FARMAKODINAMIK

NSAIDS

URIP HARAHAP

PROGRAM MAGITER FARMASI USU

2015
PERIPHERAL MECHANISMS OF PAIN
The mechanisms of NSAIDs
The mechanisms of NSAIDs
The mechanisms of NSAIDs
 EFEK SAMPING UMUM
• Disfungsi platelet
• Gastritis dan peptik ulser + bleeding (akibat
hambatnnya thd PG + efek lain)
• Gagal Ginjal Akut (bagi individu sensitif)
• Retensi Sodium+ air dan edema
• Analgesic nephropathy (injury ginjal oleh analgesik:
aspirin, phenacetin, dan paracetamol.
• Prolongation of gestation and inhibition of labor
• Hipersesitivitas (tidak imunologis tetapi karena
inhibisi PG
 GASTRIC MUCOSA
Mucosal COX-1

PGE2 and PGI2

 acid Mucosal protection

from peptic ulcers
 mucus
THROMBOXANE A2 IN PLATELETS
Platelet COX-1

In platelets there is
only COX-1exist
Tx A2 (converts arachidonic
acid to TxA2)

Platelet aggregation
& activation
 Pharmacodynamic Effects of NSAIDs

NSAIDs and Platelets/Endothelial Cells

 Reduces platelet
aggregation
 Most of these drugs will
potentiate the action of
oral anticoagulants such
as coumadin, by their
effects on platelet
aggregation
 An 80 mg dose will
increase bleeding time
for 2 folds

Note: Selective inhibition of COX-2 will inhibit the production of PGI2 but not of
thromboxaneA2, which is produced by COX-1. SO ?
RENAL CIRCULATION

 Renal Blood Flow

Pg E2

 Renal Blood Flow

 PRODUCTION AND ACTIONS OF
PROSTAGLANDINS AND THROMBOXANE.

Mesecar, 2007
Differences between
NSAIDs and
Acetaminophen
 MECHANISM OF ACTION
PROSTAGLANDIN PHYSIOLOGY

Cell membrane phospholipid

Cell membrane damage Phospholipase A2
Arachidonic acid

Cyclooxygenase 1 & 2 Lipooxygenase

Prostaglandin G2
Leukotriene B4,

Prostaglandin H2 LTC4, LTD4, LTF4

Tissue specific prostaglandins synthase

Jeffrey A. Katz
Thromboxan A2, Prostacyclin (PGI2), PGD2, PGE2, PGF2
Reaksi katalisis oleh Cyclooxygenase (COx)
= Fosfoglandin (PG) Endoperoxide Synthase

 Kedua reaksi dikatalisis

oleh cyclooxygenase.
Reaksi I :cyclooxygenase
membutuhkan molekul
oksigen 
Prostaglandin-G2.
 Rekasi II: rekasi
peroxidase  produk
akhir (Prostaglandin-
H2).
 THE COX-1 AND COX-2 ISOZYME
STORY
• Hipotesis Flower and Vane in 1972
(Nature, 240, 410-411): isozim
cyclooxygenase.
• Secara defenitif: eksistensi 2 isozim
cyclooxygenase tahun 1991 oleh Xie et al.,
(PNAS, 88, 2692-2692).
 HASIL OBSERVASI BEBERAPA DEKADE LALU
 COX-1 ditemukan dalam tubuh: paling banyak di saluran
cerna  PG (prostacyclin, PGI2, PGE2, dll.)  cytoprotective,
COX-1 juga terdapat dalam jumlah banyak di ginjal dan
platelet.
 COX-2 derivasi PG diianggap merusak karena ditemukan
terutama di lokasi peradangan dan diperkirakan memicu,
berperanserta dalam/memperburuk proses peradangan
 Ekspresi COX-2 menginduksi inflamsi oleh cytokines:
• Interleukins-1β misal (IL)-1, dan (IL)-2
• Tumor Necrosis Factor-α (TNF)-α
• Growth Factors
 Ekspresi COX-2 ditekan oleh antiinflamasi sepert:
• L-4, IL-10, IL-13
• Glucocorticoid
• Cyclooxygenase (COX) is found bound to the
endoplasmatic reticulum. It exists in 3 isoforms:
• COX-1 (constitutive) acts in physiological
conditions.
• COX-2 (inducible) is induced in inflammatory
cells by pathological stimulus.
• COX-3 (in brain).
 COX inhibitors
Nonselective
NSAIDs COX-1/COX-2
inhibitors

