Jack DeRuiter, Principles of Drug Action 2, Fall 2002
`
`NON-STEROIDAL ANTIINFLAMMATORY DRUGS (NSAIDS)
`
`I. Introduction
`
`The non-steroidal antiinflammatory drugs (NSAIDs) are widely used for the treatment of minor
`pain and for the management of edema and tissue damage resulting from inflammatory joint
`disease (arthritis). A number of these drugs possess antipyretic activity in addition to having
`analgesic and antiinflammatory actions, and thus have utility in the treatment of fever. Most of
`these drugs express their therapeutic actions by inhibition of prostaglandin biosynthesis as
`described in the sections that follow. Some of the primary indications for NSAID therapy
`include:
`• Rheumatoid Arthritis (RA): No one NSAID has demonstrated a clear advantage for the
`treatment of RA. Individual patients have demonstrated variability in response to certain
`NSAIDs. Anti-inflammatory activity is shown by reduced joint swelling, reduced pain,
`reduced duration of morning stiffness and disease activity, increased mobility, and by
`enhanced functional capacity (demonstrated by an increase in grip strength, delay in time-to-
`onset of fatigue, and a decrease in time to walk 50 feet).
`• Osteoarthritis (OA): Improvement is demonstrated by increased range of motion and a
`reduction in the following: Tenderness with pressure, pain in motion and at rest, night pain,
`stiffness and swelling, overall disease activity, and by increased range of motion. There are
`no data to suggest superiority of one NSAID over another as therapy for OA in terms of
`efficacy and toxicity. NSAIDs for OA are to be used intermittently if possible during painful
`episodes and prescribed at the minimum effective dose to reduce the potential of renal and GI
`toxicity. Indomethacin should not be used chronically because of its greater toxicity profile
`and its potential for accelerating progression of OA.
`
`• Acute gouty arthritis, ankylosing spondylitis: Relief of pain; reduced fever, swelling, redness
`and tenderness; and increased range of motion have occurred with treatment of NSAIDs.
`
`• Dysmenorrhea: Excess prostaglandins may produce uterine hyperactivity. These agents
`reduce elevated prostaglandin levels in menstrual fluid and reduce resting and active
`intrauterine pressure, as well as frequency of uterine contractions. Probable mechanism of
`action is to inhibit prostaglandin synthesis rather than provide analgesia.
`
`II. NSAID Mechanism of Action
`
`The major mechanism by which the NSAIDs elicit their therapeutic effects (antipyretic,
`analgesic, and anti-inflammatory activities) is inhibition of prostaglandin (PG) synthesis.
`Specifically NSAIDs competitively (for the most part) inhibit cyclooxygenases (COXs), the
`enzymes that catalyze the synthesis of cyclic endoperoxides from arachidonic acid to form
`prostaglandins (see Prostaglandin Chapter).
`
`Two COX isoenzymes have been identified: COX-1 and COX-2. COX-1, expressed
`constitutively, is synthesized continuously and is present in all tissues and cell types, most
`notably in platelets, endothelial cells, the GI tract, renal microvasculature, glomerulus, and
`
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`
`Jack DeRuiter, Principles of Drug Action 2, Fall 2002
`
`collecting ducts. Thus COX-1 is important for the production of prostaglandins of homeostatic
`maintenance, such as platelet aggregation, the regulation of blood flow in the kidney and
`stomach, and the regulation of gastric acid secretion. Inhibition of COX-1 activity is considered a
`major contributor to NSAID GI toxicity. COX-2 is considered an inducible isoenzyme, although
`there is some constitutive expression in the kidney, brain, bone, female reproductive system,
`neoplasias, and GI tract. The COX-2 isoenzyme plays an important role in pain and
`inflammatory processes.
`
`O
`
`O
`
`N
`
`O
`
`O
`
`O
`
`5
`
`8
`
`CH3O
`
`11
`
`14
`
`Arachidonic Acid
`
`Cl
`NSAID
`Inhibition of COX by NSAIDs
`
`COX
`
`Generally, the NSAIDs inhibit both COX-1 and COX-2. Most NSAIDs are mainly COX-1
`selective (eg, aspirin, ketoprofen, indomethacin, piroxicam, sulindac). Others are considered
`slightly selective for COX-1 (eg, ibuprofen, naproxen, diclofenac) and others may be considered
`slightly selective for COX-2 (eg, etodolac, nabumetone, and meloxicam). The mechanism of
`action of celecoxib and rofecoxib is primarily selective inhibition of COX-2; at therapeutic
`concentrations, the COX-1 isoenzyme is not inhibited thus GI toxicity may be decreased.
`
`Other mechanisms that may contribute to NSAID anti-inflammatory activity include the
`reduction of superoxide radicals, induction of apoptosis, inhibition of adhesion molecule
`expression, decrease of nitric oxide synthase, decrease of proinflammatory cytokine levels (tumor
`necrosis factor-a, interleukin-1), modification of lymphocyte activity, and alteration of cellular
`membrane functions.
