Jozef Rovenský (ed.)Gerontorheumatology10.1007/978-3-319-31169-2_29

29. Pharmacological Treatment of Rheumatic Diseases

Marta Olejárová¹

(1)

Clinic of Rheumatology, Institute of Rheumatology, Prague, Czech Republic

Marta Olejárová

Older patients (over the age of 65) and geriatric patients (over the age of 75) represent a majority of patients attending the rheumatology outpatient department. With the increasing age, both the prevalence and incidence of degenerative joint diseases grow, similarly as the frequency of crystal arthropathy (gouty arthritis, pyrophosphate arthropathy). Advanced stages of chronic inflammatory rheumatoid disease with the onset in younger and middle-aged groups of population can be observed as well. In view of aging of population in the advanced countries, the number of these patients will continue to rise.

Paradoxically, there is a lack of experience in pharmacological treatment of elderly patients, as new drugs or therapies are usually tested in middle-aged individuals without associated severe diseases; older patients are often excluded from clinical trials due to concerns about inadequate cooperation, a higher risk of adverse effects, risk of drug interactions in polypragmasia, etc. Pharmacokinetics and pharmacodynamics of a number of drugs, however, differ in elderly patients, and these differences may require substantial changes in dosage or drug dosage regimen.

29.1 General Aspects of Pharmacological Therapy in the Elderly

Physiological changes of aging alter drug efficacy (pharmacodynamics), but mainly drug pharmacokinetics, which may have a direct impact on the incidence of adverse effects. The pharmacokinetics process consists in four basic phases, namely, absorption, distribution, metabolism, and elimination. Except for absorption, all the remaining phases are altered in the elderly patients. Distribution of water and fat soluble drugs is affected by a decrease in total body water and a higher percentage of fat to lean body mass. In addition, malnutrition and hypoproteinemia, more common in older patients, may reduce the bound fraction of the drug and increase the share of its free active fraction. Drug metabolism may be influenced by a decrease in liver blood flow and liver enzyme activity, e.g., activity of cytochrome P450 isoenzymes, but conjugation mechanisms are relatively well preserved also in older patients. Drug elimination is restricted due to decreased renal function which is by about one half lower than in young adults and is thus the most serious and the most frequent clinical change of pharmacokinetics [1].

Although there is still a lack of evidence regarding pharmacodynamic changes in elderly patients, the clinical practice shows that older patients demonstrate an exaggerated response to certain drugs, e.g., CNS depressants, including opioids [2].

A major problem in older individuals is polymorbidity. In addition to the abovementioned renal insufficiency, complications may include hypertension, ischemic heart disease, ulcer diseases, and others. Treatment of these associated chronic conditions may cause drug interactions. Drugs to treat chronic diseases in the elderly are often not fully targeted, pharmacotherapy is inadequately determined, and its actual efficacy is not assessed, particularly in long-term treatment [2].

In addition, noncompliance with pharmacotherapy in elderly patients may lead to irregular drug administration resulting in under- or overdosing.

29.1.1 Analgesics Antipyretics

Paracetamol is a highly suitable analgesic for older patients. It is not addictive, it does not cause drowsiness, it is not associated with serious adverse effects observed in NSAIDs (gastro-toxicity, nephrotoxicity, etc.), and if administered at therapeutic doses, it is safe also in older patients [3]. Due to its short biological elimination half-time the risk of accumulation is low. To relieve pain, paracetamol must be administered at analgesic doses (a single dose of 650–1000 mg given three times a day maximum). The only risk is toxicity in overdosing that may occur accidentally rather in noncompliant patients. Therapeutic range of paracetamol is relatively narrow, with toxic effects occurring already with a daily dosage of 5 g (10 tablets per 500 mg).

Paracetamol may be combined with NSAIDs and opioids, although caution is required in case of hepatopathy. In the most common joint disease – osteoarthritis –paracetamol is recommended by all current international guidelines as the first choice for pain management. Meta-analyses have shown that its analgesic efficacy in osteoarthritis is comparable or only slightly lower than the effect of NSAIDs. NSAIDs are probably more effective in OA of the hip, but in the most common knee osteoarthritis, the effect is very similar [4].

29.1.2 Opioids

Opioid analgesics used to treat musculoskeletal pain in the older population include usually weak or moderate opioids (tramadol, codeine, oxycodone, etc.) and are prescribed in case of inadequate efficacy or contraindication paracetamol or NSAIDs, e.g., in advanced osteoarthritis contraindicated for operative treatment. Opioid analgesics may be also combined with NSAIDs or paracetamol. However, adverse effects are more common in the elderly, affecting primarily CNS (somnolence, confusion, delirium), often inclu-ding also constipation. It is recommended to use lower starting doses at longer intervals with slow titration of the final dose. Renal function must be carefully monitored; sometimes laxative is temporarily used to relieve constipation [5].

