CLINICAL PHARMACOLOGY
Mechanism
of Action
Angiotensin II [formed from angiotensin I in a reaction
catalyzed by angiotensin converting enzyme (ACE, kininase
II), is a potent vasoconstrictor, the primary vasoactive
hormone of the renin-angiotensin system and an important
component in the pathophysiology of hypertension. It also
stimulates aldosterone secretion by the adrenal cortex.
Losartan and its principal active metabolite block the
vasoconstrictor and aldosterone-secreting effects of angiotensin
II by selectively blocking the binding of angiotensin
II to the AT1 receptor found in many tissues,
(e.g., vascular smooth muscle, adrenal gland). There is
also an AT2 receptor found in many tissues
but it is not known to be associated with cardiovascular
homeostasis. Both losartan and its principal active metabolite
do not exhibit any partial agonist activity at the AT1
receptor and have much greater affinity (about 1000-fold)
for the AT1 receptor than for the AT2
receptor. In vitro binding studies indicate that losartan
is a reversible, competitive inhibitor of the AT1
receptor. The active metabolite is 10 to 40 times more
potent by weight than losartan and appears to be a reversible,
non-competitive inhibitor of the AT1 receptor.
Neither losartan nor its active metabolite inhibits ACE
(kininase II, the enzyme that converts angiotensin I to
angiotensin II and degrades bradykinin); nor do they bind
to or block other hormone receptors or ion channels known
to be important in cardiovascular regulation.
Pharmacokinetics
General: Losartan is an orally
active agent that undergoes substantial first-pass metabolism
by cytochrome P450 enzymes. It is converted, in part,
to an active carboxylic acid metabolite that is responsible
for most of the angiotensin II receptor antagonism that
follows losartan treatment. The terminal half-life of
losartan is about 2 hours and of the metabolite is about
6-9 hours. The pharmacokinetics of losartan and its active
metabolite are linear with oral losartan doses up to 200
mg and do not change over time. Neither losartan nor its
metabolite accumulate in plasma upon repeated once-daily
dosing.
Following oral administration, losartan is well absorbed
(based on absorption of radiolabeled losartan) and undergoes
substantial first-pass metabolism; the systemic bioavailability
of losartan is approximately 33%. About 14% of an orally-administered
dose of losartan is converted to the active metabolite.
Mean peak concentrations of losartan and its active metabolite
are reached in 1 hour and in 3-4 hours, respectively.
While maximum plasma concentrations of losartan id its
active metabolite are approximately equal, the AUC of
the metabolite is about 4 times great as that of losartan.
A meal slows absorption of losartan and decreases its
Cmax but has only minor effects on losartan AUC or on
the AUC of the metabolite (about 10% decreased).
Both losartan and its active metabolite are highly bound
to plasma proteins, primarily albumin, with plasma free
fractions of 1.3% and 0.2% respectively. Plasma protein
binding is constant over the concentration range achieved
with recommended doses. Studies in rats indicate that
losartan crosses the blood-brain barrier poorly, if at
all.
Losartan metabolites have been identified in human plasma
and urine. In addition to the active carboxylic acid metabolite,
several inactive metabolites are formed. Following oral
and intravenous administration of 14C-labeled losartan
potassium, circulating plasma radioactivity is primarily
attributed to losartan and its active metabolite. In vitro
studies indicate that cytochrome P450 2C9 and 3A4 are
involved in the biotransformation of losartan to its metabolites.
Minimal conversion of losartan to the active metabolite
(less than 1% of the dose compared to 14% of the dose
in normal subjects) was seen in about one percent of individuals
studied.
The volume of distribution of losartan is about 34 liters
and of the active metabolite is about 12 liters. Total
plasma clearance of losartan and the active metabolite
is about 600 ml/min and 50 ml/min, respectively, with
renal clearance of about 75 ml/min and 25 ml/min, respectively.
When losartan is administered orally, about 4% of the
dose is excreted unchanged in the urine and about 6% is
excreted in urine as active metabolite. Biliary excretion
contributes to the elimination of losartan and its metabolites.
Following oral 14C-labeled losartan, about 35% of radioactivity
is recovered in the urine and about 60% in the feces.
Following an intravenous dose of 14C-labeled losartan,
about 45% of radioactivity is recovered in the urine and
50% in the feces.
Special Populations
Pediatric: Losartan pharmacokinetics
have not been investigated in patients <18 years of
age.
Geriatric and Gender: Losartan pharmacokinetics have
been investigated in the elderly (65-75 years) and in
both genders. Plasma concentrations of losartan and its
active metabolite are similar in elderly and young hypertensives.
