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IMMUNOSUPPRESSIVE DRUGS IN DERMATOLOGY
IMMUNOSUPPRESSIVEDRUGS Lake DF, Briggs AD, Akporiaye ET. Immunopharmacology. In: Katzung BG, Masters SB, Trevor AJ, editors. Basic and Clinical Pharmacology. New York: The McGraw-Hills Companies Inc. 977-1000. Immunosuppressants • Reduce the abnormal immune response Clinical uses • Autoimmune disease • Post organ transplantation Neutralise toxins Inactivate viruses Eliminate pathogens Hypersensitivity Autoimmunity
IMMUNOSUPPRESSIVEDRUGS Lake DF, Briggs AD, Akporiaye ET. Immunopharmacology. In: Katzung BG, Masters SB, Trevor AJ, editors. Basic and Clinical Pharmacology. New York: The McGraw-Hills Companies Inc. 977-1000. Glucocorticoids Calcineurin Inhibitors • Cyclosporine • Tacrolimus mTOR Inhibitors • Sirolimus Mycophenolate mofetil Immunomodulatory derivatives of thalidomide • Lenalidomide Cytotoxic agents • Azathioprine • Cyclophosphamide • Leflunomide • Hydroxychloroquinine • Methotrexate, Immunosuppressive antibodies • Intravenous immunoglobulin • Antilymphocyte and anti thymocyte antibodies Monoclonal antibodies
METHOTREXATE • Dr. Yellapragada Subbarao • Edmundson and Guy – Used Mtx for Psoriasis DISCOVERY • 4-amino N10 methyl pteroyl glutamic acid • Structurally similar to folic acid except for two sites STRUCTURE Sacchidanand S, Oberai C, Inamadar AC, editors. History of Indian Dermatology. In: IADVL Textbook of Dermatology. 4th ed. Mumbai: Bhalani Publishing House; 2015. 3-18.
METHOTREXATE First • Distribution of drug throughout body • 0 . 75 hours Second • Renal excretion • 2-4 hours Third • Slow release of Mtx bound to DHFR 10 - 27 hours Peak levels • 1 – 1 . 5 hours Major active metabolite • Intracellular polyglutamate derivative Protein binding • 50% protein bound • Unbound free form – active form Excretion • 95% excreted in kidneys Callen JP, Kulp-Shorten CL. Methotrexate. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 169-81.
METHOTREXATE Shen S, O'Brien T, Yap LM, Prince HM, McCormack CJ. The use of methotrexate in dermatology: a review. Australas J Dermatol. 2012; 53(1): 1-18. Antiproliferative effect Anti Inflammatory effect Amino imidazole carboxamide ribonucleoside
METHOTREXATE Psoriasis Sezary syndrome Proliferative dermatoses • PRP, Reiter disease Immunobullous disease • Pemphigus vulgaris, Autoimmune connective tissue disorder • Dermatomyositis, Vasculitis and Neutrophilic dermatoses • Leukocytoclastic vasculitis, Behcet’s disease, Pyoderma gangrenosum Atopic dermatitis Callen JP, Kulp-Shorten CL. Methotrexate. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 169-81.
METHOTREXATE Erythrodermic psoriasis Psoriatic arthritis (Not responding to NSAID) Pustular Psoriasis Extensive severe plaque psoriasis (>20%) Psoriasis affecting ability to maintain employment Callen JP, Kulp-Shorten CL. Methotrexate. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 169-81.
METHOTREXATE Pregnancy Lactation Decreased renal function Hepatic disease Hematologic abnormalities Active infectious disease Callen JP, Kulp-Shorten CL. Methotrexate. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 169-81.
METHOTREXATE • Contraindicated in Pregnancy • There is no reason to risk use of the drug in pregnancy CATEGORY Callen JP, Kulp-Shorten CL. Methotrexate. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 169-81. Lactation is an absolute contraindication for methotrexate LACTATION
METHOTREXATE Callen JP, Kulp-Shorten CL. Methotrexate. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 169-81. Availability • 2.5, 5, 7.5, 10 and 15 mg tablets • 15 mg/1mL, 25 mg/1mL Injection • Oral, IM, IV, SC • Patients receiving intravenous methotrexate are able to tolerate higher doses because of more rapid renal clearance Regimens • Single weekly dose • Three divided doses over a 24 hour period each week Dose • Generally benefits at 10- 25 mg/week • Maximum dose 30 mg/week • 0.3 mg/kg weekly Response • Initial response in 1-4 weeks • Full therapeutic benefit in 2-3 months Folic acid • 1 mg daily • 5 mg for three doses every 12 hours • First dose given 12 hours after dose of methotrexate
METHOTREXATE • CBC and LFT after 1 week Test dose of 5-10 mg • 2 . 5 mg to 5 mg per week – until reasonable benefit without toxicity Escalation • Evaluation of scaling, erythema and induration Measurement of response to drug • 2 . 5 mg/week when maximal benefit to lowest possible dose that maintains disease control Tapering Callen JP, Kulp-Shorten CL. Methotrexate. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 169-81.
METHOTREXATE Gastrointestinal side effects • Nausea, anorexia – common • Diarrhea, vomiting, ulcerative stomatitis –less frequent Hematological toxicity • Pancytopenia • Great potential for loss of life Hepatotoxicity • Alcoholism + Mtx – Increased risk Renal toxicity • Encountered only in high dose therapies for chemotherapy for malignant disease Reproductive effects • Teratogen and Abortifacient Cutaneous effects • Hyperpigmentation • Alopecia Malignancy induction • Lymphoma - rare Pulmonary toxicity • Pneumonitis – rare Others • Erythema recall phenomenon • Methotrexate osteopathy Callen JP, Kulp-Shorten CL. Methotrexate. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 169-81.
METHOTREXATE Increases Mtx levels and Toxicity NSAID, Sulfonamides • Decreased renal excretion, displacement from plasma proteins Phenytoin, Tetracyclines • Displacement from plasma proteins Callen JP, Kulp-Shorten CL. Methotrexate. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 169-81. Simultaneously inhibit folate pathway & increases hematologic toxicity Dapsone and sulfonamides • Inhibition of dihydropteroate synthetase (enzyme converting folic acid to dihydrofolate Synergistically increase hepatotoxicity Systemic retinoids and Alcohol • Common target organ for toxicity is liver
METHOTREXATE Callen JP, Kulp-Shorten CL. Methotrexate. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 169-81. CBC and LFT • Every week for 4 weeks • Gradually decrease frequency to every 4 weeks Renal function test • Once or twice yearly Chest X ray • Annually Liver biopsy • After every 1.5 – 2 g for low risk patients • After every 1 g from high risk patients • Every 6 months – Grade IIIA liver biopsy changes
METHOTREXATE High WA, Fitzpatrick JE. Cytotoxic and Antimetabolic agents. In: Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffell DJ, Wolff K, editors. Fitzpatrick's Dermatology in General Medicine. 8th ed. New York: The McGraw-Hill Companies Inc.; 2012. 2735-59.
METHOTREXATE High WA, Fitzpatrick JE. Cytotoxic and Antimetabolic agents. In: Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffell DJ, Wolff K, editors. Fitzpatrick's Dermatology in General Medicine. 8th ed. New York: The McGraw-Hill Companies Inc.; 2012. 2735-59.
