Nsaids Apes!
Transcript of Nsaids Apes!
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Nonsteroidal Anti-inflammatory Drugs
(NSAIDs)
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Pain
Definition
An unpleasant sensory and emotional
experience associated with actual orpotential tissue damage or described in
terms of such damage
International Association for the Study of Pain
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Numeric Rating Scale (NRS)
Visual Analogue Scale (VAS)
0 10
Pain Scores
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Wong-Baker Faces Scale
Verbal scale
No
PainMild Moderate
Severe
Pain
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What are NSAIDs and how do they
work?
Drug with analgesic ( without impairingconsciousness ), antipyretic, and anti-inflamammatory effects
weak acids, PH 3-5, well absorbed fromstomach and intestinal mucosa
protein-bound in plasma ( albumin),
metabolised in the liver
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Different Pathways Of inflammation
Inflammation is induced by following 4chemical mediators .
Prostaglandins
Amines: Histamine & 5-OH Tryptamine
Small peptides; Bradykinin
Larger peptides; Interleukin-1
NSAIDs can benefit only whereprostaglandins are the chemical
mediators.
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Classification
Fenamic acid derivativesMefenamic acid
Meclofenamic acid
Flufenamic acid
Tolfenamic acid
Selective COX-2 inhibitors (Coxibs)Celecoxib (FDA alert)Rofecoxib (withdrawn from market)Valdecoxib (withdrawn from market)
Parecoxib FDA withdrawnLumiracoxib TGA cancelled registrationEtoricoxib FDA withdrawnFirocoxib used in dogs and horses
Propionic]acid derivativesNaproxenIbuprofen
Ketoprofen
Flurbiprofen
Oxaprozin
Acetic acid derivativesIndomethacin
Sulindac
Etodolac
Diclofenac (Safety alert by FDA
Enolic acid (Oxicam) derivativesPiroxicam
Meloxicam
Tenoxicam
Droxicam
Lornoxicam
Isoxicam
http://en.wikipedia.org/wiki/Fenamic_acidhttp://en.wikipedia.org/wiki/Mefenamic_acidhttp://en.wikipedia.org/wiki/Meclofenamic_acidhttp://en.wikipedia.org/wiki/Flufenamic_acidhttp://en.wikipedia.org/wiki/Tolfenamic_acidhttp://en.wikipedia.org/wiki/COX-2_inhibitorhttp://en.wikipedia.org/wiki/Celecoxibhttp://en.wikipedia.org/wiki/Rofecoxibhttp://en.wikipedia.org/wiki/Valdecoxibhttp://en.wikipedia.org/wiki/Parecoxibhttp://en.wikipedia.org/wiki/Lumiracoxibhttp://en.wikipedia.org/wiki/Etoricoxibhttp://en.wikipedia.org/wiki/Firocoxibhttp://en.wikipedia.org/wiki/Propionic_acidhttp://en.wikipedia.org/wiki/Non-steroidal_anti-inflammatory_drughttp://en.wikipedia.org/wiki/Propionic_acidhttp://en.wikipedia.org/wiki/Naproxenhttp://en.wikipedia.org/wiki/Ibuprofenhttp://en.wikipedia.org/wiki/Ketoprofenhttp://en.wikipedia.org/wiki/Flurbiprofenhttp://en.wikipedia.org/wiki/Oxaprozinhttp://en.wikipedia.org/wiki/Acetic_acidhttp://en.wikipedia.org/wiki/Indomethacinhttp://en.wikipedia.org/wiki/Sulindachttp://en.wikipedia.org/wiki/Etodolachttp://en.wikipedia.org/wiki/Diclofenachttp://en.wikipedia.org/wiki/Enolhttp://en.wikipedia.org/wiki/Oxicamhttp://en.wikipedia.org/wiki/Piroxicamhttp://en.wikipedia.org/wiki/Meloxicamhttp://en.wikipedia.org/wiki/Tenoxicamhttp://en.wikipedia.org/wiki/Droxicamhttp://en.wikipedia.org/wiki/Lornoxicamhttp://en.wikipedia.org/w/index.php?title=Isoxicam&action=edit&redlink=1http://en.wikipedia.org/w/index.php?title=Isoxicam&action=edit&redlink=1http://en.wikipedia.org/wiki/Lornoxicamhttp://en.wikipedia.org/wiki/Droxicamhttp://en.wikipedia.org/wiki/Tenoxicamhttp://en.wikipedia.org/wiki/Meloxicamhttp://en.wikipedia.org/wiki/