P-DRUG DISCUSSION: LOSARTAN

A. Pharmacologic Class
Losartan is the first of a class of antihypertensive agents called angiotensin II receptor
antagonist that is used mainly in the treatment of hypertension and heart failure. It selectively
and competitively blocks the vasoconstricting and aldosterone-secreting effects of angiotensin II
by selectively antagonising its binding to AT1 receptors blocking the blood pressure increasing
effects angiotensin II via the renin-angiotensin-aldosterone system (RAAS). Named as (2-Butyl-
4-chloro-1-{[2'-(1H-tetrazol-5-yl)-4-biphenylyl]methyl}-1H-imidazol-5-yl)methanol by the IUPAC,
other chemical names include DuP 753, Losartan Monopotassium Salt, Losartan Potassium and
MK 954. Its molecular formula is C22H23ClN6O and it has a molecular weight of 422.917 g/mol.
The 2D chemical structure is shown below.

B. Trade Names
Cozaar, Kenzar, Arbloc, Aesartan, Anzar, Artal, Besartan, Cardizar, Doxar
C. Pharmacodynamics
Losartan inhibits the vasopressor effect of both angiotensin II and angiotensin I.
Removal of the negative feedback of angiotensin II causes a doubling to tripling in plasma renin
activity and consequent rise in angiotensin II plasma concentration in hypertensive patients.
ARBs reduce activation of AT1 receptors more effectively than do ACE inhibitors. ARBs also
block the actions of angiotensin II via the AT 1 receptor regardless of the biochemical pathway
leading to angiotensin II formation. In contrast to ACE inhibitors, ARBs permit activation of AT2
receptors. ARBs also stimulate renin release; however, with ARBs, this translates into a several-
fold increase in circulating levels of angiotensin II. Because ARBs block AT1 receptors, this
increased level of AngII is available to activate also the AT2 receptors.

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, there is very little
effect on serum potassium. The effect of Losartan is substantially present within one week but in
some studies the maximal effect occurred in 3 to 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. The overall
effect of ARBs is a decrease in blood pressure.
D. Pharmacokinetics
Losartan is metabolized primarily by CYP3A4 and CYP2C9 isoenzymes to active
carboxylic acid metabolite, E-3174 (approximately 14% of an oral dose of losartan) which is
more potent than losartan as an AT1 receptor antagonist. Peak plasma levels of losartan and
EXP 3174 occur ~1-3 hours after oral administration, respectively, and the plasma half- lives are
2.5 and 6-9 hours, respectively. The plasma clearances of losartan and EXP 3174 are due to
renal clearance and hepatic clearance (metabolism and biliary excretion). The plasma clearance
of losartan and EXP 3174 is affected by hepatic but not renal insufficiency. Losartan is readily
absorbed from the GI tract and should be administered orally once or twice daily for a total daily
dose of 25-100 mg. Losartan aside from being an ARB is also a competitive antagonist of the
thromboxane A2 receptor and attenuates platelet aggregation. Bioavailability of losartan is at
25-33% and the volume of distribution of Losartan and the active metabolite is about 34 liters
and 12 liters, respectively. Both Losartan and its active metabolite are highly bound to plasma
proteins (>98%).

E. Indications
Losartan is used in the treatment of hypertension, isolated systolic hypertension, left
ventricular hypertrophy, heart failure and diabetic nephropathy (in Type 2 DM).

F. Contraindications
 Patients who are hypersensitive to any component of Losartan
 Co-administration with aliskiren in patients with diabetes and renal impairment
(GFR <60 mL/min).
 Severe hepatic impairment.
 Pregnancy.

G. Drug Interactions

No clinically significant drug interactions have been found in studies of Losartan

potassium with hydrochlorothiazide, digoxin, warfarin, cimetidine and phenobarbital. But it may:

 Decrease plasma levels w/ fluconazole and rifampicin.

 Increase serum lithium levels and toxicity.
 Antagonize hypotensive effect and increase risk of renal impairment w/ NSAIDs.
Increase the risk of hyperkalaemia w/ K-sparing diuretics (e.g. amiloride,
triamterene, spironolactone), K supplements or K-containing salt substitutes.
 Have a potentially Fatal effect: Increases nephrotoxic, hyperkalaemic and
hypotensive effect w/ aliskiren in patients w/ diabetes and renal impairment (GFR
<60 mL/min).
H. Warnings and Precautions

1. Fetal Toxicity- Use of drugs that act on the RAAS during the second and third
trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal
morbidity and death. Has a teratogenic potential Resulting oligohydramnios can be
associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal
adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death.
When pregnancy is detected, discontinue Losartan potassium tablets as soon as
possible
 2. Hypotension in Volume- or Salt-Depleted Patients- In patients with an activated
RAAS, such as volume- or salt-depleted patients (e.g., those being treated with high
doses of diuretics), symptomatic hypotension may occur after initiation of treatment with
Losartan. Therefore, correct volume or salt depletion prior to administration of Losartan.
3. Renal Function Deterioration- Changes in renal function including acute renal failure
can be caused by drugs that inhibit the RAAS and by diuretics. Patients whose renal
function may depend in part on the activity of the RAAS (e.g., patients with bilateral renal
artery stenosis, chronic kidney disease, severe congestive heart failure, or volume
depletion) may be at particular risk of developing acute renal failure on Losartan. Monitor
renal function periodically in these patients. Consider withholding or discontinuing
therapy in patients who develop a clinically significant decrease in renal function on
Losartan.
4. Hyperkalemia- may cause hyperkalemia in patients with renal disease or in patients
taking K+ supplements or K+-sparing diuretics. Monitor serum potassium periodically
and treat appropriately. Dosage reduction or discontinuation of Losartan may be
required.
5. Angioedema and cough- Incidence is less than that with ACE inhibitors
6. Overdosage symptoms: Hypotension, tachycardia, bradycardia- can occur from
parasympathetic stimulation. Management includes supportive and symptomatic
treatment. May include immediate administration of activated charcoal after oral intake.
7. Other rare postmarketing reports of anaphylaxis, abnormal hepatic function, hepatitis,
neutropenia, leukopenia, agranulocytosis, pruritus, urticaria, hyponatremia, alopecia,
and vasculitis, including Henoch- Schönlein purpura.

https://pubchem.ncbi.nlm.nih.gov

http://www.mims.com/philippines/drug/info/losartan/

https://www.drugs.com/pro/losartan.html

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