1

PEMLIHAN OBAT REMATIK PEMLIHAN OBAT REMATIK YANG AMAN UNTUK YANG AMAN UNTUK

PENDERITA GERIATRIPENDERITA GERIATRI

EDU TEHUPEIORYEDU TEHUPEIORY

SUB-DEVISI REUMATOLOGI SUB-DEVISI REUMATOLOGI BAGIAN ILMU PENYAKIT DALAM BAGIAN ILMU PENYAKIT DALAM

FAKULTAS KEDOKTERAN FAKULTAS KEDOKTERAN UNIVERSITAS HASANUDDINUNIVERSITAS HASANUDDIN

MAKASSARMAKASSAR

2

PENDAHULUANPENDAHULUAN

Mukosa lambung sangat rentang alami Mukosa lambung sangat rentang alami injuryinjury oleh hiperproduksi asam, garam oleh hiperproduksi asam, garam empedu, alkohol dan NSAIDS.empedu, alkohol dan NSAIDS.

Untuk melindungi mukosa lambung Untuk melindungi mukosa lambung terdapat terdapat cytoprotection cytoprotection yang dimediasi yang dimediasi oleh prostaglandin PG2.oleh prostaglandin PG2.

3

Nonsteroidal anti-inflammatory Nonsteroidal anti-inflammatory Drugs (NSAID) are the most used Drugs (NSAID) are the most used classes of medication world wide.classes of medication world wide.

NSAID Gastro – Enteropathy are the NSAID Gastro – Enteropathy are the most prevalent of adverse drug most prevalent of adverse drug reactions.reactions.

4

Goals of Arthritis TherapyGoals 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

Relieve pain/inflammation

Minimize risks of therapy

Retard disease progression

Provide patient education

Prevent work disability

Enhance quality of life and functional independence

5

An Historical Perspective of An Historical Perspective of NSAID-Associated GI UlcerationNSAID-Associated GI Ulceration

Endoscopic ulcer point prevalence:

10–20%1

Symptomatic ulcers/ulcer complications: 2–4% per year2

Most hospitalizations occur without previous symptoms3

Endoscopic ulcer point prevalence:

10–20%1

Symptomatic ulcers/ulcer complications: 2–4% per year2

Most hospitalizations occur without previous symptoms3

1Lichtenstein et al. Arthritis Rheum. 1995;38:5–18;2FDA Drug Bull. 1989;19:3–4; 3Armstrong, Blower. Gut. 1987;28:527–532.

1Lichtenstein et al. Arthritis Rheum. 1995;38:5–18;2FDA Drug Bull. 1989;19:3–4; 3Armstrong, Blower. Gut. 1987;28:527–532.

6

NSAID Induced Serious GI NSAID Induced Serious GI ComplicationComplication

NSAID can cause serious GI complicationNSAID can cause serious GI complicationsuch as :such as :

- Perforation- Perforation- Ulcer / obstruction- Ulcer / obstruction- Serious bleeding- Serious bleeding

Complication rate in placebo group in the Complication rate in placebo group in the MUCOSA study at six months was 0,95%MUCOSA study at six months was 0,95%

Close to FDA estimates at 2-4 % per annumClose to FDA estimates at 2-4 % per annum

7

Do Different NSAID formulations Do Different NSAID formulations Reduce Reduce

Risk of GI Complication?Risk of GI Complication? Non-acetyliated salicylates or ibuprofenNon-acetyliated salicylates or ibuprofen

@ diminishes GI complication, possibly due to @ diminishes GI complication, possibly due to use use

of lower dosageof lower dosage Enteric-coated and buffered aspirinEnteric-coated and buffered aspirin

@ similar GI toxicity to plain aspirin@ similar GI toxicity to plain aspirin Other routes of administration (IM. PR)Other routes of administration (IM. PR)

@ no reduction in risk of ulcer complications@ no reduction in risk of ulcer complications ProdrugsProdrugs

@ no reduction in risk of ulcer complications@ no reduction in risk of ulcer complications

8

Prostaglandin yang diekpresi sebagai Prostaglandin yang diekpresi sebagai constitutive mannerconstitutive manner , , ditemukan pada semua subepitelium gastro-intestinal ditemukan pada semua subepitelium gastro-intestinal terutama pada lambung dimana terjadi mekanisme terutama pada lambung dimana terjadi mekanisme inter-related inter-related mechanism,mechanism, mukosa menjadi toleransi mukosa menjadi toleransi terhadap asam terhadap asam

mekanisme tersebut adalah ;mekanisme tersebut adalah ;

(a) vasodilatasi pembuluh darah mukosa lambung meningkat (a) vasodilatasi pembuluh darah mukosa lambung meningkat yang yang

memungkinkan suplai bikarbonat yang cukup dan netralisasi memungkinkan suplai bikarbonat yang cukup dan netralisasi dari dari

back-diffused acidback-diffused acid . .

