Chapter 17 Nonopioid Analgesics: NSAIDs, COX-2 Inhibitors, and Acetaminophen Flashcards
1. NSAIDs are antihyperalgesic compounds with antiinflammatory activity determined by their ability to decrease prostaglandin formation through inhibition of COX following tissue injury. 2. There are two major isoforms of COX. COX-1 is largely constitutive and is responsible for the production of prostaglandins involved in homeostatic processes in the stomach (gastric protection), lung, and kidney, and in platelet aggregation. COX-2 is an inducible form created in the presence of inflammation,
NSAIDs are structurally diverse, but all have
antipyretic, anti-inflammatory and analgesic or antihyperalgesic
properties
How does acetaminophen differentiate from NSAIDs?
weak anti-inflammatory effects and its generally poor ability to inhibit cyclooxygenase (COX) in the presence of high concentrations of peroxides,
as are found at sites of inflammation.
Unlike NSAIDs, acetaminophen does not have an adverse effects
on platelet function or gastric mucosa
The mechanism of action of NSAIDs is
inhibition of prostaglandin
production from arachidonic acid by either reversible or irreversible acetylation of the cyclooxygenase
(COX)
COX is present in at least two isoforms
(COX-1 and COX-2) and is dispersed throughout the
body.
What is COX-1?
COX-1 isoform is constitutive, causing hemostasis, platelet aggregation, and the production of prostacyclin,
which is gastric mucosal protective. The inhibition
of the COX-1 isoform may be responsible for the adverse
effects related to the nonselective NSAIDs.
COX-2 isoform that is induced by
proinflammatory stimuli
and cytokines causing fever, inflammation, and pain, and thus the target for antipyresis, anti-inflammation, and analgesia by NSAIDs
COX-1 mediates the production of
prostaglandins that are essential in the homeostatic processes in the stomach (gastric protection), lung, and kidney, and platelet aggregation
COX-2 is generally considered to be an inducible enzyme, provoking pathologic processes such as
fever, pain, and inflammation
Where is COX-2 expressed?
COX-2, despite being the inducible isoform, is
expressed under normal conditions in a number of tissues, include brain, testis, and kidney.In inflammatory states, COX-2 becomes expressed in macrophages and other cells propagating the inflammatory process
The pain associated with inflammation and prostaglandin
production results from
the production of prostanoids in the inflamed body tissues that sensitize nerve endings and leads to the sensation of pain
NSAIDs peripheral
mechanisms of action.
Peripherally, prostaglandins
contribute to hyperalgesia by sensitizing nociceptive sensory
nerve endings to other mediators (such as histamine
and bradykinin) and by sensitizing nociceptors to respond to non-nociceptive stimuli (e.g., touch). Peripheral
inflammation induces a substantial increase in COX-2,
and prostaglandin synthase expression in the central nervous system (CNS)
NSAIDs central
mechanisms of action.
Centrally, prostaglandins are recognized to have direct actions at the level of the spinal cord enhancing nociception, notably the terminals of sensory neurons in the dorsal horn
Where in the spinal cord are COX-1 and COX-2 expressed ?
Both COX-1 and COX-2 are
expressed constitutively in dorsal root ganglia and spinal
dorsal and ventral gray matter but inhibition of COX-2 and
not COX-1 reduces hyperalgesia
interleukin-1beta (IL-1b)
the proinflammatory cytokine interleukin-1beta (IL-1b) plays a
major role in inducing COX-2 in local inflammatory cells
by activating the transcription factor NF-kB
In the CNS IL-1b causes
increased production of COX-2 and PGE2, producing hyperalgesia, but this is not the result of neural activity arising from the sensory fibers innervating the inflamed tissue or of systemic IL-1b in the plasma
Interleukin 6 (IL-6)
interleukin 6 (IL-6) triggers the formation of PGE2 in the CNS, which in turn causes increased production of COX-2 and PGE2.
Two forms of input from peripheral inflamed tissue to the CNS.
