Intravenous Induction Agents

1. Propofol

Pharmacokinetics

• Rapid onset (arm-brain circulation time), offset via redistribution
• Context-sensitive half-time ~10 min (infusion <3 hours), <40 min (up to 8 hours) - ideal for TIVA
• Extensive hepatic metabolism (high extraction ratio 0.79-0.92); extrahepatic clearance also significant
• Children have larger central compartment volume (+50%) and faster clearance (+25%) - dose requirements are higher

Induction Doses

Organ System Effects

• CVS: 25-40% reduction in systolic BP via decreased systemic vascular resistance, decreased cardiac output (-15%), stroke volume index (-20%). Heart rate typically unchanged. Baroreceptor reflex is blunted. Effect-site equilibration for hemodynamic depression lags behind hypnotic effect (~7 min vs. 2-3 min).
• Respiratory: Dose-dependent apnea and respiratory depression; decreased hypercapnic ventilatory response.
• CNS: Decreases CMRO2 and ICP; anticonvulsant; does NOT produce analgesia. Unique antiemetic property even at subhypnotic concentrations.

Advantages

• Rapid, smooth induction and recovery
• Antiemetic (reduces PONV)
• Reduced airway complications (laryngospasm, bronchospasm)
• Short context-sensitive half-time makes it excellent for TIVA

Disadvantages / Adverse Effects

• Pain on IV injection (mitigated by IV lidocaine or opioid prior to injection)
• Hypotension - caution in hypovolemic or elderly patients
• Propofol Infusion Syndrome: rare but life-threatening with prolonged high-dose infusions (especially in pediatric ICU patients) - manifests as lipemia, cardiac dysrhythmias, metabolic acidosis
• No analgesic effect

2. Barbiturates (Thiopental, Methohexital)

Pharmacokinetics

• Thiopental: Rapid onset (single dose); offset due to redistribution. Long elimination half-life - accumulates with repeated dosing or infusion, prolonging recovery.
• Methohexital: Shorter elimination half-time, greater plasma clearance, more complete recovery. Dose 1-2 mg/kg for induction.
• Both metabolized hepatically (oxidation, N-dealkylation, desulfuration).

Induction Doses

• Thiopental: 3-4 mg/kg IV
• Methohexital: 1-2 mg/kg IV

Organ System Effects

• CVS: Peripheral vasodilation causes a decrease in BP (less pronounced than propofol); some negative inotropism. Baroreceptor reflex less inhibited than with propofol, so compensatory tachycardia partially counteracts BP drop.
• Respiratory: Significant respiratory depression; usual induction dose abolishes laryngeal reflexes and can produce apnea.
• CNS: Potent cerebral vasoconstrictor - decreases CBF, cerebral blood volume, and ICP; dose-dependent reduction of CMRO2. NO analgesic effect (possible hyperalgesia). Useful in managing raised ICP. Anticonvulsant (except methohexital, which activates epileptic foci - useful for ECT).
• Porphyrin synthesis stimulated via aminolevulinic acid synthetase.

Contraindications

1. Respiratory obstruction or inadequate airway
2. Severe cardiovascular instability or shock
3. Status asthmaticus
4. Acute intermittent porphyria (absolute contraindication)
5. Inadequate equipment/IV access

3. Etomidate

Pharmacokinetics

• Rapid onset; offset via redistribution (comparable to thiopental/propofol)
• Metabolism by ester hydrolysis to inactive metabolites - excreted urine (78%) and bile (22%)
• Clearance ~5x that of thiopental; shorter elimination half-time
• Highly protein bound (77%), primarily to albumin
• Duration linearly related to dose: each 0.1 mg/kg ≈ 100 seconds unconsciousness

Induction Dose

• 0.2-0.3 mg/kg IV

Organ System Effects

• CVS (KEY feature): Minimal hemodynamic depression - preserves heart rate, cardiac output, systemic BP. Makes it the preferred agent in hemodynamically unstable patients (e.g., trauma, cardiogenic shock, compromised myocardial function).
• Respiratory: Less respiratory depression than barbiturates; apnea uncommon but possible with rapid injection.
• CNS: Potent cerebral vasoconstrictor; decreases CBF and ICP (similar to thiopental). Increases EEG excitatory spike frequency; myoclonic activity in >50% of patients (may mimic seizures but does NOT produce analgesia).
• Endocrine (KEY limitation): Inhibits 11β-hydroxylase in a dose-dependent manner - blocks cortisol synthesis for 4-8 hours after a single induction dose. This is why etomidate is NOT used as a continuous infusion.

