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54 Cards in this Set

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NSAIDS important group of drugs
Account for ~ 10% of all prescriptions
Adverse effects of NSAIDS are the most common reported internationally!!
Used in many different conditions
Have triple A properties
Analgesia
Antipyresis
antiinflammatory
Rheumatoid Arthritis a few facts
Characterized by potentially crippling JOINT disease and SYSTEMIC COMPONENTS that may shorten life

Affects more than 5 million Americans with FEMALES being affected ~ 3x more frequently

Teens to elderly
Rheumatoid Arthritis (4)
Swollen tender joints
Nocturnal pain
Early morning joint stiffness last more than 30 minutes
Acute physical disability
Rheumatoid Arthritis
Some pathological abnormalities include:
Chronic synovitis of joints
Changes in production and release of inflammatory and immunological mediators
PGs
Leukotrienes
TNF_
IL-1
Destruction of articular cartilage
Elevated levels of Rheumatoid Factor (RF)
Rheumatoid Arthritis
Goals of management include: (5)
RELIEVE PAIN
Preserve or restore function
Maintain lifestyle
Suppress or REDUCE INFLAMMATION
PREVENT SYSTEMIC COMPLICATIONS and SLOW PROGRESS OF DISEASE
Rheumatoid Arthritis Treatment involves...
Education, physical exercise, rest
Pharmacological treatment

Nutritional modification??
Omega-3 Fatty Acids may play a important role in the relief of Arthritis.
Rheumatoid Arthritis Pharmacological treatment (6)
Aspirin and NSAIDS
Acetaminophen
Steroids
DMARDS
Biological modifiers
Chondroitin & glucosamine??
Osteoarthritis (OA) a few facts
Chronic degenerative joint disease
‘wear and tear disease’
Slow progressive loss of articular cartilage in weight bearing joints (hips & knees)
Pain
Limited motion
Deformity & progressive disability
Inflammation may or may not be present in affected joints
No systemic involvement
Most common rheumatoid disease
about 60 million Americans
males and females about equally

Age is a factor … ~ 60% of over 60 group affected
Osteoarthritis (OA)
Pain in hip or knee
Morning joint stiffness < 30 minutes
Crepitus (joint popping)
Osteoarthritis (OA)
Gross pathology includes: (4)
Cartilage fibrillation
Fissuring
Erosions leading to bare areas of bone
Osteophytes are a cardinal feature (Heberden’s & Bouchard’s nodes)
Osteoarthritis (OA) Management goals include: (4)
Education of patient, caregivers and relatives
Relieve symptoms of pain and stiffness
Preserve joint motion and function
Minimize disability
Osteoarthritis (OA) TREATMENT INVOLVES: [5]
Education
Physical therapy
Various assistive devices
Surgical procedures
Pharmacological management of pain and inflammation (if present)
Osteoarthritis (OA)Pharmacological management includes: [6]
Acetaminophen
Aspirin/other NSAIDs
Capsaicin (topical)
Opioid analgesics
Intraarticular corticosteroids
glucosamine & chondroitin sulfate
Aspirin & NSAIDS
Aspirin IS an NSAID but often not included in the group

NSAIDS have NOT been shown to be more effective
But high doses of aspirin are required for the antiinflammatory effects and many can’t tolerate
frequent dosing with aspirin is a disadvantage

NSAIDS have same adverse effect profile as aspirin but the potential is lower

Aspirin is much cheaper and some still feel you should start with Aspirin
Aspirin & NSAIDS
For non-selective NSAIDS the choice is largely empirical depending on patient
What works and what can they tolerate
Differences in frequency of dosing an important compliance issue

Select the one that works the best and with which the patient will comply
Often takes a trial of 6 different NSAIDS to find the best one!!
NSAIDS
Heterogeneous group of drugs
Comparative prototype is aspirin (ASA)
They share therapeutic actions and adverse effects
Three As
Analgesic
Antipyretic
antiiflammatory
NSAIDS Primary mode of action [2]
Inhibit cyclooygenase enzymes (COX)
Inhibition of prostaglandin (PG) synthesis
NSAIDS Prostaglandin synthesis involves [2]
Conversion of membrane PL to arachidonic acid by phospholipase A2
Arachidonic acid converted to PG by COX
COX I (mostly constitutive)
Involved in ‘housekeeping’ functions
Vasodilation
Inhibition of gastric acid secretion
Mucin secretion in stomach
Regulation of platelet aggregation
Regulation of salt and water retention in kidney
Predominates in platelets, kidney, GI
Inhibited by NSAIDs, higher corticosteroids
COX 2 (mostly inducible)
Involved in inflammation and produces PGs involved in inflammation
Abundant in connective tissues and inflammatory sites
May predominate in endothelial cells
Involved in salt and water regulation in the kidney (constitutive COX 2 present in kidney)
Inhibited by non-selective NSAIDs, COX 2 inhibitors and corticosteroids
COX 3 (constitutive?)
present in CNS

