Nsaids Apes!

7/30/2019 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Selective COX-2 inhibitors (Coxibs)Celecoxib (FDA alert)Rofecoxib (withdrawn from market)Valdecoxib (withdrawn from market)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.
http://en.wikipedia.org/wiki/Mucosahttp://en.wikipedia.org/wiki/Prostaglandinshttp://en.wikipedia.org/wiki/Prostaglandinshttp://en.wikipedia.org/wiki/Mucosa


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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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