Safe prescribing in general dental practice – challenges and solutions

Allergy status

In 2017, amoxicillin was the most common drug prescribed by GDPs in England, accounting for nearly 42% of all items on FP10D.¹ The allergy status of the patient should be established before prescribing antibacterials, especially to penicillins (eg amoxicillin, co-amoxiclav) as a true hypersensitivity reaction will limit what can be prescribed. A small proportion of patients with penicillin hypersensitivity may also have a similar reaction to cephalosporins (eg cephalexin, cefradine) known as cross-reactivity (Figure 1).⁹ Many patients may think that they are allergic to penicillins from previous adverse effects, such as diarrhoea and nausea, but careful questioning may reveal reactions that are neither anaphylactic nor serious in nature.

Drug history

Alongside allergy status, it is important to find out what has been prescribed for patients and how adherent they are to their treatment. On average, patients with chronic disease only take about half of their doses as prescribed,¹⁰ and it is common for patients to forget to mention contraceptives, injections and inhaled or topical medicines. They may, when questioned, also need to be prompted to tell you about non-prescribed products, eg over-the-counter (OTC) medicines, herbal and complementary therapies, food supplements and recreational drugs. A comprehensive list and an appreciation of how the patient uses these products can help establish whether there are drug-related causes of symptoms or problems and inform dental prescribing decisions.

Hepatic and renal function

Approximately two-thirds of drugs are excreted via the kidney. If a patient has renal impairment, drugs which are excreted by the kidney, and sometimes their metabolites, can accumulate in the body and increase the risk of adverse effects. The plasma half-life of oral aciclovir, for example, increases from around 3 hours to more than 19 hours in a patient with chronic kidney disease.¹¹ In patients with renal impairment, dose adjustments are required to reduce the risk of accumulation while maintaining a therapeutic effect (Figure 2). Adjustments can be made by decreasing the dose and/or by extending the duration between each dose. Specific drug monographs within the British National Formulary (BNF) state the appropriate approach.

Patients with hepatic impairment may also require dose adjustments to take account of reduced drug metabolism. The liver metabolizes most drugs that enter the body to enable excretion by the kidneys. Dose adjustment in liver impairment is unpredictable and subject to interpatient variability. Treatment regimens have to be individually tailored to reduce accumulation risk and potential exacerbation of the adverse effects of liver disease. For example, encephalopathy in chronic liver disease can be precipitated by drugs that cause sedation, such as diazepam, or drugs that cause constipation, such as dihydrocodeine. The BNF provides guidance for individual drugs. However, it is often monitoring of outcomes and adverse effects which guides dosing and this frequently requires collaboration with, and follow-up by, doctors and other healthcare professionals.

Drug-drug interactions

The interaction between drugs, prescribed or non-prescribed, can have potentially serious consequences. Hepatic metabolism of drugs may be altered by the induction or inhibition of cytochrome P450 enzymes. Many drugs induce or inhibit these enzymes, which can result in clinically significant changes in plasma drug concentrations of other drugs. For example, carbamazepine is a potent enzyme inducer and increases the metabolism of warfarin, thereby reducing the anticoagulant effect. Inhibiting agents, such as omeprazole, macrolide antibacterials (eg erythromycin, clarithromycin), azole antifungals (eg fluconazole) and metronidazole, can increase plasma concentrations of co-administered drugs, such as warfarin, antiepileptics, some cytotoxic medicines and lithium.

Adverse drug reactions

Patients' previous ADRs should influence prescribing decisions. Susceptibility to ADRs varies dependent on the condition of patients and sometimes on their genetic profile. Many will be aware of the risk of gastrointestinal adverse events associated with non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen and diclofenac, but may not realize that their mechanism of action is to reduce prostaglandin synthesis, which can lead to renal hypoperfusion, fluid retention and acute kidney injury (AKI) in vulnerable individuals, eg patients with compromised renal function. Patients of Han Chinese and Thai family origin are more likely to have the HLA-B*1502 allele which predisposes them to Stevens-Johnson syndrome and toxic epidermal necrolysis with drugs like carbamazepine, and hence should be screened for this allele before it is prescribed for them.

