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The Facts about Drug Use

Dr Barry Stimmel, The Haworth Medical Press, 10 Alice St, Binghamton, NT 13904-1580, USA, 1993, 366pp

Family physicians often see patients who misuse drugs. This widespread problem is the source of much hidden morbidity and mortality for patients and much frustration for doctors.

Family doctors are likely to have had little formal training in identifying and intervening in this area. Their attitudes toward problem drug use probably differ little from those held by the public.

This book was written “to enable those with little or no background in science or health care to understand the often complex issues of drug use” and “is presented clearly, concisely, and without jargon.” It presents the facts about drug use with authority.

The book is divided into three parts: basic concepts, mood-altering drugs, and areas of special concern. Information is based on statistics from the United States. The regulations and laws quoted are American. Treatments discussed are based on the American system of privately funded health care.

In part 1 (basic concepts), the chapter titled “Habituation, Dependency and Addiction” is useful for defining terms and distinguishing misuse from abuse and dependency from addiction. This chapter briefly describes the neurophysiological basis for the ability of drugs to produce mood alteration, which can lead to dependency and addiction.

Part 2 discusses each different class of mood-altering drugs and provides lots of factual information. However, the chapter on opiates underemphasizes their importance as drugs of abuse in clinical practice while the chapter on heroin and on methadone maintenance is too long. In the chapter on nicotine, the nicotine patch is referred to only briefly.

In part 3 (areas of special concern), well written, factual chapters cover such topics as drugs and AIDS, drugs and pregnancy, and drugs and sports. The final chapter is one with a decidedly American slant entitled “Why has the War Against Drugs Failed?”

Three appendices covering sources for reporting drug use (American), drug testing technology, and common street names for drugs are followed by almost 400 references. This book is not written for family physicians. It does not develop skills for identifying problems or intervening in this area or even challenge attitudes. However, it would be useful for family doctors interested in the facts on drug use and as an addition to a hospital, school, or public library.

Essentials f Drug Therapy

Gordon E. Johnson, PHD W.B. Sounders Company, 55 Homer Ave, Toronto, ON M8Z 4X6, 1991, 425 pp

Essentials of Drug Therapy is a clearly written book, summarizing information on drugs that are commonly used. It is not a reference text in pharmacology or an exhaustive detailed volume, such as the Compendium of Pharmaceuticals and Specialties, but is a practical source of information for the medical student and practitioner.

The chapters are organized according to therapeutic categories and are introduced by a brief overview of the therapeutic rationale for use of pharmacologie agents. Most drug groups are included, even those used for symptomatic relief, such as antitussives and analgesics. It is somewhat surprising that laxatives are not included, but these have never been an attractive group of drugs for pharmacologists.

The text is clear and succinct. Paragraph headings facilitate rapid access to information, with paragraphs on mechanism of action and pharmacological effects, therapeutic uses, adverse effects, drug interactions, and doses.

The book should be a useful volume for the busy practitioner and the medical student.

Now finally, let us grant that all the claims made for a new drug are true, that with it we can do this or that, as alleged. There still remains the question: do we want to do all these things? Shall we tranquilize the patient merely because the means are at hand, or alert and stimulate him, willy-nilly, when he is deluded or obsessed? Do we really want to lose control of all our mild elderly diabetics through a fistful of pills? Are we to go on creating more resistant infections through giving each new antibiotic a whirl? Shall we blindly accept the asseveration that two drugs with opposing types of action invariably give a nice blended effect when used together in fixed proportions ? Do we need to risk orthostatic hypotension, ileus, visual disturbances, palpitation, paresthesias, etc., merely to obtain blood pressure reduction in a mildly hypertensive patient? How frequently is intravenous iron administration advisable? Do we want often to replace thyroid substance with a quicker-acting compound whose omission may cause distressing withdrawal symptoms? And so on and on.

