MODULE6- ANTIINFLAMMATORY Flashcards
the cyclooxygenase (COX) pathway of arachidonate metabolism produces:
- PG pathway
- Leukotrienes pathway
” Dial 1 for Housekeeping”
Dial 2 for inflammatory
prostaglandins, which have a variety of effects on
- blood vessels,
- on nerve endings,
- and on cells involved in inflammation.
The______________- of arachidonate metabolism yields leukotrienes,
which have a powerful chemotactic effect on eosinophils,
neutrophils, and macrophages and promote bronchoconstriction
and alterations in vascular permeability.
** lipoxygenase pathway**
THERAPEUTIC STRATEGIES
The treatment of patients with inflammation involves two primary __goals:
- first, the relief of symptoms and the maintenance of
function, which are usually the major continuing complaints of the patient;
- and second, the slowing or arrest of the tissue-damaging
process.
In rheumatoid arthritis, response to therapy can be
quantitated using several measures such as the :
- Disease Activity
Scale (DAS),
- the Clinical Disease Activity Index (CDAI), and
- the American College of Rheumatology Response index (ACR
Response).
The first two are continuous variables denoting both
state and change,
Disease Activity
Scale (DAS),
the Clinical Disease Activity Index (CDAI),
is solely a change measure.
American College of Rheumatology Response index (ACR
Response).
THERAPEUTIC STRATEGIES
- nonsteroidal antiinflammatory
drugs (NSAIDs) - glucocorticoids
- diseasemodifying
antirheumatic drugs (DMARDs) - biologics (a
subset of the DMARDs).
- *Salicylates and other similar agent**s used to treat rheumatic disease
- *share the capacity to suppress the signs and symptoms** of inflammation.
These drugs also exert antipyretic and analgesic effects,
but it is their anti-inflammatory properties that make them most
useful in the management of disorders in which pain is related to
the intensity of the inflammatory process.
NONSTEROIDAL
ANTIINFLAMMATORY DRUGS
Note : Since aspirin, the original NSAID, has a number of adverse
effects, many other NSAIDs have been developed in attempts to
improve upon aspirin’s efficacy and decrease its toxicity.
Chemistry & Pharmacokinetics of NSAIDS
- grouped in several chemical classes
- chemical diversity yields a broad range of pharmacokinetic
characteristics - some general properties in common
- Most of these drugs are well absorbed, and food does not substantially change their bioavailability
- highly metabolized, some by phase I followed by phase II mechanisms
and others by direct glucuronidation (phase II) alone - While renal
excretion is the most important route for final elimination, nearly
all undergo varying degrees of biliary excretion and reabsorption
(enterohepatic circulation). - Most of the NSAIDs are highly protein-bound
(∼ 98%), usually to albumin.
*
All but one of the NSAIDs are weak
organic acidsas given; the exception, ______________, is aketone prodrug that is metabolized to theacidic active drug.
nabumetone
Most of the NSAIDs (eg, ibuprofen,
ketoprofen) areracemic mixtures, while one, ___________, is provided
as a single enantiomer
naproxen
and a few have no chiral center
_________________
(eg, diclofenac).
All NSAIDs can be found in______________after repeated dosing.
** synovial fluid**
Note : Drugs with short half-lives remain in the joints longer than would be predicted from their half-lives, while drugs with **longer **half-lives disappear from the synovial fluid at a rate proportionate
to their half-lives.
Pharmacodynamics
NSAID anti-inflammatory activity
NSAID anti-inflammatory activity is mediated chiefly through
_____________________
inhibition of prostaglandin biosynthesis
Various
NSAIDs have additional possible mechanisms of action, including
- inhibition of chemotaxis,
- down-regulation of interleukin-1 production,
- decreased production of free radicals and superoxide, and
- interference with calcium-mediated intracellular events.
The selective COX-2 inhibitors do not affect
platelet function at their usual doses
are somewhat more effective in inhibiting COX-1.