Piroxicamhttp://en.wikipedia.org/wiki/Oxicamhttp://en.wikipedia.org/wiki/Enolhttp://en.wikipedia.org/wiki/Enolhttp://en.wikipedia.org/wiki/Enolhttp://en.wikipedia.org/wiki/Diclofenachttp://en.wikipedia.org/wiki/Etodolachttp://en.wikipedia.org/wiki/Sulindachttp://en.wikipedia.org/wiki/Indomethacinhttp://en.wikipedia.org/wiki/Acetic_acidhttp://en.wikipedia.org/wiki/Oxaprozinhttp://en.wikipedia.org/wiki/Flurbiprofenhttp://en.wikipedia.org/wiki/Ketoprofenhttp://en.wikipedia.org/wiki/Ibuprofenhttp://en.wikipedia.org/wiki/Naproxenhttp://en.wikipedia.org/wiki/Propionic_acidhttp://en.wikipedia.org/wiki/Non-steroidal_anti-inflammatory_drughttp://en.wikipedia.org/wiki/Propionic_acidhttp://en.wikipedia.org/wiki/Firocoxibhttp://en.wikipedia.org/wiki/Etoricoxibhttp://en.wikipedia.org/wiki/Lumiracoxibhttp://en.wikipedia.org/wiki/Parecoxibhttp://en.wikipedia.org/wiki/Valdecoxibhttp://en.wikipedia.org/wiki/Rofecoxibhttp://en.wikipedia.org/wiki/Celecoxibhttp://en.wikipedia.org/wiki/COX-2_inhibitorhttp://en.wikipedia.org/wiki/COX-2_inhibitorhttp://en.wikipedia.org/wiki/COX-2_inhibitorhttp://en.wikipedia.org/wiki/Tolfenamic_acidhttp://en.wikipedia.org/wiki/Tolfenamic_acidhttp://en.wikipedia.org/wiki/Tolfenamic_acidhttp://en.wikipedia.org/wiki/Flufenamic_acidhttp://en.wikipedia.org/wiki/Flufenamic_acidhttp://en.wikipedia.org/wiki/Flufenamic_acidhttp://en.wikipedia.org/wiki/Meclofenamic_acidhttp://en.wikipedia.org/wiki/Meclofenamic_acidhttp://en.wikipedia.org/wiki/Meclofenamic_acidhttp://en.wikipedia.org/wiki/Mefenamic_acidhttp://en.wikipedia.org/wiki/Mefenamic_acidhttp://en.wikipedia.org/wiki/Mefenamic_acidhttp://en.wikipedia.org/wiki/Fenamic_acidhttp://en.wikipedia.org/wiki/Fenamic_acidhttp://en.wikipedia.org/wiki/Fenamic_acid -
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Mechanism of Action of NSAIDs:
COX-2
Inducible
Prostaglandins
COX-1
Constitutive
Prostaglandins
Mediate pain,
inflammation, and fever
Arachidonic acid
CO2H
Non-specific
NSAIDs
GI mucosal
ProtectionHemostasis
Bakhle et al.Med Inflamm.
1996;5:305-323.Vane et al. Inflamm Res. 1995;44:1-10.
COX-2 NSAIDs
Thromboxane
GI Mucosa Platelet
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NSAIDs:Cyclooxygenase
Cyclooxygenase has 2 forms:
COX-1 (good COX) : found in all tissues
Mediates housekeeping chores
Protect gastric mucosa
Support renal function
Promote platelet aggregation
COX-2 (bad COX) : found at sites of tissue injury
Mediates inflammation and sensitize receptors to painful stimuli
Also present in brain- mediates fever and contributes to perception of pain
Mediates a cytoprotective effect in damaged GI mucosa
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Dosage of NSAID
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Acetaminophen
Mechanism of action unclear
A weak PG inhibitor
No anti-inflammatory effects
Causes liver toxicity at high doses
Max dose: 4 gm/day, if no liver disease
Newest recommendation 2.6 gm/day
Ref. 1,2
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Pharmacokinetics
Administered orally
Absorption: related to rate of gastric emptying
Peak blood conc: 30-60 min
Slightly protein bound Partially metabolized by hepatic microsomal enzyme
acetaminophen SO4 & glucuronide
Excretion: unchanged < 5%
A minor but highly active metabolite (N-acetyl-p-benzoquinone) is important liver & kidney toxicity
t1/2: 2-3 hrs
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Diclofenac (Voltaren Cataflam )
Meitifen 75mg, Formax 75mg
Rheumatoid arthritis: 150-200mg/day orally in 2-4 divided dosesOsteoarthritis: 100-150 mg/dayorally in 2-3 divided doses.
