Pashikanti | Medicinal Biochemistry

NSAIDs offer what type of relief in rheumatoid arthritis?

symptomatic relief

this means they don’t stop the progression of disease

What is the pathophysiology of RA?

caused by activation of T cells —> release pro-inflammatory cytokines = cartilage damage

What are the pro-inflammatory cytokines?

TNF-alpha

interleukins

what are characteristics of rheumatoid arthritis?

chronic inflammation

build up of fluid

pannus

cutaneous or subcutaneous nodular lesions

destruction of articular cartilage

ankylosis

what is pannus?

fibrous tissue in the synovial cavity/joint

what is ankylosis?

fusion/abnormal adhesion of bones in joints

How do DMARDs slow progression of RA?

inhibit TNF-alpha

inhibit interleukins

inhibit purine, pyrimidine metabolism/synthesis

How do glucocorticoids work in RA?

interfere with synthesis and actions of cytokines such as IL and TNF-alpha

inhibit expression of COX-2

Inhibit prostaglandins

What does the activation of TNF receptor?

induces the production of cytokines, prostaglandins and other inflammatory mediators

____ is expressed in cells of many tissues while ____ is expressed only in immunes cells

TNF-R1

TNF-R2

What are TNF-alpha inhibitors?

adalimumab (humira)

infliximab (remicade)

Golimumab (simponi)

certolizumab pegol (cimzia)

etanercept (enbrel)

What is the MOA of adalimumab?

TNF-alpha monoclonal antibody

complexes w/ TNFa, and prevents interactions w/ cell surface receptors

IL1 are produced in response to what?

inflammatory stimuli

what is the effect of IL1?

induces bone resorption and cartilage destruction

what enzymes destroy tissue?

matrix metalloproteases

a disintegrin and metalloproteases

what is IL1Ra?

an endogenous antagonist that prevents IL1 from activating IL1R

MOA of anakinra (kineret)

recombinant human IL1R

effectively prevents IL1 from binding IL1-R

Where is IL6 produced?

mainly by macrophages and T cells

what are the effects of IL6?

pro-inflammatory effects

Activate JAK/STAT pathway

activates NF-kB pathway (cause bone resorption)

MOA of toxilizumab (actemra)

humanized monoclonal antibody raised against IL6 receptor

-prevent IL6 from binding

T/F

tocilizumab prevents IL6 from binding both membrane-bound and soluble IL6 receptors

true

What are the effects of actemra stopping IL-6 signaling

decreases acute phase-reactants (CRP, ESR)

lowers hepcidin production

reduces B-cell activation

improves profiles of bone and cartilage turnover makers

inhibits differentiation of T-helper cells

Reduces bone resorption and cartilage turnover

increase Hb

decreases RF

MOA of methotrexate

unclear

binds w/ high affinity to catalytic site of dihydrofolate reductase

inhibits DHFR, inhibits purine synthesis and inhibits synthesis of RNA, DNA, proteins

What are the effects of methotrexate inhibiting 5-aminoimidazole-4-carboxamide ribonucleotide transformylase (AICART)?

the inhibitions leads to an increase of extracellular levels of adenosine which leads to increased cAMP (has anti-inflammatory effects)

cause apoptosis in activated T-cells

inhibit pro-inflammatory cytokines

What is the MOA of azathioprine (azasan)?

inhibits purine synthesis

suppresses lymphocyte proliferation

inhibits immunoglobulin production

MOA of leflunomide

inhibits pyrimidine synthesis

inhibits T-cell proliferation

inhibits production of autoantibodies by B-Cells

what does the metabolite of leflunomide inhbit?

dihydrooroate dehydrogenase

MOA of abatacept (orencia)

bind to CD80 or CD86 on APC to prevent T-helper cells from becoming activated

MOA of cyclosporine

inhibits IL1 and IL2 receptor production

MOA of rituximab (rituxan)

Monoclonal antibody that binds B-Cells

induces apoptosis and reduces inflammation

MOA of cyclophosphamide

cross-links DNA to prevent cell replication

suppresses T-/B-cell function

MOA of glucosamine

this a a major component of joint cartilage and may be help to prevent cartilage damage

T/F

Glucosamine is FDA approved

false, we have no date to support this

MOA of chloroquine, hydroxychloroquine

suppress the immune system by inhabiting toll-like receptors

What drugs do we use in Gout?

NSAIDS, corticosteroids

colchicine

uricosuric drugs

allopurinol

febuxostat

MOA of colchicine

prevent polymerization of tubulin

inhibits mitosis

inhibits deposition of uric acid crystals

T/F

colchicine has a low therapeutic index

true, we can have colchicine poisoning

Colchicine is a ____ form autumn crocus

an alkaloid derived from autumn crocus

What are uricosuric drugs?

probenecid (probalan)

sulfinpyrazone

MOA of uricosuric drugs

increase the excretion of urine

MOA of allopurinol

inhibits xanthine oxidase (this turns xanthine oxidized to uric acid)

ADRs of allopurinol

fever, rash, hepatitis, SJS