3.kuliah nsaid

NSAID (non steroid anti inflammation drugs) & opioid analgesic drugs

Nur permatasari

Overview

Definition: NSAIDs are a chemically diverse class of drugs (>70 NSAIDs in use) that have anti-inflammatory, analgesic, and antipyretic properties.

-worldwide: 70 million people/day prescribed Ds 230 million people/day take OTC NS

-USA: 80 billion aspirin tablets consumed/year constitute 4% of all prescriptions

2. Mechanism: inhibition of the inflammatory response

a. Normal inflammatory responseseries of events that aid our survival in response to injury

b. Mediated by a host of endogenous compounds

-histamine-serotonin-complement-bradykinin

-prostaglandins ** -leukotrienes

Properties of Prostaglandins

Properties of Prostaglandins

• Arachidonic acid metabolism

- released from lipid by phospholipases (PLA2)- release stimulated by a variety of stimuli (physical, chemical, hormonal,neurochemical, etc.)

• Eicosanoids: protaglandins (PG), leukotrienes- derived from arachidonic acid - arachidonic acid is a 20 carbon essential fatty acid- arachidonic acid is a component of membrane phospholipids

• Prostaglandins - released by all tissues - type of prostaglandin released depends on cell

type

Differential Actions of Cyclooxygenases

NSAIDs

COX1Constitutive

COX2InducibleInflammatory

Endothelial integrityVascular patencyGastric mucosal

integrityBronchodilationRenal functionPlatelet function

Inflammation

Unwanted side-effects

Therapeutic anti-inflammatory effects

PGE2

PGF2Proteases

PGI2

PGE2

TXA2

Housekeeping

Inhibition of Prostaglandin Synthesis

XNSAID

Uses Anti-

inflammatory agent.

Analgesics. Antipyretics. Antithrombotic

s

Arthritis Back pain Soft tissue injuries

(sprains & strains) Dental pain Post-operative pain Menstrual pain Migraine Delaying onset of

premature labour.

a. Anti-Inflammatory Actions

Inflammation is characterised by redness, pain and swelling.

These are thought to be caused by increased levels of prostaglandins.

NSAID’s reduce the prostaglandin levels therefore reducing the symptoms of inflammation.

They have varying degrees of anti-inflammatory properties.

b. Antipyretic Actions Pyrogens increase the body temperature by

activating macrophages & other cells to produce cytokines.

These increase prostaglandin E2 synthesis in the hypothalmus (the body’s thermostat) which in turn increases the body temperature.

NSAID’s inhibit prostaglandin E2 synthesis and lower the body temperature.

All NSAID’s have antipyretic properties. Aspirin, ibuprofen and paracetamol are most commonly used for this purpose.

c. Analgesic Actions

Prostaglandins cause sensitisation of nerve cells to pain.

They sensitise nociceptor fibres to bradykinins and 5HT.

The pain relieving properties of NSAID’s are thought to be due to the inhibition of prostaglandins, particularly PGE2 & PGF2

d. Antithrombotic Actions The body maintains a balance between

Thromboxane A2 (TXA2), produced by platelets & Prostaglandin I2 (PGI2), produced by the vascular endothelium.

This allows adequate platelet aggregation within the body.

NSAID’s reduce both TXA2 & PGI2 levels. Platelets can’t synthesise cyclo-oxygenase

enzymes & so become inactive. This causes the prostaglandin levels to increase &

reduces platelet aggregation.

Anti thrombotic effect of aspirin

e. Anti-cancer property

• A number of studies in both animals and in humans have shown an up-regulation of COX-2 in colonic cancers.

• A large body of epidemiological evidence points to an inverse association between aspirin use and colorectal cancerrisk.

• The mechanism, the dose and duration required for maximal efficacy still are not completely clear.

f. Prevention or relief of symptoms of Alzheimer’s Disease

Side effects Gastric irritation and ulceration.

COX 1 produces prostaglandins that have a protective effect on the stomach lining. NSAID’s inhibit this enzyme & so it loses its function. Risk factors for NSAID ulcers ??

Acute kidney failure.The kidneys are rarely damaged in normal people. Patients with heart failure, cirrhosis of the liver, renal disease or who are taking diuretics should not take NSAID’s as they cause kidney failure.

Side effects (con’t) Bleeding problems. Bronchospasm can occur (may make

asthma worse). Liver function abnormalities. Headaches, Vertigo, Tinnitus,

Dizziness (Salicylism) Metabolism. Salt & Water Retention.

Hypersensitivity reaction

Classes of NSAID’s

Table showing the different classes of NSAID’s and some examples.

Prototype Non Steroidal Anti-inflammatory Drugs

O

O

O OH

OH

O OH

Aspirin Salicylic Acid

Modes of action

O

O

O OH

Aspirin

E

OHSer350

COX (active)

OH

O OH

Salicyclic Acid

E

OSer350

COX (inactive)

O

Irreversible Inhibition -- Aspirin only!

HO OHO

COX (inactive)COX (active)

Reversible Inhibition -- All NSAIDS

Other Salicylates

OH

O NH2

Salicylamide

OH

O

O

O OH

F

FOH

O

Salsalate Diflunisal

OH

O

O

HO

O

OMg

Magnesium salicylate

Aspirin - Pharmacokinetics

• 80-90% is bound to plasma proteins, mainly albumin

• Can displace several other drugs from plasma proteinresulting in higher effective plasma concentrations

Aspirin - Dosage

Analgesic/antipyretic dose for adults is 325-650 mg every4 hrs which results in a plasma concentration of approximately 60 mg/ml. The half-life is 2-3 hours.

