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NSAIDs, Acetaminophen, & Drugs Used in Rheumatoid Arthritis & Gout.pptx
1. NSAIDs
Inflammation is a complex response to cell injury that primarily
occurs in vascularized connective tissue and often involves the
immune response.
The mediators of inflammation function to eliminate the cause of
cell injury and clear away debris, in preparation for tissue repair.
Unfortunately, inflammation also causes pain and, in instances in
which the cause of cell injury is not eliminated,
And can result in a chronic condition ofpain and tissue damage such
as that seen in rheumatoid arthritis.
The nonsteroidal anti-inflammatory drugs (NSAIDs) and
acetaminophen are often effective in controlling inflammatory pain.
2. NSAIDs
Other treatment strategies applied to the reduction of inflammation are
targeted at immune processes.
These treatment strategies include glucocorticoids and disease-modifying
antirheumatic drugs (DMARDs).
Gout is a metabolic disease associated with precipitation of uric acid crystals
in joints.
Treatment of acute episodes targets inflammation, whereas treatment of
chronic gout targets both inflammatory processes and the production
and elimination of uric acid.
3.
4. NSAIDs, Acetaminophen, & Drugs Used in Rheumatoid Arthritis & Gout
Antipyretic:-A drug that reduces fever (eg, aspirin, other NSAIDs,
acetaminophen).
Cyclooxygenase (COX), lipoxygenase (LOX): - The enzymes responsible for
prostaglandin (COX) and leukotriene (LOX) synthesis.
Cytotoxic drug Drugs that interfere with essential processes, especially DNA
maintenance and replication and cell division. Such drugs generally kill rapidly
dividing cells and are used for cancer chemotherapy and immunosuppression.
Disease-modifying antirheumatic drugs (DMARDs):-Diverse group of drugs
that modify the inflammatory processes underlying rheumatoid arthritis and
similar autoimmune conditions;
Disease-modifying antirheumatic drugs have a slow (weeks to months)
onset of clinical effects.
5. NSAIDs, Acetaminophen, & Drugs Used in Rheumatoid Arthritis & Gout
Nonsteroidal anti-inflammatory drugs (NSAIDs): Inhibitors of cyclooxygenase;
the term nonsteroidal differentiates them from corticosteroid drugs (eg,
cortisol;
Reye’s syndrome: A rare syndrome of rapid liver degeneration and
encephalopathy in children treated with aspirin during a viral infection;
Tumor necrosis factor-a (TNF-a):A cytokine that plays a central role in
inflammation;
Uricosuric agent: A drug that increases the renal excretion of uric acid.
Xanthine oxidase: A key enzyme in the purine metabolism pathway that
converts hypoxanthine to xanthine and xanthine to uric acid.
6. ASPIRIN & OTHER NONSELECTIVE NSAIDs
A. Classification and Prototypes
Aspirin (acetylsalicylic acid) is the prototype of the salicylates and other NSAIDs.
The other older nonselective NSAIDs (ibuprofen, indomethacin, many others)
vary primarily in their potency, analgesic and anti-inflammatory effectiveness,
and duration of action.
Ibuprofen and naproxen have moderate effectiveness;
indomethacin has greater anti-inflammatory effectiveness;
Ketorolac has greater analgesic effectiveness.
Celecoxib was the first member of a newer NSAID subgroup, the cyclooxygenase-
2 (COX-2)-selective inhibitors, which were developed in an attempt to reduce the
gastrointestinal toxicity associated with COX inhibition while preserving efficacy.
Unfortunately, clinical trials involving some of the highly selective COX-2
inhibitors have shown a higher incidence of cardiovascular thrombotic events
than the nonselective drugs.
8. ASPIRIN & OTHER NONSELECTIVE NSAIDs
B. Mechanism of Action
cyclooxygenase is the enzyme that converts arachidonic acid into the
endoperoxide precursors of prostaglandins, important mediators of
inflammation.
Cyclooxygenase has at least 2 isoforms: COX-1 and COX-2. COX-1 is primarily
expressed in noninflammatory cells, whereas COX-2 is expressed in activated
lymphocytes, polymorphonuclear cells, and other inflammatory cells.
Aspirin and nonselective NSAIDs inhibit both cyclooxygenase isoforms and
thereby decrease prostaglandin and thromboxane synthesis throughout the
body.
