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Plasma protein bindingThe proportion of a drug in the blood that is stuck to blood proteins rather than free to act.Read more → matters because a drug's total level in the blood can be misleading: only the free, unbound fraction is pharmacologically active, and a test that reports only the total can hide a dangerous rise in the active portion. Albumin, the main protein in blood plasma, binds acidic drugs, holding a variable fraction of the drug inactive and unable to reach its site of action. For example, imagine two patients with the same total phenytoin level, one with normal albumin and one with low albumin from malnutrition: the second patient actually has more free, active drug and is more likely to show signs of toxicity despite an identical total level. In practice, this is why the total level alone can mislead when albumin is abnormal.

Only unbound drug can cross membranes, reach receptors and be metabolised or excreted, so protein bindingThe proportion of a drug in the blood that is stuck to blood proteins rather than free to act.Read more → acts as a reservoir that buffers the active free fraction. Hypoalbuminaemia (low blood albumin, common in malnutrition, liver disease and nephrotic syndrome) raises the free fraction of highly protein-bound drugs, since less albumin is available to bind them. This happens even when the total measured level looks unchanged or only mildly high. Phenytoin is the classic example, the 'phenytoin trap': a patient with hypoalbuminaemia can have a normal-looking total phenytoin level while their free, active level is actually toxic. Displacement interactions occur when a second highly protein-bound drug competes for the same albumin binding sites, transiently raising the free fraction of the first drug. For example, imagine a patient on phenytoin with low albumin from liver disease who develops nystagmusRepeated, involuntary back-and-forth eye movements.Read more → (involuntary eye movements) and ataxiaLoss of full control of body movements, causing an unsteady, uncoordinated gait or actions.Read more → (loss of coordination and unsteady movement) despite a 'normal' total phenytoin level: the free level, not the total, explains the toxicity. In practice, this means requesting a free (unbound) level, or correcting the total level for albumin, in any hypoalbuminaemic patient on a highly protein-bound drug.

• A patient with low albumin has a total phenytoin level below range but shows signs of toxicity. What explains this?
• How clinically important are drug interactions caused purely by displacement from plasma proteins?
• Which property of a drug makes it removable by haemodialysis in overdose?

• Free (unbound) drug, the pharmacologically active fraction, unlike the protein-bound fraction, which is inactive and unavailable to reach the site of action.
• Hypoalbuminaemia, raises the free fraction of highly bound drugs like phenytoin, whereas a normal albumin keeps the bound-to-free ratio, and therefore the total level's usefulness, stable.
• Displacement interaction, a second highly protein-bound drug competes for albumin sites and transiently raises the first drug's free fraction, rather than affecting its metabolism or clearanceThe rate at which the body removes a drug from the blood.Read more → directly.
• Basic drugs (e.g. propranolol), bind mainly to alpha-1 acid glycoprotein rather than albumin, unlike acidic drugs such as phenytoin, valproate and warfarin which bind mainly to albumin.

• Assay failure would not produce clinical toxicity.
• Complete metabolism would leave the patient without effect rather than toxic.
• Toxicity is inconsistent with an inadequate dose.
• Displacement does occur; it simply matters less than was once thought.
• The effect is immediate and short-lived rather than delayed.

• Identify the drug, receptor, enzyme or pharmacokinetic change named in the stem.
• Translate it into the immediate mechanism before looking at the options.
• Use timing and the adverse-effect pattern to separate the nearest alternatives.
• Check whether the question asks for mechanism, clinical consequence, monitoring or management.