Exam 2: Lecture 5, DMARDs Flashcards
DMARDs
Disease Modifying Slow-Acting Anti rheumatic Drugs
NSAIDS cannot reverse join damage, DMARDs are used for rheumatic disorders not responding to NSAIDs
Rheumatoid disease is…
a widespread chronic inflammatory condition
DMARDs info
operate in connective tissues
heterogeneous group of slow acting anti-inflame agents
all agents have very slow onset of effect, can take months
many do not respond to DMARDs (esp Gold Salts)
Controversy still about efficacy in arthritis
Gold Salts
Cytotoxic agent
most effective for rapidly progressive disease
cannot fix existing damage, prevent more
decrease O2 metabolites production
Suppress Phagocytosis, lysosomal enzyme activity, and histamine release
taken up by macrophages
Gold Salt Toxicity
observed in 1/3 pt, 1/10 have severe symptoms
skin rashes, occasionally severe mouth ulcers proteinuria encephalopathy peripheral neuropathy Hepatitis
Methotrexate (rheumatrex)
First line
Anti-cancer med
cytotoxic immunosuppressant agent
reduce number of immune cells for inflammation response, actively dividing inflammatory cells vulnerable to effects of drug
inhibit enzyme essential for NA synth/cell rep
doses smaller than those for anticancer therapy, for sever rheumatoid arthritis
Methotrexate Toxicity
Bone marrow suppresion Leucopenia,thrombocytopenia,anemia GI toxic Hepatic toxicity Pulmonary fibrosis Renal Dysfunction
Sulfasalazine (Azulfidine)
Second line
Mechanism poorly understood, thought to be scavenger of free radicals
Drug is combo sulfonamide + salicylate, split not 2 In colon
used to treat RA. Ulcer colitis, Inflammatory Bowel disease
Sulfasalazine (Azulfidine) Toxicity
Gi Disturbance
Headache
Reversible drop in Sperm count
Possible anaphylaxis, dyscrasia (unspecified blood disorder)….this possible with other sulfonamides too
Penicillamine (Cuprimine, Depen)
A Chelating agent used in the treatment of poisoning by heavy metals
An analog of cysteine + substances that produced by penicillin hydrolysis
decrease progression of bone destruction
mechanism not clear, suggested the decrease of IL-1 formation and collagen synthesis
Penicillamine Toxicity
Anorexia Nausea Rashes Stomatitis Bone-Marrow disorders
Chelator, so don’t give with gold compounds
Hydroxychloroquine (Plaquenil)
Antimalarial drug
Usually, Well tolerated
Used to treat RA
Hydroxychloroquine (Plaquenil) Mechanism
Depress activity of T-lymphocytes
Decrease leucocytes chemotaxis
Interferes with RNA/DNA synthesis
Hydroxychloroquine (Plaquenil) Toxicity
Headache Tinnitus Arrhythmias Nausea,Vomiting Rashes Possible retina damage = streaks/flashes Eye swelling + color change
All DMARDs are related to….
Severe and Fatal Toxicities
Require monitoring
Danger of mixing DMARDs together, severe kidney damage.
Gold Salts severe toxicity
fatal dermatitis and bone marrow depression
Methotrexate severe toxicity
bone marrow depression and teratogenic fetal damage/abortion
D-Penicillamine severe toxicity
renal damage and aplastic anemia
Hydrochloroquine severe toxicity
dermatitis,bone marrow depression and RETINAL DEGENERATION
Combo Therapy with DMARDs
high toxicity, but used to treat RA
plan is designed rationally,
use non-overlapping toxicities and pharmacokinetics
Biological DMARDs
breakthrough in treatment
engineered recombinant antibodies and other proteins
hard + expensive to make
for patients that don’t respond to other DMARDs
admin with specialist supervision
Immunoglobulin Structure
produced by specific activated B cell against particular antigen, 10^20 antibody molecules in individual
Heavy + Light Chain (H+L) Antigen binding Frag (Fab) Constant region (Fc) N-terminal ends of H/L chain form Ag-binding site Single antibody can bind 2 Ag
Variable region Antibody
Top portion of the Y structure
Constant region Antibody
Bottom portion of the Y structure
Anakinra Dosing
Given daily
Etanercept Dosing
Given once or twice per week.
