Cortex

HypothalamusPAGThalamus

Opioids

NRMNRPG LC

Dorsal horn

Opioids

Opioids

DLF

5-HTEnkephalin

Noradrenaline

Nociceptiveafferent fibres (periphery)

+

+

++

+ +

+/-

+/-

– – –

–

The descending control system, showing postulat The descending control system, showing postulat ed sites of action of opioids on pain transmission. ed sites of action of opioids on pain transmission.

Opioids excite neurons in the Opioids excite neurons in the periaqueductal grey periaqueductal greymattermatter ( (PAGPAG ) and in the ) and in the nucleus reticularis nucleus reticularis paragig paragigantocellularisantocellularis ( (NRPGNRPG ), which in turn project to the r ), which in turn project to the r

ostroventral medulla, which includes the ostroventral medulla, which includes the nucleus r nucleus r aphe magnus aphe magnus ( (NRMNRM - - ). From the NRM, 5 HT and enk - - ). From the NRM, 5 HT and enk

- ephalin containing neurons run to the- ephalin containing neurons run to the substantia g substantia gelatinosaelatinosa of the dorsal horn, and exert an inhibitor of the dorsal horn, and exert an inhibitor

y influence on transmission. Opioids also act direc y influence on transmission. Opioids also act direc tly on the dorsal horn. The tly on the dorsal horn. The locus ceruleus locus ceruleus ( (LCLC ) sen ) sen ds noradrenergic neurons to the dorsal horn, whic ds noradrenergic neurons to the dorsal horn, whic

h also inhibit transmission. The pathways shown i h also inhibit transmission. The pathways shown i -n this diagram represent a considerable over simpl -n this diagram represent a considerable over simpl

ification, but depict the general organisation of the ification, but depict the general organisation of the supraspinal control mechanisms. Light pink boxes supraspinal control mechanisms. Light pink boxes

represent areas rich in opioid peptides. ( represent areas rich in opioid peptides. (DLFDLF = = dordor solateral funiculus solateral funiculus ) (For more detailed information ) (For more detailed information

, see Fields & Basbaum 1989) , see Fields & Basbaum 1989)

Non-Steroidal Anti-Inflammatory Drugs Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)(NSAIDs)

Three major effects of NSAIDs:Three major effects of NSAIDs: Anti-inflammatory effect (edema=congestion, ↑ Anti-inflammatory effect (edema=congestion, ↑

of blood flow in the blood vessels, vasodilation, of blood flow in the blood vessels, vasodilation, leakage of the fluid from the vessels & migration leakage of the fluid from the vessels & migration of the immune component) of the immune component)

Analgesic effectAnalgesic effect Antipyretic effect (only can be seen during the Antipyretic effect (only can be seen during the

increased body temperature)increased body temperature)

The effect is due to the inhibition of arachidonate The effect is due to the inhibition of arachidonate cycloxygenase (COX) which inhibit PG and cycloxygenase (COX) which inhibit PG and thromboxane production (mediators of pain and thromboxane production (mediators of pain and inflammation) inflammation)

Cycloygenase (COX)Cycloygenase (COX)2 main types2 main types1.1. COX 1COX 1 - constitutive enzyme- constitutive enzyme - regulate tissue homeostasis- regulate tissue homeostasis

2.2. COX 2COX 2 (related to inflammation and it is time (related to inflammation and it is time dependent)dependent)

- inducible enzyme- inducible enzyme - produced in inflammatory cells (when cell are - produced in inflammatory cells (when cell are

activated)activated) - produced PG (mediators of inflammation)- produced PG (mediators of inflammation)

- COX 3 (less important, the pharmacological action - COX 3 (less important, the pharmacological action is not clear)is not clear)

NSAIDs inhibit both enzymes . The NSAIDs inhibit both enzymes . The anti-inflammatory & analgesic effects anti-inflammatory & analgesic effects are due to COX 2 inhibition.are due to COX 2 inhibition.

