Chapter 11. Anti-inflammatory drugs
Treatment of arthritis and gout
At the end of this chapter, the reader should be able to:
• describe the basic features of the acute inflammatory and the immune responses
• list the important NSAIDs
• explain the theoretical difference between non-selective and COX-2-selective NSAIDs and give examples of each
• state the main aims in the treatment of rheumatoid arthritis (RA)
• list the main classes of drugs used for RA and examples of each
• explain the meaning of the acronym DMARDs
• describe the newer ‘biologic’ treatments for RA and psoriatic arthritis and how they are administered
• explain what gout is and the drugs used to treat it
Certain key events of the inflammatory process and of the immune response should be known in order to understand the mechanism of the anti-inflammatory drugs in diseases such as rheumatoid arthritis, lupus and gout.
The acute inflammatory reaction
The acute inflammatory reaction is the body’s defence mechanism against invading pathogens such as bacteria, cells infected with viruses, and neoplastic growth. The reaction consists of:
• innate, non-specific and non-immune responses
• acquired specific immune responses.
Innate response
The innate response consists of the inflammation that is produced at a site of damage. Powerful pain-producing chemicals such as the prostaglandins and bradykinin are released locally from cells to warn of a problem. Non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin and celecoxib (see below) target the systems that synthesize these prostaglandins. Bradykinin is also a vasodilator and in addition it makes the walls of the capillaries more ‘leaky’, so that proteins and leucocytes can get out of the blood and into the tissues. Vasodilators such as histamine and nitric oxide are released in order to facilitate the entry of blood cells such as leucocytes and monocytes into the area of damage. These cells will attack and kill any bacteria or neoplastic cells. Cells also release peptides called cytokines that play a major role in the inflammatory response. Knowledge of the cytokines involved in the inflammatory response has led to the introduction of powerful new so-called biologic remedies (see below).
Acquired response
Acquired specific immune responses are the responses of the immune system, which is able to recognize as foreign specific proteins of invading organisms or of neoplastic cells and make antibodies against them. A common example of the clinical use of this mechanism is preventive treatment with vaccines. In autoimmune diseases, such as arthritis, lupus, asthma and diabetes, the immune system turns on certain tissues of the body and attacks them. Several of the disease-modifying antirheumatic drugs (DMARDs; see Case History 11.1) specifically target the immune system.
CASE HISTORY 11.1
The patient, an 82-year-old lady, was brought to hospital by her neighbour, who had found her on the floor in the kitchen of her house. The patient remembered making a cup of tea and feeling dizzy and light headed. She had sustained bruising to her forehead and left arm. For the preceding 3 weeks she had experienced increasing fatigue and had noticed that whenever she arose from a sitting or lying position she temporarily felt light headed. This sensation would last for 1 to 2 minutes, during which she would support herself on any furniture to hand.
She was previously a fit and active lady. Over the last 3 months she had been treated by her GP for swelling, pain and stiffness of her left knee with diclofenac modified release 75 mg twice daily. The patient reported that these symptoms had been attributed to osteoarthritis. After routine tests, a preliminary diagnosis of gastric ulceration secondary to non-steroidal anti-inflammatory drugs was made. The patient was admitted to the medical assessment unit and tranfused four units of blood. She was placed ‘nil by mouth’ and given 40 mg of omeprazole intravenously. The following morning she underwent an oesophagogastro-duodenoscopy (OGD), which confirmed the presence of an ulcer in the gastric antrum. The ulcer was not actively bleeding. Tests for Helicobacter pylori or an underlying malignancy proved negative. The patient returned to the ward and was prescribed paracetamol 1 g four times a day and omeprazole 20 mg once a day. Two further haemoglobin concentrations were normal as was her blood pressure over the next 4 days. The patient also noted resolution of her postural symptoms and she was discharged.
The non-steroidal anti-inflammatory drugs
The NSAIDs include:
This is a large group of drugs. There are at least 50 different drugs available. Their chief use is to treat minor pain, i.e. headaches, etc., and to control the pain and stiffness in rheumatic disorders and osteoarthritis. They are believed to act by suppressing the formation within the peripheral tissues of prostaglandins, which occur naturally and are released by cell damage and during inflammation. One of the actions of prostaglandins is concerned with the production of painful stimuli, and they are also responsible for many of the features of inflammation (i.e. swelling and redness). Most of the NSAIDs have three major therapeutic actions:
• analgesic (pain relief)
• antipyretic (temperature reduction)
• anti-inflammatory (reduce tissue inflammation).
