Barbiturates, General Anesthetics, and Antiepileptic Drugs

1
Chapter 5

• Barbiturates, General Anesthetics, and
  Antiepileptic Drugs

2
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

3
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)

4
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

5
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

6
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)

7
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)

8
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)

9
Pharmacokinetics

• Barbiturates are classified by their
  pharmacokinetics
• Short half-lives (thiopental has 3 minute
  redistribution half-life)
• Longer half-lives (48 hour elimination half-life
  for pentobarbital)
• Very long half lives (24-120 hour elimination
  half-life for phenobarbital)

10
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

11
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

12
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

13
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

14
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

15
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

16
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

17
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 1970s-1990s

18
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

19
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

20
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

21
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)

22
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

23
Gamma hydroxybutyric acid

• 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

24
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

25
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

26
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

27
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

28
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