Barbiturates

1. Barbiturates 4th Year Pharmacy 2015-2016

2. Introduction • The barbiturates were used extensively as sedative–hypnotic drugs. Except for a few specialized uses, they have been replaced largely by the much safer benzodiazepine. • Barbiturates act throughout the CNS

3. Ⅱ.BARBITURATES Classification • Ultra-short-acting barbiturates: act within seconds, and their duration of action is 30min. Therapeutic use of Thiopental: anesthesia • Short-actingbarbiturates: have a duration of action of about 2h. The principal use of Secobarbital : sleep-inducing hypnotics.

4. (3)Intermediate-acting barbiturates: have and effect lasting 3-5h. The principal use of Amobarbital is as hypnotics. • (4)Long-acting barbiturates: have a duration of action greater than 6h. Such as Barbital and Phenobarbital. Therapeutic uses: hypnotics and sedative, and antiepileptic agents at low doses

5. BARBITURATES Barbiturates depress the CNS at all level in a dose-dependent fashion. Now it mainly used in anaesthesia and treatment of epilepsy; use as sedative-hypnotic agents is no longer recommended.

6. BARBITURATES Reasons: (1) have a narrow therapeutic-to-toxic dosage range. (2) suppress REM sleep. (3) Tolerance develops relatively quickly. (4) have a high potential for physical dependence and abuse. (5) potent inducers of hepatic drug-metabolizing enzymes.

7. MECHANISM OF ACTION (1) Barbiturates share with benzodiazepines the ability to enhance the action of GABA, but they bind a different site on the GABA-receptor/chloride channel, and their action seems to prolong the duration of the opening of GABA-activated chloride channels.

8. MECHANISM OF ACTION (2) At high doses, barbiturates can inhibit the release of the Ca2+-dependent neurotransmitter.

9. Synthesis of Barbiturates • Diethyl malonate + Urea = B.A.

10. Barbiturates Barbiturates are 5,5 disubstituted barbituric acid

11. Structure activity relationship of BA • General SAR • 1- 1,3 disubstituted barbiturate is inactive • 2-1,3 disubstituted thio barbiturate is inactive • 3- 5-mono substituted BA is inactive • 4- 5-mono substituted thio BA is inactive • 5- 1,3,5 trisustituted BA is inactive • 6-1,3,5 trisubstituted thio BA is inactive. • 5,5,disubstituted BA is active • 5,5 disubstituted thio BA is active.

12. Position 2 O, S • Increase lipophlic Thio barbituate increase onset ( Thiopental) • Position 5 • 1. Both hydrogen atoms at position 5 should be substituted (pka ≈ 7.6). The unsubstituted or monosubstituted are very acidic (pka ≈ 4) so the compounds are largely ionized at physiological pHs, with little lipid soluble compound available to cross the BBB

13. . 2. Polar functions at C5. 3. Methylene and benzylidene moiety. 4. Substituents with total number of carbon atoms greater than 9

14. Metabolism of BA • 1- Ring Hydroxylation • 2- OMEG &OMEA -1 Oxidation • 3- Replacement O by S • 4- Ring cleavage • H.W: Draw equation for the metabolism?

15. Pharmacokinetics • High lipid solubility allows rapid transport across the blood-brain barrier and results in a short onset. • Removal from the brain occurs via redistribution to the other tissues results in short duration of action. • Barbiturates and their metabolites the excretion via the renal route. Alkalinization of the urine expedites the excretion of barbiturates. Treatment of acute overdosage: Sodium bicarbonate.

16. Therapeutic uses • Sedative-hypnotic agents • Be used in the emergency treatment of convulsions as in status epilepticus. • Anesthetic (or be given before anesthetic) • Combination with antipyretic-analgesic • Treatment of hyperbilirubinemia and kernicterus in the neonate.

17. Adverse effects • After effect: hangover---dizzy, drowsiness, amnesia, impaired judgment, disorientation. • Tolerance: decreased responsiveness to a drug following repeated exposure because of down-regulation of receptors and induction of hepatic drug-metabolising enzymes.

18. Adverse effects • Dependence: including psychological and physiologic dependence. Withdrawal symptoms: excitation, insomnia, tremor, anxiety, hallucinations and sometimes convulsions. • Depressant effect on respiration: can cross the placental barrier during pregnancy and secrete to breast milk. • Others: Skin eruptions and porphyria

19. Treatment of acute overdosage • An overdose can result in coma, diminished reflexes, severe respiratory depression, hypotension leading to cardiovascular collapse, and renal failure. • Treatment (A.B.C): (1) supporting respiration and circulation. (2) alkalinizing the urine and promoting diuresis. (3) Hemodialysis or peritoneal dialysis.

20. Ⅲ.Nonbarbiturate sedative-hypnotics • AMIDES AND IMIDES • Alcohols • Carbamate • Aldehyde

21. Ethchlorvynol, USP. • 1-chloro-3-ethyl-1-penten-4-yn-3-ol (Placidyl), • is a mild sedative–hypnotic with • a quick onset and short duration of action (t1/2 5.6 hours). • Because of its highly lipophilic character, it is extensively metabolized to its secondary alcohol (90%) prior to itsexcretion. It reportedly induces microsomal hepatic enzymes.

22. Amides & Imides • Glutethimide, 2-ethyl-2-phenylglutarimide • (Doriden), is one of the most active nonbarbiturate hypnotics that is structurally similar to the barbiturates,especially phenobarbital. Because of glutethimide’s low aqueous solubility, • Glutethimide is used as a racemic mixture with the ( +) enantiomer being primarily metabolized on the glutarimide ring and the ( - ) enantiomer on the phenyl ring.

23. Meprobamate, USP. • 2-methyl-2-propyltrimethylene dicarbamate, 2-methyl-2-propyl-1,3- propanediol dicarbamate (Equanil) • Meprobamate is also a centrally acting skeletal muscle relaxant. The agents in this group find use in several conditions, such as strains and sprains that may produce acute • muscle spasm

24. Aldehyde Chloral hydrate is 2,2,2 trichloroacetaldehyde. (1) relatively safe hypnotic, inducing sleep in a half hour and lasting about 6h. (2) used mainly in children and the elder, and the patients when failed to other drug.