BMS 123 · Common Core (Tronc commun)Section 2.3 · Drug distribution
Section 8 of 27
Plasma protein binding
Name the plasma proteins that carry drugs, explain the free–bound equilibrium, and predict the clinical consequences of binding and of displacement.
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Why this matters
Most drugs travel in the blood attached to protein, and only the unattached fraction can act. That single fact explains why two drugs given together can suddenly become dangerous, why liver disease changes the effect of a drug whose dose has not changed, and why a blood level measured in the laboratory can mislead you if you forget about binding.
What you need to know first
You need the idea from the previous sections that a drug moves between blood and tissues, and that only a small part of a dose may be present in plasma at any time. No biochemistry is assumed: the words protein, acid and base are used in their everyday scientific sense.
Words to know (4)
Plasma protein binding
The reversible attachment of a drug to proteins in the blood, which keeps the complex inside the vessels. Warfarin is about 99% bound, so almost all of it circulates as an inactive complex.
Free drug
The unbound fraction in plasma, which can leave the vessel, reach receptors and be eliminated. Only the free 1% of warfarin produces its anticoagulant effect.
Albumin
The most abundant plasma protein, which binds neutral and acidic drugs such as aspirin. Low albumin in cirrhosis leaves more acidic drug free in the plasma.
Displacement
The replacement of one drug by another at the same protein binding site because it has a higher affinity. Aspirin, sulfonamides and chloramphenicol can displace warfarin and cause bleeding.
One idea at a timeIdea 1 / 6
In one sentence Plasma proteins and other macromolecules bind drugs and carry them through the circulation.
Plasma proteins carry drugs through the blood
Plasma proteins, and macromolecules such as glycoproteins, lipoproteins and blood cells, bind endogenous substances and foreign molecules, including drugs. Most drugs are relatively lipid-soluble and poorly soluble in plasma water, so binding to macromolecules helps to carry them inside the plasma. Different drugs have very different affinities for these carriers, ranging from almost no binding to more than 90%. Some drugs are selective for one protein and others bind several, so the carrier is not the same for every molecule. Binding turns an insoluble molecule into a transportable complex.
For example
Most of the warfarin in blood travels attached to albumin; only a tiny free fraction remains dissolved in the water of the plasma.
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Why does binding to plasma proteins help a lipid-soluble drug?
Show the answer
Because a lipid-soluble drug dissolves poorly in plasma water, and attachment to a macromolecule keeps it in the circulation for transport.
Read detailed explanations
The arithmetic and the biology of displacement
The warfarin example is worth pushing further, because the arithmetic of binding is not linear near the top of the scale. When a drug is 99% bound, the free fraction is 1%. Lower the binding to 98% and the free fraction becomes 2%: the free concentration has doubled. Lower it again to 90% and the free fraction is 10%, a tenfold rise. The lesson is that a small absolute change in binding has a large relative effect on free drug precisely when binding is already high, which is the situation for the drugs that matter most. Biology then softens the arithmetic in two ways. First, the extra free drug is available to the liver and kidney, so clearance rises and the plasma level falls back towards equilibrium, which is why the clinical effect is usually less dramatic than the raw calculation. Second, warfarin itself is partly cleared by metabolism that can be saturated or inhibited, so the final outcome depends on both binding and metabolism. Clinically, the safest statement is that displacement raises the free fraction and shortens the time to a new equilibrium, but the size of the effect must be judged in the whole patient, not from the percentage alone. This is why a patient on warfarin is monitored rather than simply told that a new medicine is safe.
