Nonsteroidal Anti-Nonsteroidal Anti-inflammatory Drugsinflammatory Drugs

• 11. Non selective drugs. Non selective drugs• Salicylates e.g. Aspirin is the prototype Salicylates e.g. Aspirin is the prototype

drugdrug• Mechanisms of actionMechanisms of action• 1- 1- AntiinflammatoryAntiinflammatory• A) Inhibit prostaglandines synthesis A) Inhibit prostaglandines synthesis

throughthrough irreversible irreversible inhibition of cyclo-inhibition of cyclo-oxygenase enzymes ( Cox-1 & Cox-2).oxygenase enzymes ( Cox-1 & Cox-2).

• B) Interferes with the chemical mediators B) Interferes with the chemical mediators of the kallikrein system.of the kallikrein system.

Mechanisms of action Mechanisms of action (cont.)(cont.)

• B) Inhibits the migration of B) Inhibits the migration of polymorphonuclear leukocytes to polymorphonuclear leukocytes to the site of inflammation.the site of inflammation.

• C) Anti-oxidant activity.C) Anti-oxidant activity.• D) Stabilizing lysosomesD) Stabilizing lysosomes

2- 2- AnalgesicsAnalgesics

• 1- For mild & moderate dull aching 1- For mild & moderate dull aching pain as antiinflammatorypain as antiinflammatory

• 2- Inhibits pain stimuli at 2- Inhibits pain stimuli at subcortical sitesubcortical site

3- 3- AntipyreticAntipyretic

• 1- COX inhibition in the C.N.S.1- COX inhibition in the C.N.S.

• 2- Inhibition of IL-12- Inhibition of IL-1

4- 4- AntiplateletAntiplatelet

• Irreversible inhibition of platelet Irreversible inhibition of platelet COXCOX

• Aspirin effect lasts 8-10 days ( life Aspirin effect lasts 8-10 days ( life of platelets ) of platelets )

Pharmacological actionsPharmacological actions

• A) AnalgesicA) Analgesic• B) AntipyreticB) Antipyretic• C) AntithromboticC) Antithrombotic• D)Anti-inflammatoryD)Anti-inflammatory• E) Uricosuric ( large dos)E) Uricosuric ( large dos)

Clinical usesClinical uses

• A) AnalgesicA) Analgesic• B) AntipyreticB) Antipyretic• C) Anti-inflammatoryC) Anti-inflammatory• D) Antithrombotic( cardioprotective)D) Antithrombotic( cardioprotective)• E) Chronic gouty arthritisE) Chronic gouty arthritis• F)Cancer pain in combination with opioid F)Cancer pain in combination with opioid

drugsdrugs

Adverse effects Adverse effects

• At therapeutic dosesAt therapeutic doses• A) Gastric upset ( intolerance)A) Gastric upset ( intolerance)• & gastric or duodenal ulceration& gastric or duodenal ulceration• B) Gouty arthritisB) Gouty arthritis• C) Asthma, rashesC) Asthma, rashes• D) Hepatotoxicity & renal toxicity are D) Hepatotoxicity & renal toxicity are

less frequent.less frequent.• E) Reye syndromeE) Reye syndrome

High doses or Prolonged High doses or Prolonged use of aspirinuse of aspirin

• A) Salicylism( tinnitus,vertigo, decreased A) Salicylism( tinnitus,vertigo, decreased hearing).hearing).

