Intravenous Anesthetic Agents

Chemical name: Thiobarbiturate.

Formulations:

• Sodium salts (6% {30mg} anhydrous sodium carbonate by weight), ampoule filled with Nitrogen at 80kPa.
• Yellow amorphous powder; 500mg, 1g.
• pH - 10.5, solution of 2.5% is obtained when 20ml of water for injection is added to 0.5g.

pKa: 7.6, 80% protein-bound.

Lipid soluble.

Metabolism:

• Hepatic; inactive thiopental carboxylic acid by oxidation, N-dealkylation, desulfuration, and destruction of the barbituric acid ring.

Excretion: Via kidney and bile.

Mechanism of Action (MOA): Acts on GABA receptors.

Onset: Within 1 arm-brain circulation.

Peak Effect: Occurs at 90 to 100 seconds.

Awakening: Typically within 5 to 10 minutes.

Rapid Fall in Plasma Concentration: Due to redistribution.

Elimination Half-life: Ranges from 3.5 to 21 hours.

Clearance: Approximately 3 to 4 ml/kg/min.

Volume of distribution: Ranges from 1.5 to 3L/kg.

Context-sensitive half-life: Less than 150 minutes.

CNS Effects:

• CMRO2 (Cerebral Metabolic Rate of Oxygen) reduction by 55%.
• Reduction in Cerebral Blood Flow (CBF).
• Reduction in Intracranial Pressure (ICP) and Intraocular Pressure (IOP).
• Benefits include decreased oxygen demand, preservation of Cerebral Perfusion Pressure (CPP), free radical scavenging, and the Robin Hood phenomenon.
• No emergence phenomenon observed.
• Absence of upper airway reflexes.

Cardiovascular Effects:

• May lead to low Blood Pressure (BP), Heart Rate (HR), and Cardiac Output (CO).

Respiratory System:

• Can cause apnea (temporary cessation of breathing) and reduced Minute Ventilation (MV).

Dosage:

• For induction: Intravenous dose typically ranges from 3 to 5mg/kg.
• For sedation: Intravenous dose ranges from 0.5 to 1.5mg/kg.

Uses: Thiopentone is used for the induction of anesthesia and maintenance.

Side Effects:

• Pain on injection, hypotension, apnea, bronchospasm, allergic reactions, thrombophlebitis, and acute intermittent porphyrias.

• Potency: Methohexital is approximately 3 times more potent than thiopental.
• Formulation: It is a white powder mixed with 6% sodium carbonate, ensuring stability for up to 6 weeks after preparation.
• Solution pH: When prepared, it forms a 1% solution with a pH around 10–11, which is similar to thiopental.
• Lipid Solubility: Methohexital is highly lipid-soluble, with approximately 75% remaining non-ionized at pH 7.4. It is also 70–80% protein-bound, giving it pharmacokinetics similar to thiopental.
• Metabolism: The drug is primarily metabolized in the liver.
• Clearance: Methohexital has a clearance rate 3 times higher than thiopental, resulting in rapid recovery after administration.
• Induction Effects: Induction with methohexital may lead to skeletal muscular twitching, laryngospasm, and hiccups.
• Dosing: Typical dosing ranges from 1 to 1.5 mg/kg in adults and 0.5 mg/kg for pediatric patients.
• Side Effects: Methohexital is less likely to cause bronchospasm and hypotension compared to thiopental.
• Volume of Distribution: It has a lower volume of distribution compared to thiopental due to its lower lipid solubility.
• Elimination Half-life: Methohexital has a relatively short elimination half-life of 1 to 2 hours.

