BMS 123 · Common Core (Tronc commun)Section 4.2 · Drug excretion and clearance
Section 15 of 27
What changes renal excretion
Explain how molecular size, urine pH, age, blood flow and kidney disease change renal excretion, and apply ion trapping to a poisoning case.
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Why this matters
Two patients can receive the same dose and end up with very different blood levels because their kidneys handle the drug differently. Urine pH, age, renal blood flow and the state of the kidney change excretion enough to turn a safe treatment into accumulation and toxicity. These factors also make ion trapping in overdose a rational manoeuvre rather than a memorised trick, and they explain why the dose that suited a healthy adult may be wrong for the next patient.
What you need to know first
You need the three renal processes from section 4.1 and the idea that a weak acid or base is charged only at some pH values. If the words pKa, ionised and perfusion are new, read the key terms below before starting the ideas.
Words to know (5)
pKa
The pH at which half of a weak acid or base is ionised; it tells you how the drug will behave at a given urine pH. A weak acid with a low pKa is largely ionised in alkaline urine.
Ionised
Carrying an electric charge. An ionised drug dissolves in water and cannot cross the lipid membranes of the tubule. An ionised salicylate stays in the urine instead of returning to the blood.
Ion trapping
Using urine pH to keep a drug in its charged form so that it stays in the urine and is excreted instead of being reabsorbed. Alkalinising the urine traps aspirin as a charged anion.
Renal perfusion
The blood flow reaching the kidney; it sets how much drug can be filtered and secreted each minute. Shock lowers renal perfusion and therefore lowers drug excretion.
Uraemia
The build-up of urea and other protein waste in the blood when the kidneys fail, which itself impairs filtration. Uraemia in chronic kidney disease raises drug levels by slowing excretion.
One idea at a timeIdea 1 / 5
In one sentence Small molecules are filtered, protein-bound drug is not, and large molecules can still be removed by active secretion into the tubule.
Molecular size decides the route, not just the speed
The notes place molecular size first among the factors affecting renal excretion. Small-molecular-weight substances undergo glomerular filtration, while large ones do not. The plasma-protein-bound fraction of a drug behaves like a macromolecule and is not filtered at all. Size is not a simple yes-or-no barrier, however: large molecular size substances may still undergo active tubular secretion, because the carriers in the proximal tubule accept big substrates as well. A large or heavily bound molecule is therefore not automatically retained by the body; it is simply moved through a different door. For a beginner, the useful habit is to ask two separate questions: can this molecule be filtered, and can it be secreted? If the answer to both is no, the kidney will remove very little of it.
For example
Heparin is too large to be filtered, but a smaller protein-bound acid such as penicillin G still reaches the urine because the anion carrier secretes it actively.
Pause and check yourself
Can a large molecule ever be excreted by the kidney?
Show the answer
Yes. It cannot be filtered at the glomerulus, but it may still be secreted into the proximal tubule by an active carrier system that accepts large substrates.
Read detailed explanations
Why charge, not concentration, decides reabsorption
It is tempting to imagine that a high concentration of drug in the filtrate must be reabsorbed, because diffusion normally runs down a gradient. In the nephron the opposite can be true. Reabsorption of a weak acid or base is not driven chiefly by how much drug is present but by how much of it is uncharged, because only the uncharged molecule can dissolve in and cross the lipid membrane of the tubule. A drug can therefore be present at a high total concentration and still be excreted, if nearly all of it is ionised. The proportion that is uncharged depends on the drug’s pKa and on urine pH. Near the pKa, small shifts in pH produce large changes in the ratio of charged to uncharged forms, which is why a modest change in urine pH can produce a disproportionate change in reabsorption. Two practical consequences follow. First, ion trapping works even when the filtrate is concentrated, because the trapped molecule simply cannot cross. Second, when clinicians want a drug to leave quickly, changing urine pH is not a guarantee: urine flow, the time the filtrate spends in the tubule, and the drug’s own lipid solubility all modify the result. The principle is reliable, the size of the effect is not.