• B) HyperapneaB) Hyperapnea• C)Respiratory alkalosisC)Respiratory alkalosis• D) Metabolic acidosesD) Metabolic acidoses• E) HyperthermiaE) Hyperthermia• F) Gastric & doudenal ulcer & bleedingF) Gastric & doudenal ulcer & bleeding• H) Glucose intoleranceH) Glucose intolerance

ContraindicationsContraindications

• A) Pregnancy A) Pregnancy • B) Haemophilic patientsB) Haemophilic patients• C) Hypersensitivity reaction to C) Hypersensitivity reaction to

aspirinaspirin• D) Viral infections mainly in D) Viral infections mainly in

childrenchildren• E) Peptic ulcersE) Peptic ulcers

Drug-Drug interactionsDrug-Drug interactions

• Potentiates the gastric irritant Potentiates the gastric irritant effect of alcoholeffect of alcohol

• Potentiates the hypoglycaemic Potentiates the hypoglycaemic effects of oral hypoglycaemic drugseffects of oral hypoglycaemic drugs

PARACETAMOLPARACETAMOL

• Is effective only as analgesic & Is effective only as analgesic & antipyretic.antipyretic.

• Has no antiinflammatory effect.Has no antiinflammatory effect.• Has no platelet effect.Has no platelet effect.• Can be used in patients with Can be used in patients with

haemophilia or peptic ulcer or haemophilia or peptic ulcer or allergic to aspirin.allergic to aspirin.

PARACETAMOL (cont.)PARACETAMOL (cont.)

• Can be used during pregnancy.Can be used during pregnancy.• In children with viral infections.In children with viral infections.

ADVERSE EFFECTS ADVERSE EFFECTS

• Mainly on liver due to its active Mainly on liver due to its active metabolite ( N-acetyl-p-benzoquinone).metabolite ( N-acetyl-p-benzoquinone).

• At therapeutic doses increases hepatic At therapeutic doses increases hepatic enzymes.enzymes.

• At high doses causes hepatic necrosis & At high doses causes hepatic necrosis & renal necrosis.renal necrosis.

• Treatment of paracetamol toxicity with Treatment of paracetamol toxicity with N-acetylcystine (SH donor ) as life N-acetylcystine (SH donor ) as life savingsaving

2-Propionic acid 2-Propionic acid derivativesderivatives

• 1. Ibuprofen1. Ibuprofen• PharmacokineticsPharmacokinetics• Rapidly absorbed after oral Rapidly absorbed after oral

ingestion.ingestion.• Half-life 1-2 hoursHalf-life 1-2 hours• Highly bound to plasma proteinsHighly bound to plasma proteins• Excreted through kidney as Excreted through kidney as

metabolites.metabolites.

IbuprofenIbuprofen

• The same mechanism & The same mechanism & pharmacological actions of aspirin pharmacological actions of aspirin ExceptExcept that it is reversible inhibitor that it is reversible inhibitor for COX enzymesfor COX enzymes

• More potent More potent as antiinflammatory as antiinflammatory than aspirinthan aspirin

Clinical usesClinical uses

• A) AnalgesicA) Analgesic• B) AntipyreticB) Antipyretic• C) Anti-inflammatoryC) Anti-inflammatory• D)Acute gouty arthritisD)Acute gouty arthritis• E) Patent ductus arteriosusE) Patent ductus arteriosus

Preparations of IbuprofenPreparations of Ibuprofen

• Oral preparations.Oral preparations.• Topical cream for osteoarthritis.Topical cream for osteoarthritis.• A liquid gel for rapid relief of A liquid gel for rapid relief of

postsurgical dental pain.postsurgical dental pain.• Intravenous route as In patent Intravenous route as In patent

ductus arteriosus ductus arteriosus

Adverse effectsAdverse effects

• 1. Gastric upset ( less frequent 1. Gastric upset ( less frequent than aspirin ).than aspirin ).

• 2. Fluid retention2. Fluid retention• 3.Hypersensetivity reactions3.Hypersensetivity reactions• 4. Ocular disturbances4. Ocular disturbances• 5. Rare hematologic 5. Rare hematologic

effects(agranulocytosis & aplastic effects(agranulocytosis & aplastic anaemia ).anaemia ).