The first is mediated by electrical activity in sensitized nerve fibers innervating the
inflamed area, which signals the location of the inflamed
tissue as well as the onset, duration, and nature of any
stimuli applied to this tissue. The second is a humoral signal
originating from the inflamed tissue, which acts to produce a widespread induction of COX-2 in the CNS
FIGURE 17-1
Site of action of NSAIDs
Administration of NSAIDs
NSAIDs are most often administered enterally, but intravenous,
intramuscular, rectal, and topical preparations are
available
NSAIDs relation to protein
NSAIDs are highly bound to plasma proteins, specifically to albumin (.90%), and therefore only a small portion of the circulating drug in plasma exists in the unbound (pharmacologically active) form
The volume of distribution of NSAIDs
is low, ranging from 0.1 to 0.3 L/kg, suggesting minimal tissue binding
NSAIDs Acid or Base?
Most NSAIDs are weak acids with pKa less than 6, and since weak acids will be 99% ionized two pH units above their pKa, these antiinflammatory
medications are present in the body mostly in the ionized form. In contrast, the coxibs are nonacidic, which may play a role in the favorable tolerability profile
Major absorptive site for orally administered NSAIDs
most NSAIDs are administered
enterally and their pH profile facilitates absorption via the
stomach, and the large surface area of the small intestine produces a major absorptive site for orally administered NSAIDs
Most of the NSAIDs are rapidly and completely absorbed from the (GI) tract, with peak concentrations occurring within
1 to 4 hr. The presence of
food tends to delay absorption without affecting peak concentration
NSAIDs available in parenteral forms in the United States
ketorolac, propacetamol,
and ibuprofen
Topical NSAIDs possess the advantage
provide local action without systemic adverse effects. They are formulated to traverse the skin to reach the adjacent joints and muscles and exert therapeutic activity, and may offer some advantage in terms of decreased adverse event
Types of Topical NSAIDs
These medications, such as diclofenac epolamine transdermal patch (Flector®) and diclofenac sodium gel (Voltaren®),
The high protein binding of the NSAIDs has particular
relevance in
the state of hypoalbuminemia or decrease albumin concentrations (e.g., elderly, malnourished). A greater
fraction of unbound NSAIDs are present in the plasma,
which may enhance efficacy but also increase toxicity.
Why does a possibility of
bleeding increased with concomitant use of NSAIDs?
NSAIDs compete for binding sites with other highly plasma
protein–bound drugs such as warfarin;
The major metabolic pathway for elimination of NSAIDs
hepatic oxidation or conjugation. Renal excretion of
unmetabolized drug is a minor elimination pathway for most NSAIDs accounting for less than 10% of the administered
dose.
most widely use analgesic,
antipyretic, and anti-inflammatory agent in the world
Acetylsalicylic acid (ASA)
Aspirin is comprised of the active compounds
acetic acid and salicylic acid, forming acetylsalicylic acid.
Aspirin inhibits the biosynthesis of prostaglandins by
means of an irreversible acetylation and consequent inactivation of COX; thus, aspirin inactivates COX permanently
Naproxen Pharmacodynamics
absorbed after enteral administration and has a half-life of 14 hr. Peak concentrations in plasma occur within 4 to 6 hr. The half-life is approximately 14 hr, but steady-state serum levels require more than 48 hr. Naproxen has a volume of distribution of 0.16 L/kg
Naproxen relation to protein
At therapeutic levels, naproxen is more than 99% albumin-bound.
Naproxen Metabolism and Elimination
Naproxen is extensively metabolized to 6-0-desmethyl
naproxen, and both parent and metabolites do not induce
metabolizing enzymes. Most of the drug is excreted in
the urine, primarily as unchanged naproxen. About 30% of them drug undergoes 6-demethylation, and most of this metabolite, as well as naproxen itself, is excreted as
glucuronide or other conjugates.
Naproxen indications
Naproxen has been used for the treatment of arthritis and other inflammatory diseases.
Ibuprofen indications
use for the relief of symptoms of acute pain, fever, and inflammation. demonstrated in the treatment of headache and migraine, menstrual pain, and acute postoperative pain.
