Pharmacology for Anaesthesia and Intensive Care

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Section IIICardiovascular drugs

Presentation and uses

Losartan is available as 25–50 mg tablets and in combination with hydrochloroth-

iazide. It is used in the treatment of hypertension where dry cough proves an unac-

ceptable side effect of ACE inhibitor therapy.

Mechanism of action

Losartan is a specific angiotensin II receptor (type AT 1 )antagonist at all sites within

the body. It blocks the negative feedback of angiotensin II on renin secretion, which

therefore increases, leading to increased angiotensin II. This has little impact due to

comprehensive AT 1 receptor blockade.

Effects

These are broadly similar to those of the ACE inhibitors.


Metabolic – as it does not block the actions of ACE, bradykinin may be broken

down in the usual manner (by ACE). As a result, bradykinin levels are not raised

and the dry cough seen with ACE inhibitors does not complicate its use.

Kinetics

Losartan is well absorbed from the gut but undergoes significant first-pass

metabolism to an active carboxylic acid metabolite (which acts in a non-competitive

manner), and several other inactive compounds. It has an oral bioavailability of

30% and is 99% plasma protein bound. Its elimination half-life is 2 hours while the

elimination half-life of the active metabolite is 7 hours. Less than 10% is excreted

unchanged in an active form in the urine. The inactive metabolites are excreted in

bile and urine.

Contraindications

Like ACE inhibitors, Losartan is contraindicated in bilateral renal artery stenosis and

pregnancy.

Comparing ARAs to ACE inhibitors

ARA use may become more widespread for the following reasons.

1. Blockade of the AT 1 -receptor is the most specific way of preventing the adverse
   effects of angiotensin II seen in heart failure and hypertension, especially as
   angiotensin II may be synthesized by alternative non-ACE pathways.


2. The AT 2 -receptor is not blocked, which may possess cardioprotective properties.


3. There is a much lower incidence of cough and angioedema and therefore
   improved compliance.