Pharmacology of Benzodiazepines and Anesthetics

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Questions and Answers

Which benzodiazepine is noted for having a short elimination half-life that makes it preferable as a hypnotic?

Estazolam

Triazolam (correct)

Lorazepam

Diazepam

What is the primary reason benzodiazepines with long half-lives may cause cumulative effects?

Short elimination half-lives

Increased urine excretion

Rapid conversion to active metabolites

Slow hepatic metabolism (correct)

Which of the following benzodiazepines is metabolized directly to inactive glucuronides?

Oxazepam (correct)

Chlordiazepoxide

Flurazepam

Midazolam

What consequence may result from multiple doses of benzodiazepines with long half-lives?

Excessive drowsiness Signup and view all the answers

What is the elimination half-life range of secobarbital in different individuals?

18-48 hours Signup and view all the answers

Which metabolic pathway is primarily involved in the metabolism of barbiturates?

Oxidation Signup and view all the answers

What is a common outcome of multiple dosing with barbiturates?

Cumulative effects Signup and view all the answers

In which of the following scenarios is glucuronide conjugation most significant for drug metabolism?

Benzodiazepines and barbiturates Signup and view all the answers

Which anesthetic is known to have little effect on uterine musculature?

Nitrous oxide Signup and view all the answers

What is the primary action of presynaptic voltage-gated sodium channels influenced by anesthetics?

Inhibit neurotransmitter release Signup and view all the answers

Which volatile anesthetic has a lesser tendency to produce arrhythmias?

Sevoflurane Signup and view all the answers

Which of the following inhaled anesthetics increases right atrial pressure in a dose-related manner?

Enflurane Signup and view all the answers

What does the blood:gas partition coefficient indicate regarding anesthetics?

Affinity for blood compared to inspired gas Signup and view all the answers

Which inhaled anesthetics are known to be the most respiratory depressants?

Isoflurane and enflurane Signup and view all the answers

How do volatile anesthetics generally affect renal function?

Decrease glomerular filtration rate Signup and view all the answers

What is the anesthetic-sparing effect of nitrous oxide?

Minimizes cardiac depressant effects Signup and view all the answers

What is required for sedative-hypnotics to induce sleep?

High enough doses Signup and view all the answers

Which barbiturates are noted for their rapid penetration of brain tissue when administered intravenously?

Thiopental and Methohexital Signup and view all the answers

Which benzodiazepines are commonly used in anesthesia?

Midazolam and Flurazepam Signup and view all the answers

What characterizes the anticonvulsant effects of certain benzodiazepines?

They inhibit the development of epileptiform activity Signup and view all the answers

What happens to respiratory and cardiovascular function at hypnotic doses in healthy patients?

Effects are comparable to natural sleep Signup and view all the answers

What is a common consequence of repeated exposure to sedative-hypnotics?

Decreased responsiveness leading to tolerance Signup and view all the answers

Which sedative-hypnotics may cause significant cardiovascular depression in hypovolemic states?

Normal doses in patients with cardiovascular diseases Signup and view all the answers

What characterizes partial cross-tolerance in sedative-hypnotics?

Tolerance occurs between sedative-hypnotics and ethanol Signup and view all the answers

What impact does a low extracellular pH have on local anesthetics?

It decreases the percentage of nonionized anesthetic. Signup and view all the answers

Which local anesthetic is NOT affected by the use of vasoconstrictors in terms of systemic absorption?

Prilocaine Signup and view all the answers

Which of the following local anesthetics has only surface action and does not penetrate through tissues effectively?

Benzocaine Signup and view all the answers

What determines the systemic absorption of injected local anesthetic?

Site of injection and drug-tissue binding. Signup and view all the answers

What major phase occurs after an initial rapid distribution of amide local anesthetics into highly perfused organs?

Slow distribution to moderately well-perfused tissues. Signup and view all the answers

Which anesthetic is classified as an ester local anesthetic?

Procaine Signup and view all the answers

Which pharmacological effect do vasoconstrictors like epinephrine have on local anesthetics?

They decrease tissue blood flow. Signup and view all the answers

Which of the following is a characteristic of amide local anesthetics?

They have rapid distribution after IV administration. Signup and view all the answers

What is the primary difference between sedatives and hypnotics?

Sedatives reduce anxiety, while hypnotics encourage sleep. Signup and view all the answers

Which of the following is a potential risk of excessive dosing with sedative-hypnotics?

Coma and death Signup and view all the answers

Which class of drugs includes Flumazenil?

Benzodiazepine antagonist Signup and view all the answers

What characterizes the dose-dependent effects of sedative-hypnotics?

They exhibit varying levels of CNS depression based on drug and dose. Signup and view all the answers

Which of the following substances is NOT classified as a barbiturate?

Zaleplon Signup and view all the answers

Which of the following is a melatonin receptor agonist?

Ramelteon Signup and view all the answers

Which of the following is a characteristic of benzodiazepines compared to barbiturates?

Benzodiazepines have a higher therapeutic index. Signup and view all the answers

What effect can treating with barbiturates at an increased dosage lead to?

General anesthesia Signup and view all the answers

What process leads to the more rapid elimination of local anesthetics from the body?

Acidification of urine Signup and view all the answers

Which of the following characteristics is TRUE about cocaine as a local anesthetic?

It is the first local anesthetic introduced into practice. Signup and view all the answers

What is one of the main mechanisms of action for local anesthetics?

Blocking voltage-dependent sodium channels Signup and view all the answers

What can lead to tachyphylaxis in local anesthetic administration?

Repeated injections causing extracellular acidosis Signup and view all the answers

What cardiovascular effect can result from the use of bupivacaine?

Severe cardiovascular toxicity Signup and view all the answers

Which of the following local anesthetics is likely to cause methemoglobinemia?

Prilocaine Signup and view all the answers

What adverse central nervous system effect can be caused by local anesthetics?

Nystagmus & muscular twitching Signup and view all the answers

Which local anesthetic is known for its intrinsic sympathomimetic action?

Cocaine Signup and view all the answers

Study Notes

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).

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Description

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.