Pharmacology- Exam2 – NSAIDS, Acetaminophen, & Medicines used in Gout

Antipyretic
A drug that reduces fever (eg, aspirin, NSAIDs, acetaminophen)
MOA: suppress prostaglandin synthesis in the CNS that is stimulated by pyrogens and thereby reduces fever

Cyclooxygenase (COX)
The enzyme at the head of the enzymatic pathway for prostaglandin synthesis

Cytotoxic drug
Drugs that interfere with essential metabolic 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; they have a slow (weeks to months) onset of clinical effects

Nonsteroidal anti-inflammatory drugs (NSAIDs)
Inhibitors of cyclooxygenase; the term nonsteroidal differentiates them from steroid drugs that mediate anti-inflammatory effects through activation of glucocorticoid receptors (eg, cortisol)

Reye’s syndrome
A rare syndrome of *rapid liver degeneration* and *encephalitis* in *children* treated with *aspirin* during a *viral* infection

Tumor necrosis factor-alpha (TNF-alpha)
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 -> to uric acid

Which NSAIDs have moderate effectiveness?
Ibuprofen and naproxen

Which NSAID has greater anti-inflammatory effectiveness?
Indomethacin

Which NSAID has greater analgesic effectiveness?
Ketorolac

Aspirin: MOA
– irreversibly inhibits COX
*COX-1:* totally shut down, so platelet can’t make more
*COX-2:* turns enzyme into lipoxygenase, converted to 15-Lipoxin A4, which is an anti-inflammatory compound
– better at inhibiting COX-1 than COX-2, meaning it’s better at preventing CV events in people who are at risk of CVD. However, not in people who are not at risk

COX-_ is primarily expressed in *non*inflammatory cells.
COX-*1* is primarily expressed in *non*inflammatory cells.

COX-_ is expressed in activated lymphocytes, polymorphonuclear cells, and other inflammatory cells.
COX-*2* is expressed in activated lymphocytes, polymorphonuclear cells, and other inflammatory cells.

Asprin’s effect on the Macula Densa
– Macula Densa determines renal blood flow and GFR
– COX-2 event, so Aspirin effects water/salt retention
COX-2 inhibition in the kidney leads to -> retention of water and sodium which can lead to -> hypertension

Nonselective NSAIDs: MOA
– acetylate and inhibit both cyclooxygenase isoforms and thereby decrease prostaglandin and thromboxane synthesis throughout the body.
– Release of prostaglandins necessary for homeostatic function is disrupted, as is release of prostaglandins involved in inflammation.

COX-2-selective inhibitors
– have less effect on the prostaglandins involved in homeostatic function, particularly those in the GI tract -> less GI toxicity and side effects
– also, little to no anti-platelet effect since COX-1 is not inhibited as strongly, if at all
Examples: Celecoxib, Rofecoxib, Valdecoxib

COX-2 selective inhibitors: Toxicity
– 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.
– Drug interaction: Celecoxib is metabolized by same CYP450 enzyme as warfarin
– Valdecoxib: increased CVD in bypass patients -> removed from market
– Rofecoxib: increased edema, HTN, and mortality -> removed from market

Major difference between the mechanisms of action of aspirin and other NSAIDs:
– 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

Analgesic effect of NSAIDs
– less well understood
– Activation of peripheral pain sensors may be diminished as a result of reduced production of prostaglandins in injured tissue
-a central mechanism is operative.

Danger of NSAIDs
– Cyclooxygenase inhibitors also interfere with the homeostatic function of prostaglandins.
– Most important, they reduce prostaglandin-mediated cytoprotection in the GI tract and autoregulation of renal function
– GI: particularly important how NSAIDs cause increased acid secretion and decreased mucus secretions -> ulcers

Aspirin: 3 therapeutic dose ranges
1. *Low range* (<300 mg/d) is effective in reducing platelet aggregation 2. *Intermediate doses* (300-2400 mg/d) have antipyretic and analgesic effects 3. *High doses* (2400-4000 mg/d) are used for an anti-inflammatory effect; also causes increased body temp

Aspirin: Pharmacokinetics
– readily absorbed and is hydrolyzed in blood and tissues to acetate and salicylic acid.
– Salicylate is a reversible nonselective inhibitor of cyclooxygenase. Duration of activity is longer than pharmacokinetic half-life of drug due to irreversible COX inhibition
– Elimination of salicylate is first order at low doses, with a half-life of 3-5 h. At high doses, half-life increases to 15 h or more and elimination becomes zero order.
– Excretion is via the kidney.