Adverse Effects

• Pain on injection and venous irritation
• High incidence of involuntary myoclonic movements
• Increased PONV compared to thiopental/propofol
• No analgesic effect
• Adrenocortical suppression (single dose clinical significance debated, but continuous infusion is contraindicated)

4. Ketamine

Pharmacokinetics

• High lipid solubility - rapid onset
• Termination of single bolus effect by redistribution
• Hepatic metabolism via CYP450 (N-demethylation) to norketamine (active, 1/3 to 1/5 potency), then hydroxylated/conjugated to inactive metabolites excreted in urine
• Lowest protein binding of all IV induction agents
• Short context-sensitive half-time - can be used for TIVA infusion

Routes & Doses

Organ System Effects

• CVS: Centrally mediated sympathetic stimulation - increases BP, heart rate, and cardiac output. Note: directly depresses myocardium (usually masked); may become apparent in critically ill patients with limited sympathetic reserve.
• Respiratory: Minimal respiratory depression; preserves hypercapnic drive. Transient apnea possible with rapid large IV doses. Bronchodilator - preferred in reactive airway disease/bronchospasm. Laryngeal reflexes partially preserved (but NOT reliably enough to protect airway).
• CNS: Cerebral vasodilator - increases CBF and CMRO2. Traditionally avoided in raised ICP (though effect can be blunted by normocapnia). Anticonvulsant properties.
• Psychomimetic (KEY side effect): Emergence reactions - vivid colorful dreams, hallucinations, out-of-body experiences, distorted senses. Lower incidence in children. Mitigated by co-administration of benzodiazepine.
• Increases salivation (sialorrhea) - anticholinergic premedication (atropine/glycopyrrolate) often given, especially in children.

Advantages

• Profound analgesia
• Cardiovascular stimulation - preferred in hypovolemic/hemodynamically unstable patients
• Bronchodilation
• Minimal respiratory depression
• Multiple routes of administration
• Useful in uncooperative/pediatric patients

5. Benzodiazepines (Midazolam, Diazepam, Remimazolam)

Key Agents

• Midazolam: Water-soluble, shortest onset of class, most common IV benzodiazepine. Dose for induction: 0.1-0.3 mg/kg IV
• Diazepam: Organic solvent formulation - pain on injection and thrombophlebitis common
• Remimazolam: Newest; ultra-short duration due to rapid clearance by plasma esterases

Pharmacokinetics

• Midazolam onset slower than propofol/barbiturates; offset also longer (especially with high doses or infusion)
• Prolonged effect in hepatic and renal failure
• Flumazenil (8-15 mcg/kg IV) is a specific antagonist - note its duration (~20 min) is shorter than most benzodiazepines, risking re-sedation

Organ System Effects

• CVS: Mild decrease in systemic BP via peripheral vasodilation; cardiac output unchanged. Less pronounced than propofol/barbiturates.
• Respiratory: Minimal depression alone; transient apnea after rapid IV bolus for induction (especially with opioid premedication). Synergistic respiratory depression with opioids.
• CNS: Decreases CMRO2 and CBF but to a lesser extent than propofol/barbiturates - ceiling effect (cannot produce isoelectric EEG). Potent anticonvulsants.

Clinical Role

• Primarily used for preoperative anxiolysis, amnesia, and conscious sedation - NOT first-line for induction (slower onset, prolonged recovery)
• Useful adjunct to attenuate emergence reactions from ketamine
• Midazolam 1-2 mg IV for preoperative sedation

Comparative Summary

Clinical Selection Guide

• Hemodynamically unstable: Etomidate (first choice) or Ketamine
• Raised ICP/neurosurgery: Thiopental or Propofol (avoid ketamine)
• Reactive airway/asthma/bronchospasm: Ketamine (avoid thiopental)
• Day surgery/ambulatory: Propofol (best recovery, antiemetic)
• TIVA: Propofol ± ketamine (remifentanil)
• ECT: Methohexital or etomidate (avoid thiopental's anticonvulsant effect)
• Uncooperative child: Ketamine IM (3-5 mg/kg) or oral midazolam premedication
• Porphyria: Propofol or Ketamine (barbiturates strictly contraindicated)