Role of Plasma Proteins in Anaesthesia

1. Key Plasma Proteins Relevant to Anaesthesia

Human Serum Albumin (HSA)

• Binds acidic drugs - benzodiazepines, opioids, barbiturates, thiopental, warfarin
• Low affinity but high capacity (many binding sites)
• Many pharmacologic agents compete for the same albumin binding sites
• Plasma levels are low in the first months of life (especially in preterm and fasted infants), in liver disease, malnutrition, and the elderly

Alpha-1-Acid Glycoprotein (AGP / Orosomucoid)

• Binds neutral and basic drugs - local anesthetics (lidocaine, bupivacaine, ropivacaine), opioids
• Affinity for local anesthetics is 5,000 to 10,000 times greater than albumin, making AGP the primary systemic toxicity protector for local anesthetics
• AGP is an acute-phase reactant - levels rise with surgical stress, infection, and inflammation
• Normal adult plasma levels: 0.7-1.0 g/L; inadequate at birth (0.2-0.3 g/L), reaching adult levels only after 1 year of age

"The affinity of AGP for local anesthetics is 5000 to 10,000 times greater than that of HSA, making AGP a highly effective systemic toxicity protector."

• Miller's Anesthesia, 10e

2. Pharmacokinetic Principles of Protein Binding

Free (Unbound) vs. Bound Drug

• Only the free (unbound) fraction of a drug is pharmacologically active and available for:
  • Crossing the blood-brain barrier
  • Receptor binding
  • Hepatic metabolism and renal excretion
  • Distribution to tissues
• A higher protein-bound fraction means lower free fraction and reduced drug effect at a given dose

Volume of Distribution (Vd)

• Drugs with high protein binding (e.g., alfentanil, remifentanil) have a smaller Vd because more drug is retained in plasma
• Drugs with low protein binding (e.g., fentanyl) have a higher Vd (300 L) due to greater tissue distribution
• As Barash states: "A high VD is observed for lipophilic opioids with low protein-binding affinity such as fentanyl (VD = 300 L), whereas a low VD is observed for remifentanil and alfentanil, due to a high clearance (remifentanil) and/or high protein binding."

Protein Binding and Drug Displacement

• There is an abundance of literature on one drug displacing another from protein-binding sites
• However, Barash (9e) cautions that this is often clinically overstated:
  • The number of unoccupied binding sites is several orders of magnitude higher than the number of anaesthetic drug molecules administered clinically
  • Even if displacement occurs, the liver has capacity to metabolize the sudden influx of free drug (flow-limited metabolism), returning free drug concentration to pre-displacement levels
  • There are no documented clinical examples of protein binding drug-drug interactions with opioids or hypnotics that are clinically relevant
• Exception: drugs with high protein binding + high hepatic extraction ratio + narrow therapeutic index may require dose adjustment

"Although most changes in protein binding will not influence clinical drug exposure... drugs that are extensively protein bound, have a high hepatic extraction ratio, and have a low therapeutic index may be the exception."

• Barash, Cullen & Stoelting's Clinical Anesthesia, 9e

3. Clinical Contexts Where Plasma Protein Binding Is Altered

A. Neonates and Infants (Paediatric Anaesthesia)

• Free fraction of all local anesthetics is increased in infants → maximum doses of all aminoamides must be significantly reduced
• AGP plasma levels may rise due to surgical stress/infection/emergency surgery, even in infants → this is protective, as it increases the bound fraction of ropivacaine and reduces systemic toxicity risk
• High hematocrit in neonates (>70%) also "entraps" local anesthetics in red cells, lowering peak plasma concentrations (Cmax) after a single injection but extending the half-life

"As the plasma concentration of the two proteins able to bind local anesthetics is low at birth, the free fraction of all local anesthetics is increased in infants; consequently, the maximum doses of all aminoamides must be significantly reduced."

• Miller's Anesthesia, 10e

B. Elderly Patients

• Albumin is often decreased in older patients → lower doses of benzodiazepines and opioids are needed
• AGP may be altered, affecting local anaesthetic dosing
• Altered plasma protein concentrations contribute to the increased drug sensitivity seen in elderly patients, along with reduced Vd for water-soluble drugs and increased Vd for lipid-soluble drugs

C. Obesity

• Plasma albumin and total plasma protein concentrations are NOT significantly changed by obesity per se
• However, blood concentrations of free fatty acids, triglycerides, cholesterol, and AGP are increased in obese patients
• Hyperlipidemia and increased AGP may affect protein binding, leading to a reduction in free drug concentration
• Relative increase in plasma protein binding compared to normal-weight individuals may be evident
• This, combined with increased Vd for lipophilic drugs and increased cardiac output, significantly alters anaesthetic drug pharmacokinetics in obese patients

