Key Points for Practice

Pharmacotherapy, i.e., the use of drugs in the prevention and treatment of disease, is predicated on the clinical application of pharmacodynamic and pharmacokinetic principles as influenced by patient-related variables. Many factors affect the drug response phenotype, e.g., age, gender, underlying disease, and genetic variations, and determine the individual effective dose of a drug required to produce a specific response and determine the success or failure of therapy.¹²

Genetic polymorphism can result in altered drug-receptor interactions or signaling pathways once a drug-receptor complex is formed causing inter-individual pharmacodynamic variations. Genomic variations can also affect oxidation/reduction and conjugation/hydrolysis reactions causing inter-individual pharmacokinetic variations. Furthermore, pharmacogenetic variations related to rare, unpredictable, i.e., idiosyncratic adverse effects have also been reported.

Because of these genomic variations, an individual may be hyporeactive, i.e., a drug’s usual effect is produced at an unexpectedly high dose or hyperreactive, i.e., the usual effect of a drug is produced at an unexpectedly low dose. An individual may also develop a tolerance following repeated exposure to a drug requiring higher doses to maintain efficacy. Tolerance that develops rapidly, following the administration of only a few doses of a drug, is referred to as tachyphylaxis.

The individual effective dose of a drug intended to produce a specific effect is usually expressed in terms of milligram per kilogram of body weight. Manufacturers’ maximum recommended dose (MRD), by definition, is for a 75 kg (165 lbs.) healthy adult. Ultimately, in determining the optimum therapeutic dose of a drug for an individual one must consider the patient’s weight, as well as other factors such as dynamic and kinetics variables related to a specific patient.

Pregnancy. Pregnancy is accompanied by various physiological changes that may affect multiple organs. These changes are important for adaptation and to facilitate fetal growth and survival. These physiological changes should not be mistaken with pathological ones and thus dentists must recognize them. The most important alterations involve the cardiovascular system (CVS), hematological system, gastrointestinal (GI) system, respiratory system and renal system. In this section we will review these changes and link them to the effects on drug pharmacokinetics.

When treating the pregnant patient, special considerations may be needed. These include changes that may be required in administering and prescribing drugs. The concern that all clinicians have is the potential adverse teratogenic effects that some drugs display. In pregnancy, it is assumed that all drugs can cross the placenta and thus affect the developing fetus. During the first 90 days (first trimester), organogenesis occurs and thus the fetus is most susceptible to teratogenesis. Therefore, avoiding medications during this time is desirable, although not always possible. Similarly, the approach of not prescribing any drugs to the pregnant patient carries its own risks. For instance, inadequately managed persistent pain may be harmful. Likewise, an untreated apical abscess may lead to systemic infection. Thus, failure to manage these conditions may harm the mother and/or the fetus. In pregnancy, drugs should be prescribed when the benefit to the mother is maximized and when the risk to the developing fetus is minimal. To determine the risks associated with the use of drugs in pregnancy, the United States Food and Drug Administration (FDA) has classified drugs based on the level of risks they pose to the fetus. Drugs in category A and B are considered safe as no adverse effects have been shown in humans. Drugs in category C are ones in which adverse effects on the fetus have been shown in some animal studies, but there are no adequate and well-controlled studies in humans. In this category drugs may still be used if the benefits outweigh the risks. Drugs in category D should be avoided as some studies demonstrated clear teratogenic effects in humans. Nonetheless, in rare circumstances, drugs in this category may be used. Finally, drugs in category X clearly should be avoided as studies in humans or animals have demonstrated fetal abnormalities and positive evidence of human fetal risk.