9. ASPIRIN & OTHER NONSELECTIVE NSAIDs
B. Mechanism of Action
Release of prostaglandins necessary for homeostatic function is disrupted, as is
release of prostaglandins involved in inflammation.
The COX-2-selective inhibitors have less effect on the prostaglandins involved in
homeostatic function, particularly those in the gastrointestinal tract.
The major difference between the mechanisms of action of aspirin and other
NSAIDs is that aspirin (but not its active metabolite, salicylate) acetylates and
thereby irreversibly inhibits cyclooxygenase, whereas the inhibition produced by
other NSAIDs is reversible.
The irreversible action of aspirin results in a longer duration of its antiplatelet
effect and is the basis for its use as an antiplatelet drug
10.
11. ASPIRIN & OTHER NONSELECTIVE NSAIDs
C. Effects
Arachidonic acid derivatives are important mediators of
inflammation;
cyclooxygenase inhibitors reduce the manifestations of
inflammation, although they have no effect on underlying tissue
damage or immunologic reactions.
These inhibitors also suppress the prostaglandin synthesis in the
CNS that is stimulated by pyrogens and thereby reduce fever
(antipyretic action).
The analgesic mechanism of these agents is less well understood.
12. ASPIRIN & OTHER NONSELECTIVE NSAIDs
C. Effects
Activation of peripheral pain sensors may be diminished as a result
of reduced production of prostaglandins in injured tissue;
Cyclooxygenase inhibitors also interfere with the homeostatic
function of prostaglandins.
Most important, Cyclooxygenase inhibitors reduce prostaglandin-
mediated cytoprotection in the gastrointestinal tract and
autoregulation of renal function.
13. ASPIRIN & OTHER NONSELECTIVE NSAIDs
Pharmacokinetics and Clinical Use
1. Aspirin—Aspirin has 3 therapeutic dose ranges:
The low range (<300 mg/d) is effective in reducing platelet aggregation;
Intermediate doses (300–2400 mg/d) have antipyretic and analgesic effects;
And high doses (2400–4000 mg/d) are used for an anti-inflammatory effect.
Aspirin is readily absorbed and is hydrolyzed in blood and tissues to acetate
and salicylic acid.
Salicylate is a reversible nonselective inhibitor of cyclooxygenase.
Elimination of salicylate is first order at low doses, with a half-life of 3–5 h.
At high (anti-inflammatory) doses, half-life increases to 15 h or more and
elimination becomes zero order.
Excretion is via the kidney.
14. ASPIRIN & OTHER NONSELECTIVE NSAIDs
Pharmacokinetics and Clinical Use
Other NSAIDs—The other NSAIDs are well absorbed after oral
administration.
Ibuprofen has a half-life of about 2 h, is relatively safe, and is the least
expensive of the older, nonselective NSAIDs.
Naproxen and piroxicam are noteworthy because of their longer half-
lives, which permit less frequent dosing.
These other NSAIDs are used for the treatment of mild to moderate
pain, especially the pain of musculoskeletal inflammation such as that
seen in arthritis and gout.
15. ASPIRIN & OTHER NONSELECTIVE NSAIDs
Pharmacokinetics and Clinical Use
Other NSAIDs are also used to treat many other conditions, including
dysmenorrhea, headache, and patent ductus arteriosus in premature
infants.
Ketorolac is notable as a drug used mainly as a systemic analgesic, not as
an anti-inflammatory (although it has typical nonselective NSAID
properties). It is the only NSAID available in a parenteral formulation.
Nonselective NSAIDs reduce polyp formation in patients with primary
familial adenomatous polyposis.
Long-term use of NSAIDs reduces the risk of colon cancer.
16. ASPIRIN & OTHER NONSELECTIVE NSAIDs
E. Toxicity
1. Aspirin—The most common adverse effect from therapeutic anti-
inflammatory doses of aspirin is gastric upset.
Chronic use can result in gastric ulceration, upper gastrointestinal bleeding,
and renal effects, including acute failure and interstitial nephritis.
Aspirin increases the bleeding time. When prostaglandin synthesis is inhibited
by even small doses of aspirin, persons with aspirin hypersensitivity (especially
associated with nasal polyps) can experience asthma from the increased
synthesis of leukotrienes.
17. ASPIRIN & OTHER NONSELECTIVE NSAIDs
E. Toxicity
This type of hypersensitivity to aspirin precludes treatment with any NSAID.
