Transcript 免疫風濕科常用藥物

免疫風濕科常用藥物
Goals of Arthritis Therapy
 Relieve pain/inflammation
 Minimize risks of therapy
 Retard disease progression
 Provide patient education
 Prevent work disability
 Enhance quality of life and functional
independence
免疫風濕科常用藥物
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NSAID
Corticosteroids
Disease-modifying anti-rheumatic drugs (DMARDs)
-- Hydroxychloroquine (Plaquenil/Geniquin) 必賴克廔/殲瘧
-- Salfasalazine ( Salazopyrine ) 斯樂
-- D-penicillamine (Metalcaptase )
Immunosuppressive agents ( Cytotoxic agnets )
-- Cyclophosphamide ( Endoxan ) 癌得星
-- Azathioprine ( Imuran ) 壓彼迅/移護寧
-- Methotrexate ( MTX )
-- Cyclosporine ( Sandimmun ) 環孢靈/新體睦
-- Cellcept (Mycophenolate Mofetil) 山喜多/
Myfortic (mycophenolic acid) 睦體康
免疫風濕科常用藥物
► Biologic
agents
-- Tumor necrosis factor inhibitors
a. Etanercept ( Enbrel 恩博)
b. Infliximab ( Remicade )
c. Adalimumab (Humira 復邁)
-- IL-1 antagonists
-- Anakinra
-- Endothelin receptor antagonist ( Bosentan )
Mechanisms of NSAIDs
Arachidonic acid
COX-1
(constitutive)
PGE2
Glucocorticoids
COX-2
(inducible)
Conventional
NSAID
Physiologic
function
GI Mucosa
Kidney
Platelet
Dubois RN. FASEB J 1998
Inflammation
Neoplasia
Cox-2 inhibitor
Celecoxib
Etoricoxib
Vioxx
 Promotes tumor
angiogenesis
 Induces tumor cell
growth
 Inhibits apoptosis
Classification of NSAIDs By Selectivity for COX
Selectivity
Weak COX inhibitors
COX-1/COX-2 inhibitors
COX-2 preferential
COX-2 selective inhibitors
Drugs
Acetaminophen,salsalate,salicylamide,
sodium salicylate, cholinemagnesium trisalicylate
Piroxicam, indomethacin, sulindac,
toletin, ibuprofen, naproxen,
fenoprofen, meclofenamate,
mefenamic acid, diflunisal,
ketoprofen,diclofenac, ketolac,
eyodolac, nabumetone, oxaprozin,
flurbiprofen
Nimesulide, meloxicam
Celebrex, rofecoxib, valdecoxib,
etoricoxib, parecoxib
Risk Factors For Serious Upper GI
Complications Associated With NSAIDs
► Hx
of:
► High-dose or
– PUD
multiple NSAIDs
– Upper GI bleeding ►Concurrent
– Older age
prednisone use
– Arthritis-related
►Prior GI side
disability
effect
消化性潰瘍、上消化道出血或胃穿孔
Peptic Ulcer, Upper GI Bleeding, Perforation
► 服用傳統NSAIDs僅一週即造成胃腸毒性
 Simon LS et al. Arthritis Rheum. 1998;41:1591-1602.
 Goldstein JL et al. Aliment Pharmacol Ther. 2003;18:125-132.
► 高或低劑量傳統NSAIDs均會引起胃腸毒性
 Pérez Gutthann S et al. Epidemiology. 1997;8:18-24.
►
許多骨關節炎患者因長期服用傳統NSAIDs而進駐胃腸科門
診或住院治療
Glucocorticoids
► Mechanism
:
-- binding to cytoplasmic receptor
-- steroid/receptor complex regulate DNA
► Actions
-- Lipocortin: inhibit phospholipase A2 to convert
membrane phospholipid to arachidonic acid
► Effects
-- Anti-inflammatory effects
-- Immunosuppressive effects
Effects of Glucocorticoids
► Effects
on leukocyte movement
a. Lymphocytes
c. Neutrophils
b. Monocyte-macrophages
d. Eosinophils
► Effects on humoral factors :
a. 減少 Ig levels
b. 減少 RES 清除 antibody-coated cells
c. 減少 prostaglandins and leukotrienes
d. 加強 actions of catecholamines
f. 抑制 histamine-induced vasodilation
g. Probably no effects on complement metabolism.