- aspirin,
- ibuprofen,
- indomethacin,
- piroxicam, and
- sulindac
The
efficacy of COX-2-selective drugs equals that of the older
NSAIDs,whileGI safety may be improved. On the other hand,
selective COX-2 inhibitors may increase the incidence of
edema and hypertension
As of August 2011, ____________ and _____ were the only COX-2 inhibitors marketed in the
USA.
celecoxib and the less selective
meloxicam
_________________, two previously marketed, selective
COX-2 inhibitors, were withdrawn from the market because
of their association with increased cardiovascular thrombotic
events.
Rofecoxib and valdecoxib
___________ has a Food and Drug Administration initiated
“black box” warning concerning cardiovascular risks. It has been
recommended that all NSAID product labels be revised to mention
cardiovascular risks.
Celecoxib
To varying
degrees, all newer NSAIDs are analgesic, anti-inflammatory, and
antipyretic, and all (_________________ and the
___________________) inhibit platelet aggregation.
except the COX-2-selective agents
** nonacetylated salicylate**s
NSAIDs are
all ______________ and can be associated with GI ulcers and bleeds
as well, although as a group the newer agents tend to cause less GI
irritation than aspirin.
gastric irritants
____________ has been observed for all of the drugs for which extensive experience has been reported.
Nephrotoxicity
Nephrotoxicity is due, in part, to_____________
of renal blood flow, which is modulated by prostaglandins.
Hepatotoxicity can also occur with any NSAID.
interference with the autoregulation
Although these drugs effectively inhibit inflammation, there is
no evidence that—in contrast to drugs such as methotrexate and
other DMARDs—they alter the course of any arthritic disorder.
They can inhibit the inflammation but cant alter the arthritic disorder. :)
Several NSAIDs (including aspirin) reduce the incidence of
____________ when taken chronically. Several large epidemiologic
studies have shown a 50% reduction in relative risk when the drugs
are taken for 5 years or longer. The mechanism for this protective
effect is unclear.
colon cancer
The NSAIDs have a number of commonalities. Although not all
NSAIDs are approved by the FDA for the whole range of rheumatic
diseases, most are probably effective in rheumatoid arthritis, seronegative
spondyloarthropathies (eg, psoriatic arthritis and arthritis associated with inflammatory bowel disease), osteoarthritis, localized
musculoskeletal syndromes (eg, sprains and strains, low
back pain), and gout (except ________, which appears to be ineffective
in gout).
tolmetin
Adverse effects are generally quite similar for all of the NSAIDs:
1. Central nervous system: Headaches, tinnitus, and dizziness.
2. Cardiovascular: Fluid retention, hypertension, edema, and rarely, myocardial infarction, and congestive heart failure.
3. Gastrointestinal: Abdominal pain, dysplasia, nausea, vomiting, and rarely, ulcers or bleeding.
4. Hematologic: Rare thrombocytopenia, neutropenia, or even aplastic anemia.
5. Hepatic: Abnormal liver function tests and rare liver failure. 6. Pulmonary: Asthma.
7. Skin: Rashes, all types, pruritus.
8. Renal: Renal insufficiency, renal failure, hyperkalemia, and proteinuria.
This long use and availability without prescription diminishes
its glamour compared with that of the newer NSAIDs. This is
now rarely used as an anti-inflammatory medication and will be
reviewed only in terms of its anti-platelet effects (ie, doses of
81–325 mg once daily).
ASPIRIN
The
salicylates are rapidly absorbed from the stomach and upper small intestine yielding a peak plasma salicylate level within____________
1–2 hours.
Aspirin is absorbed as such and is rapidly hydrolyzed (serum halflife
___________) to acetic acid and salicylate by esterases in tissue
and blood ( Figure 36–3 ).
Salicylate is nonlinearly bound to albumin.
Alkalinization of the urine increases the rate of excretion of
free salicylate and its water-soluble conjugates.
15 minutes
Mechanisms of ActionAspirin
_________________
In other
tissues, synthesis of new COX replaces the inactivated enzyme so
that ordinary doses have a duration of action of 6–12 hours.
irreversibly inhibits platelet COX so that aspirin’s antiplatelet
effect lasts 8–10 days (the life of the platelet).
Aspirin decreases the incidence of transient ischemic attacks,
unstable angina, coronary artery thrombosis with myocardial
infarction, and thrombosis after coronary artery bypass grafting
(see Chapter 34 ).
