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Indication: Hypertension.
Mechanism of Action: Type 1 Angiotensin II receptor antagonist. Through this
action losartan modulates the renin-angiotensin system at a site
different from the angiotensin converting enzyme (ACE)
inhibitors. The action of ACE inhibitors to decrease bradykinin
breakdown is possibly involved in some of the beneficial and
adverse effects of the drugs (see Figure).
Pharmacokinetics: The major route of inactivation is liver metabolism.
The elimination t1/2 of losartan averages 2 hours; the main
metabolite is active and has an average t1/2 of 5 hours (Br J
Clin Pharmacol, 35:290, 1993).
Evidence
of efficacy: There are 4 published
randomized controlled trials (RCTs) comparing the
antihypertensive efficacy of losartan (10-150 mg once daily) with
placebo (Arch Intern Med, 155:405, 1995), enalapril, 20
mg once daily, (Hypertension, 25:1345, 1995, Hypertension,
25:37, 1995) and atenolol, 50 mg once daily, (Amer J
Hypertens, 8:578, 1995). These studies demonstrate that
losartan lowers blood pressure more than placebo and similar to
enalapril and atenolol. In these studies the maximal
antihypertensive effect occurred with 50 mg losartan. There are
no data to demonstrate effectiveness of losartan in congestive
heart failure, post myocardial infarction or diabetic
nephropathy.
Adverse
effects: Other than a low
incidence of dizziness, losartan was not associated with any
adverse effects at a significantly higher rate than placebo. Dry
cough does not appear to be a problem with angiotensin II
antagonists, presumably because they do not have any effects on
bradykinin metabolism (J Hypertens, 12:1387, 1994). As
with ACE inhibitors, losartan is contraindicated during
pregnancy.
Dose
and Cost: Losartan is available in
25 ($1.10) and 50 ($1.10) mg unscored tablets, which can be
halved. The average daily cost for 12.5 to 100 mg daily is
$0.55-2.20. The daily cost range for the 9 ACE inhibitors
available in B.C. is $ 0.45-2.10.
Conclusions: Losartan, starting with a dose of 12.5 mg once
daily, may be considered in patients who require an ACE inhibitor
(see Therapeutics
Letter 8) but who
cannot tolerate it due to drug-induced dry cough. At the present
time it is not known whether angiotensin II receptor antagonists
will improve survival in heart failure or after a myocardial
infarction.
Indications: Acute gastric and duodenal ulcer, severe erosive reflux
esophagitis.
Mechanism of Action: Suppresses gastric acid secretion by inhibition of the
proton pump.
Pharmacokinetics: The major route of inactivation is liver metabolism.
After a 30 mg dose there are marked inter-individual differences
in plasma concentrations and t1/2 ,(range, 0.4-8.5 hours).
Evidence of effectiveness: Three published double-blind RCTs comparing omeprazole
with lansoprazole were found: 8 week trial for acute gastric
ulcer (Gastroenterology, 104:A80, 1993), 4 week trial
for active duodenal ulcer (Scand J Gastroenterol, 30:210,
1995) and an 8 week trial for the treatment of reflux
esophagitis (Scand J Gastroenterol, 28:224, 1993). These
studies demonstrate that lansoprazole, 30 mg daily, is
approximately equivalent to omeprazole, 20 mg daily, in healing
rate and symptom relief.
Adverse effects: The most frequent adverse effects reported in
short-term studies were diarrhea (3.3%), headache (1.5%),
constipation (1.2%), asthenia (1.1%), dizziness (1.1%), and
abdominal pain (1.0%). Concerns about long-term safety
are the same as for omeprazole (see Therapeutics Letter 3).
Dose and Cost: Available in 15 mg ($2.00) and 30 mg ($2.20) capsules
as compared with omeprazole 20 mg tablets (~$2.30).
Conclusions: Lansoprazole is a proton pump inhibitor which is
similar to omeprazole in potency, pharmacokinetics, safety and
effectiveness.
Indications: Bacterial pharyngitis/tonsillitis, otitis media,
uncomplicated skin infections, uncomplicated urinary tract
infections.
Mechanism of action: First generation cephalosporin. Inhibits bacterial cell
wall synthesis like other cephalosporins. Similar antibacterial
spectrum to cephalexin, cefaclor, cefuroxime axetil, cefixime and
amoxicillin-clavulanate.
Pharmacokinetics: Excellent oral absorption with elimination by tubular
secretion in the kidney. Average elimination t1/2 is 1.3 hours.
Evidence of effectiveness: There are at least 11 published RCTs comparing
cefprozil with other antibiotics in the treatment of the
infections listed above (Ann Pharmacother, 27:1082, 1993).
In only one of these studies was cefprozil compared with the
first line choice as defined by the Anti-Infective
Guidelines for Community-acquired Infections
(distributed to you with Letter 5). In these studies
there were no proven advantages in clinical or bacteriologic
response rate.
Adverse effects: The main adverse events in 4226 patients were diarrhea
(3.0%), nausea (2.3%), and vomiting (1.4%). Rash occurred in 2.1%
of children under 13 years of age. In the above studies
amoxicillin/clavulanate had a higher incidence of diarrhea than
cefprozil and cefprozil had a higher incidence of rash than
erythromycin.
Dose and Cost: Available in 250 mg and 500 mg tablets and 125 mg/5ml
and 250 mg/5ml suspension. Usual dose in adults is 250 mg BID
($3.06/day), and in children 15 mg/kg q12h ($0.18/kg/day). See
Anti-Infective Guidelines for comparative prices.
Conclusions: Cefprozil is a new oral cephalosporin, which
should be reserved for patients who are allergic or intolerant to
the first or second line choices.
Indications: Manifestations of acute and chronic schizophrenia.
Mechanism of action: Zuclopenthixol is the neuroleptically active
cis-stereoisomer of clopenthixol, which belongs to the
thioxanthene group of neuroleptics, eg. flupenthixol. It is a
high affinity antagonist for both dopamine D1 and D2 receptors,
and is also a weak antagonist for noradrenaline, histamine and
cholinergic receptors.
Pharmacokinetics: The major route of inactivation is liver metabolism;
average elimination t1/2 is 20 hours.
Evidence of effectiveness: In 1978 zuclopenthixol was shown to be similar in
effectiveness and twice as potent as clopenthixol. Since then at
least five double-blind RCTs comparing zuclopenthixol with
haloperidol in the treatment of acute and chronic schizophrenia
have been published. These trials demonstrate that the drugs are
similar in effectiveness and incidence of side effects (Curr
Med Res Opin, 12:594, 1992).
Adverse effects: As with other neuroleptics the incidence of adverse
effects is high; the four most common adverse effects are
drowsiness (32%), extrapyramidal symptoms(19%), dry mouth(15%),
fatigue(15%), and dizziness (11%).
Dose and cost: Available in tablets, injection and depot formulations.
The usual oral maintenance dose range is 20-60 mg daily
($0.72-2.16), as compared to haloperidol, 2.5-10 mg daily
($0.10-0.29), flupenthixol, 3-9 mg daily ($0.56-1.68), loxapine,
25-100 mg daily ($0.61-1.60) and risperidone, 3-8 mg daily
($3.23-8.36).
Conclusions: Zuclopenthixol is a thioxanthene neuroleptic similar to
flupenthixol. It has no distinctive advantages over
haloperidol and other neuroleptics and should be reserved for
selected patients who fail to respond or are intolerant to other
neuroleptics.
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