Pharmacology of Benzodiazepines and Anesthetics

CNS Pharmacology

• This lecture covers various drugs impacting the central nervous system.
• Included topics span general anesthetics, local anesthetics, sedative-hypnotics, anti-Parkinsonism drugs, antipsychotics, anti-depressants, anti-seizure medications, and alcohol.

Sedative-Hypnotic Drugs

• Sedative: an agent that reduces anxiety and exerts a calming effect.
• Hypnotic: an agent that produces drowsiness and encourages the onset and maintenance of sleep. More pronounced CNS depression occurs as dose increases.
• Graded dose-dependent depression of the CNS function is a defining characteristic of these drugs.
• Individual drugs' relationships between dose and CNS depression differ.
• Examples include older sedative-hypnotics (barbiturates and alcohols). Higher doses than needed for sleep can lead to general anesthesia. Further increases can cause medullary depression, triggering coma and death.

Benzodiazepines

• A widely-used group of sedative-hypnotics.
• Structures often include a 1,4-benzodiazepine, with a 7-membered heterocyclic ring structure.
• A substituent in the 7 position (like a halogen or nitro group) is crucial for sedative-hypnotic activity.
• Specific examples given include: Clorazepate, Chlordiazepoxide, Diazepam, Flurazepam, Alprazolam, Clonazepam, Estazolam, Lorazepam, Oxazepam, Temazepam, Triazolam, and Nitrazepam.

Barbiturates

• Examples include: Amobarbital, Butabarbital, Pentobarbital, Secobarbital (short-intermediate acting), Mephobarbital, Phenobarbital (long-acting), and Thiopental (ultra-short acting).
• With the exception of phenobarbital, most are excreted unchanged, rather than metabolized.
• Metabolism involves hepatic enzymes forming alcohols, acids, and ketones, excreted as glucuronide conjugates in the urine.

Newer Hypnotics

• Include Eszopiclone, Zaleplon, Zolpidem.
• Ramelteon, and Tasimelteon
• Suvorexant and Almorexant
• Buspirone (5-HT receptor agonists)

Other Sedative-Hypnotics

• Glutethimide and meprobamate are similar in function to barbiturates but less frequently used.
• Ethanol and chloral hydrate are additional drugs with sedative-hypnotic properties.
• Antipsychotics and antidepressants are currently used in cases of chronic anxiety. Antihistamines like Hydroxyzine and Promethazine also have peripheral effects

Biotransformation

• Converting sedative-hypnotics to more water-soluble forms is essential for excretion via the kidneys.
• Elimination half-lives depend primarily on the rate of biotransformation.
• For benzodiazepines, hepatic metabolism is common, with microsomal oxidation (phase I reaction) being frequent, especially involving CYP3A4. Metabolites are then conjugated (phase II reaction).

Newer Hypnotics (continued)

• Metabolites like desmethyldiazepam can be pharmacologically active and have prolonged half-lives (over 40 hours).
• The metabolism of benzodiazepines like alprazolam/triazolam results in short-lived active metabolites quickly conjugated into inactive glucuronides.
• Zolpidem, zaleplon, and eszopiclone are rapidly metabolized into inactive forms via oxidation and hydroxylation by hepatic cytochrome P450 enzymes, often CYP3A4.

Cumulative and Residual Effects of Benzodiazepines

• Extended half-lives of certain drugs can lead to cumulative effects like excessive sleepiness with multiple doses
• Drugs like estazolam, oxazepam, and lorazepam have short half-lives, leading to reduced buildup and less cumulative effects

Drug Interactions

• Interactions with other CNS depressants are common.
• These can lead to additive effects, sometimes useful in anesthetic practice as adjuvants (combined approaches).
• Interactions can lead to dangerous consequences, especially with the enhanced depression with multiple drug use.
• Certain interactions (additive effects) can be predicted/identified (alcoholic drinks, opioids, anticonvulsants, phenothiazines). Other less obvious ones may also occur with antihistamines, antihypertensives, and TCA antidepressants.

Excretion

• Water-soluble metabolites are primarily excreted via the kidneys.
• Phenobarbital, though, is often excreted nearly unchanged.
• Urinary alkalinization can affect the elimination rate of phenobarbital.

Mechanism of Action

• Benzodiazepines amplify GABA's effect on chloride channels, enhancing their opening frequency.
• Barbiturates increase the duration of chloride channel opening caused by GABA.
• High concentrations of barbiturates may directly increase chloride conductance. This also blocks calcium-dependent neurotransmitter release
• High concentrations suppress voltage-sensitive sodium and potassium channels.

