Pharmacogenetics: why patients respond differently to the same drug
Pharmacogenetics looks at how the genes a person inherits change that person's response to a drug, so a standard dose can work well in many people but poorly in one.
Remember
When a standard dose works poorly in someone who takes it as prescribed, inherited variation in how the body handles the drug, or in the drug's target (such as a receptor, the protein a drug binds to in order to act), can be the reason.
Doctors choose a standard dose from average results in groups of patients, but a particular person may differ from that average. Pharmacogenetics studies how the gene variants (slightly different versions of genes) that a person inherits alter the response to a drug. The closely related pharmacogenomics covers the same ground across the whole genome (a person's complete set of genes).
Genes can alter drug response in two main ways. One is the enzymes (proteins that break drugs down): a change there can leave the blood level too high or too low. The other is the drug's target, such as a receptor (a protein that a drug binds to in order to act): a change there can mean a smaller effect from the same blood level.
About 3 in 10 patients show no response to statins (drugs given to lower LDL cholesterol), and about 4 in 10 show no response to a given beta-blocker (a drug that can be prescribed for hypertension). Much of this variation is under genetic control.
CYP2D6, a drug-metabolising enzyme, is a well-studied example. People who are poor metabolisers, meaning they have reduced activity of this drug-metabolising enzyme, have greater exposure to the beta-blocker metoprolol, and their heart rate falls further. At the other extreme, a person who clears a drug unusually fast, for example through duplicated copies of an enzyme gene (an ultra-rapid metaboliser), can need larger or more frequent doses before the blood level is useful.
Poor response despite good adherence (taking tablets as prescribed) at an adequate dose, with no benefit from the outset, can have a pharmacogenetic cause. A close relative who responds unusually as well can point to an inherited cause. With adherence confirmed and no interacting drugs, a genetic cause is a reasonable leading explanation, although not the only possible one.
Key facts
- Definition
- the study of how a person's inherited genetic variation changes their response to a drug.
- Two main routes
- genes can change the enzymes that break a drug down, or the drug's target, such as a receptor.
- Both directions
- a standard dose can work too poorly in one person and too strongly in another, for example with marked bradycardia (a slow heart rate).
- Scale
- about 3 in 10 patients show no response to statins and about 4 in 10 to a given beta-blocker, with much of that variation under genetic control.
- Neighbouring terms
- pharmacokinetics is the body's effect on a drug and pharmacodynamics is the drug's effect on the body; pharmacogenetics asks why those differ between people because of inherited genes.
- Harm
- about 7% of serious adverse drug reactions (harmful, unintended effects of a medicine) can be attributed to person-to-person genetic variability.
Exam traps
- Tolerance, a loss of effect that normally follows an initial response, does not account for a drug that gave no benefit from the outset: tolerance develops during repeated exposure to a drug, whereas inherited differences are present before the first dose.
- Pharmacovigilance, the monitoring of medicines for adverse effects after they are licensed, does not explain why one person fails to respond to a standard dose, because it collects reports of suspected harm across a population.
- A difference in average response between ethnic groups does not explain how an individual will respond, because a group average is only a description.
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