ContraindicationsContraindications

• 1. Peptic ulcer1. Peptic ulcer• 2. Allergic patients to aspirin2. Allergic patients to aspirin• 3. Kidney impairment3. Kidney impairment• 4.Liver diseases4.Liver diseases• 5.Pregnancy5.Pregnancy• 6.Haemophilic patients6.Haemophilic patients• The concomitant administration of The concomitant administration of

ibuprofen antagonizes the irrevesible ibuprofen antagonizes the irrevesible platelet inhibition of aspirin( limit platelet inhibition of aspirin( limit cardioprotective effect of aspirin ).cardioprotective effect of aspirin ).

Oxicam derivativesOxicam derivatives

• PiroxicamPiroxicam• TenoxicamTenoxicam

PiroxicamPiroxicam

• Mechanism of actionsMechanism of actions• A) Non-selective inhibitors to Cox1 A) Non-selective inhibitors to Cox1

& Cox2& Cox2• B) Traps free radicalsB) Traps free radicals• C) Inhibits polymorphonuclear C) Inhibits polymorphonuclear

leukocytes migrationleukocytes migration• D) Inhibits lymphocyte function.D) Inhibits lymphocyte function.

PharmacokineticsPharmacokinetics

• Well absorbed orallyWell absorbed orally• Half- Life 45 hours Half- Life 45 hours • Given once dailyGiven once daily

Adverse effectsAdverse effects

• Less frequent gastric upset (20%) .Less frequent gastric upset (20%) .• DizzinessDizziness• TinnitusTinnitus• HeadacheHeadache• AllergyAllergy

Acetic acid derivativesAcetic acid derivatives

• 1. Diclofenac1. Diclofenac• Mechanism of actionMechanism of action• A) As aspirin ,but non-selective A) As aspirin ,but non-selective

inhibitor to cox1 & Cox2.inhibitor to cox1 & Cox2.• More potent as anti-inflammatory More potent as anti-inflammatory

than analgesic and antipyreticsthan analgesic and antipyretics

PharmacokineticsPharmacokinetics

• Accumulates in synovial FluidAccumulates in synovial Fluid

Clinical usesClinical uses

• A) Any inflammatory conditionsA) Any inflammatory conditions• B) Musculoskeletal painB) Musculoskeletal pain• C) DysmenorrhoeaC) Dysmenorrhoea• D)Acute gouty arthritisD)Acute gouty arthritis• E) FeverE) Fever• F) Locally to prevent or treat post F) Locally to prevent or treat post

opthalmic inflammationopthalmic inflammation• G) A topical gel for solar keratosesG) A topical gel for solar keratoses

Adverse effectsAdverse effects

• Gastric upsetGastric upset• Renal impairmentRenal impairment• Elevation of serum Elevation of serum

aminotransferaseaminotransferase• Salt & water retentionSalt & water retention

Preparations of DiclofenacPreparations of Diclofenac

• Diclofenac with misoprostol decreases Diclofenac with misoprostol decreases upper gastrointestinal ulceration ,but upper gastrointestinal ulceration ,but result in diarrhea.result in diarrhea.

• Diclofenac with omeprazole to prevent Diclofenac with omeprazole to prevent recurrent bleeding.recurrent bleeding.

• .1% opthalmic preparation for .1% opthalmic preparation for postoperative opthalmic inflammation.postoperative opthalmic inflammation.

• A topical gel 3% for solar keratoses.A topical gel 3% for solar keratoses.• Rectal suppository as analgesic or for Rectal suppository as analgesic or for

postoperative nausea.postoperative nausea.

Preparations of DiclofenacPreparations of Diclofenac

• Oral mouth wash.Oral mouth wash.• Intramuscular preparations.Intramuscular preparations.

Selective Cox2 inhibitorsSelective Cox2 inhibitors

• Advantages : Advantages : • 1. Highly selective inhibitors to 1. Highly selective inhibitors to

cox2 enzyme.cox2 enzyme.• 2. Potent anti-inflammatory.2. Potent anti-inflammatory.• 3. Have analgesic& antipyretic3. Have analgesic& antipyretic• 4. Highly bound to plasma proteins.4. Highly bound to plasma proteins.

