Antipyretic analgesicAntipyretic analgesic Nonsteroidal anti-inflammatory Nonsteroidal anti-inflammatory

drugsdrugs

Anton KohútAnton Kohút

Pain perceptionPain perception

AnalgesicsAnalgesics

Salicylates- AspirinSalicylates- Aspirin ParacetamolParacetamol Other nonsteroidal Other nonsteroidal

antiinflammatory drugs (NSAIDs)antiinflammatory drugs (NSAIDs) IV. Opioid analgesicsIV. Opioid analgesics

AspirinAspirin

Salicin from Willow Bark.Salicin from Willow Bark.

Biosynthesis of eicosanoidsBiosynthesis of eicosanoids

COX1 and COX2

Mechanism of action of Mechanism of action of aspirine aspirine

SalicylatesSalicylates

DrugsDrugs Acetylsalicylic Acetylsalicylic

acid (aspirin)acid (aspirin) DiflunisalDiflunisal MethylsalicylateMethylsalicylate SulfasalazineSulfasalazine Sodium salicylate Sodium salicylate

Pharmacological Pharmacological actionsactions

AnalgeticAnalgetic Antipyretic Antipyretic AntiinflammatoryAntiinflammatory AntiagregatoryAntiagregatory AnticancerogenicAnticancerogenic

Side effects of salicylatesSide effects of salicylates Gastrointestinal Gastrointestinal eeffectsffects.. Hepatic and Renal EffectsHepatic and Renal Effects Neurological effectsNeurological effects (high doses stimulation (high doses stimulation

followed by depression.followed by depression. Acid-Base balanceAcid-Base balance RespirationRespiration.. Salicylates stimulate respiration Salicylates stimulate respiration UUricosuric Effectsricosuric Effects.. Low doses may decrease Low doses may decrease

urate excretion. Large doses induce uricosuria.urate excretion. Large doses induce uricosuria. Small doses of salicylate can block the effects Small doses of salicylate can block the effects

of probenecid and other uricosuric agentsof probenecid and other uricosuric agents

Side effects of salicylates Side effects of salicylates - cont.- cont.

Oxidative Oxidative pphosphorylationhosphorylation - t - the uncoupling of he uncoupling of oxidative phosphorylation oxidative phosphorylation

Carbohydrate Carbohydrate mmetabolismetabolism- - llarge doses arge doses hyperglycemia and glycosuria and deplete liver hyperglycemia and glycosuria and deplete liver and muscle glycogen. and muscle glycogen.

Nitrogen Nitrogen mmetabolismetabolism - - in toxic doses cause a in toxic doses cause a significant negative nitrogen balance. significant negative nitrogen balance.

Fat Fat mmetabolismetabolism - - reduce lipogenesis reduce lipogenesis Endocrine Endocrine eeffectsffects- - large doses of stimulate large doses of stimulate

steroid secretion. steroid secretion. PregnancyPregnancy-- uses for uses for long periods long periods - - reduced reduced

weights weights of babiesof babies. .

Pharmacokinetics of salicylatesPharmacokinetics of salicylates

AbsorptionAbsorption after p.o. are aafter p.o. are absorbed rapidly, bsorbed rapidly, After oral administration, the nonionized salicylates After oral administration, the nonionized salicylates are passively absorbed from the stomach and the are passively absorbed from the stomach and the small intestine. small intestine.

Appreciable concentrations are found in Appreciable concentrations are found in plasma in less than 30 minutes; a peak value plasma in less than 30 minutes; a peak value is reached in about 2 hours is reached in about 2 hours

Rectal absorption is slower than after p. o. Rectal absorption is slower than after p. o. and is incomplete and unreliable; and is incomplete and unreliable;

Salicylic acid is rapidly absorbed from the Salicylic acid is rapidly absorbed from the intact skin, especially when applied in oily intact skin, especially when applied in oily liniments or ointments.liniments or ointments.

