NSAIDS Flashcards

1
Q

What’s an inflammation and why does it happen

A

Inflammation: is a normal, protective response to tissue injury.
It is caused by:
physical trauma, noxious chemicals, or microbiologic agents.

▪ Why Inflammation occurs in our body:
1) To inactivate or destroy invading organisms
2) Remove irritants
3) Set the stage for tissue repair

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2
Q

INAPPROPRIATE activation of the immune system can result in
inflammation, leading to immune-mediated diseases such as
rheumatoid arthritis (RA).

A
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3
Q

What is RA

A

white blood cells (WBCs) view the synovium
(tissue that nourishes cartilage and bone) as non-self and initiate an
inflammatory attack.
✓ WBC activation leads to stimulation of T lymphocytes, which activate
monocytes and macrophages
These cells secrete
proinflammatory cytokines,
including tumour necrosis factor
(TNF)-α and interleukin (IL)-1,
into the synovial cavity.

In addition to T-lymphocyte activation, B lymphocytes are also involved
and produce RF (Rheumatiod factor an inflammatory marker) and other
autoantibodies with the purpose of maintaining inflammation.

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4
Q

What does the cytrokines cause

A

1) ↑ cellular infiltration into the endothelium due to release of
histamines, kinins, and vasodilatory PGs
2) ↑ production of C-reactive protein by hepatocytes
3) ↑ production and release of proteolytic enzymes by chondrocytes,
leading to degradation of cartilage and joint space narrowing
4) ↑ osteoclast activity (osteoclasts regulate bone breakdown), resulting in
focal bone erosions and bone demineralization around joints
5) systemic manifestations in certain organs such as the heart

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5
Q

What is the pharmacotherapy of RA

A

anti-inflammatory and/or
✓ immunosuppressive agents that modulate/reduce the
inflammatory process, Disease-Modifying Antirheumatic
Drugs (DMRDs)

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6
Q

What is the role of prostaglandins as local mediators

A

PGs and related compounds are produced in minute quantities by
virtually all tissues.
✓ They generally act locally on the tissues in which they are synthesized,
and they are rapidly metabolized to inactive products at their sites of
action → PGs do not circulate in the blood in significant
concentrations.
✓ TXs and LTs are related lipids that are synthesized from the same
precursors as the PGs.

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7
Q

What is the precursor of prostaglandins

A

Arachidonic acid (AA) is present as a component of the phospholipids of cell membranes.
Free AA is released from tissue phospholipids by the action of
phospholipase A2 (PLA-2) via a process controlled by hormones and
other stimuli.

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8
Q

What is the cyclooxygenase pathway for making prostaglandins

A

✓ Cyclooxygenase-1 (COX-1) is responsible for the physiologic production
of prostanoids
✓ COX-1 is a constitutive enzyme that regulates normal cellular processes,
such as:
✓ gastric cytoprotection,
✓ vascular homeostasis,
✓ platelet aggregation, and
✓ reproductive and
✓ kidney functions.
✓ cyclooxygenase-2 (COX-2) causes the elevated production of
prostanoids that occurs in sites of chronic disease and inflammation
✓ COX-2 is constitutively expressed in tissues such as the brain, kidney,
and bone.
✓ Its expression at other sites is increased during states of chronic
inflammation.
✓ Differences in binding site shape have permitted the development of
selective COX-2 inhibitors (Figure 36.2).
✓ Another distinguishing characteristic of COX-2 is that its expression is
induced by inflammatory mediators like TNF-α and IL-1
✓ but can also be pharmacologically inhibited by glucocorticoids
, which may contribute to the significant anti-inflammatory effects
of these drugs

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9
Q

Alternatively, several lipoxygenases can act on AA to form LTs (Antileukotriene drugs, such as zileuton, zafirlukast, and montelukast,
are treatment options for asthma.