From kidney disease to dose: reading the warning signs
Renal impairment is not a single event but a gradient, and its effect on a drug depends on how much of that drug the kidney normally removes. A drug cleared almost entirely by the kidney loses almost all its clearance when renal function falls, so its half-life can lengthen dramatically and repeated doses accumulate. A drug cleared mainly by the liver and only partly by the kidney loses a smaller fraction and may need only a modest adjustment. This is why the useful clinical question is not simply whether the patient has kidney disease, but which proportion of this drug’s elimination the kidney provides. Three warning signs recur in practice. A rising plasma level on an unchanged dose points to reduced clearance. A duration of action that outlasts expectation — sedation that persists, bleeding that does not stop — points the same way. And a new decline in renal perfusion from dehydration, bleeding, shock, heart failure or a new medicine can reduce clearance even when the kidney itself is not diseased. Uraemia adds a further layer, because retained waste products can alter protein binding and therefore change how much free, active drug is present. The result is that monitoring matters more than a single fixed dose, and that dose changes should be followed by observation rather than assumed to be correct.
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Ion trapping: urine pH decides the fate of a drug
A weak acid and a weak base placed in urine of different pH. The charged form stays in the water and is excreted; the uncharged form diffuses back into the blood.
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01 / 5Weak acid (aspirin)
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Weak acid (aspirin)
An acidic drug loses a proton in alkaline urine and becomes a negatively charged anion. A charged molecule is water-soluble, cannot cross the lipid tubule wall, and is carried out in the urine. This is why raising urine pH with sodium bicarbonate speeds the removal of aspirin in overdose.
Schematic, not to scale. The drawing shows the principle of ion trapping; in practice urine pH is changed with medical supervision and the response is measured, not assumed.
Key points to remember
✓Small molecules are filtered, protein-bound drug is not, and large molecules may still be actively secreted.
✓Urine pH, normally 4.5–7.5, decides how much drug is charged and therefore whether it is reabsorbed.
✓Ion trapping is used in overdose: alkalinise for weak acids such as aspirin, acidify for weak bases such as quinine.
✓Newborns excrete 30–40% less than adults and the elderly excrete more slowly as organs degenerate.
✓Low renal blood flow and kidney disease reduce excretion and lead to accumulation, prolonged action and toxicity.
Go deeper
Worked example
Aspirin overdose: choosing the direction of ion trapping. A patient is brought in after taking too much aspirin, which is a weak acid. The team considers changing urine pH to help the body remove it. Work out which direction is correct and why.
Identify the acid–base behaviour of the drug: aspirin is a weak acid, so its charge depends on urine pH, and only the uncharged form can be reabsorbed.
Apply the rule: raising urine pH by alkalinisation with sodium bicarbonate ionises more of the weak acid.
Predict the fate: the charged salicylate is water-soluble and cannot diffuse back across the tubule, so it stays in the filtrate and leaves in the urine.
Check the direction: acidifying the urine would leave more aspirin uncharged and reabsorbed, which is the opposite of what is wanted, and would prolong exposure.
State the wider principle: the same logic in reverse applies to a weak base such as quinine, which is eliminated faster when the urine is acidified.
For a weak acid, alkalinising the urine increases ionisation and excretion. The manoeuvre only works in the direction that charges the drug, and it is carried out under clinical supervision with the patient monitored.
Common misconception
A common error is to believe that any change in urine pH speeds up drug removal. Only the direction that charges the drug works; the opposite change keeps it uncharged and actually increases reabsorption and prolongs its action.
Check your reasoning
A patient with heart failure and a raised blood urea is prescribed a drug that is mainly cleared by the kidney. Explain in your own words why the standard dose may be too high.
Reveal an answer
Heart failure lowers renal blood flow, so less drug reaches the kidney each minute, and uraemia impairs filtration. Both reduce renal clearance. With clearance reduced, the same dose produces a higher and longer-lasting plasma level, so the dose or the interval usually needs review and the patient needs monitoring.
Where this comes from
General Pharmacology II lecture notes — Lecture 4, Drug excretion · Section 2B, factors affecting renal drug excretion
General Pharmacology II lecture notes — Lecture 4, Drug excretion · Section 2B, ion trapping and management of overdose
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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.