`
`Central analgesic activity has been demonstrated in animal pain models by some NSAIDs such as
`diclofenac, ibuprofen, indomethacin, and ketoprofen. This may be because of the interference of
`prostaglandin (PGE1, F2 and F2a) mediated pain formation or with transmitters or modulators in
`the nociceptive system. Other proposals include the central action mediated by opioid peptides,
`inhibition of serotonin release, or inhibition of excitatory amino acids or N-methyl-D-aspartate
`receptors. NSAIDs are mainly effective against the type of pain in which PGs sensitize pain
`receptors (inflammation and tissues) including the pain of arthritis, bursitis, pain of muscular and
`vascula origin and dysmenorrhea. The effectiveness of these agents against headache may result
`from their ability to inhibit PG-mediated cerebral vascular vasodilation.
`
`Antipyretic activity of NSAIDs results from inhibition of prostaglandin E2 (PGE2) synthesis in
`
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`
`Jack DeRuiter, Principles of Drug Action 2, Fall 2002
`
`circumventricular organs in and near the preoptic hypothalamic area. Infections, tissue damage,
`inflammation, graft rejection, malignancies, and other disease states enhance the formation of
`cytokines that increase PGE2 production. PGE2 triggers the hypothalamus to promote increases
`in heat generation and decreases in heat loss.
`
`III. Other Actions of the NSAIDs
`
`The NSAIDs also express a variety of other actions in addition to their antiinflammatory,
`analgesic and antipyretic activities as outlined below:
`
`• GI Tract (N/V, ulceration and hemorrhage). In the gastric mucosa, prostaglandins play a
`cytoprotective role inhibiting the proton pump and thereby decreasing gastric acid synthesis,
`stimulating the production of glutathione that scavenges superoxides, promoting the
`generation of a protective barrier of mucous and bicarbonate, and promoting adequate blood
`flow to the gastric muscosal cells. Since NSAIDs block PG biosynthesis in the GI tract, they
`block these cytoprotective processes. The primary toxicity seen with the NSAIDs is GI
`irritation which may lead to the production of ulcers when used in large doses over a long
`period of time. This occurs quite frequently in patients with RA and it may become so severe
`that the drug must be discontinued. There have been a number of attempts to eliminate this
`side effect and some success has been achieved but since most of the compounds suppress
`the production of PGs involved in limiting the secretion of gastric acid and since this a
`consequence of their mechanism of action it has been difficult to completely eliminate this
`side effect. In additional to inhibition of PG biosynthesis, NSAID gastric irritation may also
`be due to a direct irritation of the gut by these acidic compounds.
`
`• CNS: High NSAID doses cause CNS stimulation (confusion, dizziness, etc), tinnitus, etc.
`PGE2 may also cause fever via interactions within the hypothalamus
`
`• Respiratory: Direct and indirect (increased CO2 production) stimulation of respiratory
`centers, stimulation of O2 consumption in muscle (increased CO2); respiratory alkalosis. Also
`PGI2 and the PGEs cause bonchodilation while PGF2a, PGGs, PGH2, PGD2 and TxA2 are
`bronchoconstrictors (asthma)
`
`• Acid-Base: Initial respiratory alkalosis. This is generally somewhat unique to the salicylates
`and is only seen with large doses.
`• Cardiovascular: PGH2 and PGH2 cause transient vasoconstriction, but these intermediates
`are converted to PGI2 and other PGS (PGD2 PGF2a) which are vasconstrictors. At high
`doses NSAIDs cause vasodilation and depression of the vasomotor center.
`• Uterus: PGF2a and PGE2 (in low concentrations) promoate uteral contraction while PGI2
`and PGE2 in high concentrations promote uteral relaxation. NSAIDs decrease contractility
`and prolong gestation
`• Blood clotting: PGS I2 (vascular endothelium), E2 and D2 inhibit platelet aggregation while
`TXA2 (platelets) promotes aggregation. NSAIDs may significantly increase clotting times
`and can be used for prophylaxis of thromboembolism and MI. However, patients with liver
`damage, vitamin K deficiency, hypoprothrombinemia or hemophilia should avoid aspirin
`
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`
`Jack DeRuiter, Principles of Drug Action 2, Fall 2002
`
`therapy.
`
`• Renal: The inhibition of PGE2 and PGI2 both of which produce vasodilation in the kidney
`results in a decrease blood flow to the kidneys due to constriction of afferent arterioles which
`is mediated by norepinephrine and Angiotensin II. NSAIDs may decrease sodium and fluid
`elimination resulting in edema
`• Reye’s syndrome: This is seen in children who take an NSAID such as aspirin while
`recovering from mild viral infection. Although it occurs rarely there is a 20-30% mortality
`seen with this type of side effect.
