Al-Bayan University / College of Pharmacy

Pharmacology & Toxicology Dept. 2019-2020

Fourth stage / Pharmacology III - Lecture 9 / By Dr. Atheer S. Alsabah

NSAIDs and Drugs of RA & Gout

 NSAIDs (Non-Steroidal Anti-Inflammatory Drugs)

• Classification of NSAIDs
A. According to COX- selectivity & chemical structure:

B. According to potency of major pharmacologic actions:

1. Potent antiinflammatory & good analgesic e.g. aspirin & salicylates.
2. Potent antiinflammatory & poor analgesic e.g. indomethacin, sulindac, &
phenylbutazone.
3. Moderate antiinflammatory & moderate analgesic e.g. diclofenac, ibuprofen,
naproxen, mefenamic acid, & piroxicam.
4. Poor antiinflammatory & good analgesic e.g. paracetamol & metamizole
"dipyrone".

 Aspirin "acetyl salicylic acid" (Prototype of NSAIDs)

- It has very good absorption at stomach (pH 1.5), & widely distributed cross BBB.
- Metabolized via 1st order kinetics (direct) at therapeutic dose, & zero order kinetic
(indirect "enzyme dependent") at high dose [i.e. dual method of elimination
according to concentration like phenytoin].
- Its elimination increased by alkalinization of urine.

• MOA
- Aspirin irreversibly inhibits COX enzyme (unlike all other NSAIDs), resulting in
inhibition the synthesis of physiologic PGs (via inhibiting COX-1) & pathologic
PGs (via inhibiting COX-2).

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• Pharmacologic actions of aspirin
1. Analgesic: aspirin inhibits COX enzyme resulting in inhibition of the synthesis of
PGs centrally & peripherally (dual effect, but peripherally >centrally). It is
effective for mild pain, not for pain related to MI or cancer.

2. Antipyretic: aspirin is antipyretic but not hypothermic (i.e. aspirin lowers the
elevated temperature to normal 37c but not lower than 37c).
- Aspirin act as antipyretic via:
a. ↓PGE2 synthesis in CNS.
b. ↓response of hypothalamus to endogenous pyrogen (IL1), that secreted during
inflammation & act on hypothalamus to ↑temperature.
c. At high dose, causing cutaneous vasodilation that ↓temperature by ↑sweating.

3. Antiinflammatory: aspirin inhibits COX-2 lead to inhibition of inflammatory

PGs (pathologic PGs), resulting in ↓chemotaxis, ↓edema, stabilizing membrane of
vesicles containing inflammatory mediators, & inhibit secretion of bacterial
hyaluronase enzyme that degrades hyaluronic acid.

4. Respiratory: acid-base balance depend on HCO3 & CO2 [any change in HCO3
lead to metabolic changes, while change in CO2 lead to respiratory changes. Also
↑pH lead to alkalosis, & ↓pH lead to acidosis]. Therefore;
a. ↑pH due to ↑HCO3 → metabolic alkalosis.
b. ↓pH due to ↓HCO3 → metabolic acidosis.
c. ↑pH due to ↑CO2 → respiratory acidosis.
d. ↓pH due to ↓CO2 → respiratory alkalosis.

- Aspirin at therapeutic dose (low-moderate toxic dose till 15 tablets/day) causing

metabolic acidosis (by ↑excretion of HCO3) & respiratory alkalosis (by ↑wash
out of CO2 via hyperventilation due to stimulation of respiratory center).
- Aspirin at high toxic dose (60 tablets "suicide") causing metabolic acidosis (by
↑excretion of HCO3) & respiratory acidosis (by retention of CO2 without
stimulation of respiratory center), which is the cause of death.
- Aspirin never cause metabolic alkalosis.

5. CVS: aspirin not affecting the heart.

6. GIT: 99% of aspirin in stomach is non-ionized (absorbable) which enter mucosal

cells where pH 7.4 lead to ionization & retention (aspirin ion trapping).
- Aspirin-induced ulcer depend on the dose, if high dose taken, aspirin ion trapping
cause acute gastric ulcer & hematemesis. while in pts taken normal dose but for
long term e.g. 10yrs, aspirin inhibits physiologic PGs synthesis causing thin
mucus layer formation resulting in chronic peptic ulcer with occlude bleeding.