(b) penurunan langsung produksi asam, termasuk (b) penurunan langsung produksi asam, termasuk histamine histamine stimulated stimulated dari sel patietal mukosa yang diatur oleh reseptor dari sel patietal mukosa yang diatur oleh reseptor EP2.EP2.

(c) peningkatan produksi mukus melalui P-GE2 dari sel2 otot (c) peningkatan produksi mukus melalui P-GE2 dari sel2 otot polos.polos.

PERANAN PROSTAGLANDIN

9

Menbrane phospholipids

Arachidonic acid

StomachKidneyPlateletsEndothelium

COX-1housekeeping

COX-2inflammation

MacrophagesLeukocytesFibroblastsEndothelium

TXA2, PGI2, PGE2

Gastrointestinal mucosal integrity Platelet aggregation Renal function

PGI2, PGE2 Inflammation Mitogenesis Bone formation Other functions ?

Phospholipase A2

Prostaglandin mempunyai peranan sentral dalam pertahanan / penyembuhan epitel lambung

Horrisons’s 16 ED Vol II : 2005 :1751

Mukosa lambung mengandung banyak prostaglandin dan berasal dari phospholipid oleh pengaruh phospholipase A2.Ensim yang berperan adalah ensim cyclooxygenase (COX) yang terdiri 2 isoensim (COX-1 dan COX-2).

10

Improving the GI Tolerability of Improving the GI Tolerability of NSAID TherapyNSAID Therapy

Take with foodTake with food Take with waterTake with water Take in upright positionTake in upright position Reduce Gastritis-inducing agentsReduce Gastritis-inducing agents

e.g alcohol, smokinge.g alcohol, smoking

11

Prevention of NSAID Induced UGIPrevention of NSAID Induced UGIUlcer/ComplicationUlcer/Complication

AGENTAGENT UlcersUlcers Adv. Adv. ReactionReaction

HH22RARA No/yesNo/yes NSNS

OmeprazoleOmeprazole YesYes NSNS

SulcralfateSulcralfate NoNo NSNS

MisoprostolMisoprostol YesYes YesYes

12

Major Risk Factors for Major Risk Factors for GIT ToxicityGIT Toxicity

Age, level of disability.Age, level of disability. Previous history peptic ulcer disease.Previous history peptic ulcer disease. History of taking anti ulcer medications.History of taking anti ulcer medications. NSAID dosage.NSAID dosage. Concomitant Glucocorticoid use.Concomitant Glucocorticoid use.

13

Risk Factors for GI ComplicationsRisk Factors for GI ComplicationsOccurring with NSAIDOccurring with NSAID

Patient-related factorsPatient-related factors Age>60 yearsAge>60 years

History of ulcer diseaseHistory of ulcer disease

Drug-related factorsDrug-related factors Use of relatively toxic NSAIDUse of relatively toxic NSAID

High dose of NSAID (or two NSAIDs High dose of NSAID (or two NSAIDs used concurrently)used concurrently)

Concurrent use of anti-coagulantConcurrent use of anti-coagulant

Concurrent use of corticosteroidConcurrent use of corticosteroid

Uncertain or possible risk Uncertain or possible risk factorsfactors

Duration of NSAID treatmentDuration of NSAID treatment

FemaleFemale

Underlying rheumatic diseaseUnderlying rheumatic disease

Cardiovascular diseaseCardiovascular disease

SmokingSmoking

Alcohol consumptionAlcohol consumption

Seager JM et al BMJ 2001 ; 323 : 1236 - 9

14

Altered inflammatory mediatorProduction

(decreased PG. increased TNF)

NSAID

Increased I CAM-1 andCD11/CD8 expression

Increased neutrophil – endothelialadherence

Reduced mucosalBlood flow

Oxyradical andProtease release

Gastric Mucosal Damage

ProstaglandinsAnti – TNF

TNF inhibitors

Anti – I CAM – 1Anti – CD 18

Free radicalscavengers

NSAID GASTROENTROPATHY

Schematic diagram showing the systemic component of the pathogenesis of NSAID-induced gastric injury. In particular, This diagram emphasizes the role of neutrophil adherence to the vascular endothelium in the development of mucosa injury and the various steps at which pharmacological interventions can prevent the damage. PG, prostaglandin.