Produces PGs that are pain producing neuromodulators?

Inhibited by non-selective NSAIDs, COX 2 inhibitors and corticosteroids but more selectively by acetaminophen
COX isozyme inhibiton and NSAIDs
Non-selective NSAIDs tend to produce more GI related problems because COX 1 is significantly inhibited
COX 2 selective NSAIDs appear to produce less of the GI related SE
COX 1 and COX 2 inhibitors seem to equally affect the kidney functions
NSAIDS appear to primarily work by...
inhibiting COX enzymes to decrease PG production
Aspirin
No evidence of tolerance or physical dependence
Relieves mild to moderate pain by peripheral and central effects (ÚPGE2)
Is a non-selective COX inhibitor
ASPIRIN IRREVERSIBLY ACETYLATES COX
Salicylate and other NSAIDs reversibly inhibit COX by a different mechanism
Lowers elevated temperature by interfering with central controls***
Higher than analgesic or antipyretic doses required for antiinflammatory effects

Prolongs bleeding time

Can interfere with uric acid elimination and aggravate control of gout
ASA uses include: [7]
Fever reduction (antipyresis)
Analgesia (mild to moderate)
Acute rheumatic fever
RA and OA (large doses required)
Reduction of risk of re-infarction and stroke
Prophylaxis of thrombosis
Prevention of colon cancer??? COX 2 inhibition?
COX 2 over expressed producing PGs that promote tumor growth
ASA adverse effects...
Adverse effects: ~ 15% show an intolerance to aspirin
GI system is a target of adverse effects,Gastritis, NV, Abdominal pain, Acute and chronic blood loss

GI effects are secondary to decreased PGs that regulate acid secretion, mucin and bicarb production

~15% non-immunological hypersensitivity syndrome
Inhibition of COX enzymes promote excessive production of LTs (e.g. bronchocontriction, etc.)??
Rarely … hepatotoxic
Potential renal toxicity
ASA tosicity sx's?[8]
Mild acute toxicity ------‡ SALICYLISM
Headache
Dizziness
TINNITUS
Hearing loss
Drowsiness
NVD
Mental confusion
sweating
Aspirin – Acute, severe salicylate poisoning
Direct increase medullary response to CO2
Indirect metabolic acidosis (ASA is acid) and uncoupling of oxidative phosphorylation forces anareobic metabolism to generate lactate and pyruvate
Dehydration
Sweating
Water loss through lungs
Water loss with sodium, potassium via kidneys

Hyperthermia
Uncoupling of oxidative phosphorylation
Energy lost as heat
CNS effects –
Irritability and psychosis
Convulsions and coma
Cardiovascular collapse

Death usually as a result of respiratory failure
Aspirin – Acute, severe salicylate poisoning treatment
Treatment is primarily supportive
Gastric lavage if early and if has not vomited
Correction of
Hyperthermia
Acid-base imbalances
Dehydration
Maybe …… bicarb to enhance renal elimination

It’s important to note that these severe changes seldom occur in adults …. Mostly see in children that can’t compensate well.
ASA Drug interactions?
Increased bleeding tendency with warfarin and heparin
Increased hypoglycemia with insulin and sulfonylureas
Interfere with uricosuric effects of probenecid
High incidence of Reyes syndrome associated with aspirin use in children viral illness
Avoid use
Use acetaminophen instead!!!
Other salicylate type drugs