Ibuprofen Pharmacodynamics
Ibuprofen is rapidly absorbed from the upper GI tract, with peak plasma levels achieved about 1 to 2 hr after administration. It is highly bound to plasma proteins
with an estimated volume of distribution of 0.14 L/kg,
and is primarily hepatically metabolized (90%) with less
than 10% excreted unchanged in the urine and bile. A
short plasma half-life (2 6 0.5 hr) a
Ibuprofen dosage
usual starting dose: 50 or 75 mg with immediate release capsules every 6 to 8 hr or 200 mg with extended release capsules once daily. The maximum dose is 300 mg daily of immediate-release capsules or 200 mg
daily of extended-release capsules. Ibuprofen at a dose of 1200 to 2400 mg/day has a predominantly analgesic effect for mild to moderate pain
conditions, with dosage of 3200 mg/day recommended
only under continued care of clinical professionals
Adverse Effect of Ibuprofen
at anti-inflammatory doses of more than 1600 mg per day,
renal side effects are almost exclusively encountered in
patients with low intravascular volume and low cardiac
output, particularly in the elderly.
Ketoprofen administration
capsules release the drug in the stomach, whereas capsule
pellets (extended release) are designed to resist dissolution
in the low pH of gastric fluid, but release the drug at a
controlled rate in the higher pH environment of the small
intestine
Ketoprofen Phamarcodynamics
Peak plasma levels are achieved about 1 to 2 hr
after oral administration for the capsules and the 6 to 7 hr after administration of the capsule pellets
Ketoprofen relationship to protein
Ketoprofen has
high plasma protein binding (98%–99%) and an estimated
volume of distribution of 0.11 L/kg.
Ketoprofen Metabolism
Ketoprofen is conjugated
with glucuronic acid in the liver, and the conjugate is excreted in the urine. The glucuronic acid moiety can be converted back to the parent compound. Thus, the metabolite serves as a potential reservoir for the parent drug, and this may be important in persons with renal
insufficiency
Oxaprozin Pharmacodynamics
oxaprozin peak plasma levels are not achieved until 3 to 6 hr
after an oral dose, and its half-life of 40 to 60 hr allows for
once-daily administration.36 Peak plasma concentration
occurs at about 1.5 hr after administration
Oxaprozin relationship to protein
Oxaprozin is highly bound to plasma proteins and has an estimated volume of distribution of 0.15 L/kg.
Oxaprozin Metabolism
Oxaprozin is primarily
metabolized by the liver, and 65% of the dose is excreted into the urine and 35% in the feces as metabolites
Oxaprozin Mechanism of Action
Oxaprozin diffuses readily into inflamed synovial tissues after oral administration and is capable of inhibiting both anandamide hydrolase in neurons and NF-kB activation in inflammatory cells, which are crucial for synthesis of proinflammatory and histotoxic mediators in
inflamed joints
Diclofenac Mechanism of Action
Diclofenac has COX-2 selectivity and the selective inhibitor of COX-2 lumiracoxib is an analog of diclofenac.
Diclofenac Bioavaliability
Diclofenac is rapidly absorbed
after oral administration, but in substantial first-pass
metabolism only about 50% of diclofenac is available systemically.
After oral administration, peak serum concentrations
are attained within 2 to 3 hr
Diclofenac relationship to protein
Diclofenac is highly
bound to plasma proteins and has an estimated volume of
distribution of 0.12 L/kg.
Diclofenac Excretion
Diclofenac is excreted primarily in the urine (65%), and as bile conjugates (35%).
Diclofenac Formulations
Diclofenac is available in two enteral formulations, diclofenac sodium and diclofenac potassium. Diclofenac potassium is formulated to be released and absorbed in the stomach. Diclofenac sodium, usually distributed in enteric-coated tablets, resists
dissolution in low pH gastric environments, releasing
instead in the duodenum
Diclofenac Adverse Effects
Hepatotoxicity via elevated
transaminases may occur, and transaminases should be
measured during therapy with diclofenac.
What happens to Diclofenac after after oral administration?
Uniquely, diclofenac
accumulates in synovial fluid after oral administration,
which may explain why its duration of therapeutic effect
is considerably longer than the plasma half-life of 1 to
2 hr.