Ibuprofen
– well absorbed after oral administration
– half-life of about 2 h, is relatively safe
– GI toxicity, nephrotoxicity hypersensitivity due to increased leukotrienes
– Drug Interaction: interference with aspirin’s antithrombotic action

Which NSAIDs are noted for having the longest half-lives?
Naproxen and piroxicam

Uses of other Nonselective NSAIDs
– treatment of mild to moderate pain, especially the pain of musculoskeletal inflammation such as that seen in arthritis and gout. Do not act centrally, they act peripherally
– many other conditions, including dysmenorrhea, headache, and patent ductus arteriosus in premature infants.
– reduce polyp formation in patients with primary familial adenomatous polyposis. Long-term use of NSAIDs reduces the risk of colon cancer.

Ketorolac
– notable as a drug used mainly as a systemic *analgesic,* not as an anti-inflammatory (although it has typical nonselective NSAID properties).
– only NSAID available in a *parenteral* formulation.

Aspirin: Toxicity
– most common effect from therapeutic anti-inflammatory doses = *gastric upset*
– Chronic use can result in gastric ulceration, upper GI bleeding, and *renal damage* including acute failure and interstitial nephritis.
– increases bleeding time
– aspirin hypersensitivity
– Reye’s syndrome
– there’s no specific antidote for aspirin

Aspirin hypersensitivity
– 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. This results from the pathway being re-routed to Lipoxygenase
– This type of hypersensitivity to aspirin precludes treatment with any NSAID.

High doses of aspirin: Toxicity
– tinnitus
– vertigo
– hyperventilation
– respiratory alkalosis

Very high doses of aspirin: Toxicity
– metabolic acidosis
– dehydration
– hyperthermia
– collapse
– coma
– death

Nonselective NSAIDS: Toxicity
– associated with significant *GI disturbance,* but the incidence is lower than with aspirin.
– 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 GI and renal damage with longer administration.
– Serious hematologic reactions have been noted with *indomethacin*

COX-2-selective inhibitors
– *reduced GI effects,* including gastric ulcers and serious GI bleeding.
– same risk of *renal damage,* presumably because COX-2 contributes to homeostatic renal effects.

Compare Prostacyclin & Thromboxane A2
– Prostacyclin (PGI2) is *vasoprotective,* promoting vasodilation and inhibition of platelet aggregation
– TXA2 has opposite effects

Phenacetin
– toxic prodrug that is metabolized to acetaminophen
– still available in some other countries.

_______________ is the only OTC non-anti-inflammatory analgesic commonly available in the US.
Acetaminophen

Acetaminophen: MOA
– mechanism of *analgesia = unclear*
– only a *weak COX-1 and COX-2 inhibitor* in peripheral tissues, which accounts for its lack of anti-inflammatory effect; does not directly inhibit PGH2 synthase, it binds a substrate that makes the enzyme work so it *interferes with PG synthesis*
– may inhibit a third enzyme, COX-3, in the CNS

Acetaminophen: Effects
– analgesic and antipyretic agent
– lacks anti-inflammatory or antiplatelet effects
– used in hemophiliacs

Acetaminophen: Toxicity
– at therapeutic dosages -> *negligible toxicity;* no platelet effect, no uric acid effect, no GI effect
– when taken in overdose or by patients with severe liver impairment -> dangerous *hepatotoxin*
– mechanism of toxicity: involves oxidation to cytotoxic intermediates by *phase I CYP450,* which occurs when the body has low amounts of substrates for phase II conjugations (acetate and glucuronide). Prompt administration of *acetylcysteine,* a sulfhydryl donor, required
– People who regularly consume 3 or more alcoholic drinks per day are at increased risk of acetaminophen-induced hepatotoxicity

Disease-Modifying Antirheumatic Drugs – DMARDs
– heterogeneous group of agents that have anti-inflammatory actions in several connective tissue diseases.
– called disease-modifying drugs because some evidence shows slowing or even reversal of joint damage, an effect never seen with NSAIDs.
– also called slow-acting antirheumatic drugs because it may take 6 wk to 6 mo 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, too toxic for routine chronic use
– reserved for temporary control of severe exacerbations and long-term use in patients with severe disease not controlled by other agents.

Gout
– associated with increased serum concentrations of uric acid.
– Acute and Chronic
Two Goals of Treatment:
1. Treat inflammation
2. Treat cause

Acute gout attacks
Acute gout 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 such as probenecid or sulfinpyrazone
3. reducing the conversion of purines to uric acid by xanthine oxidase, using allopurinol or febuxostat

Xanthine Oxidase
Xanthine Oxidase
– enzyme that converts purines like hypoxanthine to xanthine and xanthine to uric acid, leading possibly to crystal deposits and gout
– inhibited by allopurinol and febuxostat

NSAIDS in Gout
– such as indomethacin
– effective in inhibiting the inflammation of acute gouty arthritis.
– reduce prostaglandin formation
– inhibit crystal phagocytosis by macrophages
– along with glucocorticoids, reduce the synthesis of inflammatory mediators in the gouty joint

Colchicine
– *selective inhibitor of microtubule assembly*
– reduces leukocyte migration and phagocytosis
– may also reduce production of leukotriene B4 and decrease free radical formation.
– since it reacts with tubulin and interferes with microtubule assembly, it’s a general *mitotic poison.* Tubulin is necessary for normal cell division, motility, and many other processes.

