Antirheumatic and Antigout Drugs

Prepared By:
Badri Karki
Masters In Pharmaceutical Sciences, Clinical Pharmacy
Introduction

Rheumatoid arthritis (RA):

 a chronic, progressive and an autoimmune disease characterized
by joint inflammation, synovial proliferation and destruction of
articular cartilage.

 NSAIDs are the first line drugs and afford symptomatic relief in pain,
swelling, morning stiffness, immobility, but do not arrest the
disease process.
Pathophysiology:
 RA results from a dysregulation of the humoral and cell-mediated
components of the immune system

 Formation of Immune complexes; composed of IgM activate complement and

release of cytokines (mainly TNFα and IL-1).

 Tumor necrosis factor (TNF), interleukin-1 (IL-1), and IL-6 are proinflammatory
cytokines important in the initiation and continuance of inflammation.

 These inflammatory cells secrete lysosomal enzymes which damage cartilage

and erode bone, while PGs produced in the process cause vasodilatation and
pain.
Symptoms
 Joint pain and stiffness of more than 6 weeks’ duration
 fatigue, weakness, low-grade fever, loss of appetite
 Muscle pain and afternoon fatigue may also be present
 Joint deformity is generally seen late in the disease

Signs
 Tenderness with warmth and swelling over affected joints usually
involving hands and feet
 Distribution of joint involvement is frequently symmetrical
 Rheumatoid nodules may also be present
The goals of drug therapy in RA are:
 To prevent or control joint damage
 To prevent loss of function
 To decrease pain
 To maintain the patient’s quality of life
 To avoid or minimize adverse effects of treatment
Non-pharmacological Management:
 To improve symptoms and help maintain joint function;
 Adequate rest
 Weight reduction if obese
 Occupational therapy
 Physical therapy

 Patients with severe disease may benefit from surgical procedures such
as tenosynovectomy, tendon repair, and joint replacements.

 Patient education about the disease and the benefits and limitations of
drug therapy is important.
Classification of Anti RA Drugs:
I. Disease modifying antirheumatic drugs (DMARDs)
A. Nonbiological drugs
1. Immunosuppressants: Methotrexate, Azathioprine, Cyclosporine
2. Sulfasalazine
3. Chloroquine or Hydroxychloroquine
4. Leflunomide
B. Biological agents
1. TNFα inhibitors: Etanercept, Infliximab, Adalimumab
2. IL-1 antagonist: Anakinra
II. Adjuvant drugs
Corticosteroids: Prednisolone and others
(Gold and penicillamine are obsolete DMARDs.)
NSAIDs
 act primarily by inhibiting prostaglandin synthesis, which is only a small
portion of the inflammatory cascade.

 They possess both analgesic and anti-inflammatory properties and

reduce stiffness but do not slow disease progression or prevent bony
erosions or joint deformity.

 They should seldom be used as monotherapy for RA; instead, they

should be viewed as adjuncts to DMARD treatment.
 Aspirin, celecoxib, diclofenac, Ibuprofen, Indomethacin, Naproxen,
Piroxicam, Sulindac, Ketoprofen, Mephenamic acid, Piroxicam,
Aceclofenac, Meloxicam, Etodolac.

Toxicities:
 GI: mucosal damage, ulceration and bleeding
 Bleeding: inhibition of platelet function
 Limitation of renal blood flow : Na+ and water retention
 Delay/prolongation of labour
 Asthma and anaphylactoid reactions in susceptible individuals
Classification of Anti RA Drugs:
I. Disease modifying antirheumatic drugs (DMARDs)
A. Nonbiological drugs
1. Immunosuppressants: Methotrexate, Azathioprine,
Cyclosporine
2. Sulfasalazine
3. Chloroquine or Hydroxychloroquine
4. Leflunomide
Methotrexate
 Dihydrofolate reductase inhibitor with prominent immunosuppressant
and anti-inflammatory property.

 Inhibition of cytokine production, chemotaxis and cell-mediated immune

reaction.