Glucocorticoid
Equivalent
oral dose
( mg)
Plasma
half-life
(min)
20
90
1
1
Prednisolone
5
200
4
0.8
Methylprednisolon
e
Triamcinolone
4
200
5
0.5
4
200
5
0
0.75
300
25
0
Cortisol
Dexamethasone
Relative
Relative
antimineralcor
inflammator
-ticoid
y effect
effect
Hydrocortisone ( solu-cortef, 100 mg/amp ) 1 amp = 5# pred
Prednisolone ( 5 mg )
Methylprednisolone ( solu-medrol. 40 mg/vial ) 1 vial = 10#
Dexamethasone ( Decadron, 5 mg / vial ) = 1 vial = 5 # pred.
Glucocorticosteroids
► Indications:
almost all autoimmune disease
 Sjogren syndrome: only short term use
 A.S., Reiter’s syndrome: only for active peripheral
arthritis or enthesitis
► Adverse
Reactions:
 * Peptic ulcer
► no
definite clue of oral steroid alone increase rate of
peptic ulcer
► Steroid increases NSAID GI toxicity
 Very rare nephrotoxicity report of steroid
 Infection ( 30mg/d > 7 days)
 Osteoporosis ( 10mg/d > 3 months)
Methylprednisolone Pulse
Therapy
► Infusion
of large dose of corticosteroid in a
short period of time
► Benefits:
 rapid onset
 less puffy face/buffalo hump
 less impaction over hypothalamus-pituitaryadrenal axis
Methylprednisolone Pulse
Therapy
► Dosage:
 Children 15-17mg/kg/day
 Adult: 750-1000mg/day
► Major
complications:
 Ventricular arrhythmia & cardiac arrest
 Thromboembolism: Myocardial infarction,
CVA, Mononeuritis multiplex, especially in
APS
 Infection
Methylprednisolone Pulse
Therapy
► Minor
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
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adverse reactions:
Salt retention: mild lower leg edema
Hypertension
Hyperglycemia
peripheral vasodilatation: facial flushing
Hiccups
Psychological reaction
Methylprednisolone Pulse
Therapy
► High
risk group
 Old aged people & children
 Antiphospholipid Ab syndrome ( APS )
 History of thromboembolism
► Monitoring
 BP management: slower infusion rate, diuretic if
lower leg edema
 HR <60, management: slower infusion rate
Immunoregulatory agents
Immunomodulatory agents
► SAARDs:
 Slow-Acting AntiRheumatic Drugs
► DMARDs:
 Disease-Modificating AntiRheumatic Drugs
Hydroxychloroquine
Plaquenil®
200mg
Geniquin®
200mg
Hydroxychloroquine
lysosomal membranes, thereby
inhibiting the release of lysosomal enzymes.
► Photoprotective effects
► 抑制 Ag-Ab interaction and immune complex
formation
► 抑制 IL-1 production by monocytes
► Complexes with DNA ( blocking the
reactions between DNA and anti-DNA Abs )
► 穩定
Hydroxychloroquine
► Safe
in pregnant mother and fetus
► Beneficial effects on lupus dyslipidemia with
or without concomitant steroid
administration ( Borba and Bonfa )
► Dyslipidemia :
HDL-C,VLDL and TG are improved
Hydroxychloroquine
► Applications:
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SLE: esp with skin rash and arthritis
R.A.: 60-80% responsive after 6-8 mons treatment
Spondyloarthropathy except Psoriatic arthritis
Sjogren’s syndrome
► Dosage:
 Usual dose: 200mg (1# ) BID, PC
 Reduced dose: Renal failure
 Maximal: Hydroxychloroquine: 6mg base/kg/day
Chloroquine: 4mg base/kg/day
Hydroxychloroquine
► Contraindications:
 Relatively: Psoriasis
► Adverse
Reactions:
 Irreversible
retinopathy( hyperpigmentation)
►dose-related
 Skin hyperpigmentation /
hypopigmentation
 No life-threatening toxicity
►except
marked overdose of chloroquine: rapid
onset cardiorespiratory failure
Hydroxychloroquine
► Monitoring:
 Oph. Exam. Baseline and every 6-12 months
 Sun-exposure protection
Amsler grid ( self-testing )
Skin rashes are the most common side effect leading to cessation.
