Drug treatment of musculoskeletal and joint diseases

Chapter 22 Drug treatment of musculoskeletal and joint diseases

After reading this chapter, you should be able to:

• outline the anatomy and physiology of the synovial joint

• discuss the principles of treatment of rheumatoid arthritis and the main groups of medicines used

• discuss the rationale for the differences in treatment strategies between rheumatoid arthritis and osteoarthritis

• outline the main side-effects of non-steroidal anti-inflammatory drugs (NSAIDs)

• list the groups of patients most at risk from the side effects of NSAIDs

• outline the monitoring requirements for the disease-modifying antirheumatic drugs

• identify non-pharmacological methods that can ameliorate the symptoms of rheumatoid arthritis

• discuss the role of corticosteroids in the treatment of rheumatoid diseases

• name three drugs that can precipitate the onset of gout

• outline the pharmacological treatment options in acute gout.

INTRODUCTION

The term musculoskeletal and joint diseases includes conditions that affect the bones, joints, and ligaments, such as the various forms of arthritis, connective tissue diseases, osteoporosis, gout, soft-tissue rheumatism and back pain. These conditions can be a source of pain that affect widespread parts of the body or only defined local areas. It is estimated that more than 7 million adults in the UK, 15% of the population, have long-term health problems due to arthritis and related conditions. An even greater number, 9 million people, visit their GP each year with arthritis or related problems. The commonest condition, osteoarthritis, is increasing in prevalence as the population ages. At least 4.4 million people in the UK have radiographic evidence of moderate to severe osteoarthritis in their hands. The incidence rates of rheumatoid arthritis appear to be remaining steady, affecting approximately 0.8% of the UK population, having fallen during the 1970s and 1980s. As well as rheumatoid arthritis and osteoarthritis, there are more than 200 different types of arthritis and related conditions. Many of these occur relatively infrequently, but some such as ankylosing spondylitis, systemic lupus erythematosus, juvenile idiopathic arthritis and gout, affect significant numbers of people.

ANATOMY AND PHYSIOLOGY

Movement of the bony framework results from the contraction of muscles at the joints. Although some joints (e.g. vertebral joints) have only slight movement caused by compression of cartilage, the majority of joints in the body (e.g. the hip joint) are freely movable as the result of the contraction of muscles surrounding them and are known as synovial joints (Fig. 22.1).

Fig. 22.1 The synovial joint.

A synovial joint has a surrounding fibrous sleeve, the capsular ligament, which joins the bones together, so protecting the joint without hindering movement. The articular cartilage is a smooth surface on the parts of the bones in contact to allow free articulation of the joint. The synovial membrane secretes a thick fluid, known as synovial fluid; which lubricates the joint and holds the bones in close proximity to one another, providing nourishment for the structures within the joint cavity. As well as lining the capsule, the synovial membrane covers the bony surfaces within the joint not covered by articular cartilage. Many joints have ligaments continuous with the capsule that provide further stability. Muscles or muscle tendons stretch across the joint, and movement of bones occurs when these muscles contract and shorten or relax and lengthen. The joint structures and the muscles involved are supplied by both nerves and blood vessels. Synovial joints are predominant in the limbs, where mobility is important.

RHEUMATOID ARTHRITIS

CLINICAL FEATURES OF RHEUMATOID ARTHRITIS

Rheumatoid arthritis affects approximately 0.81% of the population and is more common in women than in men (ratio 2.7:1). There are around 12 000 new cases of rheumatoid arthritis in the UK each year. It is a chronic inflammatory autoimmune disease affecting the synovial membrane. It occurs at a ratio of 1:9:12 in the young to middle-aged to elderly populations. In affected joints, the synovium becomes thickened; the amount of synovial fluid increases and the ligaments and tissues around the joint become inflamed, causing a build-up of pressure within the joint. The joint hurts because nerve endings are irritated by the chemicals produced by the inflammation and the capsule is stretched by the swelling in the joint. Granulation tissue forms on the articular cartilages of the affected joints. In time, this may erode not only the cartilages but also bone and even ligaments and tendons in the area. As the disease progresses, there is additional and cumulative damage to the joints, leading to increasing deformity, pain and loss of function (Fig. 22.2). The course of rheumatoid arthritis is variable and unpredictable, but for a significant number of patients it is a severe disease resulting in persistent pain and stiffness, progressive joint destruction, functional decline and premature mortality. Typical clinical features of rheumatoid arthritis include:

• joint pain, swelling and tenderness

• stiffness following inactivity (often worse in the morning)

• systemic flu-like symptoms

• extra-articular features.

Fig. 22.2 Rheumatoid arthritis in the hands.