D. Renal Failure (CKD/AKI)

• Increased Vd in most CKD patients due to increased plasma volume and decreased plasma protein binding
• Plasma protein binding is highly variable in renal failure:
  • Acidic drugs: reduced binding (e.g., phenytoin - therapeutic levels are 10-20 mg/mL normally but only 4-10 mg/mL in renal failure)
  • Basic agents (e.g., amide local anaesthetics): increased binding
• "Normal" drug levels may reflect dangerously high active (unbound) drug levels in renal failure

E. Local Anaesthetics - Specific Considerations

• Local anaesthetics bind primarily to HSA and AGP once they enter the vascular compartment
• Greater lipid solubility correlates with greater plasma protein binding and also greater tissue uptake
• Protein binding of bupivacaine and ropivacaine is greater than lidocaine → lower fetal blood levels during epidural anaesthesia (less placental transfer)
• Chloroprocaine has the least placental transfer because it is rapidly hydrolyzed by plasma cholinesterase in the maternal circulation

F. Opioid Pharmacokinetics

• Opioid protein binding is to both albumin and AGP
• Physical and chemical properties affecting opioid pharmacokinetics include: molecule size, pKa, protein binding, and lipid solubility
• Protein binding affects passage across the blood-brain barrier and both PK and PD characteristics
• A small increase in pH (e.g., respiratory alkalosis) increases the nonionized form of morphine, fentanyl, sufentanil, and remifentanil → greater CNS penetration

4. Summary Table: Plasma Proteins and Anaesthetic Drug Binding

Sources

• Miller's Anesthesia, 2-Volume Set, 10e - Plasma protein binding in local anesthetics (paediatric chapter), Protein Binding (neonatal PK), Geriatric Drug Pharmacology
• Barash, Cullen & Stoelting's Clinical Anesthesia, 9e - Distribution (drug-drug interactions via protein binding), Opioid Pharmacokinetics, Drug Prescribing in Renal Failure, Pharmacologic Principles in Obesity
• Morgan & Mikhail's Clinical Anesthesiology, 7e - Local anesthetic distribution (tissue/blood partition coefficient), Placental transfer of anaesthetic agents

Role of Plasma Proteins in Anaesthesia

Key Plasma Proteins

Pharmacokinetic Importance

• Only free (unbound) fraction is pharmacologically active
• Protein binding determines:
  • Volume of distribution (Vd) - high binding → low Vd (e.g., alfentanil); low binding → high Vd (e.g., fentanyl, 300 L)
  • Drug effect intensity at the receptor
  • Rate of hepatic metabolism and renal excretion

Clinical Scenarios - "Must Know for Exams"

1. Neonates / Infants ⭐

• Both albumin and AGP are severely reduced at birth
• AGP: 0.2–0.3 g/L at birth vs. 0.7–1.0 g/L adult (reaches adult level at 1 year)
• → Free fraction of all local anaesthetics increased → reduce aminoamide doses significantly
• AGP rises with surgical stress/infection → protective (increases bound fraction of ropivacaine)
• High hematocrit (>70%) in neonates traps local anaesthetics in RBCs → lowers peak Cmax but extends half-life

2. Elderly

• Albumin decreased → higher free fraction of benzodiazepines and opioids → reduce doses
• AGP altered → affects local anaesthetic dosing

3. Renal Failure (CKD)

• Plasma protein binding is variable:
  • Acidic drugs → reduced binding (e.g., phenytoin: therapeutic range drops from 10–20 to 4–10 mg/mL)
  • Basic drugs (amide local anaesthetics) → increased binding
• "Normal" drug levels may represent dangerously high active (unbound) levels

4. Obesity

• Albumin and total protein: not significantly changed
• AGP and free fatty acids: increased → reduces free drug concentration
• Net effect: relative increase in plasma protein binding vs. normal weight

5. Local Anaesthetics

• Bind to both HSA and AGP; affinity of AGP is 5,000–10,000× greater than albumin
• Greater lipid solubility → greater protein binding AND greater tissue uptake
• Bupivacaine/ropivacaine > lidocaine in protein binding → less placental transfer

Drug Displacement - Clinically Overstated

• Unoccupied binding sites far exceed drug molecules given clinically
• Liver metabolizes any sudden influx of free drug (flow-limited metabolism)
• No documented clinically relevant protein-binding drug-drug interactions for opioids/hypnotics
• Exception: drugs with all three of - high protein binding + high hepatic extraction ratio + narrow therapeutic index

One-liner Summary for Viva

"Plasma proteins (albumin for acidic drugs, AGP for basic drugs) determine the free fraction of anaesthetic agents. Reduced protein levels (neonates, elderly, liver/renal disease) increase free drug → exaggerated effect → dose reduction required. AGP is the key protector against local anaesthetic systemic toxicity."