PharmacokineticsPharmacokinetics (cont.) (cont.)

DistributionDistribution - - distributed throughout distributed throughout most body tissues and most most body tissues and most transcellular fluids, primarily by transcellular fluids, primarily by pH- dependent passive processespH- dependent passive processes, , readily crosses the placental readily crosses the placental barrierbarrier and BBB (not diflunizal) and BBB (not diflunizal)..

The volume of distribution 13 l;. at The volume of distribution 13 l;. at high doses, increases to about 35 l high doses, increases to about 35 l

80% to 90% of the salicylate is 80% to 90% of the salicylate is bound to plasma proteins.bound to plasma proteins.

Pharmacokinetics of salicylatesPharmacokinetics of salicylates (cont.)(cont.)

EliminationEliminationThe biotransformation takes place in The biotransformation takes place in

many tissues, but particularly in the many tissues, but particularly in the liverliver. .

Are excreted in the urine as free salicylic Are excreted in the urine as free salicylic acid (10%), salicyluric acid (75%), acid (10%), salicyluric acid (75%), salicylic phenolic (10%) and acyl (5%) salicylic phenolic (10%) and acyl (5%) glucuronides, and gentisic acid (<1%). glucuronides, and gentisic acid (<1%).

Half-life for aspirin is 15 minutes; that Half-life for aspirin is 15 minutes; that for salicylates is 2 to 3 hours in low for salicylates is 2 to 3 hours in low doses and about 12 hours at usual doses and about 12 hours at usual antiinflammatory dosesantiinflammatory doses

(according to Lippincott´s Pharmacology, 2006

Effect of dose on the half-life of aspirin

Aspirin Aspirin(low dose) (high dose)

12111098

7 654

12

32

1

32

1 12111098

7 543

21

t1/2 = 3 hours t1/2 = 15 hours

Therapeutic uses:

a. Antipyretics and analgesics: Aspirin, sodium salicylate, choline salicylate, choline magnesium salicylate - used as antipyretics and analgesics: - headache, arthralgia, myalgia, - in the treatment of gout, rheumatic fever, and rheumatoid arthritis.Note: Salicylates are the drugs of choice in the treatment of rheumatoid arthritis.

b. Diflunisal, a derivate of salicylic acid, is not metabolized to salicylate - it cannot cause salicylism. Diflunisal is 3-4 times more potent than aspirin as an analgesic and an anti-inflammatory agent, but it does not have antipyretic properties. Note: Diflunisal does not enter the central nervous system (CNS) and therefore cannot relieve fever.

Cardiovascular applications: inhibition

of platelet aggregation. Low doses of aspirin are used

prophylactically to decrease the incidence of transient ischemic attack and unstable angina in men as well as that of coronary artery thrombosis. Aspirin also facilitates Aspirin also facilitates closure of the patent ductus arteriosus (PGE2 is responsible for keeping the ductus arteriosus open).

d. Colon cancer: Chronic use of aspirin may reduce the incidence of colorectal cancer.

Therapeutic Uses of Therapeutic Uses of salicylatessalicylates

(dose depends on the wanted effect)(dose depends on the wanted effect) AnalgesiaAnalgesia - - headache, arthritis, headache, arthritis, dysmenorrhea, neuralgia, and myalgia. dysmenorrhea, neuralgia, and myalgia. in in the same doses and manner as for the same doses and manner as for antipyresisantipyresis

AAntipyrentipyretic-tic- in the same doses and in the same doses and manner as for analgesiamanner as for analgesia

Rheumatoid Rheumatoid aarthritisrthritis - 2 - 2 to 6 g daily), to 6 g daily), Other usesOther uses - treatment or prophylaxis - treatment or prophylaxis

platelet hyperaggregability (dose of aspirin platelet hyperaggregability (dose of aspirin is is 40 to 325 mg40 to 325 mg per day). per day).