Sulfasalazine (Salazopyrin®)
► Mechanism:
unknown
 little absorption of
intact Sulfasalazine: insoluble
 cleaved by colonic bacteria to
► sulfapyridine:
antirheumatic effect
► 5-aminosalicytic acid: anti-inflammatory effect
► Actions:
 Onset: 4 weeks
 RA: as effective as gold or d-penicillamine, able to
retard erosion of RA
 SAE: including psoriatic arthritis
Sulfasalazine(Salazopyrin®)
► Indications:
 R.A.
 Spondyloarthropathy
 Inflammatory colitis: Ulcerative colitis,
Crohn’s disease
► Prescriptions:
 500mg QD x 1 week, 500mg BID x 1 week,
 500mg-1000mg BID x 2-4 weeks
 Maximal: 1000mg TID
®
Sulfasalazine(Salazopyrin )
► Major
Adverse Reactions:
 Hematological:
a. Leukopenia 1-3%, mostly in first 6 months
b. Hemolysis
 Skin:
►skin
rash: pruritic, maculopapule; 1-5%
►Steven-Johnson’s syndrome ( rarely )
 Lung: acute fibrosing alveolitis with eosinophilia,
reversible
Sulfasalazine
► Minor
®
(Salazopyrin )
Adverse Reactions:
 GI upset: nausea, abdominal pain
►enteric-coated
is better
 CNS: headache,lightheadedness, dizziness
 Hepatotoxicity
►close
F/U if GPT <4X elevation
►usually returning to normal within 3 months
Sulfasalazine(Salazopyrin®)
Common Adverse Effects
GI
Nausea, vomiting, anorexia, malasie,
abdominal pain, indigestion,
dyspepsia
CNS
Headache, fever, lightheadness,
dizziness
Less Common Adverse Effects
Skin
Rash ( Exanthemlike )
Hepatic
Marginal enzyme elevations
Hematologic Leukopenia, Hemolysis,
Methemoglobinemia
Cytotoxic agents
Class
Typical Agents
Mechanisms
Alkylating
agents
-Cyclophosphamide
-MMF
Cross-linkage of
DNA
Purine
analogues
Pyrimidine
analogues
-Azathioprine
Inhibition of nucleic
acid synthesis
Inhibition of nucleic
acid synthesis
Folic acid
antagonists
-Methotrexate
-Leflulomide
Binds with high
affinity to
dihydrofolate
reductase
Azathioprine
®
(Imuran )
► Mechanism:
inhibit adenine
& guanine ribonucleotides
► Actions:
 reduce circulating B cells & T cells (esp
suppressor CD8)
 reduce IgM & IgG synthesis
 reduce IL-2 synthesis
Azathioprine
®
(Imuran )
► Indications:
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R.A.