7. Hepatic: in adults (>18yrs), aspirin causes transient elevation in SGOT & SGPT.
While in children (>12-16) with viral infection & fever, aspirin causes Reyes
syndrome (rare fatal encephalopathy ccc by fulminant hepatitis & necrosis in
brain & liver). The safest antipyretic for children are paracetamol & ibuprofen.

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8. Hematic: aspirin inhibits platelets aggregation via;
a. Inhibits COX enzyme leading to ↓TXA2.
b. Acetylation of platelets membrane & preventing adhesion.
c. Inhibits ADP synthesis

- Aspirin >6gm/day lead to ↓prothrombin (factor II).

- COX enzyme in platelets (producing TXA2) is very sensitive to low doses of
aspirin 75-81mg, that not affecting COX enzyme in vascular endothelium
(producing PGI2).
- Aspirin therapy stopped 7-10days before surgery since platelets life-span is 7-
10days & aspirin irreversibly inhibits platelets COX enzyme. In case of immediate
urgent surgery, the pt requires blood transfusion (fresh blood or backed platelets).
- Other NSAIDs reversibly inhibit platelets COX enzyme, therefore just stopped
before starting surgery (not require 7-10days period).

9. Renal: RBF depend on PGE1 & PGE2, therefore analgesics that inhibit these PGs
lead to ↓RBF & for long term causing analgesic nephropathy. Also ↓RBF lead to
↑RAAS → Na-H2O retention.
- Aspirin interfere with β-blockers & loop diuretics that partially ↑PGE1 & PGE2, so
↓ their antihypertensive & diuretic effects.
- Aspirin at very high dose (toxic dose 18 tablets/day) inhibits reabsorption
transporter of uric acid (that reabsorbs 90% of uric acid) lead to ↑ uric acid
excretion, but this not applicable clinically since acute toxic dose required; in
addition aspirin at therapeutic dose compete with uric acid at excretion transporter
(that excretes 10% of uric acid) causing uric acid retention, thus aspirin C/I in
gout & hyperuricemia since ppt acute gout attack.
- Antithrombotic doses of aspirin (75-150mg/day) not affecting uric acid excretion,
thus can be used prophylactically for thrombosis in gouty pts.

10. Mitochondria: aspirin at very high dose (toxic dose 25 tablets & more) causes
uncoupling of oxidative phosphorylation & elevates temperature (all toxicant
cause hypothermia except aspirin & atropine cause hyperthermia).

• Uses of aspirin
1. Analgesic for mild-moderate pain.
2. Antipyretic at therapeutic dose (high dose cause uncoupling & hyperthermia).
3. Anti-rheumatic.
4. Antithrombotic (75-150mg/day) for;
a. Hypertension with end organ damage but not primary prevention of thrombus.
b. Evidence of CV diseases e.g. IHD & TIA.
c. Pts >50yrs with hypertension + DM.
d. Pts with 10yrs CV risk score >20% (aspirin given prophylactically).
5. Keratolytic for wart via salicylic acid or methyl salicylate but not aspirin.
6. Counter irritant e.g. gallbladder pain overcome by counter irritant via salicylic
acid or methyl salicylate patch on right shoulder.

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• Adverse effects of aspirin
- Acute GU, chronic PU, transient elevation of hepatic enzymes, Reyes syndrome,
↑bleeding tendency, analgesic nephropathy, hyperuricemia, hyperthermia (at toxic
dose), prolong labor, hypersensitivity, & induce asthmatic attack.

• C/I of aspirin
- PU, hemorrhagic blood disorder e.g. thrombocytopenia, surgery & recent
operation, severe hypertension (cause fatal bleeding), children <16yrs old, near
term pregnancy (>20weeks gestation).

