Should antihypertensives be dosed at night?

Circadian rhythm of blood pressure

·         Typically blood pressure is highest early to mid-morning and falls throughout the day

·         Blood pressure was usually lowest at night, called nighttime dipping

o   Drop in systolic pressure by >10%

o   Normal nighttime blood pressure <120/70mmHg

·         Average 24-hour range should be <130/80mmHg

·         The typical rhythm is influenced by both intrinsic and extrinsic factors such as: neurohormonal regulation, physical activity, and dietary sodium

·         Behavioral influences include: mental activity, emotional state, smoking, and alcohol

·         Platelet aggregation, catecholamines, coronary resistance, and vascular resistance increase in the early morning hours, which along with the blood pressure surge can increase the cardiovascular risk in the morning

·         Cardiovascular events and organ damage is better predicted by the 24-hour measurement than a single point measurement due to the consideration of the nighttime blood pressure

·         “Non-dippers”

o   Occurs in 35 to 40% of patients with hypertension

o   Blood pressure reduction of <10% while sleeping (normal reduction- 15-25%)

o   Occurs with increase in adrenergic and decrease in vagal activity during sleep

o   Stronger predictor of cardiovascular events versus daytime blood pressure

·         In a study by Verdecchia et. al., that compared patients with ambulatory hypertension versus those with white coat hypertension, patients who had daytime hypertension with a nighttime dipping pattern had a relative risk of 3.70 (95% CI 1.13-12.5) and those with a non-dipping pattern had a relative risk of 6.26 (95% CI 1.92-20.32) when compared to those with just white coat hypertension

·         A non-dipping pattern of blood pressure may be one of the best predictors of risk of increased cardiovascular events

·         Patients with resistant hypertension, diabetes, or chronic kidney disease are more likely to be non-dippers than patients without these conditions

o     Administration of bedtime anti-hypertensives has been shown to convert patients to dippers

Bedtime versus morning dosing

·         Historically blood pressure was given twice daily (1980’s) but changed due to the attempt to increase medication adherence

·         Bedtime dosing of at least one medication is thought to decrease both the nighttime blood pressure and cardiovascular disease

·         When blood pressure medication is administered in the morning (usually dose about 6-7am) it takes about 60 to 90 minutes to achieve peak concentrations

o   Measurements in the clinic are usually done when this medication is at its maximum concentration

o   This misses the early morning spike of blood pressure

·         Medications such as: HCTZ, atenolol, enalapril, labetalol, nadolol, pindolol, propranolol ER, nifedipine, and others have a short half-life don’t reduce morning blood pressure spikes

·         American Diabetes Association gives nighttime dosing of at least one hypertension agent a level A recommendation

o   Recommendation based on the following study:

§  661 patients  with CKD and taking at least blood pressure medication

§  332 randomized to take all anti-hypertensives in the morning and 329 were supposed to take at least one at bedtime

§  Patients with at least one blood pressure medication at bedtime at a statistically significant lower hazard ratio of events

·         HR= 0.31; CI 0.21-0.46; P<0.001

§  The decline of blood pressure was greater among those having a bedtime dose of medication with a non-dipper profile (P<0.001)

§  The proportion of patients with controlled blood pressure was significantly higher in those patients with a bedtime blood pressure medication

·         56.5% (bedtime dosing) v. 45.2% (morning dosing) (p=0.003)

·         By dosing the medication at bedtime it helps protect the patients during the nighttime period as well as the early morning surge

o   Not found to be a predictable effect

o   Quinapril dosed in the morning or evening had similar effects on the blood pressure during the day, but there was a greater reduction of blood pressure during sleep and a greater rise in morning blood pressure

·         A Cochrane review found 21 studies with 1993 patients compared morning and evening dosing

o   Significantly lower 24-hour blood pressure by 1.71mmHg

o   Morning mean systolic blood pressure was 1.62mmHg lower with evening dosing but not statistically significant

o   No difference in adverse effects with morning and evening doses

·         Risks related to evening dosing of medications

o   It is possible for blood pressures during the nadir of dippers to reach 90/60 mmHg with the medications peaking in 1 to 2 hours it could cause lows during the midnight to 4am period

§  No difference in adverse effects were found between the different dosing time

o   In one study by Hayreh et. al., there was evidence of ocular vascular disorders with nocturnal hypotension

§  166 patients with ocular disorders (anterior ischemic optic neuropathy, glaucoma, and other optic nerve head disorders) patients with visual deterioration had a significantly lower systolic blood pressure (114 +/- 2.5mmHg) than those without deterioration

§  Patients with visual field deterioration had significantly greater mean decreases in systolic blood pressures from daytime readings (46.8+/- 2.5mmHg) v. (35+/-3.1mmHg) without deterioration

§  Some patients with nocturnal hypotension had been taking their antihypertensives at  bedtime

·         The nocturnal hypotension was decreased when the nighttime dosing was discontinued