Mechanism of Action and Pharmacokinetics of 25 mg

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Questions and Answers

What is the chemical name of propofol?

2,6-diisopropylphenol

What is the main mechanism of action of propofol?

Increases duration of GABA–activated opening of chloride channel

What is the primary route of excretion for propofol?

Kidneys

What is the elimination half-life of propofol?

Prolonged due to slow release of drug from the slow peripheral compartment Signup and view all the answers

Why is propofol's elimination half-life prolonged?

Due to slow release of drug from the slow peripheral compartment Signup and view all the answers

What is the context-sensitive half-time of propofol for infusions up to 8 hours duration?

< 40 minutes Signup and view all the answers

What is the main problem with the initial suspension of propofol in Cremaphor EL?

Anaphylactoid reactions Signup and view all the answers

How is propofol now provided to prevent anaphylactoid reactions?

In an emulsion of 1% propofol, 10% soybean oil, 2.25% glycerol, and 1.2% purified egg phosphatide Signup and view all the answers

What is the pH range to which propofol emulsion is adjusted?

7.0-8.5 Signup and view all the answers

What is the preservative added to propofol to prevent bacterial growth?

Disodium edetate (Diprivan) and sodium metabisulfite (Generic) Signup and view all the answers

What is the recommended dose of propofol for induction of anesthesia in healthy adults?

1.5-2.5 mg/kg Signup and view all the answers

What is the unconsciousness level for propofol concentration?

2-6 μg/ml Signup and view all the answers

At what propofol concentration does awakening occur?

1-1.5 μg/ml Signup and view all the answers

What is the recommended dose of propofol for maintenance of anesthesia?

100-300 μg/kg/min Signup and view all the answers

What is the effect of propofol on postoperative nausea and vomiting when used as a component of any anesthetic technique?

It is reduced Signup and view all the answers

What is the recommended dose of propofol for treatment of neuraxial opioid-associated pruritis?

10 mg Signup and view all the answers

What is the effect of propofol on systemic blood pressure?

Decreased Signup and view all the answers

What is the effect of propofol on intracranial pressure (ICP)?

Normal baseline ICP ~30% decrease Signup and view all the answers

What is propofol's effect on intraocular pressure (IOP)?

30-40% decrease Signup and view all the answers

What is the effect of propofol on memory impairment at equal sedation levels?

Propofol = Midazolam > Thiopental > Fentanyl (0) Signup and view all the answers

What is the recommended dose of propofol for attenuation of bronchoconstriction in asthmatic patients?

Appropriate for use in asthmatic patients Signup and view all the answers

What is the mechanism of propofol's neuroprotection?

Antioxidant activity, resulting in free radical scavenging and subsequently reduced free radical induced lipid peroxidation Signup and view all the answers

What is the likely effect of propofol on sympathetic tone compared to parasympathetic tone?

Decrease in sympathetic tone than parasympathetic Signup and view all the answers

What is the recommended action for handling propofol to prevent bacterial growth?

Strict aseptic technique required Signup and view all the answers

What are the potential side effects of propofol on pulmonary function in COPD patients?

May produce bronchodilation Signup and view all the answers

What is the possible consequence of propofol infusion at high doses for an extended period?

Propofol Infusion Syndrome Signup and view all the answers

What is the proposed mechanism behind Propofol Infusion Syndrome?

Poisoning of the electron transport chain by propofol or a metabolite Signup and view all the answers

What is the likely impact of propofol on the ventilation of a patient following induction?

Dose-dependent depression of ventilation Signup and view all the answers

What is the potential effect of propofol on the IOP (Intraocular Pressure)?

Decreased Signup and view all the answers

What is the effect of propofol on the neuromuscular blockers?

No potentiation Signup and view all the answers

What is the role of propofol in ischemic preconditioning and postconditioning?

May provide myocardial protection following ischemia and reperfusion Signup and view all the answers

What is the potential consequence of prolonged use of propofol in the ICU?

Contents of an opened ampule should be discarded after 6 hours Signup and view all the answers

What is the significant clinical feature of propofol infusion at high doses for an extended period?

Hepatomegaly Signup and view all the answers

What is the mechanism of action of propofol at supra-clinical doses?

May activate the GABAA receptor directly Signup and view all the answers

What are the potential benefits of etomidate for patients with compromised cardiovascular status?

Maintains or improves cerebral perfusion pressure and reduces intracranial pressure Signup and view all the answers

What is the primary effect of etomidate on cerebral blood flow?

Reduces cerebral blood flow by up to 35% Signup and view all the answers

How does etomidate affect the sympathetic nervous system and blood pressure?

It does not significantly affect the sympathetic nervous system or blood pressure Signup and view all the answers

What is the impact of etomidate on respiratory function compared to other induction agents?

It has fewer respiratory depressant effects, with less depression of ventilation and a decreased ventilatory response to CO2 Signup and view all the answers

How does etomidate affect cortisol and mineralocorticoid production?

