18B07: Exam Report

Describe protein binding and its significance in pharmacology.

19% of candidates passed this question.

Descriptions of protein binding were generally too brief (e.g. a statement saying that drugs and hormones bind to proteins in the plasma rather than a description of usually reversible binding with a drug-protein equilibrium).

It was expected that the factors which determine protein binding would be described. Marks were attributed if proteins, along with characteristics of the drugs they bind, were named. Candidates achieved better marks if they named the pharmacological parameters affected by protein binding and explained how and why change occurs along with the significance of those changes. Few candidates differentiated between tissue and plasma protein binding and the different effects on the volume of distribution.

Biii / 18B07: Describe protein binding and its significance in pharmacology

Definition

Drug protein binding = the reversible interaction of drugs with proteins in plasma

→ Reversible

→ Fast

→ Obeys LAW OF MASS ACTION

FREE DRUG + FREE PROTEIN ⮂ DRUG-PROTEIN COMPLEX

Plasma Binding Protein

Albumin

  • Neutral/acidic drugs
  • High [ ] (40g/L) → ∴ high capacity

α1 Glycoprotein

  • Basic drugs
  • Acute Phase reactant
  • Low [ ] ∴ low capacity

Lipoproteins

  • Dissolves v. lipid soluble drugs

Tissue Binding

  • RBC, tissue membranes, intracellular DNA

Factors Affecting PPB

Protein Factors

  • [protein]
  • No. of available binding sites

Drug Factors

  • Protein affinity
  • [ ] drug
  • pKa → ↑ionised = ↑PPB
  • Presence of competing drugs for binding sites

Effect of PPB on PK

  • Vd
    • Inversely proportional
    • ↑PPB limits drug passage to other tissues stays in plasma & low Vd
  • t ½ – only free drug is active → bound portion acts as reservoir
  • Clearance – unbound drug has access to drug metabolism & glomerular filtration
  • Toxicity – highly PPB drugs with low access sites e.g. hypoalbuminaemia will have ↑[free drug]

↓

However this is confusing because the free drug [  ] is actually dependent on free drug clearance

↓

As [drug unbound] ↑ so does its clearance

∴no dose alteration is required in states of altered protein binding

Therapeutic Dose Monitoring

  • PPB is actually only important when you measure drug concentrations
  • Measured drug = bound + unbound

∴hypoalbuminaemia

    • Acidic drug (phenytoin) will have ↓bound-pheny = ↓measured total drug concentration
    • Free phenytoin same (as long as phenytoin clearance is normal)
    • Overall will appear that ‘total drug concentration’ is low, but the free concentration is constant
    • But if you ↑dose based on this “low” result, to achieve “therapeutic range” the free [ ] could be toxic!!
    • This is when calculating free phenytoin [] corrected for hypoalbuminaemia is important