 DMARD of first choice and the standard treatment for most patients,
including cases of juvenile RA.

 Relatively rapid onset of symptom relief(4–6 weeks)

 Oral or IM dose: 7.5–15 mg weekly

Major side effects:
 Oral ulceration and gastro-intestinal upset (low dose)
 Increased incidence of chest infection
 With prolonged therapy, dose dependent progressive liver damage
leading to cirrhosis may occurs with prolonged therapy.

Contraindication:
 in pregnancy, breast-feeding, liver disease, active infection, leucopenia
and peptic ulcer.

 not recommended for renal impaired patients.

In order to reduce toxicity with methotrexate, concomitant administration
with what vitamin is recommended?
a. Folic acid
b. Thiamine
c. Ascorbic acid
d. Pyridoxine
e. Riboflavin
What is the recommended starting dose of methotrexate when used for
rheumatoid arthritis?
a. 2.5 mg PO daily
b. 2.5 mg PO weekly
c. 7.5mgPOdaily
d. 7.5 mg PO weekly
e. 25 mg PO weekly
Azathioprine
 purine synthase inhibitor; a potent suppressant of cell-mediated
immunity
 acts after getting converted to 6-mercaptopurine by the enzyme
thiopurine methyl transferase (TPMT)
 It also suppresses inflammation.

ADRs and toxicities:

 Myelosuppression (extreme fatigue, easy bleeding or bruising,
infection)
 Hepatotoxicity
 Lymphoproliferative disorders
 less commonly used in in RA patients.

 Given along with corticosteroids, it has a steroid sparing effect, for which
it is primarily used now, especially in cases with systemic manifestations.

 It is not combined with Methotrexate.

 Other immunosuppressants like cyclosporine are rarely used in RA; are

reserved for cases not responding to other DMARDs.
Sulfasalazine:
 exerts anti-inflammatory activity in the bowel (useful in ulcerative colitis)
 suppresses the disease in significant number of RA patients.
 The mechanism of action is not known.
 Efficacy of sulfasalazine in RA is modest.

 Side effects may be unpleasant

 neutropenia/thrombocytopenia
 hepatitis is possible.

 used as a second line drug for milder cases or is combined with Mtx.
Chloroquine and hydroxychloroquine
 induce remission in up to 50% patients of RA, but take 3–6 months.
 mechanism of action is not known
 Proposed mechanisms:
 reduce monocyte IL–I, consequently inhibiting B lymphocytes.
 Interfere with antigen processing
 Lysosomal stabilization and free radical scavenging

 Their advantage is relatively low toxicity, but efficacy is also low; bony
erosions are not prevented.
Adverse effects:
 Tissue accumulation and toxicities like retinal damage and corneal
opacity
(less common and reversible in case of hydroxychloroquine, which is
preferred over chloroquine)
 rashes, graying of hair, irritable bowel syndrome, myopathy and
neuropathy.

 Chloroquine/hydroxychloroquine are employed in milder nonerosive

disease, especially when only one or a few joints are involved, or they
are combined with Mtx/sulfasalazine.
Ocular toxicity is associated with
a. Leflunomide
b. Methotrexate
c. Hydroxychloroquine
d. Infliximab
e. Adalimumab
Leflunomide
 inhibits proliferation of stimulated lymphocytes in patients with active
RA.
 Suppresses arthritic symptoms
 Depresses antibody production by B-cells.
 The active metabolite has a long t1⁄2 of 2–3 weeks
 given in a loading dose of 100 mg daily for 3 days followed by 20 mg OD.
 Can be used as an alternative to Mtx or can be added to it, but the
combination is more hepatotoxic.
 Combination with sulfasalazine improves benefit.
Adverse effects:
 Diarrhea  Thrombocytopenia
 Headache  Leucopenia
 Nausea  increased chances of chest infection
 Rashes  raised hepatic transaminases.
 loss of hair

 It is not to be used in children and pregnant/ lactating women.