`
`IV. General Structure and Properties of the NSAIDs
`
`The NSAIDs can be sub-classified on the basis of chemical structure as follows:
`
`• Salicylates
`• Propionic Acids (Profens)
`• Aryl and Heteroarylacetic Acids
`• Anthranilates (Fenamates)
`• Oxicams (“Enol Acids”)
`• Phenylpyrazolones
`• Anilides
`
`In general, NSAIDs structurally consist of an acidic moiety (carboxylic acid, enols) attached to a
`planar, aromatic functionality. Some analgesics also contain a polar linking group, which
`attaches the planar moiety to an additional lipophilic group. This can be represented as follows:
`
`COOH
`
`X
`
`NSAID General Structure
`
`As a result, the NSAIDs are characterized by the following chemical/ pharmacologic properties:
`
`• All are relatively strong organic acids with pKas in the 3-5 range. Most, but not all, are
`carboxylic acids (see drug classes). Thus, salts forms can be generated upon treatment with
`base and all of these compounds are extensively ionized at physiologic pH. The acidic group
`is essential for COX inhibitory activity!
`
`• The NSAIDs differ in their lipophilicities based on the lipophilic character of their aryl
`groups and additional lipophilic moieties and substituents.
`
`• The acidic group in these compounds serves a major binding group (ionic binding) with
`plasma proteins. Thus all NSAIDs are highly bound by plasma proteins (drug interactions!).
`
`• The acidic group also serves as a major site of metabolism by conjugation. Thus a major
`
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`
`Jack DeRuiter, Principles of Drug Action 2, Fall 2002
`
`pathway of clearance for many NSAIDs is glucuronidation (and inactivation) followed by
`renal elimination.
`V. Salicylates
`
`• Structure and Chemistry: The salicylates are derivatives of 2-hydroxybenzoic acid (salicylic
`acid). The salicylates were discovered in 1838 following the extraction of salicylic acid from
`willow bark. Salicylic acid was used medicinally as the sodium salt but replaced
`therapeutically in the late 1800s by the acetylated derivative, acetylsalicylic acid (ASA) or
`aspirin. Therapeutic utility is enhanced by esterification of the phenolic hydroxyl group as in
`aspirin, and by substitution of a hydrophobic/lipophilic group at C-5 as in diflunisal:
`
`O
`
`OH
`
`OH
`Salicylic Acid
`
`O
`
`OH
`
`O
`
`Na
`
`Sodium Salicylate
`
`F
`
`O
`
`OH
`
`O
`
`CH3
`
`O
`Acetylsalicylic Acid
`
`O
`
`OH
`
`OH
`
`F
`
`Diflunisal
`
`The salicylates are strong organic acids and readily form salts with alkaline materials. Note
`that the carboxyl group is substantially more acidic (and ionizes readily at physiologic pH)
`than the phenolic hydroxyl:
`
` R
`
`O
`
`OH
`
`OH
`Salicylic Acid
`
`NaHCO3
`(Weak Base)
`
`R
`
`O
`
`O
`
`OH
`Carboxylate
`
`Strong Base
`
`R
`
`O
`
`
`
`O
`
`O
`
`
`
`• Actions: The salicylates have potent antiinflammatory activity with mild analgesic and
`antipyretic activities. These compounds are mainly “COX-1 selective” – they are bound with
`higher affinity by COX-1. Toxicities include GI irritation, hypersensitivity reactions,
`inhibition of platelet aggregation, and ototoxicity (tinnitus). The therapeutic and certain of
`the toxic actions (i.e. gut) of aspirin can be related to its ability to inhibit COX in various
`tissues and participate in transacetylation reactions in vitro. For example, acetylation of COX
`results in irreversible inhibition of this enzyme and antiinflammatory effects in joints, and
`adverse effects in the GI tract. Also acetylation of circulating proteins may result in a
`hypersensitivity response.
`
`O
`
`OH
`
`O
`
`CH3
`
`H+
`
`O
`
`Nu
`
`5
`
`CH3
`
`O
`
`Nu
`
`Protein
`
`O
`
`OH
`
`OH
`
`Protein = COX-2 in Joints
`
`
`Protein = COX in GI Tract
`
`Protein = Circulating Proteins
`
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`
`

`
`Jack DeRuiter, Principles of Drug Action 2, Fall 2002
`
`• Absorption and Distribution: When the salicylates are administered orally they are rapidly
`absorbed from primarily the small intestines and to a lesser extent the stomach. Generally,
`esters such as acetylsalicylic acid (ASA) appear to be absorbed more slowly, yet 70% of
`aspirin is absorbed within an hour and absorption is complete within 4 hours. It appears that
`a major determinant of absorption for this class of compounds is the physical characteristic of
`the tablet.
`
`ASA is absorbed primarily intact, and then is hydrolyzed by plasma and tissue (liver)
`esterases to salicylic acid. ASA and salicylic acid is extensively bound to plasma albumin –
`the ionized carboxyl and aromatic functionalites both contribute to plasma protein binding.
`This may result in drug-drug interactions with other anionic drugs that are administered
`concurrently and are also highly bound by plasma protein.
`
`• Metabolism: Salicylic acid and drugs like ASA that are converted to salicylic acid undergo a
`variety of secondary metabolic transformations including: glycine conjugation to yield
`salicyluric acid, ring hydroxylation and carboxyl and phenol glucuronide conjugation. The
`salicylates and their metabolites are eliminated by renal mechanism.
