The document outlines the contributions of team members to a project on disease-modifying antirheumatic drugs (DMARDs) used to treat rheumatoid arthritis. It assigns team members to discuss specific DMARDs and other drug classes. It will cover D-penicillamine, azathioprine, antimalarials, sodium aurothiomalate, corticosteroids, NSAIDs, celecoxib, rituximab, abatacept, TNF-alpha antagonists, and provide a summary. The toxicity profiles, particularly renal and hepatic toxicity, of several DMARDs will be discussed including D-penicillamine, cyclosporine, azathioprine, methotrexate,
4. DMARDS
• DMARDs are fundamental to arresting the disease process in RA and
other inflammatory arthritis. While early initiation of therapy is
essential to arrest RA, sustained use is vital if disease suppression is to
be maintained, and so these drugs may be used for an unlimited period.
Prolonged therapy requires long-term monitoring for toxicity and
safety profile. Monitoring will also contribute to assessing activity of
the underlying disease.
5. THE RENAL TOXICITY OF DMARDS
• The renal toxicity of DMARDs varies widely. Cyclosporine, gold, and
D-penicillamine all have a serious potential for renal side effects,
particularly in the elderly or in patients with compromised renal
function. Concomitant use of nonsteroidal anti-inflammatory drugs
(NSAIDs) increases the potential for renal damage. In contrast,
methotrexate, azathioprine, antimalarial, sulfasalazine, leflunomide,
etanercept, and infliximab have relatively little renal toxicity.
6. SIGNIFICANT RENAL TOXICITY
•D-penicillamine
•Indications: (Licensed) RA and Wilson’s disease
•Caution: Renal impairment, concomitant nephrotoxic
drugs including gold treatment.
•Contraindications: Renal impairment (moderate to severe).
7. D-PENICILLAMINE
•Mechanism of action:
•Unknown, but it is a Chelating agent that decreases B-
cell function and reduces T-cell proliferation. The high
prevalence of toxic side has limited its use. The most
common adverse events associated are rash and
stomatitis
8. D-PENICILLAMINE
•The most common renal side effect
•Proteinuria, with a reported prevalence of 7% to 18%
typically develops within 6 to 12 months after
beginning of the treatment), may be dose-related, and
may develop into nephrotic syndrome.
9. D-PENICILLAMINE
• In most cases, proteinuria resolves spontaneously on cessation of
penicillamine; however, persistence of proteinuria for up to 1 year after
discontinuing therapy has been reported. Patients with a history of toxic
reactions to gold have been shown to have a significantly greater chance of
developing toxicity to penicillamine if the interval between the two therapies is
less than 6 months. As a chelating agent, penicillamine may mobilize stored
gold from tissues. Alternately, patients could develop cross-reactivity to the
thiol derivatives common to both drugs.
10. D-PENICILLAMINE
• The renal lesions at the electron microscopic level, consist of electron-
dense deposits in the basement membrane of renal capillaries and
fusion of epithelial cell processes. Immune complex injury, manifested
by the presence of IgG and complement deposition in the basement
membrane, was associated with the electron-dense deposits. Structural
damage as assessed by biopsy persists up to 1 year after cessation of
penicillamine.
11. D-PENICILLAMINE
•Close observation of patients who develop
proteinuria during penicillamine therapy is
essential because proteinuria may be a first sign of
more serious renal complications (e.g., nephrotic
syndrome). If the proteinuria is persistent,
penicillamine should be discontinued.
12. D-PENICILLAMINE
• Close observation of patients who develop proteinuria during
penicillamine therapy is essential because proteinuria may be a first
sign of more serious renal complications (e.g., nephrotic syndrome). If
the proteinuria is persistent, penicillamine should be discontinued.
13. CYCLOSPORINE
• USES
• Cyclosporine, used originally to prevent the rejection of transplanted
kidneys, continues to be recommended for a variety of organ transplants.
• However, it has proven effective in treating people with rheumatoid
arthritis who have not responded well to other medications & it can be
used in combination with methotrexate in rheumatoid arthritis patients
who do not respond adequately to methotrexate alone.
14. CYCLOSPORINE
•Mechanism of action:
•Cyclosporine inhibits a group of cells, known as
T-lymphocytes, which are important in the
immune system and contribute to the development
of "autoimmune" diseases, such as rheumatoid
arthritis and lupus.