At higher doses of aspirin, tinnitus, vertigo, hyperventilation, and respiratory
alkalosis are observed.
At very high doses, the drug causes metabolic acidosis, dehydration,
hyperthermia, collapse, coma, and death.
Children with viral infections who are treated with aspirin have an increased
risk for developing Reye's syndrome, a rare but serious syndrome of rapid liver
degeneration and encephalopathy.
There is no specific antidote for aspirin.
18. ASPIRIN & OTHER NONSELECTIVE NSAIDs
E. Toxicity
2. Nonselective NSAIDs—Like aspirin, these agents are associated with
significant gastrointestinal disturbance, but the incidence is lower than with
aspirin.
There is a risk of renal damage with any of the NSAIDs, especially in patients
with preexisting renal disease.
Because these drugs are cleared by the kidney, renal damage results in higher,
more toxic serum concentrations.
Use of parenteral ketorolac is generally restricted to 72 h because of the risk of
gastrointestinal and renal damage with longer administration.
Serious hematologic reactions have been noted with indomethacin.
19. ASPIRIN & OTHER NONSELECTIVE NSAIDs
E. Toxicity
3. COX-2-selective inhibitors—The COX-2-selective inhibitors (celecoxib, rofecoxib,
valdecoxib) have a reduced risk of gastrointestinal effects, including gastric ulcers and
serious gastrointestinal bleeding.
The COX-2 inhibitors carry the same risk of renal damage as nonselective COX
inhibitors, presumably because COX-2 contributes to homeostatic renal effects.
Clinical trial data suggest that highly selective COX-2 inhibitors such as rofecoxib and
valdecoxib carry an increased risk of myocardial infarction and stroke.
The increased risk of arterial thrombosis is believed to be due to the COX-2 inhibitors
having a greater inhibitory effect on endothelial prostacyclin (PGI2) formation than on
platelet TXA2 formation.
Prostacyclin promotes vasodilation and inhibits platelet aggregation, whereas TXA2
has the opposite effects.
Several COX-2 inhibitors have been removed from the market, and the others are now
labeled with warnings about the increased risk of thrombosis.
20. ACETAMINOPHEN
A. Classification and Prototype
Acetaminophen is the only over-the-counter non-anti-inflammatory analgesic
commonly available in the United States.
Phenacetin, a toxic prodrug that is metabolized to acetaminophen, is still
available in some other countries.
B. Mechanism of Action
The mechanism of analgesic action of acetaminophen is unclear.
The drug is only a weak COX-1 and COX-2 inhibitor in peripheral tissues, which
accounts for its lack of anti-inflammatory effect.
Evidence suggests that acetaminophen may inhibit a third enzyme, COX-3, in
the CNS.
C. Effects
Acetaminophen is an analgesic and antipyretic agent; it lacks anti-inflammatory
or antiplatelet effects.
21. ACETAMINOPHEN
D. Pharmacokinetics and Clinical Use
Acetaminophen is effective for the same indications as intermediate-dose
aspirin.
Acetaminophen is therefore useful as an aspirin substitute, especially in
children with viral infections and in those with any type of aspirin intolerance.
Acetaminophen is well absorbed orally and metabolized in the liver.
Acetaminophen’s half-life, which is 2–3 h in persons with normal hepatic
function, is unaffected by renal disease.
22. ACETAMINOPHEN
E. Toxicity
In therapeutic dosages, acetaminophen has negligible toxicity in most persons.
However, when taken in overdose or by patients with severe liver impairment,
the drug is a dangerous hepatotoxin.
The mechanism of toxicity involves oxidation to cytotoxic intermediates by
phase I cytochrome P450 enzymes.
This occurs if substrates for phase II conjugation reactions (acetate and
glucuronide) are lacking.
Prompt administration of acetylcysteine, a sulfhydryl donor, may be lifesaving
after an overdose.
People who regularly consume 3 or more alcoholic drinks per day are at
increased risk of acetaminophen-induced hepatotoxicity.
23. DISEASE-MODIFYING ANTIRHEUMATIC DRUGS (DMARDs)
A. Classification
This heterogeneous group of agents has anti-inflammatory actions in several
connective tissue diseases.
They are called disease-modifying drugs because some evidence shows HDL
slowing or even reversal of joint damage, an effect never seen with NSAIDs.