COX-2 COX-3
inhibitors inhibitors
• Selective (coxibs) •Antipyretic
• Preferential analgesics
 HIPOTESIS COX-2
Hipotesis umum tentang COX-2 yang diterima oleh
komunitas farmasi: inhibitor spesifik COX-2 akan
mengurangi nyeri, demam, dan peradangan tanpa
menyebabkan injuri pada gastrointestinal atau
ginjal. Ada dua prinsip utama hipotesis ini:
1. PG memediasikan inflamasi, demam, dan nyeri yang
dihasil sendiri oleh COX-2 (inducible)
2. PG penting untuk fungsi GI dan renal yang dihasilkan
sendiri oleh COX-1 (Constitutive)
 Two FormsofofCyclooxygenase
Two Forms Cyclooxygenase

Cyclooxygenase-1
Cyclooxygenase-1 (COX-1)(COX-1) Cyclooxygenase-2
Cyclooxygenase-2 (COX-2)(COX-2)

 Produces prostanoids
Produces prostanoids  Produces prostanoids
Produces prostanoids that that
that mediate
that mediate homeostatic
homeostatic mediate inflammation,
mediate pain, pain,
inflammation,
functions
functions and fever
and fever
 Constitutive  Induced
Especially - Sites of inflammation
– Gastric mucosa - Brain
- Kidney
– Kidney
– Platelets
– Vascular endothelium
 COX INHIBITOR ACTIONS
Arachidonic acid
COX-1 COX-1 COX-2
 Anti-inflammatory
 Analgesic
 Antipyretic
 Gastrointestinal toxicity
 Renal toxicity
 Platelet impairment

Mediate
Support renal and inflammation, pain,
platelet function Protect and fever
gastroduodenal
mucosa
STRUCTURES OF CYCLOOXYGENASE (COX)
ISOENZYMES
COX-1 COX-2

Active site Active site

Hydrophobic “Side
channel pocket”
Hydrophobic
channel
CHEMICAL STRUCTURES OF TYPICAL NSAIDS
Ibuprofen Naproxen Diclofenac

Fits into main cyclooxygenase

hydrophobic channel
CHEMICAL STRUCTURE OF CELECOXIB
O
NH2
S

O
N
N
CF3
Fits into COX-2
side pocket

Fits into main

CH3
cyclooxygenase
hydrophobic channel
 MECHANISM OF NSAID INHIBITION
COX-1 COX-2

NSAID
Active site
Active site
Celecoxib

Arachidonic
acid N
N
Arachidonic
acid

“Side
N pocket”
N
Celecoxib
 COX-1 Active Site COX-2 Active Site With
With Flurbiprofen Celecoxib Prototype

Derived from data in Picot et al. Derived from data in Kurumbail et al.
Nature. 1994;367:243–249. Nature. 1996;384:644–648.
• Toksisitas NSAIDs pada renal karena
hambatannya tidak selektif (inhibis COX-1 dan
COX-2)
• Jika inhibitor selektif COX-2 dirancang
mestinya tidak mempengaruhi COX-1 agar
efek samping seminimal mungkin. Untuk itu
harus dipahami biokimia dan perbedaan
struktur antara COX-1 dan COX-2.
 NSAIDs
Loss of PGI2 induced inhibition of LTB4 mediated
endothelial adhesion and activation of neutrophils