A
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10
Q

What are the actions of prostaglandins

A

✓ Many of the actions of PGs are mediated by their binding to a wide
variety of distinct cell membrane receptors that operate via G-coupled
proteins.
✓ PGs and their metabolites, produced endogenously in tissues, act as
local signals that fine-tune the response of a specific cell type.
✓ Their functions vary widely, depending on the tissue and the specific
enzymes within the pathway that are available at that particular site
✓ For example, the release of thromboxane A2 (TXA2) from platelets
during tissue injury triggers the recruitment of new platelets for
aggregation, as well as local vasoconstriction.
✓ However, prostacyclin (PGI2), produced by endothelial cells, has
opposite effects, inhibiting platelet aggregation and producing
vasodilation.
✓ The net effect on platelets and blood vessels depends on the balance of
these two prostanoids.

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11
Q

What is the therapeutic use for PG

A

✓ PGs have a major role in modulating pain, inflammation, and fever.
✓ They also control many physiological functions, such as acid secretion
and mucus production in GIT, uterine contractions, and renal blood
flow.
✓ PGs are also among the chemical mediators that are released in allergic
and inflammatory processes.
✓ This leads to many therapeutic applications for prostaglandins

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12
Q

What is Alprostadil PGE1 ANALOGUE

A

✓ It is a PGE1
analogue that is naturally (seminal vesicles, cavernous
tissues, placenta, ductus arteriosus of the fetus).
✓ It is used to treat erectile dysfunction
✓ PGE1 maintains the patency of the ductus arteriosus during pregnancy.
The ductus closes soon after delivery to allow normal blood circulation
between the lungs and the heart.
✓ Alprostadil keeps the ductus arteriosus open in neonates with
congenital heart conditions until surgery is possible (Infusion of the
drug maintains the ductus open as it naturally occurs during pregnancy,
allowing time until surgical correction is possible)

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13
Q

What is lubiprostone PGE1 ANALOGUE

A

✓ It is a PGE1 derivative
✓ It is indicated for the treatment of:
chronic idiopathic constipation, opioid-induced constipation, and irritable
bowel syndrome with constipation.
✓ MOA: It stimulates Chloride-channels in the luminal cells of the intestinal
epithelium, thereby ↑ intestinal fluid secretion.
✓ SEs: Nausea and diarrhea
✓ Nausea can be decreased if taken with food.

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14
Q

What are misoprostol PGE1 ANALOGUE

A

✓ It is used to protect the mucosal lining of the stomach during chronic
NSAID treatment. ( ↓ HCl secretion, has a GI cytoprotective effect).
✓ There is a combination product containing diclofenac and misoprostol.
✓ Misoprostol is also used off-label* in obstetric settings for:
✓ labor induction, since it ↑ uterine contractions.
✓ Misoprostol has the potential risk to induce abortion in pregnant
women. Therefore, the drug is CI during pregnancy.
✓ Its use is limited by common SE: diarrhea and abdominal pain.
*Off-label: the use of drug to treat a condition for which it has not
received approval by a regulatory agency.

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15
Q

What is Dinoprostone PGE2 Analogue

A

• Labor induction
• An abortifacient
• Route of administration: via the vagina ( as a gel or a
removable insert)
• Actions:
• Relaxation of cervical smooth muscles
• Induction of uterine contractions
• Common A/E: fever, chills, N/V, diarrhea and headache

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16
Q

What are PG F2a Analogue (prost)

A

✓ Bimatoprost, latanoprost, tafluprost, and travoprost are PGF2α analogs
✓ They are indicated for the treatment of open-angle glaucoma. By
binding to PG receptors, they ↑ uveoscleral outflow, ↓ IOP
✓ They are administered as ophthalmic solutions 1x/day and are as
effective as timolol or better in ↓ IOP
✓ Bimatoprost ↑ eyelash prominence, length, and darkness and is
approved for the treatment of eyelash hypotrichosis.
✓ Ocular reactions include blurred vision, iris color change (↑ brown
pigmentation), ↑ number and pigment of eyelashes, ocular irritation,
and foreign body sensation.

