免疫抑制藥物課件

抗風(fēng)濕性疾病的藥物大致可分為三大類：非甾體抗炎藥(NSAIDs)糖皮質(zhì)類固醇改變病情抗風(fēng)濕藥(disease

modifyinganti-rheumatic

drug，DMARD)非甾體類抗炎劑NSAIDsIndicationsPain

and

stiffness

in

inflammatoryarthritisShort

term

and

intermittent

useinosteoarthritisSoft

tissue

conditions,

includingfibromyalgia所有NSAIDs在治療OA大于6-12周，療效相同近來研究著重于改善胃腸道的耐受性COX-2特異性抑制劑（celecoxib,rofecoxib）胃腸道安全性高，由于不抑制COX-1，耐受性、安全性提高，嚴(yán)重上消化道副作用如穿孔、潰瘍和出血明顯降低COX-2特異性抑制劑適應(yīng)癥Age

over

65Using

concomitant

medications

likely

toincrease

GI

adverse

effects(e.g.steroids,

warfarin)Those

requiring

prolonged

use

ofmaximum

dose

NSAIDs(e.g.

persistentinflammatory

arthritis)Serious

co-morbidity,

e.g.

diabetesmellitus,

renal

or

hepatic

impairmentCOX-2特異性抑制劑禁忌With

caution

in

those

with

a

history

ofpeptic

ulcerationAvoided

in

those

with

previoushaemorrhage

or

perforation各種NSAIDs相比Many

NSAIDs

are

availableNone

is

unequivoclly

superior

in

termsofefficacyFrequency

of

adverse

reactions

–gastrointestinal,

hepatic,

renal

andcardiovascular

–

associated

with

eachNSAID

variesPrescribing

habits

amongrheumatologists

also

vary

widelyDisease-modifying

Drugs(DMARDs)本組藥的共同點(diǎn)是抑制淋巴細(xì)胞的生成及增殖以達(dá)到免疫抑制作用其不同點(diǎn)是各個(gè)藥物通過不同途徑，抑制不同的但為細(xì)胞合成DNA所需的核苷酸而達(dá)到抑制淋巴細(xì)胞常見不良反應(yīng)骨髓抑制、周圍血細(xì)胞減少肝功能損害腎功能損害肺纖維化脫發(fā)胃腸道癥狀感染等免疫抑制的分類(根據(jù)合成方法)微生物酵解產(chǎn)物:CsA類、FK506、rapamycin及其衍生物SDZRAD、mizoribinine(MZ)等完全有機(jī)合成物:激素類、硫唑嘌呤、來氟米特等半合成化合物:MMF、SDZIMM125、DSG(脫氧精瓜素)等生物制劑:ATG、anti-TNF

alpha

antibody等根據(jù)作用機(jī)制，可分為5類細(xì)胞因子合成抑制劑：CsA類、FK506細(xì)胞因子作用抑制劑:RPM、來氟米特DNA或RNA合成抑制劑:MZ、RS61443、可能還有來氟米特細(xì)胞成熟抑制劑:DSG非特異性抑制細(xì)胞生長誘導(dǎo)劑:SKF105685常用免疫抑制劑作用機(jī)制甲氨蝶呤干擾嘌呤和嘧啶核苷酸硫唑嘌呤干擾腺嘌呤及鳥嘌呤核苷酸來氟米特干擾嘧啶核苷酸麥考霉酚酯酸干擾鳥嘌呤核苷酸環(huán)噒酰胺交義聯(lián)結(jié)干擾DNA合成環(huán)孢素抑制IL-2的合成及釋放以抑制T淋巴細(xì)胞生長Methotrexate(MTX)IndicationsUsed

for

treatment

of

activeinflammatory

arthritis-usuallyrheumatoid

arthritis

and

psoriaticarthropathyMode

of

action

unkown,

slow

actingover4weeks-4monthsAdministrationOnce

weekly

oraldoseMay

be

given

intramuscularly

orsubcutaneously

if

response

to

oral

routeinsufficientUsual

dose

7.5-20

mg

weekly;

comes

in2.5

mg

or

10

mgtabletsFolic

acid

5

mg

the

day

after

MTXreduces

GIT

side

effectsGive

annual

influenza

vaccineSide

Effects(1)Well

tolerated

overallNausea

on

day

of

dosage

most

commonside

effectCo-prescription

of

granisetron

mayovercomes

thisLiver-

may

cause

abnormal

liver

functiontests

(LFTs),

especially

AST/ALT(SGOT,SGPT)Side

Effects(2)-enzyme

elevation

>3

times

baseline

isan

indication

to

temporarily

withdrawdrug-lesser

abnormalities

–

can

observe-persistent

LFTs

increase

–

liver

biopsymay

berequiredSide

Effects(3)Lung-

pneumonitis

has

been

described

in3-4%

on

MTX,

so

consider

chestradiograph

in

those

who

developrespiratory

symptoms,

e.g.