Side effects is due to COX 1 Side effects is due to COX 1 inhibition..GIT. (now, there are drugs inhibition..GIT. (now, there are drugs that are selective to inhibit COX 2)that are selective to inhibit COX 2)

Pharmacological action of NSAIDsPharmacological action of NSAIDs- Antipyretic actionAntipyretic action Body temp. is regulated by “thermostat” center in Body temp. is regulated by “thermostat” center in

hypothalamus that make sure the balance between hypothalamus that make sure the balance between heat gain and heat loss. NSAIDs can reset this heat gain and heat loss. NSAIDs can reset this center by vasodilatation and sweating→ heat losscenter by vasodilatation and sweating→ heat loss

Mechanism of antipyretic:Mechanism of antipyretic: - inhibition of PG in hypothalamus- inhibition of PG in hypothalamus - during inflammation, IL-1 (pyrogen) stimulates PGE - during inflammation, IL-1 (pyrogen) stimulates PGE

production by induction of COX 2 and this elevate production by induction of COX 2 and this elevate body temp.body temp.

NoteNote/during inflammation, bacterial endotoxins /during inflammation, bacterial endotoxins cause the release IL-1 (pyrogen), which stimulate cause the release IL-1 (pyrogen), which stimulate the generation of PG E in the hypothalamus, & this the generation of PG E in the hypothalamus, & this in turn will cause the elevation of the set point for in turn will cause the elevation of the set point for temperaturetemperature

- Analgesic actionAnalgesic action• Mainly effective in inflammatory pain Mainly effective in inflammatory pain

& tissue damage.& tissue damage.• Useful in arthritis, bursitis, muscle Useful in arthritis, bursitis, muscle

pain, vasceral pain, toothache, pain, vasceral pain, toothache, dysmenorrhea, postpartum pain & dysmenorrhea, postpartum pain & metastasis bone cancer.metastasis bone cancer.

• Central effect in the spinal cordCentral effect in the spinal cord

Note: PG effects BDK & 5-HTNote: PG effects BDK & 5-HT

Anti-inflammatory actionAnti-inflammatory action- Inhibit the inflammation caused by Inhibit the inflammation caused by

the interaction between Ag and Ab the interaction between Ag and Ab (e.g. rheumatoid arthritis) by (e.g. rheumatoid arthritis) by reducing the inflammatory reducing the inflammatory component involving COX-2 actioncomponent involving COX-2 action

- vasodilatation→ facilitate the - vasodilatation→ facilitate the production of histamin→ ↑ the production of histamin→ ↑ the permeability of postcapillary venule permeability of postcapillary venule → edema→ edema

- edema- edema - pain- pain

Mechanism of action of NSAIDsMechanism of action of NSAIDs The main action is to inhibit COX-2 (metabolite of The main action is to inhibit COX-2 (metabolite of

arachidonic acid)arachidonic acid) inhibition COX-1 instantaneously but reversiblyinhibition COX-1 instantaneously but reversibly The inhibition of COX-2 is time dependent (↑ by The inhibition of COX-2 is time dependent (↑ by

time)time) - the main action of COX- gives PGG2- the main action of COX- gives PGG2 - perioxidase action-converts PGG2 to PGH2- perioxidase action-converts PGG2 to PGH2

Note/Note/ NSAIDs only inhibit the main action (not the NSAIDs only inhibit the main action (not the perioxidase action)perioxidase action)

Other anti-inflammatory mechanisms:Other anti-inflammatory mechanisms:- oxygen radical (produced by neutrophil and - oxygen radical (produced by neutrophil and

macrophages) scavenging→ ↓ tissue dammagemacrophages) scavenging→ ↓ tissue dammage- Inhibit the expression of transcription factor NF-κ B-- Inhibit the expression of transcription factor NF-κ B-

aspirin (transcription of gene inflammatory aspirin (transcription of gene inflammatory mediator) → no inflammatory intermediatemediator) → no inflammatory intermediate

