenobarbital was the first of sedative
drugs classified as barbiturates
• Between 1912 and 1950, fifty barbiturates
marketed commercially
• Barbiturates are used to relieve stress, anxiety, and
to induce sleep
Sites and Mechanisms of Action
• Barbiturates reduce electrical and metabolic
activity of the brain
• Accompanied by decreases in whole brain
glucose metabolism
• Reductions follow reduction in excitatory
activity (glutamate) or augmentation in
inhibitory activity (GABA)
Sites of Action
• Amnesic properties of sedative drugs result
from glutamate antagonism
• Sedative-hypnotic effect results from
augmentation of GABA neurotransmission
• Barbiturates bind to specific sites on
GABAa receptor
• Plays a major role in anesthetic properties
of these agents
Sites of action
• Barbiturates bind to GABAa receptors and
facilitate GABA binding
• Barbiturates also capable of opening
chloride channel in the absence of GABA
• This accounts for increased toxicity of
barbiturates when compared with lack of
overdose toxicity of benzodiazepines
• benzodiazepines do not open chloride ion
channels independent of GABA availability
Uses of Barbiturates
• Barbiturate use has declined rapidly in recent
years for several reasons:
• They are lethal in overdose
• They have a narrow therapeutic to toxic range
• High potential for inducing tolerance, dependence,
and abuse
• Interact dangerously with other drugs (especially
alcohol)
Uses of Barbiturates
• Despite the disadvantages, barbiturates are
still useful
• Used as anticonvulsants (for epilepsy)
• Used as intravenous anesthetics
• Used as death inducing agents ( main
ingredient in suicide cocktails)
Sedative Induced Brain Dysfunction
• A mental status examination can be performed to
diagnose drug induced dementia. It evaluates 12
areas of mental functioning
• When sedatives are used, 5 of the 12 areas of the
mental status examination are particularly altered.
They are sensorium, affect, mental content,
intellectual function, and insight and function (see
table5.1)
Pharmacokinetics
• Barbiturates are classified by their
pharmacokinetics
• Short half-lives (thiopental has 3 minute
redistribution half-life)
• Longer half-lives (48 hour elimination halflife for pentobarbital)
• Very long half lives (24-120 hour
elimination half-life for phenobarbital)
Pharmacokinetics
• When taken orally, barbiturates rapidly and
completely absorbed
• Well distributed to most body tissues
• Ultra short-acting barbiturates are very lipid
soluble, cross blood brain barrier quickly,
induce sleep in seconds
• Longer acting barbiturates more water
soluble. Sleep delayed for 20-30 minutes
Screening for Barbiturates
• Urinalysis is used to screen for the presence
of barbiturates
• Test will be positive for as short as 30 hours
or as long as several weeks
Pharmacological Effects
• Barbiturates have low degree of selectivity
and therapeutic index
• Barbiturates are not analgesic; they cannot
be relied upon to produce sedation or sleep
in the presence of even moderate pain
• Barbiturates suppresses REM sleep, and
therefore dreaming
Pharmacological Effects
• Barbiturates are cognitive inhibitors
• They depress memory function, cognitive
function, motor skills, and judgment
• Behavior may persist for hours or days until
barbiturate is completely metabolized and
eliminated
• Overdoses or in combination with alcohol
can result in death
Pharmacological Effects
• Barbiturate-alcohol combinations have been
responsible for accidental and intentional
suicides
• Barbiturates in the liver stimulate synthesis
of enzymes that metabolize barbiturates
• This produces significant tolerance
Adverse Reactions
• Drowsiness is the primary effect produced
by barbiturates
• Impaired driving skills, judgment , and
memory during period of intoxication
• No specific antidotes
• Treatment of overdose is aimed at
supporting respiratory and cardiovascular
system until drug is eliminated
Tolerance and Dependence
• Barbiturates induce tolerance by either of these
mechanisms:
• 1. Induction of drug metabolizing enzymes in the
liver
• 2. Adaptation of neurons in the brain to the
presence of the drug
• Withdraw from barbiturates results in
hallucinations, restlessness, and disorientation
Miscellaneous
• Freely distributed to the fetus in a pregnant mother
• Barbiturate exposure during pregnancy can have
long term deleterious effects on the offspring
• Some non-barbiturate sedatives such as
methaqualone (quaalude) and meprobamate were
used recreationally in the 1970’s-1990’s
Miscellaneous
• Chloral hydrate (Noctec) is a non-selective CNS
depressant
• Withdrawl from drug causes disrupted sleep and
intense nightmares
• Combination of chloral hydrate and alcohol can
produce increased intoxication, stupor, and
amnesia
• This was called a Mickey Finn and is an example
of an early form of date rape drug
General Anesthetics
• General anesthetics are potent CNS
depressants that produce a loss of sensation
accompanied by unconsciousness
• One of two types: 1) those that are
administered through inhalation through the
lungs 2) those that are injected directly into
the vein to produce unconsciousness
Inhalation Anesthetics
• Current ones are nitrous oxide gas
• There are five volatile liquids:
• Isoflurane, halothane, desflurane, enflurane, and
sevoflurane
• Vapors are administered by anesthesia machine
• These produce a dose related depression of all
CNS functions. Result in amnesia and
unconsciousness
Inhalation Anesthetics
• Anesthetic action involves alteration of the
physiochemical processes of nerve
membranes
• There is a linear relationship between
potency and solubility in lipid
• There is a potential for abuse for nitrous
oxide (whippets)
Injectable Anesthetics
• Pentothal, Brevital, Diprovan, and Amidate
are injectable anesthetics that are available
• Mechanism of action of all these probably
involves intense CNS depression produced
secondary to facilitation of GABAa receptor
activity and to depression of excitatory
glutamate synaptic transmission
Gamma hydroxybutyric acid
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•
•
•
•
GHB is a potent CNS depressant
Structure similar to GABA
Freely crosses the blood-brain barrier
GHB increases dopamine levels in the brain
Widely implicated as a date rape drug
Antiepileptic Drugs
• Seizures are manifestations of electrical
disturbances in the brain
• Drugs suppress epileptic seizures in one of two
mechanisms:
• 1) limit the repetitive firing of neurons by
blocking sodium ion channels, thereby blocking
the depolarizing action of the ions
• 2)Enhancing GABA mediated synaptic inhibition
by reducing the metabolism of GABA, enhancing
the influx of chloride ions, or facilitating GABA
release from presynaptic nerve terminals
Antiepileptic Drugs
• Antiepileptic drugs are used in the treatment
of bipolar disorder and a variety of
explosive psychological disorders
• These disorders can be treated with CNS
depressants that stabilize neuronal
membranes either by facilitating inhibition
or by limiting excitation
Structure and Activity
• More recently introduced antiepileptic drugs were
developed because they either resembled GABA
structurally, or acted on GABA receptors to
potentiate GABA neurotransmission
• These drugs include valproic acid, gabapentin,
lamotrigine, and felbamate
• Barbiturates are used occasionally to reduce
seizures. An example would be phenobarbital, the
first effective antiepileptic drug
New Antiepileptic Drugs
• Several new drugs being evaluated are
steroid derivatives referred to as epalons.
• Epalons facilitate GABA activity. They are
devoid of hormonal action
• They exert anxiolytic, sedative, and
anticonvulsant effects
Antiepileptic Drugs in Pregnancy
• Children of epileptic mothers who received
antiseizure medication have an increased
incidence of a variety of birth defects
• Likelihood of birth defects increases from
2-3% for the general population to 7% when
the mother takes antiepileptic drugs during
pregnancy