DIFLUSINAL (Dolobid)
Not really a salicylate
Fluorinated derviative of salicylate
Twice a day dosing
Non-selective COX inhibitor
NO ANTIPYRETIC EFFECT
Uses are similar to that of aspirin …. Except when antipyretic effects are needed
Side effects ------ < aspirin
GI but < aspirin
Cross-sensitivity with aspirin and NSAIDS
Drug interactions
Increased bleeding tendency with warfarin & heparin
Decreases effectiveness of thiazides and loops
Interferes with lithium elimination to increase toxicity
NSAIDS
Many NSAIDS are available OTC and the NSAIDS make up about 10% of all prescriptions
Many individuals cannot tolerate aspirin or salicylates as starting drugs in treatment of RA or OA…… so NSAIDS are used

Most of the NSAIDS have similar antiinflammatory efficacy ….. With similar but less problematic adverse effects then with aspirin
NSAIDS and Aspirin ….. Seem to work by the same mechanism …… inhibition of PG synthesis
NSAIDS - generalities
All inhibit COX to decrease synthesis of PG
are non-selective but vary in their relative affinity for the COX isozymes
decrease capillary permeability
decrease lysosomal enzyme release
decrease release of mediators from PMN, basophils, and mast cells
affect lymphokine release from T cells
have a limited effect on lipoxygenase
NSAIDS - generalities
Are typically WEAK ACIDS
extensively bound to plasma albumin
Primarily eliminated by liver metabolism by 1st order kinetics
Share the 3 As (antipyretic, analgesic, antiinflammatory)
Antiinflammatory effects are not immediate but are maximal when steady-state levels are reached
NSAIDS useful in the treatment of? [4]
Useful in treatment of
Dysmenorrhea
RA and OA and other arthritic conditions
Acute gout
Other inflammatory conditions
NSAID toxicity
All can produce some degree of nephrotoxicity
ARF ------ large doses, PG inhibition, renal vasoconstriction

Chronically ----- Analgesic Nephropathy
May be irreversible
Occurs after few years of continuous use
Papillary necrosis
Mechanism not clear (chronic ischemia, oxidative stress?, allergic??)
All tend to have some CNS effects ranging from
Headache
Psychosis

All should be avoided in third semester of pregnancy

Some evidence suggests that chronic use may cause some cartilage damage?
NSAID drug interactions [6]
Diuretics
Beta blockers
Cyclosporin
Methotrexate
Lithium
Warfarin
indomethacin (Indocin)
One of the most toxic!
Has all the general properties of NSAIDS
Don’t usually use this to treat fever
Generally don’t start with this one in RA

Useful in treatment of gout, RA, tendonitis and other conditions with inflammation

A special use is to ‘close a patent ductus arteriosus in neonates’
Best to use briefly

A high incidence of side-effects associated with use and ~ 20% have to stop

Adverse effects are same as other NSAIDS but CNS effects are most likely with this NSAID
Frontal headaches occur in ~ 25%
Contraindictions are similar to other NSAIDS except should be avoided in pts with epilepsy, history of psychoses, etc.
ibuprofen (Motrin)
extensively used
Low cost and low toxicity profile

Utility in RA is limited because of the short duration and need for 4x/day dosing

Indications for use is similar to aspirin
less likely to produce adverse effects than aspirin or indomethacin --- but NV are still most common side-effects
May negate aspirins cardioprotective effects by antagonizing aspirins irreversible platelet inhibition
naproxen (Naprosyn; Alleve)
One of most frequently prescribed NSAIDS

T1/2 that allows 2x/day dosing

All of the typical NSAID uses
Moderate – severe post-op pain
Acute musculoskeletal disorders
RA, OA etc.
Dysmenorrhea
Acute gout
As far as toxicity risk …. About middle of the road … with ~14% incidence of GI effects

Toxicity profile similar to other NSAIDS
nabumetone (Relafen)
Only NON-acid NSAID in current use
A prodrug (ketone) converted to ‘active’ acid form which resembles naproxen

T1/2 allows Once a day dosing!!!