`
`O
`
`OH
`
`O
`
`CH3
`
`O
`
`Acetylsalicylic Acid
`
`Plasma Cholinesterase
`(Enzyme C: Major)
` and
`Albumin Esterase
`(Enzyme A: Minor)
`
` Aromatic
`Hydroxylation
`
` Glycine
`Conjugation
`
`O
`
`N
`
`COOH
`
`H
`
`OH
`Salicyluric acid
`
`O
`
`O
`
`Gluc
`
`Glucuronide
`Conjugation
`
`OH
`Acyl-Glucuronide
`
`O
`
`OH
`
`O Gluc
`
`Phenol-Glucuronide
`
`O
`
`OH
`
`OH
`
`O
`
`OH
`
`OH
`
`HO
`
`O
`
`OH
`
`OH
`
`OH
`
`2,3, 5-Trihydrobenzoic Acid
`
`HO
`
`6
`
`OH
`2,3-Dihydrobenzoic Acid
`
`AND
`
`O
`
`OH
`
`OH
`
`Gentisic Acid
`
`Page 6
`
`

`
`Jack DeRuiter, Principles of Drug Action 2, Fall 2002
`
`• Diflunisal: The difluorophenyl analogue of salicylic acid differs from other members of the
`salicylate class and that it has primarily analgesic and antipyretic activity. It is used to treat
`the pain associated with RA, OA and muscle pain. It reported causes less GI tract ulceration
`than aspirin and has lower auditory side effects. This drug is cleared primarily by phenol and
`carboxyl O-glucuronidation similar to the salicylates
`
` F
`
`O
`
`OH
`
`F
`
`Diflunisal
`
`OH
`
`Glucuronidation
`
`VI. Propionic Acid Derivatives (“Profens”)
`
`F
`
`F
`
`O
`
`OH
`
`F
`
`O
`Gluc
`Phenol Glucuronide (80%)
`
`O
`
`OH
`
`O
`
`Gluc
`
`F
`
`Ester Glucuronide (20%)
`
`• Structure and Chemistry: Some of the most useful NSAIDs are structurally derived from
`arylacetic acids. These compounds are often referred to as the “profens” based on the suffix
`of the prototype member, ibuprofen. Like the salicylates these agents are all strong organic
`acids (pKa = 3-5)and thus form water soluble salts with alkaline reagents. The (cid:31)-
`arylpropionic acids are characterized by the general structure Ar-CH(CH3)-COOH which
`conforms to the required general structure. All of these compounds are predominantly
`ionized at physiologic pH and more lipophilic than ASA or salicylic acid.
`CH3 O
`CH
`
`COOH
`
`X
`
`R
`
`OH
`
`NSAID General Structure
`
`General Structure of Propionic Acid NSAIDs
`
`The α-CH3 substitutent present in the profens increases cyclooxygenase inhibitory activity
`and reduces toxicity of the profens. The α-carbon in these compounds is chiral and the S-(+)-
`enantiomer of the profens is the more potent cyclooxygenase inhibitor. Most profen products,
`except naproxen (NaprosynTM), are marketed as the racemates. In addition to the metabolism
`described below, the profens undergo a metabolic inversion at the chiral carbon involving
`stereospecific transformation of the inactive R-enantiomers to the active S-enantiomers. This
`is believed to proceed through an activated (more acidic α-carbon) thioester intermediate.
`Normally only the S-(+) isomer is present in plasma.
`
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`
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`

`
`Jack DeRuiter, Principles of Drug Action 2, Fall 2002
`
`COOH
`CH3
`
`H
`
`R
`
`R-Enantiomer
`
`O
`
`S CoA
`
`O
`
`S CoA
`
`CH3
`
`H
`
`CH3
`
`COOH
`
`H
`CH3
`
`R
`
`S-Enantiomer
`
`O
`
`S CoA
`
`CH3
`
`Isomerization of the Racemic Profens
`
`• Actions: The members of
`this series are shown below. These compounds are
`antiinflammatory agents with analgesic and antipyretic activity. Generally the profens are
`considered to be slightly “COX-1 selective”; naproxen appears to be more selective for COX-
`2 than other members of this series. The are used for RA, OA and as analgesics and
`antipyretics. They should not be used during pregnancy or nursing; they can enter fetal
`circulation and breast milk.). They produce less GI ulceration than the salicylates, but may
`cause some thrombocytopenia, headache, dizziness, fluid retention edema.
`
`CH3 O
`
`OH
`
`CH3
`
` CH3
`
`Ibuprofen (Motrin)
`
`H
`N
`
`CH3 O
`
`OH
`
`O
`
`CH3 O
`
`OH
`
`Fenoprofen
`
`F
`
`CH3 O
`
`OH
`
`Cl
`
`Carprofen (Rimadyl)
`
`Flurbiprofen (Ansaid)
`
`O
`
`CH3 O
`
`OH
`
`CH3O
`
`CH3 O
`
`OH
`
`Ketoprofen (Orudis)
`
`Naproxen (Aleve, Anaprox)
`
`8
`
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`

`
`Jack DeRuiter, Principles of Drug Action 2, Fall 2002
`
`• Absorption and Distribution: These agents are well absorbed orally with high oral
`bioavailabilities and peak plasma times of 1-2 hours. Only ketoprofen ER and naproxen
`provide slower peak plasma levels. All of the profens >99% bound by plasma proteins.
