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Propofol - Comprehensive Notes
Miller's Anesthesia, 10e | Morgan & Mikhail's Clinical Anesthesiology, 7e | Harriet Lane Handbook, 23e
1. Overview & History
- Most commonly used IV hypnotic since its introduction in the 1970s
- Developed in the UK by Imperial Chemical Industries as ICI 35868
- Original 1977 formulation in Cremophor EL was withdrawn due to anaphylactic reactions
- Reintroduced in 1986 as a soybean oil/propofol emulsion
- Used for: induction and maintenance of general anesthesia, and procedural/ICU sedation
2. Physicochemical Characteristics
- Chemical name: 2,6-diisopropylphenol - an alkylphenol derivative
- Highly lipid-soluble; insoluble in water alone
Standard formulation (1%):
- 1% propofol
- 10% soybean oil
- 1.2% purified egg phospholipid (emulsifier)
- 2.25% glycerol (tonicity adjustment)
- Sodium hydroxide to adjust pH to 7
- EDTA added for bacteriostatic activity (to address microbial growth concerns)
Appearance: Slightly viscous, milky white emulsion (small lipid droplets in solution)
Other formulations: 2% propofol available in Europe; medium/long-chain triglyceride mixtures also available. All formulations are stable at room temperature, not light sensitive, and can be diluted with 5% dextrose.
Fospropofol (Lusedra): FDA-approved December 2008 - a water-soluble prodrug metabolized by alkaline phosphatases in the liver to active propofol. 1.86 mg fospropofol = 1 mg propofol. No pain on injection, but causes perineal paresthesias and pruritus.
3. Pharmacokinetics
| Parameter | Value |
|---|---|
| Distribution half-life (initial) | 2-8 minutes |
| Distribution half-life (slow) | 30-70 minutes |
| Elimination half-life | 4-23.5 hours |
| Context-sensitive half-time (≤8 hr infusion) | < 40 minutes |
| Volume of distribution (central compartment) | 6-40 L |
| Volume of distribution (steady state) | 150-700 L |
| Clearance | 1.5-2.2 L/min |
Key pharmacokinetic points:
- Best described by a three-compartment model
- Blood levels decrease rapidly after bolus due to redistribution and elimination
- Clearance exceeds hepatic blood flow - extrahepatic metabolism confirmed
- Major extrahepatic site: kidney (accounts for up to 30% of clearance)
- Lungs: ~20-30% first-pass elimination in humans
- Also confirmed during anhepatic phase of liver transplant
Metabolism:
- Oxidized to 1,4-diisopropyl quinol in the liver
- Conjugated with glucuronic acid -> propofol-1-glucuronide, quinol-glucuronides -> renal excretion
- <1% excreted unchanged in urine; only 2% in feces
- Metabolites excreted for >60 hours after a 2.5-hour anesthetic
- Metabolites considered inactive
Drug interactions (pharmacokinetic):
- Propofol is a CYP3A4 inhibitor - at 3 mcg/mL, reduces CYP3A4 activity by ~37%
- Midazolam raises propofol concentrations by ~25% (reduces metabolic clearance 1.94 -> 1.61 L/min)
- Alfentanil decreases propofol elimination clearance (2.1 -> 1.9 L/min)
- Combined midazolam + alfentanil increases propofol concentrations by 20-30%
- Propofol reduces clearance of high-extraction ratio drugs by decreasing hepatic blood flow
Special populations:
- Elderly: Smaller central compartment (reduced cardiac output), higher peak concentrations - reduce dose
- Children: Larger central compartment + rapid clearance - require higher induction and maintenance doses
- Obese patients: Use LBM for bolus dosing; TBW or corrected body weight (CBW = IBW + 0.4 × [TBW - IBW]) for infusions
- Hemorrhagic shock: Blood propofol concentrations increase; 2.7-fold decrease in EC50 for BIS effect
4. Mechanism of Action
Primary mechanism - GABA-A receptor potentiation:
- Binds to β subunit of GABA-A receptor (β1, β2, and β3 transmembrane domain sites are crucial)
- Indirect effect (low concentrations): Potentiates GABA-induced Cl- current, shifts concentration-response relationship leftward
- Direct effect (high concentrations): Directly activates GABA-A receptor channels
- α and γ2 subunit subtypes also modulate propofol's effects
Additional mechanisms:
- Inhibits NMDA (glutamate) receptors via sodium channel gating modulation
- Direct depressant effect on spinal cord neurons (acts on GABA-A and glycine receptors)
