Barbiturates

Malonic acid + urea à barbituric acid

Pharmacology

1. CNS

Sedation àsleepàanaesthesiaàcoma. Depress whole CNS, reticular activating system most affected. Decreases time to fall asleep & increases duration. Night awakenings are decreased. Sleep is arousable; Hangover (dizziness, irritability). Decrease in REM and stage 3 & 4. REM-NREM rhythm upset . Small doses: sedation, decreases anxiety, excitability. Impair learning, short term memory and judgement. Euphoria in addicts. Hyperalgesia in patients with severe pain. Anticonvulsant action [independent of CNS depression]

Mechanism of action of Barbiturates

Act on GABA:BZD chloride channel complex, Potentiates GABA mediated inhibition; increase Cl- conductance (GABA Mimetic action)

Inhibits Ca++ induced transmitter release

Depresses glutamate induced depolarisation via AMPA receptors

At high concentration depress Na+ and K+ also

2. Respiration: Affected only at higher doses. They don’t have selective antitussive action

3. CVS: Hypnotic doses cause only slight decrease in BP, HR; Toxic doses àganglionic blockade àmarked ¯BP. Cardiac arrest occurs at 3 times the dose of respiratory failure

4. Skeletal Muscles: Hypnotic dose have little effect on the muscles

5. Smooth muscles: At hypnotic dose GI motility slightly reduced

6. Kidney: Increases ADH + decrease in BP à decreased urine [poisoning à oliguria]

Kinetics of barbiturates

Well absorbed from GIT, widely distributed. CNS entry is depends on lipid solubility. [thiopentone instantly enters CNS à GA; phenobarbitone enters slowly]. Crosses placenta & secreted in milk.

Termination of action is by following:

Redistribution from CNS à decreases duration of action. Metabolism: in liver, by CYP; auto inducer of CYP. Excretion: lipid insoluble ones excreted unchanged. Induces hepatic microsomal enzymes

Uses of Barbiturates

1. Hypnotic to control mania/delirium – now superseded by BZD.

2. Sedative: Adjuncts; replaced by BZD

3. Anticonvulsant: phenobarbitone in epilepsy: important

4. General Anesthesia: [Thiopentone] & Preanesthetic

5. Congenital non hemolytic jaundice & kernicterus: induces conjugation of bilirubin

and decreases jaundice

ADRs of Barbiturates

Side effects: Hangover, mental confusion, impaired performation, road accidents. Idiosynchratic: Occasional stimulation. Hypersensitivity, Rashes, swelling of eyelids, lips, Tolerance, Cellular and Pharmacokinetic tolerance with repeated doses Partial cross tolerance with CNS depressants. Dependence: Physical and psychological dependence; addiction,

Withdrawal symptoms: Excitement, delirium, hallucination, convulsions,

Acute Barbuturate poisoning: Mainly suicidal and drug automation. Flabby and

comatose, shallow respiration, CVS collapse, fall in BP, renal shutdown

Treatment

Gastric lavage, activated charcoal, Assisted respiration, oxygen, vasopressors e.g., dopamine, Forced alkaline diruresis, Mannitol + sodium bicarbonate, Haemodialysis

Contraindications for barbiturates: Porphyria, liver kidney disease, Emphysema,

obstructive sleep apnoea

Drug Interactions

1. Microsomal enzyme inducer à increases metabolism of tolbutamide, griseofulvin, chloramphenicol & theophilline

2. Additive with depressants e.g. Alcohol, opioids, antihistaminics

3. Valproate à increases plasma concentration of barbiturates

Category: Pharmacology Notes