Benzodiazepines Overview

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Questions and Answers

What are the active metabolites produced by Diazepam?

Chlordiazepoxide

Temazepam (correct)

Oxazepam (correct)

Flurazepam

Which statement accurately describes the classification of BZDs based on their elimination half-life?

Long-acting BZDs have a half-life of 1-12 hours.

Short-acting BZDs have a half-life of 40-250 hours.

Intermediate-acting BZDs have a half-life of 12-40 hours. (correct)

All BZDs have a median elimination half-life of 1-12 hours.

What common side effect is associated with the use of BZDs?

Drowsiness (correct)

Extreme hallucinations

High blood pressure

Severe abdominal pain

What condition may develop due to long-term use of BZDs?

Tolerance Signup and view all the answers

Which of the following is a characteristic of delirium?

Impaired attention and cognition Signup and view all the answers

Which sedative-hypnotic medication is used for anesthesia induction?

Thiopental Signup and view all the answers

What effect does Barbiturate medication enhance in the body?

Gamma-aminobutyric acid (GABA) Signup and view all the answers

Which classification of Barbiturates has the longest elimination time?

Long-acting Signup and view all the answers

What is the approximate bioavailability of phenobarbital in adults?

90% Signup and view all the answers

What effect does repeated administration of phenobarbital have on its half-life?

It decreases the half-life. Signup and view all the answers

Which of the following adverse reactions is NOT associated with phenobarbital?

Severe asthma attacks Signup and view all the answers

What is the method of elimination for approximately 25% of phenobarbital from the body?

Renal excretion unchanged Signup and view all the answers

What should be included in the treatment of a phenobarbital overdose?

Supportive care and urinary alkalinization Signup and view all the answers

What is a known adverse effect of thiopental and thiamylal?

Histamine release Signup and view all the answers

Which enzyme's activity is increased due to chronic administration of phenobarbital?

Aminolevulinic acid synthetase Signup and view all the answers

Which tricyclic antidepressant has a half-life that generally exceeds 24 hours?

Amitriptyline Signup and view all the answers

What are the components of the opioid overdose triad?

Pinpoint pupils, respiratory depression, decreased level of consciousness Signup and view all the answers

Which type of receptors mediate sedation and respiratory depression?

Mu receptors Signup and view all the answers

Which administration route leads to peak effects within 5 to 10 minutes?

Intravenous administration Signup and view all the answers

Which of the following is a symptom associated with opiate toxicity?

Gastric aperistalsis Signup and view all the answers

What is the first priority in managing a patient who is comatose and in respiratory distress?

Control the airway Signup and view all the answers

What is the effect of highly lipid-soluble opiates in the body?

They tend to redistribute into fatty tissues Signup and view all the answers

What is the role of naloxone in opiate overdose management?

It reverses respiratory depression Signup and view all the answers

Which receptor type is responsible for the meditative effects such as hallucinatory experiences?

Sigma receptors Signup and view all the answers

What is the primary pharmacologic effect of sulfonylureas in managing type 2 diabetes?

Hyperinsulinemic state Signup and view all the answers

Which route of administration allows naloxone to take effect within minutes?

Intravenous, intramuscular, and subcutaneous Signup and view all the answers

What may be an early clinical finding in a patient experiencing sulfonylurea overdose?

Hypoglycemia Signup and view all the answers

Which option describes the correct timing for the onset of hypoglycemia after acute sulfonylurea overdose?

Less than 8 hours Signup and view all the answers

What role does activated charcoal play in the management of opiate overdose?

It binds to opiates to prevent absorption Signup and view all the answers

Which factor is NOT a risk for sulfonylurea-induced hypoglycemia?

Age under 18 years Signup and view all the answers

What should be the primary goal when managing a patient with sulfonylurea overdose?

Return to euglycemia Signup and view all the answers

What is the half-life of Nalmefene, an agent used to reverse opiate toxicity?

4 to 8 hours Signup and view all the answers

What is one ineffective conventional decontamination measure in cases of calcium channel blocker (CCB) toxicity?

Urinary alkalinization Signup and view all the answers

Which treatment may improve cardiac function and survival rates in cases of CCB overdose?

Hyperinsulinemic euglycemia (HIE) Signup and view all the answers

What role does glucagon play in managing CCB overdose?

It enhances myocardial contraction Signup and view all the answers

What is a potential consequence of antihypertensive overdose?

Refractory shock Signup and view all the answers

What mechanism does angiotensin II (AG II) utilize to raise blood pressure?

Enhanced catecholamine release Signup and view all the answers

Which agent is used to sequester lipophilic drugs in cases of calcium channel blocker toxicity?

Lipid emulsion infusion Signup and view all the answers

Which electrolyte disturbance is a common side effect of digoxin toxicity?

Hypokalemia Signup and view all the answers

What effect does methylene blue have in managing cardiovascular conditions?

