Chapter 5

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 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