↑ Leukocyte-Endothelial
Interactions

Capillary Proteases +
Obstruction Oxygen Radicals

Ischemic Endo/Epithelial
Cell Injury Cell Injury

Mucosal Ulceration
 Toxicity
Gastrointestinal toxicity

 Dyspepsia
• upper abdominal pain in the absence of
documented gastric mucosal damage
• annual prevalence 15%
• 12 weeks use : 2%-5% stopped NSAID use because
of dyspepsia
 GI bleeding and perforation
• the most frequently reported significant complication
• 7,000 deaths and 70,000 hospitalizations/year in the
USA
 Toxicity : Gastrointestinal toxicity
Stomach

 NSAIDs affect
- mucus and bicarbonate secretion
- blood flow
- epithelial cell turnover and repair
- mucosal immunocyte function
 Hemorrhagic gastric erosion
- : corpus
- : topical irritation
- NSAIDs : acidic irritation
topical irritation
Mechanisms by which NSAIDs may induce mucosal injury
Lüllmann, Color Atlas of Pharmacology – 2nd Ed. (2000)
 Toxicity : Gastrointestinal toxicity
Stomach

 Gastric/duodenal ulcer
- antral and prepyloric lesion
- inhibition of prostaglandin synthesis
- silent ulceration is common
: NSAIDs-related ulcer 70%
 Risk factors of NSAIDs gastropathy
- prior history of peptic ulcer disease
- steroid use  Other risk factors
- alcohol use • H. pylori, NSAIDs-related
- multiple NSAID use gastropathy
• NSAIDs and H.pylori infection
 Toxicity : Gastrointestinal toxicity
Small intestine and Colon

 Colitis
 NSAID enteropathy
 NSAID changes in permeability and protein
wasting
 prevented by use of misoprostol, COX-2
inhibitor
 Toxicity : Gastrointestinal toxicity
Prevention of NSAID gastropathy

 Antacids & enteric coated NSAIDs

• limited success
 Cimetidine and ranitidine
• effective in treatment, but not effective in prevention
 Sucralfate
• Basic aluminum salt of sucrose octasulfate
 forming a complex with proteins at an ulcer base
 stimulating prostaglandin synthesis in gastric mucosa
 promoting gastric mucus secretion by a prostaglandin-
independent mechanism
• Side effect : low
• preventive effect : gel formulation
 Toxicity : Gastrointestinal toxicity
Prevention of NSAID gastropathy

 Misoprostol
• Synthetic analogue of prostaglandin E1
• Preventive effect : successful
 placebo, sucralfate
• Side effect : diarrhea & relatively expensive
 high risk group
 Proton pump inhibitor (omeprazole)
• preventive effect : successful
 Toxicity : Renal toxicity
(1) Reduction in renal perfusion
 PGE2 : in the cortex
 PGI2 : in the tubules & medullary interstitial cells
• act as direct vasodilators
• attenuate vasoconstrictive effects of angiotensin II,
renal sympathetic activity, catecholamines
 Prostaglandin regulation of renal blood flow
• clinically significant in susceptible individuals, but not in
normal patients
 PGH2 & TXA2 : potential renal vasoconstrictors
• renal response depend on relative amount of PGE2, PGI2,
PGH2 and TXA2
 TOXICITY : RENAL TOXICITY
(1) REDUCTION IN RENAL PERFUSION
 Susceptible individual
: renal prostaglandin-dependent state (RPDS)
- elevated renal sympathetic nerve and/or angiotensin II activity

volume depletion, low cardiac output, hepatic cirrhosis

renal ischemia, aminoglycoside toxicity
unilateral or subtotal nephrectomy, hypertension,
diabetes
 Renal blood flow 
 glomerular filtration rate 
 water & electrolyte reabsorption in proximal tubule 
 antagonize anti-hypertensive therapy
& exacerbate congestive heart failure
 Toxicity : Renal toxicity
(2) Acute interstitial nephritis
 Acute
There renal failure
is no evidence with
that COX-2tubular necrosis
selective inhibitors  acute
confer any
overdose
additional safety benefit in terms of renal toxicity
: COX-2 is constitutively expressed in the kidney
 Allergic nephritis
- tubulointerstitial nephritis with proteinuria
- treatment : steroid and dialysis

