BMS 123 · Common Core (Tronc commun)Section 3.4 · Drug metabolism
Section 13 of 27
What changes drug metabolism
Explain enzyme induction and inhibition with named examples, describe the physiological factors that change metabolism, and predict the consequence of a pharmacokinetic interaction.
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Why this matters
Two patients can receive the same dose of the same drug and end up with very different blood levels, because metabolism is modulated by other drugs, by the environment, by age, by genetics and by disease. Induction and inhibition are the commonest mechanism behind dangerous drug–drug interactions, and they are among the few that a health worker can anticipate before harm occurs. This section turns the chemistry of 3.1 to 3.3 into bedside prediction.
What you need to know first
You need section 3.1 for CYP450 and microsomal enzymes, and sections 3.2 and 3.3 for the reactions that can be induced or inhibited, including glucuronidation with its UDP-glucuronic acid cofactor. Nothing else is assumed.
Words to know (6)
Enzyme induction
An increase in the amount of metabolising enzyme caused by a substance, so that the enzyme’s metabolic capacity rises. Rifampin and phenobarbital are classic inducers of CYP450 enzymes.
Enzyme inhibition
A reduction in metabolising capacity, produced by competition for the active site, by irreversible destruction of the enzyme or by depletion of its cofactor. Omeprazole inhibits the enzyme that metabolises warfarin, so warfarin accumulates.
Competitive inhibition
The commonest form of enzyme inhibition: a drug with higher affinity for the enzyme occupies the active site and slows the metabolism of a lower-affinity drug. Two drugs that share one CYP450 isoform compete for the same active site.
Pharmacokinetic drug–drug interaction
An interaction in which one drug changes the absorption, distribution, metabolism or excretion of another, usually by changing its concentration. Induction or inhibition of metabolism is a pharmacokinetic interaction, not a change of mechanism.
Polypharmacy
The use of several medicines at the same time, which increases the risk of drug–drug interactions; it is common in elderly patients. A patient taking six medicines has a much higher chance of an interaction than one taking two.
Enzyme polymorphism
Inherited variation in a metabolising enzyme that divides a population into phenotypes with different metabolic activity. Acetylation of isoniazid distinguishes fast, intermediate and poor acetylators.
One idea at a timeIdea 1 / 6
In one sentence Pesticides, industrial chemicals, smoke, food supplements, food additives and other drugs can either induce or inhibit metabolising enzymes.
The environment modulates metabolising enzymes
The activity of metabolising enzymes can be modulated by exposure to exogenous compounds. The notes list pesticides, industrial chemicals, smoke, food supplements, food additives and other drugs. These substances may either induce or inhibit metabolising enzymes, and the direction matters enormously: induction usually lowers the concentration of an active drug, while inhibition usually raises it. Because these exposures come from work, diet and habits rather than from prescriptions, they are easy to miss when a patient is assessed. A careful drug history therefore asks not only what medicines are taken but also what the patient eats, drinks, smokes and handles at work.
For example
A worker exposed to industrial solvents may metabolise a drug differently from a colleague who takes the same medicine at the same dose.
Pause and check yourself
Name three environmental exposures that can modify drug metabolism.
Show the answer
Pesticides, industrial chemicals and cigarette smoke are examples; food supplements, food additives and other drugs also modulate metabolising enzymes.
Read detailed explanations
Why induction takes days while inhibition acts at once
Induction and inhibition look symmetrical on a diagram but differ in time and mechanism. An inducer such as phenobarbital, rifampin, carbamazepine, phenytoin or dexamethasone increases the amount of enzyme protein, usually by switching on the gene that codes for it and increasing synthesis in the smooth endoplasmic reticulum. Making protein takes hours to days, so induction builds up slowly, reaches a new steady state after one to two weeks, and fades slowly when the inducer is stopped. For a drug that is inactivated by that enzyme, the result is a lower blood level and loss of effect; for a prodrug that must be activated, the same induction increases the effect. Inhibition is different. Competitive inhibition, the commonest form, needs only that the inhibitor be present at the same time as the substrate, so it starts with the first dose and disappears as the inhibitor is cleared. Irreversible inactivation destroys enzyme molecules and lasts until new enzyme is synthesised, which can be several days. Cofactor depletion, for example exhausting the UDP-glucuronic acid needed by Phase II enzymes, reduces capacity without touching the enzyme protein. Inhibition therefore raises the concentration of the affected drug, prolongs its effect and increases its toxicity, and it does so much faster than induction lowers it.