The transdermal application of diclofenac has shown efficacy in the treatment of
musculoskeletal disorders
such as ankle sprains, epicondylitis, and knee osteoarthritis
The advantage of the transdermal formulation is
the lack of appreciable systemic absorption (6% [158 times lower] of the systemic exposure from enteral diclofenac sodium), and accumulation of the medication at the site of
application, thereby providing local pain relief. In comparison
to enteral delivery, topical application of diclofenac
provides analgesia by peripheral activity and not central mediation
Etodolac
Etodolac has some degree of COX-2 selectivity
Etodolac Pharmacodynamic
The analgesic effect of full doseslasting up to 8 hr. After oral administration,
peak serum concentrations of 16 and 25 mg/L are attained within 2 hr of administering 200 and 400 mg,
respectively
Etodolac and Plasma Protein
Etodolac is highly bound to plasma proteins
and has an estimated volume of distribution of 0.4 L/kg.
Etodolac Excretion
Etodolac is excreted primarily in the urine, and 60% of a
dose is recovered within 24 hr. More than 60% of the
metabolites are hydroxylated with glucuronic conjugation.
Etodolac Dosage
Usual 24-Hr Adult Dose Range: 400–1200 mg
Adult Daily Dose and
Frequency200–300 mg BID, TID, QID
Indomethacin mechanism of action
This is a nonselective COX inhibitor
Indomethacin pharmacodynamics
Peak concentrations
occur 1 to 2 hr after dosing. Indomethacin is 90%
bound to plasma proteins and tissues
Indomethacin CSF, Synovial, and Plasma concentration
The concentration of the drug in the cerebrospinal fluid is low, but its concentration
in synovial fluid is equal to that in plasma within 5 hr of administration
Indomethacin Adverse Effects
GI irritation are common, including diarrhea, and
ulcerative lesions are a contraindication to indomethacin
use
Intravenous indomethacin
has FDA approval for
closure of persistent patent ductus arteriosus but its side
effect profile limits other uses
Ketorolac
Ketorolac tromethamine is a NSAID with activity at
COX-1 and COX-2 enzymes, which block prostaglandin
production
Ketorolac Peak
After oral administration, peak serum concentrations
are attained within 1 to 2 hr.
Ketorolac and Protrein
Ketorolac is highly bound to plasma proteins and has an estimated volume of distribution of 0.28 L/kg.
Ketorolac Excretion
Ketorolac is excreted primarily in the urine and has a half-life of
approximately 5 to 6 hr in healthy subjects.
Ketorolac Formulations
Administration of ketorolac is available for enteral, ophthalmic, and parenteral delivery, and is only one of two parenteral NSAIDs
currently available
Ketorolac Indications
Ketorolac has been used to treat mild to severe
pain following major surgical procedures, including general
abdominal surgery, gynecologic surgery, orthopedic
surgery, and dentistry
Ketorolac compared to Morphine
When compared to morphine,
ketorolac 30 mg intramuscular (IM) has been
shown to be equivalent to 12 mg morphine IM and 100 mg
meperidine IM
Ketorolac Adverse Effects
may precipitate or exacerbate
renal failure in hypovolemic elderly patients and
especially those with underlying renal dysfunction.
Therefore, ketorolac is recommended for limited use
(3–5 days)
Nabumetone
Nabumetone is a prodrug that undergoes hepatic biotransformation
to the active component, 6-methoxy-2-
naphthylacetic acid (6MNA), which has some degree of
COX-2 selectivity conferring less gastric irritation compared
with other NSAIDs
Nabumetone and Protein
Nabumetone is highly bound
to plasma proteins and has an estimated volume of distribution
of 0.68 L/kg.
Nabumetone Excretion
Nabumetone is excreted primarily in
the urine and has a half-life of approximately 20 to 24 hr
in healthy subjects, thereby enabling single daily dosing.
