Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: ACE inhibitors and diuretics, ramipril and diuretics, ATC code C09BA05

Mechanism of action

Ramipril
Ramiprilat, the active metabolite of the prodrug ramipril, inhibits the enzyme dipeptidylcarboxypeptidase I (synonyms: angiotensin-converting enzyme; kininase II).
In plasma and tissue, this enzyme catalyses the conversion of angiotensin I to the active vasoconstrictor substance angiotensin II, as well as the breakdown of the active vasodilator bradykinin. Reduced angiotensin II formation and inhibition of bradykinin breakdown lead to vasodilatation.

Since angiotensin II also stimulates the release of aldosterone, ramiprilat causes a reduction in aldosterone secretion. The average response to ACE inhibitor monotherapy was lower in black (Afro-Caribbean) hypertensive patients (usually a low-renin hypertensive population) than in non-black patients.

Hydrochlorothiazide
Hydrochlorothiazide is a thiazide diuretic. The mechanism of antihypertensive effect of thiazide diuretics is not fully known. It inhibits the reabsorption of sodium and chloride in the distal tubule. The increased renal excretion of these ions is accompanied by increased urine output (due to osmotic binding of water). Potassium and magnesium excretion are increased, uric acid excretion is decreased. Possible mechanisms of the antihypertensive action of hydrochlorothiazide could be: the modified sodium balance, the reduction in extracellular water and plasma volume, a change in renal vascular resistance as well as a reduced response to norepinephrine and angiotensin II.

Pharmacodynamic effects
Ramipril
Administration of ramipril causes a marked reduction in peripheral arterial resistance.
Generally, there are no major changes in renal plasma flow and glomerular filtration rate.
Administration of ramipril to patients with hypertension leads to a reduction in supine and standing blood pressure without a compensatory rise in heart rate.
In most patients the onset of the antihypertensive effect of a single dose becomes apparent 1 to 2 hours after oral administration. The peak effect of a single dose is usually reached 3 to 6 hours after oral administration. The antihypertensive effect of a single dose usually lasts for 24 hours.
The maximum antihypertensive effect of continued treatment with ramipril is generally apparent after 3 to 4 weeks. It has been shown that the antihypertensive effect is sustained under long term therapy lasting 2 years.
Abrupt discontinuation of ramipril does not produce a rapid and excessive rebound increase in blood pressure.

Hydrochlorothiazide
With hydrochlorothiazide, onset of diuresis occurs in 2 hours, and peak effect occurs at about 4 hours, while the action persists for approximately 6 to 12 hours.
The onset of the antihypertensive effect occurs after 3 to 4 days and can last up to one week after discontinuation of therapy.
The blood-pressure-lowering effect is accompanied by slight increases in the filtration fraction, renal vascular resistance and plasma renin activity.

Clinical efficacy and safety

Concomitant administration of ramipril-hydrochlorothiazide
In clinical trials, the combination led to greater reductions in blood pressure than when either of the products was administered alone. Presumably through blockade of the renin-angiotensin-aldosterone system, co-administration of ramipril to hydrochlorothiazide tends to reverse the potassium loss associated with these diuretics.
Combination of an ACE-inhibitor with a thiazide diuretic produces a synergistic effect and also lessens the risk of hypokalaemia provoked by the diuretic alone.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS) Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes)) have examined the use of the combination of an ACE- inhibitor with an angiotensin II receptor blocker.
ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus accompanied by evidence of end- organ damage. VA NEPHRON-D was a study in patients with type 2 diabetes mellitus and diabetic nephropathy. These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes and mortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension as compared to monotherapy was observed. Given their similar pharmacodynamic properties, these results are also relevant for other ACE- inhibitors and angiotensin II receptor blockers. ACE-inhibitors and angiotensin II receptor blockers should therefore not be used concomitantly in patients with diabetic nephropathy.
ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was a study designed to test the benefit of adding aliskiren to a standard therapy of an ACE-inhibitor or an angiotensin II receptor blocker in patients with type 2 diabetes mellitus and chronic kidney disease, cardiovascular disease, or both. The study was terminated early because of an increased risk of adverse outcomes. Cardiovascular death and stroke were both numerically more frequent in the aliskiren group than in the placebo group and adverse events and serious adverse events of interest (hyperkalaemia, hypotension and renal dysfunction) were more frequently reported in the aliskiren group than in the placebo group.