Do we really need all the time all the things that all the new drugs will give us? With full realization of the probable absurdity of the comparison, I am nevertheless going to liken political man’s possession of his new military weaponry with medical man’s acquisition of his new pharmaceutical arsenal. The time is not yet here when the decision will have to be made whether to drop the hydrogen bomb or not to drop it, but all the world is quivering with fear that such a moment is imminent, and men of good will everywhere are agitating for restriction of the use of this dreadful new power to those activities only of mankind wherein his best survival interests can be selectively aided. To use or not to use the new drugs for all they can do, that too is a question, our peculiar and particular medical question, and ours the solemn responsibility to answer it. For progress in this field will not be halted, and we are only now crossing the threshold into the vast drug sales room of the near future, whose walls and floors and counters and chests and racks and shelves will be loaded with bottles crying out “Use me! Or me! Or me! Or all of us together!” Shall we do it, always in all cases, all of it? Money in immense amounts is invested in the effort to tell us that this is our duty; the symptom is there, the drug is or soon will be available; the two must meet head-on invariably. “Treat your patient with these new drugs, Doctor, treat him, each one of him, or else a new kind of physician will be created who will do it.” In such exaggeration there is truth. Investigations now under way, may bestow power through drugs over metabolic processes as will make nuclear fission seem puny in potentiality for control of the world.

We doctors, while we can, must make the decision whether to give up and merely hand out the pills, or not. No individual can dictate that decision, but remember: all drugs, even the very best, are psychologically or physically potentially toxic agents — and none should be used unless unavoidable.

Publish date: 1959

Progress has been made with such giant strides in recent decades that one is tempted at times to bemoan the smallness of the territories still to be conquered. But for the pharmacologist at least, whatever the feeling may be in other circles, there exists a sufficient and powerful antidote for his ego in the large list of areas in which drugs are still badly needed. The things we might expect from these drugs, drugs that are not yet found or devised, are shown in Tables 3 and 4.

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This is a wonderful list, is it not? All this still left for the pharmacologist to do. And of course he will eventually do most of it, but there is something between him and the practitioner — a great vested interest which must sell to live. This vast pharmaceutical industry has become a familiar and essential ingredient of medical practice, and we should all generously and gladly attempt to be useful to it in recognition of a mutual interest and a shared desire. But this must not be done through yielding independence or sacrificing the intelligent approach!

Do not, I implore you, gain all the accretions to your pharmacologic knowledge from the paid sales representative, whose training is necessarily not comparable with yours, or accept the receipt of his sample as a mandate to use it. And do not believe the bromide that no one can keep up with medical advances today, for there are numerous existing abstract, year book, review and other services which make it quite possible to do so sufficiently well for practical and satisfying purposes. The expenditure of only a minimal amount of time is required too, if one’s time slices are adequately cut with this in mind. Most of you are keeping up better than you are told that you are.

And then there are the advertisements, the gorgeously colored spreads that make it difficult to find the reading matter in many of our journals. Please, if you must study the more gaudy of them at all, do so with a sour skepticism and a jaundiced and cynical eye. Be advised and aware that in some instances the journal references embodied in these advertisements are to preliminary findings that do not apply at all directly to the clinical claims that are made, and that in other instances the references are to publications that have actually been written by the pharmaceutical house staff itself for the inexperienced investigators who have made the clinical trials. The fact is that there are not enough existing facilities, and fully qualified clinical research workers, to perform the kind of studies that every new drug should have before it is made available for uncontrolled use in practice.

Publish date: 1959

During each of the past ten years the pharmaceutical industry has produced an average of approximately 400 new products. In the most recent year of record, 1957, the number is said to have been precisely 400, and 51 of these were single new chemicals. Many of the agents are produced in refined form in amounts that are absurdly small in relation to the bulk of the crude materials from which they are processed. Some typical yields of useful and familiar materials of different sorts are shown in Table 1. Add to the comparisons afforded in this table the fact that many entirely synthetic compounds are obtained through even more exhausting and expensive manipulations than are required in refining crude materials; and consider in addition the huge sums expended in research and promotion in order to make available, and to bring into the physician’s awareness, the packaged drugs awaiting his prescription — think of these things and it will easily be realized that the pharmaceutical manufacturers are obliged to interest themselves vitally in what it is that makes a new product acceptable to the doctor. To supply one observer’s version of what the requirements are, is the purpose of this presentation.

Source Of The Drug

I should say that if the new drug proposed for your use is, or is derived from, an old folk remedy the chances are good that it is worth paying attention to — not trying at once, willy-nilly, but at least watching to the extent of asking to see the records of its unbiased and controlled trials in specialized clinics. For the record of such agents is impressive, as is shown in the listing in Table 2 of valuable drugs obtained from folk medicine.

