Key Topics

• • Introduction to the factors that underlie safe drug prescribing
• • Extension and side effects associated with drug therapy, and allergic reactions
• • Drug safety issues during pregnancy
• • Clinical studies to determine safety and effectiveness of drug therapies
• • Individual reactions to drug treatment

Learning Objectives

• • Be familiar with the basic factors that underpin safe prescribing
• • Be familiar with the adverse reactions that may occur with drug therapies, and the distinction between extension and side effects
• • Be aware of the increased need for vigilance in drug prescribing if a patient may be pregnant, and also in elderly patients where polypharmacy may be an issue
• • Be aware of the need for pharmacovigilance
• • Be aware of the potential for individual variations in response to drug treatment

Introduction

By definition, a drug is a chemical that changes the function of the body. Obviously, the aim of drug therapy is to use these agents to achieve a positive, or beneficial outcome for the patient. The benefit derived may range from making the patient’s visit to the dental clinic more comfortable, through to treating a potentially life-threatening infection. However, when used inappropriately, the effect a drug has on the body may be undesirable, and hence its effects are more akin to a poison. There is really nothing inherent about a drug that makes it either safe or unsafe, it comes down to the skill of the clinician combined with careful, informed prescribing that ensures the best clinical outcomes for their patients. The benefits delivered by a drug depend upon when it is used, why it is used, how it is used, how much is used, and whether there are other drugs being used at the same time. There are also individual patient factors that may come into play.

Regulatory authorities employ a rigorous registration process to help ensure that new medications demonstrate acceptable levels of both safety and efficacy. However, the onus is still on the clinician to use these drugs in a way that optimizes the beneficial effects. A clinician must use all the current, available evidence to make their prescribing choices. The complexity of these issues may be illustrated in relation to the use of antibiotics, such as penicillin. Antibiotics save millions of lives every year, and we tend now to take for granted the benefits they produce. However, a small percentage of the population are allergic to penicillins, and severe, penicillin-induced anaphylaxis accounts for more than one thousand deaths per year. While antibiotics are primarily used to treat a confirmed bacterial infection, a proportion of the patient population may benefit from prophylactic antibiotic therapy to avoid iatrogenic infection. Finally, the development of multi-drug resistant strains of bacteria is becoming a major concern, and this is partly fuelled by the over-use of antibiotics, and may be compounded in some cases by poor patient compliance. Hence, appropriate prescribing requires all of these benefits and risks to be balanced in light of current clinical evidence.

While drug prescribing is a smaller component of dental practice as opposed to medical practice, the dental practitioner must be aware of all the potential issues around, not just the medications they use and prescribe, but also any other medications their patients may be taking.

Determining drug safety

Therapeutic index

Safe and effective drug prescribing is basically informed by risk-benefit analyses. One commonly used measure of that balance is the therapeutic index, which is determined by the lethal dose in 50% of a population (LD₅₀) divided by the effective dose, again for 50% of a population (ED₅₀). Basically, the larger the therapeutic index, the safer the drug is, at least in theory. In other words, the bigger the difference between the dose required to produce the beneficial effects of the drug, as compared to its toxic effects, the greater the margin of safety. However, there are a number of significant limitations to this measure. First, the LD₅₀ value is not a clinical measurement, but rather is derived from animal studies. In addition, a measure like LD₅₀ does not necessarily reflect the kind of adverse effects that one may see in the clinic. For example, from its therapeutic index, penicillin is an extremely safe drug. Unfortunately, the risk of allergic reactions is not reflected by this measure. In a similar manner, perhaps the most notorious drug in the history of medicine, thalidomide, also has a very high therapeutic index. Its capacity to cause gross malformations in the developing foetus is not reflected by this ‘safety’ measure.

Extension and side effects with drug therapy

All drugs have the potential to produce harmful as well as beneficial effects, and most commonly, any unwanted effects are normally related to the main mechanism of action of the drug. As such, many of these adverse events are predictable once one understands the mechanism of action of the drug. Often the unwanted effects simply reflect the basic action of the drug. For example, a common issue with sedative drugs is tendency to cause drowsiness, or anti-coagulant therapies may cause excessive bleeding. Such problems are referred to as extension effects, and are commonly associated with higher doses of the drug. Such reactions are predictable, and in most cases the problems can be prevented by appropriate dosing, or may be reversed by reducing the dose.

Drugs may also produce adverse effects that are unrelated to the therapeutic goal of the treatment, and these are referred to as side effects. In many cases these effects may be both predictable and dose-dependent. One of the goals of drug development is to try to enhance the beneficial effects of a drug, while reducing the unwanted effects. The development of bronchodilators for the treatment of asthma illustrates how drug therapy can be improved by a better understanding of the molecular and cellular action of drugs. The first synthetic bronchodilator to be developed was isoprenaline, a non-selective beta-adrenergic agonist. Isoprenaline stimulates both β1 and β2 adrenergic receptors. Stimulation of the β2-adrenoceptors on airway smooth muscle produces bronchodilation, and hence delivers the beneficial effects of the therapy. However, stimulation of the β1-adrenoceptors on the heart will cause tachycardia and palpatations, which is unpleasant, and potentially dangerous in some patients. The cardiac effects are predictable, given the nature of the drug, but are also unwanted. The subsequent development of selective β2 agonists, such as salbutamol, resulted in the beneficial effects of the bronchodilator being retained, while the cardiovascular side effects were significantly reduced. However, it is not always so straightforward to reduce unwanted effects. Opioid analgesics, such as morphine, have a tendency to cause nausea and vomiting in approximately 40% of patients. However, this tendency to cause nausea and vomiting appears to be inseparable from the analgesic effects, and occurs at the same doses.

Unfortunately, sometimes we have little choice but to tolerate side effects, because there are no viable alternatives available. For example, the side effects with cancer chemotherapy are often very severe but, in terms of a risk–benefit decision, our choices are limited. However, on-going research and development is starting to yield effective cancer treatments, such as imatinib, which exhibit a significantly improved beneficial–side effect profile.

From the dentistry perspective, probably one of the most common issues associated with systemic medication is the problem of xerostomia, and therefore one must examine ways of minimizing the impact this may have on one’s patients.

Drug allergy