METHOTREXATE Callen JP, Kulp-Shorten CL. Methotrexate. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 169-81. Discontinue or reduce dose TLC < 3500/mm3 Platelet count <100,000/mm3 Liver transaminase – Increase in Twice upper normal limit
ACUTE METHOTREXATE TOXICITY Accidental overdose of methotrexate tablets by patients Cause Acute renal failure Hypoalbuminemia Concomitant use of drugs interacting with Mtx Predisposing factors Madke B, Singh AL. Acute methotrexate toxicity. Indian J Drugs Dermatol 2015;1:46-9
ACUTE METHOTREXATE TOXICITY Long standing history of chornic plaque psoriasis Sudden onset of erosions and ulcers in psoriatic plaques and oral mucosa Careful history must be elicited with regard to Mtx usage CBC – signs of myelosuppression, LFT and RFT – organ involvement, Serum methotrexate level Madke B, Singh AL. Acute methotrexate toxicity. Indian J Drugs Dermatol 2015;1:46-9 Trunk showing eroded psoriatic plaques
ACUTE METHOTREXATE TOXICITY Madke B, Singh AL. Acute methotrexate toxicity. Indian J Drugs Dermatol 2015;1:46-9 Folinic acid rescue (Leucovorin) • Folinic acid is reduced form of folic acid • It does not require dihyrofolate reductase for conversion to tetrahydrofolate Dose • 10 mg/m2 BSA, repeated every 6 hourly to ensure serum mtx levels less than 0.01 micromol/L. • The administered dose is guided by serum mtx concentration. • By rough estimates, it should be at least as high as the last given dose of mtx Hydration, oral hygiene and care of eroded plaques Alkalinization of urine with sodium bicarbonate • Prevents precipitation of methotrexate in renal tubules Management of myelosuppression • G-CSF
CYCLOSPORINE Bhutain T, Lee CS, Koo JYM. Cyclosporine. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 199-211. • Borel isolated • Tolypocladium inflatum gams • Initially antifungal agent • Immunosuppressive property SOURCE • Neutral cyclic peptide • 11 aminoacids STRUCTURE • Two formulations – Original Sandimmune, and Neoral • Neoral – more bioavailable, more consistently absorbed microemulsion formulation FORMULATIONS
CYCLOSPORINE • 2 to 4 hours Peak levels • Poor, absorbed back into intestinal lumen (efflux transporter P-glycoprotein) • Taken after fat rich meal Bioavailability • CYP3A4 enzyme system in liver Metabolism • Hepatobiliary Excretion Bhutain T, Lee CS, Koo JYM. Cyclosporine. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 199-211.
CYCLOSPORINE Amor KT, Ryan C, Menter A. The use of cyclosporine in dermatology: part I. J Am Acad Dermatol. 2010;63:925–946 IL-2 activates T- cells, IFN-γ and GM-CSF Nuclear factor of activated T cells
CYCLOSPORINE Psoriasis Atopic Dermatiti s • Lichen planus, Pityriasis rubra pilaris Papulosqumaous dermatoses • Pemphigus, Bullous pemphigoid Immunobullous disease • Dermatomyositis, SLE, Scleroderma Autoimmune connective tissue disorder • Behcet’s disease, Pyoderma gangrenosum Neutrophilic dermatoses • Alopecia areata, Lichen planopilaris Alopecia • Granuloma annulare, sarcoidosis Granulomatous dermatoses • Chronic actinic dermatitis Photosensitivity dermatoses • Chronic urticaria, solar urticaria, cold urticaria Urticaria Bhutain T, Lee CS, Koo JYM. Cyclosporine. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 199-211.
CYCLOSPORINE Bhutain T, Lee CS, Koo JYM. Cyclosporine. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 199-211. Patients with severe flare-ups Severe psoriasis, having contraindications/failed/not tolerating other systemic therapies Major life events where substantial clearing is critically important
CYCLOSPORINE Bhutain T, Lee CS, Koo JYM. Cyclosporine. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 199-211. Significantly decreased renal function Uncontrolled hypertension Hypersensitivity Clinically cured or persistent malignancy Cutaneous T cell lymphoma
CYCLOSPORINE Bhutain T, Lee CS, Koo JYM. Cyclosporine. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 199-211. Patient can lactate while she is on cyclosporine LACTATION • Risk cannot be ruled out – human studies are lacking • Animal studies may or may not show risk • Potential benefits may justify potential risk CATEGORY
CYCLOSPORINE Availability • 50 mg, 100 mg capsules • 100mg/mL oral solution Severe inflammatory or Recalcitrant psoriasis • Starting dose 5 mg/kg in two divided doses • Tapered in decrements of 1 mg/kg daily every week Generalised stable plaque psoriasis • Starting dose – 2 . 5 to 3 mg/kg daily • If no improvement by 1 month – increments of 0 . 5 to 1 mg/kg daily ever 2 weeks • Maximum dose 5 mg/kg daily Atopic dermatitis • 2 . 5 to 3 mg/kg body weight Duration • Should be given for 3-6 months • Maximum 1 year Bhutain T, Lee CS, Koo JYM. Cyclosporine. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 199-211.
CYCLOSPORINE Bhutain T, Lee CS, Koo JYM. Cyclosporine. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 199-211. • Cyclosporine at maximum dermatologic dosage Phase 1 • Maintain cyclosporine 4 mg/kg/day while introducing acitretin, later taper off cyclosporine Phase 2 • Maintain with acitretin Phase 3A • Maintain with acitretin and UVB or PUVA Phase 3B
CYCLOSPORINE • Renal dysfunction Renal • Hypertension Cardiovascular • Hyperkalemia, hyperuricemia, hypomagnesemia, Hyperlipidemia Laboratory abnormalities • Hypertrichosis, ginigival hyperplasia Mucocutaneous • Tremor, headache, paraesthesia Neurologic • Nausea, abdominal discomfort, diarrhea Gastrointestinal • Myalgia, lethargy, arthralgia Musculoskeletal Bhutain T, Lee CS, Koo JYM. Cyclosporine. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 199-211.
CYCLOSPORINE Drugs Increasing cyclosporine levels by CYP3A4 inhibition • Macrolides - Erythromycin • Doxycycline • Azole antifungals – Ketoconazole, Itraconazole, fluconazole • HIV-1 protease inhibitors - Ritonavir • H2 antihistamines - Cimetidine, ranitidine • Corticosteroids – Methylprednisolone • Calcium channel blockers • Grape fruit juice Bhutain T, Lee CS, Koo JYM. Cyclosporine. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 199-211. Drugs reducing cyclosporine drug levels by CYP3A4 induction • Antituberculous drugs – Rifampicin • Anticonvulsants - Carbamazepine Drugs used in combination with cyclosporine potentiating renal toxicity • Aminoglycosides – Tobramycin • NSAID – Indomethacin, diclofenac • Antifungal agents – Amphotericin B Increases risk of hyperkalemia with concurrent use • ACE inhibitors • Potassium sparing diuretics Interaction with statins • Cyclosporine increases levels of simvastain, atorvastatin • Muscle pain and weakness • Alternatives – Pravastatin, Rosuvastatin
CYCLOSPORINE Blood pressure Serum creatinine CBC LFT Fasting Lipid profile Potassium, magnesium, uric acid Every 2 weeks for first 2 months, Then every 4 weeks Bhutain T, Lee CS, Koo JYM. Cyclosporine. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 199-211.
CYCLOSPORINE Ryan C, Amor KT, Menter A. The use of cyclosporine in dermatology: part II. J Am Acad Dermatol. 2010;63:949–972
CYCLOSPORINE Ryan C, Amor KT, Menter A. The use of cyclosporine in dermatology: part II. J Am Acad Dermatol. 2010;63:949–972
AZATHIOPRINE Synthetic purine analogue Drug of choice for organ transplantation during 60s and 70s Anti-inflammatory properties along with immunosuppressive property Badalamenti SS, Kerdel FA. Azathioprine. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 182-9.
AZATHIOPRINE Absorption • >88% through GI tract Peak plasma levels • Less than 2 hours Conversion • Rapidly converted to 6 mercaptopurine Active metabolite • 6-Thioguanine Badalamenti SS, Kerdel FA. Azathioprine. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 182-9.
AZATHIOPRINE 6-THIOURIC ACIDS ACTIVE INACTIVE INACTIVE
AZATHIOPRINE Active metabolites • 6-TG monophoshpate and other 6-TG metabolites Structurally similar to endogenous purines adenine and guanine • Substitutes a thiol group for amino or hydroxyl group respectively Incorporated into DNA and RNA • Inhibits purine metabolism and cell division • Depression of T cell mediated function • Diminished antibody production in B cell Badalamenti SS, Kerdel FA. Azathioprine. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 182-9.
AZATHIOPRINE Organ Transplantatio n Severe Rheumatoid arthritis Immunobullous disease • Pemphigus vulgaris, Bullous pemphigoid Autoimmune connective tissue disorder • Dermatomyositis, SLE, DLE Vasculitis • Leukocytoclastic vasculitis, PAN, Wegener’s granulomatosis Neutrophilic dermatoses • Behcet’s disease, Pyoderma gangrenosum Dermatitis and papulosquamous disorder • Contact dermatitis, atopic dermatitis, lichen planus, psoriasis Photodermatoses • Chronic actinic dermatitis, Badalamenti SS, Kerdel FA. Azathioprine. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 182-9.
AZATHIOPRINE Pregnancy Hypersensitivity to azathioprine Low TPMT activity Active infection Badalamenti SS, Kerdel FA. Azathioprine. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 182-9.