(From Huckstep RL Sherry E 1994 Color guide – orthopaedics and trauma. Churchill Livingstone, Edinburgh. With permission of Elsevier.)

Ankylosing spondylitis is another autoimmune inflammatory arthritic disease in which the sacroiliac and vertebral joints become ossified.

PRINCIPLES OF TREATMENT OF RHEUMATOID ARTHRITIS

Curative treatment, although highly desirable, has yet to be achieved. At present, the goals of management in rheumatoid arthritis are to relieve pain, stiffness and swelling; to prevent disease progression and deformities; to improve morbidity and function of joints; and as far as possible to maintain the patient’s normal lifestyle.

Drug treatment is only one element of the overall management that should also involve a combination of interventions, including exercise, physiotherapy, occupational therapy, education, emotional support and rest. The management plan should be individualised based on considerations such as joint function, degree of disease activity and the patient’s age, gender, occupation and response to previous therapy.

DRUG TREATMENT OF RHEUMATOID ARTHRITIS

SIMPLE ANALGESIA

Analgesics are used early in the treatment of rheu-matoid arthritis and are often an adjunct to non-steroidal anti-inflammatory drugs (NSAIDs) and disease-modifying anti-rheumatic drugs (DMARDs). Paracetamol, codeine and combination medications containing paracetamol are effective in reducing pain in rheumatoid arthritis. Combination analgesic preparations reduce the scope for effective titration of the individual component in the management of pain. Simple analgesics should be used in place of NSAIDs if possible, and DMARDs should be introduced early to suppress disease activity.

NON-STEROIDAL ANTI-INFLAMMATORY DRUGS

Mode of action

Non-steroidal anti-inflammatory drugs are effective in providing symptomatic relief of pain and stiffness but do not influence the progression of rheumatoid arthritis. NSAIDs have anti-inflammatory, analgesic and antipyretic properties.

It is believed that NSAIDs produce their anti-inflammatory effect by inhibition of prostaglandin synthesis. There are over 20 different naturally occurring prostaglandins, which are widely distributed throughout the body because they are synthesised by virtually every tissue. Prostaglandins are formed in the body by the enzymatic oxygenation of arachidonic acid and linoleic acid, the key enzyme involved being cyclo-oxygenase (COX). Prostaglandins are very potent chemicals with a broad range of activities, which include:

• inhibition of gastric acid secretion

• bronchial relaxation

• vasodilator and hypotensive activity, including control of blood flow through the renal medulla

• mediation of some aspects of inflammation.

In rheumatoid arthritis, it appears that control over the balanced production of prostaglandins is, to some extent, lost, and this results in excessive production of prostaglandins involved in inflammation. Adminis-tration of NSAIDs blocks the action of the enzyme COX, which effectively reduces the synthesis of prostaglandins. The therapeutic outcome is a reduction in pain, tenderness, swelling and temperature in the affected joints; decreased stiffness; and increased joint movement. COX is present in different forms; COX-1 is present in the stomach and produces prostaglandins that protect the gastric mucosa, and COX-2 is present only at sites of inflammation.

CHOICE OF NSAID

Patient response to NSAIDs is highly variable, and therapeutic trials with several NSAIDs may be necessary to determine the best agent. It is estimated that 60% of patients will respond to any one NSAID. The drug should be changed after 1 week if there has been no response and an analgesic effect is the desired outcome, or after 3 weeks if an anti-inflammatory effect is desired. Approximately 10% of patients will not find any NSAID beneficial. As a general principle, NSAIDs should be prescribed initially at the lowest recommended dose and only one NSAID should be prescribed at any one time.

There are over 20 NSAIDs available, and these vary in half-life, dose, potency and side-effect frequency. They are also available in a variety of dosage forms, such as modified-release oral preparations, suppositories, injections and topical preparations. Ibuprofen is the most commonly used first-line agent, as it combines good efficacy with fewer side effects than other NSAIDs, but its anti-inflammatory properties are weaker. Many patients with rheumatoid arthritis find ibuprofen relatively ineffective even on maximal doses of 600 mg three times a day. Naproxen is a good choice, as it combines good efficacy with a low incidence of side-effects (but more than ibuprofen) when taken at a dose of 500 mg twice daily. Diclofenac has actions and side-effects similar to those of naproxen. Fenoprofen is as effective as naproxen, and flurbiprofen may be slightly more effective. Both are associated with slightly greater gastrointestinal side-effects than ibuprofen. Fenbufen may have a lower risk of gastrointestinal bleeding but has a high risk of rashes, especially in seronegative rheumatoid arthritis, in psoriatic arthritis and in women.

