Pharmacology of NSAIDS

MUSTAFA .DS

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Inflammatory stimulus
(+)

Ex

Membran posfolipase

Phospholipids

Phospholipase A2

In

Arachidonic acid
Cyclooxy genase (COX)

5-lipoxygenase

Leucotrienes

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15-lipoxygenase

Lipoxins

Endoperoxides

PGs

TxA2

Phospholipase
-----

Steroids

Arachidonic acid

Cyclooxygenase

Lipoxygenases

NSAIDs
----Like aspirin

Lipoxygenase inhititors

Prostaglandins

PGF2

PGaE2

-----

PMNs

PGI2
Lymphokines

algesic

pyrexia

vasodilation

The events of the inflammtory response and mechanisms of anti-flammatory

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The Cyclooxygenases

Also known as PGH synthase

2 isoforms have been described

COX 1 (PGH Synthase-1)

COX 2 (PGH Synthase-2)

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Catalyzes the synthesis of PGs used in normal bodily

functions (eg. Gastric cytoprotection)
housekeeping enzyme
Acutely expressed as a part of the inflammatory
response to cell damage
Involved in normal renal development and vascular
prostacyclin production
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PROSTANOIDS (PGs & Txs)

PGI2 (prostacyclin) is located
predominantly in vascular
endothelium. Main effects:
vasodilatation
inhibition of platelet aggregation
TxA2 is found in the platelets.
Main effects:
platelet aggregation
vasoconstriction
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PGE2 causes:

inhibition of gastric acid secretion

contraction of pregnant uterus
contraction of GI smooth muscles

PGF2 main effects:

contraction of bronchi
contraction of miometrium
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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).
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COX inhibitors
NSAIDs

COX-2
inhibitors
Selective (coxibs)
Preferential
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Nonselective
COX-1/COX-2
inhibitors

COX-3
inhibitors
Antipyretic
analgesics
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Nonselective
COX-1/COX-2
inhibitors
(Classical NSAIDs)
Salicylates
Phenylacetates
Indolacetates
Enolates
Fenamates
Propionates
De rivatives
Butylpyrazolidindionesof acid
Pyrazolones

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COX-2
inhibitors
(1) Selective COX-2
inhibitors (Coxibs)
Celecoxib
Etoricoxib
Parecoxib
(2) Preferential
COX-2 inhibitors
Meloxicam
Nimesulide
Nabumetone
Diklofenac
Etodolac
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Anti-inflammatory drug Mechanism of

Action

Decrease Prostaglandin synthesis

Irreversible (ASA) or reversible inhibition of

Cyclooxygenase (COX 1 and COX 2)
Degree of inhibition varies

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Indomethacin and Sulindac COX 1

Ibuprofen and meclofenemate COX 1 = COX 2
Aspirin COX 1 COX 2
Glucocorticoids COX 2

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NSAID Mechanism of Action

Other:

Inhibition of chemotaxis of neutrophils

Decreased sensitivity to bradykinen, histamine
Reestablishment of normal cell death (apoptosis)

Role of these effects in treatment of clinical

inflammation is unclear

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NSAID Pharmacokinetics

General similarities:

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Complete oral absorption

Negligible 1st pass metabolism
Tightly bound to albumen
Small volume of distribution

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NSAID Pharmocokinetics

Some PK diversity related to chemical class:

Acetic Acid derivatives:

Fenemates:

Nabumetone

Oxicams:

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Meclofenemate and Mefenamic Acid

Napthylalkanones:

Diclofenac, Indomethacin, Sulindac, Etoldolac, Tolmetin

Meloxicam and Piroxicam

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NSAID Pharmocokinetics

NSAID chemical classes (continued):

Proprionic Acids:

Pyrrolizine carboxylic Acid

Ketorolac

Selective COX 2 Inhibitors

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Fenoprofen, flurbiprofen, ibuprofen, ketoprofen,

naproxen, and oxaprozin

Celecoxib, etoricoxib, rofecoxib, valdecoxib, parecoxib

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NSAID Adverse Drug Reactions

GI

All non-selective NSAIDS are associated with GI

toxicity

Gastritis, bleed, perforation, gastric and duodenal ulcer

Endoscopic lesions 2/3 of patients
Incidence of symptomatic ulcers (upper GI), gross
bleeding or perforation

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3-6 mo Rx 1%
1 yr Rx 2-4 %

Anti-platelet effects increases risk of bleed from GI

lesion
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NSAID Adverse Drug Reactions

GI (cont)

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Pts more pre-disposed to GI toxicity if pre-existing

ulcer or dyspepsia, H.Pylori infection, older age,
and some medications
Indomethacin, piroxicam and sulindac associated
with increased incidence of GI adverse events
Safer GI profile: etodolac, meloxicam,
nabumetone
Ketorolac- GI toxicity over all other (in spite of
COX-2 preference)
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NSAID Adverse Drug Reactions

Renal

Prostaglandin activity in kidney:

Decreased PG synthesis results in

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Na+ reabsorption
K+ secretion
r/t Renin
PG also dilate blood vessels in kidney
Na + and H2O retention
Peripheral edema
Acute Renal failure
Interstitial nephritis
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NSAID Adverse Drug Reactions

Renal (cont)

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Toxicity dose dependent

Association with NSAIDS with longer t/2
Sulindac and nabumetone renal sparing
NSAID HTN

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NSAID Adverse Drug Reactions

CNS

Overuse of NSAIDS rebound HA

Aseptic meningitis

Hepatic

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Elevated transaminases in 15%

1% incidence of significant hepatotoxicity

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NSAID Adverse Drug Reactions

Miscellaneous

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Pancreatitis
Thrombocytopenia
Anemia
ADR from opthalmic products: localized burning,
stinging
uterine contractions (use not recommended
during labor
Stevens-Johnson or TEN syndrom
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Important NSAID Drug-Drug

Interactions

PG inhibition effects:

Reduced renal Na+ excretion

Impaired resistance to hypertensive stimuli
Reduced renal lithium excretion

Other NSAID effects ixn

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Inhibition of platelet function ( likelihood of bleed)

Highly protein bound (albumin)

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Important Drug-Drug Interactions

NSAID interact with the following:

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ACE Inhibitors decreased antihypertensive response

Furosemide decreased diuretic, natriuretic and
antihypertensive response
Beta-adrenergic blockers decreased antihypertensive
response
Anti-coagulants (oral) inhibition of platelet function,
predisposing to bleed. Some agents increase
hypoprothrombinemic response (unlikely with doclofenac,
ibuprofen or naproxen) r/t displacement from protein
binding sites
Phenytoin Decreased hepatic phenytoin metabolism
Aspirin: antagonism of anti-platelet effect.

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General Observations about Clinical Use

NSAIDS are equally effective in analgesia, antipyretic and antiinfllammatory effects.

Widely used in rheumatic and non-rheumatic conditions:
Acute and chronic pain ( including perioperative pain)
Chemoprevention
Dental pain
Dysmenorrhea
Gout
Headache
Tendonitis
Bursitis
Rheumatoid Arthritis
Osteoarthritis

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General Observations about Clinical Use

Analgesic dose < anti-inflammatory dose

Patient response may be variable
If patient fails therapy with an agent from one
class, use of an agent from another class is
reasonable.
2 weeks of therapy at max anti-inflammatory
dose before switching

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Individual Agents

Salicylates

Aspirin (acetylsalicylic acid)

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t/2 = 0.25 hrs

< 2% excreted unchanged in urine
Anti-inflammatory dose: 1200-1500 mg TID
Saturable binding to albumin
Alkalinization of urine to rate of excretion
Rarely used for anti-inflammatory properties; mostly for
effects on platelet aggregation
Salicylism

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Individual Agents

Salicylates

Nonacetylated salicylates

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Magnesium/ Choline Salicylate (Arthropan, Magan)

Sodium Salicylate (generic)
Salicylsalicylate (Disalcid)
All are effective for inflammation, but < ASA
Preferable in patients with asthma, bleeding tendencies,
and renal dysfucntion

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Individual Agents

Proprionic Acid Derivatives

Ibuprofen

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t/2 = 2 hrs
< 1% excreted unchanged in urine
Anti-inflammatory dose is 600 mg 4x daily or 800 mg tid
2400 mg /day = 4 grams of asa/day
Analgesia is achieved with 400 mg doses
If used with ASA, anti-inflammatory effect of ASA is
decreased
Concommitant use with ASA also inhibits ASA platelet
disaggregation
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Individual Agents

Proprionic Acid Derivatives

Ibuprofen

Causes less fluid retention and less likely to decrease

UO than indomethacin
Less GI toxicity compared to ASA
Effective in Rx of patent ductus arteriosis
Contraindications:

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Nasal polyps
Asthma
ASA allergy

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Individual Agents

Proprionic Acid Derivatives

Naproxen & Naproxen Sodium

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t/2 = 14 hrs
< 1% excreted in urine
Recommended AI dose is 375 mg BID
Free fraction is 41% higher in women
Upper GI bleed > OTC Ibuprofen
Other SE: allergic pneumonitis,
leukocytoclasticvasculitis, and pseudoporphyria

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Individual Agents

Proprionic Acid Derivatives

Fenoprofen

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= 2.5 hrs
30% excreted unchanged in urine
Usual dose: 600 mg 4 x daily
High incidence of Interstitial nephritis
More likely to cause nausea, dyspepsia, peripheral
edema, pruritis, tinnitis and drug interactions

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Individual Agents

Proprionic Acid Derivatives

Flurbiprofen

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t/2 = 3.8 hrs

< 1% excreted by urinary route; extensive hepatic
metabolism
Usual dose is 300 mg tid, but 200-400 mg/day is = ASA
and other NSAIDS
Affects TNF
ADRs similar but also causes cogwheel rigidity, ataxia,
tremor, myoclonus