• D/I of aspirin
1. Interferes with β-blockers & loop diuretics (esp. indomethacin).
2. Antagonizes probenecid effect.
3. Displaces warfarin from its plasma protein binding.
4. Antacid form chemical complex with aspirin.

• Acute toxicity of aspirin

- It is manifested by hyperpyrexia due to uncoupling, metabolic acidosis &
hyperventilation (tachypnea) which is early sign of acute toxicity, also
hematemesis, & dehydration.
- It is treated by:
1. Gastric lavage.
2. IV fluids e.g. 5% dextrose (for dehydration).
3. Na-bicarbonate (for metabolic acidosis & alkalinization of urine).
4. Vit. K (IM or slow IV).
5. Hemodialysis for severe toxicity (aspirin plasma level 100mg/dL), esp. in pts with
renal failure.

 Indomethacin (Indocid®)
- It has more potent antiinflammatory effect (> aspirin), with no intrinsic analgesic
activity (poor analgesic), also inhibits phospholipases A & C, ↓neutrophil
migration, & ↓ B & T-cells proliferation.
- It is more toxic causing neurotoxicity, thus avoided in dysmenorrhea (related to
↑PGF2α) which instead treated by diclofenac, ibuprofen, or ketoprofen.
- Commonly delay labor by delay uterine contraction via inhibition of PGs
synthesis in uterus.
- DOC for closure of ductus arteriosus.

 Sulindac
- Prodrug related to indomethacin, its t1/2 16hrs, with antiinflammatory effect <
indomethacin. It prevent cataract related to diabetes.

 Diclofenac (Voltaren®, Olfen®)

- Well known & well tolerated NSAIDs with less gastric irritation but more
nephrotoxic.
- Used for moderate pain with inflammation & preferred over others in renal &
biliary colics (over pethidine which cause urine retention), OA (since accumulated
in synovial fluid), post-operative pain, solar keratosis (topical), for nausea (rectal).

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 Ibuprofen (Brufen®)
- Safe in children but in female >30yrs ↑risk of hypertension, & its
antiinflammatory effect > aspirin.
- Its GI complains < aspirin, & cause ccc agranulocytosis, aplastic anemia, &
thrombocytopenia.
- Ketoprofen more toxic than others & also inhibits lipoxygenase enzyme.
- Fenoprofen rarely used since causes interstitial nephritis (heavy proteinuria).
- Flurbiprofen pre-operative analgesic & ↓miosis during operation, also affecting
TNFα & NO. biosynthesis.
- NSAIDs-induced hypertension depend on term of use & usually occur after
2months of regular use except flurbiprofen induce hypertension within short term,
thus used in treatment of hypotension.

 Naproxen (Naprox®)
- Long t1/2 14hrs, less S/E, & DOC in RA, OA, & acute gout.

 Mefenamic acid (Ponstan®)

- It has analgesic & antipyretic effects similar to aspirin but antiinflammatory effect
< aspirin.
- Its S/E (toxic >aspirin), causing severe diarrhea in adults (not used >7days in
adults), non-oliguric ARF in elderly, agranulocytosis, hemolytic anemia, &
↓seizure threshold.

 Piroxicam (Feldin®)
- Longer t1/2 36hrs, also inhibits polymorph-nuclear (PMN) leukocytes migration,
↓O2 radicals production, & inhibits lymphocytes function.
- Useful in RA, OA, ankylosing spondylitis, & acute gout.

 Ketorolac
- It has typical NSAIDs properties but used systemically as analgesic & replace
morphine in mild-moderate post-operative pain. Renal toxicity more common
with chronic use.

 Paracetamol "acetaminophen" (Paracetol®, Panadol®)

- It is active metabolite of phenacetin, with t1/2 2-3hrs (at toxic dose, t1/2 4-8hrs), &
has potent antipyretic activity (inhibits COX-3 in CNS).
- It have several advantages over aspirin:
1. Doesn't irritate gastric mucosa.
2. Doesn't inhibit platelets aggregation.
3. Doesn't change uric acid excretion.
4. Doesn't interact with oral antidiabetic drugs & uricosuric agents.
5. Safe antipyretic for small children with viral infection.