Inflammatory Bowel Disease - Inflammatory Bowel Disease - mesalaminemesalamine (5-amino-salicyclic acid) (5-amino-salicyclic acid)

AspirinAspirinUsual doseUsual dose EffectEffect

80 – 160 mg80 – 160 mg AntiplateletAntiplatelet

325 – 1000 mg325 – 1000 mg Analgesic, antipyreticAnalgesic, antipyretic

325 mg – 6 grams325 mg – 6 grams Antiinflammatory, Antiinflammatory, tinnitustinnitus

6 – 10 grams6 – 10 grams Respiratory alkalosisRespiratory alkalosis

10 – 20 grams10 – 20 grams Fever, dehydration, Fever, dehydration, acidosisacidosis

> 20 grams> 20 grams Shock, comaShock, coma

(according to Lippincott´s Pharmacology, 2006

Dose-dependent effects of salicylate

0

10

50

100

150 Lethal

Severe

Mild

Intoxication

Anti-inflammatory

AnalgesicAntipyreticAntiplatelet

Plas

ma

conc

etra

tion

ofsa

licyl

ate

(mg/

dL)

Gastric bleeding Impaired blood clottingHypersensitivity reactions

TinnitusCentral hyperventilation

Vasomotor collapse; Coma; Dehydration

Preventive use of aspirinePreventive use of aspirine

Paracetamol Paracetamol (acetaminophen)(acetaminophen)

ParacetamolParacetamol

Pharmacological propertiesPharmacological propertiesanalgesic and antipyretic effectsanalgesic and antipyretic effects is only a weak inhibitor of COX.is only a weak inhibitor of COX. no effects on platelets, or the excretion of no effects on platelets, or the excretion of

uric acid.uric acid.PharmacokineticsPharmacokinetics is rapidly and completely absorbed from the is rapidly and completely absorbed from the

gastrointestinal tract. gastrointestinal tract. peak concentration in plasma in 30 to 60 peak concentration in plasma in 30 to 60

minutes, and the half-life in plasma is about minutes, and the half-life in plasma is about 2 hours 2 hours

After large doses of paracetamol, the After large doses of paracetamol, the metabolite (N-acetyl-benzoquinoneimine) is metabolite (N-acetyl-benzoquinoneimine) is formed -and hepatic necrosis can result.formed -and hepatic necrosis can result.

HNCOCH3 HNCOCH3 HNCOCH3

Sulfate OH Glucuronide

ParacetamolCytochrome P-450mixed function oxidase

NCOCH3

HNCOCH3

HNCOCH3

Glutathione

Glutathione

Nucleophilichepatic cell

proteins

O

OH

OHCell macro-molecules

Cell death

Mercapturic acid(nontoxic)

Toxic intermediate

Therapeutic doses Toxic doses

(according to Lippincott´s Pharmacology, 2006

Metabolism of paracetamol

Paracetamol (cont.)Paracetamol (cont.)

Therapeutic UsesTherapeutic Uses is a suitable substitute for aspirin for is a suitable substitute for aspirin for

analgesic or antipyretic uses; analgesic or antipyretic uses;

Toxic EffectsToxic Effects In therapeutic dosageIn therapeutic dosage is usually is usually well well

tolerated.tolerated. acute overdosage ( 2-3 g) is a dose-acute overdosage ( 2-3 g) is a dose-

dependent, potentially fatal dependent, potentially fatal hepatic hepatic necrosis.necrosis. Renal tubular necrosis and Renal tubular necrosis and hypoglycemic coma also may occur. hypoglycemic coma also may occur.

Toxicity is potentiated by ethanolToxicity is potentiated by ethanol antidot - antidot - N-acetylcysteine.N-acetylcysteine.

Nonsteroidal Nonsteroidal antiinflammatory drugsantiinflammatory drugs

NSAIDsNSAIDs

IInflammation represents a series nflammation represents a series of homeostatic events that have of homeostatic events that have evolved to aid in our survival in evolved to aid in our survival in the face of pathogens and tissue the face of pathogens and tissue injry. injry.