Classification of Anti RA Drugs:
I. Disease modifying antirheumatic drugs (DMARDs)
B. Biological agents
1. TNFα inhibitors: Etanercept, Infliximab, Adalimumab
2. IL-1 antagonist: Anakinra
TNFα inhibitors
 TNF inhibitors mainly suppress macrophage and T-cell function;
inflammatory changes in the joint regress and new erosions are slowed.

 Quicker response than nonbiologic DMARDs has been obtained.

 generally added to Mtx when response to the Mtx is not adequate or in

rapidly progressing cases.

 Increased susceptibility to opportunistic infections, including

tuberculosis and pneumocystis pneumonia.
Etanercept:
 a recombinant fusion protein of TNF-receptor and Fc portion of human
IgG1

 Dose: 25–50 mg s.c. once or twice weekly

 Pain, redness, itching and swelling occur at injection site and chest
infections may be increased.
Infliximab:
 a chimeral monoclonal antibody which binds and neutralizes TNFα

 Dose: 3–5 mg/kg is infused i.v. every 4–8 weeks.

 An acute reaction comprising of fever, chills, urticaria, bronchospasm,

rarely anaphylaxis may follow the infusion.

 Susceptibility to respiratory infections is increased and worsening of CHF

has been noted.
Adalimumab:
 a recombinant monoclonal anti-TNF antibody

 Dose: 40 mg s.c every 2 weeks.

 Injection site reaction and respiratory infections are the common

adverse effects.
IL-1 antagonist
Anakinra:
 a recombinant human IL-1 receptor antagonist

 Though clinically less effective than TNF inhibitors, it has been used
in cases who have failed on one or more DMARDs.

 Dose: 100 mg s.c. daily.

 Local reaction and chest infections are the main adverse effects.
All of the following statements are true about disease modifying
antirheumatic drugs except:
a. Should be started within 3 to 4 months of diagnosis of RA
b. Can reduce or prevent joint damage
c. Shown to work within 1 to 2 days of starting therapy
d. Classified as nonbiological or biological
e. Can preserve joint function
Classification of Anti RA Drugs:
II. Adjuvant drugs
Corticosteroids: Prednisolone and others

(Gold and penicillamine are obsolete DMARDs.)

Corticosteroids:
 Glucocorticoids have potent immunosuppressant and anti-inflammatory
activity

 can be inducted almost at any stage in RA along with first or second line
drugs, if potent anti-inflammatory action is required while continuing the
NSAID ± DMARD.

 Symptomatic relief is prompt and marked but they do not arrest the
rheumatoid process.

 Joint destruction may be slowed and bony erosions delayed.

Which of the following disease modifying antirheumatic drugs can be
administered orally?
a. Certolizumab
b. Anakinra
c. Abatacept
d. Leflunomide
e. Etanercept
GOUT
Hyperuricemia - a elevated serum uric acid level
 In most laboratories, the upper limit of normal is 7 mg/dL (uricase
method).

 The upper limit of normal is about 1 mg/dL lower for women than for
men.

 Gout is a disease that is characterized by recurrent painful acute

attacks of urate crystal-induced arthritis.
 Most gout victims are men (7 to 9 times more often than women); most
women with the disease are postmenopausal.

 The risk of developing gout increases as the serum uric acid level rises.
Virtually all gout patients have a serum uric acid level > 7 mg/dL.

 Gout has a familial tendency

Factors associated with hyperuricemia and gout:
 Obesity
 Hypertension
 Hyperlipidemia
 Atherosclerosis
 Diabetes
 Alcohol abuse
Uric acid production and excretion

 Uric acid, an end product of purine metabolism, is produced from both

dietary and endogenous sources.

 The body has a total uric acid content of 1.0 to 1.2 g

 Uric acid has no known biological function.