`
`• Metabolism: All of these agents are carboxylic acids and thus are cleared, in part, as acyl-
`glucuronides (inactive). The other metabolic transformations different profens undergo are
`determined by the structure of the additional lipophilic functionality present in each
`compound and can be summarized as follows:
`
`Alkyl Substituted (Ibuprofen): ω, ω-1 and benzylic oxidation (loss of activity)
`Electron rich Aryl (Flurbiprofen, Fenoprofen): Ring oxidation (loss of activity)
`Electron deficient Aryl (Ketoprofen): No additional metabolism
`Methoxynaphthyl: Oxidative-O-dealkylation
`
`CH3 O
`CH
`
`OH
`
`CH3
`
`HOCH2
`
`2-Hydroxylmethyl (25%)
` Activity?
`
`CH3
`
`HOOC
`
`CH3 O
`CH
`
`OH
`
`2-Carboxy (37%)
`Activity?
`
`CH3 O
`CH
`
`OH
`
`CH3 O
`CH
`
`OH
`
`CH3 O
`CH
`
`O
`
`Gluc
`
`CH3
`
`OH
`
`CH3
`
`CH3
`
`CH3
`
`OH
`
`CH3
`
`CH3
`
`Acyl-Glucuronide
`Inactive
`
`CH3
`
`H
`
`COOH
`
`COOH
`
`H
`CH3
`
`CH3
`
` CH3
`(R)-Ibuprofen
`
`CH3
`
` CH3
`
`(S)-Ibuprofen
`
`9
`
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`

`
`Jack DeRuiter, Principles of Drug Action 2, Fall 2002
`
`O
`
`CH3
`H
`COOH
`
`O
`
`COO
`
`Gluc
`
`H
`CH3
`
`(R)-Fenoprofen
`
`Acyl-Glucuronide (45%)
`
`O
`
`COOH
`
`H
`CH3
`
`(S)-Fenoprofen
`
`HO
`
`O
`
`COOH
`
`H
`CH3
`
`4-Hydroxy (5%)
`Active?
`
`O
`
`COO
`
`Gluc
`
`H
`CH3
`
`HO
`4-Hydroxy-Acyl-Glucuronide (45%)
`
`F
`
`F
`
`CH3
`H
`COOH
`
`(R)-Flurbiprofen
`
`COOH
`
`H
`CH3
`
`(S)-Flurbiprofen
`
`10
`
`F
`
`CH3
`H
`COOH
`
`F
`
`CH3
`H
`COOH
`
`HO
`
`4'-Hydroxy (45%): Inactive
`
`HO
`
`OH
`
`3',4'-Dihydroxy (5%): Inactive
`
`F
`
`CH3
`H
`COOH
`
`CH3O
`
`OH
`
`3'-hydroxy-4'-Methoxy (25%): Inactive
`
`Page 10
`
`

`
`Jack DeRuiter, Principles of Drug Action 2, Fall 2002
`
`O
`
`CH3
`H
`COOH
`
`(R)-Ketoprofen
`
`O
`
`COOH
`
`H
`CH3
`
`(S)-Ketoprofen
`
`COOH
`
`H
`CH3
`
` CH3O
`
`Naproxen (S-Enantiomer)
`
`O
`
`CH3
`H
`COO
`
`Gluc
`
`Acyl-Glucuronide (>80%): Inactive
`
`COO
`
`Gluc
`
`H
`CH3
`
`CH3O
`
`Acyl-Glucuronide (65%): Inactive
`
`COOH
`
`H
`CH3
`
`HO
`
`Naproxen-O-Desmethyl (30%): Inactive
`
`• Profen Half-life and Elimination: All of the profens are eliminated primarily in the urine as
`metabolites. Ibuprofen and flurbiprofen also have a significant non-renal component of
`elimination. All drugs in this class with the exception of lfurbiprofen and naproxen have half-
`lives of less than 4 hours.
`
`• Nabumetone (RelafenTM): This agent is a prodrug which contains the non-acidic ketone
`(alkanone) functionality which is quickly metabolized to give the naphthylacetic acid
`derivative which is the active form of the drug and has a long half-life (24hrs) . This
`structure fits nicely into the analgesic pharmacophore identified previously and is closely
`related in structure to the propionic acids (profens). This compound was designed in an
`attempt to circumvent some of the gastrointestinal problems normally associated with the
`acidic functionality of these agents.
`
`• Nabumetone exhibits antiinflammatory, analgesic and antipyretic properties and is used for
`RA and OA. It is somewhat selective for COX-2. Since no potent inhibitor of
`cyclooxygenase is present in the stomach, fewer GI problems are seen (GTD50/ED50 =21
`while for aspirin GTD50/ED50= 0.41). GTD50 is that dose which caused GI damage in 50% of
`the subjects. In spite of this, the most frequently reported side effect is still GI upset. This
`compound has a relatively long plasma half-life of 24 hours.