16. CYCLOSPORINE
• Nephrotoxicity:
• Renal dysfunction including structural kidney damage is a potential
consequence of cyclosporine and therefore renal function must be monitored
during therapy. Care should be taken in using cyclosporine with nephrotoxic
drugs, so patients require frequent monitoring of serum creatinine. An
increase in serum creatinine and BUN may occur during therapy and reflect a
reduction in the glomerular filtration rate. The frequency and severity of
serum creatinine elevations increase with dose and duration of cyclosporine
therapy. These elevations are likely to become more pronounced without dose
reduction or discontinuation.
18. MINIMAL RENAL TOXICITY
PLUS HEPATIC TOXICITY
• Azathioprine
• Indications:
• (Licensed) RA, dermatomyositis and polymyositis, autoimmune and
chronic active hepatitis, pemphigus vulgaris.
• (Unlicensed) Vasculitis, such as polyarthritis and giant cell arteritis and
systemic lupus erythematosus, psoriasis and psoriatic arthritis, severe
eczema, bullous dermatoses including pemphigoid, inflammatory bowel
diseases, such as ulcerative colitis and Cohn's disease.
20. AZATHIOPRINE
•Mechanism of action:
• Azathioprine is a purine analog that interferes with the synthesis
of adenine and guanine. Azathioprine suppresses T-lymphocyte
function, decreases immunoglobulin synthesis, and reduces IL-2
secretion.
• Hematologic or gastrointestinal adverse events or infections.
Azathioprine was shown to be as effective as penicillamine but less
effective than Methotrexate and sulfasalazine.
21. CYCLOPHOSPHAMIDE (CYTOXAN®)
•Class: Antineoplastics, Alkylating; DMARDs,
Immunomodulators
•Mechanism of Action
• As an alkylating agent, the mechanism of action of the
active metabolites (4-hydroxycyclophosphamide ) may
involve cross-linking of DNA, which may interfere
with growth of normal and neoplastic cells.
22. ANTIMALARIAL
•Because of their safety and ease of use, the antimalarial
drugs hydroxychloroquine and chloroquine are frequently
drugs of choice for early RA therapy.
•Indications: (Licensed) RA, connective tissue diseases
(systemic and discoid lupus) and some photosensitive
dermatological conditions
23. ANTIMALARIAL
• Caution: Patients with renal and liver impairment.
• Mechanism of action:
• The antimalarial are thought to inhibit processing and presentation of
antigen to T cells by increasing pH within intracellular vacuoles. Making
the interior of the vacuoles more alkaline prevents degradation of foreign
protein into antigens and impedes interactions between autoantigens and
major histocompatibility complex proteins. Both actions may interfere
with antigen recognition by the T-helper cell
24. ANTIMALARIAL
• Because up to 40% of a dose of hydroxychloroquine is excreted
unchanged in the urine, patients with abnormal renal function may
have an increased risk of retinal damage attributable to overdosing.
Although considered safe, antimalarial were reported to cause a
significant decrease in renal function. The use of chloroquine should
be restricted in elderly patients and in patients with compromised
renal function.
25. LEFLUNOMIDE
• Mechanism of action
• Leflunomide is an isoxazol derivative converted by first-pass metabolism in the liver and
gut to an active metabolite, A77 1726. In the dose range used in RA therapy (#20
mg/day), A77 1726 blocks de novo synthesis of pyrimidines by inhibiting dihydroorotate
dehydrogenase, the rate-limiting enzyme in pyrimidine production (60,61). After
stimulation, CD41 T cells proliferate rapidly, a process that requires an expansion of the
pyrimidine nucleotide pool within lymphocytes by 8- to 16-fold to support synthesis of
new DNA . Down-regulation of pyrimidine synthesis inhibits new DNA formation and
proliferation of T cells, a process that is thought to be important in the development of
the autoimmunity of RA.
27. LEFLUNOMIDE
•Dosing: Renal Impairment
•No specific dosage adjustment is recommended. There
is no clinical experience in the use of leflunomide in
patients with renal impairment. The free fraction of
M1 is doubled in dialysis patients. Patients should be
monitored closely for adverse effects requiring dosage
adjustment
28. LEFLUNOMIDE
•Dosing: Hepatic Impairment
•Not recommended for use in patients with pre-existing
liver disease or in patients with significant hepatic
impairment (ALT >2 times ULN). Patients should have
LFTs monitored closely. Discontinue leflunomide if ALT
>3 times ULN
29. LEFLUNOMIDE
• Drug elimination procedure: To achieve nondetectable serum
concentrations (<0.02 mg/L) of (M1) administer the following:
• Cholestyramine: 8 g administered 3 times/day for 11 days. Verify serum
concentrations by 2 separate tests ≥14 days apart. If plasma concentrations
are still high, additional cholestyramine treatment may be considered.
