Nonsteroidal Anti- Nonsteroidal Anti- inflammatory Drugs inflammatory Drugs • 1 1 . Non selective drugs . Non selective drugs • Salicylates e.g. Aspirin is the Salicylates e.g. Aspirin is the prototype drug prototype drug • Mechanisms of action Mechanisms of action • 1- 1- Antiinflammatory Antiinflammatory • A) Inhibit prostaglandines synthesis A) Inhibit prostaglandines synthesis through through irreversible irreversible inhibition of inhibition of cyclo-oxygenase enzymes ( Cox-1 & Cox- cyclo-oxygenase enzymes ( Cox-1 & Cox- 2). 2). • B) Interferes with the chemical B) Interferes with the chemical mediators of the kallikrein system. mediators of the kallikrein system.
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Nonsteroidal Anti- inflammatory Drugs 1. Non selective drugs1. Non selective drugs Salicylates e.g. Aspirin is the prototype drugSalicylates e.g. Aspirin.
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• 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.
• 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).
• 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
• 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 ).
• 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
• 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
• 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.
• 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.
• 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.
• 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.
• 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 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.