`
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`
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`
`Jack DeRuiter, Principles of Drug Action 2, Fall 2002
`
`CH3O
`
`Nabumetone
`
`O
`
`CH3
`
`O
`
`CH3
`
`HO
`
`6-Hydroxynaphthylbutanone
`
`OH
`
`O
`
`CH3O
`
`Naphthyl Acetic Acid: Active!
`
`OH
`
`O
`
`HO
`
`6-Hydroxy-naphthyl Acetic Acid
`
`H OH
`
`CH3
`
`O-Glucuronides
`
`HO
`
`6-Hydroxynaphthylbutanols
`
`VII. Aryl and Heteroarylacetic Acids
`
`• General Structure and Chemistry: These compounds are also derivatives of acetic acid, but in
`this case the substituent at the 2-position is a heterocycle or related carbon cycle. This does
`not significantly effect the acidic properties of these compounds. The heteroarylacetic acid
`NSAIDs marketed in this country can be further subclassified as the indene/indoles, the
`pyrroles and the oxazoles as shown below:
`
`COOH
`
`X
`
`R
`
`OH
`
`Heterocycle
`
`NSAID General Structure
`
`O
`General Structure for Heterocyclic Acetic Acids
`
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`

`
`Jack DeRuiter, Principles of Drug Action 2, Fall 2002
`
`A. Indene and Indole Acetic Acids:
`
`F
`
`O
`
`OH
`
`CH3O
`
`CH3
`
`O
`
`OH
`
`N
`
`O
`
`O
`
`N
`
`CH3
`
`S
`
`O
`Sulindac (Clinoril)
`
`Cl
`
`Indomethacin (Indocin)
`
`H
`
`CH3
`
`CH3CH2
`Etodolac (Lodine)
`
`O
`
`OH
`
`•
`
`•
`
`•
`
`Indomethacin Structure and Actions: contains a benzoylated indole nitrogen. The methyl
`group at the 2 position of the indole ring prevents free rotation about the C-N bond and keeps
`the two aromatic rings in the correct relationship for COX binding and therapeutic activity.
`Indomethacin is “COX-1” selective” and produces primarily antiinflammatory actions with
`some analgesic and antipyretic activity. It is used for RA, OA, ankylosing spondylitis, to
`suppress uterine contraction (preterm labor), and to promote closure of patent ductus artiosus
`in neonates (premature infants). GI ulceration and hemorrhage (these limit use). CNS
`toxicity ranging from headaches to delusions to psychoses and suicidal tendencies occur
`along with bone marrow depression: aplastic anemia and thrombocytopenia
`
`Indomethacin Kinetics: Well absorbed orally and should be taken with meals to reduce GI
`upset. Peak plasma levels are attained within 1-2 hours and half-life is 4.5 hours.
`
`Indomethacin Metabolism: The metabolism of indomethacin involves glucuronidation of the
`carboxyl group along with demethylation (increasing resemblance to 5-HT and CNS
`toxicity) and glucuronidation of the resulting phenol. In addition, the amide is more
`susceptible to hydrolysis than may normally be expected due to decreased resonance
`stabilization.
`
`• Sulindac Structure: This relationship between aromatic rings observed for indomethacin is
`preserved by restricted rotation about the carbon-carbon double bond in sulindac. In this
`agent the indole N has been eliminated which reduces the drugs resemblance to 5-HT and
`therefore fewer CNS side effects are seen. This compound has pharmacologic actions similar
`to indomethacin (COX-1 selective and antiinflammatory primarily). However, sulindac is a
`prodrug function; it is reduced to a sulfide which is 50X more active. (see metabolism
`below). It is used for RA, OA, AS, acute gout and to inhibit uterine contractions. Overall
`sulindac produces less GI ulceration, probably as a result of its prodrug function. Some CNS
`toxicity, hepatic damage and prolongs clotting time.
`
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`

`
`Jack DeRuiter, Principles of Drug Action 2, Fall 2002
`
`CH3O
`
`O
`
`OH
`
`N
`
`H
`N-Desbenzoyl-O-Desmethyl
` Indomethacine: Inactive
`
`HO
`
`O
`
`OH
`
`N
`
`O
`
`Cl
`O-Desmethyl-Indomethacin:
` Inactive
`
`CH3O
`
`O
`
`OH
`
`N
`
`H
`N-Desbenzoyl-Indomethacine:
` Inactive
`
`CH3O
`
`O
`
`O
`
`Gluc
`
`N
`
`O
`
`Cl
`
`Indomethacin-O-Glucuronide
`
` CH3O
`
`O
`
`OH
`
`N
`
`O
`
`Cl
`
`Indomethacin (Indocin)
`
`• Sulindac Kinetics: Rapidly and extensively absorbed when given orally and achieve Tp
`within 1 to 2 hours. The half-life for sulindac is 7-8 hours. The active sulfide has half-life of
`18 hrs.
