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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.