Epidemiologic studies suggest that long-term use of aspirin at
low dosage is associated with a lower incidence of colon cancer,
possibly related to its COX-inhibiting effects.
colon cancer decrease incidence
Adverse Effects
In addition to the common side effects listed above, aspirin’s
main adverse effectsatantithrombotic doses are______________.
_____________ rarely if ever occur
at antithrombotic doses.
- gastric upset (intolerance) and
- gastric and duodenal ulcers
- Hepatotoxicity, asthma, rashes, GI bleeding, and renal toxicity
The antiplatelet action of aspirin contraindicates its use by
patients with __________
hemophilia
. Although previously not recommended
during pregnancy, aspirin may be valuable in treating ______________
preeclampsiaeclampsia.
These drugs include magnesium choline salicylate, sodium salicylate,
and salicyl salicylate. All are effective
anti-inflammatory drugs, although they may be less effective analgesics
than aspirin.
NONACETYLATED SALICYLATES
Because NONACETYLATED SALICYLATES they are much less effective than
aspirin as COX inhibitorsand theydo not inhibit platelet aggregation,
they may be preferable when COX inhibition is undesirable
such as in patients with ______________
The nonacetylated salicylates are administered in doses up to
3–4 g of salicylate a day and can be monitored using serum salicylate
measurements.
- asthma,
- those with bleeding tendencies,
- and even (under close supervision) those with renal dysfunction.
COX-2 SELECTIVE INHIBITORS
Celecoxib
Meloxicam
_____________ were developed in an attempt
to inhibit prostaglandin synthesis by the COX-2 isozyme induced
at sites of inflammation withoutaffecting the action of the constitutively
active “housekeeping” COX-1 isozyme found in the GI
tract, kidneys, and platelets.
COX-2 selective inhibitors, or** coxibs**,
What is the MOA of Cox 2 selective inhibitors?
Coxibs selectively bind to and block the
active site of the COX-2 enzyme much more effectively than that of
COX-1
COX-2 inhibitors have analgesic, antipyretic, and anti-inflammatory
effects similar to those of non-selective NSAIDs but
with an approximate halving of GI adverse effects.
Likewise, COX-2 inhibitors at usual doses have no impact on platelet aggregation, which is mediated by thromboxane produced by the COX-1 isozyme.
In contrast, they do inhibit COX-2-mediated prostacyclin synthesis in the vascular endothelium.
As a result, COX-2 inhibitors do not offer the cardioprotective effects of traditional nonselective NSAIDs, which has resulted in some patients taking low-dose aspirin in addition to a coxib regimen to maintain this effect.
Unfortunately, because COX-2 is constitutively active within the kidney, recommended doses of COX-2 inhibitors cause renal toxicities similar to those associated with traditional NSAIDs. Clinical data have suggested a higher incidence of cardiovascular thrombotic events associated with COX-2 inhibitors such as ______________-, resulting in their withdrawal from the market.
rofecoxib and valdecoxib
” ROX VALDEZ”
is a selective COX-2 inhibitor—about 10–20 times
more selective for COX-2 than for COX-1.
is associated with fewer endoscopic ulcers than most
other NSAIDs.
Celecoxib
Probably because it is a sulfonamide, celecoxib
may cause___________. It does not affect platelet aggregation at usual doses.
rashes
celecoxib interacts occasionally with warfarin— as would be expected of a drug metabolized via___________
Adverse effects are the common toxicities listed above.
CYP2C9.
_______________is an enolcarboxamide related to piroxicam that preferentially inhibits COX-2 over COX-1, particularly at its lowest therapeutic dose of 7.5 mg/d.
It is not as selective as celecoxib and may be considered “preferentially” selective rather than “highly” selective.
Meloxicam
It is associated with fewer clinical GI symptoms and complications than piroxicam, diclofenac, and naproxen.
