Lodoz Mechanism of Action

Pharmacotherapeutic group: Combination of an adrenoceptor blocking agent (β1-selective) and a thiazide diuretic. ATC code: C07BB07.
Pharmacology: Pharmacodynamics: Clinical studies have shown that the antihypertensive effects of these two drugs 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 is a highly β1-selective adrenoceptor blocking agent with no intrinsic sympathomimetic activity and without significant membrane-stabilizing activity.
As with other β1-receptor blocking drugs, the mechanism of bisoprolol's antihypertensive effect has not been completely established. However, it has been shown that the drug produces a marked decrease in plasma renin and a reduction in heart rate.
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.
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 also Precautions).
Pharmacokinetics: Bisoprolol: Absorption: Tmax 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 the 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 a dose (unchanged) as well as the metabolites are excreted in urine. The total clearance is approximately 15 l/h.
Hydrochlorothiazide: Absorption: The bioavailability of hydrochlorothiazide shows between-subject variability and ranges from 60-80%. Tmax 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 drug by glomerular filtration and active tubular secretion. The terminal t½ 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 Cmax.
Hydrochlorothiazide crosses the placental barrier and is excreted in human milk.
Toxicology: Preclinical safety data: Bisoprolol or hydrochlorothiazide have not been found to be hazardous to humans according to the standard preclinical toxicity tests (long-term toxicity, mutagenicity, genotoxicity and carcinogenicity tests). Like other beta-blockers, bisoprolol at high doses has been found in animal experiments to cause toxic effects to the mother (decreased food intake and body weight gain) and to the embryo/foetus (increased late resorptions, reduced birth weight of the offspring, retardation of the physical development up to the end of lactation). However, bisoprolol as well as hydrochlorothiazide were not teratogenic. There was no increase in toxicity when both components were given in combination.