Maximum Daily Dose: 225 mg
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Pharmacokinetics
Rapidly absorbed following oral administration 99% protein bound t1/2: 1-2 hrs
Accumulates in synovial fluid t1/2 of 2-6 hrs 30% biliary clearance, urine (65%)
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Etodolac (Lodine )
Lonine 200mg
Acute pain: 200-400 mg every 6-8
hours, Rheumatoid arthritis, osteoarthritis:
Initial: 600-1200 mg/day given in
divided doses: Maximum Daily Dose:: 1200 mg
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Pharmacokinetics
Rapidly well absorbed
80% bioavailability
Strongly bound to plasma proteins (99%) Enterohepatic circulation
t1/2: 7 hrs
Excreted in the urine
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Ketorolac (Toradol )
Keto Inj 30mg, Kop Inj 30mg, Keto, Painoff10mg
IM: 60 mg x 1 or 30 mg q6h (maximum daily
dose: 120 mg). IV: 30 mg x 1 or 30 mg q6h (maximum daily
dose: 120 mg).
Oral: 20 mg, followed by 10 mg every 4 to 6
hours (Max 40 mg/day) Note: The maximum duration of treatment (for
parenteral and oral) is 5 days.
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Ketorolac (Keto) is a very potent NSAID and isused for moderately severe acute pain that
usually requires narcotics
Ketorolac (Keto) causes ulcers more frequentlythan other NSAID. Therefore, it is not used for
more than five days.
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Pharmacokinetics
Rapidly absorbed after oral or IM administration
Also given IV
Peak concentration: 30-50 min.
Almost totally protein bound t1/2: 4-6 hrs
Excreted in the urine (90%)
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Sulindac (Clinoril )
Unidac 200mg
Adults: 150-200 mg twice daily or 300-
400 mg once daily;
Should be administered with food or milk.
Maximum Daily Dose : 400 mg
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Pharmacokinetics
90% absorbed after oral administration
Peak concentration: 1 hr
t1/2: 7 hrs
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Meloxicam (Mobic )
Subic 7.5mg Oral: Initial: 7.5 mg once daily; may
increased dose of 15 mg once daily
maximum dose: 15 mg/day
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Pharmacokinetics
An enolcarboxamide
Slightly COX-2 selective
Slowly absorbed t1/2: 20 hrs
Clearance: 40% decreased in elderly
Slightly less ulcerogenic
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Piroxicam (Feldene )
Tonmax Inj 20mg, Foglugen 20mg
Adults: 10-20 mg/day once daily
May be taken with food to decrease GI adverse
effect.
Maximum Daily Dose : 20 mg
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Pharmacokinetics
Rapidly absorbed from the stomach & upper intestine
Peak plasma concentration: 1 hr
99% protein bound
Elimination: renal
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Flurbiprofen (Ansaid )
Flufen50 mg,Lefenine100mg, Flur Di FenPatch 12mg
Inflammatory disease: 50-100 mg/dose 3-
4 times/day (maximum dose: 400 mg/day )
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Tenoxicam
Tencam 20mg, Sutondin 20mg, Tencaminj 20mg
Adults: 20-40 mg/day ,1-2 times daily
Acute gout: 40mg x 2days, then 20mg qd
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Ibuprofen (Motrin )
Purfen 400mg ,Mac Safe syr, Arfen inj 400mg
Inflammatory disease: 400-800 mg/dose 3-4 times/day
Analgesia/pain/fever/dysmenorrhea: 200-400 mg/dose
every 4-6 hours maximum dose: 3200 mg/day
in severe hepatic impairment: avoid use
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Pharmacokinetics
Rapidly absorbed after oral or IM administration
Also given IV
Peak concentration: 30-50 min.
Almost totally protein bound t1/2: 4-6 hrs
Excreted in the urine (90%)
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Naproxen (Naprosyn )
Napton 750mg
Rheumatoid arthritis, osteoarthritis, and
ankylosing spondylitis: 250-500 mg orallytwice daily
May increase to 1.5 g/day
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Pharmacokinetics
Is a naphthylpropionic acid
A nonselective COX inhibitor
Elimination serum t1/2: 12 hrs
High albumin binding Prep: SR formulation, oral susp
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Aspirin - Dosage
Analgesic/antipyretic dose for adults is 325-650 mg every4 hrs which results in a plasma concentration ofapproximately 60 g/ml. The half-life is 2-3 hours.
