Pharmacology of anti-rheumatoid and anti-gout drugs

1. Antirheumatoid and Antigout Drugs
Dr. Syed Salman Farookh

2. Antirheumatoid Drugs
• These are the drugs which can suppress the rheumatoid process,
bring about a remission and retard disease progression, but do not
have nonspecific anti-inflammatory or analgesic action.
• Rheumatoid arthritis(RA) is an autoimmune disease in which there is
joint inflammation, synovial proliferation and destruction of articular
cartilage

3. Classification

4. Methotrexate (Mtx)
It is a dihydrofolate reductase inhibitor with prominent immunosuppressant
and anti-inflammatory action
• Mechanism of action:
Inhibition of cytokine production, chemotaxis and cell medicated immune
response
• Pharmacokinetics:
- Variable oral bioavailability
- Absorption affected by food
- Excreted in urine

5. • Adverse effects:
- Nodulosis, Oral ulcerations, GI upset
- Dose dependent progressive liver damage leading to cirrhosis
• Contraindications:
- Pregnancy, breastfeeding
- Liver disease
- Active infection
- Leukopenia
- Peptic ulcers

6. • Status in rheumatoid arthritis:
- DMARD of first choice and standard treatment
- Rapid symptomatic relief in 4-6 weeks
- No anti-inflammatory action and thus not able to control pain and
inflammation seen in acute attack
- Relatively safer and much less toxic
- Dose: 7.5-15mg weekly

7. Azathioprine
Purine antimetabolite which acts after getting converted to 6-
mercaptopurine
• Mechanism of action:
Potent suppressor of cell mediated immunity, selectively affects
differentiation and function of T cells and natural killer cells and also
suppresses inflammation
• Status in rheumatoid arthritis:
- Given along with corticosteroid because of steroid sparing effect
- Dose: 50-150 mg/day

8. Cyclosporine
Cyclosporine is a peptide antibiotic but is considered a DMARD.
• Mechanism of action:
- Through regulation of gene transcription, it inhibits IL-1 and IL-2
receptor production and secondarily inhibits macrophage–T-cell
interaction and T-cell responsiveness. Hence T-cell–dependent B-cell
function is also affected.
• Pharmacokinetics:
- Cyclosporine absorption is incomplete and somewhat erratic,
although a microemulsion formulation improves its consistency and
provides 20–30% bioavailability.
- Grapefruit juice increases cyclosporine bioavailability by as much as
62%. Cyclosporine is metabolized by CYP3A and consequently is
subject to many drug interactions

9. • Dose: Its usual dosage is 3–5 mg/kg per day divided into two doses
• Adverse effects:
- Leukopenia, thrombocytopenia and to a lesser extent, anemia are
predictable.
- High doses can be cardiotoxic and neurotoxic
- sterility may occur after chronic dosing at antirheumatic doses,
especially in women.
- Bladder cancer is very rare but must be looked for, even 5 years after
cessation of use.

10. Sulfasalazine
A compound of sulfapyridine and 5-amino salicylic acid, it splits off in
the colon by bacterial action and absorbed systemically
• Mechanism of action:
- Suppresses the generation of superoxide radicals
- Also inhibits elaboration of cytokine by inflammatory cells
• Adverse effects:
- Neutropenia, thrombocytopenia, hepatitis
• Status in rheumatoid arthritis:
- Used as second line drug for milder cases
- Dose: 1-3 g/day in 2-3 divided doses

11. Chloroquine and hydroxychloroquine
Antimalarial drugs effective in rheumatoid arthritis with advantage of
low toxicity
• Mechanism of action:
- Reduce monocyte interleukin 1
- Consequently, inhibit B lymphocytes
- May also interfere with antigen processing
- May stabilize lysosomes and play a role in free radical scavenging

12. • Adverse effects:
- Retinal damage, corneal opacity
- Rashes, graying of hair, irritable bowel syndrome, myopathy and
neuropathy
• Status in rheumatoid arthritis:
- Employed in milder nonerosive disease especially when only one or
few joints are involved
- Combined with methotrexate or sulfasalazine
- Dose: Chloroquine- 150mg base per day
HCQS- 400mg/day for 4-6 weeks followed by 200mg/day