cough,fever,

dyspnoeaDiarrhoea,

mouth

ulcers,

abdominaldiscomfort

–

may

respond

to

anincrease

in

folic

acid

dosageSide

Effects(4)Leucopoenia/thrombocytopenia

–uncommonTeratogenic

–

should

not

be

used

inpregnancyConception

should

be

avoided

for

6months

after

cessation

of

treatment

inboth

men

and

womenInteractionsDiclofenac(potentiation

of

MTX

effects);trimethoprim(folate

antagonism)Retinoids(e.g.

isotretinoin)Alcohol

consumption

increases

risk

oftoxicitySafety

MonitoringFBC

and

LFTs

monthly

for

first

3

monthsof

therapy

and

every

2

monthsafterwardsWhen

to

Withhold

MTXLiver

enzymes

>

3

times

baselineSerious

concomitant

medical

illnessAcute

infectionAcute

pulmonary

symptomsPregnancySkin

rash

or

oral

ulcersIt

is

not

necessary

to

stop

methotrexatebefore

or

after

surgery

–

no

evidence

ofexcess

infection

or

delayed

wound

healing

inthose

remaining

onMTXSulfasalazine5-氨基水楊酸和磺胺吡啶用于抗風(fēng)濕作用不甚清楚,可能: 對(duì)腸道菌群作用抑制前列腺素合成抑制脂氧酶代謝

抑制白細(xì)胞功能IndicationsInflammatory

arthritis

–

RA,

psoriaticarthritis,

seronegative

arthritisOnset

of

action

delayed

for

severalweeks

to

monthsDoseStart

at

500

mg

twice

dailyIncrease

after

1

week

to

maintenancedose

of

1g

twice

dailySide

EffectsNausea,

anorexia,

headache,

mouthulcers

most

commonSome

patients

report

yellowdiscoloration

of

skin,

urine

or

contactlensesOligospermia(usually

reversible)SkinrashAlopeciaMood

–

depression,

irritabilityDrug

MonitoringFBC

and

LFTs

monthly

for

3

months,then

every

3

monthsWhen

to

Stop

TreatmentWCC

drops

below

4000

(neutrophils

<2000)Platelets

below

100000LFTs

>

twice

normalHydroxychloroquineIndicationsSLERASjogren’s

syndromeDose200

–

400

mg

daily

–

do

notexceed6.5mg/kg

(higher

doses

associated

witheye

toxicity)400

mg

daily

for

3

months

–

200

mgdailySide

EffectsRashDepigmentation

of

hair

and

skin

–reversibleEyes

–

retinopathy

and

corneal

deposits(rare

if

daily

dose

<6.5mg/kg)LeucopeniaThrombocytopeniaGIT

intoleranceMonitoringEyes

–

ophthalmology

review.

Needforthis

is

controversial

if

6.5

mg/kg

per

dayis

not

exceeded.

Some

recommendreview

only

after

5

years

of

therapyAzathioprineIndicationsConnective

tissue

diseaseRADoseMaintenance

of

100-150

mg

daily

dependingon

body

weight

and

hepatic

and

renalfunction

(maximum

2.5

mg/kg)Give

annual

flu

vaccineCheck

ror

thiopurine

S-methyltransferase(TPMT)

deficiency

beforestarting

aathioprine

if

available

locally.Enzyme

deficiency

inhibits

drug

metabolism,causing

toxicitySide

EffectsHypersensitivity

(uncommon)

–

flu-likereaction

–

discontinue

immediatelyGIintoleranceIncreased

risk

of

malignancy

with

long-term

useMalaiseLeucopeniaThrombocytopeniaMonitoringMonthly

FBC

andLFTSDiscontinue

therapy

if-

WCC

<

4000-

platelets

<

150

000AvoidAllopurinol–

inhibits

metabolism

ofazathioprine

and

may

lead

todrugtoxicityGoldIndicationsRA

–

now

rarely

usedAdministered

as

deep

intramuscular(IM)injectionInitially

as

test

dose

of

10

mg,

followedby

50

mg

weekly

dose

until

1g

has

beengiven,

then

50

mg

IM

monthlyAuranofin,瑞得商品名為金諾芬3mg

2/日或3mg

3/日較肌注安全,偶有皮疹Side

Effects(1)ItchRashMouth

ulcersThrombocytopeniaNeutropeniaPneumonitisProteinuriaSide

Effects(2)If

“trace”

on

>2

consecutive

occasions,stop!

–

recheck,

restart

if

absentIf

proteinuria

>

1+persists,stop

and

do24-hour

urine.