• Activated charcoal: 50 g every 6 hours for 24 hours was shown to decrease
plasma concentrations of M1 by 37% in 24 hours and 48% in 48 hours
30. METHOTREXATE
•Mechanism of Action
•Methotrexate is a folate antimetabolite It is
irreversibly binds to and inhibits dihydrofolate
reductase, inhibiting the formation of reduced folates,
and thymidylate synthetase, resulting in inhibition of
purine and thymidylic acid synthesis, thus interfering
with DNA synthesis, repair, and cellular replication.
31. METHOTREXATE
• Renal Dose Adjustments
• Avoid the use of methotrexate in patients with CrCl less than 10 mL/min.
CrCl greater than or equal to 10 less than 50 mL/min: Administer at 30%
to 50% the recommended dose.
CrCl greater than or equal to 50 less than 60 mL/min: Administer at 70%
the recommended dose.
CrCl greater than or equal to 60 less than 80 mL/min: Administer at 75%
the recommended dose.
32. METHOTREXATE
• Side effect of methotrexate
• Hepatic side effects: including hepatotoxicity, acute hepatitis, chronic fibrosis and
cirrhosis, decrease in serum albumin, and liver enzyme elevations have been reported.
• Methotrexate can cause acute elevations of liver function tests (elevated serum
transaminases in 15% of patients with rheumatoid arthritis (RA) on low-dose therapy)
or chronic hepatotoxicity (fibrosis and cirrhosis).
• Chronic hepatotoxicity typically develops only after chronic use of higher doses (2 years
or more of total doses of 1.5 grams or more), is more likely in patients who ingest
ethanol, who are aged, who are obese, who have chronic renal insufficiency, or who
have diabetes.
33. METHOTREXATE
• Side effect of methotrexate
• Renal side effects At low doses, MTX is not nephrotoxic. However, high dose MTX can affect the
kidneys in two different ways:
1. MTX can precipitate in the tubules and directly induce tubular injury. The risk is increased in the
presence of acidic urine (since MTX and its two major metabolites are poorly soluble at an acid
pH), with volume depletion and when high plasma MTX concentrations are sustained.
2. MTX also causes a transient decline in glomerular filtration rate (GFR) after each dose, with
complete recovery within six to eight hours.
• The mechanism involves afferent arteriolar constriction or mesangial cell constriction.
• The effect can be exacerbated when additional nephrotoxic drugs are administered.
34. SODIUM AUROTHIOMALATE
•Indications:
• (Licensed) RA, juvenile idiopathic arthritis.
• (Unlicensed) skin diseases including pemphigus.
•Caution: renal or hepatic impairment (moderate)
•Contraindications: Severe renal or hepatic impairment.
35. Mycophenolate mofetil (MMF
• Mechanism of action
• Mycophenolate mofetil (MMF, CellCept(R)) is a prodrug of mycophenolic
acid (MPA), an inhibitor of inosine monophosphate dehydrogenase
(IMPDH).
• MPA is a fivefold more potent inhibitor of the type II isoform of IMPDH,
which is expressed in activated lymphocytes, than of the type I isoform of
IMPDH, which is expressed in most cell types. MPA has therefore a more
potent cytostatic effect on lymphocytes than on other cell types.
• This is the principal mechanism by which MPA exerts
immunosuppressive effects.
37. Mycophenolate mofetil (MMF
• Dosing Modifications
• Renal impairment
• MMF: In severe renal impairment (glomerular filtration rate [GFR] <25
mL/min/1.73 m²), not to exceed 1 g q12hr
• Multiple dosing of mycophenolate mofetil in patients with severe chronic
renal impairment has not been studied
• No dosage adjustment needed in renal transplant patients experiencing
delayed graft function postoperatively
• The pharmacokinetics of mycophenolate mofetil are not altered by
hemodialysis.
38. Mycophenolate mofetil (MMF
•Dosing Modifications
•Hepatic Insufficiency
• hepatic MPA glucuronidation processes appeared to be relatively
unaffected by hepatic parenchymal disease
• Effects of hepatic disease on this process probably depend on the
particular disease. Hepatic disease with other etiologies, such as
primary biliary cirrhosis, may show a different effect.
• patients with severe hepatic impairment (aminopyrine breath test
less than 0.2% of dose) due to alcoholic cirrhosis, MMF was
rapidly converted to MPA.
40. SULFASALAZINE
• Usually used in conjunction with analgesic and/or NSAIA therapy, at
least until the beneficial effects of sulfasalazine are apparent.
• Administration of sulfasalazine alone is not a complete treatment for
rheumatoid arthritis, and the drug only should be used as one part of a
comprehensive treatment program, including non-drug therapies such
as rest and physical therapy.