• Chemical Structure: Etomidate is classified as an imidazole derivative.
• Formulation: It is available in 10 ml ampoules, with each ampoule containing 2 mg/ml of etomidate dissolved in water and 35% propylene glycol.
• pH: The solution has a pH of approximately 8.1.
• Lipid Solubility: Etomidate exhibits high lipid solubility.
• Protein Binding: Approximately 75% of etomidate is bound to proteins in the blood.
• Metabolism: Etomidate is metabolized by hepatic enzymes and plasma esterases.
• Excretion: About 75% of the drug is excreted in the urine, and 13% is eliminated in the feces within the first 24 hours after administration.
• Clearance: Etomidate has a clearance rate approximately 6 times greater than thiopental.
• Induction Dose: The typical induction dose of etomidate is 0.3 mg/kg.
• CNS Effects: Etomidate results in a decrease in cerebral metabolic rate of oxygen consumption (CMRO2), cerebral blood flow (CBF), and intracranial pressure (ICP).
• Incidence of Nausea and Vomiting: Etomidate is associated with a high incidence of nausea and vomiting (N and V).
• Cardiovascular Effects: It has minimal effects on healthy patients and those with cardiac disease. There are no significant changes in heart rate (HR), stroke volume (SV), or cardiac output (CO), but it decreases mean arterial pressure (MAP).
• Suitability: Etomidate is suitable for patients with hypotension, hypovolemia, and cardiovascular disorders due to its minimal impact on cardiovascular parameters.
• Respiratory Effects: It reduces tidal volume (TV) by 26% and minute ventilation (MV) but increases respiratory rate (RR). Transient apnea, especially in adults, may occur.
• Pain on Injection: There is a high incidence of pain on injection, reported in 25 to 50% of cases.
• No Histamine Release: Etomidate does not cause histamine release or bronchial reactivity.
• Adrenal Corticoid Synthesis Inhibition: Etomidate inhibits adrenal corticoid synthesis in a concentration-dependent manner, resulting in reversible blockage of 11-β-hydroxylase. This can lead to hypotension, hyponatremia, and sudden death, particularly when used as an infusion in the ICU.
• Antagonism: Etomidate's effects can be antagonized by GABA antagonists.
• Myotonic Activity: Myotonic activity and dyskinesia are sometimes observed after etomidate administration, but there are no epileptogenic EEG changes. However, grand mal seizures and epileptogenic activity may occur in patients with seizure foci.
• Usage: Etomidate is used for induction, total intravenous anesthesia (TIVA), in elderly patients, sick patients, and outpatient surgery.

• Chemical Name: Arylcyclohexylamine.
• Formulations: Ketamine is available as a clear aqueous solution in concentrations of 1%, 2%, and 10%.
• Lipid Solubility: Ketamine is lipid-soluble.
• pH: The pH of ketamine solutions ranges from 3.5 to 5.5.
• pKa: Ketamine has a pKa of 7.5.
• Metabolism: Ketamine undergoes hepatic metabolism, resulting in the formation of norketamine and hydroxynorketamine.
• Excretion: Ketamine is primarily excreted via the kidneys.
• Mechanism of Action (MOA): Ketamine acts on the NMDA receptors, affecting the thalamocortical and limbic systems.
• Onset: Ketamine induces anesthesia within one arm-brain circulation time.
• Peak Effect: The peak effect is typically reached within 90 to 100 seconds.
• Awakening: Patients usually awaken within 10 to 20 minutes after ketamine administration.
• Rapid Fall in Plasma Concentration: Ketamine exhibits a rapid decline in plasma concentration following a single dose due to redistribution.
• Elimination Half-Life: The elimination half-life of ketamine is approximately 2 to 3 hours.
• Clearance: Ketamine has a clearance rate of 12 to 14 ml/kg/min.
• Volume of Distribution: The volume of distribution for ketamine is 3L/kg.
• Context Sensitive Half-Life: Ketamine has a context-sensitive half-life of less than 40 minutes.
• CNS Effects: Ketamine affects cerebral metabolic rate of oxygen consumption (CMRO2), cerebral blood flow (CBF), intracranial pressure (ICP), and intraocular pressure (IOP). It can improve perfusion in incomplete cerebral ischemia and is known for inducing dissociative anesthesia. Ketamine may lead to the emergence phenomenon and affects upper airway reflexes. It can also cause salivation and lacrimation, as well as nystagmus.
• Cardiovascular Effects: Ketamine increases blood pressure (BP), heart rate (HR), and cardiac output (CO).
• Respiratory System: Higher doses of ketamine can result in apnea. Ketamine also has bronchodilatory effects and decreases minute ventilation (MV).
• Doses: For induction, the recommended intravenous (IV) dose is 0.5 to 2 mg/kg, while the intramuscular (IM) dose is 4 to 6 mg/kg. Maintenance doses range from 15 to 45 μg/kg/min IV with nitrous oxide or 30 to 90 μg/kg/min IV. For sedation and analgesia, the IV dose is 0.2 to 0.8 mg/kg, and the IM dose is 2 to 4 mg/kg.
• Usage: Ketamine is utilized for induction, maintenance, sedation, analgesia, and pre-emptive analgesia.
• Side Effects: Ketamine may lead to apnea and the emergence phenomenon.