Organ-Level Effects

• Sedation: Low doses of benzodiazepines, barbiturates, and other sedative-hypnotics calm and decrease anxiety, but also affect psychomotor and cognitive function
• Hypnosis: High doses of sedative-hypnotics induce sleep.
• Anesthesia: High doses of certain drugs can cause deep CNS depression (stage III).
• Anticonvulsants: Reduce and regulate seizure activity. Specific drugs (BZs) and phenobarbital treat generalized tonic-clonic seizures.
• Muscle relaxation: Some sedative hypnotics limit muscle activity.

Tolerance and Physiological Dependence

• Tolerance reduced responsiveness to the drug from repeated use. Higher dose needed to maintain effect.
• Physiological dependence continuous use is needed for preventing withdrawal or abstinence syndrome. Common symptoms include anxiety, insomnia, CNS excitability (potentially convulsions).

Clinical Uses

• Sedative-hypnotics are key in anxiety relief, sleep disorders, pre/intra-surgery procedures, epilepsy/seizure managements, and diagnostic/psychiatric uses.

General Anesthetics

• Analgesia decreased pain awareness, sometimes with amnesia.
• General anesthesia complete state of unconsciousness, analgesia, amnesia, skeletal muscle relaxation, loss of reflexes.
• Stages: Analgesia, Excitement, Surgical Anesthesia, and Medullary Depression.
• Balanced anesthesia: combines pre-operative meds, neuromuscular blockers, inhaled and IV anesthetics.
• Types of IV Anesthetics: Barbiturates (Thiopental, Methohexital), Benzodiazepines (Midazolam, Diazepam), Propofol, Ketamine, Opioid analgesics (Morphine, Fentanyl, Sufentanil, Alfentanil, Remifentanil), Miscellaneous sedative hypnotics (Etomidate, Dexmedetomidine, Droperidol)
• Inhalation Anesthetics: Volatile liquids (Halothane, Enflurane, Methoxyflurane, Isoflurane, Desflurane, Sevoflurane) and Gas (Nitrogen oxide).

Mechanisms of Action: General Anesthetics

• Inhibiting presynaptic voltage-gated sodium channels in the glutamatergic synapse. Disrupts neurotransmitter release.

Solubility: General Anesthetics

• Blood-gas partition coefficients describe an anesthetic's relative affinity for blood vs. inspired gas. A lower coefficient indicates lower solubility and faster response.

General Anesthetics: Organ Level Effects

• CNS: Inhibit motor and autonomic systems, depressing respiratory functions while increasing cerebral blood flow.
• Cardiovascular (CV): Hypnotic doses affect heart rates similarly to natural sleep. Larger doses can, however, affect patient with heart conditions and lead to depression.
• Urinary System effects on glomerular filtration rate depending on concentration.
• Respiratory: Generally depress respiration; effects can be managed mechanically by assisted or controlled ventilation.
• Liver: Some anesthetics are hepatotoxic, leading to possible effects like jaundice and impaired liver function.
• Malignant hyperthermia: A life-threatening condition that can develop during induction with certain drugs.
• Reproductive System: Risk for miscarriage/abortion with long-term exposure.
• Blood: Nitrous oxide can cause methionine synthase deficiency and megaloblastic anemia.

Toxicity and adverse effects

• Barbiturates: lightheadedness, dizziness, drowsiness, unusual excitement, bleeding sores, chest pain, skin rash, muscle/joint pain, sore throat, swollen facial areas.
• Benzodiazepines: sedation, ataxia, anterograde amnesia, lightheadedness, paradoxic excitement in children, menstrual irregularities.
• Local anesthetics: sleepiness, lightheadedness, sedation, visual/auditory disturbances, circumoral/tongue numbness, metallic taste, restlessness, nystagmus, muscle twitching, tonic-clonic convulsions, altered cardiac/CVS functions.
• Flumazenil: agitation, confusion, and nausea (important for reversing effects of overdose)

Additional Notes

• FDA classifications of these drugs exist in terms of pregnancy risks (categories).

This quiz explores the pharmacological properties of benzodiazepines, such as their elimination half-lives and metabolism, as well as anesthetic agents and their effects. Test your knowledge on key concepts related to drug interactions, half-lives, and metabolic pathways in this specialized area of pharmacology.