Counteracts vasoplegia post coronary artery bypass Signup and view all the answers

Study Notes

Benzodiazepines (BZDs)

Diazepam, a long-acting BZD, produces active metabolites: oxazepam, desmethyldiazepam, and temazepam, which increase the duration of drug action.
Classified by elimination half-life:
- Short-acting: 1-12 hours
- Intermediate-acting: 12-40 hours
- Long-acting: 40-250 hours
Increased potency increases the risk of undesired effects.
Common side effects include drowsiness, lethargy, and fatigue.
Higher doses can lead to impaired motor coordination, dizziness, vertigo, slurred speech, blurry vision, mood swings, euphoria, hostile or erratic behavior.
Repeated doses over a prolonged period can lead to significant accumulation in fatty tissues.
Overmedication symptoms: impaired thinking, disorientation, confusion, slurred speech.
Long-term use can lead to tolerance, dependence, and withdrawal.
Neurotoxicity: anterograde amnesia, sedation, drowsiness, motor impairment, inattentiveness, ataxia.
More prominent in elderly populations due to metabolic changes associated with aging.
Loss of inhibition can lead to out-of-character behavior, increasing risk of dangerous situations.
High-risk sexual behavior and reckless driving.
Delirium: acute condition characterized by impaired attention and cognition, leading to increased morbidity, mortality, and longer hospital stays.

Barbiturates

Sedative-hypnotic medications used for treating seizure disorders, neonatal withdrawal, insomnia, preoperative anxiety, and inducing coma to address increased intracranial pressure (ICP).
Helpful in inducing anesthesia.
Thiopental, introduced in 1934, is used for general anesthesia induction.
Enhance postsynaptic GABA activity by interacting with alpha- and beta subunits of the GABA-A receptor.
Increase chloride ion flux, resulting in postsynaptic hyperpolarization.

Barbiturate Classifications

Ultra-short-acting: methohexital and thiopental.
Short-acting: pentobarbital and secobarbital.
Intermediate-acting: amobarbital and butalbital.
Long-acting: phenobarbital and primidone.

Barbiturate Pharmacokinetics

Absorption: Phenobarbital is rapidly absorbed with a time-to-peak concentration of 2 to 4 hours. Bioavailability is approximately 90% in adults.
Distribution: Highly lipid-soluble barbiturates cross the blood-brain barrier rapidly but rapidly redistribute to peripheral tissues.
Metabolism: Oxidation is the primary biotransformation, terminating biological activity. Phenobarbital is metabolized by cytochrome P450. Repeated administration decreases half-life due to enzyme induction. Chronic administration increases aminolevulinic acid (ALA) synthetase, potentially exacerbating porphyria in patients with the condition.
Elimination: About 25% of phenobarbital is excreted unchanged in the urine. Renal excretion can be increased by osmotic diuresis or urine alkalinization.

Barbiturate Adverse Effects

Phenobarbital monotherapy in pregnant women can correlate with congenital defects in infants.
Thiopental and thiamylal release histamine.
Thiopental extravasation can cause severe tissue necrosis. Treatment includes hyaluronidase and phentolamine.
Mild liver injury.
Severe adverse drug reactions: DRESS (drug reaction with eosinophilia and systemic symptoms), Stevens-Johnson syndrome, and toxic epidermal necrolysis (TEN).
Tolerance: gradual loss of effectiveness requiring dose increases to maintain the same effect. This is partly explained by liver enzyme induction.

Barbiturate Overdose

CNS depression, respiratory failure, hemodynamic instability.
No specific antidote exists, treatment involves supportive care and urinary alkalinization.
Multiple-dose activated charcoal is effective for phenobarbital and primidone overdose.
Hemodialysis and hemoperfusion may be considered in life-threatening toxicity.
During recovery, patients with chronic barbiturate misuse can experience seizures and autonomic instability.

Tricyclic Antidepressants

Rapidly absorbed from the gastrointestinal tract and undergo first-pass metabolism.
Highly protein bound with a large volume of distribution, resulting in a long elimination half-life exceeding 24 hours (31-46 hours for amitriptyline).
Large ingested quantities in self-poisoning alter pharmacokinetics.
Overdose symptoms: pinpoint pupils, respiratory depression, decreased level of consciousness ("opioid overdose triad").

Opioids

Opioid receptors:
- Mu: analgesia, euphoria, sedation, respiratory depression, gastrointestinal dysmotility, physical dependence.
- Kappa: analgesia, diuresis, miosis, dysphoria.
- Delta: analgesia, inhibition of dopamine release, cough suppression.
Sigma receptors are no longer considered opioid receptors due to naloxone's lack of antagonism.
Tolerance develops rapidly with opioids.

