Immunology: Anti Rheumatoid and Gout Drugs

Anti-Rheumatoid and Gout Medication

1. NSAIDs (Non-Steroidal Anti-Inflammatory Drugs)

2. DMARDs (Disease modifying anti-rheumatic drugs)

3. Immunosuppressants (Azathioprine and Cyclosporin)

4. Glucocorticoids

5. Cytokine-targeted drugs

Pharmacology of NSAIDs:

-Reduce symptoms of disease but do not retard its progress. May make it worse.

-Release of lysosomal enzymes, the generation of toxic oxygen radicals and lympocyte activation are all controlled by prostaglandins (PGE2, PGI2)

-NSAIDs have also been shown to increase the production of inflammatory mediators such as IL-1

  • Thus the long term use of NSAIDs could exacerbate tissue damage
  • Arthritis progressed more rapidly with a strong COX inhibitor than a weak one

DMARDs–>A.K.A Slow Acting Anti-rheumatic Drugs/SAARDs

-Some of these drugs change the course of disease by retarding the structural damage to joint as well as reducing inflammation

-Often mechanism of action is not known.

  • DMARDs

1) Sulphasalazine

-First line choice of DMARD

(A) Introduction

-Can produce remission in active rheumatoid arthritis (RA), can also be used in chronic inflammatory bowel disease

-Doses used in RA are greater than those normally used in bowel disease. Thus side effects more likely.

*** Drug is often a combination of sulphonamide with its salicylate. It is split into its component parts by bacteria in the colon.

Mechanism of action is unclear-However, 5-amino salicylic acid produced in the colon is a toxic scavenger for free oxygen radicals produced by neutrophils


(B) Adverse effects

1. Gastrointestinal disturbances (Because drug is split into active metabolite in the GIT)

2. Malaise

3. Headache

4. Skin reactions and leukopenia (lack of leukocytes) can occur but are REVERSIBLE upon the stopping of drug

5. ***Impaired folic acid absorption neccessitating folic acid supplement (necessary for DNA synthesis)

-6. Decreased Sperm counts

7. Blood diseases such as aplastic anemia, agranulocytosis, absence of leukocytes, Megaloblastic anemia, purpura, thrombocytopenia (lack of platelets), hypoprothrombinemia, methemoglobinemia, congenital neutropenia, myelodysplastic syndrome.

8. Anaphylatic type reactions may occur in some patients

Nevertheless, it is a front-line drug used in the treatment/remission of RA.

  • GOLD compounds (includes salts)

-Used in patients whom diagnosis of RA has not been made, preferentially before any deformities have occurred

*Used in conjunction with anti-inflammatory analgesics (NSAIDS)

*Those with a high titre of Rheumatoid factor (RF) [This is an antibody IgM made against IgG] would tend to respond better

Sodium aurothiomalate (inj)

Auranofin (oral)

Aurothioglucose (inj)

(a) Mechanisms of action: (9 Pathways)

-Exert Anti-inflammatory, anti-analgesic, immunomodulating actions by modifying a variety of cellular and humoral immune response

***Inhibits mitogen-induced lymphocyte proliferation

-Reduce release and activity of lysosomal enzymes

-Decrease the production of oxygen radicals by phagocytes

-Inhibits the chemotaxis of neutrophils

-Reduce the release of mast cell mediators

-Release of serum immunoglobulins

-Reduce titre of RF in RA

-Auranofin but not aurothiomalate inhibits the induction of IL-1 and TNF-a

(b) Pharmacokinetics aspects:

Sodium aurothiomalate (i.m.) or aurofin (p.o)  are most commonly used

-Oral form is less effective but causes fewer and less side effects

-t1/2 is 7 days initially but increases with treatment, so drug is usually given weekly at first and then monthly subsequently.

-Distribution is wide (not only in inflammed synovium) but also in tissue macrophages, kidney and liver.                                                                   

-Gold remains in tissues some time after treatment is stopped with excretion being mostly renal but also GIT

(c) Adverse effects

-Serious toxic effects occur 1 in 10 (10%)

-If therapy is stopped early when symptoms occur, the incidence of toxic effects is relatively low.

1. Skin rashes

2. Proteinuria (Excess protein excreted in urine-Indicates microglomerular capillaries damaged)

3. Mouth Ulcers

4. Decrease in white blood cell number

5. Decrease in platelet number

6. Encephalopathy (Inflammation of brain membrane), peripheral neuropathy and hepatitis may occur

****Note: Treatment of serious adverse effects would be chelating agents such as Dimercaprol. 

  • Penicillamine (Dimethylcysteine)

-Dimethylcysteine is one of the substances produced by hydrolysis of penicillin. It is an effective chelator of many metals and is valuable in poisoning.


(a) Mechanisms of action: Mode of action is unclear

-75% of patients with RA respond to penicillamine

-Main response is not seen for several months!!!