- Paracetamol toxicity is more dangerous than aspirin toxicity since it is

asymptomatic. It is occur after ingestion of over dose (10-15gm) in suicidal
attempt, where hepatotoxicity started with early N, V, D, & abdominal pain. The
fatal dose is 20-25gm, that cause liver failure esp. in alcoholics.
- N-acetyl cysteine & methionine are antidotes that reduce liver capacity to oxidize
paracetamol to its toxic metabolite NAPQI (reactive instable toxic metabolite).
Also gastric lavage is effective.

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 Metamizole "Dipyrone" (Novalgen®)
- It has potent analgesic & antipyretic effects, & highly effective in malignant
intractable fever.
- No longer used because causing aplastic anemia, agranulocytosis, & fatal
anaphylactoid reaction.

 Meloxicam (Mobic®)
- It is preferentially inhibits COX-2 over COX-1 (not COX-2 selective).
- Its t1/2 48hrs, has lesser GI upset than others, & useful for RA & OA.

 Selective COX-2 inhibitors (e.g. celecoxib, etoricoxib, rofecoxib, valdecoxib)

- They have similar analgesic, antipyretic, & antiinflammatory effects of non-
selective NSAIDs, with half GI adverse effects, & no cardioprotective effect of
aspirin but associated with higher incidence of CV thrombotic events (↑TXA2
synthesis), therefore rofecoxib & valdecoxib were withdrawn.
- Celecoxib (Celebrex®) is sulfonamide derivative (cross sensitivity with sulfa
drugs), t1/2 11hrs, & useful for RA & OA.
- Etoricoxib (Atoxi®) is bipyridine derivative (no cross sensitivity with sulfa
drugs), t1/2 22hrs, & approved for RA, OA, acute gout, & acute musculo-skeletal
pain.

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 DMARDs/SAARDs (Disease Modifying Anti-Rheumatic Drugs / Slow Acting
Anti-Rheumatic Drugs):
- Rheumatoid arthritis (RA) is chronic inflammatory disease of small joints esp.
of hands in adults, affect 70% females & 30% males, & symmetrical both hands.
- Pathogenesis: a.a. arginine converted to citrulline which bind proteins forming
citrullinated protein that causing irritation, where T-lymphocytes recognized it as
foreign protein & attack joints producing cytokines esp. TNFα, IL1B, IL2, & B-
cells that produce anti-citrullinated protein antibodies; finally acute inflammation
causing cartilage deformity (autoimmune reaction). In addition to extra-articular
symptoms like splenomegaly & pneumonia.
- Diagnosis: depend on rheumatoid factor (RF) load in blood which is +ve in 80%
of pts (non-specific), & anti-citrullinated protein antibodies (specific).
- Treatment:
A. Symptomatic therapy include NSAIDs & corticosteroids.
B. Immunosuppressive therapy include DMARDs/SAARDs, require 6wks-6months
to give evident effect. They include the followings:
1. Sulfasalazine.
2. Penicillamine.
3. Chloroquine & hydroxychloroquine.
4. Gold salts: e.g. aurothioglucose, Na-aurothiomalate, & auranofin.
5. Immunosuppressive agents: e.g. cyclosporine, methotrexate "MTX",
azathioprine "AZT", mycophenolate mofetil, leflunomide, & cyclophosphamide.
6. Biologic modifiers (immunosuppressive mAbs): e.g. anti-TNFα (adalimumab,
etanrecept, infliximab), IL2-Rc antagonists (daclizumab, basiliximab), CD-
antagonists (alefacept, muromonab, efalizumab, abatacept), & IL1-Rc antagonist
(anakinra).

 Sulfasalazine
- It is 1st choice in RA, produces remission in active RA. Also used for IBD.
- It metabolized to 5-amino salicylic acid & sulfapyrine which (unlike to IBD)
considered the active moiety in treatment of RA.
- S/E include megaloblastic anemia, methemoglobinemia, headache, & rash.