41. SULFASALAZINE
• Mechanism of action
• Sulfasalazine inhibits inflammation by decreasing production of
cyclooxygenase and lipoxygenase pathway products, by inhibiting
inflammatory cytokines, and by interfer-ing with second-
messenger–mediated cellular activation
• Dose:
• Dosing in Hepatic & Renal Impairment : There are no dosage
adjustments provided in manufacturer's labeling; use with
extreme caution
42. SULFASALAZINE
• Hepatic & Renal Impairment :
• Hepatic impairment: Hepatic failure*, hepatitis fulminant*, hepatitis,
jaundice*, hepatitis cholestatic*, cholestasis*.
• Renal impairment: Proteinuria, hematuria, crystalluria, nephrotic
syndrome, interstitial nephritis, nephrolithiasis*.
• Adequate fluid intake must be maintained during sulfasalazine therapy to
reduce the risk of crystalluria and stone formation.
• In case of severe renal failure (GFR <10ml/min) do not use.
43. SULFASALAZINE
•Fatalities related to renal and liver damage have been
reported in patients receiving the drug.
•An increased incidence of adverse effects has been
reported in patients receiving sulfasalazine daily
dosages of 4 g or more or those with serum total
sulfapyridine concentrations exceeding 50 mcg/mL.
44. CORTICOSTEROIDS
• Medications, such as prednisone, may be used until a DMARD takes
effect to control symptoms of JA or to prevent complications,. They may
be administered by mouth or by injection directly into a joint. When
taking oral corticosteroids, it is important not to stop taking them too
quickly because taking the drugs more than a couple of weeks can
cause your adrenal glands to slow or even stop their own cortisol
production. Thus, stopping quickly could lead to a dangerous cortisol
deficiency. Gradually decreasing, or tapering, the dosage, however,
gives your own adrenal glands time to resume their normal function.
45. CORTICOSTEROIDS
•Prednisone is a synthetic, intermediate-acting
glucocorticoid that is widely used in the therapy of severe
inflammation, autoimmune conditions, hypersensitivity
reactions and organ rejection. Prednisone is converted to
prednisolone, its active form, in the liver.
46. CORTICOSTEROIDS
•Methylprednisolone is a synthetic, intermediate-
acting glucocorticoid that widely used in the
therapy of severe inflammation, autoimmune
conditions, hypersensitivity reactions and organ
rejection.
48. NON-STEROIDAL ANTI-
INFLAMMATORY DRUGS (NSAIDS)
• Commonly used NSAIDs include ibuprofen, naproxen, ketoprofen and diclofenac.
• Hepatotoxicity. hepatotoxic reactions need to be considered when prescribing NSAIDs.
Overall, the incidence of liver disorders attributable to NSAIDs has been estimated at
approximately 5 per 100 000 persons/ year, and there appears to be a clinically relevant
difference among individual drugs in hepatotoxic potential
• Renal Adverse Events. NSAID administration has been associated with the occurrence of
renal adverse events including fluid and electrolyte disturbances, tubulointerstitial
nephritis, papillary necrosis, glomerular lesions and acute renal failure. Up to 5% of
patients may experience renal adverse events as a consequence of NSAID treatment
49. NON-STEROIDAL ANTI-
INFLAMMATORY DRUGS (NSAIDS)
• Dosing Modifications
• a- Ibuprofen
• Significantly impaired renal function: Monitor closely; consider reduced dosage if
warranted
• Severe hepatic impairment: Avoid use
• b-Naproxen: CrCl <30 mL/min: Use not recommended
• c-Diclofenac: Use caution in hepatic disease & renal impairment
• d-Ketoprofen: Use caution in hepatic disease & renal impairment
50. SELECTIVE COX-2 INHIBITOR
• Celecoxib
• No steroidal Anti-inflammatory Drug (NSAID), COX-2 Selective
• Dosing: Renal Impairment
• Advanced renal disease: Use is not recommended; however, if Celecoxib
treatment cannot be avoided, monitor renal function closely.
• Severe renal insufficiency: Use is not recommended
• Abnormal renal function tests (persistent or worsening): Discontinue use.
51. SELECTIVE COX-2 INHIBITOR
•Celecoxib
• Dosing: Hepatic Impairment
• Moderate hepatic impairment : Reduce dose by 50%.
• Severe hepatic impairment : Use is not recommended.
• Abnormal liver function tests (persistent or worsening):
Discontinue use.