NSAIDs NSAIDs NSADS act as :NSADS act as : 11. . cytokine inhibitorscytokine inhibitors ( IL-1, TNF, IL-8), antibodies or ( IL-1, TNF, IL-8), antibodies or

antibody fragments. Antagonists to various peptides antibody fragments. Antagonists to various peptides that contribute to cytokine-mediated responses (that contribute to cytokine-mediated responses (e.g.,e.g., substance P, bradykinin) also are in development.substance P, bradykinin) also are in development.

2.2. inhibitors of cell adhesion moleculesinhibitors of cell adhesion molecules (these (these include soluble fragments of receptors to bind cell include soluble fragments of receptors to bind cell adhesion molecules and use of antibodies, peptides, and adhesion molecules and use of antibodies, peptides, and carbohydrate moieties to block cell adhesion molecules.carbohydrate moieties to block cell adhesion molecules.

3. phospholipase A2 inhibitors3. phospholipase A2 inhibitors - glucocorticoids - glucocorticoids but whose toxicity will be less frequent and severe than but whose toxicity will be less frequent and severe than that of the steroids).that of the steroids).

4. inhibitors of lipooxygenase and leukotriene 4. inhibitors of lipooxygenase and leukotriene receptorsreceptors, ,

5. isoform specific inhibitors of cyclooxygenase5. isoform specific inhibitors of cyclooxygenase (meloxicam).(meloxicam).

Classification of NSAIDsClassification of NSAIDs

IndomethacinIndomethacin

Pharmacological Pharmacological ppropertiesroperties

has prominent has prominent antinflammatory and antinflammatory and analgesic-antipyretic analgesic-antipyretic propertiesproperties, , is more potent is more potent than aspirin.than aspirin.

effects of indomethacin are effects of indomethacin are evident in patients with evident in patients with rheumatoid and other rheumatoid and other types of arthritis, types of arthritis, including acute gout.including acute gout.

is evidence for both a is evidence for both a central and a peripheral central and a peripheral action; it also is an action; it also is an antipyretic.antipyretic.

is also inhibitor of is also inhibitor of polymorphonuclear polymorphonuclear leukocytes.leukocytes.

Pharmacokinetics Pharmacokinetics After p. o. oral ingestion the After p. o. oral ingestion the

peak concentration within 2 peak concentration within 2 hours.hours.

Its concentration in synovial Its concentration in synovial fluid is equal to that in fluid is equal to that in plasma within 5 hours.plasma within 5 hours.

Indomethacin is converted Indomethacin is converted primarily to inactive primarily to inactive metabolites, including those metabolites, including those formed by O-demethylation formed by O-demethylation (about 50%), conjugation (about 50%), conjugation with glucuronic acid (about with glucuronic acid (about 10%), and N-deacylation. 10%), and N-deacylation.

10% - 20% of the drug is 10% - 20% of the drug is excreted unchanged in the excreted unchanged in the urineurine, in part by tubular , in part by tubular secretion.secretion.

The half-life averages about 3 The half-life averages about 3 hours.hours.

IndomethacinIndomethacin

Therapeutic usesTherapeutic usesAnalgesic-antipyreticsAnalgesic-antipyreticsTreatment of ankylosing Treatment of ankylosing

spondylitis and spondylitis and osteoarthrosis, osteoarthrosis, treatment of acute gout treatment of acute gout

in obstetrics and in obstetrics and neonatal medicine. - neonatal medicine. - as a tocolytic agent to as a tocolytic agent to suppress uterine suppress uterine contractions.contractions.

- cardiac failure in - cardiac failure in neonates caused by a neonates caused by a patent ductus arteriosus patent ductus arteriosus

Side effectsSide effectsabout 20% must about 20% must

discontinue its use. discontinue its use. Most adverse effects are Most adverse effects are dose-related.dose-related.