AZATHIOPRINE • Positive evidence for risk to human fetus • However, benefits may outweigh risks of the drug CATEGORY Badalamenti SS, Kerdel FA. Azathioprine. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 182-9. Not recommended in lactating women LACTATION
AZATHIOPRINE Badalamenti SS, Kerdel FA. Azathioprine. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 182-9. Availability • 25, 50 mg tablets Dose • 1 – 2.5 mg/kg/day Duration • Therapeutic immunosuppressive effects take 6-12 weeks to develop Pemphigus • Most frequently used adjuvant with corticosteroids • Less toxic, less effective than cyclophosphamide, needs less monitoring • Regimen is used in unmarried patients, younger patients whose family is not complete
AZATHIOPRINE • Neutropenia, Pancytopenia • Correlates with low TPMT activity Myelosuppression • Transaminase elevations • Severe hepatocellular toxicity Hepatic • HPV, HSV, scabies • True opportunistic infections uncommon in dermatology patients Infections • Congenital malformations Teratogenicity • Erythema multiforme, urticaria, erythema nodosum Hypersensitivity syndrome • Gastritis, pancreatitis Gastrointestinal • Cutaneous SCC, Lymphomas • Not convincingly demonstrated in dermatology patients Malignancies Badalamenti SS, Kerdel FA. Azathioprine. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 182-9.
AZATHIOPRINE Drugs having potential for increasing myelosuppression in combination with azathioprine ACE inhibitor • Decreases WBC Methotrexate • Plasma levels of 6- MP metabolites increase Allopurinol • Increases myelosuppressive action by inhibiting xanthine oxidase Badalamenti SS, Kerdel FA. Azathioprine. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 182-9. Azathioprine decreases anticoagulant property of warfarin
AZATHIOPRINE Badalamenti SS, Kerdel FA. Azathioprine. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 182-9. CBC LFT • Every 2 weeks for first 2 months • Every 2 months thereafter Frequency TPMT assay – Baseline – Not for follow up
AZATHIOPRINE TPMT VALUE DOSE OF AZATHIOPRINE Less than 6.3 U/mL No treatment with azathioprine 6.3 – 15 U/mL 1 mg/kg daily 15.1 – 26.4 U/mL 2-2.5 mg/kg Badalamenti SS, Kerdel FA. Azathioprine. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 182-9.
CYCLOPHOSPHAMIDE Alkylating agents Cyclophosphamide Chlorambucil Melphalan Cytotoxic agent Derivative of nitrogen mutard Causes apoptosis Cell cycle non specific Immunosuppressive and steroid sparing agent High WA. Cytotoxic agents. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 219-24.
CYCLOPHOSPHAMIDE Bioavailability • About 75% Peak plasma levels • 1-2 hours Metabolism • Hepatic metabolism via cytochrome P450 system Cyclophosphamide 4-Hydroxycyclophosphamide Aldophosphamide Phosphoramide mustard and Acrolein High WA. Cytotoxic agents. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 219-24. Carboxyphosphamide (60% excreted as carboxyphosphamide in urine
CYCLOPHOSPHAMIDE Prodrug – metabolically inactive Primary metabolites – Covalent bonds with nucleophilic centres of DNA Alkylation and DNA damage Damage – overwhelms cell repair mechanisms Results in cell death Cell cycle non specific Greater effect on B cells than T cells High WA. Cytotoxic agents. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 219-24.
CYCLOPHOSPHAMIDE Mycosis fungoides (Advanced disease) Immunobullous disease • Pemphigus vulgaris, Bullous pemphigoid, Cicatricial pemphigoid Vasculitis • Leukocytoclastic vasculitis, PAN, Churg-Strauss syndrome, Wegener’s granulomatosis etc Autoimmune connective tissue disorder • Dermatomyositis, Scleroderma, Severe cutaneous lupus erythematosus Neutrophilic dermatoses • Behcet’s disease, Pyoderma gangrenosum High WA. Cytotoxic agents. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 219-24.
CYCLOPHOSPHAMIDE High WA. Cytotoxic agents. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 219-24. Drug allergy Depressed bone marrow function Pregnancy Lactation Prior history of bladder cancer Cyclophosphamide should not be first line therapy for men or women who have not completed family
CYCLOPHOSPHAMIDE • Positive evidence for risk to human fetus • However, benefits may outweigh risks of the drug CATEGORY High WA. Cytotoxic agents. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 219-24. Breast feeding is contraindicated LACTATION
CYCLOPHOSPHAMIDE High WA. Cytotoxic agents. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 219-24. Availability • 50 mg tablets • 500 mg injection Daily dose • 1-3 mg/kg/day • 1 – 1 . 5 mg/kg/day (Adjuvant) Duration • Therapeutic effect apparent after 4-6 weeks Parenteral pulse dose • 10-15 mg/kg monthly Autoimmune diseases • Used as adjuvant along with corticosteroids
CYCLOPHOSPHAMIDE Reproductive • Amenorrhea, ovarian failure • Azoospermia, Genitourinary • Hemorrhagic cystitis (Acrolein) • Dysuria, microscopic hematuria • Bladder fibrosis, vesicoureteral reflux Carcinogenesis • Bladder carcinoma • Leukemia, lymphoma, squamous cell carcinoma Gastrointestinal • Anorexia, stomatitis, hepatotoxicity • Nausea, vomiting, diarrhea (seen in 70%) Hematologic • Anemia, leukopenia, thrombocytopenia Dermatologic • Alopecia – Anagen effluvium • Pigmentation of skin and nails • Pigmented band on teeth • Urticaria or bullous eruption (Steven-Johnson Syndrome) High WA. Cytotoxic agents. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 219-24.
CYCLOPHOSPHAMIDE Reduces cyclophosphamide levels • Dexamethasone • Prednisolone • Phenytoin • Rifampicin Increases cyclophosphamide levels • Fluconazole • Ciprofloxacin • Chlorpromazine • Allopurinol • Cimetidine High WA. Cytotoxic agents. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 219-24.
CYCLOPHOSPHAMIDE Sacchidanand S, Oberai C, Inamadar AC, editors. Immunobullous Disorder. In: IADVL Textbook of Dermatology. 4th ed. Mumbai: Bhalani Publishing House; 2015. 957-8. 10– 15 mg/kg dissolved in 200 mL of 5% dextrose infused over 1 hour, Followed by hydration with 500 mL of 5% dextrose given IV for 5-6 hours after the pulse Mesna (50% of dose of cyclophosphamide) is added to infusion of cyclophosphamide to avoid risk of bladder toxicity Advised to drink 2-3 Liters of water per day and to void frequently
CYCLOPHOSPHAMIDE High WA. Cytotoxic agents. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 219-24. CBC & Urinalysis • Weekly for 2months • Every 2 weeks for 2 months • Monthly with stable dose • Decrease dose or discontinue if WBC < 4000 or Platelets < 1,00,000 • RBCs in urine – decrease dose or discontinue, refer to urologist for cystoscopy LFT • Every month for first 6 months • Later Every 3 months
MYCOPHENOLATEMOFETIL Schadt CR, Zwerner JP. Mycophenolate mofetil and mycophenolic acid. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 190-8. Mycophenolic acid is derived from Penicillium stoloniferum SOURCE MMF is 2- morpholinoethyl ester of MPA STRUCTURE Mycophenolate mofetil is the prodrug of Mycophenolic acid FORMULATIONS
MYCOPHENOLATEMOFETIL Mycophenolate mofetil Mycophenolic acid Glucoronidation in liver Glucuronide of MPA (MPAG) Recycle to liver via enterohepatic circulation Schadt CR, Zwerner JP. Mycophenolate mofetil and mycophenolic acid. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 190-8. Bioavailability • 94% • Better taken on empty stomach Protein binding • Mycophenolic acid is 97% protein bound Peak plasma levels • First peak – 1 hours • Second peak – 6 to 12 hours (Enterohepatic recycling) Metabolism • MPA – active, MPAG – not active Excretion • 90% of administered dosage excreted in urine as MPAG
MYCOPHENOLATEMOFETIL De novo purine synthesis Inosine monophosphate Xanthosine mono phosphate Guanosine monophosphate MPA – non competitive inhibitor of IMPDH Type II Most nucleated cells in body – Salvage pathway De novo purine synthesis – T and B lymphocytes Broad therapeutic index Action similar to Azathioprine Schadt CR, Zwerner JP. Mycophenolate mofetil and mycophenolic acid. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 190-8. Inosine Monophosphate Dehydrogenase Mycophenolic acid
MYCOPHENOLATEMOFETIL Renal, Cardiac and liver allograft prevention Dermatoses • Psoriasis, atopic dermatitis, chronic actinic dermatitis Immunobullous disease • Pemphigus vulgaris, Bullous pemphigoid, Cicatricial pemphigoid Autoimmune connective tissue disorder • SLE, DLE, Diffuse systemic sclerosis, Dermatomyositis Vasculitis • Wegener’s granulomatosis, Microscopic polyangiitis, Churg-Strauss syndrome, Hypocomplementemic urticarial vasculitis Schadt CR, Zwerner JP. Mycophenolate mofetil and mycophenolic acid. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 190-8.