John L. Walace ; Gastroenterology 1997;112 :1000 – 1016

15

Acid

EROSIONS

HEALING (spontaneousOr therapeutic)

Epithelial effects (due to prostaglandin depletion)• HCI secretion• Mucin secretion• HCO3 secretion• Surface active phospolipid secretion• Epithelial cell proliferation

• Direct toxicity“ ion trapping”

Endothelial effects• Stasis Ischemia

ULCER

Mechanisms by which NSAIDs may induce mucosal injury. (Adapted from J Scheiman et al: J Clin Outcomes management 3:23, 1996)

Horrisons’s 16 ED Vol II : 2005 :1751

16

Normal Gastric Protective MechanismsNormal Gastric Protective Mechanisms

Acid and pepsinAcid and pepsin Stomach lumen pH 1–

2

Stomach lumen pH 1–

2PG-dependent protective factors

Mucous layer thickness

pH gradient

Bicarbonate secretion

Mucosal blood flow

PG-dependent protective factors

Mucous layer thickness

pH gradient

Bicarbonate secretion

Mucosal blood flow

Mucous layerMucous layer

Gastric epithelium

Gastric epithelium

Gastric pitGastric pit

HCO3 -HCO3 -HCO3

-HCO3 -HCO3

-HCO3 -HCO3

-HCO3 -

HCIHCIHCIHCI

pH 7pH 7

17

APAKAH SATU OAINS LEBIH BAIK DARI APAKAH SATU OAINS LEBIH BAIK DARI YANG LAINNYA SEHUBUNGAN DENGAN YANG LAINNYA SEHUBUNGAN DENGAN

KEMUNGKINAN MENIMBULKAN KEMUNGKINAN MENIMBULKAN KERUSAKAN PADA SALURAN CERNA ?KERUSAKAN PADA SALURAN CERNA ?

Lebih 10 tahun berbagai macam penelitian farmako-epidemiologik Dan meta-analisis yang memungkinkan a ranking of sorts sesuai dengan

pengalaman klinik ( lihat tabel) :

18

Tabel 1. Ranking of sorts of NSAID

LANGMAN et al. GARCIA RODRIGUEZ

CSM ranking odds ratio 95% CI odds ratio 95% CI

OVERALLIBUPROFENDICLOFENACNAPROXENKETOPROFENINDOMETHACINPIROXICAMAZAPROPAZONE

1256*

1112

4.52.04.29.1

23.711.313.731. 5

3.6 – 5.61.4 – 2.82.6 – 6.8

5.5 – 15.17.6 – 74.26.3 – 20.37.1 – 26.3

10.3 – 96.9

4.72.93.93.15.46.3

18.023.4

3.8 – 5.71.78 – 5.02.3 – 6.51.7 – 5.9

2.6 – 11.33.3 – 12.28.2 – 39.66.9 – 79.5

* not ranked by COMMITTEE SAFETY IN MEDICINES (CSM). Marketed before yellow card system. Odds ratios and 95% CI for acute GI bleeding (LANGMAN, hospital-based, case-controlled study) or bleeding and perforation (GARCIA RODRIGUEZ, GP cohort study). The CSM rank order of reports of serious GI toxicity is expressed per million prescriptions in the first five years of marketing.

A. Tyndall, P Hasler. Eular 2004Adapted from JAMA 1994

19

The Available Anti-Ulcer The Available Anti-Ulcer Strategies IncludeStrategies Include

Prevention of gastric acid secretion.Prevention of gastric acid secretion. Neutralization of gastric acid.Neutralization of gastric acid. Mucosal cytoprotectionMucosal cytoprotection

20

Ensim COX berperan penting pada pembentukan Ensim COX berperan penting pada pembentukan prostaglandin.prostaglandin.