- Inhibits acetylcholine release in hippocampus and prefrontal cortex (via hippocampal GABA-A)
- α2-adrenoreceptor system indirectly contributes to sedative effects
CNS correlates:
- Suppresses the default mode network (posterior cingulate, medial frontal cortex, bilateral parietal cortices)
- PET imaging: reduced activity in thalamic and precuneus regions during hypnosis
- Increases dopamine in nucleus accumbens -> sense of well-being (and abuse potential)
- Decreases serotonin in area postrema (via GABA receptors) -> antiemetic effect
5. Pharmacodynamics
Central Nervous System
Onset and duration:
- Onset: Rapid - one arm-brain circulation (~30-45 seconds)
- Peak effect: 90-100 seconds after 2.5 mg/kg
- Duration: 5-10 minutes after 2-2.5 mg/kg
Doses for loss of consciousness:
- ED50 (bolus): 1-1.5 mg/kg
- Age effects: ED95 is 2.88 mg/kg in children <2 years; decreases progressively with age
Sedative (subhypnotic) effects:
- Anxiolysis, amnesia
- EEG: dose-dependent progression - beta activity -> alpha slowing -> burst suppression -> flat EEG
- Anti-emetic at subhypnotic doses (0.5-1 mg/kg or infusion of 10-20 mcg/kg/min)
Cerebral hemodynamics:
- Decreases CBF by 53-79% and CMR by 48-58% in surgical doses
- Decreases ICP and cerebral blood volume
- CO2 responsiveness preserved
- Autoregulation preserved, even at burst-suppression doses
- Neuroprotection: experimental evidence of reduced ischemic injury comparable to pentobarbital; protection is not durable with severe ischemia
Anticonvulsant:
- ECT seizures are shorter after propofol induction vs. methohexital - consistent with anticonvulsant effect
- Dystonic/choreiform movements can occur but systematic studies do not confirm proconvulsant activity
- Safe for awake intracranial resection of seizure foci
Cardiovascular System
- Induction dose (2-2.5 mg/kg) causes 25-40% reduction in systolic BP
- Decreases: cardiac output (-15%), stroke volume index (-20%), SVR (-15-25%), LVSWI (-30%)
- Mechanism of vasodilation: ↓ sympathetic activity + direct effect on smooth muscle Ca2+ mobilization + ↓ prostacyclin synthesis + ↓ angiotensin II-mediated Ca2+ entry + K+-ATP channel activation + NO stimulation
- Heart rate: Does not change significantly; propofol inhibits baroreflex tachycardic response and decreases cardiac parasympathetic tone
- Effect-site equilibration: Hypnotic effect: 2-3 min; hemodynamic effect: ~7 min (BP continues to fall after loss of consciousness)
- Minimal effect on SA node or AV conduction; suppresses supraventricular tachycardias
- During infusion maintenance, hemodynamic depression is much less than after bolus induction
- Global myocardial O2 supply/demand ratio likely preserved (↓ MBF and ↓ MVO2 in parallel)
- Cardiac surgery note: Postoperative troponin levels and hemodynamic function are better with volatile agents (sevoflurane/desflurane) than propofol - volatile agents preferred for cardiac surgery
Respiratory System
- Causes apnea after induction doses
- Depresses upper airway reflexes (beneficial for LMA insertion)
- Decreases tidal volume and respiratory rate during sedation
- Does not trigger malignant hyperthermia - safe choice in susceptible patients
Other Effects
- No analgesic effect (important clinical consideration)
- No effect on evoked EMG or twitch tension
- Antiemetic at subhypnotic doses
- Does not affect neuromuscular blocking drugs, but acceptable intubating conditions achieved after propofol alone
- Tolerance does not develop after long-term infusions
- Immunosuppression: Inhibits phagocytosis and killing of S. aureus and E. coli
6. Clinical Uses and Dosing
| Indication | Dose |
|---|---|
| Induction (adults) | 1.5-2.5 mg/kg IV |
| Induction (elderly/compromised) | 1-1.5 mg/kg IV (reduce by ~30-50%) |
| Induction (children <2 yrs) | ~2.88 mg/kg IV (ED95) |
| Maintenance (infusion) | 100-200 mcg/kg/min |
| Maintenance blood target (alone) | 2.5-4.5 mcg/mL |
| Maintenance blood target (with N2O or opioid) | 2.5-8 mcg/mL |
| Sedation | 25-75 mcg/kg/min |
| Antiemetic (rescue) | 10-20 mg IV bolus |
Infusion schemes: After induction, start at 100-200 mcg/kg/min and titrate. Optimal propofol + opioid TIVA: propofol 1-1.5 mg/kg -> 140 mcg/kg/min x 10 min -> 100 mcg/kg/min + alfentanil 30 mcg/kg -> 0.25 mcg/kg/min.
