By Duy Thai, 1997 Pharmacology Semester 1 page 1 of 4
STEROIDAL ANTI-INFLAMMATORY DRUGS
& DRUGS USED TO TREAT RHEUMATOID ARTHRITIS AND GOUT
• Steroidal anti-inflammatory drugs are also known as corticosteroids
Functions
• Anti-inflammatory
• Immunosuppressant
Mechanisms of action
• Corticosteroids, being steroids, are highly lipophilic and can thus penetrate cell membranes fairly easily.
• They bind to intracellular receptors which modify gene transcription.
• Corticosteroids have wider ranging effects than NSAIDs because they inhibit a wider variety of enzymes by
reducing their synthesis:
• Inhibit phospholipase A2
• Inhibit COX 2 (not COX 1)
• Inhibit cytokine system
Glucocorticoid
Glucocorticoid Reduction in the synthesis of:
receptor Cytokines
COX 2
Phospholipase A2
nGRE
Negative
glucocorticoid
response element
• Glucocorticoids bind to a glucocorticoid receptor in the cytosol.
• Once bound, the drug-receptor complex (in this case the negative glucocorticoid response element) goes into the
cell nucleus and acts on the promoter region of a gene to block the transcription of cytokines, COX 2 and
phospholipase A2.
• By inhibiting phospholipase A2 we are able to achieve a higher level of anti-inflammation by reducing the
synthesis of all eicosanoids (both prostinoids and leukotrienes).
• The nGRE inhibits the transcription of certain genes. There is also the formation of a +GRE which increases the
transcription and synthesis of lipocortin 1.
Glucocorticoid
Increased synthesis of
Glucocorticoid lipocortin 1
receptor
mRNA
+GRE
Positive
glucocorticoid
response element
By Duy Thai, 1997 Pharmacology Semester 1 page 2 of 4
• Lipocortin 1 is an endogenous anti-inflammatory agent.
• Normally, phospholipase A2 is inactive and must be activated for it to breakdown phospholipids into arachidonic
acid. If it were always active, cell membranes would be constantly breaking down.
• Lipocortin 1 binds to the inactive phospholipase A2 and keeps it inactive.
• Normally, inflammation will activate protein kinase C which converts lipocortin 1 into an inactive form
• It then releases phospholipase A2 which can now become active.
• Corticosteroids act to increase the synthesis of lipocortin.
• Note that the inflammatory system is still active (we have done nothing to inhibit it) and so it is still acting to
inactivate lipocortin. However, since at the same time, we are stimulating the synthesis of active lipocortin at a
faster rate, there will be a net increase in lipocortin levels. Lipocortin is thus more likely to hold phospholipase A2
in an inactive form. Also, there is reduced synthesis of phospholipase A2 which makes it even better, because lots
of lipocortin can find and bind easily with small levels of PLA2.
Uses
• Usage of these drugs are associated with a higher level and more severe adverse effects.
• Anti-inflammatory
• E.g. Asthma. Local inhalation of beclomethasone.
• Topical (local)administration to a specific site
• E.g. On the skin, or eyes
• A topical administration is useful to try and diminish the systemic side effects
• Rheumatoid arthritis
• Treated with prednisolone
• This is a systemic treatment and is often used only as a last resort. We tend to use NSAIDs as the first
resort.
Adverse effects
• Suppression of endogenous glucocorticoid synthesis.
• High levels of steroids negatively feed back on the pituitary to decrease the release of ACTH from the
anterior pituitary. ACTH, apart from stimulating the release of adrenal hormone, is also trophic to the
adrenal cortex. Hence, reduced ACTH will eventually lead to atrophy of the adrenal glands.
• If we try to remove steroid treatment, we often get symptoms similar to a withdrawal effect, e.g. fever, muscle pain
• If steroid treatment is initiated, it is often for life. In order to stop treatment, we need to slowly reduce the
dosage over a long period of time to minimise withdrawal effects.
• Suppression of the response to infection or injury
• These drugs are immunosuppressants and also suppress wound repair due to the reduction in protein
synthesis.
• E.g. For an eye infection, we may treat the inflammation but the micro-organisms which caused the
inflammation is still around (because the body’s immune system has not responded to eliminate the
organism) and so things can get worse.
• E.g. Sometimes a combination of steroid treatment with NSAIDs are given. NSAIDs may cause gastric
ulceration and GIT disorders, but the steroids only exacerbate the adverse effects of NSAIDs because they
suppress the repair of the ulcers.
• The point is that we must treat the cause, not the symptoms. We may be able to treat the inflammation
associated with a wound but will not get any wound repair.