It is also important to recognize that a patient's dental symptoms could be due to an ADR. Oral adverse effects, such as xerostomia, due to anticholinergic medicines like oxybutynin and amitriptyline, are well known to increase the risk of oral disease. Drug-induced gingival enlargement is known to be caused by calcium-channel blockers (eg amlodipine) in patients with poor oral hygiene.¹² A more recent example has been the attribution of anti-resorptive (eg RANKL inhibitors such as denosumab) and anti-angiogenic medicines (eg bevacizumab, sunitinib and aflibercept) in causing medication-related osteonecrosis of the jaw (MRONJ) akin to that caused by bisphosphonate (eg alendronic acid) therapy.^13,14,15 GDPs play an integral role in pharmacovigilance by reporting suspected ADRs for all prescription, OTC, herbal and homeopathic medicines using the MHRA yellow card scheme (https://yellowcard.mhra.gov.uk/).

Pregnancy and breastfeeding

Where possible, drugs should be avoided in pregnancy owing to potential harmful effects (eg carbamazepine is known to increase the risk of spina bifida and associated defects). If prescribing for a pregnant woman, it is important to establish the stage of pregnancy. Generally, the most vulnerable time of exposure is the first trimester when embryonic organ formation occurs. While desirable, it is not always possible to avoid drug treatment. If pain control is needed, NSAIDs, such as ibuprofen and diclofenac, should be avoided but paracetamol is considered safe if used at therapeutic doses and in short, occasional courses. Some antibacterials (eg penicillins and cephalosporins) are considered safe throughout pregnancy while others should be avoided. Metronidazole, for example, may have teratogenic effects if used in the first trimester and tetracyclines, such as doxycycline, have the potential to discolour the unborn baby's teeth if used in the second and third trimester.

It is important to remember that a drug that is safe to use during pregnancy is not necessarily safe for the breastfeeding patient. Virtually all drugs are excreted into breast milk to some extent and hence have the potential to affect a breastfed baby. Breastfeeding is, however, extremely beneficial to mother and child, and safe approaches to medicine use, such as taking medicines immediately after breastfeeding and avoiding modified release preparations, will allow treatment to continue while minimizing exposure to the child. The BNF provides information on drug use in pregnancy along with advice on use in breastfeeding.

Anticoagulants and antiplatelets

Since their introduction in 2008, the use of direct oral anticoagulants (DOACs) has increased and they have now surpassed warfarin as the anticoagulant of choice.¹⁶ For DOACs there is no test to determine degree of anticoagulation. Procedures with a lower bleeding risk, such as simple extractions, can be conducted if the patient has normal renal function. DOACs have a much shorter serum half-life than warfarin and hence, for procedures with a higher risk of bleeding (eg complex extractions or more than three extractions at once), patients should be advised that, on the morning of the procedure, they should omit morning doses of twice daily DOACs (eg apixaban, dabigatran, etexilate) and delay doses of once daily DOACs (eg rivaroxaban, edoxaban) until four hours after haemostasis. On the other hand, patients taking antiplatelets (eg low-dose aspirin, clopidogrel, prasugrel and ticagrelor) are not recommended to omit doses prior to treatment, even if on dual antiplatelet therapy. Instead, for dental treatments associated with a higher risk of bleeding, a staged approach to treatment (eg multiple visits) should be considered along with local measures to achieve haemostasis (eg absorbable sutures or oxidized cellulose).

Biotherapeutics

Since the introduction of the monoclonal antibodies trastuzumab, infliximab and rituximab in the late 1990s, there has been rapid growth in the number of biotechnology-derived pharmaceuticals reaching the market. It is estimated that, at present, there are about 4000 biopharmaceuticals in clinical development accounting for more than 40% of drugs in the current drug pipeline.¹⁷ The majority of licensed biopharmaceuticals target cancer or immune-mediated diseases. Many biotherapeutics for both cancer and immune disease will be given in conjunction with systemic anticancer chemotherapy (SACT) (ie cytotoxic treatments) which leave the immune system compromised and the patient susceptible to infection. Each product will have its own unique safety profile and associated ADRs. Evidence of oral complications with these products is currently limited to case reports,¹⁸ and it is difficult to identify which of the adverse effects (eg xerostomia, oral mucositis) are due to concomitant SACT.