GITGIT some fatal cases of some fatal cases of

hepatitis and jaundice hepatitis and jaundice have been reported. have been reported.

most frequent is severe most frequent is severe frontal headache. frontal headache.

hematopoietic reactions hematopoietic reactions include neutropenia, include neutropenia, thrombocytopenia, and, thrombocytopenia, and, rarely, aplastic anemiararely, aplastic anemia. .

diclofenac, felbinac, ibuprofen, ketoprofen, diclofenac, felbinac, ibuprofen, ketoprofen,

piroxicam, naproxen, flurbiprofen and others.piroxicam, naproxen, flurbiprofen and others.

Gout is a form of arthritisGout is a form of arthritis

Development of goutDevelopment of gout

Antirheumatic Drugs  Antirheumatic Drugs  ((drugs used to treatdrugs used to treat

rheumatoid arthritis)rheumatoid arthritis)

The major classes of The major classes of antirheumatic drugs include:antirheumatic drugs include:

1.1. Nonsteroidal Anti-Inflammatory Nonsteroidal Anti-Inflammatory Drugs (NSAIDsDrugs (NSAIDs:: ibuprofenibuprofen naproxennaproxen indomethacinindomethacin . .

2.2. Corticosteroids: Corticosteroids: prednisone and prednisone and dexamethasone.dexamethasone.

IIs classified as an auto-s classified as an auto-immune disease immune disease

Physicians now use Physicians now use Disease Modifying Anti-Disease Modifying Anti-Rheumatic DrugsRheumatic Drugs ( (DMARDs)DMARDs) and and Slow-Slow-Acting Antirheumatic DrugsActing Antirheumatic Drugs (SAARDs). (SAARDs).

The major classes of antirheumatic drugs The major classes of antirheumatic drugs include:include:

1.1. Nonsteroidal Anti-Inflammatory Drugs Nonsteroidal Anti-Inflammatory Drugs (NSAIDs(NSAIDs:: ibuprofenibuprofen (Motrin, Nuprin or (Motrin, Nuprin or Advil), Advil), naproxennaproxen (Naprosyn, Aleve) (Naprosyn, Aleve) indomethacinindomethacin (Indocin). (Indocin).

2.2. Corticosteroids: Corticosteroids: prednisone and prednisone and dexamethasone.dexamethasone.

DMARDs influence the disease process itself DMARDs influence the disease process itself and do not only treat symptomsand do not only treat symptoms

--Antimalarials Antimalarials DMARDs include DMARDs include chloroquinechloroquine (Aralen) and hydroxychloroquine (Plaquenil).(Aralen) and hydroxychloroquine (Plaquenil).

- - Immunosuppresive cytotoxic drugsImmunosuppresive cytotoxic drugs:: methotrexate, mechlorethamine, methotrexate, mechlorethamine, cyclophosphamide, cyclophosphamide, leflunomide, leflunomide, cyclosporine A, cyclosporine A, chlorambucil, and chlorambucil, and azathioprine.azathioprine.

- Slow-Acting Antirheumatic Drugs Slow-Acting Antirheumatic Drugs (SAARDs)(SAARDs):: are a special class of DMARDs are a special class of DMARDs and the effect of these drugs is slow and the effect of these drugs is slow acting and not so quickly apparent as acting and not so quickly apparent as that of the NSAIDs. Examplethat of the NSAIDs. Example is is aurothioglucoseaurothioglucose (gold salt) (gold salt)..

- Monoclonal antibody:Monoclonal antibody: etanercept, etanercept, infliximab anti-TNFdrugs infliximab anti-TNFdrugs

- Anakinra Anakinra (recombinant interleukin-(recombinant interleukin-1 receptor antagonist) 1 receptor antagonist)

Monoclonal antibody:Monoclonal antibody:

anti-TNF drugs:anti-TNF drugs: Adalimumab, etanercept, infliximab, etanercept, infliximab, leflunomide,leflunomide, Remicade Remicade