`
`• Sulindac Metabolism: Sulindac is a prodrug and therefore must be converted to an
`active form. This activation requires reduction to the sulfide which is then capable of
`inhibiting cyclooxygenase. Alternatively, sulindac may be oxidized to the inactive sulfone.
`In the case of sulindac, glucuronidation of the carboxyl group may still occur but since the
`methoxy group has been replaced by a F substituent, ring demethylation does not occur.
`
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`

`
`Jack DeRuiter, Principles of Drug Action 2, Fall 2002
`
`F
`
`O
`
`OH
`CH3
`
`F
`
`Oxidation
`(Minor)
`
`O
`
`OH
`CH2OH
`
`OH
`
`CH3
`
`S
`
`O
`
`O
`
`OH
`CH3
`
`CH3
`
`S
`
`O
`Sulindac (Clinoril)
`
`Conjugates
`
`F
`
`CH3
`
`S
`
`O
`
`O
`Sulfone: Inactive!
`
` F
`
`O
`
`OH
`CH3
`
`CH3
`
`S
`
`Sulfide (Active)
`
`• Etodolac (Lodine): Analogue of indomethacin and similar profile; antiinflammatory mainly
`with analgesic and antipyretic acitvity and uricosuric action. It is used for RA, OA and as a
`post-operative analgesic. It may cause GI ulceration and hemorrhage at high doses. This drug
`is well absorbed and has a half-life 7 hours.
`
`B. Arylacetic Acids: The Pyrrole Acetic Acids
`
`O
`
`O-
`
`N
`
`H3N
`
`O
`
`OH
`
`OH
`OH
`
`O
`
`O-Na+
`
`H3
`
`OC
`
`N
`
`CH3
`
`Tometin (Tolectin)
`
`Ketorolac Tromethamine
`
`• Tolmetin (Tolectin): Non-selective COX inhibitor with actions similar to other members in
`this class and it is used for RA, OA and AS. It is the shortest acting member of this class due
`in part to rapid Phase I oxidation of the para-methyl group to a benzylic alcohol initially and
`
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`
`Jack DeRuiter, Principles of Drug Action 2, Fall 2002
`
`eventually to the acid. These metabolites are subsequently glucuronidated and eliminated.
`As a result of this, tolmetin’s half-life is typically less than 5 hours.
`O
`
`O Gluc
`
`H3
`
`OC
`
`N
`
`CH3
`Acyl-Glucuronide: Inactive
`
`O
`
`OH
`
`H3
`
`OC
`
`N
`
`HOOC
`
`4-Carboxy-Tometin: Inactive
`
`O
`
`O-Na+
`
`H3
`
`OC
`
`N
`
` CH3
`Tometin (Tolectin)
`
`• Ketorolac which lacks this benzylic methyl group is not susceptible to the type of oxidation
`observed for tolmetin and as a result its half-life is longer (4-6 hours). This drug is unique in
`that it is formulate for orally and IM administration. Good oral activity with primarily
`analgesic activity, but also has antiiflammatory activity and antipyretic actions. Use
`management of post-operative pain
`O
`
`O
`
`O-
`
`N
`
`O
`
`Ketorolac
`
`O Gluc
`
`N
`
`O
`
`Acyl-Glucuronide (20%): Inactive
`
`O
`
`OH
`
`N
`
`O
`
`HO
`
`4'-Hydroxy-Ketorolac (10%): Inactiv
`
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`

`
`Jack DeRuiter, Principles of Drug Action 2, Fall 2002
`
`C. Arylacetic Acids: Oxazole Acetic Acids
`
`• A recent addition (1993) to this class of agents is oxaprozin (DayproTM) another non-
`seelective COX inhibitor. It differs slightly in that substitution of the propionic moiety is at
`the 3 position rather that at the 2 position as in other agents of this class. It is metabolized by
`glucuronidation and uncharacterized oxidation products.
`
`O
`
`OH
`
`O
`
`N
`
`Oxaprozin (Daypro)
`
`VIII. Anthranilates
`
`• Structure and Chemistry: These agents are considered to be N-aryl substituted derivatives of
`anthranilic acid which is itself a bioisostere of salicylic acid. These agents retain the acidic
`properties that are characteristic of this class of agents; however, note that while mefenamic
`acid and meclofenamic acid are derivatives of anthranilic acid, diclofenac is derived from 2-
`arylacetic acid. The most active fenamates have small alkyl or halogen substituents at the
`2’,3’ and/or 6’ position of the N-aryl moiety (meclofenamate is 25 times more potent than
`mefenamate- see below). Among the disubstituted N-aryl fenamates the 2’,3’-derivatives are
`most active suggesting that the substituents at the 2’,3’-positions serve to force the N-aryl
`ring out of coplanarity with the anthranilic acid. Hence this steric effect is proposed to be
`important in the effective interaction of the fenamates at their inhibitory site on
`cyclooxygenase.
