M3L2-5

Disease Modifying Anti-rheumatic Drugs

DMARDS

DMARDS

• Immunosuppressants (suppress immune system = stops inflammation mediators) - affect progression

DMARDS

• Full effects: 6-12 months

DMARDS

• AKA: SAARDS - Slow Acting Antirheumatic Drugs

Slow Acting Antirheumatic Drugs

SAARDS

Non biological DMARDs

conventional DMARDS, small molecular weight.

Biological DMARDS

products of recombinant DNA, high molecular weight.

METHOTREXATE

Also an anti-neoplastic agent, for cancer & rheumatoid arthritis

METHOTREXATE

Considered as the first line DMARD

METHOTREXATE

For cancer: 100mg/day — target CA cell

METHOTREXATE

For cancer: 100mg/day — target CA cell

METHOTREXATE

• MOA:

  • Block the NICAR transformylase (important for the products of Purine - converted to uric acid = inflammation of joints)

METHOTREXATE

MOA: Inhibition of dihydrofolate reductase (DHF) = converts DHF to tetrahydrofolate that is important for purine biosynthesis

METHOTREXATE

MOA: Inhibit thymidylate synthase

• Both inhibit DNA synthesis

METHOTREXATE

• Toxic effects:

  • Hepatotoxicity - dose dependent

    • Rescue drug: Leucovorin (Folinic acid)

Leucovorin (Folinic acid)

Rescue drug for Hepatotoxicity of Methotrexate

ANTIMALARIALS

• Ex. Chloroquine

  • Hydroxychloroquine (Plaquenil®)

ANTIMALARIALS

• MOA:

  • Inhibit T cell response to mitogens

  • Inhibit chemotaxis

  • Inhibit DNA and RNA synthesis

ANTIMALARIALS

• Use: 2nd line DMARDS

ANTIMALARIALS

• Toxic effects: Cinchonism (tinnitus, headache, dizziness, optic neuritis)

SULFASALAZINE

• Prodrug ➠ Sulfapyridine + 5-amino salicylate (5 ASA or Mesalamine)

  • Sulfapyridine = for RA (rheumatoid arthritis)

  • 5-ASA = for IBD (Irritable Bowel Disease)

SULFASALAZINE

• T/E:

  • Sulfonamide associated effects (SJS as the ADR)

  • GI effect (Diarrhea & Stomach Cramps)

LEFLUNOMIDE

• Prodrug

• Active product: A77 1726

LEFLUNOMIDE

• Inhibit dihydroorotate dehydrogenase = inhibit RNA synthesis (

• inflammation since it inhibits T-cell & B-cell) 

  • RNA synthesis is important for T-cell & B-cell production

MYCOPHENOLATE MOFETIL

• Prodrug

• Active product: mycolic acid — inhibit inosine monophosphate dehydrogenase; cam also inhibit RNA synthesis which lowers the T-cell & B-cell production)

MYCOPHENOLATE MOFETIL

• May be useful in vasculitis and Wegener’s granulomatosis, inhibits cancer

GOLD COMPOUNDS

• Ex. Parenteral: Aurothiomalate, Aurothioglucose

• Oral:Auranofin

GOLD COMPOUNDS

• Obsolete because of toxicities (No longer use)

  • High incidence of hypersensitivity reaction

  • Nephrotic syndrome

  • Antidote for Gold poisoning: Dimercaprol, BAL

Dimercaprol, BAL 

Antidote for Gold Poisoning

CYCLOPHOSPHAMIDE

Suppresses T-cell and B-cell function (Lowers inflammation)

CYCLOPHOSPHAMIDE

• Prodrug - Converted to:

  • Phosphoramide mustard

  • Acrolein 

    • Responsible for causing Hemorrhagic cystitis (has blood during urination)

    • Rescue drug: MESNa (Mercaptoethanesulfonate Na or Na-2-mercaptoethane sulfonate

MESNa

Rescue drug for Cyclophosphamide

CYCLOSPORINE

Inhibits interleukin-1 and interleukin-2 receptor production

CYCLOSPORINE

Inhibits macrophage T-cell interaction and T-cell responsiveness

Abatacept

T-cell activation inhibitor

Rituximab

 B-cell depleting agent

Tocilizumab

•  IL-6 inhibitor

Anakinra

 IL-1 neutralizing agent

Adalimumab, Infliximab, Etanercept

•  TNF-alpha inhibitor

PO

• Prednisone (Pred, Prend)

• Dexamethasone (Decilone)

• Methylprednisolone (Medrol)

IV

• Methylprednisolone (Solu-Medrol)

• For life threatening SLE, pulsatile or intermittent administration = 1000 for within 3 days 2)

OA

Intrasynovial, given every 4-6 months

GOUT

• Increase uric acid in the body

  • UA Go to joints —> recognized as foreign —> arthritis

ACUTE GOUT

• Acute monoarticular arthritis — usually affect only one big toe = Podagra of gout