 Xanthine oxidase catalyzes the reaction that occurs as the final step in
the degradation of purines to uric acid.
 The body ultimately excretes uric acid;
via the kidneys (300–600 mg/day; two-thirds of total uric acid) and
via the GI tract (100–300 mg/day; one-third of the total uric acid)

 At a pH of 4.0 to 5.0 (i.e., in urine), uric acid exists as a poorly soluble

free acid
 At physiological pH, it exists primarily as monosodium urate salt
 Causes:
 Hyperuricemia and gout may be primary or secondary.

 Primary hyperuricemia and gout apparently result from an innate

defect in purine metabolism or uric acid excretion.

 The exact cause of the defect usually is unknown.

 Principally for therapeutic purposes, patients with primary

hyperuricemia and gout can be classified as overproducers or under
excretors of uric acid.
Secondary hyperuricemia and gout
 develop during the course of another disease or as a result of drug therapy.

 Hematological causes
 Lymphoproliferative disorders
 Myeloproliferative disorders
 Certain hemolytic anemias and hemoglobinopathies
 Chronic renal failure
 Drug-induced disease
 Diabetic ketoacidosis, psoriasis, and chronic lead poisoning
Drug-induced disease
 Aspirin and other salicylates
 Cytotoxic drugs
 Diuretics (except spironolactone)
 Ethambutol and nicotinic acid
 Cyclosporine, pyrazinamide and levodopa
 Ethanol
Clinical presentation:

Depends upon the type of hyperuricemia / gout

 Asymptomatic hyperuricemia
 Acute gouty arthritis
 Intercritical gout
 Chronic tophaceous gout
Asymptomatic hyperuricemia
 characterized by an elevated serum uric acid level but has no signs or
symptoms of urate deposition disease (arthritis, tophi, or urolithiasis).

 Urate lowering drug treatment for most patients is not required.

General interventions
 encouraging maintenance of good urine output
 avoidance of high purine meats and fish, and
 regular medical exams to check serum urate levels and gout related
signs.
Acute gout
 manifests as sudden onset of severe inflammation in a small joint due to
precipitation of urate crystals in the joint space.

 The most common site of the initial attack is the first metatarsophalangeal
joint; an attack there is known as podagra.

 Other sites that may be affected include the instep, ankle, heel, knee, wrist,
elbow, and fingers.

 The joint becomes red, swollen and extremely painful: requires immediate
treatment.
Intercritical gout
 symptom-free period after the first attack.

 This phase may be interrupted by the recurrence of acute attacks.

 Prophylaxis may consist of low-dose colchicine 0.6 mg once or twice

daily in the patient with normal renal function.

 Low-dose NSAIDs may also be used alternatively (naproxen 250 mg

twice daily or indomethacin 25 mg twice daily).
Chronic tophaceous gout.
 This rare clinical presentation may develop if hyper- uricemia and
gout remain untreated for many years.

 Allopurinol and probenecid may be given in combination to treat

severe cases.
For acute gout
 NSAIDs, Colchicine, Corticosteroids

For chronic gout/hyperuricemia

 Uricosurics
 Probenecid, Sulfinpyrazone

 Uric Acid Synthesis inhibitors

 Allopurinol, Febuxostat
NSAIDs:
 Naproxen, piroxicam, diclofenac, indomethacin or etoricoxib is given in
relatively high and quickly repeated doses.

 They are quite effective in terminating the attack, but may take 12–24
hours.

 After the attack is over, they may be continued at lower doses for 3–4
weeks while drugs to control hyperuricemia take effect.

 They are not recommended for long term management due to risk of
toxicity.
Colchicine
 an alkaloid from Colchicum autumnale
 The traditional drug for relieving pain and inflammation and ending the
acute attack

 Most effective when started within 24 hours after symptoms begin.

 Colchicine apparently impairs leukocyte migration to inflamed areas and
disrupts urate deposition and the subsequent inflammatory response.
 It has no effect on serum urate levels.
Toxicity (high and dose related)
 dose limiting adverse effects:
 Nausea, vomiting, watery or bloody diarrhea and abdominal cramps

 In overdose:
 kidney damage, CNS depression, intestinal bleeding; death is due to
muscular paralysis and respiratory failure.