Target-controlled infusion (TCI): Pharmacokinetic model-driven systems are widely used. The Eleveld model is widely validated. A 2025 systematic review confirms TCI produces stable, predictable propofol concentrations across populations (PMID: 40289063).
Pediatric notes (Harriet Lane Handbook):
- Rapid onset; brief recovery (5-15 min) with bolus administration
- Has antiemetic and euphoric effects; no analgesic effects
- Caution: respiratory depression, apnea, hypotension
7. Side Effects and Contraindications
| Side Effect | Notes |
|---|---|
| Pain on injection | Very common; use large antecubital vein; pre-treat with lidocaine 1-2 mg/kg or small propofol dose, opioids, ketamine, NSAID |
| Apnea | After induction; prepare airway management |
| Hypotension | 25-40% fall in SBP; worst with bolus induction |
| Myoclonus | Involuntary movements on induction; not epileptiform |
| Thrombophlebitis | Rare; avoid dorsum of hand veins |
| PRIS | See below |
| Fetal neurotoxicity | FDA warning (Dec 2016) - animal studies show concern for fetal brain development with prolonged/repetitive exposure |
| Microbial contamination | Fat emulsion is an excellent growth medium; use within 12 hours of opening; strict aseptic technique |
8. Propofol Infusion Syndrome (PRIS)
- Rare but potentially fatal complication
- Classic threshold: infusion ≥4 mg/kg/h for ≥48 hours, but cases reported with lower doses and as short as 3 hours
Clinical features (diagnostic criteria):
- Acute refractory bradycardia leading to asystole, PLUS one or more of:
- Metabolic acidosis (base deficit >10 mmol/L)
- Rhabdomyolysis
- Hyperlipidemia
- Enlarged or fatty liver
Additional features: Cardiomyopathy with acute cardiac failure, skeletal myopathy, hyperkalemia, hepatomegaly, lipemia
Pathophysiology: Mitochondrial dysfunction -> impaired fatty acid oxidation -> muscle injury -> release of intracellular toxic contents
Risk factors:
- Poor oxygen delivery
- Sepsis
- Serious cerebral injury
- High propofol doses
- Genetic disorders of fatty acid metabolism (e.g., MCAD deficiency)
- Low carbohydrate supply
Early warning sign: Rising triglycerides/lipemia preceding full syndrome
9. Drug Interactions Summary
| Drug | Interaction |
|---|---|
| Midazolam | ↑ propofol concentration ~25%; ↓ propofol clearance |
| Alfentanil/fentanyl | ↓ propofol clearance; reduce propofol infusion rate |
| Opioids (general) | Synergistic hypnosis; reduce propofol dose |
| CYP3A4 substrates | Propofol inhibits CYP3A4; ↑ levels of co-administered drugs |
| High-extraction drugs | ↑ levels due to propofol reducing hepatic blood flow |
10. Key Comparisons
| Feature | Propofol | Thiopental | Etomidate |
|---|---|---|---|
| Antiemetic | Yes | No | No |
| Pain on injection | Yes | Minimal | Minimal |
| Cardiovascular stability | Poor | Moderate | Best |
| PONV | Lowest | High | High |
| Malignant hyperthermia safe | Yes | Yes | Yes |
| Adrenal suppression | No | No | Yes |
| Context-sensitive half-time | Short (<40 min) | Long | Short |
Sources: Miller's Anesthesia, 2-Volume Set, 10e | Morgan & Mikhail's Clinical Anesthesiology, 7e | The Harriet Lane Handbook, 23e | PMID 40289063 (TCI systematic review, 2025)
Please attach a small small notes on all hard words or medical terms in simple language
Here is a Quick Reference Glossary of all the hard medical/scientific terms used in the Propofol notes, explained in plain language:
📖 Glossary of Medical Terms – Propofol Notes
Chemistry & Formulation Terms
| Term | Simple Explanation |
|---|---|
| 2,6-diisopropylphenol | The chemical name of propofol - a phenol (ring-shaped carbon molecule) with two isopropyl (3-carbon) arms attached |
| Alkylphenol | A family of chemicals made of a benzene ring + carbon chains attached; propofol belongs to this family |
| Lipid-soluble | Dissolves easily in fat; this is why propofol crosses the brain barrier so quickly |
| Emulsion | A mixture of oil droplets suspended in water (like salad dressing that's been shaken) - what propofol looks like (milky white) |