Similarly, while ____________ is known to inhibit synthesis of thromboxane A 2 , even at supratherapeutic doses, its blockade of thromboxane A 2 does not reach levels that result in decreased in vivo platelet function (see common adverse effects above).
meloxicam
NONSELECTIVE COX INHIBITORS
Diclofenac
Diflunisal
Etodolac
Flurbiprofen
Ibuprofen
Indomethacin
Ketoprofen
Ketorolac
Nabumetone
Naproxen
Oxaprozin
Piroxicam
Sulindac
Tolmetin
______________ is a phenylacetic acid derivative that is relatively nonselective as a COX inhibitor.
Gastrointestinal ulceration may occur less frequently than with some other NSAIDs.
Diclofenac
A preparation combining____________ decreases upper gastrointestinal ulceration but may result in diarrhea.
diclofenac and misoprostol
Another combination of ____________ was also effective with respect to the prevention of recurrent bleeding, but renal adverse effects were common in high-risk patients.
diclofenac and omeprazole
Diclofenac, 150 mg/d, appears to impair renal blood flow and glomerular filtration rate.
_____________ occurs more commonly with this drug than with other NSAIDs.
Elevation of serum aminotransferases
A 0.1% ophthalmic preparation is promoted for prevention of
postoperative ophthalmic inflammation and can be used after
intraocular lens implantation and strabismus surgery.
Diclofenac
A topical gel
containing _____________ is effective for solar keratoses.
3% diclofenac
Diclofenac
in___________ form can be considered for preemptive analgesia
and postoperative nausea.
In Europe, diclofenac is also available
as an oral mouthwash and for intramuscular administration.
rectal suppository
Although ____________ is derived from salicylic acid, it is not metabolized
to salicylic acid or salicylate.
It undergoes an enterohepatic
cycle with reabsorption of its glucuronide metabolite followed by cleavage of the glucuronide to again release the active moiety.
This is subject to capacity-limited metabolism, with serum
half-lives at various dosages approximating that of salicylates
( Table 36–1 ). In rheumatoid arthritis the recommended dose is
500–1000 mg daily in two divided doses.
It is claimed to be particularly
- *effective for cancer pain with bone metastases** and for
- *pain control in dental (third molar) surgery.**
Diflunisal
A _______________ is a clinically useful analgesic for painful oral lesions.
Because its clearance depends on renal function as well as hepatic
metabolism, should be limited in patients with
significant renal impairment.
2% diflunisal oral
ointment
- racemic acetic acid derivative with an intermediate
half-life ( Table 36–1 )
- does not undergo chiral inversion in the body. The dosage of etodolac is 200–400 mg three to four times daily.
Etodolac
- is a propionic acid derivative with a possibly more
complex mechanism of action than other NSAIDs. - Its ( S )(–) enantiomer inhibits COX nonselectively, but it has been shown in rat tissue to also affect tumor necrosis factor-α (TNF-α) and nitric
oxide synthesis. - Hepatic metabolism is extensive; its ( R )(+) and ( S )
(–) enantiomers are metabolized differently, and it does not undergo chiral conversion. - It does demonstrate enterohepaticbcirculation.
- also available in a topical ophthalmic formulation
for inhibition of intraoperative miosis. - intravenously is effective for **perioperative analgesia in minor ear, neck, **and nose surgery and in lozenge form for sore throat.
Flurbiprofen
Although its adverse effect profile is similar to that of other NSAIDs in most ways,___________ is also rarely associated with cogwheel rigidity, ataxia, tremor, and myoclonus.
flurbiprofen
FLUR
_________ is a simple derivative of phenylpropionic acid
( Figure 36–1 ). In doses of about 2400 mg daily
- is equivalent to 4 g of aspirin in anti-inflammatory effect.
- Pharmacokinetic characteristics are given in Table 36–1 .
Ibuprofen
- Oral ibuprofen is often prescribed in lower doses (<2400 mg/d), at which it has __________________
- It is available over the counter in low-dose forms under several trade names.
analgesic but not anti-inflammatory efficacy.
is effective in closing patent ductus arteriosus in
preterm infants, with much the same efficacy and safety as indomethacin.
The oral and intravenous routes are equally effective for
this indication.
A topical cream preparation appears to be absorbed into fascia and muscle; an (S ) (–) formulation has been tested.
This was more effective than placebo cream in the
treatment of primary knee osteoarthritis.