Common unwanted effects of NSAIDsCommon unwanted effects of NSAIDsGIT disturbancesGIT disturbances- Most commonMost common- Caused by COX-1 inhibition (affect the mucosal Caused by COX-1 inhibition (affect the mucosal

lining of the GIT)lining of the GIT) ((PGE provide a cytoprotective effect against gastric ulcer by PGE provide a cytoprotective effect against gastric ulcer by

inhibition of gastric acid secretion)inhibition of gastric acid secretion)- Common effects:Common effects: dyspepsia, dyspepsia, diarrhea & constipation (depends on the agent), diarrhea & constipation (depends on the agent), nausea & vomiting, nausea & vomiting, gastric bleeding,gastric bleeding, ulceration ulceration

Treatment of GI disturbance is by giving misoprostol Treatment of GI disturbance is by giving misoprostol (PG analog)(PG analog)

COX-2 selective agent produces less gastric COX-2 selective agent produces less gastric damagedamage

Skin reaction Skin reaction ((mefenamic acid & sulindacmefenamic acid & sulindac)) 22ndnd most common most common Mild rashes, urticaria & photosensitive Mild rashes, urticaria & photosensitive

reaction (very rare)reaction (very rare)

Adverse renal effectsAdverse renal effects

Acute renal insufficiency Acute renal insufficiency (with chronic consumption & high (with chronic consumption & high

dose) dose) - occur through PGE2, PGI2 & - occur through PGE2, PGI2 & prostacyclin (maintain renal blood flow) prostacyclin (maintain renal blood flow) inhibition.inhibition.

Analgesic nephropathy Analgesic nephropathy (with chronic consumption & high (with chronic consumption & high

dose) dose) – chronic nephritis & renal papillary – chronic nephritis & renal papillary necrosisnecrosis

Other unwanted effects (< common)Other unwanted effects (< common)

Bone marrow disturbanceBone marrow disturbance

Liver disorder (likely occur if there is Liver disorder (likely occur if there is renal impairment)renal impairment)

Precipitate asthma-(especially with Precipitate asthma-(especially with aspirin)aspirin)

Table of classification…wantedTable of classification…wanted

Some important NSAIDsSome important NSAIDsSalicylates (irritating)Salicylates (irritating) Most common is aspirinMost common is aspirin Pharmacological propertyPharmacological property 1. analgesia1. analgesia - relief low intensity pain (superficial - relief low intensity pain (superficial

rather than visceral pain e.g. headache rather than visceral pain e.g. headache myalgia)myalgia)

- via peripheral action- via peripheral action 2. antipyresis2. antipyresis - lower elevated body temp. (rapid & - lower elevated body temp. (rapid &

effective)effective) - toxic dose- sweating & increase - toxic dose- sweating & increase

dehydrationdehydration

3. Neurological effect3. Neurological effect - CNS toxicity-stimulation followed by depression - CNS toxicity-stimulation followed by depression

(action of Ach & nicotine)(action of Ach & nicotine) - confusion, dizziness, tinnitus, high-tone deafness, - confusion, dizziness, tinnitus, high-tone deafness,

delirium, psychosis, stupor delirium, psychosis, stupor (nearly unconscious)(nearly unconscious) & coma. & coma. - nausea, vomiting- through the stimulation of - nausea, vomiting- through the stimulation of

medullary CTZmedullary CTZ

4. Rispiration4. Rispiration

- increase O- increase O22 consumption & CO consumption & CO2 2 productionproduction

- stimulate medulla respiratory center → - stimulate medulla respiratory center → hyperventilationhyperventilation

- toxic effect- respiratory depression & circulatory - toxic effect- respiratory depression & circulatory collapsecollapse

- respiratory acidosis (↑ CO- respiratory acidosis (↑ CO2 2 production)production)

5. Acid-base balance & electrolyte5. Acid-base balance & electrolyte

- disturb acid-base balance & electrolyte - disturb acid-base balance & electrolyte patternpattern

6. Cardiovascular effect6. Cardiovascular effect

- Depress circulation-directly or by central - Depress circulation-directly or by central vasomotor paralysisvasomotor paralysis

- high dose cause non-cardiogenic pulmonary - high dose cause non-cardiogenic pulmonary edema.edema.