Kidney plays an important elimination role …. reduce doses when kidneys aren’t working well
Side effects and uses are similar to others
Less effect on GI tract
Expensive (~ 2x naproxen)
piroxicam (Feldane)
Long half-life due to enterohepatic cycling
Allows once a day dosing!!
Indications and side-effects similar to other NSAIDS but
Aspirin may decrease piroxicam levels by 20%

Use cautiously in elderly --- improved compliance may increase nephrotoxic potential and GI ulceration and bleeding risk.
Selective COX 2 inhibitors
celecoxib (Celebrex)**
meloxicam (Mobic)**
rofecoxib (Vioxx)
valdecoxib (Bextra)
COX 2 inhibitors
RELATIVELY more selective for COX 2
Less effect on GI tract and coagulation (procoagulants?)
GI still are most common adverse effects
kidney function impaired as with other NSAIDs
Dosing is once or 2x/day
Drug interactions still being defined but seems less than other NSAIDS
Primarily
increased incidence of MIs associated with use of COX 2 inhibitors ?? (not cardioprotective) has forced these from the market … except for celecoxib (Celebrex) & meloxicam (Mobic)

Some cancers highly express COX 2
Over expression has been associated with decreased survival rate
COX 2 inhibitors may be useful in prevention and treatment of such tumors!!
GI toxicity of NSAIDS lowest
celecoxib (Celebrex)
nabumetone ( Relafen)
etodolac (Lodine)
sulindac (Clinoril)
GI toxicity of NSAIDS-medium
diclofenac (Votaren)
*ibuprofen (Motrin)
*aspirin (generic)
tolmetin (Tolectin)
*ketoprofen (Orudis)
*naproxen (Naprosyn)
GI toxicity of NSAIDS-highest
flurbinoprofen (Ansaid)
fenoprofen (Nalfon)
meclofenamate (Meclomen)
piroxicam (Feldane)
indomethacin (Indocin)
oxaprozin (Daypro)
Misoprostol and NSAIDS
NSAIDs inhibit PG synthesis to
Increase gastric acid production
Decrease protective bicarb and mucin production
Misoprostol a PGE1 analog
Decreases gastric acid production
Stimulates bicarb and mucin production
Combination of diclofenac + misoprostol (Arthrotec) is a useful combined product for patients that are high risk for GI toxicity.
Can prescribe separately
Proton pump inhibitors may also be used to decrease GI toxicities
Acetaminophen - not an NSAID!!
No significant antiinflammatory effects
Used as an analgesic and antipyretic
Inhibits COX mostly in CNS
COX 2
COX 3
Kinetics
Mostly eliminated by phase 2 reactions
Small portion metabolized by hepatic P450 system
Half life and dose are similar to aspirin
Acetaminophen - not an NSAID!!
Has little or no effect on:
Platelet aggregation
CV system
Respiration
Acid-base balance
Uric acid secretion
Doesn’t significantly produce:
Gastric irritation
GI erosion
bleeding
Used for pain and fever relief
Especially when aspirin can’t be used
Kids with viral infections
Patients on anticoagulants
Gouty patients on uricosurics
Adverse effects
Dose-dependent hepatic necrosis
Usually in acute overdose
Acetaminophen – acute toxicity
NV anorexia abdominal pain
Severe hepatic necrosis
When you see effects of the damage --- it’s too late!!
NAC (N-acetylcysteine) given in 24hr usually will protect liver
Get blood levels ---- estimate time of poisoning ---- if level is high ----- start giving large doses of very stinky stuff (rotten egg smell) …. IV prep is now available!!

Kidneys may also suffer necrosis
A severe hypoglycemia may be seen with acute toxicity
DMARDS & BIOLOGICAL MODIFIERS
DMARDS are more toxic than NSAIDS
Traditionally DMARDS were reserved for later in disorder

Many DMARDS appear to SLOW PROGRESS OF RA

Most have no antipyretic or analgesic properties

The mechanism of most of them is not well defined --- although many seem to interfere with function of lymphocytes and may work by inhibiting the immune system
DMARDS & BIOLOGICAL MODIFIERS
In more recent years
Realized that:
RA progresses aggressively and rapidly in majority of RA
many DMARDS can slow the progress if introduced earlier
Sooooooo now many start with them as soon as RA is diagnosed

MTX has been introduced earlier in RA with significant impact on the disorder
DMARDS-<ETHOTREXATE (MTX)
Gold standard’ of treatment in RA (DMARD of choice for most RA pts)
Anti-rheumatic mechanism is unknown

Today is most frequently chosen as the initial treatment of RA usually along with selective COX II inhibitors or etanercept
Anti-RA effects began earlier than gold, penicillamine, antimalarial ( ~ 6 weeks)

SE less severe in treatment of RA because lower doses than in cancer chemo ---- but greater tendency for hepatic problems (cirrhosis), pneumonitis and mucosal ulcers