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Hypertension Canada provides annually updated, evidence-based guidelines for the diagnosis, assessment, prevention, and treatment of hypertension in adults and children. This year, the adult and pediatric guidelines are combined in one document. The new 2018 pregnancy-specific hypertension guidelines are published separately. For 2018, 5 new guidelines are introduced, and 1 existing guideline on the blood pressure thresholds and targets in the setting of thrombolysis for acute ischemic stroke is revised. The use of validated wrist devices for the estimation of blood pressure in individuals with large arm circumference is now included. Guidance is provided for the follow-up measurements of blood pressure, with the use of standardized methods and electronic (oscillometric) upper arm devices in individuals with hypertension, and either ambulatory blood pressure monitoring or home blood pressure monitoring in individuals with white coat effect. We specify that all individuals with hypertension should have an assessment of global cardiovascular risk to promote health behaviours that lower blood pressure. Finally, an angiotensin receptor-neprilysin inhibitor combination should be used in place of either an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker in individuals with heart failure (with ejection fraction < 40%) who are symptomatic despite appropriate doses of guideline-directed heart failure therapies. The specific evidence and rationale underlying each of these guidelines are discussed.

Hypertension Canada provides annually updated, evidence-based guidelines for the diagnosis, assessment, prevention, and treatment of hypertension. This year, we introduce 10 new guidelines. Three previous guidelines have been revised and 5 have been removed. Previous age and frailty distinctions have been removed as considerations for when to initiate antihypertensive therapy. In the presence of macrovascular target organ damage, or in those with independent cardiovascular risk factors, antihypertensive therapy should be considered for all individuals with elevated average systolic nonautomated office blood pressure (non-AOBP) readings ≥ 140 mm Hg. For individuals with diastolic hypertension (with or without systolic hypertension), fixed-dose single-pill combinations are now recommended as an initial treatment option. Preference is given to pills containing an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker in combination with either a calcium channel blocker or diuretic. Whenever a diuretic is selected as monotherapy, longer-acting agents are preferred. In patients with established ischemic heart disease, caution should be exercised in lowering diastolic non-AOBP to ≤ 60 mm Hg, especially in the presence of left ventricular hypertrophy. After a hemorrhagic stroke, in the first 24 hours, systolic non-AOBP lowering to < 140 mm Hg is not recommended. Finally, guidance is now provided for screening, initial diagnosis, assessment, and treatment of renovascular hypertension arising from fibromuscular dysplasia. The specific evidence and rationale underlying each of these guidelines are discussed.

Due to high basal interindividual variation in cytochrome P450 3A (CYP3A) activity and susceptibility to drug interactions, there has been interest in the application of efficient probe drug phenotyping strategies, as well as endogenous biomarkers for assessment of in vivo CYP3A activity. The biomarkers 4b-hydroxycholesterol (4bHC) and 6b-hydroxycortisol (6bHCL) are sensitive to CYP3A induction and inhibition. However, their utility for the assessment of constitutive CYP3A activity remains uncertain. We investigated whether endogenous plasma biomarkers (4bHC and 6bHCL) are associated with basal CYP3A metabolic activity in healthy subjects assessed by a convenient single-time-point oral midazolam (MDZ) phenotyping strategy. Plasma 4bHC and 6bHCL metabolic ratios (MRs) were analysed in 51 healthy adult participants. CYP3A activity was determined after administration of an oral MDZ microdose (100 lg). Simple linear and multiple linear regression analyses were performed to assess relationships between MDZ oral clearance, biomarkers and subject covariates. Among study subjects, basal MDZ oral clearance, 4bHC and 6bHCL MRs ranged 6.5-, 10-and 13-fold, respectively. Participant age and alcohol consumption were negatively associated with MDZ oral clearance (p = 0.03 and p = 0.045, respectively), while weight and female sex were associated with lower plasma 4bHC MR (p = 0.0003 and p = 0.032, respectively). Neither 4bHC nor 6bHCL MRs were associated with MDZ oral clearance. Plasma 4bHC and 6bHCL MRs do not relate to MDZ single-time-point metabolic phenotype in the assessment of constitutive CYP3A activity among healthy individuals.It is well recognized that cytochromes P450 3A4 (CYP3A4) and CYP3A5 are important human drug-metabolizing enzymes with high interindividual variability in hepatic and intestinal activities. This is due to environmental, genetic, developmental, disease and seasonal control, including significant susceptibility to drug interactions [1][2][3][4][5][6]. Indeed, active CYP3A5 is genetically determined [7] while reduced CYP3A activity is associated with CYP3A4*22 [8], and peroxisome proliferator-activating receptor alpha (PPARa rs4253728) [9] while increased CYP3A activity is linked with CYP oxidoreductase POR*28 [10] polymorphism. Importantly, drug interactions such as those caused by enzyme inhibition with itraconazole and enzyme induction after rifampin treatment can result in a dramatic 400-fold range in CYP3A activity in human beings [11]. Furthermore, conditions including cirrhosis [12], chronic hepatitis C infection [13], critical illness [14], cancer [15,16] and kidney disease [17][18][19] are associated with reduced CYP3A activity. Given such wide differences in enzyme activity among individuals, there has long been interest in various methods to quantify in vivo CYP3A function.The most widely used and accepted method to assess CYP3A activity is to examine midazolam (MDZ) pharmacokinetics [20,21]. CYP3A phenotyping with MDZ has several advantages including rapid and specific elimina...

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