MYCOPHENOLATEMOFETIL Pregnancy Drug allergy Lactation Peptic ulcer disease Hepatic or renal disease Drugs interfering with enterohepatic circulation (Cholestyramine) Concomitant azathioprine Schadt CR, Zwerner JP. Mycophenolate mofetil and mycophenolic acid. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 190-8.
MYCOPHENOLATEMOFETIL • Positive evidence for risk to human fetus • However, benefits may outweigh risks of the drug CATEGORY Schadt CR, Zwerner JP. Mycophenolate mofetil and mycophenolic acid. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 190-8. Decision should be made between physician and patient to discontinue either nursing or medication LACTATION
MYCOPHENOLATEMOFETIL Schadt CR, Zwerner JP. Mycophenolate mofetil and mycophenolic acid. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 190-8. Availability • 500 mg – Mycophenolate mofetil • 360 mg – Mycophenolate sodium enteric coated – less GI side effects Daily dose • 25 – 35 mg/kg for T cell mediated diseases • 35 – 55 mg/kg for antibody mediated diseases • 1 . 5 to 2 g/day divided twice daily • Divided doses as absorbed well Practical approach • First line agent in Induction and maintenance treatment of Lupus nephritis • Start 500 mg ODHS for 1 week • Increased in 500 mg increments every 2-4 weeks until a dose of 1.5 g twice daily • Starting at low dose minimises GI effects Limitations • Cost • Clinical response is slow
MYCOPHENOLATEMOFETIL Schadt CR, Zwerner JP. Mycophenolate mofetil and mycophenolic acid. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 190-8. Gastrointestinal • Most common, dose dependent • Nausea, diarrhea, vomiting Hematologic • Anemia, Neutropenia, thrombocytopenia Genitourinary • Urgency, frequency, dysuria • Does not cause nephrotoxicity Neurologic • Weakness, headache, insomnia, tinnitus Teratogenicity • First trimester loss • Anomalies of face, external ear, heart, esophagus, kidneys and distal limbs Carcinogenecity • Lymphoproliferative disorders • Non melanoma skin cancer
MYCOPHENOLATEMOFETIL Decreases gastric absorption • Antacids, PPI, Iron Decreases enterohepatic circulation • Penicillins, cephalosporins, macrolides, fluoroquinolones • Cholestyramine Protein binding displacement • Salicylates • Phenytoin • Theophylline Increases risk of seizures • Narcotics • NSAID Schadt CR, Zwerner JP. Mycophenolate mofetil and mycophenolic acid. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 190-8. Acyclovir • MMF increases blood levels of acyclovir
MYCOPHENOLATEMOFETIL CBC RFT LFT Frequency • Every 2 weeks following dose escalation • Every 2 months once dose is stable Schadt CR, Zwerner JP. Mycophenolate mofetil and mycophenolic acid. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 190-8.
INTRAVENOUS IMMUNOGLOBULIN Source • Derived from a purified human plasma pool of more than 1000 healthy blood donors Composition • IgG in supraphysiologic levels • Traces of other immunoglobulins Uses • Kawasaki’s disease • Dermatomyositis • Autoimmune blistering diseases • Toxic epidermal necrolysis George T, Luger AT. Intravenous immunoglobulin therapy. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 389-96.
INTRAVENOUS IMMUNOGLOBULIN Peak serum concentration • Immediate Distribution • 60% intravascular and 40% extravascular Half life • 3-5 weeks George T, Luger AT. Intravenous immunoglobulin therapy. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 389-96. Structure of IV Immunoglobulin
INTRAVENOUS IMMUNOGLOBULIN • Binds to surface receptors on B cells • Down-regulation of pathogenic autoantibody production Reduced antibody production • Binds to C3 and C5 convertases • Blocks complement activation Effects of complement system • Down-regulate expression of co-stimulatory molecules • Interferes with T-cell activation Effects of T cell activation • Anti-Fas receptor antibodies of IVIg inhibits apoptosis • Toxic epidermal necrosis Effects of Fas/Fas ligand • Reduced dose requirements of systemic corticosteroids • Synergistically suppress lymphocyte activation Synergistic effect with corticosteroids George T, Luger AT. Intravenous immunoglobulin therapy. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 389-96.
INTRAVENOUS IMMUNOGLOBULIN Vasculitis • Kawasaki disease (FDA approved) Autoimmune connective tissue diseases • Dermatomyositis • SLE • Scleroderma Autoimmune bullous dermatoses • Permphigus • Bullous pemphigoid • Toxic epidermal necrosis • Pemphigoid gestationis • Cicatricial pemphigoid • Epidermolysis bullosa acquisita • Linear IgA bullous dermatosis Other • Chronic autoimmune urticaria • Atopic dermatitis • Psoriasis • Pyoderma gangrenosum George T, Luger AT. Intravenous immunoglobulin therapy. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 389-96.
INTRAVENOUS IMMUNOGLOBULIN CONTRAINDICATION COMMENT Anaphylaxis secondary to previous infusions Absolute contraindication Congestive heart failure Increased risk of fluid overload Renal failure Increased risk of fluid overload IgA deficiency Increased risk of anaphylaxis Rheumatoid arthritis Increased risk of renal failure Cryoglobulinemia Increased risk of renal failure George T, Luger AT. Intravenous immunoglobulin therapy. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 389-96.
INTRAVENOUS IMMUNOGLOBULIN George T, Luger AT. Intravenous immunoglobulin therapy. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 389-96. • Risk cannot be ruled out – human studies are lacking • Animal studies may or may not show risk • Potential benefits may justify potential risk CATEGORY
INTRAVENOUS IMMUNOGLOBULIN George T, Luger AT. Intravenous immunoglobulin therapy. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 389-96. Most common regimen • 2 g/kg/cycle • 3 consecutive days • One cycle every 3-4 weeks Alternate regimen • 400 mg/kg daily • 5 consecutive days Infusion rate • Slow infusion • Over 4-4.5 hours Duration • Initial improvement in few weeks • Clinical control 4-6 months • Tapering by increasing time interval between cycles • End point – 2 infusions 16 weeks apart
INTRAVENOUS IMMUNOGLOBULIN Infusion related effects • Headache, myalgia, chills, flushing, fever, nausea, vomiting, chest pain, blood pressure changes, tachycardia Anaphylaxis • Patients with IgA deficiency Risk of fluid overload • Patients with significant cardiac or kidney disease needs careful monitoring Hematologic effects • Neutropenia, hemolysis Neurologic effects • Aseptic meningitis, headache, photophobia Thromboembolic events • Cerebral and myocardial infarction in older patients Risk of transmission of infection • Donors carefully selected and screened Cutaneous effects • Dermatitis, erythema multiforme, purpura, alopecia George T, Luger AT. Intravenous immunoglobulin therapy. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 389-96.
INTRAVENOUS IMMUNOGLOBULIN CBC RFT and LFT Immunoglobulin levels (IgA) Rheumatoid factor and cryoglobulins Blood pressure Heart rate Auscultate lungs and heart – signs of fluid overload George T, Luger AT. Intravenous immunoglobulin therapy. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 389-96.