Anti-inflammatory dose is usually 4-6 g daily whichresults in a plasma concentration of 150-300 g/ml. Thehalf-life is usually 12 hours.
Fatal dose is 10-30 g resulting in plasma concentrationsexceeding 450 g/ml. The half-life can be as long as15-30 hours.
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Pharmacokinetics
Rapidly absorbed from the stomach & upper small
intestine
Peak plasma level: 1-2 hrs
80-90% protein bound
t1/2: 3-5 hrs
Cross BBB & placental barrier
Undergoes hepatic metabolism Excretion: kidneys
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MECLOFENAMATE &
MEFENAMIC ACID
Fenamic acid derivatives
Inhibit both COX
Peak plasma level: 30-60 min t1/2: 1-3 hrs
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CELECOXIB
Highly selective COX-2 inhibitor
Absorption: 20-30% decreased by food
t1/2: 11 hrs
Highly protein bound
Clearance affected by hepatic impairment
Effective dose: 100-200mg b.i.d.
Does not affect platelet aggregation
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ROFECOXIB
A furanose derivative A potent highly selective COX-2 inhibitor
Well absorbed
Dosage range: 12.5-50mg/d
Slightly less protein-bound (87%)
t1/2: 17 hrs
Metabolized by cytosolic liver enzymes
Does not inhibit platelet aggregation
Have little effect on gastric mucosal PGs
Associated with fewer gastric or duodenal gastroscopic ulcers
C ti ti b t COX 1/COX 2 COX 2
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Comparative action between
COX inhibitors
COX-1/COX-2
inhibitors
COX-2
inhibitors
1. Analgesic action (+) (+) (+)
2. Antipyretic action (+) (+)
3. Antiinflammatory action (+) (+) (+)
4. Antiplatelet aggregatory (+) (-)
5. Gastric mucosal damage (+) (+) (+) (+)
6. Renal salt / water retention (+) (+)
7. Ductus arteriosus closure (+) ?
8. Cardiotoxicity
(-) (+) (+)
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Side effect of NSAIDs
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Side effects of NSAIDs
Cardiovascular
80% increase in AMI risk with newer COX-2
and high dose traditional NSAID
Heart failure risk
( with CHF history x10, without x2)
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GIT
The acidic molecules directly irritate the gastric mucosa,
Inhibition of COX-1 reduces the levels of protective prostaglandins.
Inhibition of prostaglandin synthesis in the GI tract causes
Increased gastric acid secretion,
Diminished bicarbonate secretion,
Diminished mucous secretion and
Diminished trophic effects on epithelial mucosa.
Risk of ulceration increases with duration of therapy, and withhigher doses. In attempting to minimise GI ADRs, it is prudent to
use the lowest effective dose for the shortest period of time, apractice which studies show is not often followed.
Recent studies show that over 50% of patients taking NSAIDs havesustained damage to their small intestine.
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Table:NSAIDs
Drug*High Risk Moderate Risk Low Risk
Aspirin (Bokey, Tapal) X
Celecoxib (Celebrex) X
Diclofenac (Cataflam, Eunac) X
Etodolac X
Flurbiprofen X
Ibuprofen X X
Indomethacin X X
Ketoprofen X
Ketorolac (Keto) X
Meloxicam ** X
Nabumetone X
Naproxen (Anaprox) X
Piroxicam X
Sulindac (Weisu) X
** Meloxicam risk increases with doses >7.5 mg.
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NSAIDs reduce the blood flow to the kidneys leading tosalt & fluid retention.
This can lead to edema and hypertension.
If high doses are used for longer periods of times as inchronic conditions, can lead to renal failure.
Combination with nephrotoxic agents increase the riskof renal failure.
Renal failure is especially a risk if the patient is alsoconcomitantly taking an ACE inhibitor and a diuretic.NSAIDs are excreted by kidneys.
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During pregnancy
Not recommended during pregnancy,
particular 3rd trimester
Cause early closure of fetal ductus
arteriosus, and fetal renal toxicity,
premature birth
Acetaminophen ia more safe during
pregnancy
In France, NSAID and aspirin is contra-
indicated after 6 months of pregnancy
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Drugs ResultDiuretics Decrease diuresis
Beta-blockers Decrease antihypertensive effect
ACE inhibitors Decrease antihypertensive effectAnticoagulants Increase of GI bleeding
Sulfonylurea Increase hypoglycemic risk
Cyclosporine Increase nephrotoxicityAlcohol Increase of GI bleeding
Drug interactions with NSAIDs
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The End