Inhibits cortisol and mineralocorticoid production for up to 72 hours after a single induction dose Signup and view all the answers

What is the mechanism of action of etomidate on the GABA receptor?

Acts as a positive allosteric modulator, increasing the affinity of the receptor for GABA and resulting in increased chloride conductance and hyperpolarization of the postsynaptic cell membrane Signup and view all the answers

What are the properties of etomidate that make it useful for various indications?

Anxiolytic, sedative, anticonvulsant, skeletal muscle relaxation, and amnesic properties Signup and view all the answers

What are the potential effects of etomidate on seizure threshold to local anesthetic exposure?

Can increase seizure threshold to local anesthetic exposure Signup and view all the answers

What is the primary cause of a modest decrease in blood pressure due to etomidate administration?

Primarily due to decreased systemic vascular resistance Signup and view all the answers

How does etomidate affect the neuromuscular junction?

Minimal musculoskeletal effects, as skeletal muscle relaxation occurs via interaction with spinal interneurons, not at the neuromuscular junction Signup and view all the answers

What is the mechanism of action of flumazenil?

Acts as a competitive antagonist, preventing or reversing the effects of other benzodiazepines in a dose-dependent manner Signup and view all the answers

What is one of the main uses of flumazenil?

Reversing residual benzodiazepine-induced sedation and suspected benzodiazepine overdose Signup and view all the answers

What is the primary metabolite of midazolam, and what is its activity compared to the parent compound?

The primary metabolite is 1-hydroxymidazolam, which has approximately 50% activity of the parent compound. Signup and view all the answers

What drugs may delay the metabolism of midazolam?

Cimetidine, erythromycin, calcium channel blockers, and some anti-fungals may delay the metabolism of midazolam. Signup and view all the answers

What is the hepatic clearance of midazolam compared to diazepam and lorazepam?

The hepatic clearance of midazolam is 10 times greater than that of diazepam and 5 times greater than that of lorazepam. Signup and view all the answers

What are the clinical uses of midazolam for preoperative anxiolysis?

Midazolam is used as oral premedication in children and for nasal premedication. It is also used for IV sedation. Signup and view all the answers

What are the unique features of lorazepam compared to diazepam and midazolam?

Lorazepam has lower lipid solubility, resulting in delayed onset of effect in the CNS, and despite higher clearance and similar volume of distribution to diazepam, its effects last longer due to higher affinity for the GABA receptor. Signup and view all the answers

What is the principle metabolite of diazepam, and how does it compare to diazepam?

The principle metabolite of diazepam is desmethyldiazepam, which is only slightly less potent than diazepam. Signup and view all the answers

What may lead to prolonged elimination half-time of diazepam in patients?

Prolonged elimination half-time of diazepam may occur due to decreased protein binding with increased volume of distribution, decreased hepatic blood flow, or cirrhosis. Signup and view all the answers

What is the unique feature of lorazepam's metabolism compared to diazepam and midazolam?

Lorazepam is metabolized via hepatic glucuronidation to inactive metabolites, which are excreted by the kidneys. It is relatively unaffected by inhibition of cytochrome P-450 or changes in hepatic function. Signup and view all the answers

What are the clinical uses of lorazepam for induction, maintenance, and sedation?

Lorazepam is used for induction, maintenance, and sedation, with specific dosages for each purpose. Signup and view all the answers

What are the clinical uses of lorazepam for preoperative anxiolysis?

Lorazepam is used as oral premedication in adults. Signup and view all the answers

What is the dose range for midazolam induction and maintenance?

The induction dose for midazolam is 0.05-0.15 mg/kg, while the maintenance dose is 0.05 mg/kg as needed or 1 mcg/kg/min. Signup and view all the answers

What is the dose range for lorazepam induction, maintenance, and sedation?

The induction dose for lorazepam is 0.1 mg/kg, the maintenance dose is 0.02 mg/kg as needed, and the sedation dose is 0.5-1 mg repeated or 0.07 mg/kg IM. Signup and view all the answers

What is the adult induction dose of thiopental?

1-2 mg/kg Signup and view all the answers

What is the drug of choice for electroconvulsive therapy (ECT)?

Thiopental Signup and view all the answers

What is the potency of S(+) ketamine compared to R(-) ketamine?

4x greater affinity for phencyclidine binding site on NMDA receptor Signup and view all the answers

What is the primary mechanism of action of ketamine?

Produces dose-dependent CNS depression resulting in a 'dissociative state' Signup and view all the answers

What is the main receptor affected by ketamine?

NMDA Signup and view all the answers

What is the main pharmacokinetic characteristic of ketamine that contributes to its rapid onset of action?

High lipid solubility Signup and view all the answers

What is the primary route of metabolism for ketamine?

Hepatic microsomal enzymes Signup and view all the answers

What is the main active metabolite of ketamine?

Norketamine Signup and view all the answers

What is the main effect of ketamine on the voltage-gated sodium channels?