Selective Cox2 inhibitorsSelective Cox2 inhibitors

• 5. Lower incidence of gastric upset5. Lower incidence of gastric upset• 6. No effect on platelet aggregation 6. No effect on platelet aggregation

(cox1 )(cox1 )• 7. Renal toxicities ( they are not 7. Renal toxicities ( they are not

recommended for patients with severe recommended for patients with severe renal insufficiency)renal insufficiency)

• 8. High incidence of cardiovascular 8. High incidence of cardiovascular thrombotic events with some of them as thrombotic events with some of them as rofecoxib.rofecoxib.

Selective Cox2 inhibitorsSelective Cox2 inhibitors

• 9- They are recommended in 9- They are recommended in postoperative patients undergoing bone postoperative patients undergoing bone repair.repair.

• 10- Also, indicated in primary familial 10- Also, indicated in primary familial adenomatous polyposis, dysmenorrhea, adenomatous polyposis, dysmenorrhea,

• Acute gouty arthritis, acute Acute gouty arthritis, acute musculoskeletal pain , ankylosing musculoskeletal pain , ankylosing spondylitis.spondylitis.

CelecoxibCelecoxib

• Absorption is decreased by food.Absorption is decreased by food.• Half-life 11hoursHalf-life 11hours• Highly bound to plasma proteinsHighly bound to plasma proteins• No effect on platelet aggregationNo effect on platelet aggregation• Metabolized in liver by CYP2C9 to in Metabolized in liver by CYP2C9 to in

active metabolite.active metabolite.• Its clearance is decreased in liver Its clearance is decreased in liver

impairment.impairment.• Given twice daily.Given twice daily.

Clinical usesClinical uses

• Rheumatoid arthritisRheumatoid arthritis• OsteoarthritisOsteoarthritis

Side effectsSide effects

• Dyspepsia & heart burn.Dyspepsia & heart burn.• edema & renal adverse effects.edema & renal adverse effects.• Allergy (skin rash ).Allergy (skin rash ).

Drug interactionsDrug interactions

• With warfarrin potentiate With warfarrin potentiate its,through interfering with its its,through interfering with its metabolism. actionsmetabolism. actions

MeloxicamMeloxicam

• Relatively selective Cox2 inhibitors.Relatively selective Cox2 inhibitors.• Safer than piroxicam.Safer than piroxicam.

PharmacokineticsPharmacokinetics

• Given orally ,rectally, I.M.,I.V.Given orally ,rectally, I.M.,I.V.• Metabolized in liver to inactive Metabolized in liver to inactive

metabolites.metabolites.• Excreted in urine 50% and in feces Excreted in urine 50% and in feces

50%.50%.• Half-life 20 hours.Half-life 20 hours.• Given once daily.Given once daily.

Clinical usesClinical uses

• AnalgesicAnalgesic• Rheumatoid arthritisRheumatoid arthritis• Osteoarthritis.Osteoarthritis.

Adverse effectsAdverse effects

• Gastric upset Gastric upset • Skin rash Skin rash • HeadacheHeadache

Drug interactionsDrug interactions

• Cholestyramine increases the Cholestyramine increases the clearance of the drug .clearance of the drug .

NabumetoneNabumetone

• Well absorbed orally.Well absorbed orally.• Metabolized in liver to active Metabolized in liver to active

metabolities.metabolities.• Half-life 26 hours.Half-life 26 hours.• Taken once daily.Taken once daily.

Clinical usesClinical uses

• Rheumatoid arthritisRheumatoid arthritis• OsteoarthritisOsteoarthritis

Adverse effectsAdverse effects

• Gastric upsetGastric upset• Allergy (skin rash ).Allergy (skin rash ).• Headache Headache • TinnitusTinnitus• PseudoporphyriaPseudoporphyria• PhotosensitivityPhotosensitivity

Slow acting anti-inflammatory Slow acting anti-inflammatory drugs(Disease modifying drugs ).drugs(Disease modifying drugs ).

