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Pharmacology > DMARDs > Flashcards

DMARDs Flashcards

1
Q

first line therapy for RA

A

methotrexate if preferred, NSAIDs for rapid symptom relief, important to start DMARDs immediately to avoid permanent joint damage.

combination therapy for patient who do not reach remission within 3 to 6 months

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2
Q

glucocorticoids - chemistry

A

lipophilic and well absorbed from GI tract, hepatic metabolism to active component

mimics the actions of endogenous cortisol

intracellular receptor - induces transcription - causes transrepression of inflammatory genes

drug use leads to feedback inhibition of the HPA axis which decreases the release of cortisol. Abrupt cessation of glucocorticoids can cause a cortisol deficit

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3
Q

cortisol- effects

A

maintain metabolic homeostasis: carbs, protein, lipid metabolism and electrolyte balance

cardiovascular, skeletal muscle and CNS effects

suppression of the immune system - inhbits PG and leukotriene synthesis, reduces macrophage activity, reduce numbers of circulating WBC and inhibition of neutrophil release of collagenase and lysosomal enzymes

certain hormones only work in the presence of cortisol

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4
Q

Glucocorticoid use in RA

A

bridging therapy - low-dose for immediate symptom control while waiting for the effects of DMARDs

intra-articular therapy - injection into joint, limited to few joints. used for management of acute exacerbation of RA and control of extra-articular manifestations.

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5
Q

general effects of glucocorticoid therapy

A

pallative - not curative or specific

dosing is trial and error, start large and taper down until minimally effective dose is achieved

duration is administration influences toxicity, dosing accumulates

In life-threatening disease - large dose with tapering

exhibits withdrawal

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6
Q

Glucocorticoids adverse effects

A

dose dependent - cumulative

hypertension, hyperglycemia, central obesity with cervical fatpad and moon face with erythema

skeletal muslce wasting and thin fragile skin

menstrual irregularties and hirsiutism

increased ocular pressure -> cataracts

causes growth retardation in children

osteoporosis

euphoria or depression

increased risk of infection and impaired wound healing

peptic ulcers

(CUSHING)

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7
Q

what are the complications of abrupt glucocorticoid withdrawal?

A

abrupt adrenal insufficiency - severe abdominal pains, vomiting, diarrhea, profound muscle weakness, hypotension, hyponatremia, hyperkalemia and shock

shock leads to death

disease flare ups

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8
Q

General charateristics of DMARDs

A

They have little anti-inflammatory or analegesic effects

clinical benefit is delayed for weeks to months

serology titers decrease with treatment (RF, CRP, ESR)

Retards the development of bone erosion

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9
Q

Methotrexate - PK

A

folate antimetabolite - used for anticancer and in smaller doses RA - can be given orally for RA

50% protein binding with narrow therapeutic window

polyglutamated within cell into active form then renally excreted

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10
Q

Methotrexate - mech of effect

A

DHFR inhibition - blocks DNA/RNA synthesis

TYMS inhibition - blocks formation of thimydylate which impairs DNA synthesis and repair

AICAR formyl transferase inhibition - accumulation of AICAR. AICAR inhibits adenosine and AMP deaminases - produces antiinflammatory affect mediation by of adenosine

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11
Q

Methotrexate anti-inflammatory affects

A

suppression of neutrophils, macrophages, DCs, lymphocytes and PMN chemotaxis

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12
Q

Methotrexate antiproliferation

A

direct inhibitory effect on proliferation, stimulation of apoptosis, inhibits pro-inflammatory cytokines linked to rheumatoid synovitis

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13
Q

methotraxate therapy in RA

A

oral - once weekly

long term efficacy

toxicites are well understood and managed

combination with other agents increase efficacy

approved for idiopathic juvenile arthritis

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14
Q

methotraxate adverse effects

A

GI toxic - hepatotoxicity: can be reduced with folate rescue

bone marrow toxicitiy

nephrotoxicity

lymphomas

pneomonitis

dermatologic

phototoxicity

opportunistic infection

infertility and menstrual irregulatities

contraindicated in pregnancy or breast feeding

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15
Q

folate rescue

A

taken once daily to reduce incidence of GI and liver function abnormalities

not working? leucovorin, weekly (5,10-MTFH)

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16
Q

methotraxate drug interactions

A

inhibitors of OAT and p-GP increases MTX concentration

OAT - NSAIDS, aspirin, penecillins, sulfonamindes, probenecid

p-GP - cyclosporine

plasma protein binding drugs displace MTX and increase free MTX

all increasing risk of toxicitie

warfarin - increased risk of bleeding

leflunomide and azathioprine - additive - hepatotoxicity

17
Q

Sulfasalazine

A

azo-linked and cleaved -> sulfapyridine + 5-aminosalicylic acid

sulfapyridine is the active form in RA

metabolism is rate dependent on N-acetyltransferase

sulfonamides displace MTX

onset: 6 weeks – 3 months

MOA is unknown but supresses T cells, inhibits B cell proliferation, inhibits release of cytokine release and decreases formation of RF

higher efficacy in combination therapy but can be used alone if patients done tolerate MTX

SAFE IN PREGNANCY

approved for juvenile idiopathic arthritis

18
Q

Sulfasalazine - AEs

A

common - headache, GI effects and rash, folate def. reversible infertility

hemolytic anemia in G6PD def patients

stevens-johnson syndrome - toxis epidermal necrolysis in predisposed individuals

hepatotoxicity, agranulocytosis, neutropenia, pulmonary toxicity and hypersensitivity reactions

discontinues at first sign of rash or severe side effects

19
Q

Sulfasalazine Drug Interactions

A

plasma protein binding - competes

additive effects - dermatological, hepatotoxicity, blood dyscrasias and pulmonary toxicity

mesalamine - can interfere with absorption of digotoxin, increased risk of bruising or bleeding when given with heparin