CONCLUSION Immunosuppressive drugs – management of more severe inflammatory diseases. Side effects limit therapeutic potential Thorough analysis of clinical history, indications, contraindications and potential toxicity

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seminar-immunosuppressivedrugsindermatology-171225050613.pdf

  • 2. IMMUNOSUPPRESSIVEDRUGS Lake DF, Briggs AD, Akporiaye ET. Immunopharmacology. In: Katzung BG, Masters SB, Trevor AJ, editors. Basic and Clinical Pharmacology. New York: The McGraw-Hills Companies Inc. 977-1000. Immunosuppressants • Reduce the abnormal immune response Clinical uses • Autoimmune disease • Post organ transplantation Neutralise toxins Inactivate viruses Eliminate pathogens Hypersensitivity Autoimmunity
  • 3. IMMUNOSUPPRESSIVEDRUGS Lake DF, Briggs AD, Akporiaye ET. Immunopharmacology. In: Katzung BG, Masters SB, Trevor AJ, editors. Basic and Clinical Pharmacology. New York: The McGraw-Hills Companies Inc. 977-1000. Glucocorticoids Calcineurin Inhibitors • Cyclosporine • Tacrolimus mTOR Inhibitors • Sirolimus Mycophenolate mofetil Immunomodulatory derivatives of thalidomide • Lenalidomide Cytotoxic agents • Azathioprine • Cyclophosphamide • Leflunomide • Hydroxychloroquinine • Methotrexate, Immunosuppressive antibodies • Intravenous immunoglobulin • Antilymphocyte and anti thymocyte antibodies Monoclonal antibodies
  • 4. METHOTREXATE • Dr. Yellapragada Subbarao • Edmundson and Guy – Used Mtx for Psoriasis DISCOVERY • 4-amino N10 methyl pteroyl glutamic acid • Structurally similar to folic acid except for two sites STRUCTURE Sacchidanand S, Oberai C, Inamadar AC, editors. History of Indian Dermatology. In: IADVL Textbook of Dermatology. 4th ed. Mumbai: Bhalani Publishing House; 2015. 3-18.
  • 5. METHOTREXATE First • Distribution of drug throughout body • 0 . 75 hours Second • Renal excretion • 2-4 hours Third • Slow release of Mtx bound to DHFR 10 - 27 hours Peak levels • 1 – 1 . 5 hours Major active metabolite • Intracellular polyglutamate derivative Protein binding • 50% protein bound • Unbound free form – active form Excretion • 95% excreted in kidneys Callen JP, Kulp-Shorten CL. Methotrexate. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 169-81.
  • 6. METHOTREXATE Shen S, O'Brien T, Yap LM, Prince HM, McCormack CJ. The use of methotrexate in dermatology: a review. Australas J Dermatol. 2012; 53(1): 1-18. Antiproliferative effect Anti Inflammatory effect Amino imidazole carboxamide ribonucleoside
  • 7. METHOTREXATE Psoriasis Sezary syndrome Proliferative dermatoses • PRP, Reiter disease Immunobullous disease • Pemphigus vulgaris, Autoimmune connective tissue disorder • Dermatomyositis, Vasculitis and Neutrophilic dermatoses • Leukocytoclastic vasculitis, Behcet’s disease, Pyoderma gangrenosum Atopic dermatitis Callen JP, Kulp-Shorten CL. Methotrexate. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 169-81.
  • 8. METHOTREXATE Erythrodermic psoriasis Psoriatic arthritis (Not responding to NSAID) Pustular Psoriasis Extensive severe plaque psoriasis (>20%) Psoriasis affecting ability to maintain employment Callen JP, Kulp-Shorten CL. Methotrexate. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 169-81.
  • 9. METHOTREXATE Pregnancy Lactation Decreased renal function Hepatic disease Hematologic abnormalities Active infectious disease Callen JP, Kulp-Shorten CL. Methotrexate. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 169-81.
  • 10. METHOTREXATE • Contraindicated in Pregnancy • There is no reason to risk use of the drug in pregnancy CATEGORY Callen JP, Kulp-Shorten CL. Methotrexate. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 169-81. Lactation is an absolute contraindication for methotrexate LACTATION
  • 11. METHOTREXATE Callen JP, Kulp-Shorten CL. Methotrexate. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 169-81. Availability • 2.5, 5, 7.5, 10 and 15 mg tablets • 15 mg/1mL, 25 mg/1mL Injection • Oral, IM, IV, SC • Patients receiving intravenous methotrexate are able to tolerate higher doses because of more rapid renal clearance Regimens • Single weekly dose • Three divided doses over a 24 hour period each week Dose • Generally benefits at 10- 25 mg/week • Maximum dose 30 mg/week • 0.3 mg/kg weekly Response • Initial response in 1-4 weeks • Full therapeutic benefit in 2-3 months Folic acid • 1 mg daily • 5 mg for three doses every 12 hours • First dose given 12 hours after dose of methotrexate
  • 12. METHOTREXATE • CBC and LFT after 1 week Test dose of 5-10 mg • 2 . 5 mg to 5 mg per week – until reasonable benefit without toxicity Escalation • Evaluation of scaling, erythema and induration Measurement of response to drug • 2 . 5 mg/week when maximal benefit to lowest possible dose that maintains disease control Tapering Callen JP, Kulp-Shorten CL. Methotrexate. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 169-81.
  • 13. METHOTREXATE Gastrointestinal side effects • Nausea, anorexia – common • Diarrhea, vomiting, ulcerative stomatitis –less frequent Hematological toxicity • Pancytopenia • Great potential for loss of life Hepatotoxicity • Alcoholism + Mtx – Increased risk Renal toxicity • Encountered only in high dose therapies for chemotherapy for malignant disease Reproductive effects • Teratogen and Abortifacient Cutaneous effects • Hyperpigmentation • Alopecia Malignancy induction • Lymphoma - rare Pulmonary toxicity • Pneumonitis – rare Others • Erythema recall phenomenon • Methotrexate osteopathy Callen JP, Kulp-Shorten CL. Methotrexate. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 169-81.
  • 14. METHOTREXATE Increases Mtx levels and Toxicity NSAID, Sulfonamides • Decreased renal excretion, displacement from plasma proteins Phenytoin, Tetracyclines • Displacement from plasma proteins Callen JP, Kulp-Shorten CL. Methotrexate. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 169-81. Simultaneously inhibit folate pathway & increases hematologic toxicity Dapsone and sulfonamides • Inhibition of dihydropteroate synthetase (enzyme converting folic acid to dihydrofolate Synergistically increase hepatotoxicity Systemic retinoids and Alcohol • Common target organ for toxicity is liver
  • 15. METHOTREXATE Callen JP, Kulp-Shorten CL. Methotrexate. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 169-81. CBC and LFT • Every week for 4 weeks • Gradually decrease frequency to every 4 weeks Renal function test • Once or twice yearly Chest X ray • Annually Liver biopsy • After every 1.5 – 2 g for low risk patients • After every 1 g from high risk patients • Every 6 months – Grade IIIA liver biopsy changes
  • 16. METHOTREXATE High WA, Fitzpatrick JE. Cytotoxic and Antimetabolic agents. In: Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffell DJ, Wolff K, editors. Fitzpatrick's Dermatology in General Medicine. 8th ed. New York: The McGraw-Hill Companies Inc.; 2012. 2735-59.
  • 17. METHOTREXATE High WA, Fitzpatrick JE. Cytotoxic and Antimetabolic agents. In: Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffell DJ, Wolff K, editors. Fitzpatrick's Dermatology in General Medicine. 8th ed. New York: The McGraw-Hill Companies Inc.; 2012. 2735-59.
  • 18. METHOTREXATE Callen JP, Kulp-Shorten CL. Methotrexate. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 169-81. Discontinue or reduce dose TLC < 3500/mm3 Platelet count <100,000/mm3 Liver transaminase – Increase in Twice upper normal limit
  • 19. ACUTE METHOTREXATE TOXICITY Accidental overdose of methotrexate tablets by patients Cause Acute renal failure Hypoalbuminemia Concomitant use of drugs interacting with Mtx Predisposing factors Madke B, Singh AL. Acute methotrexate toxicity. Indian J Drugs Dermatol 2015;1:46-9
  • 20. ACUTE METHOTREXATE TOXICITY Long standing history of chornic plaque psoriasis Sudden onset of erosions and ulcers in psoriatic plaques and oral mucosa Careful history must be elicited with regard to Mtx usage CBC – signs of myelosuppression, LFT and RFT – organ involvement, Serum methotrexate level Madke B, Singh AL. Acute methotrexate toxicity. Indian J Drugs Dermatol 2015;1:46-9 Trunk showing eroded psoriatic plaques
  • 21. ACUTE METHOTREXATE TOXICITY Madke B, Singh AL. Acute methotrexate toxicity. Indian J Drugs Dermatol 2015;1:46-9 Folinic acid rescue (Leucovorin) • Folinic acid is reduced form of folic acid • It does not require dihyrofolate reductase for conversion to tetrahydrofolate Dose • 10 mg/m2 BSA, repeated every 6 hourly to ensure serum mtx levels less than 0.01 micromol/L. • The administered dose is guided by serum mtx concentration. • By rough estimates, it should be at least as high as the last given dose of mtx Hydration, oral hygiene and care of eroded plaques Alkalinization of urine with sodium bicarbonate • Prevents precipitation of methotrexate in renal tubules Management of myelosuppression • G-CSF
  • 22. CYCLOSPORINE Bhutain T, Lee CS, Koo JYM. Cyclosporine. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 199-211. • Borel isolated • Tolypocladium inflatum gams • Initially antifungal agent • Immunosuppressive property SOURCE • Neutral cyclic peptide • 11 aminoacids STRUCTURE • Two formulations – Original Sandimmune, and Neoral • Neoral – more bioavailable, more consistently absorbed microemulsion formulation FORMULATIONS
  • 23. CYCLOSPORINE • 2 to 4 hours Peak levels • Poor, absorbed back into intestinal lumen (efflux transporter P-glycoprotein) • Taken after fat rich meal Bioavailability • CYP3A4 enzyme system in liver Metabolism • Hepatobiliary Excretion Bhutain T, Lee CS, Koo JYM. Cyclosporine. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 199-211.