(3) Minimal change nephrotic syndrome

 Discontinuing the drug typically results in complete

remission in a few weeks
 Toxicity : Hematologic toxicity
(1) Inhibition of TXA2 formation
 PGH2  TXA2 in platelet : platelet activator, vasoconstrictor
 PGH2  PGI2 in vascular endothelium : platelet inhibitor,
vasodilator
 When NSAIDs inhibit COX
• platelet have no nucleus  unable to form additional COX
• vascular endothelium  able to create more COX
 Irreversible inhibition : aspirin
• takes 7 to 10 days for platelet to recover
• BT tend to normalize sooner : uninhibited platelet from BM
 Reversible inhibition : non-aspirin NSAIDs
• resolve when the drug is mostly eliminated
• single dose of ibuprofen : 24 hours
 Renal Autoregulation
Autoregulation is the maintenance of a
near normal intrarenal hemodynamic
environment (RBF, RPF, FF and GFR)
despite large changes in the systemic
blood pressure
 RENAL AUTOREGULATION
• RBF - blood perfusing the kidneys each minute
(1200 ml/min)
• Renal Plasma Flow (RPF) - plasma flowing to
kidneys each minute (670 ml/min or 55-60% of
RBF)
• GFR - amount of plasma filtered each minute by the
glomeruli. (Normal GFR -125 ml /min for men and
100 ml/min for women)
• Filtration Fraction (FF) - the ratio of GFR to RPF
(Normal - .18 - .22)
 RENAL AUTOREGULATION

F = P RAP
RBF ~
R Raff + Reff

F = Flow RBF = Renal blood flow

P = Pressure Changes RAP = Renal arterial pressure
R = Resistance Raff = Afferent arteriolar resistance
Reff = Efferent arteriolar resistance
 RENAL BLOOD FLOW (RBF)
• Major sites of renal vascular resistance -
Glomerular afferent (Raff ) and efferent
(Reff) arterioles
• Changes in Raff and Reff affect RBF.
 INTRARENAL AUTOREGULATION

Vasodilators Vasoconstrictors
– PGs – Renin
– Kinins – Angiotensin II
– NO – Endothelin
– ANP – ADH

RBF
GFR
Figure : RBF/GFR is maintained by a balance between vasodilators and
vasoconstrictors of Afferent and Efferent arterioles
 INTRARENAL MECHANISMS FOR
AUTOREGULATION
Afferent Efferent
Arteriole Arteriole
RBF
PGC
Glomerulus Reff / Raff ratio =N

Tubule

GFR. N Engl J Med 357;8 August 23, 2007

Figure - shows normal conditions

normal renal perfusion pressure and a normal GFR.
 INTRARENAL MECHANISMS FOR AUTOREGULATION
MAP
UNDER DECREASED PERFUSION PRESSURE
Afferent
Arteriole
RBF Efferent
PGC Arteriole

Ang II
PGE

Reff / Raff ratio =

GFR. N Engl J Med 357;8 August 23, 2007

Figure: shows reduced perfusion pressure within the autoregulatory range.