Anti-inflammatory dose is usually 4-6 g daily which results in a plasma concentration of 150-300 mg/ml. The half-life is usually 12 hours.

Fatal dose is 10-30 g resulting in plasma concentrations exceeding 450 mg/ml. The half-life can be as long as15-30 hours.

Aspirin Toxicity - Salicylism

• Mild intoxication with aspirin

• Commonly experienced when the daily dose exceeds 4 g

• Characterized by tinnitis, high frequency hearing loss, headache, nausea, dimness of vision.

• Symptoms are usually reversible within 2-3 days after withdrawal of the drug.

Analgesia without Anti-inflammation

HO NH

O

O NH

O

Acetaminophen Phenacetin

Acetaminophen (Tylenol)**

• Does not have significant anti-inflammatory properties and as a result is not considered a true NSAID. • Inhibits COX-3• Does not have the same degree of complications from the development of ulcerations. One of the first drugs of choicein the management of mild to moderate chronic pain.• Conventional oral dose is 325 to 1000 mg.

Acetaminophen-Pharmacokinetics

•A small percentage undergoes cytochrome P450 mediatedN-hydroxylation forming a highly reactive intermediate.

• Associated with hepatoxicity when taken in large doses(10 to 15 g).

• Neutralized with the sulphydryl reducing agent N-acetylcysteine*

Side effects

Pharmacokinetics

COX-2 Hypothesis (1990s)

Normal Tissue Inflammation Site

Physiolgical ProstaglandinProduction

PathologicalProstaglandinProduction

COX-1Constitutive

COX-2Inducible

Arachidonic Acid

Normal Functions Inflammation, pain, fever

NSAIDs COX-2Inhibitors

CytokinesGrowth factors+

COX-II Selective NSAIDS

N N

SO

OH2N

CF3

celecoxib

O

SO

O

O

rofecoxib

COX-II Selective NSAIDS

ON

SH2N O

O

valdecoxib

N N

SOO

Cl

etoricoxib

COX-2 Inhibitors - Do they meet expectations?

• Renal and cardiac complications at least as great as conventional NSAIDS

• No anti-thrombic activity

• Gastrointestinal ulcerations reduced in short-term studies (approximately 1-2 years)-long-term benefit - results still are not clear

NSAID Cost/Convenience Comparison for Arthritis

Drug Cox1/Cox2

Cost

Ibuprofen 1 10.48

Naproxen 1 43.61

Diclofenac 1 54.47

Etodolac 1 76.18

Nabumetone 1 76.23

Piroxicam 1 68.21

Meloxicam 4 59.40

Celecoxib 7 75.00

Rofecoxib 35 77.70

Valdecoxib 30 85.80

Gout

N

N NH

NNH2

N

N NH

NOH

H2N

adenine

guanine

N

N NH

NOH

hypoxanthine

N

N NH

NOH

xanthine

HO

N

N NH

NOH

uric acid

HOOH

xanthineoxidase

xanthineoxidase

adenine deaminase

guaninedeaminase

Gout Treatment Strategies

Treatment of Acute Gout:• indomethacin or other NSAID• corticosteroids (rarely used today)• colchicine – second line therapy

Treatment of Chronic Gout:1) Increase uric acid excretion uricosuric agents - probenecid2) Decrease uric acid production metabolic inhibition - allopurinol3) Decrease inflammatory response colchicine (low dose)

Colchicine

OO

O

O

O

NH

O

•Functions by blocking polymerization of tubulin to microtubules

•Blocks leukocyte migration and phagocytosis•Relieves pain in 12-24 h for acute attacks

•Also used to prevent future attacks•Tox: diarrhea

Uricosuric Agents

O

OHSO

ON

Probenecid

NN

O

O

SO

Sulfinpyrazone Benzbromarone

Allopurinol & Rasburicase

N

N NH

N

OH xanthineoxidase N

N NH

N

OH

HOallopurinol alloxanthine

Rasburicase : catalizes the enzymatic oxidation of uric acid into the soluble and

inactive metabolite allantoin

DISEASE-MODIFYING ANTIRHEUMATIC DRUGS

The term DMARD is a latex concept that can be stretched to cover a heterologous group of agents with unrelated chemical structures and different mechanisms of action. Included in this category are methotrexate, sulfasalazine, gold compounds, penicillamine and chloroquine

The DMARDs were often referred to as second-line drugs, with the implication that they are only resorted to when other therapies (e.g. NSAIDs) failed. Today, however, DMARD therapy may be initiated as soon as a definite diagnosis has been reached.

Antirheumatoid drugs

These comprise non-steroidal anti-inflammatory drugs , disease-modifying antirheumatic drugs (DMARDs) and anticytokine agents.

•DMARDs: • include sulfasalazine, methotrexate (a folate

antagonist), gold compounds, chloroquine (an antimalarial), penicillamine and azathioprine (an immunosuppressant)

• are slow-acting drugs and can improve symptoms and reduce the inflammatory process

• retard progress of the disease but do not halt it entirely.

•Anticytokine agents (e.g. infliximab, etanercept) are used in Crohn's disease and psoriatic arthropathy, as well as in rheumatoid arthritis.