Lactation and the neonate. Milk is generally more acidic (pH 6.8) than plasma (pH 7.4); therefore, basic drugs become more concentrated in milk because of the phenomenon of pH trapping, while acidic drugs are limited in their ability to enter milk. Prescribing precautions can be found in the “Dosage and Administration,” “Contraindications,” “Warning and Precautions”, and “Adverse Effects” sections, and “Lactation” subsection of specific drug labeling.⁶

Females and males of reproductive potential. The FDA requires pregnancy testing or contraception before, during, or after therapy with some drugs and warnings about possible drug-related fertility effects. Prescribing precautions can be found in the “Dosage and Administration,” “Contraindications,” “Warning and Precautions”, and “Adverse Effects” sections, and “Females and Males of Reproductive Potential” subsection of specific drug labeling.⁶

Pediatric patients. Often there is a paucity of specific pharmacokinetic and pharmacodynamic data for the pediatric population. Dosage forms designed with the adult population in mind and the dosages cannot easily be individualized for children. Even when appropriate dosage forms for children are available palatability, resistance to taking medications, and adherence issues related to parent/guardian/caregiver may further hinder optimal therapy.

Although there are many rules and formulae to calculate drug dosages for children, weight-based dosing recommendations by manufacturers provide the most reasonable approach.⁶ The maximum safe dose of a drug should be carefully calculated for each child. Prescribing precautions can be found in the “Dosage and Administration,” “Contraindications,” “Warning and Precautions”, and “Adverse Effects” sections, and “Lactation” subsection of specific drug labeling.⁶

Geriatric. The aging process includes 3 types of physiological changes: changes in cellular homeostatic mechanisms, which may include regulation of body temperature, as well as blood and extracellular fluid volumes; those related to a decrease in organ mass; and those involving a decline in, and loss of, the functional reserves of the body's systems. The prescription and use of multiple drugs to deal with concomitant multiple diseases is known as polypharmacy. Numerous studies have shown that the elderly take more prescription and over-the-counter (OTC) medications than younger adults. The most commonly used classes of OTC medications include analgesics, laxatives, vitamins and minerals. At any given time, an elderly patient takes, on average, 4 or 5 prescription drugs and 2 or 3 OTC medications .

Herbal supplements have long been used by older people as a substitute for high-cost prescription medications as well as because of their overall popularity. The unmonitored use of herbal supplements can be a serious risk in this population, who are commonly given prescription medications to control multiple disorders. For instance, many herbal preparations, such as ginkgo, ginseng, garlic and ginger, have anti-platelet and anticoagulation properties and, thus, may potentiate the effects of other anticoagulation drugs, such as warfarin. Synergistic interactions may also occur between herbal medicines and other anti-platelets drugs, such as ASA and nonsteroidal anti-inflammatory drugs (NSAIDs). Thus, geriatric patients who take warfarin and other anti-platelet medications should be advised about these interactions with herbal products.

The high prevalence of polypharmacy among the elderly may lead to inappropriate drug use, medication errors, drug interactions and adverse drug reactions. Adverse drug reactions and drug interactions are common reasons for admission to hospital of older people, are common in elderly patients in hospital and are an important cause of morbidity and mortality. The incidence of adverse drug reactions in the elderly is 3–4 times that seen in young adults. The medications most often associated with adverse reactions and interactions are anticoagulants, anticonvulsants and cardiovascular agents. The most consistent risk factor for adverse drug reactions is number of drugs being taken, i.e., the risk rises exponentially as the number of drugs increases. Other factors that contribute to the incidence of adverse drug reactions are changes in pharmacokinetics and pharmacodynamics and comorbidities associated with the elderly patient. The symptoms of adverse drug reactions may be harder to detect in the elderly and may be misinterpreted as symptoms of a disease or even "normal aging."

Although polypharmacy is acceptable in many cases of multiple comorbidities, prescribers must consider older adults' physiology. For instance, many elderly patients are prescribed warfarin concurrently with an NSAID, a selective serotonin reuptake inhibitor (SSRI) or a lipid-lowering agent, which may increase the risk of bleeding (already increased by use of warfarin alone).

To avoid adverse drug reactions and drug interactions, the dentist should regularly review the patient's medical history and medication list and carefully assess the need for and consequences of pharmacologic intervention. Finally, close monitoring and thorough evaluation of pharmacotherapy is important in preventing adverse drug reactions and drug interactions.