-Purported mechanism:

Reduces RF and concentration of immune complexes in the plasma and sinovial fluid. Reduction of IL-1 generation and partly by preventing the maturation of newly synthesised collagen. 

Indications: The drug is a powerful chelating agent–>Thus, used in cases of heavy metal toxicity (Pb+ poisoning, Hg poisioning). Also used to treat Wilson’s disease (accumulation of copper in liver, kidneys and brain)

(b) Adverse effects

-Seen in 40% of patients treated and may require immediate cessation of therapy

1. Anorexia, nausea, vomitting

2. Disturbances in taste (zinc levels decrease)

3. Proteinuria in 20% of cases

4. Rashes and stomatitis (mouth ulcers)

5. Drop in platelet no. (thrombocytopenia)

6. Drop in white blood cell no. (Leukopenia), Aplastic anemia (Decrease in number of RBC and WBC, suppression in bone marrow)

***Should NOT BE GIVEN WITH GOLD COMPOUNDS  as it is a metal chelator

  • Chloroquine

-Anti-malarial drug

-Chloroquine has anti-inflammatory and immunomodulatory effects for Rheumatoid disease.

-Relatively non-toxic and achieves good response in 50% of patients

(a) Mechanism of action:

-Inhibits mitogen-induced lymphocyte cell proliferation

-Decreases leukocyte chemotaxis

-Decreases lysosomal enzyme release (concentrated in the lysosomes of phagocytic cells such as macrophages and interferes with the action of acid hydrolases stored there)

-Decreases generation of toxic oxygen radicals which induces respiratory burst

-Reduces the generation of IL-1

(b) Adverse Reactions

Accumulates in many organs (ESP. Eye)

1. Where it causes retinal damage that can be irreversibly damaged (for those on prolonged, high dose therapy), DISTURBANCES in vision, Difficulty in reading words

-In practice when used to treat RA, this occurs very rarely.

  • Methotrexate **** (VERY CRUCIAL DRUG) and Trimetoprim

-Folic acid antagonist which has immunosuppressing properties.

Indications for Methotrexate: Also used as a cytotoxic in cancer therapy and in treatment of severe psoriasis


(a) Mechanisms of action:

-Methotrexate inhibits dihydrofolic acid reductase (DHFR)

-Structurally similar to Folic acid

-Dihydrofolates must be reduced to tetrahydrofolates by this enzyme before they can be used as carriers of one-carbon groups in the synthesis of nucleotide and thymidylate (see below).

-No purines or thymidine formed since DHFR enzyme blocked. (Both trimethoprim and methotrexate work here)

Methotrexate impedes DNA synthesis, repair and cellular replication

Thus, actively proliferating tissues such as malignant cells, bone marrow, fetal cells, bucal and intestinal mucosa, urinary bladder cells are more sensitive to this effect. 

When cell proliferatoin in malignant tissues is greater than normal tissues,  methotrexate may impair malignant growth but no damage to healthy tissues

Mechanism in RA: Unknown but might affect immune function

*Effects of methotrexate on articular swelling and tenderness can be seen as early as 3-6 wks.

*No clear evidence that it induces remission of rheumatoid arthritis nor has a beneficial effect demonstrated on bone erosions and radiologic changes (deformity, joint impairment)

(b) Adverse effects

1. Ulcerative stomatitis

2. Leukopenia

3. Nausea

4. Abdominal distress

5. Other side effects (malaise, undue fatigue, chills and fevers, dizziness)

6. Decreased resistance to function/Increased susceptibility to viral/fungal/bacterial infections

-Pneumocystis carnii pneuomnia, nocardiosis, histoplasmosis, cryptococcosis, Herpes zoster, Herpes simplex etc

***7. Pulmonary system: Interstitial pneumonitis deaths have occurred. Chronic Interstitial obstructive pulmonary disease has occurred. Pulmonary fibrosis (excessive connective tissue made in lungs) can be a problem with long term use.

Incidence occurance: Elevated liver functions test (15%), nausea/vomitting 10%, Stomatitis 3%. Thrombocytopenia 3%,







-This is a metabolic and genetic disease due to an overproduction of purines (DNA) which leads to production and accumulation of uric acid.

-Characterised by intermittent attacks of acute arthritis produced by deposition of sodium urate crystals in the synovial tissues of joints (refer to top)


***Inflammatory response is invoked

–>Activates kinin, complement and plasmin system

–>Generation of lipo-oxygenase products (LTB4) + Local accumulation of neutrophils

–>These products/cells engulf the crystals by phagocytosis which causes generation of tissue-damaging toxic oxygen metabolites.

–>Lysis of cells with proteolytic enzymes occur

–>Urate crystals also induce production of IL-1,  TNF-a, IL-5, IL-6




***Certain drugs may influence the development of gout by causing:


(a) Overproduction of urate:

Why? Due to excessive cell destruction releasing nucleic acids. Excessive cell destruction occurs when myeloproliferative or lymphoproliferative disorders (e.g. leukemias) are treated with cytotoxic drugs.