Terdapat 2 isoform ensim COX, yaitu : Terdapat 2 isoform ensim COX, yaitu : COX-1 : diekpresikan COX-1 : diekpresikan constitutive manner constitutive manner berperan berperan

menjaga integritas mukosa lambung, ginjal dll menjaga integritas mukosa lambung, ginjal dll ( ( housekeeping housekeeping ). ).

COX-2 : COX-2 : inducibleinducible berperan pada proses inflamasi yang berperan pada proses inflamasi yang diekresi dalam makrofag, lekosit, fibroblast dan sel diekresi dalam makrofag, lekosit, fibroblast dan sel sinovia.sinovia.

Kedua ensim ini dihambat OAINS dan inhibisi terhadap Kedua ensim ini dihambat OAINS dan inhibisi terhadap cox-1 dapat mengakibatkan kerusakan pada saluran cerna cox-1 dapat mengakibatkan kerusakan pada saluran cerna terutama lambung sedangkan inhibisi COX-2 tidak terutama lambung sedangkan inhibisi COX-2 tidak menimbulkan kerusakan pada saluran cerna.menimbulkan kerusakan pada saluran cerna.

ENSIM CYCLOOXYGENASE

21

Untuk menghindarkan kerusakan pada saluran Untuk menghindarkan kerusakan pada saluran cerna terutama lambung, dibuat berbagai COX-2 cerna terutama lambung, dibuat berbagai COX-2 inhibitor inhibitor ada yang ada yang selektifselektif dan dan spesifikspesifik : :

SelektifSelektif ; : ; : An in vitro measure of relative An in vitro measure of relative amounts of drug required to inhibit each each amounts of drug required to inhibit each each enzymeenzyme

Tells little about clinical relevanceTells little about clinical relevance

SpesifikSpesifik ; ; An in vivo conceptAn in vivo concept

Clinically relevant inhibition of COX-2 without Clinically relevant inhibition of COX-2 without inhibition of COX-1inhibition of COX-1

22

PERKEMBANGAN KLINIK DENGAN OAINSPERKEMBANGAN KLINIK DENGAN OAINS

Dengan dosis yang sesuai kemanjuran Dengan dosis yang sesuai kemanjuran dari berbagai OAINS adalah sama.dari berbagai OAINS adalah sama.

Respons penderita secara individu jelas Respons penderita secara individu jelas sekali berbeda.sekali berbeda.

Seorang penderita respons yang lain Seorang penderita respons yang lain tidak.tidak.

Hipotesis : (a) variasi dalam absorpsi obat Hipotesis : (a) variasi dalam absorpsi obat (b) bioavailability (c) efek biologis obat.(b) bioavailability (c) efek biologis obat.

23

EFEK SAMPINGEFEK SAMPING

Bisa pada lambung dan duodenum.Bisa pada lambung dan duodenum. Dispepsi, mual, nausea , ulkus lambung.Dispepsi, mual, nausea , ulkus lambung. Hanya berkisar 1 – 2 %,Hanya berkisar 1 – 2 %, Terdapat beberapa mekanisme oleh Terdapat beberapa mekanisme oleh

OAINS pada saluran cerna :OAINS pada saluran cerna : (a) OAINS menekan produksi PG (b) (a) OAINS menekan produksi PG (b)

menurunkan aliran mikro-sirkulasi (c) menurunkan aliran mikro-sirkulasi (c) menaikkan menaikkan leucocyte adherens leucocyte adherens terhadap terhadap endotil vaskuler (d) mempengaruhi endotil vaskuler (d) mempengaruhi produksi mediator inflamasi.produksi mediator inflamasi.

24

GI Events* Associated With NSAIDsGI Events* Associated With NSAIDs

Most Patients AsymptomaticMost Patients Asymptomatic

N = 141N = 141 N = 1,921N = 1,921

Armstrong, Blower.Gut. 1987;28:527–532.Armstrong, Blower.

Gut. 1987;28:527–532.Singh et al.

Arch Intern Med.1996;156:1530–1536.

Singh et al.Arch Intern Med.

1996;156:1530–1536.

WithoutsymptomsWithoutsymptoms

WithsymptomsWithsymptoms

42%58%58% 81%81%19%

*Bleeding, perforation, and gastric outlet obstruction*Bleeding, perforation, and gastric outlet obstruction

25

GI Mortality Associated With TypicalNSAIDs vs Other Causes in US

GI Mortality Associated With TypicalNSAIDs vs Other Causes in US

Fries et al. Am J Med. 1991;91:213–222;Wilson, Crouch. Science. 1987;236:267–270.Fries et al. Am J Med. 1991;91:213–222;Wilson, Crouch. Science. 1987;236:267–270.