• 1.Used as a second line in treating 1.Used as a second line in treating arthritis.arthritis.

• 2.When the disease is progressing 2.When the disease is progressing & causing deformties.& causing deformties.

• 3. Can not repair existing 3. Can not repair existing damage,but prevent further injury.damage,but prevent further injury.

Slow acting anti-inflammatory Slow acting anti-inflammatory drugs(Disease modifying drugs ).drugs(Disease modifying drugs ).

• 4. Have no analgesic effects4. Have no analgesic effects• 5. Need weeks or months to act.5. Need weeks or months to act.

HydroxychloroquineHydroxychloroquine

• Mechanism of actionMechanism of action• 1. Suppress T lymphocytes1. Suppress T lymphocytes• 2. Decrease leukocytes action2. Decrease leukocytes action• 3. Stabilize lysosomal activity3. Stabilize lysosomal activity• 4. Inhibits DNA& RNA synthesis4. Inhibits DNA& RNA synthesis• 5. Traps free radicals5. Traps free radicals

Clinical usesClinical uses

• Arthritis used in a large doses & Arthritis used in a large doses & long durationlong duration

Adverse effectsAdverse effects

• 1. Nausea & vomiting1. Nausea & vomiting• 2. Cinchonism ( tinnitus.vertigo )2. Cinchonism ( tinnitus.vertigo )• 3. Irreversible retinal damage3. Irreversible retinal damage• 4. Ototoxicity4. Ototoxicity• 5. Corneal deposits5. Corneal deposits• 6. Allergic skin reaction6. Allergic skin reaction• 7. Hepatitis7. Hepatitis

MethotrexateMethotrexate

• Mechanism of actionMechanism of action• 1. Dihydrofolate reductase inhibitor1. Dihydrofolate reductase inhibitor• 2. Immunosuppressive agent2. Immunosuppressive agent

Adverse effectsAdverse effects

• 1. Nausea1. Nausea• 2. Mucosal ulcers2. Mucosal ulcers• 3. Bone marrow depression which 3. Bone marrow depression which

can be reversed by leucovorin.can be reversed by leucovorin.• 4. Hepatotoxicity is dose related.4. Hepatotoxicity is dose related.

Anti- TNF-alpha drugsAnti- TNF-alpha drugs

• InfliximabInfliximab• 1. Is a chimeric(25%mouse 1. Is a chimeric(25%mouse

&75%human).&75%human).• 2. Binds with high affinity to human TNF-2. Binds with high affinity to human TNF-

alpha.alpha.• 3. Given as I.V. infusion3. Given as I.V. infusion• 4. Half-life 8-12 days.4. Half-life 8-12 days.• 5. Given at 0,2,6 weeks followed by 5. Given at 0,2,6 weeks followed by

intervals of rest 4-6 weeks.intervals of rest 4-6 weeks.

InfliximabInfliximab

• Improvement reaches up to 60%Improvement reaches up to 60%• Can be used in combination with Can be used in combination with

methotrexate reduce the methotrexate reduce the prevalence of human antichimeric prevalence of human antichimeric antibodies.antibodies.

Clinical usesClinical uses

• Rheumatoid arthritisRheumatoid arthritis• Ulcerative colitisUlcerative colitis• PsoriasisPsoriasis• Psoriatic arthritisPsoriatic arthritis• Giant cell arteritisGiant cell arteritis• SarcoidosisSarcoidosis

Adverse effectsAdverse effects

• 1. Upper respiratory tract infections.1. Upper respiratory tract infections.• 2. Cough.2. Cough.• 3. Nausea.3. Nausea.• 4. Headache.4. Headache.• 5. Rash.5. Rash.• 6- Activate latent tuberculosis6- Activate latent tuberculosis• 7- Infusion site reaction7- Infusion site reaction

LeflunomideLeflunomide

• 1. Immunosuppressive drug used in 1. Immunosuppressive drug used in the treatment of R.A.the treatment of R.A.