`
`COOH
`
`X
`
`O
`
`OH
`
`NH2
`
`NSAID General Structure
`
`Anthranilic Acid
`
`OH
`
`O
`
`NH
`
`R
`
`General Anthranilate Structure
`
`Actions: The anthranilates have primarily antiinflammatory with some analgesic and antipyretic
`activity and are non-COX selective. The anthranilates are used as mild analgesics and
`occasionally to treat inflammatory diseases. Diclofenac is used for RA, OA, AS and post-op pain,
` Meclofenanamte for RA (as a secondary agent), and Mefenamic acid as an analgesic for
`dysmennorhea. The utility of the class of agents is limited by a number of adverse reactions
`
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`

`
`Jack DeRuiter, Principles of Drug Action 2, Fall 2002
`
`including nausea and vomiting, diarrhea, ulceration, headache, drowsiness and hematopoietic
`toxicity.
`
`OH
`
`O
`
`NH
`
`CH3
`
`CH3
`Mefenamic Acid (Ponstel)
`
`OH
`
`O
`
`NH
`
`Cl
`
`Cl
`
`CH3
`
`O
`
`NH
`
`OH
`
`Cl
`
`Cl
`
`Meclofenamate (Meclomen)
`
`Diclofenac (Voltaren)
`
`• Anthranilate Absorption and Distribution: The “true” anthranilates are well absorbed from
`the GI tract producing peak plasma levels within 2-4 hours; meclofenanmate is more
`lipophilic and absorbed more quickly. Diclofenac is less extensively absorbed but provide
`peak plasma levels within 2 hours. Diclofenac and meclofenamate are >99% bound by
`plasma proteins; the binding of mefenamic acid (less lipophilic) is lower.
`
`• Anthranilate Metabolism: Both mefenamic acid and meclofenamic acid are metabolized by
`benzylic oxidation of the ortho methyl group and ring oxidation followed by eventual
`glucuronidation. Diclofenac is metabolized by acyl-O-glucuronidation and oxidation of the
`aromatic rings.
`
`OH
`
`O
`
`NH
`
`Cl
`
`Cl
`
`Cl
`
`O
`
`NH
`
`OH
`
`Cl
`
`OH
`
`OH
`4'-Hydroxy (Major)
`
`3'-Hydroxy (Minor
`
`O
`
`NH
`
`OH
`
`Cl
`
`Cl
`
`HO
`
`Cl
`
`O
`
`NH
`
`OH
`
`Cl
`
`Diclofenac (Voltaren)
`
`5-Hydroxy (Minor)
`
`O Gluc
`
`O
`
`NH
`
`Cl
`
`Cl
`
`Diclofenac-O-Glucuronide
`
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`

`
`Jack DeRuiter, Principles of Drug Action 2, Fall 2002
`
`OH
`
`O
`
`NH
`
`Cl
`
`Cl
`
`HOCH2
`
`OH
`3'Hydroxymethyl-
`4'Hydroxy (35-45%)
`
`OH
`
`O
`
`NH
`
`Cl
`
`Cl
`
`HOCH2
`3'-Hydroxymethyl (50-60%)
` Active
`
`OH
`
`O
`
`NH
`
`Cl
`
`Cl
`
`CH3
`
`OH
`4'-Hydroxy (5-7%)
`
`OH
`
`O
`
`NH
`
`Cl
`
`HO
`
`Cl
`
`CH3
`
`5-Hydroxy (3-6%)
`
`OH
`
`O
`
`NH
`
`Cl
`
`Cl
`
`CH3
`Meclofenamate (Meclomen)
`
`• Anthranilate Half-life and Elimination: All of the anthranilates are cleared efficiently by
`metabolism as shown above. The anthranilates and their metabolites show more
`balanced excretion than other NSAIDs, with a greater fraction being eliminated in the
`feces.
`
`IX. Oxicams (Enolic Acids)
`
`• Structure and Chemistry: Oxicams (Piroxicam and Meloxicam) are characterized by the 4-
`hydroxybenzothiazine heterocycle. The acidity of the oxicams is attributed to the 4-OH with
`the enolate anion being stabilized by intramolecular H-bonding to the amide N-H group.
`Also, the presence of the carboxamide substituent at the 3-position of the benzothiazine ring
`contributes toward acidity by stabilizing the negative charge formed during ionization
`(resonance stabilization). Although these compounds are acidic (pKa = 6.3), they are
`somewhat less acidic than carboxylic acids NSAIDs. Yet the oxicams are primarily ionized
`at physiologic pH and acidity is required for COX inhibitory activity.
`
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`
`Jack DeRuiter, Principles of Drug Action 2, Fall 2002
`
`• Actions: Higher COX-2 selectivity than many other NSAIDs, particularly meloxicam.
`These agents have utility in treatment of RA and OA.
`
`CH3
`
`S
`
`N
`
`OH
`
`O
`
`N H
`
`CH3
`
`N
`
`S
`
`O
`O
`Meloxicam (Mobic)
`
`OH
`
`O
`
`N
`
`N H
`
`CH3
`
`N
`
`S
`
`O
`
`O
`
`Piroxicam (Fe