Anti-Rhumatics in Renal and Liver impairment

Anti-Rhumatics

in renal & Liver

Impairment

Team_2…PharmD7

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TEAM2 MEMBERS…Name Contribution

Rehab aly rayan Intro, d-penicillamine, azathioprine, antimalarial, sodium aurothiomalate, summery, conclusion, PPT

Doaa aly hegy Sulfasalazine, final edition

Ereeni alfons Mycophenolate mofetil(mmf)

Eman ali sayed Cyclosporine

Amaal shetewy Corticosteroids

Dina mohamed magdy Rituximab

Gehan basiony Leflonomide, cyclophosphamide, celecoxib

Rania sakr Abatacept

Dina esmat -----

Riham abdelrahman Methotrexate

Sabrin abdel salamhegazy Nsaids

Sherin taha Tnf


TO BE DISCUSSED…1. DMARDS

1. Significant renal toxicity (Auranofin (oral gold), D-Penicillamine And Cyclosporine)

2. Minimal renal toxicity plus hepatic toxicity (Azathioprine, Hydroxychloroquine, Leflunomide, Methotrexate, Mycophenolate mofetil (MMF), Sodium aurothiomalate, Sulfasalazine. Cyclophosphamide)

2. Corticosteroids

3. NSAIDS

4. Celecoxib

5. Biologic agents: (Rituximab, Abtacept)

6. TNF-alpha antagonists

7. Summery


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.


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.


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).


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


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.


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.

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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.

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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.

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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.

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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.

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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.

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CYCLOSPORINE

•Nephrotoxicity & Hepatotoxicity

•Cyclosporine, cause nephrotoxicity and hepatotoxicity. The risk increases with increasing doses of cyclosporine.

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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.

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CYCLOSPORINE

•Hepatotoxicity:

•Cases of hepatotoxicity and liver injury including cholestasis, jaundice, hepatitis, and liver failure have been reported in patients treated with cyclosporine

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MINIMAL RENAL TOXICITYPLUS 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.

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AZATHIOPRINE

•Cautions: Localized or systemic infection including hepatitis B or C and history of tuberculosis (hepatotoxicity).

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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.

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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.

http://reference.medscape.com/drugs/antineoplastics-alkylating

http://reference.medscape.com/drugs/dmards-immunomodulators

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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

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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

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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.

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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.

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LEFLUNOMIDE

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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

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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

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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

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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.

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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.

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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.

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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.

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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.

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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.

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Mycophenolate mofetil (MMF

• Metabolism

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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.

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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.

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Mycophenolate mofetil (MMF

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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.

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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

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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.

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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.

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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.

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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.

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CORTICOSTEROIDS

•Methylprednisolone is a synthetic, intermediate-acting glucocorticoid that widely used in the therapy of severe inflammation, autoimmune conditions, hypersensitivity reactions and organ rejection.

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NON-STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDS) • Osteoarthritis

• Rheumatoid Arthritis

• Other Musculoskeletal Disorders

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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

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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

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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.

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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.

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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

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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)

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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.

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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.

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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.

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TNF-Α ANTAGONISTSINFLIXIMAB, 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

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TNF-Α ANTAGONISTSINFLIXIMAB, ETANERCEPT, ADALIMUMAB, CERTOLIZUMAB, GOLIMUMAB

•Renal toxicity

•No evidence on the effect of TNF-α antagonists on renal function or any dose adjustments required.

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SUMMERY

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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.

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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

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REFERENCES

• K. Chakravarty et al. BSR/BHPR guideline for disease-modifying anti-rheumatic drug (DMARD) therapy in consultation with the British Association of Dermatologists. [Homepage on the Internet]. 2008 [cited 2014 Apr 13]. Available from: Oxford University, the British Society for Rheumatology Web site: http://[email protected]

• Schiff MH, Whelton A. Renal Toxicity Associated With Disease-Modifying Antirheumatic Drugs Used for the Treatment of Rheumatoid Arthritis. Seminars in Arthritis and Rheumatism 2000; 30(3):196-208.

• Chakravarty, K., McDonald, H., Pullar, T. et al. (2008) BSR/BHPR guideline for disease-modifying anti-rheumatic drug (DMARD) therapy in consultation with the British Association of Dermatologists. Rheumatology 47(6), 924-925.

• Bsr/ Bhpr Dmard Guideline Group. Quick reference guideline for monitoring of disease modifying anti-rheumatic drug (DMARD) therapy. Bsr/ Bhpr Dmard Guideline Group [homepage on the Internet]. 2009 [cited 2014 Apr 17].

• eoarthritis in Peripheral Joints – Diagnosis and Treatment. BRITISH COLUMBIA MEDICAL ASSOCIATION [homepage on the Internet]. 2008 [cited 2014 Apr 17]. Available from: Ministry of Health Services.

http://[email protected]

Health & Medicine

Anti-Rhumatics in Renal and Liver impairment