Opioid Toxicokinetics

Administration: IV, topical, inhaled, IM, oral.
Peak effects:
- IV: 5-10 minutes
- Oral: 90 minutes
- Nasal: 10-15 minutes
Absorption primarily occurs in the small intestine with oral administration.
Liver breakdown to inactive compounds excreted primarily by the kidneys.
Highly lipid-soluble, redistributing into fatty tissues and prolonging half-life.

Opioid Overdose Evaluation

History obtained from family, friends, bystanders, and emergency medical service providers: amount of drug ingested, congestion, ingestion time.
Respiratory depression, generalized CNS depression, miosis.
Examination: possible needle track marks if intravenous opiates are abused.
Peripheral vasodilatation can cause moderate to severe hypotension.
Nausea and vomiting due to gastric aperistalsis and slowed intestinal motility.

Opioid Overdose Management

Comatose and respiratory distressed patients require airway control before any other intervention.
Endotracheal intubation is recommended for patients unable to protect their airways.
Naloxone administered to reverse respiratory depression.
Lowest naloxone dose to reverse apnea is recommended to minimize agitation and aggression in drug abusers.
Restraints may be necessary in combative or violent patients.
ABCDE protocol followed for initial treatment.
Supportive care is the primary initial treatment.
Activated charcoal can decontaminate the gastrointestinal tract.
Whole bowel irrigation may be considered in cases of drug packets containing opiates.

Naloxone

Competitive opioid receptor antagonist.
Administration routes: IV, IM, subcutaneous, intranasal.
Onset of action within minutes regardless of route (endotracheal or IV).
Second dose can be administered every 2-3 minutes.
Nalmefene is a newer agent with a longer half-life (4-8 hours).

Sulfonylureas

Mainstays in type 2 diabetes management.
Hyperinsulinemic effect is the primary pharmacologic effect.
Overdose primarily results in hypoglycemia due to subsequent hyperinsulinemia.
Bind to the sulfonylurea receptor on pancreatic beta cells, reducing adenosine 5′-triphosphate conductance.

Sulfonylurea Overdose

Key factors: onset and duration of action.
Peak plasma concentrations occur within 1-8 hours.
Hypoglycemia onset occurs within 8 hours.
Risk factors: advanced age (over 65 years), inadequate caloric intake, concurrent medication use (e.g., beta-blockers, insulin), recent sulfonylurea initiation.
Overdose prolongs duration of effect, but onset remains unchanged.

Sulfonylurea Overdose Clinical Findings

Hypoglycemic state.
Clinical response due to:
- Neuroglycopenic effects: direct reduction of intracellular ATP.
- Counterregulatory hormonal response: epinephrine, norepinephrine, cortisol, and growth hormone release.

Sulfonylurea Overdose Management

Goal is to restore euglycemia.
Activated charcoal binds sulfonylureas to prevent absorption.

Calcium Channel Blockers (CCBs)

Overdose can lead to: seizures, myocardial infarction, acute respiratory distress syndrome (ARDS), renal failure, bowel infarction and ischemia, stroke.
Endotracheal intubation may be considered for worsening toxicity due to rapid hemodynamic deterioration risk.
Atropine is mostly ineffective in severe CCB toxicity.
IV crystalloids should be used for initial resuscitation while being aware of fluid overload risk due to drug-induced inotropic failure.
Conventional decontamination measures are ineffective.
Calcium may improve hypotension and conduction disturbances but is less effective in bradycardia.
Hyperinsulinemic euglycemia (HIE) can improve cardiac function and survival rate.
Methylene inhibits guanylate cyclase, counteracting post-coronary artery bypass vasoplegia.
Lipid emulsion infusion can sequester lipophilic drugs like verapamil and diltiazem, reducing their volume of distribution.

Glucagon and CCB Overdose

Glucagon from pancreatic alpha cells activates adenylate cyclase via G proteins, leading to positive chronotropic and inotropic effects.
Improves heart rate, cardiac output, and reverses AV blocks in animal models of CCB overdose.
Refractory hypotension and shock may require catecholamine infusion.
Phosphodiesterase inhibitors like milrinone can provide inotropic support.
Levosimendan enhances myofilament response to calcium and increases myocardial contraction.

Antihypertensive Overdose

Can lead to shock refractory to catecholamine and vasopressin therapy.
Antihypertensives can be both vasodilatory and cardiotoxic in overdose.
IV Angiotensin II (AG II) has been used to treat shock.
AG II increases aldosterone secretion, raises blood pressure via various mechanisms: antidiuretic hormone secretion, vasoconstriction via a G-protein coupled receptor, enhanced catecholamine release.

Digoxin

Cardiac glycoside derived from the foxglove plant (Digitalis species).
Toxicity can present acutely after overdose or chronically in patients on digoxin who develop acute kidney injury.

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Description

This quiz focuses on benzodiazepines, including their classification based on elimination half-life, common side effects, and risks associated with use. It also highlights the neurotoxicity and long-term effects of these medications, particularly in elderly populations.