7. GIT effects7. GIT effects

- epigastric pain, nausea & vomiting- epigastric pain, nausea & vomiting

- high dose- gastric ulceration, execerbation of - high dose- gastric ulceration, execerbation of peptic ulcer, GI haemorrhage, & erosive peptic ulcer, GI haemorrhage, & erosive gastritisgastritis

8. Hepatic & renal effect8. Hepatic & renal effect

- high dose cause hepatic injury (>160 - high dose cause hepatic injury (>160 μgm/ml)μgm/ml)

- salt & water retention- salt & water retention

- reduced renal function (in patient with - reduced renal function (in patient with CHF or hypovolemia)]CHF or hypovolemia)]

9. Uricosuric effect9. Uricosuric effect

- in low dose (1-2 gm/day)- ↓ urate - in low dose (1-2 gm/day)- ↓ urate excretion (↑ plasma urate conc.), block excretion (↑ plasma urate conc.), block probancid & other uricosuric agentsprobancid & other uricosuric agents

- intermediate dose (2-4 gm/ml- intermediate dose (2-4 gm/ml

- high dose (>5 gm/ day)-uricosuria (↓ - high dose (>5 gm/ day)-uricosuria (↓ plasma urate conc.)plasma urate conc.)

10. Effect on blood10. Effect on blood (used as (used as antiplatelet agent)antiplatelet agent)

- prolong bleeding time (irriversible - prolong bleeding time (irriversible acetylation of platelet cycloxygenase acetylation of platelet cycloxygenase →↓ TXA→↓ TXA

- should be avoided in sever hepatic - should be avoided in sever hepatic damage, hypothrombinaemea, Vit. K damage, hypothrombinaemea, Vit. K deficiency or hemophilia deficiency or hemophilia (→ severe (→ severe

bleeding)bleeding)

- -

11. Metabolic effect11. Metabolic effect - oxidative phosphorylation (inhibit ATP - oxidative phosphorylation (inhibit ATP

reaction)reaction) - carbohydrate metabolism (in high - carbohydrate metabolism (in high

dose → hyperglycemia, glucosuria, dose → hyperglycemia, glucosuria, deplet liver & muscle glycogen, glucose deplet liver & muscle glycogen, glucose metabolism blood glucose conc.)metabolism blood glucose conc.)

- Nitrogen metabolism (-ve a.a in urine)- Nitrogen metabolism (-ve a.a in urine) - fat metabolism- lipogenesis by the - fat metabolism- lipogenesis by the

incorporation of acetate into FA→ ↓ FFA incorporation of acetate into FA→ ↓ FFA in plasma, accumulation of fats in the in plasma, accumulation of fats in the musclesmuscles

12. Endocrine effect12. Endocrine effect

- high dose – stimulate steroid - high dose – stimulate steroid secretionsecretion

- long term use- ↓ thyroid uotake & - long term use- ↓ thyroid uotake & clearance of iodineclearance of iodine

13. Local irritant effect13. Local irritant effect

- by destroying endothelial cells- by destroying endothelial cells

Pharmacokinetics:Pharmacokinetics: rapidly absorbed in the stomach & rapidly absorbed in the stomach &

upper small intestine after oral upper small intestine after oral intakeintake

rapidly absorbed from the skinrapidly absorbed from the skin Metabolites- SA, Phenolic glucoronide Metabolites- SA, Phenolic glucoronide

& acyl glucoronide& acyl glucoronide Excreted in urineExcreted in urine Aspirin t Aspirin t ½ ½ 15 min.s15 min.s