Acetylation polymorphism and isoniazid: fast, intermediate and poor acetylators
Acetylation of a number of drugs is polymorphic, which means that the population is not one group but a small number of distinct phenotypes. For isoniazid, the notes describe three. Fast acetylators have functional enzyme activity; intermediate acetylators have diminished activity; poor acetylators have little or no activity. The trait is inherited, and its incidence varies markedly among different populations, so the same dose can produce very different blood levels in different parts of the world. The clinical consequence is a trade-off rather than a simple rule. A poor acetylator clears isoniazid slowly, so the drug stays in the body longer and accumulates; a fast acetylator clears it quickly, so the drug may be present for a shorter time. Other drugs handled by the same N-acetyltransferase enzymes, such as dapsone, follow the same split. Polymorphism of this kind is why modern teaching treats the dose as a starting point and looks for individual variation from genetics, age, disease and other drugs before concluding that a treatment has failed. It also explains why the same medicine can be well tolerated in one population and troublesome in another.
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Induction and inhibition side by side
Induction builds more enzyme over days and lowers the level of an active drug. Inhibition reduces enzyme activity at once, so the drug accumulates, its effect is prolonged and toxicity becomes more likely.
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01 / 5Induction
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Induction
Certain substances stimulate the synthesis of metabolising enzymes and increase their metabolic capacity. Induction builds up over hours to days, reaches a new steady state after one to two weeks, and fades slowly when the inducer is stopped.
Schematic comparison, not to scale. The lists are representative examples from the lecture notes, not a complete list of inducers and inhibitors.
Key points to remember
✓Environmental exposures — pesticides, industrial chemicals, smoke, food supplements, additives and other drugs — induce or inhibit metabolising enzymes.
✓Inducers named in the notes include alcohol, cigarette smoke, phenobarbital, rifampin, carbamazepine, dexamethasone and phenytoin.
✓Inhibition works by competition, irreversible inactivation or cofactor depletion; it raises concentration, prolongs effect and increases toxicity.
✓Inhibitors named in the notes include omeprazole, cimetidine, erythromycin, ketoconazole, ritonavir and grapefruit juice.
✓Physiological factors: age, sex and pregnancy, genetic polymorphism such as acetylation of isoniazid, and organ disease (cirrhosis, cardiac failure, hypothyroidism).
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Worked example
Two prescriptions change one patient’s warfarin level. A patient takes warfarin and is stable. The prescriber first adds omeprazole for gastritis, and later the patient starts rifampin for tuberculosis. Predict what happens to warfarin metabolism, to the anticoagulant effect, and to the patient.
Warfarin is eliminated mainly by hepatic metabolism, so its steady blood level reflects a balance between the dose taken and the rate at which liver enzymes clear it.
Omeprazole inhibits the enzyme that handles warfarin. Competition for the active site slows warfarin metabolism, so its plasma concentration rises.
The higher concentration inhibits coagulation more strongly than before, so bleeding and haemorrhage become more likely even though the warfarin dose has not changed.
Rifampin does the opposite: it induces new enzyme protein, so warfarin is metabolised faster, its concentration falls, and anticoagulation may become insufficient.
Both events are pharmacokinetic interactions: the mechanism of warfarin is unchanged, but the amount present is not. The response is to anticipate, monitor and adjust rather than to blame the drug.
Induction and inhibition pull the same concentration in opposite directions. Whenever a medicine is added to or stopped in a patient taking a narrow-margin drug, ask which direction the interaction will push.
Common misconception
Beginners often think that an inducer increases the effect of a drug and that inhibition weakens it. The opposite is usually true. An inducer builds more enzyme, so an active drug is removed faster and its effect falls; an inhibitor slows removal, so the drug accumulates and both its effect and its toxicity rise. The exception is a prodrug, whose activation rises with induction.
Check your reasoning
A patient taking several medicines develops a new symptom. Before blaming the new symptom on a disease, how would you decide whether it comes from a metabolic drug interaction?
Reveal an answer
Check whether any recently added or stopped medicine is a known inducer or inhibitor, whether the affected drug is metabolised by CYP450 or by conjugation, and whether its blood level would be expected to rise or fall. If the symptom is an exaggeration of the affected drug’s known effect, an interaction becomes much more likely, and the timing of the change supports or weakens the hypothesis.
Where this comes from
BMS 123 General Pharmacology II lecture notes · Lecture 3: Factors affecting drug metabolism — environmental, induction, inhibition and physiological factors
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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.