• 2. Undergoes rapid conversion in 2. Undergoes rapid conversion in intestinal mucosa & plasma to intestinal mucosa & plasma to active metabolities.active metabolities.

PharmacokineticsPharmacokinetics

• Orally effectiveOrally effective• Half-life 15 daysHalf-life 15 days• Highly bound to plasma proteinsHighly bound to plasma proteins• Cholestyramine increases its Cholestyramine increases its

clearanceclearance

Mechanism of actionMechanism of action

• 1. Inhibits dihydroorotate 1. Inhibits dihydroorotate dehydrogenase which lead to dehydrogenase which lead to inhibition of ribonucleotide inhibition of ribonucleotide synthesis & arrest the stimulated synthesis & arrest the stimulated cells in G1 phase.cells in G1 phase.

• 2. Inhibits T cell proliferation & 2. Inhibits T cell proliferation & production of autoantibodies by production of autoantibodies by ββ cells.cells.

Mechanism ( cont.)Mechanism ( cont.)

• Increase interleukin 10 receptorIncrease interleukin 10 receptor• mRNA.mRNA.• Decrease interleukin 8 receptor Decrease interleukin 8 receptor

type A m RNA.type A m RNA.• Decrease TNF-Decrease TNF-αα- dependent NFkB- dependent NFkB

Clinical usesClinical uses

• Rheumatoid arthritisRheumatoid arthritis• Can be given with methtrxateCan be given with methtrxate

Adverse effectsAdverse effects

• DiarrheaDiarrhea• Elevated liver enzymesElevated liver enzymes• Mild alopeciaMild alopecia• Weight gainWeight gain• Increased blood pressureIncreased blood pressure• Leukopenia & thrombocytopeniaLeukopenia & thrombocytopenia• Contraindicated in pregnancyContraindicated in pregnancy

SulfASALAZINESulfASALAZINE

• MECHANISM OF ACTIONMECHANISM OF ACTION• Through its active metabolite Through its active metabolite

sulfapyridine &the parent drug sulfapyridine &the parent drug itself.itself.

• Suppression of T cell .Suppression of T cell .• Inhibition of B cell proliferationInhibition of B cell proliferation

PharmacokineticsPharmacokinetics

• Only 10-20% of orally administered Only 10-20% of orally administered sulfa is absorbed.sulfa is absorbed.

• Fraction undergoes enterohepatic Fraction undergoes enterohepatic circulation into the bowel.circulation into the bowel.

• Reduced by intestinal bacteria to Reduced by intestinal bacteria to liberate 5-aminosalicylic acid liberate 5-aminosalicylic acid

Pharmacokinetics Pharmacokinetics

• And sulfapyridine which is well absorbed And sulfapyridine which is well absorbed while 5-aminosalicylic remains while 5-aminosalicylic remains unabsorbed.unabsorbed.

• Excreted partly unchanged as Excreted partly unchanged as sulfasalazine in urine sulfasalazine in urine

• Sulfapyridine metabolized in liver by Sulfapyridine metabolized in liver by acetylation &hydroxylation acetylation &hydroxylation

• Half-life 6-17 hours.Half-life 6-17 hours.

Clinical usesClinical uses

• Rheumatoid arthritis reduce the Rheumatoid arthritis reduce the rate of appearance of new joint rate of appearance of new joint damage.damage.

• Juvenile chronic arthritisJuvenile chronic arthritis• Ankylosing spondylitis.Ankylosing spondylitis.

Adverse effectsAdverse effects

• Nausea, vomitingNausea, vomiting• HeadacheHeadache• Skin rashSkin rash• Hemolytic anemiaHemolytic anemia• MethemoglobinemiaMethemoglobinemia• Reversible infertility in men Reversible infertility in men • Neutropenia & thrombocytopenia (rare)Neutropenia & thrombocytopenia (rare)