If

protein

loss

<

500mg/24

h,

continue

cautiously

andmonitorNB:

can

cause

membranousglomerulonephritisMonitoringFBC

and

urinalysis

before

each

injectionCiclosporin(Cyclosporin)IndicationsRA

–

active

despite

other

DMARDSLess

commonly

used

since

advent

ofbiologic

therapiesDose2.5-3

mg/kg

in

divided

doses

for

6weeksMaintenance

–

titrate

according

toefficacy

and

tolerability

up

to

maximumof

5

mg/kg

per

dayOnset

of

clinical

response

–

1-3

monthsGive

annual

flu

vaccineContraindicationsImpaired

renal

functionUncontrolled

hypertensionUncontrolled

infectionMalignancyPregnancy

andbreast-feedingSide

Effects(1)Renal

toxicityReduce

dose

if

serum

creatinineexceeds

normal

range

or

increase>50%

of

retreatment

levelsRepeat

creatinine

1

week

later;

if

stillelevated,

stop

cyclosporinHypertensionLiver

function

–

a

slight

increase

inliverenzymes

is

expectedSide

Effects(2)HyperlipidaemiaHyperkalaemiaAnaemiaGum

hyperplasiaConvulsionsGastric

intoleranceHypertrichosisImmunosuppressionMonitoringFBS

and

ESRU&E,

creatinine,

urate,

LFTsFasting

lipids,

magnesiumBlood

pressureAbove

tests

at

baseline,

at

fortnightlyintervals

for

first

3

months,

thenmonthlyCyclophosphamideIndicationsRA

–

particularly

with

vasculitis,

SLE,Wegener’s

granulomatosis,

polyarteritisnodosaDoseUsually

given

in

pulsed

IV

doses

forsevere

SLE

or

systemic

vasculitis(0.5-1.0g/m2體表面積每3-4周一次)Can

also

be

given

orally

1

mg-1.5mg/kg

dailyConsider

adding

oral

septrin(sulfamethoxazole/trimethoprim)

forPneumocystis

carinii

prophylaxisSide

EffectsGIT

upsetHairlossAmenorrhoea/azoospermia

–

usuallyreversible

on

discontinuation

of

therapybut

may

cause

gonadal

failure

–considerovary

protectionChemical

or

haemorrhagic

cystitis

–advise

patient

about

adequate

fluidintake(1-2L/day)Side

Effects(2)Pulmonary

fibrosisDrug

interactionsallopurinolpotentiates

effects

of

sulfonylurea

orother

hypoglycemic

agentsMonitoringCheck

FBC

and

ESR

fortnightly

for

first

8weeks

and

then

monthly

thereafterConsider

stopping

therapyIf

any

of

the

following

develops: Leucopenia ThrombocytopeniaSevere

dysuriaSignificant

pulmonary

symptomsLeflunomideInhibits

the

production

of

pyrimidineribonucleotides

and

hence

cellreplicationLoading

dose

100

mg

daily

for

2-3

days,thereafter

10-20

mg

daily(loading

dosemay

be

omitted

–

reduces

side

effects)Adverse

effects

–

headache,

vomiting,diarrhoea,

alopecia,

hypertension,marrow

toxicity,

weight

lossMen

and

women

should

not

reproducewhile

taking

leflunomide(teratogenic)FBC

every

2

weeks

for

3

months,

LFTsmonthly

for

6

monthsExtremely

long

half-life

so

washoutwithcholestyramine

may

be

needed

fortoxicity

or

unexpected

pregnancy麥考酚酸嗎啉乙酯(Mycophenolate

mofetil

,驍悉)選擇性抑制次黃嘌呤單磷酸脫氫酶阻斷鳥苷酸合成用于SLE、RA等0.5 2/日對(duì)骨髓有抑制作用Biological

AgentsEtanerceptA

recombinant

TNF

alpha

receptor,

Fc

fusionproteinBinds

to

TNF

alpha,

blocking

its

interactionwith

cell

surface

receptorsSelf

administered,

25

mg

subcutaneouslytwice

weeklyAdverse

effects

–

injection

site

reactions.

Rarereports

of

pancytopenia,

aplastic

anaemiaLong-term

safety

unknown;

possible

increasepredisposition

to

malignancy

or

infection.Some

reports

of

demyelinationOnset

of

action

in

weeks

–

often

givenin

conjunction

withMTXChest

radiograph

and

tuberculin

testbefore

treatmentDuration

of

therapy

unknownInfliximabAlso

anti-TNF

alphaA

monoclonal

antibody

which

bindstoboth

serum

and

membrane

boundTNFalpha

inhibiting

its

functionAdminstered

by

IV

infusion

(3

mg/kgover

2

h)

at

0,

2,

6

weeks

andthereafter

every

8

weeksGiven

in

conjunction

withMTXAdverse

ef