Non-melanoma skin cancer:
Based on available data from epidemiological studies, cumulative dose-dependent association between HCTZ 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 HCTZ 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 HCTZ: 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 section 4.4).

Pharmacokinetic Properties

5.2 Pharmacokinetic properties

Ramipril
Absorption
Following oral administration ramipril is rapidly absorbed from the gastrointestinal tract; peak plasma concentrations of ramipril are reached within one hour. Based on urinary recovery, the extent of absorption is at least 56 % and is not significantly influenced by the presence of food in the gastrointestinal tract. The bioavailability of the active metabolite ramiprilat after oral administration of 2.5 mg and 5 mg ramipril is 45 %.
Peak plasma concentrations of ramiprilat, the sole active metabolite of ramipril are reached 2-4 hours after ramipril intake. Steady-state plasma concentrations of ramiprilat after once daily dosing with the usual doses of ramipril are reached by about the fourth day of treatment.

Distribution
The serum protein binding of ramipril is about 73 % and that of ramiprilat about 56 %.

Biotransformation
Ramipril is almost completely metabolised to ramiprilat, and to the diketopiperazine ester, the diketopiperazine acid, and the glucuronides of ramipril and ramiprilat.

Elimination
Excretion of the metabolites is primarily renal. Plasma concentrations of ramiprilat decline in a polyphasic manner. Because of its potent, saturable binding to ACE and slow dissociation from the enzyme, ramiprilat shows a prolonged terminal elimination phase at very low plasma concentrations. After multiple once-daily doses of ramipril, the effective half-life of ramiprilat concentrations was 13-17 hours for the 5-10 mg doses and longer for the lower 1.25-2.5 mg doses. This difference is related to the saturable capacity of the enzyme to bind ramiprilat. A single oral dose of ramipril produced an undetectable level of ramipril and its metabolites in breast milk. However, the effect of multiple doses is not known.

Patients with renal impairment (see section 4.2).
Renal excretion of ramiprilat is reduced in patients with impaired renal function, and renal ramiprilat clearance is proportionally related to creatinine clearance. This results in elevated plasma concentrations of ramiprilat, which decrease more slowly than in subjects with normal renal function.

Patients with liver impairment (see section 4.2).
In patients with impaired liver function, the metabolism of ramipril to ramiprilat was delayed due to diminished activity of hepatic esterases, and plasma ramipril levels in these patients were increased. Peak concentrations of ramiprilat in these patients, however, are not different from those seen in subjects with normal hepatic function.

Hydrochlorothiazide

Absorption
Following oral administration about 70 % of hydrochlorothiazide is absorbed from the gastrointestinal tract. Peak plasma concentrations of hydrochlorothiazide are reached within 1.5 to 5 hours.

Distribution
The plasma protein binding of hydrochlorothiazide is 40 %.

Biotransformation
Hydrochlorothiazide undergoes negligible hepatic metabolism.
Elimination
Hydrochlorothiazide is eliminated almost completely (> 95 %) in an unchanged form through the kidneys; 50 to 70 % of a single oral dose is eliminated within 24 hours. The elimination half-life is 5 to 6 hours.

Patients with renal impairment (see section 4.2)
Renal excretion of hydrochlorothiazide is reduced in patients with impaired renal function, and renal hydrochlorothiazide clearance is proportionally related to creatinine clearance. This results in elevated plasma concentrations of hydrochlorothiazide, which decrease more slowly than in subjects with normal renal function.

Patients with liver impairment (see section 4.2)
In patients with hepatic cirrhosis the pharmacokinetics of hydrochlorothiazide has not changed significantly. The pharmacokinetics of hydrochlorothiazide has not been studied in patients with cardiac failure.

Ramipril and Hydrochlorothiazide
The concurrent administration of ramipril and hydrochlorothiazide does not affect their bioavailability. The combination product can be considered as bioequivalent to products containing the individual components.