Mild local anesthetic-like effect Signup and view all the answers

What is the main mechanism by which ketamine is cleared from the body?

Rapid clearance in the liver Signup and view all the answers

How do barbiturates act on GABAA receptors at low concentrations?

They enhance the effect of GABA and decrease its dissociation rate. Signup and view all the answers

What is the primary mode of metabolism for barbiturates?

Hepatic oxidation Signup and view all the answers

What are the effects of barbiturates on the Central Nervous System (CNS)?

They cause proportional decreases in CMRO2 and CBF, reducing intracerebral pressure. Signup and view all the answers

How do barbiturates affect mean arterial pressure and intracerebral pressure?

They decrease mean arterial pressure less than ICP, improving cerebral perfusion. Signup and view all the answers

What is the maximum decrease in CMRO2 achieved by barbiturates in the CNS?

Around 50-55% Signup and view all the answers

What is the primary effect of barbiturates on the cardiovascular system?

They induce peripheral vasodilation and decreased contractility, increasing heart rate and decreasing cardiac output. Signup and view all the answers

Which intravenous induction agents cause dose-dependent respiratory depression?

All except ketamine and etomidate Signup and view all the answers

What are the mechanisms of neuroprotective effect of barbiturates?

Reverse steal (Robin Hood) effect, free radical scavenging, and liposomal membrane stabilization Signup and view all the answers

What are the contraindications for the use of barbiturates?

Severe cardiovascular instability or shock, porphyria, and allergic reactions Signup and view all the answers

What are the primary side effects and complications associated with barbiturate use?

Cardiovascular and respiratory side effects Signup and view all the answers

What are some other uses of barbiturates?

As a lethal injection combination, in truth serum, as a recreational drug, and as an intravenous induction agent Signup and view all the answers

What are the potential complications of thiopental infusions?

High context sensitivity and accumulation of the active metabolite pentobarbital with multiple bolus dosing or prolonged infusion Signup and view all the answers

Study Notes

Barbiturates act on GABAA receptors: At low concentrations, they enhance the effect of GABA and decrease its dissociation rate. At high concentrations, they directly activate the opening of chloride channels and act on glutamate, adenosine, and neuronal nicotinic acetylcholine receptors.
Barbiturates are metabolized primarily by hepatic oxidation. Their metabolism can be influenced by drugs that induce hepatic oxidative microsomes, such as barbiturates themselves.
Barbiturates have various organ system effects:
- Central Nervous System (CNS): They cause proportional decreases in CMRO2 and CBF, reducing intracerebral pressure. They decrease mean arterial pressure less than ICP, improving cerebral perfusion. Maximum decrease in CMRO2 is around 50-55%, which requires hypothermia.
- Cardiovascular: Barbiturates induce peripheral vasodilation and decreased contractility, increasing heart rate and decreasing cardiac output.
- Respiratory: All intravenous induction agents except ketamine and etomidate cause dose-dependent respiratory depression, making respiratory parameters return to near normal within 15 minutes, with awakening occurring before normal respirations return.
Barbiturates have been used in the past for neuroprotection during neurosurgery and following acute brain injuries. However, they have not been shown to be superior to other techniques for decreasing ICP following acute brain injury.
Barbiturates were previously used for neuroprotection in procedures like carotid endarterectomy, temporary occlusion of cerebral arteries, profound induced hypotension, and cardiopulmonary bypass.
Mechanisms of neuroprotective effect of barbiturates include reverse steal (Robin Hood) effect, free radical scavenging, and liposomal membrane stabilization. They can also block excitatory amino acids (EAA) at higher concentrations, functioning as anticonvulsants.
Barbiturates have various contraindications: severe cardiovascular instability or shock, porphyria, and allergic reactions. Porphyria is a group of disorders with multiple subtypes, including acute intermittent porphyria, which is triggered by induction of heme synthesis.
Barbiturate use has side effects and complications: cardiovascular and respiratory side effects are dose-dependent, and no significant differences exist between the barbiturates in terms of cardiovascular or respiratory side effects. At low blood levels, thiopental has been described as having an antianalgesic effect.
Barbiturates have other uses: as a lethal injection combination, in truth serum, as a recreational drug, and as an intravenous induction agent.
Thiopental, a commonly used barbiturate, has a high context sensitivity and may lead to accumulation of the active metabolite pentobarbital with multiple bolus dosing or prolonged infusion.
Dosages for barbiturates vary for adults, children, and infants, and must be reduced in premedicated patients.
Barbiturates can affect pregnancy, hypovolemia, obesity, females, and the elderly by decreasing the volume of the central compartment and the intermediate compartment.
Thiopental infusions are used to treat status epilepticus and methohexital dosing is approximately 2 mg/kg.

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Test your knowledge on the mechanism of action and pharmacokinetics of a 25 mg drug dosage, including its effects on GABAA receptors, metabolism, and interactions with other drugs.