Nabumetone Indications
When compared with other NSAIDs, nabumetone has
tended to show efficacy54 and tolerability in the treatment
of arthritis
Mefenamic Acid
Mefenamic acid blocks prostaglandin synthesis but also the tissue response to prostaglandins
Mefenamic Acid peak serum concentration
Peak serum concentrations are attained within 2 to 4 hr and the half-life is 3 to 4 hr
Mefenamic Acid and protein
Mefenamic acid is highly bound to plasma
proteins and is excreted primarily in the urine
Mefenamic Adverse Effects
Mefenamic acid has been associated with severe pancytopenia and many other side effects. Hence, therapy is not to occur for
more than 1 week
Meloxicam MAO
The enolic acid derivative shows nonselectivity, except for meloxicam which shows relative COX-2 selectivity
Meloxicam Dosage
7.5 mg is more selective for COX-2 and at 15 mg
meloxicam becomes less selective
Meloxicam Peak Serum, Protein, Half-life
After oral administration,
peak serum concentrations are attained within 5 to
10 hr after administration. Meloxicam is highly bound to plasma proteins and has an estimated half-life of approximately 15 to 20 hr in healthy subject
COX-2 inhibitors
celecoxib, rofecoxib, and valdecoxib)
What does all of the coxibs have in common?
They all achieve sufficient brain concentrations to have a central analgesic effect, and all reduce prostaglandin
formation in inflamed joints
the relative degree of selectivity for
COX-2 inhibition is
lumiracoxib= etoricoxib > valdecoxib = rofecoxib»_space;celecoxib
Celecoxib
After oral administration,
peak serum concentrations are attained 2 to 3 hr
after administration
Celecoxib : Plasma protein, metabolism, half-life
Celecoxib is highly bound to plasma proteins, is excreted primarily by hepatic metabolism, and has a half-life of approximately 11 hr in healthy subjects
Does Celecoxib have increased risk of bleeding?
Celecoxib does not interfere with platelet aggregation;
thus, perioperative administration can be conducted as part of a multimodal analgesic regimen without increased
risk of bleeding
Celecoxib Adverse Effect
NSAID-induced GI complications are one of the most common drug related
serious adverse events, but celecoxib preferentially
inhibits the inducible COX-2 isoform and not the
constitutive COX-1 isoform, thus conferring some gastroprotective effect
Etoricoxib Mechanism of Action
Etoricoxib is a second-generation, highly selective (COX-2) inhibitor with anti-inflammatory and analgesic properties. It shows dose-dependent inhibition
of COX-2 across the therapeutic dose range,
without inhibition of COX-1
Etoricoxib effect on prostaglandin synthesis and platelet function
does not inhibit gastric
prostaglandin synthesis; and has no effect on platelet
function.
Acetaminophen (paracetamol [APAP])
an analgesic and antipyretic medication that produces its analgesic effect by inhibiting central prostaglandin synthesis with minimal inhibition of peripheral prostaglandin synthesis
Acetaminophen:
Peak Serum Concentration, Plasma proteins,
Volume of Distribution
Half-life
After oral administration, peak serum concentrations are attained within 0.5 to 3 hr. A small portion of acetaminophen is bound to plasma proteins (10%–50%) and has an estimated
volume of distribution of 0.95 L/kg. The half-life of is ~ 2 to 3 hr in healthy pts
Acetaminophen Elimination
Acetaminophen is
eliminated from the body primarily by formation of glucuronide and sulfate conjugates in a dose-dependent manner
Acetaminophen and NSAIDs Differences
acetaminophen’s weak anti-inflammatory effects and its generally poor ability to inhibit COX in the presence of high concentrations of peroxides as are found at sites of inflammation
Acetaminophen effect on platelet function or the gastric mucosa
Does not have an adverse effect on platelet function or the gastric mucosa.
Acetaminophen Metabolism
It is absorbed rapidly, with peak plasma levels seen within 30 min to 1 hr, and is metabolized in the liver by conjugation and hydroxylation to inactive metabolites, with a duration of action of 4 to 6 hr.