  • 24. CYCLOSPORINE Amor KT, Ryan C, Menter A. The use of cyclosporine in dermatology: part I. J Am Acad Dermatol. 2010;63:925–946 IL-2 activates T- cells, IFN-γ and GM-CSF Nuclear factor of activated T cells
  • 25. CYCLOSPORINE Psoriasis Atopic Dermatiti s • Lichen planus, Pityriasis rubra pilaris Papulosqumaous dermatoses • Pemphigus, Bullous pemphigoid Immunobullous disease • Dermatomyositis, SLE, Scleroderma Autoimmune connective tissue disorder • Behcet’s disease, Pyoderma gangrenosum Neutrophilic dermatoses • Alopecia areata, Lichen planopilaris Alopecia • Granuloma annulare, sarcoidosis Granulomatous dermatoses • Chronic actinic dermatitis Photosensitivity dermatoses • Chronic urticaria, solar urticaria, cold urticaria Urticaria Bhutain T, Lee CS, Koo JYM. Cyclosporine. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 199-211.
  • 26. CYCLOSPORINE Bhutain T, Lee CS, Koo JYM. Cyclosporine. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 199-211. Patients with severe flare-ups Severe psoriasis, having contraindications/failed/not tolerating other systemic therapies Major life events where substantial clearing is critically important
  • 27. CYCLOSPORINE Bhutain T, Lee CS, Koo JYM. Cyclosporine. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 199-211. Significantly decreased renal function Uncontrolled hypertension Hypersensitivity Clinically cured or persistent malignancy Cutaneous T cell lymphoma
  • 28. CYCLOSPORINE Bhutain T, Lee CS, Koo JYM. Cyclosporine. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 199-211. Patient can lactate while she is on cyclosporine LACTATION • Risk cannot be ruled out – human studies are lacking • Animal studies may or may not show risk • Potential benefits may justify potential risk CATEGORY
  • 29. CYCLOSPORINE Availability • 50 mg, 100 mg capsules • 100mg/mL oral solution Severe inflammatory or Recalcitrant psoriasis • Starting dose 5 mg/kg in two divided doses • Tapered in decrements of 1 mg/kg daily every week Generalised stable plaque psoriasis • Starting dose – 2 . 5 to 3 mg/kg daily • If no improvement by 1 month – increments of 0 . 5 to 1 mg/kg daily ever 2 weeks • Maximum dose 5 mg/kg daily Atopic dermatitis • 2 . 5 to 3 mg/kg body weight Duration • Should be given for 3-6 months • Maximum 1 year Bhutain T, Lee CS, Koo JYM. Cyclosporine. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 199-211.
  • 30. CYCLOSPORINE Bhutain T, Lee CS, Koo JYM. Cyclosporine. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 199-211. • Cyclosporine at maximum dermatologic dosage Phase 1 • Maintain cyclosporine 4 mg/kg/day while introducing acitretin, later taper off cyclosporine Phase 2 • Maintain with acitretin Phase 3A • Maintain with acitretin and UVB or PUVA Phase 3B
  • 31. CYCLOSPORINE • Renal dysfunction Renal • Hypertension Cardiovascular • Hyperkalemia, hyperuricemia, hypomagnesemia, Hyperlipidemia Laboratory abnormalities • Hypertrichosis, ginigival hyperplasia Mucocutaneous • Tremor, headache, paraesthesia Neurologic • Nausea, abdominal discomfort, diarrhea Gastrointestinal • Myalgia, lethargy, arthralgia Musculoskeletal Bhutain T, Lee CS, Koo JYM. Cyclosporine. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 199-211.
  • 32. CYCLOSPORINE Drugs Increasing cyclosporine levels by CYP3A4 inhibition • Macrolides - Erythromycin • Doxycycline • Azole antifungals – Ketoconazole, Itraconazole, fluconazole • HIV-1 protease inhibitors - Ritonavir • H2 antihistamines - Cimetidine, ranitidine • Corticosteroids – Methylprednisolone • Calcium channel blockers • Grape fruit juice Bhutain T, Lee CS, Koo JYM. Cyclosporine. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 199-211. Drugs reducing cyclosporine drug levels by CYP3A4 induction • Antituberculous drugs – Rifampicin • Anticonvulsants - Carbamazepine Drugs used in combination with cyclosporine potentiating renal toxicity • Aminoglycosides – Tobramycin • NSAID – Indomethacin, diclofenac • Antifungal agents – Amphotericin B Increases risk of hyperkalemia with concurrent use • ACE inhibitors • Potassium sparing diuretics Interaction with statins • Cyclosporine increases levels of simvastain, atorvastatin • Muscle pain and weakness • Alternatives – Pravastatin, Rosuvastatin
  • 33. CYCLOSPORINE Blood pressure Serum creatinine CBC LFT Fasting Lipid profile Potassium, magnesium, uric acid Every 2 weeks for first 2 months, Then every 4 weeks Bhutain T, Lee CS, Koo JYM. Cyclosporine. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 199-211.
  • 34. CYCLOSPORINE Ryan C, Amor KT, Menter A. The use of cyclosporine in dermatology: part II. J Am Acad Dermatol. 2010;63:949–972
  • 35. CYCLOSPORINE Ryan C, Amor KT, Menter A. The use of cyclosporine in dermatology: part II. J Am Acad Dermatol. 2010;63:949–972
  • 36. AZATHIOPRINE Synthetic purine analogue Drug of choice for organ transplantation during 60s and 70s Anti-inflammatory properties along with immunosuppressive property Badalamenti SS, Kerdel FA. Azathioprine. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 182-9.
  • 37. AZATHIOPRINE Absorption • >88% through GI tract Peak plasma levels • Less than 2 hours Conversion • Rapidly converted to 6 mercaptopurine Active metabolite • 6-Thioguanine Badalamenti SS, Kerdel FA. Azathioprine. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 182-9.
  • 39. AZATHIOPRINE Active metabolites • 6-TG monophoshpate and other 6-TG metabolites Structurally similar to endogenous purines adenine and guanine • Substitutes a thiol group for amino or hydroxyl group respectively Incorporated into DNA and RNA • Inhibits purine metabolism and cell division • Depression of T cell mediated function • Diminished antibody production in B cell Badalamenti SS, Kerdel FA. Azathioprine. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 182-9.
  • 40. AZATHIOPRINE Organ Transplantatio n Severe Rheumatoid arthritis Immunobullous disease • Pemphigus vulgaris, Bullous pemphigoid Autoimmune connective tissue disorder • Dermatomyositis, SLE, DLE Vasculitis • Leukocytoclastic vasculitis, PAN, Wegener’s granulomatosis Neutrophilic dermatoses • Behcet’s disease, Pyoderma gangrenosum Dermatitis and papulosquamous disorder • Contact dermatitis, atopic dermatitis, lichen planus, psoriasis Photodermatoses • Chronic actinic dermatitis, Badalamenti SS, Kerdel FA. Azathioprine. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 182-9.
  • 41. AZATHIOPRINE Pregnancy Hypersensitivity to azathioprine Low TPMT activity Active infection Badalamenti SS, Kerdel FA. Azathioprine. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 182-9.
