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54 Cards in this Set
- Front
- Back
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NSAIDS important group of drugs
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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 |
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Rheumatoid Arthritis a few facts
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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 |
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Rheumatoid Arthritis (4)
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Swollen tender joints
Nocturnal pain Early morning joint stiffness last more than 30 minutes Acute physical disability |
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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) |
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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 |
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Rheumatoid Arthritis Treatment involves...
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Education, physical exercise, rest
Pharmacological treatment Nutritional modification?? Omega-3 Fatty Acids may play a important role in the relief of Arthritis. |
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Rheumatoid Arthritis Pharmacological treatment (6)
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Aspirin and NSAIDS
Acetaminophen Steroids DMARDS Biological modifiers Chondroitin & glucosamine?? |
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Osteoarthritis (OA) a few facts
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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 |
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Osteoarthritis (OA)
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Pain in hip or knee
Morning joint stiffness < 30 minutes Crepitus (joint popping) |
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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) |
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Osteoarthritis (OA) Management goals include: (4)
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Education of patient, caregivers and relatives
Relieve symptoms of pain and stiffness Preserve joint motion and function Minimize disability |
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Osteoarthritis (OA) TREATMENT INVOLVES: [5]
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Education
Physical therapy Various assistive devices Surgical procedures Pharmacological management of pain and inflammation (if present) |
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Osteoarthritis (OA)Pharmacological management includes: [6]
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Acetaminophen
Aspirin/other NSAIDs Capsaicin (topical) Opioid analgesics Intraarticular corticosteroids glucosamine & chondroitin sulfate |
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Aspirin & NSAIDS
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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 |
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Aspirin & NSAIDS
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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!! |
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NSAIDS
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Heterogeneous group of drugs
Comparative prototype is aspirin (ASA) They share therapeutic actions and adverse effects Three As Analgesic Antipyretic antiiflammatory |
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NSAIDS Primary mode of action [2]
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Inhibit cyclooygenase enzymes (COX)
Inhibition of prostaglandin (PG) synthesis |
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NSAIDS Prostaglandin synthesis involves [2]
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Conversion of membrane PL to arachidonic acid by phospholipase A2
Arachidonic acid converted to PG by COX |
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COX I (mostly constitutive)
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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 |
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COX 2 (mostly inducible)
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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 |
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COX 3 (constitutive?)
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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 |
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COX isozyme inhibiton and NSAIDs
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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 |
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NSAIDS appear to primarily work by...
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inhibiting COX enzymes to decrease PG production
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Aspirin
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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 |
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ASA uses include: [7]
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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 |
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ASA adverse effects...
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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 |
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ASA tosicity sx's?[8]
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Mild acute toxicity ------‡ SALICYLISM
Headache Dizziness TINNITUS Hearing loss Drowsiness NVD Mental confusion sweating |
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Aspirin – Acute, severe salicylate poisoning
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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 |
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Aspirin – Acute, severe salicylate poisoning treatment
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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. |
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ASA Drug interactions?
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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!!! |
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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 |
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NSAIDS
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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 |
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NSAIDS - generalities
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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 |
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NSAIDS - generalities
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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 |
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NSAIDS useful in the treatment of? [4]
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Useful in treatment of
Dysmenorrhea RA and OA and other arthritic conditions Acute gout Other inflammatory conditions |
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NSAID toxicity
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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? |
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NSAID drug interactions [6]
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Diuretics
Beta blockers Cyclosporin Methotrexate Lithium Warfarin |
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indomethacin (Indocin)
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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. |
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ibuprofen (Motrin)
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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 |
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naproxen (Naprosyn; Alleve)
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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 |
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nabumetone (Relafen)
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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) |
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piroxicam (Feldane)
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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. |
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Selective COX 2 inhibitors
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celecoxib (Celebrex)**
meloxicam (Mobic)** rofecoxib (Vioxx) valdecoxib (Bextra) |
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COX 2 inhibitors
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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!! |
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GI toxicity of NSAIDS lowest
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celecoxib (Celebrex)
nabumetone ( Relafen) etodolac (Lodine) sulindac (Clinoril) |
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GI toxicity of NSAIDS-medium
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diclofenac (Votaren)
*ibuprofen (Motrin) *aspirin (generic) tolmetin (Tolectin) *ketoprofen (Orudis) *naproxen (Naprosyn) |
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GI toxicity of NSAIDS-highest
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flurbinoprofen (Ansaid)
fenoprofen (Nalfon) meclofenamate (Meclomen) piroxicam (Feldane) indomethacin (Indocin) oxaprozin (Daypro) |
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Misoprostol and NSAIDS
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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 |
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Acetaminophen - not an NSAID!!
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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 |
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Acetaminophen - not an NSAID!!
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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 |
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Acetaminophen – acute toxicity
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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 |
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DMARDS & BIOLOGICAL MODIFIERS
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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 |
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DMARDS & BIOLOGICAL MODIFIERS
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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 |
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DMARDS-<ETHOTREXATE (MTX)
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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 |