Therapeutic uses:Therapeutic uses: Systemic useSystemic use - sodium salicylate, aspirin, salsalate (hydrolyzed to SA), - sodium salicylate, aspirin, salsalate (hydrolyzed to SA),

choline salicylate, Mg. salicylatecholine salicylate, Mg. salicylate - diflunisal- potent anti-infl. agent than aspirin. Used in - diflunisal- potent anti-infl. agent than aspirin. Used in

osteoarithritis, musculoskeletal strains. Not to be osteoarithritis, musculoskeletal strains. Not to be converted to SA, cause less S/E, less antiplatelate, no converted to SA, cause less S/E, less antiplatelate, no anti-pyretic effect (poorly absorbed by the CNS)anti-pyretic effect (poorly absorbed by the CNS)

Local usesLocal uses -- mesalamine- used locally in inflamatorry bowel mesalamine- used locally in inflamatorry bowel

syndrome, ulcerative colitis (not effective orally, poorly syndrome, ulcerative colitis (not effective orally, poorly absorbed from the stomach & small intestineabsorbed from the stomach & small intestine

- sulfasalazine- contains mesalazine (IBS, ulcerative - sulfasalazine- contains mesalazine (IBS, ulcerative colitis)colitis)

ToxicityToxicity Salicylism Salicylism ((mild salicylate poisoning/intoxicationmild salicylate poisoning/intoxication))

- - headache, dizziness, blurred vision, mental headache, dizziness, blurred vision, mental confusion, lassitude, drawsiness, sweating, thirsty, confusion, lassitude, drawsiness, sweating, thirsty, hyperventilation, nausea, vomiting, & diarrhea.hyperventilation, nausea, vomiting, & diarrhea.

- sever intoxication-CNS disturbance (coma) , skin - sever intoxication-CNS disturbance (coma) , skin eruption, alteration in the acid- base balance & eruption, alteration in the acid- base balance & dehydration. in children- hyperpyrexia dehydration. in children- hyperpyrexia

- Haemorrhage – occational (in adult at therapeutic - Haemorrhage – occational (in adult at therapeutic dose)dose)

- toxicity in adults- non-allergic pulmonary odema, - toxicity in adults- non-allergic pulmonary odema, neurological abnormalities, acid-bace abnormality, neurological abnormalities, acid-bace abnormality, prolonged prothrombin timeprolonged prothrombin time

- treatment – cardiovascular/ respiratory support & - treatment – cardiovascular/ respiratory support & cprrect acid-base balancecprrect acid-base balance

Para-aminophenol derivativePara-aminophenol derivative Paracetamol (PCT) (acetaminophen)Paracetamol (PCT) (acetaminophen)Pharmacological propertyPharmacological property - analgesic and antipyretic similar to aspirin - analgesic and antipyretic similar to aspirin

(in the brain no peroxide conc. → effective)(in the brain no peroxide conc. → effective) - weak anti-inflammatory, week inhibitor of - weak anti-inflammatory, week inhibitor of

COX due to the peroxides produced during COX due to the peroxides produced during inflammationinflammation

- no effect on CV, Respiratory system, acid-- no effect on CV, Respiratory system, acid-base balance & GITbase balance & GIT

- no effect o blood- no effect o blood - quite safe- no effect on the platelet- quite safe- no effect on the platelet

PharmacokinaticsPharmacokinatics Rapid & complete absorption from the Rapid & complete absorption from the

GIT (unlike aspirin)GIT (unlike aspirin) Hepatic conjugation with glucoronic Hepatic conjugation with glucoronic

acid (60%) , sulfuric acid (30%) and acid (60%) , sulfuric acid (30%) and cystein 5%.cystein 5%.

