What are Barbiturates drugs? Barbiturates are the derivatives of barbituric acid which is a condensation product of urea with malonic acid. Barbituric acid itself is devoid of any hypnotic activity.
Barbiturates drugs are hardly soluble in water; however, their sodium salts form alkaline solutions in water. Conventionally, they are divided according to their duration of action as:
- Long acting (8 hours or more) e.g. Phenobarbitonc.
- Intermediate acting (4 to 8 hours) e.g. Amylobarbitone, Butobarbitonc, and Pentobarbitone.
- Short acting (less than 4 hours) e.g. Secobarbitone (quinalbarbitone).
- Ultra short acting: Replacement of the oxygen attached to C2 by sulphur enhances markedly the lipid solubility of the compounds. Because of rapid onset and short duration of action, they are used for IV anesthesia, e. g., Thiopentone.
Barbiturates Mechanism of action
Barbiturates drugs Pharmacological actions
Barbiturates drugs act at multiple sites in the CNS and are less selective than BDZ.
Central Nervous System: Barbiturates can cause varying depth of depression of the CNS from a mild sedation through hypnosis to general anesthesia. Thus, they depress the CNS in a dose-dependent manner, acting at multiple sites.
Sedation and hypnosis: Phcnobarbitone given in small doses acts as a daytime sedative. Larger doses produce sleep. The sleep resembles natural sleep with characteristic sleep EEG pattern of high voltage and low frequency. However, they
Cause more reduction in duration of REM sleep and number of cycles than BDZ
Exhibit hangover (residual sedation and headache on waking) more than with BDZ.
Cannot induce sleep in presence of pain, whereas BDZ can; and
Cause rebound increase in REM sleep on sudden withdrawal; this can lead to increased dreaming and nightmares during the withdrawal period, especially in addicts. Further,
Hypnotic doses of barbiturates drugs produce motor in coordination.
Barbiturates drugs reduce anxiety but may cause distortion of judgement. They also impair vigilance and attention to external stimuli.
In old people and children, however, barbiturates may occasionally produce dysphoria or excitement and a state of confusion.
Anesthetic effect: Thiobarbiturates IV produce general anesthesia.
Anticonvulsant and antiepileptic effect: Barbiturates drugs administered in anesthetic doses inhibit or abolish drug induced convulsions and those due to epilepsy and tetanus. Phenobarbilone and mephobarbitone have a selective antiepileplic action in the prevention of grand mal epileptic seizures.
Barbiturates effects on Respiration: Respiration is normally maintained as a result of :
A neurogenic drive originating in the reticular activating system.
A chemical drive depending upon the concentration of carbon dioxide and pH of the arterial blood which directly modify the activity of the medullary respiratory center; and
A hypoxic drive mediated through the carotid and the aortic body chemoreceptors.
Spinal cord: Both the polysynaptic and the monosynaptic reflexes of the spinal cord are depressed by barbiturates drugs.
Gastrointestinal tract: They do not affect the motility of the gut significantly.
Kidney: Barbiturate anesthesia results in reduction of urinary output as a result of decrease in the GFR, and stimulation of secretion of ADH. Acute barbiturate poisoning is often associated with oliguria largely due to severe hypotension.
Liver: In patients intolerant of barbiturates drugs, hepatic involvement may occur along with dermatitis and damage to other parenchymatous organs.
Barbiturates drugs exert various actions on certain liver enzymes :
On acute administration, barbiturates drugs combine with various subtypes of CYP450 enzymes and competitively inhibit the metabolism of drugs and endogenous steroids.
Chronic administration causes induction of hepatic microsomal enzymes leading to inaclivation of certain drugs, including barbiturates themselves. This may explain the phenomenon of tolcrance to barbiturates.
They induce delta-amino-levulinic acid (A I A) synthetase, a mitochondrial enzyme, and aldehyde dehydrogenase, a cytoplasmic enzyme. Increase in ALA synthetase results in an increase in ALA and porphobilinogen synthesis. In patients suffering from acute intermittent porphyria, barbiturates may precipitate a severe attack resulting in paralysis and even death.
Phenobarbitone increases the hepatic glucuronyl transferase and the bilirubin- binding Y-protein and stimulates the metabolism of bilirubin.
Barbiturates drugs Absorption, fate and excretion
Barbiturates are weak acids and maximum absorption occurs from the stomach where the barbiturates exist in an unionized form.
Given orally, sodium salts are uniformly and rapidly absorbed but because of their extreme alkalinity, they may cause epigastric distress. Satisfactory absorption also occurs from the intestine and the rectum.
Following absorption, a fraction of the drug in blood is reversibly bound to plasma albumin. The barbiturates drugs are distributed in all tissues and body fluids. They readily cross the placental barrier and small amounts may be secreted in milk. No harmful effects on the suckling infant are known.
The factors which affect the distribution and fate of barbiturates drugs are their
- Lipid solubility.
- Degree of protein binding, and
- Extent of ionization.
The short acting barbiturates drugs are highly soluble in lipids. Hence, these compounds have a rapid onset of action. They are more rapidly metabolized, but at the same time tend to get completely reabsorbed by the kidney tubules.
Barbiturates drugs exist in the plasma in an ionized and a non-ionized form. An increase in pH (alkalinization) of blood and urine increases the ionization of the barbiturates drugs causing an efflux of barbiturates from the tissues such as brain into the plasma. The ionized form does not cross the biological membranes and is excreted in urine.
Side effects and Adverse reactions of barbiturates drugs
- Intolerance: They may cause excitement (with hypnotic doses) headache, nausea, vomiting, diarrhea and lassitude. Occasionally, barbiturates themselves may produce paroxysmal pain.
- Barbiturate Allergy
- Anemia: Prolonged phenobarbitone therapy may produce megaloblastic anemia which responds to folic acid.
- Depression of fetal respiration: Barbiturates drugs, if administered to a woman during labor, may depress the fetal respiration.
- Porphyria : Barbiturate administration may precipitate an attack of acute intermittent hepatic porphyria.
- Drug automatism : If a barbiturate is being employed as a hypnotic, because of confusion and amnesia, a patient may repeatedly take the barbiturate at night and poison himself. This phenomenon is known as drug automatism.
Drug interactions of barbiturates drugs
Important drug interactions are:
- Severe CNS depression: other CNS depressants (alcohol, benzodiazepines and antihistaminics) and monoamine oxidase inhibitors.
- Hepatic microsomal enzyme induction with diminished efficacy of other drugs