  • 42. AZATHIOPRINE • Positive evidence for risk to human fetus • However, benefits may outweigh risks of the drug CATEGORY Badalamenti SS, Kerdel FA. Azathioprine. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 182-9. Not recommended in lactating women LACTATION
  • 43. AZATHIOPRINE Badalamenti SS, Kerdel FA. Azathioprine. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 182-9. Availability • 25, 50 mg tablets Dose • 1 – 2.5 mg/kg/day Duration • Therapeutic immunosuppressive effects take 6-12 weeks to develop Pemphigus • Most frequently used adjuvant with corticosteroids • Less toxic, less effective than cyclophosphamide, needs less monitoring • Regimen is used in unmarried patients, younger patients whose family is not complete
  • 44. AZATHIOPRINE • Neutropenia, Pancytopenia • Correlates with low TPMT activity Myelosuppression • Transaminase elevations • Severe hepatocellular toxicity Hepatic • HPV, HSV, scabies • True opportunistic infections uncommon in dermatology patients Infections • Congenital malformations Teratogenicity • Erythema multiforme, urticaria, erythema nodosum Hypersensitivity syndrome • Gastritis, pancreatitis Gastrointestinal • Cutaneous SCC, Lymphomas • Not convincingly demonstrated in dermatology patients Malignancies Badalamenti SS, Kerdel FA. Azathioprine. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 182-9.
  • 45. AZATHIOPRINE Drugs having potential for increasing myelosuppression in combination with azathioprine ACE inhibitor • Decreases WBC Methotrexate • Plasma levels of 6- MP metabolites increase Allopurinol • Increases myelosuppressive action by inhibiting xanthine oxidase Badalamenti SS, Kerdel FA. Azathioprine. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 182-9. Azathioprine decreases anticoagulant property of warfarin
  • 46. AZATHIOPRINE Badalamenti SS, Kerdel FA. Azathioprine. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 182-9. CBC LFT • Every 2 weeks for first 2 months • Every 2 months thereafter Frequency TPMT assay – Baseline – Not for follow up
  • 47. AZATHIOPRINE TPMT VALUE DOSE OF AZATHIOPRINE Less than 6.3 U/mL No treatment with azathioprine 6.3 – 15 U/mL 1 mg/kg daily 15.1 – 26.4 U/mL 2-2.5 mg/kg Badalamenti SS, Kerdel FA. Azathioprine. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 182-9.
  • 48. CYCLOPHOSPHAMIDE Alkylating agents Cyclophosphamide Chlorambucil Melphalan Cytotoxic agent Derivative of nitrogen mutard Causes apoptosis Cell cycle non specific Immunosuppressive and steroid sparing agent High WA. Cytotoxic agents. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 219-24.
  • 49. CYCLOPHOSPHAMIDE Bioavailability • About 75% Peak plasma levels • 1-2 hours Metabolism • Hepatic metabolism via cytochrome P450 system Cyclophosphamide 4-Hydroxycyclophosphamide Aldophosphamide Phosphoramide mustard and Acrolein High WA. Cytotoxic agents. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 219-24. Carboxyphosphamide (60% excreted as carboxyphosphamide in urine
  • 50. CYCLOPHOSPHAMIDE Prodrug – metabolically inactive Primary metabolites – Covalent bonds with nucleophilic centres of DNA Alkylation and DNA damage Damage – overwhelms cell repair mechanisms Results in cell death Cell cycle non specific Greater effect on B cells than T cells High WA. Cytotoxic agents. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 219-24.
  • 51. CYCLOPHOSPHAMIDE Mycosis fungoides (Advanced disease) Immunobullous disease • Pemphigus vulgaris, Bullous pemphigoid, Cicatricial pemphigoid Vasculitis • Leukocytoclastic vasculitis, PAN, Churg-Strauss syndrome, Wegener’s granulomatosis etc Autoimmune connective tissue disorder • Dermatomyositis, Scleroderma, Severe cutaneous lupus erythematosus Neutrophilic dermatoses • Behcet’s disease, Pyoderma gangrenosum High WA. Cytotoxic agents. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 219-24.
  • 52. CYCLOPHOSPHAMIDE High WA. Cytotoxic agents. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 219-24. Drug allergy Depressed bone marrow function Pregnancy Lactation Prior history of bladder cancer Cyclophosphamide should not be first line therapy for men or women who have not completed family
  • 53. CYCLOPHOSPHAMIDE • Positive evidence for risk to human fetus • However, benefits may outweigh risks of the drug CATEGORY High WA. Cytotoxic agents. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 219-24. Breast feeding is contraindicated LACTATION
  • 54. CYCLOPHOSPHAMIDE High WA. Cytotoxic agents. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 219-24. Availability • 50 mg tablets • 500 mg injection Daily dose • 1-3 mg/kg/day • 1 – 1 . 5 mg/kg/day (Adjuvant) Duration • Therapeutic effect apparent after 4-6 weeks Parenteral pulse dose • 10-15 mg/kg monthly Autoimmune diseases • Used as adjuvant along with corticosteroids
  • 55. CYCLOPHOSPHAMIDE Reproductive • Amenorrhea, ovarian failure • Azoospermia, Genitourinary • Hemorrhagic cystitis (Acrolein) • Dysuria, microscopic hematuria • Bladder fibrosis, vesicoureteral reflux Carcinogenesis • Bladder carcinoma • Leukemia, lymphoma, squamous cell carcinoma Gastrointestinal • Anorexia, stomatitis, hepatotoxicity • Nausea, vomiting, diarrhea (seen in 70%) Hematologic • Anemia, leukopenia, thrombocytopenia Dermatologic • Alopecia – Anagen effluvium • Pigmentation of skin and nails • Pigmented band on teeth • Urticaria or bullous eruption (Steven-Johnson Syndrome) High WA. Cytotoxic agents. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 219-24.
  • 56. CYCLOPHOSPHAMIDE Reduces cyclophosphamide levels • Dexamethasone • Prednisolone • Phenytoin • Rifampicin Increases cyclophosphamide levels • Fluconazole • Ciprofloxacin • Chlorpromazine • Allopurinol • Cimetidine High WA. Cytotoxic agents. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 219-24.
  • 57. CYCLOPHOSPHAMIDE Sacchidanand S, Oberai C, Inamadar AC, editors. Immunobullous Disorder. In: IADVL Textbook of Dermatology. 4th ed. Mumbai: Bhalani Publishing House; 2015. 957-8. 10– 15 mg/kg dissolved in 200 mL of 5% dextrose infused over 1 hour, Followed by hydration with 500 mL of 5% dextrose given IV for 5-6 hours after the pulse Mesna (50% of dose of cyclophosphamide) is added to infusion of cyclophosphamide to avoid risk of bladder toxicity Advised to drink 2-3 Liters of water per day and to void frequently
  • 58. CYCLOPHOSPHAMIDE High WA. Cytotoxic agents. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 219-24. CBC & Urinalysis • Weekly for 2months • Every 2 weeks for 2 months • Monthly with stable dose • Decrease dose or discontinue if WBC < 4000 or Platelets < 1,00,000 • RBCs in urine – decrease dose or discontinue, refer to urologist for cystoscopy LFT • Every month for first 6 months • Later Every 3 months
  • 59. MYCOPHENOLATEMOFETIL Schadt CR, Zwerner JP. Mycophenolate mofetil and mycophenolic acid. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 190-8. Mycophenolic acid is derived from Penicillium stoloniferum SOURCE MMF is 2- morpholinoethyl ester of MPA STRUCTURE Mycophenolate mofetil is the prodrug of Mycophenolic acid FORMULATIONS
  • 60. MYCOPHENOLATEMOFETIL Mycophenolate mofetil Mycophenolic acid Glucoronidation in liver Glucuronide of MPA (MPAG) Recycle to liver via enterohepatic circulation Schadt CR, Zwerner JP. Mycophenolate mofetil and mycophenolic acid. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 190-8. Bioavailability • 94% • Better taken on empty stomach Protein binding • Mycophenolic acid is 97% protein bound Peak plasma levels • First peak – 1 hours • Second peak – 6 to 12 hours (Enterohepatic recycling) Metabolism • MPA – active, MPAG – not active Excretion • 90% of administered dosage excreted in urine as MPAG
  • 61. MYCOPHENOLATEMOFETIL De novo purine synthesis Inosine monophosphate Xanthosine mono phosphate Guanosine monophosphate MPA – non competitive inhibitor of IMPDH Type II Most nucleated cells in body – Salvage pathway De novo purine synthesis – T and B lymphocytes Broad therapeutic index Action similar to Azathioprine Schadt CR, Zwerner JP. Mycophenolate mofetil and mycophenolic acid. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 190-8. Inosine Monophosphate Dehydrogenase Mycophenolic acid
  • 62. MYCOPHENOLATEMOFETIL Renal, Cardiac and liver allograft prevention Dermatoses • Psoriasis, atopic dermatitis, chronic actinic dermatitis Immunobullous disease • Pemphigus vulgaris, Bullous pemphigoid, Cicatricial pemphigoid Autoimmune connective tissue disorder • SLE, DLE, Diffuse systemic sclerosis, Dermatomyositis Vasculitis • Wegener’s granulomatosis, Microscopic polyangiitis, Churg-Strauss syndrome, Hypocomplementemic urticarial vasculitis Schadt CR, Zwerner JP. Mycophenolate mofetil and mycophenolic acid. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 190-8.