13. Leflunomide
An immunomodulator
• Mechanism of action:
- Inhibits proliferation of activated lymphocytes
- Also inhibits dihydro-orotate dehydrogenase and pyrimidine synthesis
in actively dividing cells
- Depresses antibody production by B cells
• Pharmacokinetics:
- Rapidly converted to an active metabolite ( Teriflunomide) in body
- Active metabolite has a long t½ of 2-3 weeks, hence it is given in a
loading dose of 100mg daily for 3 days followed by 20mg OD

14. • Adverse effects:
- Diarrhea, headache, nausea, rashes, loss of hair, thrombocytopenia,
leucopenia
- Increased chances of chest infections
- Raised hepatic transaminases
• Contraindications:
- Children, pregnant and lactating mothers
• Status in rheumatoid arthritis:
- Alternative adjuvant to methotrexate
- Suppresses arthritic symptoms and retards radiological progression of
disease
- Dose: 100mg daily for 3 days as loading dose followed by 20mg OD

15. Tofacitinib
• It is a new synthetic drug approved for severe cases of RA that are not
responding to Mtx
• Tofacitinib can be used alone or concurrently with Mtx, but should not be
combined with azathioprine, cyclosporine or biological DMARDs
• It is a JAK-3 and JAK-1 kinase inhibitor, interferes with the JAK-STAT
signaling pathway and DNA transcription and thus production of
inflammatory mediators and release of cytokines is inhibited.
• Adverse effects are headache, insomnia, diarrhea, hypertension, anemia,
susceptibility to respiratory infections, flaring of tuberculosis and liver
damage.
• Dose: 5 mg BD orally

16. Etanercept
Genetically engineered fusion protein composed of 2 soluble TNF p75
receptor moieties linked to Fc portion of human IgG
• Mechanism of action:
- Serves as exogenously administered soluble TNFa receptor which prevents
TNFa from binding to membrane bound TNF receptors( TNFR1 and TNFR2)
• Adverse effects:
- Development of antibodies against it
- Drug induced lupus and activation of latent tuberculosis or opportunistic
infections
- Local pain, swelling or itching at site of injection
• Status in rheumatoid arthritis:
- Usually used in combination with methotrexate
- Dose: 25mg SC thrice a week

17. Infliximab
Chimeric monoclonal antibody( 75% human and 25% mouse)
• Mechanism of action:
- Cross links membrane bound TNFα receptors and inhibits activated T cells
macrophage function
- Downregulates macrophage and T cell function thus preventing release of other
proinflammatory cytokines
• Adverse effects:
- Upper respiratory tract infections, nausea, headache
- Activation of latent tuberculosis and opportunistic infections
- Infusion site reaction
- Development of antibodies on long term use.
• Status in rheumatoid arthritis:
- Usually used in combination with methotrexate
- Dose: 3-5 m/kg IV infusion for over 2 hours at 0-, 2- and 6-week interval and at 8
weeks interval thereafter

18. Adalimumab
• Recombinant anti TNF monoclonal antibody
• Similar to infliximab in pharmacological profile
• Less immunogenic than infliximab
• Dose: 40mg SC every other week

19. Anakinra
• Recombinant human IL-1 receptor antagonist
• Used in cases failed with one or more DMARDs
• Dose: 100mg SC daily
• Local reaction and chest infection are seen as adverse effects

20. Rituximab
Rituximab is a chimeric monoclonal antibody.
• Mechanism of action:
- It targets CD20 B lymphocytes
- Depletion of these cells takes place through cell mediated and
complement-dependent cytotoxicity and stimulation of cell apoptosis
- Depletion of B lymphocytes reduces inflammation by decreasing the
presentation of antigens to T lymphocytes and inhibiting the
secretion of proinflammatory cytokines.
• Pharmacokinetics:
- Rituximab is given as two intravenous infusions of 1000 mg,
separated by 2 weeks. It may be repeated every 6–9 months, as
needed.