• Chemical Name: Alkylphenol, medium- and long-chain triglycerides.
• Formulations: Propofol is available in emulsion form, appearing as a milky white liquid, with concentrations of 1% and 2%.
• Lipid Solubility: Propofol is lipid-soluble and has a shelf life of 36 months.
• pH: Propofol has a pH of 7.
• pKa: The pKa of propofol is 11.
• Metabolism: Propofol undergoes hepatic metabolism, primarily through conjugation (glucuronide and sulfate formation), leading to the formation of inactive metabolites.
• Excretion: Propofol is excreted via the kidneys and, to some extent, extrahepatic excretion occurs in the lungs.
• Mechanism of Action (MOA): Propofol acts on the GABA receptors.
• Onset: Propofol induces anesthesia within one arm-brain circulation time.
• Peak Effect: The peak effect is typically reached within 90 to 100 seconds.
• Awakening: Patients usually awaken within 5 to 10 minutes after propofol administration.
• Rapid Fall in Plasma Concentration: Propofol exhibits a rapid decline in plasma concentration after a single dose, primarily due to redistribution and elimination.
• Elimination Half-Life: The elimination half-life of propofol ranges from 1 to 3 hours.
• Clearance: Propofol has a clearance rate of 20 to 30 ml/kg/min.
• Volume of Distribution: The volume of distribution for propofol ranges from 2 to 10 L/kg.
• Context Sensitive Half-Life (for Infusion Up to 8 Hours): Propofol has a context-sensitive half-life of less than 40 minutes.
• CNS Effects: Propofol affects cerebral metabolic rate of oxygen consumption (CMRO2), cerebral blood flow (CBF), intracranial pressure (ICP), and intraocular pressure (IOP). It has a positive neuroprotective property and can reduce infarct size when administered immediately or within 1 hour after an ischemic insult.
• Cardiovascular Effects: Propofol leads to a decrease in blood pressure (25 to 40%), reduced heart rate, and decreased cardiac output (CO).
• Respiratory System: Propofol-induced apnea is dose-dependent (approximately 25 to 30%). Additionally, it causes bronchodilation and decreased minute ventilation (MV).
• Dosage:
  • Induction: 1 to 2.5 mg/kg IV
  • Maintenance: 50 to 150 μg/kg/min
  • Sedation: 25 to 75 μg/kg/min
  • Anti-emetic: 10 to 20 mg/kg or 10 μg/kg/min
• Recovery Profiles:
  • Response to Verbal Command: Approximately 5 minutes after discontinuation of nitrous oxide.
  • Eye Opening: Around 6 minutes.
  • Orientation: Typically achieved at 9 minutes.
• Uses: Propofol is employed for induction, maintenance, sedation, anti-emetic therapy, antipruritic treatment, anticonvulsant therapy, and managing chronic refractory headaches.
• Special Considerations: Propofol is unlicensed for use in children under 3 years of age due to potential metabolic acidosis and myocardial infarction associated with prolonged use in the intensive care unit (ICU).
• Side Effects: Propofol administration may result in pain on injection, hypotension, apnea, allergic reactions, thrombophlebitis, and excitatory side effects such as myoclonus.