When the carrier protein itself changes
Binding is only as stable as the protein that provides it, and protein levels move in disease. Albumin falls in hepatic cirrhosis, in nephrosis where protein is lost in the urine, after trauma and with aging. When albumin falls, the same total amount of a bound drug has fewer sites to occupy, so a larger fraction circulates free and the patient can become toxic at a dose that was previously safe. This is especially important for a drug with a narrow margin, and it explains why a normal-looking total level must be interpreted with the patient’s albumin in mind. The opposite can happen with α1-acid glycoprotein, which binds weak basic drugs such as lidocaine and is an acute-phase protein: its level rises in inflammation, infection, trauma and myocardial infarction. More binding sites mean a smaller free fraction at the same total concentration, so the measured total may look adequate while the free, active concentration is low. Other changes act indirectly. A fat-rich meal raises free fatty acids, which compete with acidic drugs for albumin. In pregnancy the plasma volume expands and albumin may fall. The general rule is that binding is a relationship between drug and protein, and either partner can change.
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Plasma protein binding
Drug binds reversibly to plasma proteins; the complex stays inside the vessel while the free drug leaves to diffuse into tissues and produce the effect.
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01 / 5Albumin
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Albumin
The most abundant plasma protein and the main carrier of neutral and acidic drugs, such as aspirin. Each albumin molecule offers several binding sites, and a drug may occupy one of them while leaving the others available to different molecules.
Schematic, not to scale. The number of drawn binding sites is illustrative; real albumin carries several sites and a drug’s bound fraction ranges from zero to more than 90% depending on the molecule.
Key points to remember
✓Plasma proteins and macromolecules bind drugs reversibly and carry lipid-soluble molecules through the plasma.
✓Albumin binds neutral and acidic drugs, α1-acid glycoprotein weak bases, lipoproteins weak basic lipophilic drugs, and globulins carry steroids and fat-soluble vitamins.
✓Only free drug leaves the vessel, acts at receptors and is eliminated; the bound complex is an inactive reserve.
✓Extensive binding gives a low Vd, a slower onset, a longer duration of action and slow elimination.
✓Displacement by a higher-affinity drug raises the free fraction and can cause toxicity, as when aspirin displaces warfarin.
Go deeper
Worked example
Why a 1% change in binding matters. A patient takes warfarin, which is 99% bound to albumin. Imagine 100 units of warfarin in the plasma: 99 units are on the protein and 1 unit is free. The patient is then given a drug that displaces warfarin, and binding falls to 98%. Work out what happens to the free fraction.
Before displacement: 100 units total, 99 bound and 1 free. The free fraction is 1%.
After displacement: binding falls from 99% to 98%, so 98 units are bound and 2 units are free.
Compare the free drug: it has risen from 1 unit to 2 units. The free concentration has doubled even though the total amount of warfarin is unchanged.
Relate the increase to the drug’s margin: warfarin has a narrow therapeutic margin, so doubling the free anticoagulant can push coagulation too far.
Note the limit of the calculation: the liver also metabolises the extra free drug, so the rise in effect is smaller than the arithmetic suggests and varies between patients.
A one-point fall in binding doubled the active fraction. This is why displacement interactions are dangerous for a highly bound drug with a narrow margin, and why the free fraction matters more than the total concentration.
Common misconception
Beginners often assume that the total amount of drug in the blood is what matters, so an unchanged blood level means an unchanged effect. In fact a change in binding can double the free, active fraction while the total level and the dose stay the same.
Check your reasoning
A patient with cirrhosis has low plasma albumin and takes a highly bound drug. The measured total drug level is normal. Why should you still worry about toxicity?
Reveal an answer
Because fewer binding sites mean that a larger share of the same total amount is free. The free concentration, which produces the effect, is higher than it would be with normal albumin, so the patient can be toxic even though the total measured level looks reassuring.
Where this comes from
GENERAL PHARMACOLOGY II lecture notes (PHM112), St. Louis University Institute, Douala · Lecture 2: Drug Distribution, section 1.5.1 (plasma protein binding and drug–drug interactions)
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About this course and its sources
Bilingual lessons organised from the supplied BMS 123 General Pharmacology II lecture notes (Principles of Pharmacokinetics and Principles of Pharmacodynamics). Diagrams are original educational schematics; pharmacology, nursing and French-language review are pending.