If a drug is offered because it has been discovered by search among the chemically close relatives of an active drug for another one of the same sort, you will be well advised to be hesitant in accepting it until full trials have been made by others better placed for such trials than yourself. Good drugs have often been developed through such approaches admittedly, but since these searches are usually begun merely to turn up for competitive reasons another drug as good as the one of established value, there is no obligation to believe a priori that the new agent is better than the old. It may be just as good and no more toxic, and this in itself may sometimes assure it a place in the armamentarium since there are instances in which there is advantage in having two strings to one’s bow — but let the qualified investigators determine the facts of the case while you continue to use the agent whose worth you know. Now, if the new drug has been evolved in attempting to improve an original compound through chemical modification, I should advise again to delay transferring patients to it until its clinical status has been proved by investigators qualified to make the controlled trials. There is a tendency among sales representatives of some pharmaceutical houses to maintain that certain chemical configurations reliably confer specific pharmacologic attributes upon compounds in which they are incorporated. But the actual fact is that invariability and predictability have not yet been achieved in this field of structure-activity relationships. One wants to know in each instance, first, whether the chemical configuration in question has really been shown by disinterested investigators to possess the attributes claimed for it; second, whether the structure to which it has been attached is one that is likely thereby to have the desired pharmacologic action conferred upon it or strengthened in it; and, third, whether the attachment has been made at a point that will potentiate or may actually weaken and possibly even pervert the action of the basic structure. These things the individual practitioner surely will not know.

Publish date: 1959

Research geared to meet women’s special needs.

A total of almost 400 drugs are now in various stages of development to meet the special needs of women. The drugs, many of which offer innovative therapeutic approaches, are intended to treat diseases that either disproportionately affect women or are among the leading causes of death. The top causes of death in women are heart disease, cancer, cerebrovascular disease, chronic obstructive pulmonary disease, pneumonia, diabetes, adverse drug reactions, Alzheimer’s disease, nephritis and septicemia.

Drug Research

Cancer drugs are far in the research lead. Between the early 1970s and the early 1990s, the incidence rate for lung cancer more than doubled and the death rate rose 182% in women. Of the 94 drugs being developed for cancer in women, 44% are targeted for breast cancer, 30% are for lung cancer and 20% for ovarian cancer. Uterine cancer, including endometrial cancer, is the most common malignancy of the female genital system, followed by ovarian cancer. The second largest number of investigational drugs are for obstetric/gynecologic disorders.

Cardiovascular Issues

Much attention has been paid to cancers in women, but cardiovascular disease is the leading cause of death. Heart attacks alone claim 250,000 lives annually and of those women who suffer a heart attack, 44% die within a year, compared to 27% of men. Cur-rently, 48 drugs are in development for cardiovascular disease.

Musculoskeletal disorders

Women suffer high incidences of musculoskeletal disorders. Osteoporosis, for example, affects one in every four women past age 50. And about 23 million women, including half of women over 65 years of age, suffer from arthritis. A total of 55 drugs are being developed to treat musculoskeletal disorders.

Antipsychotic drugs

Women are 60% more likely than men to experience major depression. Most of the antipsychotic drugs in research are for treatment of depression.

James McCormack, Glen Brown, Marc Levine, Robert Rangno, John Ruedy
W.B. Saunders Company, 55 Horner Ave, Toronto, ON M8Z 4X6
1996/550

Strengths

Evidence-based approach for making drug therapy decisions

Weaknesses

Missing key information

Audience

Any clinician who prescribes drug therapy, particularly useful for teaching practices

This book is not just another multi-authored reference book. It is designed to wean clinicians away from “habitual or intuitive solutions” and to encourage decisions based on explicit factors. To achieve these goals, the book has a section on drug therapy for disease states to help readers make therapeutic choices that are reasonable if not optimal and to provide information on initiating, altering, or terminating a drug.

For each clinical condition a set of questions is asked. For example, in treating depression, before choosing a therapeutic agent you are asked to consider treatment goals, evidence to support drug therapy, when to consider drug therapy, initial treatment, dosage, the length of the initial treatment regimen, the efficacy parameters and patient assessment interval, when to add an additional drug if initial therapy fails, and the length of drug therapy.

This is good medicine. The process reinforces a framework for making therapeutic decisions and subsequently managing patients appropriately. The text also has sections on common drug-induced adverse reactions and drug monographs. Both these sections use questions to develop rational therapeutic decisions.