Ibuprofen
A ____________, 400 mg, provides prompt relief and good overall
efficacy in postsurgical dental pain.
liquid gel preparationof ibuprofen
In comparison with indomethacin, ibuprofen decreases urine output ____________ and ___________.
less and also causes less fluid retention
Ibuprofen is relatively contraindicated in individuals with___________________.
Aseptic meningitis (particularly in patients with systemic lupus erythematosus), and fluid retention have been reported. Interaction with anticoagulants is uncommon.
- nasal polyps,
- angioedema,
- and bronchospastic reactivity to aspirin.
What will happen with ibuprofen and aspiren administered together?
The concomitant administration of ibuprofen and aspirin antagonizes the irreversible platelet inhibition induced by aspirin.
Thus, treatment with ibuprofen in patients with increased cardiovascular risk may limit the cardioprotective effects of aspirin.
Furthermore, the use of ibuprofen concomitantly with aspirin may decrease the total anti-inflammatory effect.
Ibuprofen Common adverse effects are listed on page 638; rare hematologic effects include_____ and ___________
agranulocytosis and aplastic anemia.
______________, introduced in 1963, is an indole derivative
( Figure 36–1 ).
- It is a potent nonselective COX inhibitor
- and may also inhibit phospholipase A and C,
- reduce neutrophil migration,
- and decrease T-cell and B-cell proliferation.
- It differs somewhat from other NSAIDs in its indications and toxicities.
Indomethacin
It has been used to accelerate closure of patent ductus arteriosus.
has been tried in numerous small or uncontrolled
trials for many other conditions, including **Sweet’s syndrome, juvenile **rheumatoid arthritis, pleurisy, nephrotic syndrome, diabetes insipidus, urticarial vasculitis, postepisiotomy pain, and prophylaxis of heterotopic ossification in arthroplasty.
Indomethacin
An _________ is efficacious for conjunctival
inflammation and to reduce pain after traumatic corneal abrasion.
Gingival inflammation is reduced after administration of indomethacin oral rinse.
Epidural injections produce a degree of pain
relief similar to that achieved with methylprednisolone in postlaminectomy
syndrome.
ophthalmic preparation
At usual doses, indomethacin has the common side effects listed above. The GI effects may include pancreatitis.
Headache is experienced by 15–25% of patients and may be associated with dizziness, confusion, and depression.
Rarely, psychosis with hallucinations has been reported.
Renal papillary necrosis has also been observed. A number of interactions with other drugs have been reported (see Chapter 66 ).
Indomethacin
________________ prolongs indomethacin’s half-life by inhibiting both renal and biliary clearance.
Probenecid
is a propionic acid derivative that inhibits both COX
(nonselectively) and lipoxygenase.
Its pharmacokinetic characteristics
are given in Table 36–1 . Concurrent administration of
probenecid elevates ketoprofen levels and prolongs its plasma
half-life
Ketoprofen
- is an NSAID promoted for systemic use mainly as an analgesic, not as an anti-inflammatory drug (although it has typical NSAID properties).
- Pharmacokinetics are presented in Table 36–1 .
- The drug is an effective analgesic and has been used successfully to replace morphine in some situations involving mild to moderate postsurgical pain.
- It is most often given intramuscularly or intravenously, but an oral dose formulation is available. When used with an opioid, it may decrease the opioid requirement by 25–50%. An ophthalmic preparation is available for ocular inflammatory conditions. Toxicities are similar to those of other NSAIDs (see page 638), although renal toxicity may be more common with chronic use.
Ketorolac
- is the only nonacid NSAID in current use;
- it is converted to the active acetic acid derivative in the body.
- It is given as a ketone prodrug that resembles naproxen in structure ( Figure 36–1 ).
- Its half-life of more than 24 hours ( Table 36–1 )
- permits once-daily dosing,
- and the drug does not appear to undergo enterohepatic circulation.
- Renal impairment results in a doubling of its half-life and a 30% increase in the area under the curve.
- Its properties are very similar to those of other NSAIDs, though it may be less damaging to the stomach than some other NSAIDs when given at a dosage of 1000 mg/d.
- Unfortunately, higher dosages (eg, 1500–2000 mg/d) are often needed, and this is a very expensive NSAID. Like naproxen has been associated with pseudoporphyria and photosensitivity in some patients. Other adverse effects mirror those of other NSAIDs
Nabumetone
- is a naphthylpropionic acid derivative.