17
Q

What are pgi analogs

A

✓ Epoprostenol, the pharmaceutical form of naturally occurring
prostacyclin,
✓ and the synthetic analogs of prostacyclin iloprost and treprostinil are
potent pulmonary vasodilators
✓ used for the treatment of pulmonary arterial hypertension.
✓ These drugs mimic the effects of prostacyclin in endothelial cells,
producing a significant ↓ in pulmonary arterial resistance with a
subsequent ↑ in cardiac index and oxygen delivery.
✓ These agents all have a short half-life.
✓ Epoprostenol and treprostinil are administered as a continuous IV
infusion,
✓ and treprostinil may also be administered orally or via inhalation or SC
infusion.
✓ Inhaled iloprost requires frequent dosing due to the short half-life
(7-9)
✓ Dizziness, headache, flushing, and fainting are the most common
adverse effects
✓ Bronchospasm and cough can also occur after inhalation of iloprost

18
Q

What are NSAIDS

A

✓ The NSAIDs are a group of chemically dissimilar agents that differ in
their antipyretic, analgesic, and anti-inflammatory activities.
✓ The class includes derivatives of salicylic acid (aspirin), diflunisal,
salsalate,
propionic
acid
(ibuprofen),
fenoprofen,
flurbiprofen,
ketoprofen, naproxen, oxaprozin, acetic acid (diclofenac), etodolac,
indomethacin, ketorolac, nabumetone, sulindac, tolmetin, enolic acid
(meloxicam),piroxicam, fenamates (mefenamic acid), meclofenamate
✓ , and the selective COX-2 inhibitor (celecoxib).
✓ They act primarily by ↓ COX enzymes that catalyse the first step in
prostanoid biosynthesis→ ↓ PGs synthesis with both beneficial and
unwanted effects.
✓ Differences in safety and efficacy of the NSAIDs may be explained by
relative selectivity for the COX-1 or COX-2 enzyme.
✓ ↓COX-2 → the anti-inflammatory and analgesic actions of NSAIDs
✓ ↓COX-1 → prevention of cardiovascular events and most AEs

19
Q

What are the antiinflammatory effects of aspirin and NSAIDS

A

↓COX → ↓ PGs → modulates aspects of inflammation in which PGs act
as mediators.
✓ NSAIDs ↓inflammation in arthritis, but they neither arrest the
progression of the disease nor induce remission

20
Q

How can NSAIDS give an analgesic effect

A

✓ PGE2 is thought to sensitize nerve endings to the action of bradykinin,
histamine, and other chemical mediators released locally by the
inflammatory process.
✓ Thus, by ↓ PGE2 synthesis→ ↓ the sensation of pain.
✓ As COX-2 is expressed during times of inflammation and injury, it is
thought that inhibition of this enzyme is responsible for the analgesic
activity of NSAIDs.
✓ No single NSAID has demonstrated superior efficacy over another, and
all agents are generally considered to have equivalent efficacy.
✓ The NSAIDs are used mainly for the management of mild to moderate
pain arising from musculoskeletal disorders (EXCEPT: ketorolac, which
can be used for more severe pain but for only a short duration).

21
Q

How can NSAIDS give antipyretic actions

A

✓ Fever occurs when the set-point of the anterior hypothalamic
thermoregulatory center is elevated.
✓ This can be caused by PGE2
synthesis,
✓ which is stimulated when endogenous fever-producing agents
(pyrogens), such as cytokines, are released from WBCs that are
activated by:
✓ infection, hypersensitivity, malignancy, or inflammation.
✓ The NSAIDs lower body temperature in patients with fever by impeding
PGE2 synthesis and release.
✓ These agents essentially reset the “thermostat” toward normal.
✓ This rapidly lowers the body temperature of febrile patients by
increasing heat dissipation as a result of peripheral vasodilation and
sweating.
✓ NSAIDs have NO effect on normal body temperature.

22
Q

What are the antiinflammatory and analgesic uses for NSAIDS

A

✓ NSAIDs are used in the treatment of osteoarthritis??, gout, and RA.
✓ These agents are also used to treat common conditions (for example,
headache, arthralgia, myalgia, and dysmenorrhea) requiring analgesia.
✓ Combinations of opioids and NSAIDs may be effective in treating pain
caused by malignancy.
✓ Furthermore, the addition of NSAIDs may lead to an opioid-sparing
effect, allowing for lower doses of opioids to be utilized.
✓ The salicylates exhibit analgesic activity at lower doses. Only at higher
doses do these drugs show anti-inflammatory activity (Figure 36.9).
✓ For example, two 325-mg aspirin tablets administered four times daily
produce analgesia, whereas 12 to 20 tablets per day produce both
analgesic and anti-inflammatory activity.