29.1.3 Nonsteroidal Anti-inflammatory Drugs

Nonsteroidal anti-inflammatory drugs (NSAIDs) should be used in elderly patients with caution, and where possible their administration should be avoided or minimized in terms of dosage and length of therapy. Each indication must be carefully considered. Older patients primarily have an altered pharmacokinetics, while the pharmacodynamic effect is probably the same as in younger population.

Drug absorption does not change in the elderly, while their distribution alters in view of the above described involutional tissue changes. NSAIDs have a high degree of plasma protein binding, resulting in an increased free drug fractionin hypoproteinemia with potential toxic effects. NSAID elimination is decreased in the elderly and the dosage should be adjusted accordingly. In NSAIDs with short- to medium-term elimination, half-time of renal elimination does not significantly change, but caution is necessary in NSAIDs with long biological half-time as it may get further extended and result in drug accumulation (piroxicam, phenylbutazone, and others) [6].

NSAIDs toxicity grows with increasing age; therefore, it has been generally accepted that NSAIDs should be avoided in elderly patients or at least their dosage minimized and used for the shortest possible time [7]. In addition to common GIT disturbances, older patients suffer more frequently from renal adverse effects (salt and water retention, renal insufficiency), adverse effects affecting CNS (confusion, impairment of cognitive functions and memory), as well as hepatotoxicity [8]. Advanced age has been established as a risk factor of NSAID gastropathy, including severe complications during long-term treatment with nonselective NSAIDs. The risk of gastropathy and their severe complications is lower with the use of COX-2 selective inhibitors (coxibs). Renal adverse effects are also more common in older population. Their risk with the use of coxibs and nonselective NSAIDs is comparable [6].

Another issue in long-term NSAID therapy may be their impact on blood pressure, i.e., hypertension decompensation. Also this risk is higher in the elderly, particularly those with a previous history of hypertonia. The risk of hypertension decompensation has to be taken into account primarily in coxibs.

Certain nonselective NSAIDs have also antiaggregation effect; therefore, bleeding complications may be encountered during the therapy. Coxibs do not have the antiaggregation effect and in addition they inhibit prostacyclin synthesis. Bleeding complications do not occur with this type of therapy; however, in case of long-term treatment, coxibs are associated with a higher risk of cardiovascular disease [9].

Therefore, in older patients, NSAIDs are second-line analgesics; less toxic preparations with short or medium biological half-time are preferable; long-term administration of nonselective NSAIDs and their use in patients with increased gastrointestinal risk requires gastroprotective prophylaxis (proton pump inhibitors, misoprostol).

Older patients should be informed in detail about potential adverse effects of the therapy (gastrointestinal disturbances, vomiting, abdominal pain, melena, swellings, increased blood pressure, etc.) and actively checked for them during follow-ups.

In older patients with polypragmasia, drug interactions should be considered. Since most NSAIDs are extensively bound to plasma proteins, they may displace other drugs from binding sites and thus increase their activity (e.g., oral antidiabetics, oral anticoagulants, sulfonamides). Hypoglycemizing effect was observed mainly in older NSAIDs, while in the newly developed (nimesulide, meloxicam), it has not been reported, yet. NSAIDs may reduce the efficacy of certain antihypertensive drugs (diuretics, beta-blockers, and ACE inhibitors).

The increased risk of adverse effects should be pointed out also in case of combination of NSAIDs; patients often receive various NSAIDs from various physicians, and older patients may also be more likely to self-medicate, buy OTC or “over the counter” NSAIDs, and use them with other NSAIDs.

As compared to the systemic treatment, topical NSAID therapy (gels, creams, sprays) is very suitable for the elderly. Systemic adverse effects, except for allergy reactions, have not been observed with local NSAIDs application which is adequately effective and at the same time a safe alternative for pain management in the elderly. The use of topical NSAIDs has been increasingly used in the clinical practice [10].

29.1.4 Glucocorticoids

Administration of low-dose oral glucocorticoids is the method of choice in mild inflammatory rheumatic diseases in the elderly. Particularly in elderly-onset rheumatoid arthritis, this therapy (where necessary in combination with NSAIDs) is often sufficient. Glucocorticoids are also the medication of choice to treat typical geriatric rheumatic diseases (polymyalgia rheumatica, giant cell arteritis).

In older patients a higher incidence of certain adverse effects has to be taken into account (hyperglycemia and decompensation of diabetes, glucocorticoid-induced osteoporosis, glucocorticoid-induced cataract, acceleration of atherosclerosis, glaucoma, glucocorticoid-induced myopathy).

It is therefore recommended to use in older patients the lowest possible doses (preferably up to 7.5 mg/daily) and to combine glucocorticoids with calcium and vitamin D. NSAIDs with a higher risk of NSAID-induced gastropathy should be avoided [11].

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