| Soybean oil / egg phospholipid | Natural fatty substances used to keep propofol's oil droplets stable in water |
| Glycerol | A simple sugar-alcohol used to make the solution match the saltiness of blood (tonicity) |
| EDTA | A chemical (ethylenediaminetetraacetic acid) added to prevent bacteria from growing in the fat-rich solution |
| Bacteriostatic | Stops bacteria from growing (doesn't kill them, just prevents multiplication) |
| Tonicity | How concentrated a solution is compared to blood; must match blood to avoid cell damage |
| Fospropofol | A water-soluble "inactive" form of propofol that the body converts into active propofol - called a prodrug |
| Prodrug | A drug that is inactive when given but becomes active after the body processes it |
| Alkaline phosphatase | An enzyme (body's chemical tool) found in the liver that cuts fospropofol apart to release propofol |
Pharmacokinetics Terms (What the Body Does to the Drug)
| Term | Simple Explanation |
|---|---|
| Pharmacokinetics | The study of how the body absorbs, distributes, breaks down, and removes a drug |
| Distribution half-life | How long it takes for the drug to spread from blood into body tissues - when this happens fast, the drug's effect wears off quickly |
| Elimination half-life | How long it takes for half the drug to be permanently removed from the body |
| Context-sensitive half-time | How long it takes for the drug level to fall by 50% after stopping an infusion - depends on how long the drip was running |
| Volume of distribution | Imagine how much water you'd need to dilute the drug to match the blood concentration - large volume = drug spreads widely into tissues |
| Central compartment | The blood + highly perfused organs (heart, lungs, liver) where drug goes first |
| Clearance | How much blood the body completely "cleans" of a drug per minute |
| Redistribution | Drug moves from blood into fat and muscle, making the effect wear off even before it's fully broken down |
| Three-compartment model | A mathematical way to describe how propofol distributes into three "pools" - blood, fast tissues, slow tissues |
| Extrahepatic metabolism | Drug breakdown that happens outside the liver (propofol is also broken down by kidneys and lungs) |
| Anhepatic phase | The period during a liver transplant when the patient has no liver at all - propofol is still metabolized during this time |
| CYP3A4 | A specific liver enzyme responsible for breaking down many drugs; propofol slows it down, causing other drugs to build up |
| Glucuronic acid / Glucuronide | A molecule the body adds to propofol to make it water-soluble so the kidneys can flush it out in urine |
| EC50 | The drug concentration that produces 50% of the maximum possible effect |
| Extraction ratio | How efficiently the liver removes a drug from the blood as it passes through - "high extraction" drugs are removed very efficiently |
Mechanism of Action Terms
| Term | Simple Explanation |
|---|---|
| GABA | Gamma-aminobutyric acid - the brain's main "calming" chemical; it slows nerve activity |
| GABA-A receptor | A protein on nerve cells that GABA binds to, opening a channel that lets chloride (Cl-) flow in and quiets the nerve |
| β subunit | A specific piece/component of the GABA-A receptor protein where propofol attaches |
| Chloride current | The flow of negatively charged chloride ions into a nerve cell, which makes the cell less excitable (calmer) |
| NMDA receptor | A nerve-cell receptor for glutamate (the brain's "excite" chemical); propofol partially blocks it, adding to its calming effect |
| Glutamate | The brain's main "exciting" chemical - the opposite of GABA |
| Sodium channel gating | The opening and closing of channels that let sodium into nerve cells (affects how easily nerves fire) |
| Default mode network (DMN) | A set of brain areas active when you're daydreaming or at rest; propofol disrupts this network to cause unconsciousness |