They are also called slow-acting antirheumatic drugs because it may take 6
week to 6 month for their benefits to become apparent. Corticosteroids can be
considered anti-inflammatory drugs with an intermediate rate of action (ie,
slower than NSAIDs but faster than other DMARDs). However, the
corticosteroids are too toxic for routine chronic use (Chapter 39) and are
reserved for temporary control of severe exacerbations and long-term use in
patients with severe disease not controlled by other agents.
24. DISEASE-MODIFYING ANTIRHEUMATIC DRUGS (DMARDs
B. Mechanisms of Action and Effects
The mechanisms of action of most DMARDs in treating rheumatoid arthritis are
complex.
Cytotoxic drugs (eg, methotrexate) probably act by reducing the number of
immune cells available to maintain the inflammatory response;
Many of these DMARDs drugs are also used in the treatment of cancer.
Other drugs appear to interfere with the activity of T lymphocytes (eg,
sulfasalazine, hydroxychloroquine, cyclosporine, leflunomide, mycophenolate
mofetil, abatacept),
Other drugs appear to interfere with the activity of B lymphocytes (rituximab), or
macrophages (gold compounds).
Biologic agents that inhibit the action of tumor necrosis factor-α (TNF-α), including
infliximab, adalimumab, and etanercept, have also shown efficacy in rheumatoid
arthritis, as has the recombinant human interleukin-1 receptor antagonist anakinra.
25. DISEASE-MODIFYING ANTIRHEUMATIC DRUGS (DMARDs)
C. Pharmacokinetics and Clinical Use
Sulfasalazine, hydroxychloroquine, methotrexate, cyclosporine, penicillamine,
and leflunomide are given orally.
Anti-TNF-α drugs are given by injection.
Gold compounds are available for parenteral use (gold sodium thiomalate and
aurothioglucose) and for oral administration (auranofin) but are rarely used.
Increasingly, DMARDs, particularly low doses of methotrexate, are initiated
fairly early in patients with moderate to severe rheumatoid arthritis in an
attempt to ameliorate disease progression.
Some of these drugs are also used in other rheumatic diseases such as lupus
erythematosus, arthritis associated with Sjögren’s syndrome, juvenile
rheumatoid arthritis, ankylosing spondylitis, and in other immunologic
disorders
26. DISEASE-MODIFYING ANTIRHEUMATIC DRUGS (DMARDs
D. Toxicity
All DMARDs can cause severe or fatal toxicities.
Careful monitoring of patients who take these drugs is mandatory.
27.
28. DRUGS USED IN GOUT
A. Classification and Prototypes
Gout is associated with increased serum concentrations of uric acid.
Acute attacks involve joint inflammation initiated by precipitation of uric
acid crystals.
Treatment strategies include (1) reducing inflammation during acute
attacks (with colchicine, NSAIDs, or glucocorticoids;
(2) accelerating renal excretion of uric acid with uricosuric drugs
(probenecid or sulfinpyrazone); and (3) reducing (with allopurinol or
febuxostat) the conversion of purines to uric acid by xanthine oxidase.
29. Anti-Inflammatory Drugs Used for Gout
Mechanisms:
NSAIDs such as indomethacin are effective in inhibiting the
inflammation of acute gouty arthritis.
These agents act through the reduction of prostaglandin
formation and the inhibition of crystal phagocytosis by
macrophages.
Colchicine, a selective inhibitor of microtubule assembly,
reduces leukocyte migration and phagocytosis; the drug may
also reduce production of leukotriene B4 and decrease free
radical formation.
30. Anti-Inflammatory Drugs Used for Gout
Effects:
NSAIDs and glucocorticoids reduce the synthesis of inflammatory
mediators in the gouty joint.
Because it reacts with tubulin and interferes with microtubule
assembly,
Colchicine is a general mitotic poison.
Tubulin is necessary for normal cell division, motility, and many
other processes.
31. Anti-Inflammatory Drugs Used for Gout
3. Pharmacokinetics and clinical use:
An NSAID or a glucocorticoid is preferred for the treatment of acute gouty
arthritis.
Although colchicine can be used for acute attacks, the doses required cause
significant gastrointestinal disturbance, particularly diarrhea.
Lower doses of colchicine are used to prevent attacks of gout in patients with
a history of multiple acute attacks.
Colchicine is also of value in the management of familial Mediterranean fever,
a disease of unknown cause characterized by fever, hepatitis, peritonitis,
pleuritis, arthritis, and, occasionally, amyloidosis.