  • 63. MYCOPHENOLATEMOFETIL Pregnancy Drug allergy Lactation Peptic ulcer disease Hepatic or renal disease Drugs interfering with enterohepatic circulation (Cholestyramine) Concomitant azathioprine Schadt CR, Zwerner JP. Mycophenolate mofetil and mycophenolic acid. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 190-8.
  • 64. MYCOPHENOLATEMOFETIL • Positive evidence for risk to human fetus • However, benefits may outweigh risks of the drug CATEGORY Schadt CR, Zwerner JP. Mycophenolate mofetil and mycophenolic acid. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 190-8. Decision should be made between physician and patient to discontinue either nursing or medication LACTATION
  • 65. MYCOPHENOLATEMOFETIL Schadt CR, Zwerner JP. Mycophenolate mofetil and mycophenolic acid. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 190-8. Availability • 500 mg – Mycophenolate mofetil • 360 mg – Mycophenolate sodium enteric coated – less GI side effects Daily dose • 25 – 35 mg/kg for T cell mediated diseases • 35 – 55 mg/kg for antibody mediated diseases • 1 . 5 to 2 g/day divided twice daily • Divided doses as absorbed well Practical approach • First line agent in Induction and maintenance treatment of Lupus nephritis • Start 500 mg ODHS for 1 week • Increased in 500 mg increments every 2-4 weeks until a dose of 1.5 g twice daily • Starting at low dose minimises GI effects Limitations • Cost • Clinical response is slow
  • 66. MYCOPHENOLATEMOFETIL Schadt CR, Zwerner JP. Mycophenolate mofetil and mycophenolic acid. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 190-8. Gastrointestinal • Most common, dose dependent • Nausea, diarrhea, vomiting Hematologic • Anemia, Neutropenia, thrombocytopenia Genitourinary • Urgency, frequency, dysuria • Does not cause nephrotoxicity Neurologic • Weakness, headache, insomnia, tinnitus Teratogenicity • First trimester loss • Anomalies of face, external ear, heart, esophagus, kidneys and distal limbs Carcinogenecity • Lymphoproliferative disorders • Non melanoma skin cancer
  • 67. MYCOPHENOLATEMOFETIL Decreases gastric absorption • Antacids, PPI, Iron Decreases enterohepatic circulation • Penicillins, cephalosporins, macrolides, fluoroquinolones • Cholestyramine Protein binding displacement • Salicylates • Phenytoin • Theophylline Increases risk of seizures • Narcotics • NSAID Schadt CR, Zwerner JP. Mycophenolate mofetil and mycophenolic acid. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 190-8. Acyclovir • MMF increases blood levels of acyclovir
  • 68. MYCOPHENOLATEMOFETIL CBC RFT LFT Frequency • Every 2 weeks following dose escalation • Every 2 months once dose is stable Schadt CR, Zwerner JP. Mycophenolate mofetil and mycophenolic acid. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 190-8.
  • 69. INTRAVENOUS IMMUNOGLOBULIN Source • Derived from a purified human plasma pool of more than 1000 healthy blood donors Composition • IgG in supraphysiologic levels • Traces of other immunoglobulins Uses • Kawasaki’s disease • Dermatomyositis • Autoimmune blistering diseases • Toxic epidermal necrolysis George T, Luger AT. Intravenous immunoglobulin therapy. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 389-96.
  • 70. INTRAVENOUS IMMUNOGLOBULIN Peak serum concentration • Immediate Distribution • 60% intravascular and 40% extravascular Half life • 3-5 weeks George T, Luger AT. Intravenous immunoglobulin therapy. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 389-96. Structure of IV Immunoglobulin
  • 71. INTRAVENOUS IMMUNOGLOBULIN • Binds to surface receptors on B cells • Down-regulation of pathogenic autoantibody production Reduced antibody production • Binds to C3 and C5 convertases • Blocks complement activation Effects of complement system • Down-regulate expression of co-stimulatory molecules • Interferes with T-cell activation Effects of T cell activation • Anti-Fas receptor antibodies of IVIg inhibits apoptosis • Toxic epidermal necrosis Effects of Fas/Fas ligand • Reduced dose requirements of systemic corticosteroids • Synergistically suppress lymphocyte activation Synergistic effect with corticosteroids George T, Luger AT. Intravenous immunoglobulin therapy. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 389-96.
  • 72. INTRAVENOUS IMMUNOGLOBULIN Vasculitis • Kawasaki disease (FDA approved) Autoimmune connective tissue diseases • Dermatomyositis • SLE • Scleroderma Autoimmune bullous dermatoses • Permphigus • Bullous pemphigoid • Toxic epidermal necrosis • Pemphigoid gestationis • Cicatricial pemphigoid • Epidermolysis bullosa acquisita • Linear IgA bullous dermatosis Other • Chronic autoimmune urticaria • Atopic dermatitis • Psoriasis • Pyoderma gangrenosum George T, Luger AT. Intravenous immunoglobulin therapy. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 389-96.
  • 73. INTRAVENOUS IMMUNOGLOBULIN CONTRAINDICATION COMMENT Anaphylaxis secondary to previous infusions Absolute contraindication Congestive heart failure Increased risk of fluid overload Renal failure Increased risk of fluid overload IgA deficiency Increased risk of anaphylaxis Rheumatoid arthritis Increased risk of renal failure Cryoglobulinemia Increased risk of renal failure George T, Luger AT. Intravenous immunoglobulin therapy. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 389-96.
  • 74. INTRAVENOUS IMMUNOGLOBULIN George T, Luger AT. Intravenous immunoglobulin therapy. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 389-96. • Risk cannot be ruled out – human studies are lacking • Animal studies may or may not show risk • Potential benefits may justify potential risk CATEGORY
  • 75. INTRAVENOUS IMMUNOGLOBULIN George T, Luger AT. Intravenous immunoglobulin therapy. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 389-96. Most common regimen • 2 g/kg/cycle • 3 consecutive days • One cycle every 3-4 weeks Alternate regimen • 400 mg/kg daily • 5 consecutive days Infusion rate • Slow infusion • Over 4-4.5 hours Duration • Initial improvement in few weeks • Clinical control 4-6 months • Tapering by increasing time interval between cycles • End point – 2 infusions 16 weeks apart
  • 76. INTRAVENOUS IMMUNOGLOBULIN Infusion related effects • Headache, myalgia, chills, flushing, fever, nausea, vomiting, chest pain, blood pressure changes, tachycardia Anaphylaxis • Patients with IgA deficiency Risk of fluid overload • Patients with significant cardiac or kidney disease needs careful monitoring Hematologic effects • Neutropenia, hemolysis Neurologic effects • Aseptic meningitis, headache, photophobia Thromboembolic events • Cerebral and myocardial infarction in older patients Risk of transmission of infection • Donors carefully selected and screened Cutaneous effects • Dermatitis, erythema multiforme, purpura, alopecia George T, Luger AT. Intravenous immunoglobulin therapy. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 389-96.
  • 77. INTRAVENOUS IMMUNOGLOBULIN CBC RFT and LFT Immunoglobulin levels (IgA) Rheumatoid factor and cryoglobulins Blood pressure Heart rate Auscultate lungs and heart – signs of fluid overload George T, Luger AT. Intravenous immunoglobulin therapy. In: Wolverton SE. Comprehensive Dermatologic Drug Therapy. 3rd ed. Amsterdam: Elsevier Inc.; 2013. 389-96.
  • 78. CONCLUSION Immunosuppressive drugs – management of more severe inflammatory diseases. Side effects limit therapeutic potential Thorough analysis of clinical history, indications, contraindications and potential toxicity