ITP
Lupus nephritis
SLE with refractory skin rash
► Prescription
 25mg (0.5# ) QD, slowly increased (>4wks)
with increment 25mgQD (maxima: 50mg BID)
Azathioprine
► Adverse
®
(Imuran )
Reactions:
 Bone marrow suppression
►not dose-related
 Hepatotoxicity: usually reversible
Cyclophosphamide
®
(Endoxan )
► Mechanism:
 cross-linked DNA, cytotoxic effect to resting &
dividing lymphocytes
► Actions:
 decrease T-cell (esp Helper CD4 cell) &
activated T cells
 decrease B cell
Cyclophosphamide (Endoxan®)
► Indications:
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
Lupus nephritis
SLE with CNS involvement
Pulmonary involvement of autoimmune disease
Vasculitis syndrome: polyarteritis nodosa,
Wegner’s granulomatosis
► Prescriptions:
 IV pulse therapy: start from 10mg/kg every time,
reduced dose under CCr
► Increase
dose by 50-100mg under WBC count 2 weeks
after latest pulse therapy
 Oral 50mg QOD, slowly increased under
therapeutic effect and WBC count: more potent,
more toxic
Cyclophosphamide
► Adverse
®
(Endoxan )
Reactions:
 Bone marrow suppression: dose-related
►Leukopenia
is most frequently
►reduced dose if WBC <2500; DC if WBC <2000
 Hemorrhagic cystitis
►due
to urinary metabolite: Acrolein
►related to duration of urine retention
►reduced by mesna
►less frequent by IV pulse therapy
Cyclophosphamide
®
(Endoxan )
 Infertility: Azoospermia, Premature ovarian
failure
►Female:
Age-related > 24 y/o, child baring age
►Male: cumulative dose >18gm
 Carcinogenesis
►12.8X
of all cancers
►10.9X for non-Hodgkin’s lymphoma
►10X for bladder Ca
►* our experience: most common: Cervical Ca
 Direct toxicity to skin: skin necrosis
Cyclophosphamide
®
(Endoxan )
► Monitoring:
 WBC: best indicator
►WBC:3000-3500:
optimal dose
►WBC<2500: reduced dose
►WBC<2000: DC
 Close F/U any sign of malignancy
Methotrexate
®
(MTX )
► Mechanism:
 Folic acid analogue
 inhibit dihydrofolate reductase, thymidylate
synthetase, AICAR activity
 IL-1 & IL-2 suppression
► Actions:
 decreased RF-IgM production
 decreased IL-1 secretion, production & binding
 decreased IL-6 activity
Methotrexate
®
(MTX )
► Indications:
 R.A.
 Spondyloarthropathy esp. psoriatic arthritis
 SLE with active peripheral
arthritis/Jaccoud’s deformity
 Myositis
 Bronchial asthma: as steroid sparing agent
 Chronic recurrent urticaria: as steroid
sparing agent
Methotrexate
®
(MTX )
► Contraindications:
 chronic renal failure
 relative: age >60
► Adverse
Reactions:
 Mucositis: stomatitis & dyspepsia: most
common
►Folic
acid minimizes stomatitis
 Pulmonary fibrosis: usually reversible
 Hepatotoxicity
 Bone marrow suppression
Methotrexate (MTX®)
► Prescription:
 initial dose:7.5mg/week(2#-3#/week)
 most recomand prescription: serial q12h x3
doses in 1 week
► Monitoring
 WBC, Hb & MCV, Platelet: every 4-8 weeks
►decreased
dose if MCV increased markedly
►make sure of Folic acid supplement
►close F/U renal function
 GOT/GPT: every 4-8 weeks
 Chest X-ray: at least every 6 months
Cyclosporin
► Mechanism:
 suppress IL-2 synthesis and release
 suppress T-cell response & interaction
► Indications:
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
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
SLE with lupus nephritis
R.A.