Excreted in urine t Excreted in urine t ½ ½ 2 hr.s2 hr.s CYP 450-mediated N-hydroxylation to CYP 450-mediated N-hydroxylation to

form N-acetyl-benzoquinoneimine form N-acetyl-benzoquinoneimine (NAB)(NAB)

Therapeutic useTherapeutic useAnalgesic /antipyretic substitute for Analgesic /antipyretic substitute for

aspirinaspirin

ToxicityToxicity- Well toleratedWell tolerated- Occasional skin rash & allergy in certain Occasional skin rash & allergy in certain

individuals.individuals.- Overdose - hepatotoxicity (fetal hepatic Overdose - hepatotoxicity (fetal hepatic

necrosis), also renal tubular necrosis, necrosis), also renal tubular necrosis, hypoglycemiahypoglycemia & coma & coma

Note / the dose should >4gm/day (8 Note / the dose should >4gm/day (8 tab/day) → glucoronic acid will be tab/day) → glucoronic acid will be saturated→ liver damage and death within saturated→ liver damage and death within 2-4 days2-4 days

Mechanism of hepatotoxicityMechanism of hepatotoxicity- Involve the production of metabolic Involve the production of metabolic

intermediate (NAB) N-acetyl-intermediate (NAB) N-acetyl-benzoquinoneimine (reactive electrophilic benzoquinoneimine (reactive electrophilic electrophilic )electrophilic )

- In normal condition- NAB is conjugated In normal condition- NAB is conjugated with GSH (glutation) & metabolized to with GSH (glutation) & metabolized to mercapturic acid & excreted.mercapturic acid & excreted.

- In overdose- GSH depleted & hepatocytes In overdose- GSH depleted & hepatocytes become susceptible to oxidant injury & become susceptible to oxidant injury & reactive intermediate can bind covalently reactive intermediate can bind covalently to macromolecules & cause dysfunction of to macromolecules & cause dysfunction of enzymeenzyme→ hepatotoxicity→ hepatotoxicity

- Early symptoms- nausea, vomiting, Early symptoms- nausea, vomiting, anorexia, diaphoresis (sweating) anorexia, diaphoresis (sweating) abdominal pain…..persist for week or abdominal pain…..persist for week or more.more.

- Hepatic damage – within 2-4 daysHepatic damage – within 2-4 days- Increased aminotransferase & Increased aminotransferase &

bilirubin, prolong prothrombin timebilirubin, prolong prothrombin time- Antidote- administration of sulfydryl Antidote- administration of sulfydryl

compounds (acetylcystein, compounds (acetylcystein, methionine) replenish GSH (inactivate methionine) replenish GSH (inactivate intermediate by conjugation) intermediate by conjugation)

Indole & indene acetic acidsIndole & indene acetic acidsIndomethacineIndomethacineAnalgesic, anti-inflammatory and antipyreticAnalgesic, anti-inflammatory and antipyretic- Potent inhibitor of COXPotent inhibitor of COX- It also inhibitmotility of polymorphnuclear It also inhibitmotility of polymorphnuclear

leukocytesleukocytes- Uncouples oxidative phosphorylation & Uncouples oxidative phosphorylation &

depress mucopolysaccharide biosynthesisdepress mucopolysaccharide biosynthesis- Rapid & complete absorptionRapid & complete absorption- Metabolized by O-demethylation (50%), Metabolized by O-demethylation (50%),

glucoronic acid conjugation (10%) & N-glucoronic acid conjugation (10%) & N-deacylation (small portion)deacylation (small portion)

- Plasma t Plasma t ½ ½ 2.5 hr.s2.5 hr.s

- Propancid can increase indomethacine Propancid can increase indomethacine plasma conc.(block tubular excretion)plasma conc.(block tubular excretion)

- Used as antipyretic in certain Used as antipyretic in certain conditions..long term fever (eg. Fever in conditions..long term fever (eg. Fever in Hodgkin's disease)Hodgkin's disease)

- Adverse effects- Adverse effects- 1.1. GI disturbanceGI disturbance (gastric ulcer, (gastric ulcer,

pancreatitis… pancreatitis… give proton pump inhibitor e.g omprazolegive proton pump inhibitor e.g omprazole)) 2. CNS effects2. CNS effects (long term usage lead to (long term usage lead to

sever frontal headache , vertigo, dizziness, sever frontal headache , vertigo, dizziness, lightheadedness, depression, psychosis, lightheadedness, depression, psychosis, hallucination, mental confusion and suicidal hallucination, mental confusion and suicidal attempt.attempt.