Mechanism of action of NSAIDs
Two enzymes are concerned with the formation of prostaglandins: cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). Prostaglandins produced by COX-2 are responsible for pain and inflammation, whereas those from COX-1 have a protective effect on the stomach lining. Most NSAIDs block both COX-1 and COX-2 and, although they relieve pain and inflammation, may cause peptic ulcers. NSAIDs have been introduced which inhibit COX-2 preferentially (see below), and may possibly be less likely to cause stomach ulceration, although at the time of writing this is a controversial issue.
The salicylates
Aspirin (acetylsalicylic acid)
Administration and absorption
Aspirin is usually given by mouth and is rapidly absorbed from both the stomach and the ileum.
Activation and distribution
Once in the circulation and tissues, aspirin is converted into the active metabolite salicylate, especially in the liver. Aspirin is therefore a prodrug. In higher therapeutic doses, some of the salicylate becomes bound to plasma proteins. This plasma binding can lead to aspirin allergy. This happens because when aspirin binds to plasma proteins it may combine chemically with the protein by acetylating it. This changes the nature of the protein so that the immune system regards the altered protein as foreign and forms antibodies against it. The next time aspirin is taken, an allergic response may occur. Small molecules such as aspirin that combine with larger molecules such as proteins and turn them ‘foreign’ are called haptens.
Metabolism and excretion
Approximately 25% of aspirin is excreted unchanged. The rest is metabolized, mainly in the liver, and excreted. Urinary excretion of aspirin is enhanced in alkaline urine, since the filtered drug is charged and does not easily get back into the circulation. Thus, in cases of aspirin poisoning, the patient’s urine is made alkaline (e.g. with sodium bicarbonate) to facilitate aspirin excretion.
Analgesic and anti-inflammatory action
Aspirin’s therapeutic effects, as stated above, are due to its inhibition of prostaglandins, which are important in the production of both pain and inflammation. Aspirin is non-selective in that it inhibits both COX-1 and COX-2. The newer, COX-2-selective NSAIDs are described below. Aspirin is effective against pain of low intensity and particularly that of rheumatoid arthritis and acute rheumatic fever, when its anti-inflammatory properties are combined with its analgesic action. It is also useful in other minor pains such as headaches, sore throats and toothache (which can of course be very severe).
Antipyretic action (reducing body temperature)
Aspirin is antipyretic. It will lower a raised body temperature. The control of body temperature is regulated by a centre in the hypothalamus, which balances heat production, resulting from metabolism, against heat loss. This is achieved either by increasing heat production by raising metabolism by such means as shivering, or by increasing heat loss by sweating and by dilating blood vessels in the skin. When a patient develops a fever, the heat-regulating mechanism is set at a higher level than normal. Aspirin acts on this centre by inhibiting prostaglandin production in the hypothalamus, and this ‘resets’ temperature control to normal levels in the hypothalamus as long as the aspirin therapy is maintained. Heat loss is achieved by sweating and by dilatation of blood vessels of the skin. Aspirin is used until the body eliminates the cause of pyrexia (raised body temperature). These effects are seen only in patients with a raised temperature, because aspirin does not lower the normal body temperature to any appreciable degree.
Therapeutic use of aspirin
To relieve pain, aspirin is given orally as a tablet, and gastric irritation (see later) may be reduced if it is given with a meal. Aspirin is rapidly metabolized and excreted, so dosage every 4 hours is usually required to keep the patient free of pain. To suppress inflammation, larger doses may be needed. Salicylates in high doses are particularly useful in the treatment of acute rheumatic fever. Within 2 or 3 days of starting the drug, the patient’s temperature should have dropped to normal levels and the swelling and pain in the joints will have disappeared.
Although aspirin is classically known as a drug for the treatment of pain and inflammation, it is now rapidly becoming a drug that is used more and more for the prevention and treatment of a wider range of problems. Some clinicians regard aspirin as more of a cardiovascular drug, since in lower doses it is used to inhibit platelet aggregation (see p. 102). There is evidence that the regular use of aspirin reduces the risk of colon and rectal cancer, and may also reduce the risk of Alzheimer’s disease.
Adverse effects of therapeutic doses
In normal doses, aspirin is a gastric irritant and, in about 70% of people, produces slight bleeding from the stomach. If it is taken continuously over a long period, this may lead to anaemia. More rarely, aspirin causes a severe haematemesis (vomiting blood), usually from a superficial erosion of the stomach wall, which results in loss of the protective action of prostaglandins on the gastric mucosa and to local damage. This bleeding may occur with both aspirin and soluble aspirin. Although severe bleeding is rare when considered against the enormous amount of aspirin consumed, it should not be used in:
• those with a history of peptic ulcer
• haemophilia or other bleeding disorders
• liver disease
• patients receiving anticoagulant drugs.