______ or _____________ are preferred for the treatment of acute gouty arthritis.
*NSAIDs* or *glucocorticoids* are preferred for the treatment of acute gouty arthritis.

Colchicine: Clinical Use and Precautions
– doses required cause significant *GI disturbance,* particularly diarrhea.
– Lower doses are used to prevent attacks of gout in patients with a history of multiple acute attacks.
– also of value in the management of *familial Mediterranean fever*

Familial Mediterranean Fever
– disease of unknown cause characterized by fever, hepatitis, peritonitis, pleuritis, arthritis, and, occasionally, amyloidosis.
– managed by colchicine

Toxicity of Gout medications
– 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.

Uricosuric Agents: MOA
– Normally, over 90% of the uric acid filtered by the kidney is reabsorbed in the proximal tubules.
– *Probenecid and 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, 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.

Uricosuric Agents: Effects
– inhibit the secretion of a large number of other weak acids like penicillin and methotrexate in addition to inhibiting the reabsorption of uric acid

True or False:
Uricosuric drugs are used orally to treat chronic gout. These drugs are of no value in acute episodes.
True

Uricosuric Agents: Toxicity
– can cause an attack of acute gout during the early phase of their action, this can be avoided by simultaneously administering colchicine or indomethacin.
– These are *sulfonamides,* so may share allergenicity with other classes of sulfonamide drugs like diuretics, antimicrobials, and oral hypoglycemic drugs
– increased uric acid in kidney tubules can precipitate and form stones; must drink lots of water to prevent this.
– increased UA in plasma is a risk factor for CVD

Allopurinol: MOA
– inhibit xanthine oxidase to reduce production of uric acid
– converted to *oxypurinol* or *alloxanthine* by xanthine oxidase; *alloxanthine is an irreversible suicide inhibitor* of the enzyme
– allopurinol and alloxanthine inhibit other enzymes involved in purine and pyrimidine metabolism

Febuxostat / Uloric: MOA
– a *nonpurine* reversible inhibitor of xanthine oxidase; therefore, does not interfere with purine metabolism
– *more selective* and *more efficacy* than allopurinol and alloxanthine, but no evidence that it will prevent next gout attack any better
– takes longer for mobilization to be acheived, so need to wait longer after the first attack before starting this

Xanthine Oxidase Inhibitors: Effects
– increases [hypoxanthine] and [xanthine] (more soluble)
– decreases [uric acid] (less soluble) -> *less precipitation of uric acid crystals in joints and tissues*
– Clinical trials suggest that febuxostat is more effective than allopurinol in lowering serum uric acid.

Xanthine Oxidase Inhibitors: Pharmacokinetics and Clinical Use
– given orally in the management of chronic gout.
– Like uricosuric agents, these drugs are usually withheld for 1-2 weeks 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.

Allopurinol: Toxicity
– causes GI upset and rash
– rarely may cause peripheral neuritis, vasculitis, or bone marrow dysfunction including aplastic anemia.
– interferes with anti-cancer drugs and warfarin clearance

Xanthine Oxidase Inhibitors: Drug Interactions
– Allopurinol inhibits the metabolism of mercaptopurine and azathioprine, drugs that depend on xanthine oxidase for elimination.
– Febuxostat can cause liver function abnormalities, headache, and GI upset.

Most Toxic NSAIDs
– Indomethacin
– Piroxicam
– Diclofenac
– Tolmetin

Least Toxic NSAIDs
– Aspirin
– Salicylates
– Ibuprofen

Which NSAID has the least evidence of causing cardiovascular incidents?
Naproxen

Pegloticase, Krystexxa
– Porcine uricase (“pig” rhymes with “Peg”)
– contains polyethylene glycol, which extends efficacy
– for people who don’t respond to other treatments
– inject every 2-4 weeks
– “chews up” uric acid in plasma
– use prednisone, antihistamine because the body recognizes the pig enzyme as foreign

Pegloticase, Krystexxa: Side effects
1. gout flares, resulting from mobilization from plasma
2. anaphylaxis, so it’s only given in hospital setting
3. caution using in people with CVD

Rilonacept
– fusion protein: one side is an IL-4 receptor, while the other is an immunoglobulin
– has nothing to do with uric acid!
– IL-1 is an important mediator in gout,
– this drug *”gobbles up” IL-1*
– used in chronic gout, but it’s expensive
– only in people unable to be treated by other methods

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