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MEMORANDUM
From: Leo Offerhaus, MD, PhD, former RA Pharmaceuticals, WHO/EURO; former consultant pharmaceuticals EU/PHARE for Romania and Bosnia/Hercegovina
To: Coordinator WHO EDL Committee meeting Geneva 15 April 2002
Date: March 22, 2002.
Subject: Revision Essential Drugs List
Introduction: Though since many years I am no longer a member of the Advisory Committee on Essential Drugs I have maintained an interest in the development of the list and its proposed changes. Unfortunately I did not receive the relevant documents until today, and only indirectly through the courtesy of the moderators of HealthNet. Nevertheless I would like to make some comments on the “Suggestions for review”.
Many of the drugs mentioned on the list date back from the fifties, and literature about those is difficult to obtain, being published in the “pre-Medline” (i.e. before 1966) period. On the other hand, as I have been engaged in internal medicine and clinical pharmacology since 1970, I have personal therapeutic experience with some of them.
1. Chloral hydrate. As a hypnotic the drug has been obsolete in Western medicine since the early seventies. It is a poor anticonvulsant. The best description of its properties can be found in Bochner et al. (Handbook of Clinical Pharmacology). It has a nasty taste, and causes a wide range of disturbing side effects. It is quite toxic; its main metabolite is trichloracetic acid, which competes for protein binding with oral anticoagulants (Koch-Weser and Sellers, New Engl J Med 1971;285:547). It was widely used in hospitals as an “emergency” hypnotic in agitated elderly patients, but for that purpose it has been fully superseded by antipsychotic agents like haloperidol etc.
2. Ephedrine. Has already been banned in sports medicine because of its amphetamine-like and addictive effects. It is no longer used as an antiasthmatic because there are many better fully studied alternatives. It is a highly unspecific drug which also substantially raises blood pressure and heart rate (Dollery, Therapeutic Drugs Vol.1), and insomnia is a common side effect. Absorption and metabolism are unpredictable, and the dose-effect relationship is therefore highly variable. Used as nose drops its use has been superseded by shorter acting synthetic alternatives. It is a dangerous drug which should be abandoned.
3. Ipecacuanha. The use of ipecac as emetic in the treatment of intoxications is based on a very old British tradition. It has never been used on any scale on the European continent. The practice has been largely abandoned because of the inherent danger of aspiration pneumonia in patients with impaired level of consciousness. Gastric aspiration/lavage is much safer and can easily be performed by trained personnel. There is no longer any valid indication for its use.
4. Methyldopa. This is a moderately effective antihypertensive which has over the years been kept on the list on the basis of one – now very dated - single British trial in pregnant hypertensives, mainly because of its relative safety. The main problem is that data on the definite outcome of pregnancy and maternal mortality/morbidity in methyldopa-treated pre-eclampsia patients are not up to modern trial standards. But the same applies to alternatives like α-blockers or calcium-antagonists. Labetalol is now widely used but carries some risk of fetal growth retardation. If doubt persists, keep it on the list. Cost is not prohibitive.
5. Procainamide. Again an “old” but proven antiarrhythmic, but here the issue is a much wider one: Whether the use of any antiarrhythmic improves cardiac morbidity/mortality. Flecainide, despite its disadvantages, is now the most widely used drug, but can hardly be called “essential”. Mexiletine is a reasonable alternative – but why keep this group of drugs on the list? Restrict indications??
6. Reserpine. Has now been totally abandoned as an antihypertensive. For many years I had personal experience with this drug in the sixties. The main problem is that the effective antihypertensive dose of bid or tid ¼ mg after some months of treatment almost always causes serious depression, which might even end in suicide. Additionally gastric haemorrhage is a real danger. The lower dose of tid 0.1 mg has no effect at all, though it increases somewhat the effect of diuretics. There is no valid reason to keep it on the list.
7. Captopril vs enalapril (See Memo by Dr.Mendis, CVD). The conclusion is right, the arguments wrong. Captopril should not be replaced by enalapril because of its short duration of action, but because at the safe dose recommended it is not very effective, but – because of its thiol group – at doses which have the same blood pressure lowering effect as enalapril – it causes a number of serious side effects. The somewhat shorter duration of action has nothing to do with the short half life of the parent drug (2 hrs) because the effect is caused by active metabolites, and these are converted back to captopril by flip-flop kinetics: The duration of action is therefore much longer than would be expected on the basis of its kinetics. Captopril was kept on the EDL because enalapril was still covered by patent. That is no longer the case.
8. Aminofylline – theophylline. Parenteral aminofylline should only be used by experienced physicians and only in emergencies, preferably when serum level monitoring is possible. The oral form is unsuitable because the drug is highly basic, causes gastrointestinal problems and its absorption is unpredictable. Anhydrous theophylline made by a reputable manufacturer still has a modest place in asthma treatment, but could possibly lose its predicate “essential”. Even so quality is an essential property.
9. Dextromethorphan. Cough is a symptom, not a disease. Cough medication is mostly administered to pacify parents or nursing staff. The drug is already in the hands of addicts. Remove??
10. Propranolol in migraine. Like metoclopramide/acetylsalicylic acid it is relatively safe, cheap and effective. The alternative is one of the very expensive triptans, which widely tend to be (mis)used for the wrong indication – this might not be a cost-effective measure.
11. Drugs for malignant disorders. Over the course of years this list – under the pressure of medical and patient groups – has grown out of proportion. The majority of these drugs should only be used in specialized oncology units with appropriate nursing, laboratory, transplantation and isolation facilities. My experience in Eastern Europe has been that the great majority of oncology departments in developing countries do not fulfill the conditions under which most of these drugs should be used: Under uncontrolled conditions such drugs might cause more harm than benefit. The list should be very critically reviewed in the light of the countries and available local facilities, as well as suitability for outpatient treatment.
12. Codeine as an analgesic. As an additive to acetylsalicylic acid or paracetamol enhancement of the effect can only be proven at doses which exceed the dose limit which is legally permitted in the majority of countries. There are very few analgesics between the OTC drugs and opioids, so the choice is difficult. Some advocate tramadol, but opinions differ.
13. Salbutamol as “tocolytic”. The usefulness of this practice is debatable. Particularly fenoterol has been studied in trials and found deficient. Fetal mortality is not improved by postponing parturition by such means. Under the circumstances the predicate “essential” does no longer apply.
14. Selenium sulfide. This again was, many years ago, placed on the list under the influence of a dermatological pressure group. In comparison to newer drugs its efficacy is minimal. The drug could hardly be called “essential” – its is a typical OTC product and not a medicine in the usual sense.
15. Copper-containing IUDs. Advice should be sought whether the Cu ion adds substantially to the efficacy of the IUD. It only makes the IUD far more expensive. In addition IUDs do not prevent HIV infection and other sexually transmitted diseases, and may therefore give a false feeling of safety.
16. Nonoxil in combination with condoms or diaphragms. The addition gives a false sense of safety and should now be discouraged. Whether it further lowers the risk of pregnancy remains uncertain.
17. Fluorescein. Remains indispensable for the diagnosis of corneal injury, though the injectable form occasionally gives rise to anaphylactic reactions. Risk is well known.
18. Iodine containing contrast media. The choice should be determined by expert radiologists. Whether they should stay on the EDL is mainly determined by local logistics as they are only be used inside hospital.
19. Diethyltoluolamide (DEET). I have been told that the standard strength in some African regions is too low to keep mosquitoes at bay, but the higher strength is only sold by a few specialized stores. Even so it seems indispensable in malaria-infested regions.