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Barbiturates are sedative-hypnotics primarily utilized for sedation in critical patients and, less commonly, as anti-seizure agents. These drugs exert pronounced effects on the central nervous system and can induce severe cardiovascular and pulmonary depression**. Barbiturates function by binding to an allosteric site of GABA-A receptor--a separate allosteric site than alcohol and benzodiazepines. Unlike benzodiazepines, which enhance the frequency of channel opening, barbiturates extend ion channel opening in the presence of GABA.

Specifically, agents like phenobarbital latch onto a distinct allosteric site on the GABA-A receptor, amplifying GABA's effect. This results in heightened chloride ion movement across neuronal membranes, leading to hyperpolarization and subsequently suppressing synaptic transmission across the CNS. Thiopental, a rapid-onset barbiturate, is favored for induction of anesthesia. Additionally, barbiturates stimulate the CYP450 enzymes, potentially altering the metabolism of various drugs. However, their clinical application is curtailed by pronounced sedative side effects, including significant cardiovascular and pulmonary depression, as well as hypotension, and physical dependence. The significant side effect profile, coupled with the risk of tolerance and withdrawal, makes it prudent to exercise caution with barbiturates, especially in elderly patients or when used concurrently with other CNS depressants.

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What makes barbiturates potent inducers of the Cytochrome P450 system?

Barbiturates, exemplified by phenobarbital, are powerful inducers of the Cytochrome P450 system. Their mechanism involves promoting the synthesis of P450 enzymes. Consequently, the metabolic rate of drugs processed by these enzymes accelerates, potentially diminishing the efficacy of such drugs.

How do barbiturates bind to the GABA-A receptor and potentiate GABA-A transmission in the CNS?

Barbiturates interact with an allosteric site on the GABA-A receptor, separate from GABA's own binding location. This interaction augments the receptor's receptivity to GABA. As a result, there's an elongation in the time the GABA-A receptor stays open. This amplifies GABA-A transmission within the CNS, heightening its inhibitory activities and producing barbiturates' signature effects, including sedation and anesthesia.

Why are IV Barbiturates used for induction of anesthesia and in the management of seizures?

IV-administered barbiturates, like thiopental and phenobarbital, are chosen for anesthesia induction owing to their swift onset and brief action duration. Thiopental's lipid-friendly nature enables it to quickly penetrate brain tissues, ushering in prompt anesthesia. Phenobarbital exhibits similar traits, making it invaluable for promptly addressing seizures. In addition, primidone, a related barbiturate, serves as a remedy for both seizures and essential tremors.

What are the risks associated with barbiturates use?

Barbiturates, when administered, can precipitate profound cardiac and respiratory downturns, plummeting blood pressure, and intense CNS suppression, potentially culminating in a coma. These hazards are particularly pronounced in elderly patients. Prolonged barbiturate consumption can also foster tolerance—where escalating dosages become necessary to achieve an equivalent effect—and physical dependency, characterized by withdrawal symptoms upon abrupt cessation.

How does thiopental get rapidly redistributed in the body after administration?

Upon IV introduction, thiopental's high affinity for lipids facilitates its swift entry into the brain, navigating the blood-brain barrier. Yet, its plasma concentrations diminish rapidly as thiopental reallocates to other high blood flow tissues, including skeletal muscles and fat stores. This redistribution underpins its rapid action onset and fleeting anesthesia duration.