Plasma concentrations of losartan were about twice as
high in female hypertensives as male hypertensives, but
concentrations of the active metabolite were similar in
males and females. No dosage adjustment is necessary (see
DOSAGE AND ADMINISTRATION).
Race: Pharmacokinetic differences
due to race have not been studied.
Renal Insufficiency: Plasma
concentrations of losartan are not altered in patients
with creatinine clearance above 30 ml/min. In patients
with lower creatinine clearance, AUCs are about 50% greater
and they are doubled in hemodialysis patients. Plasma
concentrations of the active metabolite are not significantly
altered in patients with renal impairment or in hemodialysis
patients. Neither losartan nor its active metabolite can
be removed by hemodialysis. No dosage adjustment is necessary
for patients with renal impairment unless they are volume-depleted
(see WARNINGS, Hypotension - Volume Depleted Patients,
and DOSAGE AND ADMINISTRATION).
Hepatic Insufficiency: Following
oral administration in patients with mild to moderate
alcoholic cirrhosis of the liver, plasma concentrations
of losartan and its active metabolite were, respectively,
5-times and about 1.7-times those in young male volunteers.
Compared to normal subjects the total plasma clearance
of losartan in patients with hepatic insufficiency was
about 50% lower and the oral bioavailability was about
2-times higher. A lower starting dose is recommended for
patients with a history of hepatic impairment (see DOSAGE
AND ADMINISTRATION).
Pharmacodynamics and Clinical Effects
Losartan inhibits the pressor effect of angiotensin II
(as well as angiotensin I) infusions. A dose of 100 mg
inhibits the pressor effect by about 85% at peak with
25-40% inhibition persisting for 24 hours. Removal of
the negative feedback of angiotensin II causes a 2-3 fold
rise in plasma renin activity and consequent rise in angiotensin
II plasma concentration in hypertensive patients. Losartan
does not affect the response to bradykinin, whereas ACE
inhibitors increase the response to bradykinin. Aldosterone
plasma concentrations fall following losartan administration.
In spite of the effect of losartan on aldosterone secretion,
very little effect on serum potassium was observed.
In a single-dose study in normal volunteers, losartan
had no effects on glomerular filtration rate, renal plasma
wflow or filtration fraction. In multiple dose studies
in hypertensive patients, there were no notable effects
on systemic or renal prostaglandin concentrations, fasting
triglycerides, total cholesterol or HDL-cholesterol or
fasting glucose concentrations. There was a small uricosuric
effect leading to a minimal decrease in serum uric acid
(mean decrease <0.4 mg/dl) during chronic oral administration.
The antihypertensive effects of losartan potassium were
demonstrated principally in 4 placebo-controlled 6-12
week trials of dosages from 10 to 150 mg per day in patients
with baseline diastolic blood pressures of 95-115. The
studies allowed comparisons of two doses (50-100 mg/day)
as once-daily or twice-daily regimens, comparisons of
peak and trough effects, and comparisons of response by
gender, age, and race. Three additional studies examined
the antihypertensive effects of losartan and hydrochlorothiazide
in combination.
The 4 studies of losartan monotherapy included a total
of 1075 patients randomized to several doses of losartan
and 334 to placebo. The 10 and 25 mg doses produced some
effect at peak (6 hours after dosing) but small and inconsistent
trough (24 hour) responses. Doses of 50, 100 and 150 mg
once daily gave statistically significant systolic/diastolic
mean decreases in blood pressure, compared to placebo
in the range of 5.5- 10.5/3.5-7.5 mmHg, with 150 mg dose
giving no greater effect than 50-100 mg. Twice-daily dosing
at 50-100 mg/day gave consistently larger trough responses
than once-daily dosing at the same total dose. Peak (6
hour) effects were uniformly, but moderately, larger than
trough effects, with the trough-to-peak ratio for systolic
and diastolic responses 50-95% and 60-90%, respectively.
Addition of a low dose of hydrochlorothiazide (12.5 mg)
to losartan 50 mg once daily resulted in placebo-adjusted
blood pressure reductions of 15.5/9.2 mmHg.
Analysis of age, gender, and race subgroups of patients
showed that men and women, and patients over and under
65, had generally similar responses. Losartan potassium
was effective in reducing blood pressure regardless of
race, although the effect was somewhat less in black patients
(usually a low-renin population).
The effect of losartan is substantially present within
one week but in some studies the maximal effect occurred
in 3-6 weeks. In long-term, follow-up studies (without
placebo control) the effect of losartan appeared to be
maintained for up to a year. There is no apparent rebound
effect after abrupt withdrawal of losartan. There was
essentially no change in average heart rate in losartan-treated
patients in controlled trials.
|
|