- It is the only NSAID presently marketed as a single enantiomer.
- Naproxen’s free fraction is significantly higher in women than in men, but half-life is similar in both sexes ( Table 36–1 ).
- Naproxen is effective for the usual rheumatologic indications and is available in a slowrelease formulation, as an oral suspension, and over the counter.
- A topical preparation and an ophthalmic solution are also available.
- The incidence of upper GI bleeding in over-the-counter use is low but still double that of over-the-counter ibuprofen (perhaps due to a dose effect).
- Rare cases of allergic pneumonitis, leukocytoclastic vasculitis, and pseudoporphyria as well as the common
NSAID-associated adverse effects have been noted.
Naproxen
________ is another propionic acid derivative NSAID. As noted
in Table 36–1 , its major difference from the other members of this subgroup is a very long half-life (50–60 hours), although does not undergo enterohepatic circulation.
It is mildly uricosuric,
making it potentially more useful in gout than some other
NSAIDs.Otherwise, the drug has the same benefits and risks
that are associated with other NSAIDs.
Oxaprozin
Piroxicam
Piroxicam, an oxicam ( Figure 36–1 ), is a nonselective COX inhibitor
that at high concentrations also inhibits polymorphonuclear
leukocyte migration, decreases oxygen radical production, and
inhibits lymphocyte function. Its long half-life ( Table 36–1 )
permits once-daily dosing.
Piroxicam can be used for the usual rheumatic indications.
When piroxicam is used in dosages higher than 20 mg/d, an
increased incidence of peptic ulcer and bleeding is encountered.
Epidemiologic studies suggest that this risk is as much as 9.5 times
higher with piroxicam than with other NSAIDs (see common
adverse effects above).
is a sulfoxide prodrug.
It is reversibly metabolized to the
active sulfide metabolite, which is excreted in bile and then
reabsorbed from the intestine.
The enterohepatic cycling prolongs
the duration of action to 12–16 hours.
In addition to its rheumatic disease indications
suppresses familial intestinal polyposis and it may inhibit the
development of colon, breast, and prostate cancer in humans.
It
appears to inhibit the occurrence of GI cancer in rats. The latter effect may be caused by the sulfone rather than the sulfide.
Sulindac
Among the **more severe adverse reactions Sulindac **, _____________have all been observed.
Like diclofenac,
- *thisv may have some propensity to cause elevation of serum**
- *aminotransferases;** it is also sometimes associated with cholestatic liver damage, which disappears when the drug is stopped
Stevens-Johnson
epidermal necrolysis syndrome,
thrombocytopenia,
agranulocytosis,
and nephrotic syndrome
All NSAIDs, including aspirin, are about equally efficacious with
a few exceptions—______________ seemsnot to be effective for gout,
tolmetin
and
________________ is less effective than other NSAIDs (eg, indomethacin) for
ankylosing spondylitis.
aspirin
Thus, NSAIDs tend to be differentiated on the basis of toxicity
and cost-effectiveness.
For example, the GI and renal side effects
of____________ limit its use.
ketorolac
Some surveys suggest that ____________ and ___________ are the NSAIDs associated with the greatest toxicity,
indomethacin
and tolmetin
NSAIDS_______ are least toxic. The selective
COX-2 inhibitors were not included in these analyses.
salsalate, aspirin, and ibuprofen
For patients with renal insufficiency, ______________
may be best.
nonacetylated salicylates
________________ are associated with more liver
function test abnormalities than other NSAIDs.
Diclofenac and sulindac
The relatively
expensive, selective COX-2 inhibitor ____________is probably _safest
for patients at high risk for GI bleeding_ but may have ahigher riskof cardiovascular toxicity.
celecoxib
_____________ plus omeprazole or misoprostol may be appropriate in patients at highest risk for GI bleeding; in this subpopulation of patients, they are cost-effective despite their high acquisition costs.
Celecoxib or a nonselective NSAID
So that there is no best NSAID for all patients.
There may, however, be one or two best NSAIDs for a specific
person.
;)