Abatacept and Golimumab Dosing
Given once monthly
Adalimumab, Certolizumab, Infliximab, Rituximab Dosing
Given every two weeks.
Biopharmaceuticals Therapy Limitations
only given to severely affected patients, when other therapy failed.
~30% don’t respond to them
Discontinued if no benefit seen 2/4 weeks
combo of drugs is more effective
Biopharmaceutical Adverse effects
Precipitate latent infections (Tuberculosis/Hep B)
Encourage opportunistic infections
Provoke onset of psoriasis-like syndrome (Rare)
Hypersensitivity, injection site reactions and mild GI symptoms
Gout is a
genetically determined metabolic disorder characterized by high conc of uric acid in the blood
Chronic Gout causes
Genetic defect = increase purine synthesis
Renal Deficiency (genetic or caused by thiazides)
Lesch-Nyhan Syndrome (Excessive uric acid synthesis)
Acute gout attacks can be provoked by…
Excessive Alcohol consumption, diet rich in purines or kidney disease
Mechanism for Gout Attack
Purines -> Xanthine -> Uric Acid ->Uric Acid Crystals -> Phagocytosis by Neutrophils -> Inflammation Mediators Release -> Lysosomal Enzyme release ->Acute inflammation
Gout Treatment Strategies
Reduce Inflammation (Indomethacin/ Colchicine)
reduce conversion of purines to uric acid (Allopurinol)
Increase uric acid excretion (Probenecid,Sulfinpyrazone)
Colchicine (Colchrys)
Plant alkaloid, reserved for acute gout attacks
Mitotic Poison
can be used to treat Mediterranean fever
Colchicine Mechanism
Selective inhibitor of microtubule assembly, bind to tubulin
Disrupts mobility of granulocytes into affected area
blocks cell division by binding mitotic spindles
reduces production of Leukotrienes (LTB4)/ Reduce inflammation
Mediterranean fever
Fever, Hepatitis, peritonitis, arthritis
Colchicine Toxicity
Nausea/Vomiting/Abdominal Pain/ Sever Diarrhea
Possible sever liver/kidney damage
- Not to be used during pregnancy *
Fatal dose as little as 8mg in 24hrs, close monitoring
IV no longer approved
Allopurinol (Zyloprim)
1st line agent for chronic gout treatment
not effective in acute attack
Purine Analog
Allopurinol Mechanism
Competitive inhibits last two steps in uric acid biosynthesis
Inhibit Xanthine Oxidase
Decrease uric acid conc, precipitation of uric acid crystals in joints and tissues
- Selective in humans but can severely impair purine metabolism in some protozoa*
Allopurinol Toxicity
Well tolerated in most patients, oral admin
skin rashes in 3% of patients
Bone marrow depression
Hepatic Toxicity and Nephrotoxicity
** Rare peripheral neuritis/ vasculitis, very rare bind to lens resulting in cataracts **
Uricosuric Agent
Reduce inflammation
Block proximal tubule reabsorption of uric acid
Uricosuric agents are organic acids - increase uric acid secretion
Uricosuric Agents examples
Probenecid (Generic)
Sulfinpyrazone (Anturane)
Uricosuric Agent Toxicity (of the 2 examples)
Both agents similar toxicity
rarely aplastic anemia
Gi irritation more active (sulfinpyrazone)
Nephrotic syndrome mostly (probenecid)
Probenecid (Generic)
blocks kidney tubule secretion of penicillin
was developed to prolong penicillin level in blood
used occasionally to increase antibiotic conc
