Sedatives, Anxiolytics & Drugs of Abuse MCQ

Central nervous system pharmacology covers the anxiolytics and sedatives dentists use (benzodiazepines, nitrous oxide), the opioids and their reversal (naloxone), and the substances of abuse a clinician will meet in practice. The dominant target is the GABA-A receptor, where benzodiazepines and barbiturates potentiate inhibition; nitrous oxide and ketamine act mainly through NMDA antagonism. The substance-use cases are also pharmacology cases: cocaine and methamphetamine stack with epinephrine to drive hypertensive crises and arrhythmias, ethanol interacts with metronidazole and warfarin, and chronic cannabis use changes the chairside dental encounter.

Benzodiazepines and Flumazenil

• Benzodiazepines bind allosterically at the GABA-A receptor and increase the frequency of chloride channel opening when GABA is present, producing anxiolysis, sedation, hypnosis, anticonvulsant effects, and skeletal muscle relaxation.
• Common dental benzodiazepines are triazolam (oral preoperative anxiolysis), midazolam (IV/IM/IN for moderate sedation, short acting), and diazepam (older long-acting agent); lorazepam is used for status epilepticus and acute anxiety.
• Triazolam (oral) and midazolam are metabolized by CYP3A4 and are markedly potentiated by grapefruit juice, azole antifungals, and macrolides; oxazepam and lorazepam ('LOT' agents) skip phase I metabolism and are preferred in liver impairment.
• Flumazenil is the competitive benzodiazepine antagonist for reversal of oversedation; it has a short half-life relative to many benzodiazepines, so monitor for re-sedation, and it can precipitate seizure in chronic benzodiazepine users.

Barbiturates and the GABA Story

• Barbiturates also act at GABA-A but INCREASE THE DURATION of chloride channel opening; at high concentrations they directly activate the channel even without GABA, which is why they have a much lower therapeutic index than benzodiazepines.
• Phenobarbital is still used for seizures in some settings; thiopental is the classic short-acting IV induction agent (now largely replaced by propofol).
• Barbiturates are potent CYP inducers, especially CYP3A4 and CYP2C9, which lowers the levels of many co-administered drugs (including warfarin and oral contraceptives).
• Acute barbiturate overdose is dangerous because there is no specific antagonist (flumazenil does not reverse barbiturates); supportive care and respiratory support are the mainstays.

Nitrous Oxide

• Nitrous oxide produces analgesia and minimal-to-moderate sedation primarily through NMDA receptor antagonism (and stimulation of central opioid pathways); it has a rapid onset and rapid recovery because of low blood and tissue solubility.
• Routine dental titration uses 30 to 50 percent nitrous oxide in oxygen; the patient must always receive at least 30 percent oxygen and is given 100 percent oxygen for several minutes at the end of the appointment to prevent diffusion hypoxia.
• Diffusion hypoxia occurs because nitrous oxide rapidly washes out of the blood at the end of a case; if room air is breathed, the large volume of nitrous oxide dilutes alveolar oxygen, transiently lowering arterial oxygen saturation.
• Chronic recreational nitrous oxide abuse oxidizes the cobalt in vitamin B12, inactivating it and producing megaloblastic anemia and subacute combined degeneration of the spinal cord; nitrous oxide is also a known greenhouse gas and scavenging systems are used in the operatory.

Ketamine and the Dissociative Sedatives

• Ketamine is an NMDA receptor antagonist that produces a 'dissociative' anesthesia (eyes open, analgesia, amnesia) and is sometimes used in pediatric sedation and in emergency airway management.
• Ketamine is sympathomimetic: it raises blood pressure, heart rate, and cardiac output through indirect catecholamine release, which can be useful in shock but is a hazard in uncontrolled hypertension or coronary disease.
• Other ketamine effects include increased salivation (often co-administered with glycopyrrolate or atropine) and emergence reactions (vivid dreams, hallucinations), reduced by benzodiazepine premedication.
• Propofol (used in dental sedation and general anesthesia) is unrelated mechanistically (GABA-A potentiation with some other targets) but is mentioned for context; it has rapid onset and recovery, and the IV emulsion can sting on injection.

Ethanol Pharmacology and Drug Interactions

• Ethanol is metabolized to acetaldehyde by alcohol dehydrogenase and then to acetate by aldehyde dehydrogenase; methanol and ethylene glycol use the same pathway and produce toxic metabolites that are treated with fomepizole (or ethanol).
• Disulfiram inhibits aldehyde dehydrogenase, producing nausea/flushing/headache when alcohol is consumed (a deterrent); metronidazole, some cephalosporins, and griseofulvin produce a similar 'disulfiram-like' reaction.
• ACUTE ethanol intake INHIBITS hepatic CYP and can raise the levels of co-administered drugs (including warfarin), while CHRONIC heavy use INDUCES CYP (especially CYP2E1) and lowers levels (including warfarin, sometimes) and raises acetaminophen toxicity risk.
• Withdrawal from chronic heavy ethanol use can cause tremor, seizures, and delirium tremens; benzodiazepines are the first-line treatment.

Stimulants and Cannabis

• Cocaine blocks the reuptake of norepinephrine, dopamine, and serotonin; in dentistry the acute-intoxication concern is sympathomimetic stacking with epinephrine, producing hypertensive crisis and arrhythmia.
• Methamphetamine and amphetamines release catecholamines presynaptically; chronic methamphetamine use produces 'meth mouth,' a pattern of rampant smooth-surface and cervical caries from xerostomia, bruxism, and sugar cravings.
• Elective dental procedures with epinephrine are deferred during acute cocaine or methamphetamine intoxication; patients in long-term recovery can receive dental care with usual precautions.
• Cannabis (delta-9-tetrahydrocannabinol, THC) activates CB1 receptors centrally and peripherally; acute effects include tachycardia, dry mouth, and anxiety. Acute intoxication is a relative contraindication to epinephrine and elective sedation; chronic use is associated with xerostomia and caries.