Normal glomerular capillary pressure is maintained by afferent vasodilatation
and efferent vasoconstriction.
REDUCED PERFUSION PRESSURE WITH A NSAID.
Reff / Raff ratio
Efferent
RBF Afferent
Arteriole Arteriole

PGE
PGC Ang II
Θ
NSAID

GFR
N Engl J Med 357;8 August 23, 2007

Figure: Loss of vasodilatory PGs increases afferent resistance causing drop in the
glomerular capillary pressure below normal values and the fall in GFR
 REDUCED PERFUSION PRESSURE WITH AN ACEI
OR ARB. Reff / Raff ratio

Efferent
RBF Afferent
Arteriole
Arteriole

PGE
PGC Ang II

Θ
ACEI /ARB

GFR N Engl J Med 357;8 August 23, 2007

Figure: Loss of angiotensin II action reduces efferent resistance;

this causes the glomerular capillary pressure to drop below normal values and
the GFR to decrease.
 RENAL AUTOREGULATION FAILURE

• Renal autoregulation breaks down as

MAP falls below 80 mm Hg,
• Further adjustments in intra-renal
hemodynamics are unable to maintain
RBF and GFR
• Hallmark of ARF

After age 30, RBF/ GFR decreases progressively with age; at 80 years it is nearly
half of that at 20 years
 RENAL AUTOREGULATION FAILURE
Afferent glomerular arteriolar vasoconstriction
– Sepsis
– Hypercalcemia
– Hepatorenal syndrome
– Cyclosporine or tacrolimus
– Radiocontrast agents
Failure to increase efferent arteriolar resistance
– ACEI
– Angiotensin-receptor blockers
Renal - artery stenosis

N Engl J Med 357;8 August 23, 2007

 RENAL AUTOREGULATION FAILURE
Failure to decrease arteriolar resistance
• Structural changes in renal arterioles and small
arteries
– Old age, Atherosclerosis
– Chronic HTN, Malignant or accelerated HTN
– CKD
• Reduction in vasodilatory prostaglandins
– NSAIDs
– Cyclooxygenase-2 inhibitors

N Engl J Med 357;8 August 23, 2007

www.freelivedoctor.com
 ANTICIPATED SAFE

 Keamanan dan cost-effective penggunaan NSAIDs dapat

dicapai dengan membatasi durasi terapi, penggunaan obat
yang tepat, mengurangi duplikasi terapi, menurangkan risiko
ADRs GI dengan mentritmen yang tepat, mencegah co-
therapy atau menggunakan COX-2 inhibitors, serta
meminimalkan interaksi obat .
 Physicians will be more aware of the costs of various NSAIDs,
as well as the costs of preventive GI co-therapies and COX-2
inhibitors.

© Copyright 1999 – 2004 Affiliated Computer

Services, Inc. All Rights Reserved
 Use of COX-2 inhibitors in the absence of risk
factors for GI toxicity

 NSAID non-selektif dan selektif COX-2 inhibitor dilaporkan

memiliki khasiat analgesik yang setara.
 Penggunaan selektif COX-2 inhibitor tanpa faktor risiko biaya
tidak efektif karena COX-2 inhibitor lebih mahal ketimbang
NSAID nonselektif generik.

© Copyright 1999 – 2004 Affiliated Computer

Services, Inc. All Rights Reserved
 Increased risk of adverse events: NSAID use with
H2 receptor antagonist or sucralfate therapy
 Penggunaan NSAIDs sebagai terapi profilaksis pada
asimtomatik GI tidak dianjurkan karena potensi gejala GI akan
tertutupi tanpa mengurangi risiko komplikasi GI yang serius.
 Terapi Co-profilaksis mungkin diperlukan bagi pasien dengan
faktor risiko toksisitas GI.
• Misoprostol has been approved by the FDA for prophylaxis
against gastric and duodenal ulcers associated with NSAID
use.
• Proton pump inhibitors may be an acceptable alternative.
• H2 receptor antagonists, sucralfate and antacids have not
been found to effectively prevent NSAID-induced ulcers.

© Copyright 1999 – 2004 Affiliated Computer

Services, Inc. All Rights Reserved
 Therapeutic Duplication:
Concurrent use of >1 NSAID

Multiple NSAIDs should not be used concurrently

due to increased risk of GI adverse effects and lack
of evidence of increased efficacy.