• Composition: Althesin is a mixture of two steroids, alphaxalone and alphadolone, in a 3:1 ratio, dissolved in cremophor EL. Other similar formulations include minaxolone.
• Dosage: The recommended dosage for Althesin is 0.05 mg/kg.
• Onset: Althesin typically takes around 30 seconds to induce anesthesia.
• Duration of Action: The duration of action for Althesin is approximately 5 to 10 minutes longer than an equal dose of thiopentone.
• CNS Effects: Althesin reduces cerebral metabolic rate of oxygen consumption (CMRO2), cerebral blood flow (CBF), and intracranial pressure (ICP).
• Musculoskeletal System (MSS): Althesin may cause dose-dependent tremors.
• Cardiovascular System (CVS): Althesin tends to maintain normal cardiac output (CO) by increasing heart rate (HR) and causing less cardiodepression.
• Respiratory System: Althesin can lead to brief hyperventilation, apnea, and suppressed laryngeal reflex.
• Nausea and Vomiting: Althesin is associated with less nausea and vomiting as compared to some other anesthetics.
• Metabolism: Approximately 60% to 70% of Althesin is metabolized through biliary excretion, while the remaining 20% to 30% is excreted in the urine.
• Withdrawal: Althesin was withdrawn from use due to issues related to hypersensitivity.

• Chemical Structure: Propanidid is a derivative of eugenol.
• Physical Properties:
  • Propanidid is a pale yellow oil that is slightly soluble in water.
  • The pH of Propanidid is approximately 4-5.
  • It is typically dissolved in a mixture of polyoxylated castor oil, sodium chloride, and water to create a 5% aqueous solution.
• Dosage: The recommended dosage for Propanidid is 5 to 6 mg/kg.
• Mechanism of Action (MOA): Propanidid acts on the GABA receptors.
• Cardiovascular System (CVS) Effects: Propanidid may initially reduce blood pressure (BP) and cardiac output (CO) during hypotension but rapidly increases CO. It also tends to increase heart rate (HR).
• Respiratory System: Propanidid can lead to brief hyperventilation and secondary apnea. In some cases (10%), it may cause cough, hiccup, and laryngospasm.
• Incidence of Nausea and Vomiting: Propanidid is associated with a high incidence of nausea and vomiting compared to other agents.
• Excretion: Within 2 hours of administration, approximately 90% of Propanidid is excreted in the urine, with up to 6% excreted in the feces.
• Rapid Recovery: Propanidid allows for rapid recovery, making it suitable for outpatient surgery.
• Side Effects: Potential side effects of Propanidid include hypersensitivity reactions, hypotension, and bronchospasm.
• Common Uses: Propanidid is commonly used in procedures such as electroconvulsive therapy (ECT) and dental extractions.

• Water Solubility: Midazolam is water-soluble.
• pH-Dependent Properties: The opening of the benzodiazepine ring in Midazolam is pH-dependent and occurs below a pH of approximately 4.0. This pH-dependent behavior leads to increased lipid solubility at physiological pH levels.
• Onset of Action: Midazolam typically has an onset of action within 67 to 72 seconds.
• Respiratory Depression: Midazolam is associated with minimal respiratory depression.
• No Hangover Effects: One notable advantage of Midazolam is that it does not produce hangover effects.
• Elimination Half-Life: The elimination half-life of Midazolam ranges from 2 to 2.5 hours.
• Cardiovascular Stability: Midazolam is considered cardiostable as it reduces venous return, causes mild myocardial depression, and lowers systemic vascular resistance (SVR) by 15 to 33%.