No text is perfect. Inevitably some key information is missing. I could not find a specific therapeutic approach to necrotizing fasciitis. Also, the book does not provide advice on how to switch from one group of antidepressants to another. Nevertheless, once I got used to the directed format, I found it is easy to use and helpful in making reasonable if not optimal drug therapy decisions.

Studies have shown that the most commonly used antiepileptic drugs (AEDs) reduce blood levels of oral contraceptives (OCs) by about 40%. But how many physicians know this? After seeing five epileptic patients in two years at Johns Hopkins Hospital with unexpected and inconvenient pregnancies that occurred during OC and AED therapies, Krauss et al decided to conduct a national survey to see how aware physicians are of the interactions between antiepileptic drugs and oral contraceptives. They were interested to find out how many physicians know that hepatic enzyme-inducing AEDs increase the metabolism of oral contraceptives, thus reducing blood levels. They also wanted to find out if physicians know that antiepileptic drugs increase the risk of birth defects two- to threefold (or more in high-risk patients).

The Johns Hopkins team sent questionnaires to 1,000 neurologists and 1,000 obstetricians; the response rate was 15.5%. Although 91% of the neurologists and 75% of the obstetricians reported that they treat epileptic women of childbearing age, only 4% of the neurologists and none of the obstetricians knew which of the six most commonly used antiepileptic drugs induce the more rapid metabolism of oral contraceptive, and which do not. Yet, 27% of the neurologists and 21% of the obstetricians reported that OC failures occurred in their patients during AED therapy. In addition, almost half of neurologists and one fourth of obstetricians underestimated the risks of birth defects for women taking antiepileptic drugs.

Certain AEDs-phenytoin, phenobarbital, carbamazepine, oxcarbazepine, primidone, and ethosuximide-induce the cytochrome P450 enzymes that metabolize synthetic estrogens (e.g., ethinyl estradiol and mestranol), causing a 40% reduction in serum levels. In addition, free progestin levels are decreased as a result of increased synthesis of hormone- binding globulins. The antiepileptic drugs valproic acid, gabapentin, vigabatrin, lamotrigine, topiramate, and tiagabine do not appear to induce hepatic P450 enzymes and are unlikely to interfere with oral contraceptives. The effect of felbamate on oral contraceptives is still under investigation.

The recommendation for women on antiepileptic drugs is to increase the oral contraceptive dose to 50 mcg estradiol, particularly if breakthrough bleeding occurs. However, according to Krauss et al, pregnancy may occur even at the highest dose level, sometimes with no warning of irregular bleeding. Because high doses increase the risk of thromboembolism (particularly in smokers and women over age 35), other forms of contraception should be considered as an alternative to oral contraceptives. An effective choice is the depot form of medroxyprogesterone (Depo-Provera), a potent contraceptive that has not been associated with failures due toantiepileptic drugs . By contrast, the levonorgestrol implant (Norplant) is not an effective alternative, according to Krauss et al. More than 30 unplanned pregnancies have occurred in women on AEDs who used Norplant.

“Our survey suggests that a large number of women in the United States with epilepsy are at risk for unplanned pregnancies while taking oral contraceptives,” said the Johns Hopkins investigators. Women with epilepsy should discuss reproductive issues with both a neurologist (who may be more familiar with the effects of antiepileptic drugs on oral contraceptives) and an obstetrician (who may be more familiar with the risks of birth defects).

Question. My 10-year-old daughter has just been prescribed Depakote for absence epilepsy. How will this drug affect her quality of life? We are particularly concerned with her ability to learn and continue to be creative/intellegent.

Answer. My experience with valproate [Depakote] has been in adults, in which population it is very well-tolerated and rarely the cause of any significant cognitive problems; it can sometimes cause drowsiness, but this is usually mild and dose-related. You may be interested in a Swiss study by Despland [ref: Schweiz Rundsch Med Prax Oct 1994] that reviewed the literature on valproate use in epilepsy from 1976 to 1994 (the drug has been used in Switzerland since 1967). This author found valproate “to be a remarkably safe and effective antiepileptic drug…in children and adults.”

It is associated with fewer neurologic side effects than other major antiepileptic drugs, and “…had minimal impact on cognitive function and was associated with fewer cognitive and behavioral problems than phenytoin [Dilantin] and phenobarbital.”