| Nucleus accumbens | A part of the brain associated with reward and pleasure; propofol raises dopamine here (explains the sense of well-being and abuse potential) |
| Dopamine | A brain chemical linked to reward, pleasure, and motivation |
| Serotonin | A brain chemical involved in mood, nausea/vomiting, and sleep; propofol lowers it in the vomiting center |
| Area postrema | The brain's "vomiting center" - propofol reduces serotonin here, which is why it prevents nausea |
| Thalamus / Precuneus | Brain regions involved in consciousness and awareness; propofol reduces activity here during sedation |
| α2-adrenoreceptor | A receptor for adrenaline-like chemicals; involved in sedation (also targeted by dexmedetomidine) |
Pharmacodynamics Terms (What the Drug Does to the Body)
| Term | Simple Explanation |
|---|---|
| Pharmacodynamics | The study of what a drug actually does to the body - its effects and mechanisms |
| ED50 | The dose effective in 50% of patients (half the people will fall asleep at this dose) |
| ED95 | The dose effective in 95% of patients |
| Burst suppression | A pattern on brain monitoring (EEG) where the brain alternates between short bursts of activity and silence - seen with very deep anesthesia |
| EEG (Electroencephalogram) | A recording of the brain's electrical activity using scalp electrodes |
| BIS (Bispectral Index) | A number (0-100) calculated from the EEG to estimate depth of anesthesia; 40-60 = general anesthesia |
| Spectral entropy | Another EEG-based number used to measure depth of sedation |
| CBF (Cerebral Blood Flow) | How much blood flows through the brain per unit time |
| CMR (Cerebral Metabolic Rate) | How much oxygen and glucose the brain is consuming - its "activity level" |
| ICP (Intracranial Pressure) | Pressure inside the skull; propofol lowers it |
| CPP (Cerebral Perfusion Pressure) | The pressure driving blood into the brain = Mean Arterial Pressure - ICP |
| CBV (Cerebral Blood Volume) | The total amount of blood inside the brain's blood vessels |
| Autoregulation | The brain's ability to keep blood flow constant despite changes in blood pressure; propofol preserves this |
| CO2 responsiveness | The brain's normal response of widening blood vessels when CO2 rises; preserved with propofol |
| Anticonvulsant | A drug that prevents or stops seizures |
| Neuroprotection | Protection of brain cells from damage (e.g., during reduced blood supply) |
Cardiovascular Terms
| Term | Simple Explanation |
|---|---|
| Systolic blood pressure (SBP) | The top number in a blood pressure reading; represents peak pressure when the heart contracts |
| Mean arterial pressure (MAP) | The average blood pressure throughout the whole heartbeat cycle |
| SVR (Systemic Vascular Resistance) | The resistance of all blood vessels to blood flow; when this drops, blood pressure drops |
| Cardiac output | How much blood the heart pumps per minute |
| Cardiac index | Cardiac output adjusted for the person's body size |
| Stroke volume index | How much blood the heart ejects with each beat, adjusted for body size |
| LVSWI (Left Ventricular Stroke Work Index) | A measure of how hard the left heart is working per beat |
| Vasodilation | Widening of blood vessels, causing blood pressure to drop |
| Inotropic effect | Effect on the strength of the heart's contraction (positive = stronger, negative = weaker) |
| Lusitropic effect | Effect on how well the heart relaxes after contracting |
| Baroreflex | The body's automatic response to low blood pressure - normally speeds up the heart; propofol blunts this |
| Sinoatrial (SA) node | The heart's natural pacemaker that sets the rhythm |
| Parasympathetic tone | The "rest and digest" nervous system's influence on the heart - slows heart rate |
| Supraventricular tachycardia (SVT) | A fast abnormal heart rhythm originating above the ventricles; propofol suppresses it |
| Prostacyclin | A chemical made by blood vessel walls that keeps vessels open; propofol inhibits its synthesis |
| Nitric oxide (NO) | A gas produced in blood vessels that causes them to relax and widen |
