Ziac Mechanism of Action

Pharmacology: Pharmacodynamics: Clinical studies have shown that the antihypertensive effects of bisoprolol and hydrochlorothiazide are additive, and the efficacy of the lowest dose, 2.5 mg/6.25 mg, in the treatment of mild-to-moderate essential hypertension has been demonstrated.
The pharmacodynamic effects, including hypokalemia (hydrochlorothiazide), and bradycardia, asthenia, and headache (bisoprolol) are dose-related. Combining both drugs at one-fourth/half the doses used in single-agent therapy (2.5 mg/6.25 mg) aims to reduce those effects.
Bisoprolol: Bisoprolol is a highly selective beta₁-adrenoceptor blocking agent with no intrinsic sympathomimetic activity and without significant membrane-stabilizing activity.
As with other beta₁-receptor blocking agents, the mechanism of bisoprolol's antihypertensive effect has not been completely established. However, it has been shown that bisoprolol produces a marked decrease in plasma renin and a reduction in heart rate.
Hydrochlorothiazide: Non-melanoma skin cancer: Based on available data from epidemiological studies, cumulative dose dependent association between hydrochlorothiazide and NMSC has been observed. One study included a population comprised of 71,533 cases of BCC and of 8,629 cases of SCC matched to 1,430,833 and 172,462 population controls, respectively. High hydrochlorothiazide use (≥50,000 mg cumulative) was associated with an adjusted OR of 1.29 (95% CI: 1.23-1.35) for BCC and 3.98 (95% CI: 3.68-4.31) for SCC. A clear cumulative dose response relationship was observed for both BCC and SCC. Another study showed a possible association between lip cancer (SCC) and exposure to hydrochlorothiazide: 633 cases of lip-cancer were matched with 63,067 population controls, using a risk-set sampling strategy. A cumulative dose-response relationship was demonstrated with an adjusted OR 2.1 (95% CI: 1.7-2.6) increasing to OR 3.9 (3.0-4.9) for high use (~25,000 mg) and OR 7.7 (5.7-10.5) for the highest cumulative dose (~100,000 mg) (see Precautions).
Hydrochlorothiazide is a thiazide diuretic with antihypertensive activity. Its diuretic effect is due to inhibition of active Na+ transport from the renal tubules to the blood, affecting Na+ reabsorption.
Pharmacokinetics: Bisoprolol: Absorption: T_max varies from 1-4 hours. Bioavailability is high (88%); hepatic first-pass extraction is very low; and absorption is not affected by the presence of food.
Kinetics are linear for doses from 5-40 mg.
Distribution: Plasma protein binding is 30%, and the volume of distribution is high (approximately 3 L/Kg).
Biotransformation: 40% of a bisoprolol dose is metabolized in the liver. Bisoprolol metabolites are inactive.
Elimination: The plasma elimination half-life is 11 hours.
Renal clearance and hepatic clearance are approximately comparable, and half of a dose (unchanged) as well as the metabolites are excreted in the urine. The total clearance is approximately 15 L/h.
Hydrochlorothiazide: Absorption: The bioavailability of hydrochlorothiazide shows between-subject variability and ranges from 60-80%. T_max varies from 1.5-5 hours (mean >4 hrs).
Distribution: Plasma protein binding is 40%.
Elimination: Hydrochlorothiazide is not metabolized and is excreted almost entirely as unchanged substance by glomerular filtration and active tubular secretion. The terminal t_½ of hydrochlorothiazide is approximately 8 hours.
The renal clearance of hydrochlorothiazide is reduced and the elimination half-life prolonged in patients with renal and/or cardiac insufficiency. The same applies to elderly subjects, who also show an increase in C_max. Hydrochlorothiazide crosses the placental barrier and is excreted in human milk.