[e-drug] Methyl xanthenes to be deleted from 13th Model EML 2003

[Norman Olson <nolsonmd@aol.com>]

E-drug: Methyl xanthenes to be deleted from 13th Model EML 2003
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I write to urge the removal of aminophylline and theophylline from the
13th Model List of Essential Drugs. Aminophylline has been on the list
since 1977 and was joined by theophylline, another methyl xanthene,
in 1997. There is a long sub-Saharan habit of using salbutamol and
aminophylline tablets and injection for asthma, with steroid therapy
where that fails. This has persisted to the present, at time when these
first two drugs are rarely used in industrialized countries. Oral and
injectable aminophylline and oral theophylline are among the most
toxic and relatively ineffective drugs still in common use. These
methyl xanthenes have little effect on bronchospasm, most of their
action being on increasing the respiratory effort. Toxicity has been
common in industrialized countries despite periodic blood levels being
a routine part of therapy. Similar toxicity is usually avoided to some
degree in developing countries only by using doses that are known to
be ineffective or suboptimal. Where any convincing advantage has
been shown in their use, it is in research studies showing only
marginal benefits and performed where patient monitoring is quite
sophisticated, dosing is carefully controlled, serum drug levels are
mandatory, and there are ancillary means of respiratory support.
There is now evidence that caffeine could be substituted for
aminophylline for the apnea of prematurity, an alternative use of
aminophylline. Theophylline is also out-moded and offers no
significant improvement over aminophylline. It should be removed for
the same reasons: there are more effective, safer, and less
expensive treatments now available. Salbutamol spray in low cost
metered dose inhalers (MDI) is available from many sources. An MDI
can be used by patients of all ages with appropriate re-useable
devices, even by one home-made from common plastic beverage
bottles. Yet, MDIs are infrequently used, considered relatively
expensive (even though 200 sprays cost only $1.70), and rarely
stocked by many low-cost, mission, or charity hospitals. Today, there
is little reason to use salbutamol in any other presentation than as
aerosols. Though the least expensive and most effective therapy, it
benefits few patients with asthma in developing countries. It probably
would gain more acceptance if aminophylline, theophylline, and
non-aerosol salbutamol were all removed from the list. Steroid
sprayMDIs, though nearly twice the cost of salbutamol spray MDI, are
used even less often in developing countries even though they are
now the primary therapy in industrialized countries, clearly cost
effective, and even lifesaving. 

Also, why should there be any difficulty in finding affordable
salbutamol solution for nebulizer use (not on the List) in developing
countries, either as calibrated dropper bottles or as ready to use unit
dose 0.083% in plastic vials? This would be considered an essential
drug by any hospital in an industrialized country and certainly be used
more frequently in that setting than either dopamine (on the List) or
dobutamine. When procurable, it is also among the least expensive of
generic drugs, costing less than using salbutamol injection in a
compressor nebulizer (instead of a syringe for IM injection, as
intended). Is it just an oversight that it is not on the Essential Drug
List? This may in itself contribute to its poor availability. Another factor
is that no cogeners are presently being promoted by the
pharmaceutical industry, so there is little medical media attention to
the use of such treatments. Aerosolized beta-2 agonist therapy by
nebulizer for asthma receives less attention than the very popular,
affordable, effective generic low-dose aspirin for anticoagulation. It is
just a "given" that it works very well and is not a fertile area for drug
company exploitation. In an industrialized country, the uninitiated
patient presenting with severe bronchospasm and acute dyspnea is
usually treated with salbutamol aerosol by compressor/nebulizer, not
with MDIs. But a salbutamol MDI is equally effective in a compliant
patient and still (easily) a more effective treatment for acute
bronchospasm than is the "Listed" aminophylline-salbutamol by
injection in a distressed patient. Although distressed patients will not
empty their lungs well before inhaling the spray and may attempt to
swallow the dose, salbutamol by MDI will still act more rapidly and
effectively with a wider margin of safety.

Used nebulizers as gifts for developing countries are readily available
(often discarded after single patient use by home-care companies). I
just bought 12 new ones for $30 each, wired for 220/50hz complete
with neb chambers-tubing, from Nidek, in Birmingham, Alabama.
They will each last for years. Battery models are available. Inverters
can easily supply power from a 12-volt auto source. The best patient
and staff education in this regard is demonstrating the much quicker
and complete relief from salbutamol mist than with the more toxic and
actually more expensive salbutamol/aminophylline tablets or injection
administered systemically. Tocolysis with salbutamol or terbutaline is
becoming known as an exercise in futility by leading researchers in
the field of premature labor, so that is not a reasonable excuse to
retain it on the list. Meter dose inhalers would be a better alternative
even in the most isolated dispensary. If they can afford either
salbutamol or aminophylline, they can better afford salbutamol spray.
The next step is to obtain true asthma control by promoting
aerosolized steroids as meter dose inhalers for treating the actual
cause of chronic asthma, the endobronchial inflammation. Then the
concept of salbutamol spray as "rescue" treatment or for use in mild
asthma can be "sold" and will eliminate much of the small risk of
desperate overdosing even with salbutamol spray. In this time of two-
tiered care in a world of relative plenty, there still are inexpensive
highly effective "new" treatments that have not yet been widely
adopted in poor countries by all in need of them.

Norman D. Olson, MD
Global Health Ministries
Adj. Clin. Assoc. Prof. of Medicine
Stanford University
e-mail: nolsonmd@aol.com

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