23
Q

What are the anti pyretic uses for NSAIDS

A

✓ Aspirin, ibuprofen, and naproxen may be used to treat fever.
✓ Aspirin should be avoided in patients >20 years old with viral infections,
such as varicella (chickenpox) or influenza→ to prevent Reye syndrome

24
Q

What are the cardiovascular applications for NSAIDS

A

✓ Aspirin is used to ↓ platelet aggregation.
✓ Low-dose aspirin ↓COX-1–mediated production of TXA2→ ↓TXA2-
mediated VC & platelet aggregation and the subsequent risk of
cardiovascular events.
✓ As aspirin irreversibly ↓COX-1 (Figure 36.10) the antiplatelet effects
persist for the life of the platelet.
✓ Chronic use of low doses allows for continued inhibition as new platelets
are generated.
✓ Low doses (doses less than 325 mg; many classify it as doses of 75 to
162 mg—commonly 81 mg) of aspirin are used prophylactically to:
1) reduce the risk of recurrent cardiovascular events and/or death in
patients with previous MI or unstable angina pectoris
2) reduce the risk of recurring transient ischemic attacks (TIAs) and stroke
or death in those who have had a prior TIA or stroke
3) reduce the risk of cardiovascular events or death in high-risk patients
such as those with chronic stable angina or diabetes.
✓ Aspirin is also used acutely to ↓ the risk of death in acute MI and in
patients undergoing certain revascularization procedures.

25
Q

What are the external applications for NSAIDS

A

✓ Salicylic acid is used topically to treat acne, corns, calluses, and warts.
✓ Methyl salicylate (“oil of wintergreen”) is used externally as a
cutaneous counterirritant in liniments, such as arthritis creams and
sports rubs.
✓ Diclofenac is available in topical formulations (gel or solution) for
treatment of osteoarthritis in the knees or hands

26
Q

What are the pharmacokinetics for aspirin

A

✓ After oral administration, aspirin is rapidly deacetylated by esterases
in the body, thereby producing salicylate.
✓ Unionized salicylates are passively absorbed mostly from the upper
small intestine (dissolution of the tablets is favoured at the higher pH
of the gut)
✓ Salicylates (except for diflunisal ) cross both the BBB and the placenta
and are absorbed through intact skin (especially methyl salicylate).
✓ Salicylate is converted by the liver to water-soluble conjugates that are
rapidly cleared by the kidney, resulting in first-order elimination and a
serum half-life of 3.5 hours.
✓ At anti-inflammatory dosages (more than 4 g/day), the hepatic
metabolic pathway becomes saturated, and zero-order kinetics are
observed, leading to a half-life of 15 hours or more (Figure 36.11).
✓ Being an organic acid, salicylate is secreted into the urine and can
affect uric acid excretion.
✓ Therefore, aspirin is avoided in gout or in patients taking
probenecid

27
Q

✓ Most NSAIDs are well absorbed after oral administration and circulate
highly bound to plasma proteins.
✓ The majority are metabolized by the liver, mostly to inactivate
metabolites.
✓ Few (for example, nabumetone and sulindac) have active metabolites.
✓ Elimination of active drug and metabolites is primarily via the urine.

A
28
Q

What are the side effects for NSAIDS

A

a.
Gastrointestinal:
✓ The most common AEs of NSAIDs are GI related, ranging from dyspepsia
to bleeding.
Normally, PGI2 ↓ gastric acid secretion, and PGE2
and PGF2α ↑ mucus in
both the stomach and small intestine.
✓ Agents that ↓COX-1 → ↓beneficial levels of these PGs→ ↑gastric acid
secretion, ↓mucus protection, and ↑ risk for GI bleeding and ulceration.
✓ Agents with a higher relative selectivity for COX-1 may have a higher
risk for GI events compared to those with a lower relative selectivity
for COX-1.
✓ NSAIDs should be taken with food or fluids to diminish GI upset.
✓ If NSAIDs are used in patients with a high risk for GI events, PPI or
misoprostol should be used concomitantly to prevent NSAID-induced
ulcers