Occasionally, aspirin causes bronchospasm and thus an asthma-like attack, due to reduced production of prostaglandins.
Adverse effects of larger doses
In large doses, aspirin produces effects on the eighth cranial nerve, i.e. dizziness, tinnitus, deafness and vomiting. This is associated with hyperventilation due to stimulation of the respiratory centre and to acidosis. In very high doses, aspirin can actually increase body temperature.
Aspirin should not be given to children under 12 years as it may rarely precipitate Reye’s syndrome by causing coma and liver damage that can prove fatal. There is some recent evidence that aspirin should not be given to older children either (Editorial 2002a). The Committee on Safety of Medicines in the UK has recommended that aspirin should not be given to children aged 12–15 years who are feverish.
Treatment of aspirin poisoning
In cases of aspirin poisoning, patients suffer acidosis and should receive gastric lavage and forced alkaline diuresis, provided renal and circulatory functions are adequate.
Drug interactions
Aspirin increases the effects of anticoagulants and oral hypoglycaemic drugs, partly by displacing them from their plasma-binding sites. Aspirin interferes with the effects of drugs such as probenecid and sulfinpyrazone, which are used to treat gout by increasing urate secretion (see below). In lower doses, aspirin actually inhibits urate secretion, so it should be avoided in gout altogether.
Other preparations of aspirin
• Soluble aspirin is a mixture of aspirin with calcium carbonate and citric acid. Its actions are similar to those of aspirin. It is more soluble, which aids absorption, and has been claimed to be less irritant to the stomach, but it may still cause bleeding.
• Benorilate (also known as benorylate) is a combination of paracetamol and aspirin that splits into its component drugs after absorption.
Mefenamic acid is a mild analgesic but is probably a little more powerful than aspirin. Its action may last longer than that of aspirin, but it may produce diarrhoea. It can also cause acute renal failure in the elderly.
Paracetamol
Paracetamol (called acetaminophen in the USA) is a widely used minor analgesic and antipyretic. Although it has some cyclooxygenase inhibiting properties, this action is very weak in the peripheral tissues and it has practically no anti-inflammatory action. Its analgesic effect may be mediated by some action on the central nervous system, which is not yet understood. Its main advantage is that, unlike NSAIDs, it does not cause indigestion or gastric bleeding.
Therapeutic use
Paracetamol is given orally in tablet form. It is well absorbed and peak plasma concentrations are achieved usually well within 60 minutes. It is partly bound to plasma proteins and inactivated by metabolism in the liver.
Paracetamol is the preferred mild analgesic and antipyretic for children under 12 years old, as it does not cause Reye’s syndrome. In this age group it is frequently given as an oral suspension. The child should be over 3 months old, except for post-immunization pyrexia, when 2 months is acceptable.
It is not very effective in rheumatoid arthritis because of its poor anti-inflammatory action.
Adverse effects
Adverse effects are uncommon at normal dosage, but in overdose it causes dangerous liver damage. The margin of safety is relatively low, and doses as low as two to three times the maximum therapeutic dose can be harmful to the liver (see p. 445 for treatment of overdosage). There is also some evidence that large doses taken over a long period may damage the kidneys.
Analgesic mixtures with aspirin or paracetamol
There are many analgesic mixtures in which aspirin or paracetamol is combined with a small dose of weak opiate; thus, the risk of dependence is minimal. These combinations are a little stronger than aspirin or paracetamol alone and are used for more severe pain. Whether in fact they are more effective than the single drugs is debatable and certainly the risk of adverse effects and of danger in overdose is increased. Nevertheless, they are very popular and some are available over the counter.
Among those in common use are:
• Co-codamol tablets*: codeine phosphate+ paracetamol.
• Co-dydramol tablets: dihydrocodeine tartrate+ paracetamol.
• Co-proxamol tablets: dextropropoxyphene+paracetamol.
• Tylex: codeine phosphate+paracetamol.
NSAIDs and the uterus
Prostaglandins can cause contraction of the uterus and are important in the initiation of labour. NSAIDs, by preventing prostaglandin formation, are useful in reducing period pains and have also been used to prevent premature labour.
Older NSAIDs
Examples of older NSAIDs are:
• indometacin (Indocid)
• phenylbutazone.
Indometacin and phenylbutazone have been available for many years. Both are associated with problematic side-effects. Indometacin is an NSAID which has been used in various forms of arthritis and in acute gout. It is effective but minor adverse effects, particularly on the gastrointestinal tract, are common. Phenylbutazone is a powerful NSAID. Unfortunately, it has a number of serious adverse effects, including agranulocytosis, gastric bleeding, salt and water retention, and rashes. Its use is therefore restricted to the treatment of ankylosing spondylitis in hospital.
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