 Penicillamine
- It is penicillin metabolite used as chelating agent for heavy metals poisoning.
- In RA, it modify immunologic process (↓RF level) by ↓IL1 generation & prevent
maturation of newly synthesized collagen.
- S/E include aplastic anemia, thrombocytopenia, nephrotic syndrome, renal
damage, & GI upset.

 Chloroquine & hydroxychloroquine

- They are antimalarial drugs, also used for RA, SLE, & sjogren syndrome.
- In RA, 65% of pts improved within 3-6months & discontinued if no effect within
6months.
- MOA: unknown exact MOA, but may be due to inhibition of DNA & RNA
synthesis in T & B-cells, stabilizing lysosomes by ↑pH & prevent degranulation of
vesicles, & inhibit PGs synthesis by inhibiting phospholipase A2.
- S/E include retinal damage (accumulated in the eye may ppt retinopathy &
produce blindness), corneal opacity, 8th nerve damage, aplastic anemia,
ototoxicity, & GI upset.

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 Gold salts
- They are water soluble salts e.g. aurothioglucose (50% elemental gold IM inj.),
Na-aurothiomalate (50% elemental gold IM inj.), & auranofin (29% elemental
gold oral tablets).
- Useful only when given early but not effective in late stage of RA where cartilage
deformity occur since they prevent further joints destruction but not repair the
existing damage.
- MOA: unknown exact MOA, but may be due to inhibition of phagocytosis & ↓
cytokines release; with inhibition of migration of PMNs at inflamed area.
- S/E mostly with IM inj. e.g. encephalopathy, peripheral neuropathy, aplastic
anemia, agranulocytosis, thrombocytopenia, nephrotic syndrome, stomatitis, &
dermatitis. While oral tablets cause less S/E with severe diarrhea.

 Immunosuppressive agents
- They are selectively suppressing immune response & prevent progression of RA.

- Cyclosporine: it is antibiotic affect T-cells esp. T-helper cells > B-cells. Its S/E
include nephrotoxicity, hepatotoxicity, hypertension, gingival hyperplasia,
hyperkalemia, & hirsutism.
- MTX: it is folate antagonist "antimetabolite" affect folate-dependent cytokines
produced by T-lymphocytes. It is 2nd important therapy of RA after biologic
modifiers, given once wkly (with folic acid after 2days to avoid S/E) for 5months.
S/E include bone marrow suppression, megaloblastic anemia, & hepatitis.
- Leflunomide: inhibit enzyme responsible for synthesis of uridine monophosphate
(UMP), which necessary for DNA & RNA synthesis in immune cells.

 Biologic modifiers (immunosuppressive mAbs):

- They are recent, effective, & expensive drugs; very useful in RA. They are
avoided in pts with history of malignancy or hepatitis since they ↓ immunity.

 Gout:
- Hyperuricemia is elevation of uric acid level above 3-7mg/dL, while gout is
clinical manifestation.

- Uric acid elevated due to high purine diet e.g. meat & vegetables, malignancy esp.
hematologic management (tumor lysis syndrome), & very rare case Lesch-Nyhan
syndrome (genetic defect ccc by hyperuricemia). Generally, 90% of uric acid
elevation related to renal excretion efficiency via excretion transporter.

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- 80% of uric acid renally cleared, in PCT there are 2 transporters; excretion
transporter (excretes 10% of uric acid) & reabsorption transporter (reabsorbs 90%
of uric acid). Uric acid is important antioxidant in the body against oxidative
stress within normal level.
- Aspirin at very high dose (toxic dose 18 tablets/day) inhibits reabsorption
transporter of uric acid (that reabsorbs 90% of uric acid) lead to ↑uric acid
excretion, but this not applicable clinically since acute toxic dose required; in
addition aspirin at therapeutic dose compete with uric acid at excretion transporter
(that excretes 10% of uric acid) causing uric acid retention, thus aspirin C/I in
gout & hyperuricemia since ppt acute gout attack.
- Deposition of uric acid as crystals at joint of big toe causes chronic gout; but
when macrophages engulf these crystals & unable to phagocytized it due to
absence of uricase enzyme in human, this resulting in acute gouty attack (rupture
of macrophages & release of inflammatory mediators ppt acute inflammation).