Juvenile chronic arthritis
Psoriasis & Psoriatic arthritis
Behcet’s disease
Dermatomyositis, Polymyositis
Progressive systemic sclerosis
Cyclosporin
► Prescription:
contact with AIR fellow
 start from 2.5mg/kg/day in divided dose: q12h
► Adverse
Reactions:
 Nephrotoxicity:
► dose-related:
usually >5mg/kg/day
 Hypertention
► avoid
K-sparing diuretic: possible hyperkalemia
► Calcium channel blocker: might raise cyclosporin level
 Hepatotoxicity: dose related
FK506 ( Tacrolimus ) : Topic use in atopic dermatitis
and cutaneous lupus
Cellcept (Mycophenolate Mofetil)
►
• Mechanism
– Reversible inhibition of inosine-5’-monophosphate
dehydrogenase (IMPDH) by mycophenolic acid
• Indications
–
–
–
–
SLE and Lupus nephritis
Pemphigus/Pemphigoid
Autoimmune hepatitis
ITP
Cellcept
250mg
Myfortic
180mg
Cellcept (Mycophenolate Mofetil)
• Prescription
– Start from 500mg BIDAC (2# BIDAC)
– Raised 250-500mg/1-2 weeks to optimal dose
• Adverse reaction
– GI: abdominal pain, nausea, diarrhea
– Hepatotoxicity: GPT elevation
– Bone marrow suppression
• Leukopenia
• Anemia: esp renal insufficiency case
– Increased CMV infection in renal/heart transplantation
cases
Danazol
► Danazol:
a derivative of the synthetic
steroid ethisterone, a modified testosterone
► Indication
-ITP
-Anti-phospholipid Ab syndrome
► Contra-indication:
-Pregnancy
► Adverse
effect:
-Hirsutism, decreased breast, testis size
-Body weight gain
► Prescription:
600-900mg/day, in dividing dose, BID
Dose
Target
Indication
Side effect
AP
breastfeed
Constitutional,
cutaneous,
musculoskeletal
GI, Retina, skin
AP (o)
Feed (x)
1.Steroid-sparing /c mildto moderate disease
2.Maintenance of CYC
Acute
myelotoxicity( esp.
combine Allopurinol)
AP(O)
Feed (x)
1.GI: mucositis,
hepatotoxicity (esp.
combine alchol)
2. Alopecia
3. MTX-induced
pneumonitis
AP (X):
discontinue
6 months
Antimalarial
HCQ:
200mgQD or
BID
Azathioprine
2-2.5mg/kg/D
Methotrexate
7.5-15mg/wk
Cyclosporine
2.5-5mg/kg/D
Inhibit proliferation
of T cell and
selectively inhibits
T-cell-mediated
responses
Proteinuria, leukopenia,
thrombocytopenia,
complement levels
HTN, hepatic and
renal toxicity,
hypertrichosis,
gingival hypertrophy
AP (O)
Feed (X)
Mycophenol
ate moferil
500-1500mg
BID
Both T and B cell
Lupus nephritis
GI (nausea, bloating,
diarrhea),cytopenia
AP (?)
Feed (?)
Decrease T and B
cell proliferation
More favorable than CYC
or MTX
Leflunomide
Both cellular and
humoral immune
function
Thanks for your attention
Dapsone
► 屬sulfone類
► Indications:
 SLE with refractory skin rash
 Some kinds of vasculitis
► Contraindication:
 G6PD deficiency
Dapsone
►
Adverse Reactions:
 Hemolytic anemia
► dose-related
 Allergic reaction: pruritic skin rash, fever
(1)最常見為腸胃道不適，包括噁心、嘔吐、食慾不振。
(2)溶血反應及 methemoglobinemia，可發生於每日劑量超過
300mg時，但在G6PD缺乏病患身上，少劑量亦可發生。
(3)開始用藥時可發生”sulfone-syndrome”，即
mononucleosis-like 症候群，臨床表現有黃疸、發燒、皮疹
及淋巴結腫大，但繼續增加劑量後可減緩其症狀。
(4)嚴重肝功能障礙病患需減量
► Monitoring
 CBC every 4-8 weeks,close F/U MCV
Drugs for Gouty arthritis
► Confirming
diagnosis is most important:
 Synovial fluid aspiration is the only definite
diagnosis
► Acute
attack: NSAID & Steroid are most
effective
 but never double NSAID: IM & oral
► Colchicine:
low dose usage; 1# BID-TID
 Decreased or DC Colchicine after 1 year without
attack
Drugs for Gouty arthritis
Uric acid lowering agents:
► Never change (add or DC) 2 weeks
within acute attack
► Xanthine oxidase inhibitor: Allopurinol
 close F/U renal function
 start from 1# QD, increment 1# every 2-3
months till U.A: <5.0
 close F/U any sign of skin rash/oral ulcer
Drugs for Gouty arthritis
► Uricosuic
agent: Benzbromarone
 only for undersecretion type: 24hrs urine UA<
800-1000mg/day
 Contraindications:
►Chronic
renal failure, Cr>2.0
►Urolithiasis