ACUTE GOUT

• Address the joint arthritis, not uric acid lowering agent

ACUTE GOUT

• Drugs → for pain and inflammation

COLCHICINE

• Inhibit tubulin polymerization = inhibit microtubule synthesis = inhibit chemotaxis

COLCHICINE

• 1st line agent in acute gout

COLCHICINE

• T/E: watery diarrhea, bloody diarrhea, peripheral neuropathy

NSAID

Inhibit COX

NSAID

• C/I NSAID: Aspirin, Tolmetin, Salicylates (can cause urination)

NSAID

• Drugs used: Indomethacin, Ibuprofen

GLUCOCORTICOIDS

“Steroids”

GLUCOCORTICOIDS

• MOA: induce immunosuppression

GLUCOCORTICOIDS

• Used for not more than 5 days - can lead to adrenal insufficiency (Addison’s Disease)

  • Stops producing natural corticoids

  • Stops the hypothalamus (endocrine system) in producing cortisol (which is glucocorticoids)

Gouty nephropathy

presence of renal uric acid stones

Chronic tophaceous gout

Presence of tophi = inflammatory bumps; subcutaneous deposits of monosodium uric crystals

Give colchicine (1st 2-3 weeks of therapy), Colchicine + Hypourecemics

• Treatment step for chronic gout

HYPOURICEMIC AGENTS

• Lower blood uric acid levels

HYPOURICEMIC AGENTS

• Concepts:

  • Xanthine oxidase: Responsible for oxidation of xanthine and hypoxanthine into uric acid.

  • Urate oxidase/Uricase: Convert uric acid into allantoin which is readily excreted in the urine Hypouricemic

ALLOPURINOL

MOA: Inhibit xanthine oxidase = hypouricemic

ALLOPURINOL

• Purine analogue

ALLOPURINOL

1st line agent for chronic tophaceous gout

FEBUXOSTAT

• MOA: Inhibit xanthine oxidase = hypouricemic

FEBUXOSTAT

Non purine

PEGLOTICASE, RASBURICASE

Recombinant uricase

Uricase

absent in mammals

URICOSURIC AGENTS

1. Penicillamine

2. Sulfinpyrazone

3. Probenecid

URICOSURIC AGENTS

• Sulfinpyrazone & Probenecid

  • MOA: inhibit reabsorption of uric acid (URAT1 - Uric acid transporter 1 that is eliminated in urine)

URICOSURIC AGENTS

• Penicillamine 

• MOA: chelator, focus complex (Soluble) with uric acid ready for excretion (for the mgt of Wilson’s Disease)

URICOSURIC AGENTS

• Enhance urine excretion of uric acid

URICOSURIC AGENTS

• High risk of renal uric acid stone formation

• Remedy: frequent hydration

Sulfinpyrazone & Probenecid

• MOA: inhibit reabsorption of uric acid (URAT1 - Uric acid transporter 1 that is eliminated in urine)

Penicillamine

• MOA: chelator, focus complex (Soluble) with uric acid ready for excretion (for the mgt of Wilson’s Disease)

INFLAMMATION

• A non-specific immune response against an adverse stimulus.

  1. Microbial invasion

  2. Physical Injury

INFLAMMATION

Purpose: For protection and a part of healing process

Calor

Heat

Rubor

Redness

Swelling

Tumor

Dolor

Pain

Functio laesa

Loss of Function

NSAIDs, Glucocorticoids

Relief of symptoms and the maintenance of function

DMARD’s

• Slowing or arrest of the tissue-damaging process

Weak cox inhibitor

• 1st line agent for pain in OA

ACETAMINOPHEN

• Weak cox inhibitor in the periphery:

  • Analgesic effect: Weak cox inhibitor - 1st line agent for pain in OA

  • Antipyretic: High antipyretic effect than analgesic

  • Anti Inflammatory: No inflammatory effect

ACETAMINOPHEN

• Advantages:

  • vs. Aspirin: No hyperuricemia

  • Safe in pregnancy, lactation, children

ACETAMINOPHEN

• Major risk: hepatotoxicity —> NAPQI (N-acetyl-p-benzoquinone imine)

N-acetyl-p-benzoquinone imine

NAPQI

ACETAMINOPHEN

• Risk factors for APAP induced hepatotoxicity

  • > 4g/day (8 tabs per day)

  • Pre-existing liver disease

  • Concomitant use of CYP1A2 inducers

Nabumetone

All are weak organic acids except

Nabumetone

 non-acidic, only prodrug NSAID

NSAIDs

MOA: block COX enzyme = inhibit PG synthesis

NSAIDs

• Majority of the side effects are due to the blockade of COX1 by nonselective NSAIDs

COX1

Constitutive enzyme/homeostatic enzyme

COX1

Produce PGs for maintenance function (homeostasis)

COX1

• Cytoprotection 

COX1

• Renal vasodilation = enhance diuresis

COX2

• Responsible for pain & inflammation

COX2

• Inducible

COX2

Formation is due to adverse stimuli