Annual risk of death (%)Annual risk of death (%)

0.250.250.200.200.150.150.100.100.050.050.000.00 0.400.400.350.350.300.30

Cigarette smokingCigarette smoking

CancerCancer

NSAID useNSAID use

Motor vehicle accidentMotor vehicle accident

Home accidentHome accident

Airplane crash (frequent flyer)Airplane crash (frequent flyer)

26

GI complications associated with nonselective NSAIDs remain an

important public health issue

• Most prominent toxicity is GI ulceration, bleeding, and perforation

• Serious NSAID-related GI complications result in 107,000 hospitalizations and 16,500 deaths annually in the US1

• Up to 80% of those hospitalized for NSAID- related GI complications had non prior GI adverse event1

Singh G, Triadafilopoulos G. Epidemiology of NSAID induced gastrointestinal

complication. J Rheumatol. 1999; 26 : 18 - 24

27

The Use of Proton Pump Inhibitor The Use of Proton Pump Inhibitor Agents for prevention and treatment Agents for prevention and treatment

G-D Erosions and UlcerationG-D Erosions and Ulceration The Scandinavian Collaborative UlcerThe Scandinavian Collaborative Ulcer

Recurrence (SCUR) Study.Recurrence (SCUR) Study.

OMEPOMEP PLACEBOPLACEBO

Peptic Ulcer (PU)Peptic Ulcer (PU) 4.7 %4.7 % 16.7%16.7%

DyspepsiaDyspepsia 8.2 %8.2 % 20 %20 %

One/ more PUsOne/ more PUs 3.6 %3.6 % 16.5%16.5%

28

Omeprazole Vs Misoprostol for NSAID-Omeprazole Vs Misoprostol for NSAID-Induced UlcerInduced UlcerManagement (OMNIUM) study (GDU and Management (OMNIUM) study (GDU and Erosions)Erosions) Study consisted of healing phase and Study consisted of healing phase and

prophylactic phase.prophylactic phase.

## In the 8-week healing phase : In the 8-week healing phase :

- Omeprazole 20 mg/day - Omeprazole 20 mg/day 75 % 75 %

- Omeprazole 40 mg/day - Omeprazole 40 mg/day 75% 75%

- Misoprostol 200 mcg QID- Misoprostol 200 mcg QID 71 % 71 %

## Treatment failure (6 months) Treatment failure (6 months)

- Omeprazole 20 mg/day - Omeprazole 20 mg/day 36,6 % 36,6 %

- Misoprostol 200 mcg/day- Misoprostol 200 mcg/day 48,6 % 48,6 %

- Placebo - Placebo 67,7 % 67,7 %

29

The Ranitidin Vs Omeprazole for NSAID – The Ranitidin Vs Omeprazole for NSAID – Associated UlcerAssociated UlcerTreatment (ASTRONAUT) :Treatment (ASTRONAUT) :

Healing – prophylactic phaseHealing – prophylactic phase

20 mg omeprazole /day20 mg omeprazole /day

40 mg omeprazole /day40 mg omeprazole /day

150 mg Ranitidine 2 x 1 /day150 mg Ranitidine 2 x 1 /day

Result after 8 weeks :Result after 8 weeks :

80% : 79% : 63%, respectively significant 80% : 79% : 63%, respectively significant improvementimprovement

in their NSAID-induced GU and erosions.in their NSAID-induced GU and erosions.

30

SUMMARYSUMMARY

Improving the GI tolerability of NSAID Improving the GI tolerability of NSAID Therapy : Take with food, take with water, Therapy : Take with food, take with water, take in upright position and reduced take in upright position and reduced inducing agents e.g alcohol and smoking.inducing agents e.g alcohol and smoking.

PPI is the most effective empiric therapy PPI is the most effective empiric therapy for NSAID associated dyspepsia.for NSAID associated dyspepsia.

PPI 40 and 20 mg/day have the same PPI 40 and 20 mg/day have the same effectiveness in patient with gastrophaty effectiveness in patient with gastrophaty induced by selective and non selective induced by selective and non selective NSAIDs.NSAIDs.