• Behavioural disturbances
• Cataract, glaucoma
• An increase in intraocular pressure is the normal response to steroidal treatment.
• Fluid and electrolyte disturbances.
• Similarity to aldosterone or cortisol – increased reabsorption of Na, increased secretion of K.
Metabolic effects
• Osteoporosis
By Duy Thai, 1997 Pharmacology Semester 1 page 3 of 4
• Muscle wasting
Due to mimicking the actions of cortisol.
• Hyperglycemia
• Inhibition of bone growth in children
• Steroids cause fusion of the epiphyseal plates.
• A lot of children are given steroids to treat asthma – not good!
• The use of topical steroids is more desirable to reduce the systemic effects.
• Both NSAIDs and steroid treatment aim to treat the symptoms (reduce pain, inflammation and discomfort),
but may not do a good job in treating the cause of the disease. Unless the cause is treated, the disease will
keep on getting worse.
Anti rheumatoid drugs
• NSAIDs are the first line of defense
• Alternatively, specific drugs used to treat the rheumatoid arthritis can be used. These drugs do not have
general anti-inflammatory effects.
• The drugs are often known as Slow acting anti rheumatoid drugs (SAARDs) or Disease modifying anti
rheumatoid drugs (DMARDs).
• The following drugs used for rheumatoid arthritis are effective but we do not know their mechanism of
action.
• Gold compounds
• Aurothiomalate
• Intramuscular injection
• Auranofin
• Oral, less common
• ↓ lymphocyte proliferation
• ↓ lysosomal enzyme release
• ↓ superoxide production
• ↓ neutrophil chemotaxis
• ↓ IL-1 synthesis
• May take months to see a beneficial effect.
• Adverse effects:
• Commonly allergic type reactions at the skin and mucous membranes
• Renal injury
• Blood dyscrasias (any adverse change in blood function)
• Chloroquine
• Is used in the treatment of malaria
• An anti-inflammatory only in rheumatic disease
• Less adverse systemic effects but tends to seriously affect the eyes
• The cornea of the patient undergoing this treatment needs to be monitored
carefully. Retinopathy which occurs may be irreversible, causing blindness.
• Very slow onset (months)
• Sulphasalazine
• A combination of sulphonamide and salicylate
• A free radical scavenger?
• Free radicals cause cell injury and inflammation
• Has marked GI irritation and so is only available with an enteric coating.
• Methotrexate
• Immunosuppresant
• Folate antagonist
• Also used to treat cancer (see lecture “enzymes 1”)
• Penicillamine
• Adverse effects similar to gold compounds.
• Not as effective, most probably be obsolete soon.
• All these drugs are slow releases, with the effects being seen in weeks to months. Once the effects are
observed, they will slow the disease progress, not just treating the inflammation.
By Duy Thai, 1997 Pharmacology Semester 1 page 4 of 4
Drugs used in the treatment of gout
• Gout is due to an accumulation of uric acid (a breakdown product of adenosine). High concentrations of uric
acid leads to crystallisation and deposition in the synovium of joints, resulting in arthritic pain.
• Acute treatment of gout involves:
• NSAIDs (but NOT aspirin because aspirin inhibits the excretion of uric acid)
• Colchicine
• Glucocorticoids
• Chronic treatment involves:
• Allopurinol
• Colchicine
• Probenecid
Adenosine
Hypoxanthine
Xanthine oxidase
Xanthine
Xanthine oxidase
Uric acid
Synovial deposition
(inflammation, classically
in the big toes)
• Colchicine
• An antimitotic agent. It interferes with tubulin, which prevents leukocyte migration
• Reduced leukocytes in the synovial joints affected by gout would reduce the pain and
discomfort as a result of the cytokines released by neutrophils.
• Can be used as an acute treatment
• Also can be used as a chronic treatment as prevention (prohpylacticaly) in conjunction with
allopurinol.
• Allopurinol
• An analogue of hypxanthine
• It thus competitively inhibits the enzyme xanthine oxidase, preventing hypoxanthine from binding.
• The product of allopurinol with xanthine oxidase is alloxanthine.
• Alloxanthine is an irreversible inhibitor of xanthine oxidase.
• Thus, there is decreased synthesis of uric acid and the concentrations fall.
• Probenecid
• A uricosuric agent (increases the excretion of uric acid)
• It inhibits the tubular reabsorption of uric acid in the kidneys
• It has a limited use, not as effective as allopurinol
• It is used when a person has an inability to excrete uric acid (in most patients, an increased uric
acid is mainly due to an increase in production and so allopurinol is better suited).