3. Haemopoietic reactions3. Haemopoietic reactions (leucopenia, (leucopenia, thrombocytopenia, aplastic anemia, thrombocytopenia, aplastic anemia, impaired platelet function, impaired platelet function,

SulindacSulindac- Less potent than indomethacineLess potent than indomethacine- Prodrug- converted to sulfide metabolite (500 Prodrug- converted to sulfide metabolite (500

times >potent vs. sulindac)times >potent vs. sulindac)- Oxidized to sulfone & then reduced to sulfide Oxidized to sulfone & then reduced to sulfide - t t ½ ½ 7 hr.s7 hr.s- Sulfide metabolite t Sulfide metabolite t ½ ½ 18 hr.s18 hr.s- Therapeutic uses- rheumatoid arthritis, Therapeutic uses- rheumatoid arthritis,

osteoarthritis, ankylosing spondylitis (chronic osteoarthritis, ankylosing spondylitis (chronic inflammation of the spine and the sacroiliac inflammation of the spine and the sacroiliac joints) , acute goutjoints) , acute gout

- S/E: less vs. indomethacine, mild GIT (nausea , S/E: less vs. indomethacine, mild GIT (nausea , abdominal pain) & CNS effects (drowsiness, abdominal pain) & CNS effects (drowsiness, dizziness, headache, nervousness, skin rash, dizziness, headache, nervousness, skin rash, pruritis)pruritis)

EtodolacEtodolac- Selective COX-2 Selective COX-2 - Rapidly & completely absorbed orallyRapidly & completely absorbed orally- t t ½ ½ 7 hr.s7 hr.s

- Uses- postoperative analgesia (6-8 Uses- postoperative analgesia (6-8 hr.s of analgesia), osteo and hr.s of analgesia), osteo and rheumatoid arthritisrheumatoid arthritis

- Less GI toxicityLess GI toxicity- S/E: skin rash & CNS effectsS/E: skin rash & CNS effects

Heteroaryl acetic acidHeteroaryl acetic acid Tolmetin & ketorolac (heteroacyl acetic Tolmetin & ketorolac (heteroacyl acetic

derivatives)derivatives) Diclofenac (phenylacetic acid derivatives)Diclofenac (phenylacetic acid derivatives) TolmetinTolmetin- Effective anti-inflammatoryEffective anti-inflammatory- t t ½ ½ 5 hr.s5 hr.s- Metabolized to carboxylic acidMetabolized to carboxylic acid- Uses- osteo & rheumatoid, juvenile Uses- osteo & rheumatoid, juvenile

arthritisarthritis- Better toleratedBetter tolerated- S/E: GI effects (most common), CNS effect S/E: GI effects (most common), CNS effect

less vs. ASA (tinnitus, vertigo, deafness)less vs. ASA (tinnitus, vertigo, deafness)

KetorolacKetorolac

Potent analgesic, moderate anti-Potent analgesic, moderate anti-inflammatoryinflammatory

Used parenterally by IV, damaged by Used parenterally by IV, damaged by gasric aciditygasric acidity

Inhibit PG biosynthesis & platelet Inhibit PG biosynthesis & platelet aggregation, promotes gastric aggregation, promotes gastric ulcerationulceration

Uses- postoperative pain, short term Uses- postoperative pain, short term pain (not more than 5 days pain)pain (not more than 5 days pain)