Patients with liver disease. In the presence of liver disease, adverse drug effects are primarily related to altered pharmacokinetic processes. To estimate the ability of the liver to metabolize drugs, determine the patient’s Child-Pugh score (Table 2).^13-15 Prescribing precautions can be found in the “Dosage and Administration,” “Contraindications,” “Warning and Precautions” and “Adverse Effects” sections of specific drug labeling.⁶

Patients with chronic renal disease. Drug dosages are most commonly based on the estimated creatinine clearance determined by the Cockcroft-Gault equation, i.e., eCrCl in mL/min = (140 - age x weight in kg x 0.85 (for females) ÷ S_cr in mg/dL x 72).¹⁶ The normal range for men and women ≥40 years of age is 107-139 mL/min and 87-107 mL/min, respectively. It is of note that after 20 years of age, eCrCl is reduced by 6.5 mL/min every 10 years.

Figure 8.

Figure 8.

eCrCl, a surrogate for glomerular filtration rate (GFR), and estimated percent renal function.

The eCrCl is used as a surrogate of GFR (Figure 8). In general, if the eCrCl is >50 mL/min, no dosage adjustment is required; if it is 10-50 mL/min, some drugs should be reduced by 25-50%.; if it is <10 mL/min, some drugs should be reduced by up to 75%, while others should be avoided.¹⁶ Prescribing precautions can be found in the “Dosage and Administration,” “Contraindications,” “Warning and Precautions” and “Adverse Effects” sections of specific drug labeling.⁶

Non-adherence. It is a generally accepted that many patients do not adhere to their prescribed therapeutic regimen.^17-20 Non-adherence can be intentional (actively choosing not to adhere) or unintentional (e.g., passively inconsistent medication-taking behavior including forgetfulness or carelessness). Determinants of non-adherence include the disease, the patient, the practitioner, the treatment regimen, economic factors, and the interaction of each of these factors.

A patient’s trust in the clinician and/or the treatment protocol as established during the office visit is important. Patients tend to be adherent if they have a good understanding of the illness and the therapy. Therefore, good communication between clinicians and patients is a major factor affecting adherence. A positive experience during the office visit, along with individualized regimens and good follow-up on the part of clinicians, improve adherence.

When an illness is serious or disabling, the patient will likely follow the therapeutic regimen. The longer the duration of treatment, the less likely it is that the patient will adhere to the regimen over time. This is especially true if symptoms are relieved before drug therapy is to be discontinued. The regimen itself may also be discouraging or confusing because of multiple drug use, scheduling of dosages, and side effects. Finally, cost may be a major contributing factor.

In children, the major reason for non-adherence is a dislike for the taste or smell of the medication. If it is frustrating to the parent/guardian/caregiver to give the medication, they are more likely to skip doses or discontinue the medication with the disappearance of symptoms. If the child is attending school, the regimen should be convenient and coordinated with the school schedule. Consider recommending specific times rather than generalize.

Common causes of non-adherence in elderly patients include failure to fill prescriptions due to transportation problems and expense. Other factors include a lack of trust or confidence in the doctor or therapy and poor comprehension of the regimen. Difficulty in opening packages or swallowing pills, poor memory, visual or hearing impairment may also contribute to non-adherence. Repetition of directions with written instructions and clear labeling are helpful.

Prescriptions. Drugs fall into two major categories: non-prescription, i.e., over-the-counter, and prescription drugs.^1-3 Prescription drugs are further divided into legend drugs and scheduled drugs. Legend drugs require a prescription because they are considered to be potentially harmful if not used under supervision by a licensed practitioner. Legend drugs are known as such because their labels bear the legend “Caution: Federal Law Prohibits Dispensing Without a Prescription.”

The prescription of scheduled drugs, i.e., controlled substances, is even more strictly controlled by Federal regulations. A licensed practitioner who administers, prescribes, or dispenses controlled substances must register under Controlled Substances Act of 1970 with the Drug Enforcement Administration (DEA) and obtain a DEA number, which must be included on every prescription for a controlled substance.^1-3 Many States have additional, sometimes more strict requirements.

A prescription is a written, verbal, or electronic order (1) from a licensed practitioner, (2) to a licensed pharmacist, (3) for a particular medication, (4) for a specific patient, (5) at a particular time. It has three components: a heading, a body, and a closing (Figure 9). These elements identify the prescriber and the patient; inform the pharmacist of the name, strength, and formulation of the drug to be dispensed; and provide instructions to the patient for self-administration of the drug.