- Treatment of gout:
A. Hypouricemic agents (for chronic gout)
1. Uricosuric agents (↑uric acid excretion) e.g. probenecid.
2. Xanthine oxidase inhibitors (↓uric acid synthesis) e.g. allopurinol & febuxostat.
3. Recombinant uricase (↑uric acid metabolism) e.g. pegloticase.

B. Antiinflammatory agents (for acute gout) e.g. NSAIDs (esp. indomethacin &
naproxen, but not aspirin), corticosteroids (intra-articular inj.), & colchicine.

 Probenecid
- At small dose (1tablet/day), it inhibits excretion transporter of uric acid (that
excretes 10% of uric acid).
- At large dose (2 or more tablets/day), it inhibits reabsorption transporter of uric
acid (that reabsorbs 90% of uric acid).
- S/E include GI irritation & upset, aplastic anemia, & rare interstitial nephritis in
genetically predisposed pts.

- Precautions of probenecid:
a. Avoided in acute gout since probenecid causes mobilization of crystals during
acute inflammation & aggravates the acute gouty attack.
b. Avoid aspirin since it causes uric acid retention & reducing uricosuric activity of
probenecid.
c. ↑water intake to avoid crystalluria & alkalinize the urine by using Na-bicarbonate
to facilitate uric acid excretion.

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 Allopurinol (Zyloric® , Hyporic®)
- Xanthine oxidase inhibitor, t1/2 2hrs but its active metabolite oxypurinol t1/2 24hrs
thus given once daily at morning.
- It is widely used in pts with >2 acute attacks/year, malignancy, & for life span in
pts with Lesch-Nyhan syndrome.
- S/E include acute gouty attack (if necessary, give steroid or NSAIDs prior to
allopurinol but not aspirin), GI upset, aplastic anemia, allergy, skin rash, & rare
St. Johnson syndrome.
- D/I include ↓metabolism of 6MP, AZT, cyclophosphamide, probenecid,
theophylline & warfarin; also ↓excretion of penicillins & cephalosporins.

 Febuxostat
- 1st non-purine, potent, selective xanthine oxidase inhibitor, used for chronic gout
& in case of allopurinol intolerance.
- 80% absorbed orally, metabolized hepatically, & cleared with its metabolites
renally in about 5%.
- S/E include N, D, headache, & liver function abnormality.

 Pegloticase
- Recombinant porcine like-uricase, metabolizes uric acid to allantoin which more
soluble & execrable form. Used for chronic gout.
- In severe form of acute gouty attack (tophi), recombinant uricase e.g. rasburicase
(t1/2 8hrs) can be used; also pegloticase (t1/2 12days) once every 2weeks for uric
acid nephropathy.

 Colchicine
- Plant alkaloid, inhibits mitosis by binding micro-tubular protein "tubulin" &
preventing its polymerization into microtubules esp. in neutrophils &
macrophages, resulting in inhibition of leukocytes migration & phagocytosis.
- Its dose is 0.6mg tablet initially (at 1st sign of acute gouty attack) followed by
0.6mg tablet 1hr later then 0.6mg tablet every 12hrs (max. dose 2.4mg/day).
- Used for acute gout, familial mediterranean fever "FMF", behcet's disease, sarcoid
arthritis, & hepatic cirrhosis.
- S/E include GI upset (esp. diarrhea), at high doses causes liver damage,
neutropenia, aplastic anemia, alopecia, myopathy, & neuropathy.
- Caution in CV, renal, & hepatic diseases; & C/I in pregnancy.
- Colchicine inhibits insulin secretion, histamine release, body temperature, &
respiratory center; & enhances effects of CNS depressants & sympathomimetics.

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