Indomethacin, some glucocorticoids, and colchicine are used orally;
parenteral preparations of glucocorticoids and colchicine are also available
32. Anti-Inflammatory Drugs Used for Gout
Toxicity:
NSAIDs can cause renal damage, and indomethacin can
additionally cause bone marrow depression.
Short courses of glucocorticoids can cause behavioral
changes and impaired glucose control.
Because colchicine can severely damage the liver and
kidney, dosage must be carefully limited and monitored.
Overdose is often fatal.
33. Uricosuric Agents
Mechanism:
Normally, over 90% of the uric acid filtered by the kidney is reabsorbed in
the proximal tubules.
Uricosuric agents (probenecid, sulfinpyrazone) are weak acids that
compete with uric acid for reabsorption by the weak acid transport
mechanism in the proximal tubules and thereby increase uric acid
excretion.
At low doses, these agents may also compete with uric acid for secretion
by the tubule and occasionally can elevate, rather than reduce, serum uric
acid concentration.
Elevation of uric acid levels by this mechanism occurs with aspirin (another
weak acid) over much of its dose range.
34. Uricosuric Agents
Mechanism:
Normally, over 90% of the uric acid filtered by the kidney is
reabsorbed in the proximal tubules.
Uricosuric agents (probenecid, sulfinpyrazone) are weak acids that
compete with uric acid for reabsorption by the weak acid transport
mechanism in the proximal tubules and thereby increase uric acid
excretion.
At low doses, these agents may also compete with uric acid for
secretion by the tubule and occasionally can elevate, rather than
reduce, serum uric acid concentration.
Elevation of uric acid levels by this mechanism occurs with aspirin
(another weak acid) over much of its dose range.
35. Uricosuric Agents
Effects:
Uricosuric drugs inhibit the secretion of a large number of other
weak acids (eg, penicillin, methotrexate) in addition to inhibiting
the reabsorption of uric acid.
Pharmacokinetics and clinical use—Uricosuric drugs are used
orally to treat chronic gout, caused by under-excretion of uric
acid.
These drugs are of no value in acute episodes.
36. Uricosuric Agents
Toxicity:
Uricosuric drugs can precipitate an attack of acute gout during
the early phase of their action.
This can be avoided by simultaneously administering colchicine
or indomethacin.
Because they are sulfonamides, the uricosuric drugs may share
allergenicity with other classes of sulfonamide drugs (diuretics,
antimicrobials, oral hypoglycemic drugs).
37. Xanthine Oxidase Inhibitors
Mechanism:
The production of uric acid can be reduced by inhibition of
xanthine oxidase, the enzyme that converts hypoxanthine to
xanthine and xanthine to uric acid.
Allopurinol is converted to oxypurinol (alloxanthine) by xanthine
oxidase; alloxanthine is an irreversible suicide inhibitor of the
enzyme.
The newer drug febuxostat is a nonpurine inhibitor of xanthine
oxidase that is more selective than allopurinol and alloxanthine,
which inhibit other enzymes involved in purine and pyrimidine
metabolism.
38. Xanthine Oxidase Inhibitors
Effects:
Inhibition of xanthine oxidase increases the concentrations of the more
soluble hypoxanthine and xanthine and decreases the concentration of
the less soluble uric acid.
As a result, there is less likelihood of precipitation of uric acid crystals in
joints and tissues. Clinical trials suggest that febuxostat is more effective
than allopurinol in lowering serum uric acid.
39. Xanthine Oxidase Inhibitors
Pharmacokinetics and clinical use:
The xanthine oxidase inhibitors are given orally in the management
of chronic gout.
Like uricosuric agents, these drugs are usually withheld for 1–2 week
after an acute episode of gouty arthritis and are administered in
combination with colchicine or an NSAID to avoid an acute attack.
Allopurinol is also used as an adjunct to cancer chemotherapy to
slow the formation of uric acid from purines released by the death of
large numbers of neoplastic cells.
40. Xanthine Oxidase Inhibitors
Toxicity and drug interactions:
Allopurinol causes gastrointestinal upset, rash, and rarely,
peripheral neuritis, vasculitis, or bone marrow dysfunction,
including aplastic anemia.
It inhibits the metabolism of mercaptopurine and
azathioprine, drugs that depend on xanthine oxidase for
elimination.
Febuxostat can cause liver function abnormalities, headache,
and gastrointestinal upset.