Tranquilizers and SedativeHypnotics Barbiturates Prof Farsi T Abachi

Tranquilizers and Sedative-Hypnotics Barbiturates Prof. Farsi T. Abachi PHD Pharmacy 2015

Barbiturates • All derivatives of Barbituric acid • Produce a wide spectrum of central nervous system depression, from mild sedation to coma. • Nonspecific depressant. • In moderate amounts, these drugs produce a state of intoxication that is remarkably similar to alcohol intoxication. Symptoms include: 1 - Slurred speech 2 - loss of motor coordination 3 -Impaired judgment. • Barbiturates were widely diverted from medical use and used on the street in the 60 s where they were called “downers” and sold under a variety of different names.

History Barbituric acid was first created in 1864 by a German • scientist named Adolf von Baeyer. It was a combination of urea from animals and malonic acid from apples. Its first derivative utilized as medicine was used to put • dogs to sleep but was soon produced by Bayer as a sleep aid in 1903 called Veronal • Phenobarbital was soon discovered and marketed as • well as many other barbituric acid derivatives Prescribed as sedatives, anesthetics, anxiolytics, and • anti-convulsants Also popular and abused in pop culture because of their • alcohol like effects

Classification of ba 1 - long acting BA over 6 h • E. g. Phenobarbital • 2 - Intermediate acting BA 3 -6 h • Eg. Butabarbital • 3 - Short acting BA 0, 5 -3 h • E. g. Cyclobarbital • 4 -Ultrashort acting BA less than 30 min. • E. g. Thiapental •

Synthesis of BA. Malonic Acid Urea Barbituric Acid Barbituric acid is synthesized by a condensation reaction that results in the release of H 2 O (dehydration) and the heterocyclic pyrimidine Further substitution of side chains on the ring produce the pharmacologically active barbiturates

General SAR of Barbiturates

5, 5 dihydrogen BA is unactive • 5, 5 dihydrogen thio BA is unactive • 1, 3 di substituted BA is not active • 1, 3 disubstituted thio BA is not active • 1, 3, 5, 5 tetra substituted thio BA is not active • Only 5, 5 disubstituted is active •

- 5, 5 disubstituted with R 2 & R 3 for maxiumum activity • - R= C 5—C 6 long chain for good activity, and enhance potency. C 9 • increase lipophlicity. - Branching of R , cyclic or uncaturated C=C • Enhanced short duration of action • - N-methyl decrease activity of BA • -Replace ( S ) in position 2 ( thiopental) on set of action • Replace phenyl group increase duration e. g. phenbarbital. • •

Barbiturate products 1 - phenobarbital ( Luminal ) • 5 -ethyl 5 -phenyl BA • 2 - Butabarbital • 5 -ethyl 5( 1 methyl butyl)BA • 3 - Thiopental • 5 -ethyl 5(1 -methyl pentyl)BA • •

Metabolism of BA 1 - Ring hydroxylation • 2 - Omega & Omega -1 oxidation • 3 - Desulfuration • 4 - Ring Closure ( Opening ) •

Uses: • Sedatives, hypnotics, anesthetics and anticonvulsants. • The primary differences among many of these products are how fast they produce an effect and how long those effects last. Barbiturates are classified as ultrashort, intermediate, and long-acting. • The ultrashort-acting barbiturates produce anesthesia within about one minute after intravenous administration. • Those in current medical methohexital (Brevital®), thiamyl (Surital®) and thiopental (Pentothal®).

• Barbiturate abusers prefer short-acting and intermediate-acting barbiturates that include • Amobarbital (Amytal®), pentobarbitalts (Nembutal®), secobarbital(Seconal®), and Tuinal (an amobarbital/secobarbital combination product). • After oral administration, the onset of action is from 15 to 40 minutes, and the effects last up to six hours. These drugs are primarily used for insomnia and preoperative sedation. Veterinarians use pentobarbital for anesthesia and euthanasia. • Long-acting barbiturates include phenobarbital (Luminal®) and mephobarbital (Mebaral®), Effects of these drugs are realized in about one hour and last for about 12 hours, and are used primarily for daytime sedation and the treatment of seizure disorders.

How are Barbiturates Consumed? • Orally – In pill, tablet or liquid form • Injection – • Into the blood stream • Into muscle tissue • Directly under the skin • Inserted into the body via suppository.

Short term effects • Small doses relieve tension; large doses produce drowsiness, staggering, blurred vision, impaired thinking, slurred speech, impaired perception of time and space, slowed reflexes and breathing, and reduced sensitivity to pain. • Overdoses can cause unconsciousness, coma and death.

Long-Term Effects • Long-term, high-dose use may result in effects similar to chronic intoxication (impaired vision, memory and judgment, and slurred speech), as well as depression or mood swings. Changes in liver function may result in faster metabolism of other drugs. Babies of chronic users may have difficulty in breathing and feeding, disturbed sleep patterns, sweating, irritability and fever.

dependence • Regular use induces tolerance, making increased doses necessary to produce the desired effect. • The margin between an effective dose and a lethal dose gradually narrows. Psychological dependence can occur with regular use, as can physical dependence. Withdrawal symptoms including restlessness, anxiety, insomnia, delirium, seizures and may result in death. Marilyn Monroe died of barbiturate overdose in 1962

3 - miscellenous sedative-hypnotics There are many types of sedative non-BA • 1 -Imides • 2 -Amides • 3 -Alcohols • These types are similar in structure , characteristics, and chemical • properties.

1 - Imides • 3 - ethyl -3 -phenyl glutaimide • It is effective as sedative-hypnotic • At high doses will be toxic •

2 - Amides ( Carbamate ) • 2 -Methyl 2 - propyl 1, 3 propandiol dicarbamate • A carbamate with hypnotic, sedative, and some muscle relaxant • properties, although in therapeutic doses reduction of anxiety rather than a direct effect may be responsible for muscle relaxation. Meprobamate has been reported to have anticonvulsant actions against petit mal seizures, but not against grand mal seizures.

3 - Alcohol • Ethchlorvynol is a sedative and hypnotic drug. It has been used to • treat insomnia. 1 -chloro-3 -ethyl -1 -propene- 4 -yne-3 -ol.

Another example for alcohol is chlorohydrate • Trichloro gem diol ( Two OH at same c atom) •