CYCLO-OXYGENASE (COX)-2

Standard NSAIDs act by direct inhibition of both COX-1 and COX-2 via blockade of the COX enzyme site. The subsequent inhibition of prostaglandins reduces inflammation but also has collateral effects on platelet aggregation, renal homeostasis and gastric mucosal integrity. In an effort to reduce the side effects of NSAIDs, particularly gastrointestinal side effects, agents have been developed that selectively block COX-2 with minimal effect on COX-1.

There are four COX-2 selective agents available: etodolac, meloxicam, etoricoxib and celecoxib. Etodolac and meloxicam inhibit COX-2 up to 50 times more than COX-1, and newer agents celecoxib and etoricoxib are even more COX-2 selective. Celecoxib and etoricoxib are thought to inhibit COX-2, whereas meloxicam and etodolac are thought to have high COX-2 selectivity rather than complete inhibition. COX-2 selective agents are recommended only for use in patients who are at particularly high risk of developing gastroduodenal ulcer, perforation or bleeding, but they are not recommended for routine use.

Side-effects of NSAIDs

Toxicity is a major factor, and side-effects are related to dose and duration of therapy. Common side-effects are gastrointestinal toxicity (there is a linear increase in risk with age), fluid retention and hypertension. Other less common but potentially serious side-effects are renal disease and hypersensitivity (including asthma). Uncommon and not usually serious side-effects are headaches, dizziness, tinnitus, rash (particularly with fenbufen) and abnormal liver function tests (particularly with diclofenac).

The use of NSAIDs is associated with gastrointestinal toxicity (see Ch. 11). The following side-effects occur to a varying extent with all preparations and all routes of administration:

• gastric erosions

• peptic ulceration

• small bowel inflammation and bleeding

• perforation

• haematemesis or melaena

• occult gastrointestinal blood loss and anaemia.

The annual relative risk of mortality attributed to NSAID-related gastrointestinal adverse effects is four times that for those not using NSAIDs. The rate of NSAID-related serious gastrointestinal complications requiring hospitalisation has decreased in recent years. The reason for this is likely to be multifactorial. Intensive education programmes have alerted physicians and patients to the use of newer, less toxic NSAIDs and non-NSAID analgesics in populations at high risk. There has also been a much wider use of gastroprotective therapy such as proton pump inhibitors, prostaglandin analogues and H₂-receptor antagonists. Of these, proton pump inhibitors are the most effective and most commonly used. Although selective inhibitors of COX-2 are associated with a lower risk of serious upper gastrointestinal side-effects (they can still cause dyspepsia) than non-selective NSAIDs, concerns have emerged concerning their cardiovascular safety. In December 2004, the Committee on Safety of Medicines (CSM) issued advice that any patient receiving a COX-2 selective inhibitor who has ischaemic heart disease or cerebrovascular disease should be switched to alternative treatment as soon as possible. Celecoxib and etoricoxib are contraindicated in ischaemic heart disease, cerebrovascular disease, peripheral arterial disease and moderate to severe congestive heart failure. There is no justification for prescribing a COX-2 selective agent in combination with gastroprotective agents.

Risk factors for NSAID-associated gastroduodenal ulcers include a previous history of ulcer, higher doses of NSAIDs, combination use of NSAIDs, concomitant use with oral corticosteroids and comorbidity. Cigarette smoking and significant alcohol consumption possibly may also increase the risk. It is important to note that the use of an enteric-coated, parenteral or rectal NSAID preparation is not protective. The systemic effects of NSAIDs are the predominant cause of damage.

NSAID (both COX-2 selective and non-selective) use is also associated with renal disease. Prostaglandins regulate and maintain intrarenal perfusion, particularly under conditions in which renal blood flow may be reduced (e.g. dehydration or blood loss, cardiac failure, chronic renal failure, diuretic use or hypertension). By inhibiting prostaglandin synthesis under these conditions, NSAIDs may further impair intrarenal blood flow, contributing to renal impairment (or overt renal failure), hyperkalaemia, oedema and hypertension. These problems are particularly likely in the elderly.

Following reports of severe cystitis, the Committee on Safety of Medicines (CSM) has recommended that tiaprofenic acid should not be given to patients with urinary tract disorders and should be stopped if urinary symptoms develop.

The CSM has also warned that worsening of asthma can be related to the ingestion of NSAIDs, either prescribed or purchased over the counter.

Strategies to minimise the risk of NSAID toxicity are summarised in Box 22.1.

Tags: Pharmacology and Medicines Management for Nurses

May 13, 2017 | Posted by admin in NURSING | Comments Off

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