20
Q

Hydroxychloroquine

A

rapidly absorbed from GI tract, high volume of distribution - especially in melanin-containing tissues

hepatic metabolism - nonCYP

30-50 day half life, onset 6 weeks – 3 months

concentrates inside acidic vesicles, lysosomes, increases pH and disrupts T cell function.

decreases leukocyte chemotaxis, inhibits DNA and RNA synthesis

combination therapy

21
Q

Hydroxychloroquine - adverse effects

A

common - GI: nausea, vomiting, cramping and diarrhea, headache and lightheadedness

serious - skin reactions, psychosis, seizures. myopathy, retinal damage

retinopathy is irreversible and requires ophthalmic monitoring, corneal deposits is reversible

22
Q

Hydroxychloroquine and pregnancy

A

considered safe at recommended doses

inters breast milk

contraindicated in children

23
Q

Leflunomide

A

prodrug similar to MTX, metabolite enters enterohepatic circulation which causes a longer half life

high protein binding

18 day half life - can be longer, takes 4 to 8 weeks to be effective

competitive inhibitor of dihydroorate dehydranase - inhibits pyrimidine synthesis

not approved for use in children or pregnancy, excreted in breast milk

24
Q

Leflunomide - effects in RA

A

inihbits T cell proliferation
interfers with DC function
reduces production of autoantibodies
inhbits leukocyte adhesion to endothelium
decreased synovial infiltration by lymphocytes
blocks NF-kB

used for people who do not respond to MTX and are not eligible for other Rx

25
Q

Leflunomide - toxicities

A

fulminant liver failure, hepatic necrosis and cirrhosis

diarrhea and nausea

bone marrow suppression - pancytopenia, agranulocytosis, thrombocytopenia

concurrent use with MTX or other immunosuppressants increases risk

increased risk of lymphoma

increased risk of infection

steven-johnson syndrome

26
Q

remedy for severe Leflunomide toxicity

A

cholestrramine will sequester in the gut for more rapid elimination

27
Q

Leflunomide - drug interactions

A

with any drug which also causes these toxicities :

Hepatotoxicity
Myelosuppression
Immunosuppression
Pulmonary toxicity
Peripheral neuropathy
Skin reactions

inhibits CYP2C9

28
Q

Class Properties of Targeted Immunosuppressants

A

given paraentally - IV and SubQ

tofacinitinib - oral

Target specific mediators of inflammation or receptors

used with non-biologic DMARDs but not together

adverse effects - myelosuppression; hepatic injury; lupuslike
syndrome; hypertension, heart failure; immunological
reactions

immunization before administration

screen for TB, HBV, HCV, PML

excretion in breast milk

29
Q

Infliximab

A

Chimeric Monoclonal Antibody

Binds to both soluble and membrane-bound TNFα preventing the cytokine from binding to its receptor

IV - every 8 weeks

uses - Rheumatoid arthritis, psoriatic arthritis, active alkylosing spondylitis, Crohn’s disease, plaque psoriasis, JIA in children ≥ 4yo

HBV / TB reactivation, hypersensitivity - IR can be mouse portion of drug, infection, hepatic toxic

30
Q

Etanercept

A

Fusion Protein - Binds to soluble TNFα preventing the cytokine from binding to its receptor

RA - SubQ 1-2x weekly, uses - Rheumatoid arthritis, psoriatic arthritis, active alkylosing spondylitis,
plaque psoriasis, JIA in children ≥ 2yo

AE - infection, HBV/TB reactivation, injection site reaction, hypersensitivity

31
Q

Abatacept

A

fusion protein CTLA-4 to IgG

blocks costimulatory action → inhibits T cell activation

used for RA w or w/o MTX and for JIA in children

AE - typical of class (adverse effects - myelosuppression; hepatic injury; lupuslike
syndrome; hypertension, heart failure; immunological reactions)

32
Q

Rituximab

A

Depletes CD20+ B cells

IV infusion, 24 weeks, half life 18 days

use - CD20+ B cell lymphomas, autoimmune diseases, RA

AE - Infusion/hypersensitivity reactions; rash; hypo- or hypertension; arrhythmia; reactivation of HBV infection; PML

not for pregnancy or children

33
Q

Tocilizumab

A

Inhibition of IL-6 receptor

I.V. q4 weeks; t½terminal up to 13 days

use - RA treatment as monotherapy or combined with methotrexate Adults and JIA in children ≥ 2yo

AE - infection risk, neutropenia, thrombocytopenia, increased liver enzymes, increased LDL and GI perforation

34
Q

Anakinra

A

IL-1 receptor antagonist

SubQ times daily, half-life 4 to 6 hours

downregulates inflammatory response

uses - RA, JIA, neonatal-onset multisystem inflammatory disease, mediterranean fever, gout, pericarditis

AE - typical of class

35
Q

TOFACITINIB

A

oral JAK3 enzyme inhibitor

moderate protein binding and hapatic metabolism CYP 3A4 and C19

AE - Lymphocytopenia and neutropenia; gastrointestinal perforation; hepatotoxicity; lipid abnormalities

CYP mediated and biologics drug interactions

inhibition prevents - intracellular activity of immune cells, reduction of NK cells, serum IgG, IgM, IgA and CRP and increased B cells.

36
Q

Rx RA during pregnancy

A

Low-dose glucocorticoid

Hydroxychloroquine and sulfasalazine

Pharmacology (23 decks)

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