b. Increased risk of bleeding (antiplatelet effect):
✓ TXA2 ↑platelet aggregation, whereas PGI2 ↓ it.
✓ Aspirin irreversibly ↓ COX-1–mediated TXA2 formation, while other
NSAIDs reversibly inhibit the production of TXA2.
✓ Because platelets lack nuclei, they cannot synthesize new enzyme
when inhibited by aspirin, and the lack of thromboxane persists for the
lifetime of the platelet (3 to 7 days).
✓ Because of the decrease in TXA2 production, platelet aggregation (the
first step in thrombus formation) is reduced, producing an antiplatelet
effect with a prolonged bleeding time.
✓ For this reason, aspirin is often held, or not given, at least 1 week prior
to surgery.
✓ NSAIDs other than aspirin are not utilized for their antiplatelet effect
but can still prolong bleeding time.
✓ As agents become more COX-2 selective, they are expected to have less
effect on platelet inhibition and bleeding time.
✓ NSAIDs can also block aspirin binding to COX when used concomitantly.
✓ Patients who take aspirin for cardio protection should avoid
concomitant NSAID use if possible.

c.
Actions on the kidney:
✓ NSAIDs prevent the synthesis of PGE2 and PGI2, prostaglandins that are
responsible for maintaining renal blood flow (Figure 36.12).
✓ ↓PGs → retention of Na+
/H2O → edema in some patients
✓ Patients with a history of HF or kidney disease are at particularly high
risk.
✓ These effects can also mitigate (decrease) the beneficial effects of
antihypertensive medication

d. Cardiac effects:
✓ Aspirin, with a very high degree of COX-1 selectivity, has shown a
cardiovascular protective effect due to a ↓TXA2.
✓ Agents with higher relative COX-2 selectivity have been associated with
an ↑risk for cardiovascular events, possibly by ↓PGI2 production
mediated by COX-2.
✓ All NSAIDs except aspirin→↑risk for cardiovascular events (MI & stroke).
✓ Use of NSAIDs, other than aspirin, is discouraged in patients with
established cardiovascular disease.
✓ For patients with cardiovascular disease in whom NSAID treatment
cannot be avoided, naproxen appears to be the least likely to be
harmful.
✓ NSAID use should be limited to the lowest dose possible for the
shortest duration.

29
Q

What are the drug interactions with NSAIDS and the toxicity

A

f. Drug interactions:
✓ Salicylate is roughly 80%-90% plasma protein bound (albumin) and can
be displaced from protein binding sites →↑conc. of free salicylate.
✓ Alternatively, aspirin can displace other highly protein-bound drugs,
such as warfarin, phenytoin, or valproic acid, resulting in higher free
concentrations of these agents (Figure 36.13).
g. Toxicity:
✓ Salicylate intoxication may be mild or severe.
✓ The mild form is called salicylism and is characterized by nausea,
vomiting, marked hyperventilation, headache, mental confusion,
dizziness, and tinnitus (ringing or roaring in the ears).
When large doses of salicylate are administered, severe salicylate
intoxication
may
result
(Figure
36.9).
Restlessness,
delirium,
hallucinations, convulsions, coma, respiratory and metabolic acidosis,
and death from respiratory failure may occur.
✓ Children are particularly prone to salicylate intoxication. Ingestion of as
little as 10 g of aspirin can cause death in children.

30
Q

Most NSAIDs are pregnancy risk category C in the first two trimesters.
[Note: Acetaminophen is preferred if analgesic or antipyretic effects are
needed during pregnancy.]
✓ In the third trimester, NSAIDs should generally be avoided due to the
risk of premature closure of the ductus arteriosus.