Topical –allergic conjuctivitis & ocular Topical –allergic conjuctivitis & ocular inflammation inflammation

DiclofenacDiclofenac- non-selective COX inhibitornon-selective COX inhibitor- Inhibit COX, reduce arachidonate in Inhibit COX, reduce arachidonate in

leukocytesleukocytes- t t ½ ½ 1-2 hr.s1-2 hr.s- Metabolized by CYP450 2C into 4-Metabolized by CYP450 2C into 4-

hydroxydiclofenachydroxydiclofenac- Uses- rheumatoid & osteoarthritis, Uses- rheumatoid & osteoarthritis,

ankylosing spondylitisankylosing spondylitis- S/E: GI disturbance (common), CNS S/E: GI disturbance (common), CNS

effects, skin, rashes, allergy, fluid effects, skin, rashes, allergy, fluid retention, edemaretention, edema

Arylpropionic acid Arylpropionic acid effective COX inhibitor, better tolerated in terms of adverse effective COX inhibitor, better tolerated in terms of adverse

effects vs. ASA & indomethacineeffects vs. ASA & indomethacine

Ibuprofen, naproxen (20x > ASA), flurbiprofen, fenoprofen Ibuprofen, naproxen (20x > ASA), flurbiprofen, fenoprofen ( equipotent with ASA), ketoprofen & oxaprozin( equipotent with ASA), ketoprofen & oxaprozin

Under investigation: carprofen, piprofen, indobufen & Under investigation: carprofen, piprofen, indobufen & tiaprofenic acidtiaprofenic acid

IbuprofenIbuprofen- The 12st memberThe 12st member- Rapidly absorbed after oralRapidly absorbed after oral- t t ½ ½ 2 hr.s2 hr.s- Rapid & complete excretionRapid & complete excretion- Metabolites- hydroxylated & carboxylated compoundsMetabolites- hydroxylated & carboxylated compounds- Uses- in GI intolerance for other analgesicsUses- in GI intolerance for other analgesics- S/E: less epigastric pain, nausea, heartburn, “fullness” vs. S/E: less epigastric pain, nausea, heartburn, “fullness” vs.

ASA & indomethacineASA & indomethacine

NaproxenNaproxen- Fully absorbed from the GIT- Fully absorbed from the GIT- Metabolism- 6-demethylation, excretion as - Metabolism- 6-demethylation, excretion as

glucoronideglucoronide- S/E: equal to indomethcine but better tolerated - S/E: equal to indomethcine but better tolerated

(nausea, vomiting, dizziness, CNS effect)(nausea, vomiting, dizziness, CNS effect)

FenoprofenFenoprofen - Equally potent as ASAEqually potent as ASA- Metabolic transfprmationMetabolic transfprmation- Into 4-hydroxy analogInto 4-hydroxy analog- t t ½ ½ 3 hr.s3 hr.s- GI effects- abnormal discomfort & dyspepsia, GI effects- abnormal discomfort & dyspepsia,

less intenseless intense- Also CNS effectsAlso CNS effects

FlurbiprofenFlurbiprofen- Used as antiplatelet in EuropeUsed as antiplatelet in Europe- t t ½ ½ 6 hr.s6 hr.s- Metabolized by hydroxylation & conjugationMetabolized by hydroxylation & conjugation- Potential for soft tissue treatmentPotential for soft tissue treatment- Adminstration by transcutaneous patchAdminstration by transcutaneous patch

KetoprofenKetoprofen- Stabelize lysosomal membranes & antagonize BDK Stabelize lysosomal membranes & antagonize BDK

actionaction- t t ½ ½ 2 hr.s2 hr.s- Conjugate with glucoronic acidConjugate with glucoronic acid- S/E: common GI effects but mild & less frequentS/E: common GI effects but mild & less frequent- Also cause fluid retention & increase plasma Also cause fluid retention & increase plasma

creatininecreatinine- Excreted in urineExcreted in urine