Hydralazine: the blood-pressure drug where the right dose depends on an enzyme
Hydralazine has been in use for so long that a gene test for it feels almost anachronistic, which is what makes its 2025 guideline interesting: an old drug turns out to have a clean, dose-shifting genetic signal that was hiding in plain sight.
Also sold as: Apresoline, BiDil component.
What hydralazine is
Hydralazine is a vasodilator, a drug that relaxes blood vessels to lower blood pressure. It is one of the older antihypertensives and is still used, including in heart failure where it is often paired with a nitrate. It is taken several times a day and titrated up to effect, which is exactly the setting where knowing a person's likely dose range in advance is useful.
Why your genes come into it
NAT2 is the enzyme that acetylates hydralazine, and it sorts people into slow, intermediate and rapid acetylators depending on the gene variants they carry. The published guidance labels these as poor, intermediate and rapid metabolizer groups, and for NAT2 those are the same thing said two ways. Slow acetylators clear hydralazine less efficiently, so they reach higher blood levels from a given dose and the guidance starts them low and titrates with care. Faster acetylators clear it more efficiently, so they tend to need a higher maintenance dose to get the same blood-pressure effect, and starting them too low risks treating them with a dose that was never going to work. The gene does not change what hydralazine does, only how much of it a given dose leaves in the body.
What published guidance says
The rows below restate CPIC's published guidance for each possible NAT2 result. They describe the dose range a prescriber is likely to aim for, not a dose for anyone to set alone. Hydralazine is titrated to blood-pressure response and its dose is adjusted over time by the prescriber managing it, so this is context that explains why two people end up on very different doses, not an instruction.
NAT2
| If your NAT2 result is | What that means | Published CPIC guidance |
|---|---|---|
| Intermediate Metabolizer | Predicted to have reduced plasma concentrations and efficacy of hydralazine compared to NAT2 poor metabolizers. | Per CPIC (A): "Consider a starting total daily dose of at least 75 mg. Titrate up to 300 mg total daily hydralazine dose as tolerated. NAT2 intermediate metabolizers typically require a 50-100% higher maintenance dose compared to poor metabolizers." |
| Poor Metabolizer | Predicted to have increased hydralazine plasma concentrations compared to NAT2 rapid and intermediate metabolizers, which may lead to both increased efficacy and adverse effects, including drug-induced systemic lupus erythematosus. | Per CPIC (A): "Initiate therapy at a total daily dose of 40 to 75 mg. Carefully titrate dose upward to clinical effect or guideline-recommended dose; use caution with total daily hydralazine doses of 200 mg or more." |
| Rapid Metabolizer | Predicted to have reduced plasma concentrations and efficacy of hydralazine compared to NAT2 poor metabolizers. | Per CPIC (A): "Consider a starting total daily dose of at least 75 mg. Titrate up to 300 mg total daily hydralazine dose as tolerated. NAT2 rapid metabolizers typically require a 50-100% higher maintenance dose compared to poor metabolizers." |
Can your DNA file answer this?
NAT2 is not part of the standard chip or variant-file report, and the reason is how the acetylator type is built. It depends on which variants sit together on the same copy of the chromosome, and a chip that reads each position on its own cannot tell someone carrying two variants on one copy from someone carrying one on each. Aligned reads can often resolve that arrangement, so Aimosti reads NAT2 from a BAM or CRAM file as part of the Deep Read panel, and where the reads cannot settle it the result is reported as Indeterminate. A consumer chip file cannot answer this one reliably.
A genotyping chip reads only a few hundred thousand pre-selected positions, about 0.02% of your genome, chosen for common variation. It does not sequence the rest, so it cannot find the rare or novel pathogenic variants the clinical and carrier modules look for: a “no finding” from chip data means “this chip never looked”, far more so than with whole-genome sequencing. Chip data suits common-variant traits, pharmacogenomic tag SNPs, and haplogroup ancestry, not clinical or carrier screening.
Common questions
I have heard hydralazine can cause a lupus-like reaction. Is that genetic?
There is a recognised association: a lupus-like syndrome linked to hydralazine has been reported more in slow acetylators and at higher cumulative doses, which is part of why acetylator status has long been of interest for this drug. The published dosing guidance is built around blood levels and effect rather than that reaction specifically, so treat the lupus link as background and any new symptoms on the drug as a reason to contact the prescriber promptly.
If I am a slow acetylator, is hydralazine dangerous for me?
Not dangerous as such, but it is a reason to start low and titrate carefully, because you reach higher levels from a given dose than a fast acetylator would. That is what the guidance builds in. The dose is still set by your blood-pressure response over time, with the genotype as a starting expectation rather than a fixed number.
Why would a fast acetylator need a higher dose?
Because they clear the drug more efficiently, so more of each dose is removed before it acts, and a dose that suits a slow acetylator can be too little for them. The practical risk at the fast end is undertreatment: a blood pressure that stays high on a dose that looked reasonable. The guidance accounts for that by expecting a higher maintenance dose in this group.