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 ( 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 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 1970’s-1990’s

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