 Chronic therapy with colchicine is not recommended because it causes

aplastic anemia, agranulocytosis, myopathy and loss of hair.
Corticosteroids:
a. Corticosteroid intra-articular injections
b. Systemic corticosteroid therapy

Corticosteroid intra-articular injections

 particularly effective in patients with acute single-joint gout.
 triamcinolone 8 mg in smaller joints (10 mg in the knee),
 methylprednisolone acetate (5 to 25 mg per joint), or
 betamethasone 3 to 6 mg
Systemic corticosteroid therapy
 especially when either NSAIDs or colchicine cannot be given or have not
been effective.
 oral prednisone (20 to 60 mg/day initially, with the dose tapered during
a period of 5 to 7 days)
 IM betamethasone (7 mg) or IV methyl- prednisolone 125 mg
Uricosuric Drugs

Probenecid
 a highly lipid-soluble organic acid developed in 1951 to inhibit renal tubular
secretion of penicillin so that its duration of action could be prolonged.

 It competitively blocks active transport of organic acids at all sites; that in

renal tubules being the most prominent.

 Probenecid does not have any other significant pharmacological action; it is

neither analgesic nor anti-inflammatory.
Adverse Effects:
 Probenecid is generally well tolerated.
 Dyspepsia is the most common side effect.
 It should be used cautiously in peptic ulcer patients.
 Rashes and other hypersensitivity phenomena are rare.
 Toxic doses cause convulsions and respiratory failure.
Interactions
 probenecid inhibits the urinary excretion of penicillin, cephalosporins,
sulfonamides, Mtx and indomethacin.

 It inhibits biliary excretion of rifampicin. Pyrazinamide and ethambutol

may interfere with uricosuric action of probenecid.

 Probenecid inhibits tubular secretion of nitrofurantoin which may not

attain antibacterial concentration in urine.

 Salicylates block uricosuric action of probenecid.

Sulfinpyrazone
 a pyrazolone derivative, related to phenylbutazone, having uricosuric
action, but is neither analgesic nor anti-inflammatory.

 It inhibits tubular reabsorption of uric acid, but smaller doses can

decrease urate excretion as do small doses of probenecid.

 has been withdrawn in USA because of more gastric irritation and other
side effects.

 Sulfinpyrazone inhibits platelet aggregation as well.

Uric Acid Synthesis Inhibitors
Allopurinol
 First choice of drug in chronic gout

 Hypoxanthine analogue, a substrate as well as inhibitor of xanthine oxidase,

the enzyme responsible for uric acid synthesis.

 Allopurinol itself is a short-acting (t1/2 2 hours) competitive inhibitor of

xanthine oxidase.

 But its major metabolite alloxanthine (oxypurine) is a long-acting (t1/2 24

hours).
Adverse effects
(Uncommon)
 Hypersensitivity reaction: rashes, fever, malaise and muscle pain;
subsides on stopping the drug.

 Stevens-Johnson syndrome is a rare but serious risk.

 Gastric irritation, headache, nausea and dizziness are infrequent; do

not need withdrawal.

 Liver damage is rare.

Precautions and contraindications:
 Liberal fluid intake is advocated during allopurinol therapy.

 It is contraindicated in hypersensitive patients, during pregnancy and

lactation.

 It should be cautiously used in the elderly, children and in patients with

kidney or liver disease.

Caution:
 Allopurinol as well as uricosurics should not be started during acute
attack of gout.
Febuxostat
 nonpurine xanthine oxidase inhibitor
 the plasma t1/2 is ~ 6 hours.
 an alternative drug for treating symptomatic gout only in patients
intolerant to allopurinol, or in those with some contraindications

Adverse effect:
 liver damage (liver function needs to be monitored during febuxostat
therapy)
 Diarrhea, nausea and headache

 It is not indicated in malignancy associated hyperuricemia.

Interaction:
 By inhibiting xanthine oxidase, it has the potential to interact with
mercaptopurine, azathioprine and theophylline; should not be given to
patients receiving these drugs.