21. • Adverse effects:
- About 30% of patients develop rash with the first 1000-mg treatment
- Serious, and sometimes fatal, bacterial, fungal, and viral infections are
reported for up to 1 year of the last dose of rituximab
- Rituximab is associated with reactivation of hepatitis B virus (HBV)
infection
- Fatal mucocutaneous reactions have been reported in patients
receiving rituximab

22. Corticosteroids
Potent immunosuppressant and anti-inflammatory activity and can be
induced at any stage of rheumatoid arthritis
• Pharmacological actions:
- Prompt symptomatic relief
- May slow joint destruction and delay bony erosions but do not arrest
rheumatoid process
• Status in rheumatoid arthritis:
- As supplement to NSAIDs, 5-10mg prednisolone is used orally
- In severe rheumatoid arthritis with single or few joint involvement, intra-
articular injection of soluble glucocorticoid is used.

23. Anti-Gout Drugs
• Gout is a metabolic disorder characterized by hyperuricemia( normal
plasma urate 2-6mg/dl)
• Uric acid, a product of purine metabolism has lower water solubility
esp. at low pH. When blood urate levels are high it precipitates and
deposits in joints, kidney and subcutaneous tissue(tophi)
• Acute gouty arthritis manifests as sudden onset of severe
inflammation in a small joint( commonest is metatarso-phalangeal
joint of great toe) due to precipitation of urate crystals in the joint
space. The joint becomes red, swollen and extremely painful.

24. Classification

25. NSAIDs
• One of the strong anti-inflammatory drugs ( naproxen, piroxicam,
diclofenac, indomethacin or etoricoxib) given in relatively high and
quickly repeated doses.
• They are quite effective in terminating the attack
• They also inhibit chemotactic migration of leucocytes into the
inflamed joint.

26. Colchicine
• Colchicine, a plant alkaloid is used for the treatment of acute gouty
attacks.
• It is neither a uricosuric nor an analgesic agent, although it relieves
pain in acute attacks of gout.
• Mechanism of action:
- Colchicine binds to tubulin, a microtubular protein causing its
depolymerization. This disrupts cellular functions such as the mobility
of granulocytes, thus decreasing their migration into the affected
area. Furthermore, colchicine blocks cell division by binding to mitotic
spindles.

27. • Pharmacokinetics:
- Colchicine is administered orally and is rapidly absorbed from the GIT.
- It is recycled in the bile and is excreted unchanged in feces or urine
- Inhibitors of CYP2A4 retard colchicine metabolism and enhance its
toxicity
• Adverse effects:
- Nausea, GI disturbance, Diarrhea, Agranulocytosis, Aplastic anemia,
Alopecia
• Dose: 0.5 – 1.5mg orally

28. Corticosteroids
• Intraarticular injection of a soluble steroid( e.g., triamcinolone
acetonide 10 mg in small finger/toe joints, 30mg in wrist) suppresses
symptoms of acute gout.
• Crystalline preparations should not be used.
• It is indicated when only one or few joints are involved and in those
not tolerating NSAIDs/colchicine
• Systemic steroids are highly effective but are reserved for patients
with renal failure /history of peptic bleed in whom NSAIDs are
contraindicated. Prednisolone 40-60mg may be given on one day,
followed by tapering doses over 1-2 weeks.

29. Probenecid
It is highly lipid soluble organic acid
• Mechanism of action:
- Competitive blocking of active transport sites for reabsorption of uric acid
by OATP at all sites esp. in renal tubules.
• Pharmacological action:
- Promotion of excretion of uric acid thus reducing its blood level
- Decreases urate pool, promotes reabsorption of tophaceous deposits thus
relieving arthritis
- Inhibition of secretion of penicillin in proximal tubules, thus increasing its
blood level

30. • Pharmacokinetics:
- Completely absorbed, 90% plasma protein bound
- Partly conjugated in liver and excreted in urine
• Adverse effects:
- Dyspepsia
- Allergic dermatitis, rashes and hypersensitivity reaction
- Convulsions, nephrotic syndrome and respiratory failure
- Deposition of urate crystals in the renal tubules/pelvis

31. • Interactions:
- Aspirin blocks uricosuric action
- Inhibits biliary excretion of rifampicin
- Inhibits urinary excretion of penicillin, cephalosporin, methotrexate
and indomethacin
- Inhibits tubular secretion of nitrofurantoin
- Impairs hepatic metabolism of heparin, necessitating dose reduction
of heparin when given concurrently

