ANTIRHEUMATIC DRUGS

 

By: Dr. Faiza Nasar (Pharm .D, M.Phil.).

ANTIRHEUMATIC DRUGS

RHEUMATOID ARTHRITIS

•       Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease whose hallmark feature is a persistent symmetric polyarthritis that affects the hands and feet.

•       Any joint lined by a synovial membrane may be involved.

•       RA is theorized to develop when a genetically susceptible individual experiences an external trigger (e.g., cigarette smoking, infection, or trauma) that triggers an autoimmune reaction. 

SIGN & SYMPTOMS

•       Pain or aching in more than one joint.

•       Stiffness in more than one joint.

•       Tenderness and swelling in more than one joint.

•       The same symptoms on both sides of the body (such as in both hands or both knees)

•       Weight loss.

•       Fever.

•       Fatigue or tiredness.

•       Weakness.

FEATURES OF RHEUMATOID ARTHRITIS

DRUGS FOR RA

•       Nonsteroidal anti-inflammatory drugs (NSAIDs)

•       Disease-modifying anti-rheumatic drugs (DMARDs)

•       Synthetic

•       Biologic

•       Glucocorticoids  

NON-STEROIDAL ANTIINFLAMMATORY DRUGS

•       Cyclo-oxygenase (COX) inhibitors

•       Do not slow the progression of the disease

•       Provide partial relief of pain and stiffness

•       Non-selective COX inhibitors

•       Ibuprofen

•       Diclofenac sodium

•       COX–2 selective inhibitors

•       celecoxib

COX-2 INHIBITORS

•       COX-2 selective inhibitors appear to be as effective NSAIDs

•       Associated with less GI toxicity

•       However increased risk of CV events 

GLUCOCORTICOIDS

•       Glucocorticoids are potent anti-inflammatory drugs that are commonly used in patients with RA to provide symptomatic.

•       Timely dose reductions and cessation are necessary to avoid adverse effects associated with long-term use.

•       PREDNISOLONE is a common glucocorticoid in treatment of RA.

•       Hydrocortisone, Dexamethasone, Methylprednisolone, Triamcinolone, Dexamethasone, Betamethasone are other glucocorticoids used in treatment of RA.

•       ADR’s: weight gain, increase blood glucose levels, high bp, insomnia, allergic reactions.

DMARD’S

•       DISEASE MODIFYING ANTI-RHEUMATIC DRUGS (DMARD’S).

•       There are two main groups of DMARDs:

1. Traditional DMARDs
2. Biologics.

TRADITIONAL DMARD’S

•       These are the older traditional or conventional DMARDs.

1. Methotrexate
2. Sulfasalazine
3. Hydroxychloroquine
4. Leflunomide
5. Azathioprine

METHOTREXATE (MTX)

•       Methotrexate is a folic acid antagonist that inhibits cytokine production and purine nucleotide biosynthesis, leading to immunosuppressive and anti-inflammatory effects.

•       It is dihydrofolate reductase inhibitor

•       ↓ thymidine & purine nucleotide synthesis

•       “Gold standard” for DMARD therapy

•       7.5 – 30 mg weekly

PHARMACOKINETICS

•       Absorption variable

•       Elimination mainly renal

ADR’S OF MTX

•       Hepatotoxicity

•       Bone marrow suppression

•       Dyspepsia, oral ulcers

•       Cirrhosis of the liver, and an acute pneumonia-like syndrome may occur with chronic administration.

•       Teratogenicity

SULFASALAZINE

•       Its mechanism of action in treating RA is unclear.

•       The onset of activity is 1 to 3 months.

•       It is associated with GI adverse effects (nausea, vomiting, anorexia) and leukopenia.

HYDROXYCHLOROQUINE

•       Hydroxychloroquine is used for early, mild RA, and may be combined with methotrexate.

•       Its mechanism of action in autoimmune disorders is unknown, and onset of effects takes 6 weeks to 6 months.

•       Hydroxychloroquine has less adverse effects on the liver and immune system than other DMARDs.

•       However, it may cause ocular toxicity, including irreversible retinal damage, CNS disturbances, GI upset, and skin discoloration.

LEFLUNOMIDE

•       Leflunomide  is an immunomodulatory agent.

•       After biotransformation, leflunomide becomes a reversible inhibitor of dihydroorotate dehydrogenase (DHODH), an enzyme necessary for pyrimidine synthesis.

•       Leflunomide may be used as monotherapy in patients who have intolerance or contraindications to use of methotrexate in RA, or it may be used in combination with methotrexate for patients with suboptimal response to methotrexate alone.

•       Common adverse effects include headache, diarrhea, and nausea.

•       Other effects are weight loss, allergic reactions, including a flu-like syndrome, skin rash, alopecia, and hypokalemia.

•       The drug is not recommended in patients with liver disease as it can be hepatotoxic.

•       Leflunomide is contraindicated in pregnancy.

•       Monitoring parameters include signs of infection, complete blood count, electrolytes, and liver enzymes.

LEFLUNOMIDE

AZATHIOPRINE

•       Azathioprine is prodrug of mercaptopurine.

•       It is well absorbed by GIT and metabolized to mercaptopurine.

•       Azathioprine causes immunosuppression by interfering with purine nucleic acid synthesis.

•       ADR’s: bone marrow suppression, skin rash, fever, GI disturbances and jaundice.

COMMON DMARD’S COMBINATIONS

•       Triple Therapy

•       Methotrexate, Sulfasalazine, Hydroxychloroquine

•       Double Therapy

•       Methotrexate & Leflunomide

•       Methotrexate & Sulfasalazine

•       Methotrexate & Hydroxychloroquine

MINOCYCLINE

•       Minocycline a tetracycline antibiotic.

•        It has been shown to be effective in the treatment of early RA.

•       It is generally not utilized as first-line therapy.

•        Minocycline can be used as monotherapy or in combination with other DMARDs.

•       ADR’s: Black stools, blood in urine or stools, blurred vision, eye pain, chest pain and dizziness

BIOLOGICS

•       T-Cell Co-stimulation

•       Abatacept

•       Monoclonal Antibodies to TNF

•       Infliximab

•       Adalimumab

•       Soluble Receptor Inhibitor for TNF

•       Etanercept

•       Receptor Antagonist to IL-1

•       Anakinra 

•       Monoclonal Antibody to CD-20

•       Rituximab

ADVERSE DRUG REACTIONS ASSOCIATED WITH BIOLOGIC DMARD’s

•       Following ADR’s are associated with all biologic DMARD’s:

•       Increased risk of infections (bacterial & viral).

•       Reactivation of TB, Herpes, HBV and HCV.

•       ADR’s associated with anti-TNF alpha drugs:

•       Worsen the CHF

•       Lymphomas

•       Drug induced allergic reactions

•       ADR’s associated with IL-6 inhibitors:

•       Hyperlipidemia

•       Elevated LFT’s

TUMOUR NECROSIS FACTOR- ALPHA

•       TNF-alpha is a potent inflammatory cytokine

•       TNF-alpha is produced mainly by macrophages and monocytes

•       TNF-alpha is a major contributor to the inflammatory and destructive changes that occur in RA

•       Blockade of TNF-alpha results in a reduction in a number of other pro-inflammatory cytokines (IL-1, IL-6, & IL-8)

Useful Links

1. Tablet, manufacturing flow of Tablets in Pharmaceutical
2. Capsule Manufacturing Flow in Pharmaceuticals
3. Diagrammatic Flow Chart for Dry Syrup Manufacturing
4. DRUG DOSAGE FORMS
5. Difference Between USP and BP Syrup
6. Elixirs