The American Geriatrics Society advocates the dose of Acetaminophen
4 g as the total daily dose in elderly persons, with the exceptions of patients with hepatic insufficiency or
history of alcohol abuse for whom a maximum dose reduction of 50% to 75% is recommended
A useful method of assessing the efficacy of medications,
the “number needed to treat” (NNT), evaluates the efficacy of active treatment compared to placebo
number needed to treat” (NNT)
measures how many patients need to receive a certain treatment in order for one patient to derive a clear benefit. In pain studies, this translates into
the number of patients needed to treat with a certain drug in order for one patient to achieve at least a 50% decrease in pain intensity
Number Needed to Treat calculations
This value is calculated by 1/([goal achieved active group/total active] – [goal achieved placebo
group/total placebo]); the 95% confidence interval
(CI) of NNT can be obtained by taking the reciprocal
value of the 95% CI for absolute risk reduction
NSAIDs adverse effects
GI ulceration and bleeding, disturbance of platelet function, sodium and water retention, nephrotoxicity, and hypersensitivity reactions
The three most common adverse drug reactions to NSAIDs are
GI, dermatologic, and
neuropsychiatric
risk factors for the
development of NSAID-induced gastropathy
history of GI complications, high-dose or multiple
NSAIDs, advanced age, concomitant corticosteroid use, and alcohol use
GI-protective agents that attenuate the complications associated with long-term NSAID use
misoprostol, H2-receptor antagonist, and proton
pump inhibitors).Other strategies: selective COX-2 inhibitors such as celecoxib,
which are less ulcerogenic in the GI tract as compared
with nonselective NSAID
NSAIDs causes decrease renal function and renal failure by
The proposed mechanism is reduction in prostaglandin production leading to increased reduced renal
blood flow with subsequent medullary ischemia may result from NSAID use in susceptible individuals
The risk factors for NSAID-induced renal toxicity
chronic NSAID use, high-dose or multiple NSAIDs, volume depletion, congestive heart failure, vascular disease, hyperreninemia, shock, sepsis, systemic lupus
erythematous, hepatic disease, sodium depletion, nephrotic syndrome, diuresis, concomitant drug therapy (diuretics, ACE inhibitors, beta blockers, potassium supplements), and advanced age
The mechanism by which almost all NSAIDs
produce hepatoxicity
immunologic or metabolic, with dose-related toxicity being seen in aspirin and acetaminophen
Acetaminophen Metabolism
Acetaminophen is almost entirely metabolized in
the liver, and the minor metabolites are responsible for the hepatotoxicity seen in overdoses
Mechanisms of acetaminophen hepatotoxicity include
depletion of hepatocyte
glutathione, accumulation of the toxic metabolite NAPQI, mitochondrial dysfunction, and alteration of innate immunity
Acetaminophen Hepatotoxicity Risk factors
include concomitant depression, chronic pain, alcohol or narcotic use, and/or using several
preparations simultaneously
The lowest dose of acetaminophen to cause hepatotoxicity
between 125 and 150 mg/kg.90,91 The threshold dose to cause hepatotoxicity is 10 to 15 g of acetaminophen for adults and 150 mg/kg for children. The most recognized dosing
limit is 4 g/24 hr in healthy adult patients
Thromboxane A2 (TXA2)
Thromboxane functions
as a vasoconstrictor, and facilitates platelet aggregation. Thromboxane A2 (TXA2), produced by activated platelets, has prothrombotic properties, stimulating activation of
new platelets as well as increasing platelet aggregation
Inhibition of cyclooxygenase reduces the production of
thromboxane and prostacyclin
Endothelial-derived prostacyclin (PGI2)
functions in concert with thromboxane, primarily inhibiting platelet activation,
thus preventing the formation of hemostatic plug
COX inhibition on thromboxane and prostacyclin production
Nonselective NSAIDs inhibit both the COX-1 and
COX-2, thereby reducing production of thromboxane
and prostacyclin. The imbalance of thromboxane and prostacyclin may lead to a thrombogenic situation
Aspirin effect on Platelets
Low-dose aspirin (81 mg/day)
is a platelet aggregation inhibitor, thereby reducing thrombotic events related to platelet aggregation. Aspirin at larger doses 1.5 to 2 g/day has been described to result in a paradoxical thrombogenic effect.
Celecoxib effect on platelet
Celecoxib is an antiinflammatory agent that primarily inhibits COX-2, an inducible enzyme not expressed in platelets, and thus does not interfere with platelet aggregation