Figure 9.

Figure 9.

Essential Elements of a Prescription.

As noted earlier, while drugs have the capacity to enhance health, they all have the potential to cause harm if prescribed or taken inappropriately. For this reasons it is recommended that healthcare professionals who prescribe medications exercise critical thinking skills to ensure the safe and effective use of therapeutic agents. The following steps, along with ongoing self-directed learning, reflect a disciplined approach to prescription writing and avoiding errors:^21-23

Step 1- Be clear about the reasons for prescribing

• Establish an accurate diagnosis whenever possible; although, at times one may prescribe medications based on a presumptive or working diagnosis.

• Set a clear therapeutic objective.

Step 2 - Consider the patient’s drug history before prescribing

• Obtain an accurate list of current and recent medications (including over-the-counter and alternative medicines) and a history of prior adverse drug reactions.

Step 3 - Identify other factors that might alter the benefits and risks of treatment

• Consider individual risk factors that might influence therapy, e.g., weight of the patient, physiological changes with age and pregnancy, or impaired hepatic and renal function.

Step 4 - Take into consideration the patient’s expectations

• Seek to form a partnership with the patient when selecting treatments, making sure patient understands and agrees with the reasons for taking the medication.

Step 5 - Select efficacious, safe, and cost-effective drugs appropriate for the patient

• The likely beneficial effects of a drug should outweigh any potential harms and, whenever possible, this decision should be based on published evidence.

• Choose the best formulation, dose, route of administration, frequency of dosing, and duration of treatment.

Step 6 - Adhere to guidelines

• Be aware of evidence-based recommendations developed by Federal and state agencies, and professional organizations, e.g., opioid prescribing guidelines.

• Prescribe only the necessary quantity of a drug to a patient.

• Balance specific drug selection considering the needs of the patient and cost.

• Use reliable informational resources, e.g., DailyMed.

Step 7 - Write unambiguous prescriptions

• Write the strength of a drug’s unit dose in the metric system, e.g., in grams (g) or milligrams (mg) for solid formulations and in milligram per milliliter (mg/ml) for liquid formulations.

  • When the unit dose is 1 gram or more it should be written in grams, e.g., write 2 g, not 2000 mg.

  • When the unit dose is 1 milligram or more, but less than 1 gram, it should be written in milligrams, e.g., write 200 mg, not 0.2 g.

  • When writing dosage strength, always use leading zeros, e.g., write 0.5 ml versus .5 ml, which can be mistaken for 5 ml.

  • Avoid trailing zeroes, e.g., write 5 mg versus 5.0 mg, which can be mistaken for 50 mg.

  • Under directions for the patient it may be necessary to convert milliliters to a convenient household measurement.

  • When prescribing a controlled substance, in addition to writing the number of tablets or capsules to be dispensed, the amount must also be written-out longhand, e.g., Disp #20 (twenty) tablets.

• Avoid using abbreviations and write-out instructions in full; for example, “Take two tablets four times a day for 5 days”.

Step 8 - Monitor the beneficial and adverse effects of therapeutic agents

• Know what to look for.

• Understand how to alter the therapeutic regimen as a result of this information.

• Know how to report adverse drug reactions.

Step 9 - Communicate the reasons for and document prescribing decisions

• Communicate clearly with the patient as well as the pharmacist.

• Inform the patient about how to take the medicine, what benefits might arise, and what potential adverse effects they may experience.

• Document prescribing decisions in the health record accurately.

Step 10 - Prescribe within limitations of knowledge, skills, and experience

• Always keep relevant knowledge and skills up to date.

• Be prepared to seek the advice and support of qualified professional colleagues.

• Verify all information on prescriptions.

Adverse drug effects (ADE). A noted earlier, there are no “absolutely” safe biologically active agents. Whether a drug will do harm to an individual depends on the patient’s age, genetic makeup, and preexisting conditions; and other drugs that the patient may be taking. A discussion of mechanisms of ADEs, common ADEs associated with drugs dispensed by U.S. community pharmacies, and less common ADEs in the head and neck area is presented elsewhere.^24-26