A
31
Q

What is celecoxib

A

✓ Celecoxib, a selective COX-2 inhibitor, is significantly more selective for
inhibition of COX-2 than COX-1 (Figure 36.14).
✓ Unlike the inhibition of COX-1 by aspirin (which is rapid and
irreversible), the inhibition of COX-2 is reversible.
1. Therapeutic uses:
✓ Celecoxib is approved for the treatment of RA, osteoarthritis, and acute
mild to moderate pain.
✓ Celecoxib has similar efficacy to NSAIDs in the treatment of pain.
2. Pharmacokinetics:
✓ Celecoxib is readily absorbed after oral administration. It is extensively
metabolized in the liver by cytochrome P450 (CYP2C9) and is excreted
in feces and urine.
✓ The half-life is about 11 hours, and the drug may be dosed once or
twice daily.
✓ The dosage should be reduced in those with moderate hepatic
impairment, and celecoxib should be avoided in patients with severe
hepatic or renal disease.
3. Adverse effects:
✓ Headache, dyspepsia, diarrhea, and abdominal pain are the most
common adverse effects.
✓ Celecoxib, when used without concomitant aspirin therapy, is
associated with less GI bleeding and dyspepsia than other NSAIDs.
However, this benefit is lost when aspirin is added to celecoxib therapy.
3. Adverse effects:
✓ Patients who are at high risk of ulcers and require aspirin for
cardiovascular prevention should avoid the use of celecoxib.
✓ Like other NSAIDs, the drug has a similar risk for cardiovascular events.
✓ Celecoxib should be used with caution in patients who are allergic to
sulfonamides.??
✓ Patients who have had anaphylactoid reactions to aspirin or
nonselective NSAIDs may be at risk for similar effects with celecoxib.
✓ Inhibitors of CYP2C9, such as fluconazole , may increase serum levels of
celecoxib.

32
Q

Diflunisal gives no antipyretic effect

Indomethacin is very potent but CNS side effects

Piroxicam and meloxicam are long half life
Naproxen is the safest

A
33
Q

What is acetaminophen

A

Acetaminophen (paracetamol) ↓PGs synthesis in the CNS.
✓ This explains its antipyretic and analgesic properties.
✓ Acetaminophen has less effect on COX in peripheral tissues (due to
peripheral inactivation), which accounts for its weak anti-inflammatory
activity.
✓ Acetaminophen does NOT affect platelet function or ↑ bleeding time.
✓ It is NOT considered to be an NSAID.
A. Therapeutic uses
✓ Acetaminophen is a suitable substitute for the analgesic and antipyretic
effects of NSAIDs for those patients:
✓ with gastric complaints/ risks,
✓ in those whom a prolongation of bleeding time is not desirable,
✓ as well as those who do not require the anti-inflammatory action of
NSAIDs
Acetaminophen is the analgesic/antipyretic of choice for children with
viral infections or chickenpox (due to the risk of Reye syndrome with
aspirin).
B. Pharmacokinetics
✓ Acetaminophen is rapidly absorbed from the GI tract. A significant firstpass metabolism occurs in the luminal cells of the intestine and in the
hepatocytes.
✓ Under normal circumstances, acetaminophen is conjugated in the liver
to form inactive glucuronidated or sulfated metabolites.
✓ A portion of acetaminophen is hydroxylated to form N-acetyl-pbenzoquinoneimine, or NAPQI, a highly reactive metabolite that can
react with sulfhydryl groups and cause liver damage.

At normal doses of acetaminophen, NAPQI reacts with the sulfhydryl
group of glutathione, which is produced by the liver, forming a nontoxic
substance (Figure 36.16).
✓ Acetaminophen and its metabolites are excreted in urine. The drug is
also available in intravenous and rectal formulations.
C. Adverse effects
✓ At normal therapeutic doses??, acetaminophen is virtually free of
significant adverse effects.
✓ With large doses of acetaminophen, the available glutathione in the
liver becomes depleted, and NAPQI reacts with the sulfhydryl groups of
hepatic proteins, forming covalent bonds
✓ Hepatic necrosis, a very serious and potentially life threatening
condition, can result

✓ Patients with hepatic disease, viral hepatitis,
✓ or a history of alcoholism are at higher risk of acetaminophen induced
hepatotoxicity.
✓ [Note: N-acetylcysteine, which contains sulfhydryl groups to which the
toxic metabolite can bind, is an antidote in cases of overdose]
✓ Acetaminophen should be avoided in patients with severe hepatic
impairment.