Side effects of valproate can include weight gain, mild GI effects, tremor, and hair loss, but these may respond to dosage adjustment or other measures. Keep in mind, also, that seizures themselves often leave childen feeling helpless, scared, and “different” from other kids, so that the valproate may, indeed, be an important ally in your daughter’s quality of life. I would suggest, in any case, that you discuss the question of long-term effects on learning and creativity with your daughter’s physician.

The FDA has approved a novel antiepileptic agent – topiramate (Topamax/Ortho-McNeil)-for the adjunctive treatment of adults with partial-onset seizures. Topiramate was identified by scientists at the National Institutes of Health during random screening of promising drug candidates, and was developed by the R.W. Johnson Pharmaceutical Research Institute. The drug blocks voltage-sensitive sodium channels, enhances the activity of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), and blocks the action of the excitatory neurotransmitter glutamate. It also inhibits carbonic anhydrase, although this may not contribute to anticonvulsant activity.

In five placebo-controlled, double-blind clinical trials, topiramate significantly reduced the frequency of epileptic seizures, including refractory partial seizures. In dosage studies- topiramate given at 200, 400, 600, 800, and 1,000 mg per day-the 200-mg dose gave inconsistent results, and increasing the dose beyond 400 mg per day did not increase efficacy. One trial included 45 patients who received 400 mg/day; 44% responded with at least a 50% reduction in seizure frequency, compared with baseline. In a second trial, 35% of 23 patients who received the 400-mg/day dose showed a 50% reduction in seizure rate. By comparison, 24% of patients receiving the 200-mg/day dose showed a seizure reduction rate of about 27%, and approximately 36 to 46% of patients responded to 600, 800, and 1,000 mg/day with a 36 to 46% reduction in seizure rates (response generally decreased as the dosage was increased). Placebo patients showed little or no response, and often showed increases in seizure frequency. Based on overall clinical results, topiramate appears to be a more potent anticonvulsant than Warner Lambert’s gabapentin (with response rates of 22-26%) and GlaxoWellcome’s lamotrigine (seizure reduction, 25-36%).

Topiramate is given 50 mg/day initially, with a gradual increase during an 8-week titration period to a total of 400 mg/day in two divided doses. Oral bioavailability is about 80%, and food has no clinically significant effect on absorption. At dosages of 200 to 800 mg, serum concentrations are linearly dose related and there is not much intersubject variability. Plasma protein binding is less than 20%. Single-dose studies in healthy adults have revealed that the drug is about 20% metabolized, but with multiple dosing in patients taking other antiepileptic drugs, up to 50% of the dose is metabolized. Elimination is primarily renal, with 50 to 80% of the dose excreted as unchanged topiramate; elimination half-life is 20 to 30 hours. Age, gender, race, baseline seizure rate, and concomitant antiepileptic drugs do not appear to affect efficacy, although topiramate may interact with phenytoin (Dilantin/Warner Lambert) and carbamazepine (Tegretol/Novartis). Addition of topiramate to a regimen that includes phenytoin may require adjustment of the phenytoin dose; addition or withdrawal of phenytoin and/or carbamazepine to the topiramate regimen may require adjustment of the dose of topiramate.

At the 200- to 400-mg dose range, the most frequent adverse effects in clinical trials were psychomotor slowing (incidence about 17%), difficulty concentrating (8%), speech and language problems (about 6%), somnolence (30%), and fatigue (11-12%). These reactions were generally dose related. Similar side effects (although less frequent) were seen with lamotrigine and gabapentin. During clinical studies, 1.5% of topiramate-treated patients developed kidney stones, which represents a two- to fourfold increase over the normal rate of stone formation. This may be due to carbonic anhydrase inhibition, and is managed by increasing fluid intake. Another side effect thought to be related to carbonic anhydrase inhibition is paresthesia. Use of topiramate with other carbonic anhydrase inhibitors should be avoided. Approximately 11% of patients withdrew from clinical trials because of adverse events, primarily central nervous system (CNS) effects, paresthesias, and, at higher dosages, anorexia and weight loss.

Although topiramate has been approved only for adults, Johnson & Johnson is studying the drug in pediatric patients with epileptic disorders, including generalized seizures and Lennox-Gastaut syndrome.