| K+-ATP channels | Potassium channels in vessel walls linked to the cell's energy state; opening them causes vasodilation |
| Troponin | A protein released into blood when heart muscle is damaged; used to measure cardiac injury |
Respiratory Terms
| Term | Simple Explanation |
|---|---|
| Apnea | Complete stopping of breathing - a common side effect after propofol induction |
| Tidal volume | The amount of air breathed in with each normal breath |
| Upper airway reflexes | Protective reflexes (coughing, gagging) that guard the airway; propofol suppresses them, allowing LMA insertion |
| LMA (Laryngeal Mask Airway) | A tube-like device placed in the throat (not into the windpipe) to keep the airway open during anesthesia |
| Malignant hyperthermia (MH) | A rare, life-threatening reaction to certain anesthetic gases causing the body's temperature to skyrocket; propofol does NOT trigger it |
Side Effect & Complication Terms
| Term | Simple Explanation |
|---|---|
| Myoclonus | Sudden involuntary muscle jerks - can occur when propofol is given, not dangerous |
| Thrombophlebitis | Inflammation and clot formation in a vein at the injection site |
| PONV (Postoperative Nausea and Vomiting) | Feeling sick or vomiting after surgery/anesthesia; propofol greatly reduces this |
| Phagocytosis | The process by which immune cells "eat" and destroy bacteria; propofol slightly impairs this |
| Rhabdomyolysis | Breakdown of muscle tissue, releasing harmful proteins into the blood that can damage the kidneys |
| Metabolic acidosis | A buildup of acid in the blood (base deficit >10 mmol/L in PRIS) from impaired metabolism |
| Cardiomyopathy | Disease/weakening of the heart muscle |
| Hepatomegaly | Enlarged liver |
| Lipemia / Hyperlipidemia | Too much fat in the blood; a warning sign of PRIS |
| Hyperkalemia | Too much potassium in the blood; dangerous for the heart |
| Mitochondrial dysfunction | The cell's "power plants" stop working properly - the core problem in PRIS |
| MCAD deficiency | A genetic condition where the enzyme for burning medium-length fatty acids is missing - a risk factor for PRIS |
| Fatty acid oxidation | The process of burning fat for energy; impaired in PRIS |
| Asystole | Complete stopping of the heartbeat - the fatal endpoint of severe PRIS |
| Fetal neurotoxicity | Harm to the developing baby's brain; the FDA warned about this with prolonged propofol use in pregnancy |
Clinical / Procedural Terms
| Term | Simple Explanation |
|---|---|
| TIVA (Total Intravenous Anesthesia) | Anesthesia maintained entirely with IV drugs (propofol + opioid) rather than inhaled gases |
| TCI (Target-Controlled Infusion) | A pump that automatically adjusts propofol infusion rate to maintain a target blood or brain concentration |
| ECT (Electroconvulsive Therapy) | A psychiatric treatment using brief electrical seizures to treat severe depression; propofol can be used for sedation |
| Induction | The phase of anesthesia when the patient is first put to sleep |
| Maintenance | Keeping the patient asleep during the surgical procedure |
| Monitored Anesthesia Care (MAC) | A level of sedation lighter than general anesthesia, where the patient can still breathe independently |
| LBM (Lean Body Mass) | Body weight minus all fat - used for propofol bolus dosing in obese patients |
| TBW (Total Body Weight) | The patient's actual weight on the scale |
| IBW (Ideal Body Weight) | The "expected" weight for a person's height - a calculated number |
| CBW (Corrected Body Weight) | A middle-ground weight used for dosing obese patients: IBW + 0.4 × (TBW - IBW) |
| Arm-brain circulation | The time it takes blood to travel from the arm vein (where propofol is injected) to the brain (~30-45 seconds) |
| Carotid endarterectomy (CEA) | Surgery to remove blockage from the carotid artery in the neck |
These terms are presented in the order they appear in the notes. Use this glossary alongside the main notes for quick reference while studying.
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