52. ABATACEPT
•Abatacept is currently approved for use in people with
rheumatoid arthritis who have had an inadequate response
to one or more DMARDs. It is useful in delaying the
progression of structural damage and reducing symptoms
of rheumatoid arthritis. However, it should not be used in
combination with anakinra or TNF antagonists
53. ABATACEPT
• Mechanism of action:
• Abatacept is a selective co-stimulation modulator as it inhibits the
costimulation of T cells. for the treatment of rheumatoid arthritis.
•Uses in renal patients:
• Abatacept is identified as the first personaized,targeted treatment
for kidney disease, and specifically for FSGS(focal segmental
glomerulosclerosis)
54. RITUXIMAB
• Mechanism of action:
• Rituximab, a monoclonal antibody directed against the CD20 molecule found on pre-B cells
and mature B cells (but not on plasma cells), was introduced in the late 1990s. Recently, this
antibody has been used to treat autoimmune diseases, especially those associated with a
prominent humoral component and with potentially pathogenic autoantibodies. Rituximab has
also been utilized in the transplant setting, to diminish levels of alloreactive antibodies in
highly sensitized patients, to manage ABO-incompatible transplants, and to treat rejection
associated with B cells and antibodies. A role for rituximab in depleting B cells and
compromising their antigen-presenting function seems likely; rituximab might also inhibit T-
cell activation. A synergistic effect has been noted in vitro following administration of
corticosteroids to B-cell lines, with accentuation of B-cell cytotoxicity; this observation might
be relevant to certain studies, as some regimens have utilized both agents simultaneously.
55. RITUXIMAB
Do not use if :
•if you have a history of hepatitis B, hepatitis C, or other
viral infections (e.g., chickenpox, cytomegalovirus,
herpes, JC virus, parvovirus, shingles, West Nile virus);
an autoimmune disorder (e.g., lupus).
•if you have a history of kidney, liver.
56. RITUXIMAB
• Serious Side Effects
Hepatic side effects including hepatitis B virus reactivation with fulminant
hepatitis, hepatic failure, and death have been reported in some patients with
hematologic malignancies treated with rituximab.
Renal side effects have included tumor lysis syndrome (TLS) (0.04% to 0.05%)
within the first 12 to 24 hours following the first rituximab infusion. TLS is
characterized by a rapid reduction in tumor volume and includes renal
insufficiency, hyperkalemia, hypocalcaemia, hyperuricemia, or
hyperphosphatemia.
57. TNF-Α ANTAGONISTS
INFLIXIMAB, ETANERCEPT,
ADALIMUMAB, CERTOLIZUMAB,
GOLIMUMAB
• Hepatotoxicity
• Severe hepatic reactions, including acute liver failure, jaundice, hepatitis and cholestasis, have been reported
rarely in post marketing data in patients receiving REMICADE®. Autoimmune hepatitis has been diagnosed in
some of these cases. Severe hepatic reactions occurred between 2 weeks to more than 1 year after initiation of
REMICADE®; elevations in hepatic aminotransferase levels were not noted prior to discovery of the liver injury
in many of these cases. Some of these cases were fatal or necessitated liver transplantation. Patients with
symptoms or signs of liver dysfunction should be evaluated for evidence of liver injury. If jaundice and/or
marked liver enzyme elevations (e.g., ≥ 5 times the upper limit of normal) develop, REMICADE® should be
discontinued, and a thorough investigation of the abnormality should be undertaken. In clinical trials, mild or
moderate elevations of ALT and AST have been observed in patients receiving REMICADE® without progression
to severe hepatic injury
63. CONCLUSION
• The incidence of renal toxicity with DMARD use varies with individual
agents and is higher during treatment with cyclosporine, parenteral gold,
and penicillamine. Use of other DMARDs such as methotrexate does not
appear to cause acute renal toxicity but may result in gradual reduction of
renal function with resultant increase in serum drug concentration to
toxic levels. This effect is particularly evident in susceptible populations,
such as the elderly and those with diminished renal function. Concomitant
use of NSAIDs that independently contribute to renal toxicity poses an
additional risk of serious renal complications.
64. CONCLUSION
• Few long-term studies have been conducted to assess renal toxicity associated with
multiple drug therapy of RA. Current RA treatment guidelines suggest early and
aggressive use of DMARDs and subsequent application of DMARD combinations in
those patients refractory to DMARD monotherapy. Careful monitoring of renal
function must be an integral part of such treatment programs. The potential for
renal toxicity should always be considered susceptible to renal damage. Newer
DMARDs with negligible nephrotoxicity, such as leflunomide and the new anti–
tumor necrosis factor agents will prove useful both as single agents and in
combination therapy for the treatment of such patients
65.
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