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Individual Agents

Proprionic Acid Derivatives

Ketoprofen

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t/2 = 1.8 hr
< 1% excreted in urine
Usual dose = 70 mg tid
Half-life affected by probenicid
Also binds to lipooxygenase, but still equi-effective to
other NSAIDS

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Individual Agents

Proprionic Acid Derivatives

Oxaprozin

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t/2 = 58 hrs
1-4% urinary excretion
Usual dose: 1200-1800 mg daily
No enterohepatic circulation
5 days between dose adjustments
Uricosuric, so useful in gout

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Individual Agents

Acetic Acid Derivatives

Indomethacin

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t/2 = 4-5 hrs (can be prolonged by probenicid)

16% excreted renally
Usual dose = 50-70 mg tid
Primarily used for gout, aklylosing spondylitis and patent
ductus arteriosis
Small clinical trials conducted for Rx of other conditions

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Individual Agents

Acetic Acid Derivatives

Sulindac

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t/2 = 8 hrs
7% excreted unchanged in urine
Usual AI dose = 200 mg bid
Prodrug
Significant enterohepatic circulation
Hepatotoxicity
Use in CA
< effect on renal COX
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Individual Agents

Acetic Acid Derivatives

Etodolac

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t/s = 6.5 hrs

Renal excretion: < 1%
AI dose is 200-300 mg 4 x daily
Slightly more selective for COX 2
Claims to have less GI toxicity
Niche in rx of pain s/p cardiac bypass

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Individual Agents

Acetic Acid Derivatives

Diclofenac

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t/2 = 1.1 hrs

< 1% excreted unchanged in urine
Usual AI dose = 50-75 mg 4 X daily (IR product)
Long acting product available
20% incidence of SE
Hepatic toxicity
Arthrotec

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Individual Agents

Acetic Acid Derivatives

Tolmetin

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t/2 = 1 hr
7% excreted unchanged in urine
Usual AI dose = 400 mg 4 x daily
Not used much anymore
Not effective for gout
Allergic IGM-mediated thrombocytopenia purpura

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Individual Agents

Fenemates

Meclofenemate

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t/2 = 3 hrs
2-4% excreted unchanged in urine
Usual AI dose is 100 mg po 4 x daily
Less effective than ASA for inflammation, but more toxic
ADRs similar to other NSAIDS,
Increased incidence of diarrhea, abd. Pain
Contraindicated in pregnancy and children
Rx limited to 1 week
Enhances effects of warfarin
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Individual Agents

Napthylalkanones

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Nabumetone (Relafen)
Prodrug
t/2 = 26 hrs
1% excreted unchanged in urine
No enterohepatic circulation
Usual dose = 1000 to 2000 mg daily
GI toxicity dose dependent
Pseudoporphyria and photosensitivity
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Individual Agents

Oxicams

Piroxicam

t/2 = 57 hours
4-10% excreted unchanged in urine
Usual AI dose = 20 mg daily
20% incidence of GI toxicity
Increased incidence of GI toxicity at higher doses
SJ syndrome
Other pharmacological effects

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Uncertain clinical significance

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Individual Agents

Oxicams

Meloxicam

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t/2 = 20hrs
No data on % excreted unchanged in urine
Usual AI dose is 7.5 to 15 mg daily
??Fewer GI symptoms than piroxicam, diclofenac,
naproxen
Inhibits synthesis of thromboxane A
Preference for COX 2 vx COX 1

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Individual Agents

Pyrrolizine carboxylic acid

Ketorolac

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t/2 = 4-10 hrs

58% excreted unchanged in urine
Usual dose is 10 mg 4 x daily
Recommended for Rx of surgical pain only
Can replace morphine for some types of pain
Decreases opioid requirements
High incidence of GI toxicity
FDA approved for 5 days of therapy only
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Individual Agents

Selective COX 2 Inhibitors (general info)

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Also known a COXibs

Developed to circumvent GI toxicities of NSAIDS
Analgesic, antipyretic, anti-inflammatory
platelet aggregation
Renal toxicity = other NSAIDS
Not recommended in severe renal insufficiency
Increased risk of CV effects???
Bone healing
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COXibs

Mainly used for OA, RA

Other uses: FAP, dysmenorrhea, acute gouty
arthritis, musculoskeletal pain, ankylosing
spondylitis
Prostacyclin production prothrombotic state
Metabolized by P450 enzymes drug drug
ixns

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COXibs

Celecoxib

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t/2 = 11 hours
27% excreted unchanged in urine
AI dose = 100 to 200 mg BID
10-20 x more selective for COX 2 than COX 1
Efficacy in OA, RA = other NSAIDS
Sulfonamiderashs, SJS
Other SE = to other NSAIDS (edema, renal)
HTN
Interacts with warfarin
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Other COXibs

Rofecoxib

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Pulled from market in 2004 r/t increased incidence

of MI and stroke in trials investigating GI toxicities
Valdecoxib was voluntarily pulled from market in
2005

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