(b) Underexcretion of urate:

-Caused by most Diuretic (Link to hypertension-THA), Aspirin (Link to NSAIDs lecture), alcohol and a rise in blood lactic acid that inhibits tubular secretion of urate.


(c) Diet may also cause development of gout. Purines are present in significant amounts that inhibits tubular secretion of urate.

-Patients should avoid excesses of foods that contain purines e.g. sweetbread, kidney and liver.

-Gout prone patients tend to be overweight and loss of weight lowers the plasma urate



Common Mechanisms by which Gout is reduced/treated: 

Mechanism 1: By inhibiting uric acid synthesis (allupurinol/Zyloprim) 

Mechanism 2: By increasing uric acid excretion (uricosuric agents: Probenacid and sulphinpyrazone)

Mechanism 3: By inhibiting leukocyte migration into joint (Colchicine)

Mechanism 4: By generating anti-inflammatory and analgesic effects (NSAIDS, corticosteroids either orally or injected into joint)


Mechanism 1: Inhibiting uric acid synthesis (Allopurinol)

-Inhibits synthesis of uric acid by inhibiting xanthine oxidase enzyme. It is an analogue of hypoxanthine and inhibits enzyme competitively

Allopurinol is readily absorbed from gut and metabolised in the liver to alloxanthine (xanthine oxidase inhibitor)

Allopurinol reduces concentration of relatively insoluble urates and uric acid in tissues while increasing the concentration of more soluble xanthines and hypoxanthines. Deposition of urate crystals in tissues is reversed and formation of renal stones is inhibited.


***Thus, allopurinol is a drug of choice for long term gout, but ineffective for acute gout attack and may make it worse!!!


Allopurinol Pharmacokinetics:

Given orally, well absorbed in GIT, half life is 2-3 hours, converted to alloxanthine which has t1/2 of 18-30 hours. Renal excretion is a balance between Glomerular filtration and probenacid-sensitive tubular reabsorption.


Allopurinol Adverse effects:

1. May cause acute gout. Why? Negative feedback mechanism???

2. Allergies

3. GIT disturbances


****Allopurinol drug interactions:

1. Prevent oxidation of active drug Mercaptopurine to an inactive metabolite (This Mercaptopurine is an anti-metabolite used in cancer chemotherapy–>This combination of drugs lead to dangerous potentiation)

2. Allopurinol  also potentiates effect of immunosuppressant azathioprine, anticancer drug cyclophosphamide  and oral anticoagulants (e.g. Warfarin)


Mechanism 2: Increased excretion of uric acid in kidneys (Probenacid and Sulphinpyrazone)





-Increase uric acid excretion by a direct action on renal tubule (competitively inhibits uric acid reabsorption in the proximal convoluted tubule) 

Probenacid and sulphinpyrazone


(a) Probenacid mechanism of action:

-Competitively inhibits the active transport of organic ions across the kidney tubule (PCT)

-Prevents both reabsorption from the tubular fluid and secretion into it, inhibition of urate reabsorption increases its excretion in the urine.

-Urine must be kept at pH 6 or above to prevent crystals of urate being formed in the urine.

-To achieve this, potassium citrate or sodium bicarbonate (urinary alkalinisers) are used alongside.


*Therapeutic Points: Probenacid should be used with urinary alkalinisers to prevent urate crystals from precipitating from urine.

(b) Adverse effects:

-Causes GIT upsets in some patients

-Blocking of renal tubular excretion prolongs effects of a range of organic acids such as penicillins, acyclovir (anti-viral for herpes) and naproxen (NSAID)


Mechanism 3: Inhibiting leukocyte migration into joint (Cholcicine)

-Akaloid compound

(a) Cholchicine mechanism of action:

-Colchicine binds to tubulin, resulting in depolymerisation of microtubules.

-Results in decreased cell motility and cell mitosis (cell cycle halted)

-Extravasation of inflammatory cells such as neutrophils affected


(b) Cholchicine pharmacokinetics

-Absorbed from gut, some metabolised in liver and some excreted unchanged in bile (i.e. bile, liver, gut)

-Enhances gastrointestinal toxicity

-Used either in moderate doses to treat an acute attack. Used in low doses for prolonged period of time to reduce risk of recurrent attacks.


(c) Cholchicine Adverse effects

1. Largely gastrointestinal (Nausea, vomitting and abdominal pain)

2. Severe diarrhea occurs

3. Renal damage can occur. Blood disorders rarely occur


*Effects might be due to inhibition of mitosis in the rapidly reproducing cells of GI mucosa


Mechanism 4: NSAIDs (Aspirin/Salicylates)

****Should be avoided in the treatment of gout as even small doses will competitively inhibit urate excretion, causing urate to be retained.


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