32. • Therapeutic uses:
- Its second line adjuvant to allopurinol
- Co-administered with colchicine/NSAIDs for initial 1-2 months to
avoid precipitation of acute gout
- Should be given along with plenty of fluid and urinary alkalizers to
avoid urate crystals.
- Dose: 250mg BD start and after 1 week increased to 500mg BD for
months
- Other use: To prolong duration of action and obtain sustained blood
level of penicillin, ampicillin in gonorrhea, SABE, etc

33. Allopurinol
• Allopurinol is a hypoxanthine analog, and it is a substrate as well as
inhibitor of xanthine oxidase.
• Mechanism of action:
- Allopurinol is xanthine oxidase inhibitor. Xanthine oxidase
metabolizes xanthine (produced from purines) to uric acid thus it
lowers uric acid concentrations and reduces precipitation of uric acid
in the joints or kidneys.

34. • Pharmacokinetics:
- It is about 90% absorbed from the gastrointestinal tract.
- Peak plasma levels normally occur at 1.5 hours.
- Following one oral dose of 300 mg of allopurinol, maximum plasma
levels of about 3 mcg/mL of allopurinol measured
• Adverse effects:
- Hypersensitivity reactions( rashes, fever, malaise, muscle pain)
- Gastric irritation, headache, nausea and dizziness
- Liver damage
- Stevens Johnson syndrome

35. • Interactions:
- Inhibition of degradation of 6-mercaptopurine and azathioprine
- Probenecid shortens ½ life of alloxanthine and allopurinol prolongs
half life of probenecid
- Inhibition of metabolism of warfarin and theophylline
• Contraindications:
- Absolute: Hypersensitive patients, during pregnancy and lactation
- Relative : Elderly, children, liver & chronic diseases
• Dose: 100mg OD stat, gradually increasing to 300mg /day
(maintenance dose) maximum 600mg/day

36. • Other uses (Leishmaniasis) :
- More useful in cutaneous leishmaniasis
- Benefits by inhibiting leishmaniasis donovani by altering its purine
metabolism
- Also used as adjuvant to sodium stibogluconate in resistant cases
- Dose: 300mg QID for 15 days
• Other uses ( Cancer chemotherapy):
- In cancer chemotherapy and immunosuppressive therapy to
potentiate action of 6-mercaptopurine or azathioprine

37. Febuxostat
Febuxostat is a non purine xanthine oxidase inhibitor
• Mechanism of action:
- Febuxostat is a potent and selective inhibitor of xanthine oxidase, thereby
reducing the formation of xanthine and uric acid without affecting other enzymes
in purine and pyrimidine metabolic pathway
• Pharmacokinetics:
- It is >80% absorbed when administered orally
- Maximum conc achieved in approx. 1 hour and a half life of 4-18 hours.
- Extensively metabolized in liver and excreted in urine
- Dose: 40-80mg daily orally
• Adverse effects:
- gout flares, joint pain, nausea, mild rash, liver problems

38. • Adverse effects:
- gout flares, joint pain
- nausea
- mild rash
- liver problems.

39. Pegloticase
• It is the newest urate-lowering therapy for the treatment of refractory
chronic gout
• It is a recombinant mammalian uricase
• Mechanism of action:
- Pegloticase metabolizes uric acid to allantoin. This reduces the risk of
precipitates, since allantoin is five to ten times more soluble than uric
acid and can be easily eliminated by the kidney.

40. • Pharmacokinetics:
- The recommended dose for pegloticase is 8mg every 2 weeks administered
as an intravenous infusion.
- It is a rapidly acting drug, achieving a peak decline in uric acid level within
24-72 hours.
- The serum half life ranges from 6 to 14 days.
- It has been shown to maintain low urate levels up to 21 days after a single
dose at doses of 4-12mg, allowing for IV doing every 2 weeks.
• Adverse effect:
- Gout flare, Anaphylaxis reaction, Nephrolithiasis, arthralgia, muscle spams,
headache, anemia and nausea
- Less frequent are URTI, peripheral edema, UTI and diarrhea. Hemolytic
anemia in patients with G6PD deficiency.

41. Thank you