OAINs

NONSTEROIDAL ANTI-INFLAMMATORY

DRUGS ( NSAIDs)

Dwi Indria AnggrainiFakultas Kedokteran Universitas Lampung

INTRODUCTION

Inflammationnormal, protective response

to tissue injury caused by physical trauma,noxious chemicals, or microbiologic agents

triggered by the release ofchemical mediators from injured tissues and

migrating cells (Hist, PG, Brad, IL-1)

The drugs act by interrupting the inflammatory response through one mechanism or another

The salicylates (e.g.,acetosal/aspirin®) and the newer NSAIDs posses excellent anti-

inflammatory activity due to their inhibition of prostaglandins (PG)

biosynthesis

Many of these drugs acetylate and irreversibly inactive COX → block the

synthesis of the prostaglandins PGE2, PGI2,

and PGF2α, which are believed to be involved in inflammation – associated

vasodilation, pain, and edema

Additionally, acetosal inhibits the synthesis of

thromboxane A2 (TX2) due to blockade of platelet

cyclooxygenase →bleeding time ↑

Acetaminophen although an excellent analgesic and antipyretic, does not possess anti-inflammatory activity

The NSAIDs and the salicylates are the drugs of first choice for RA and many of

the NSAIDs are also useful in the treatment of acute gout

Unlike narcotics, these agents have no tolerance or addiction liability

INTRODUCTION (cont)

SYNTHESIS OF PROSTAGLANDINS

NSAIDs

Aspirin & Other Salicylates

Propionic Acid Derivates

Indoleacetic AcidsOxicam Derivates

Fenamates

Phenylbutazone

Other Agents

Aspirin and other salicylates

• a weak organic acid that is unique among the NSAIDs in irreversibly (and thus inactivating) cyclooxygenase. Aspirin

•is not metabolized to salicylate; can not cause salicylate intoxication•3-4 x more potent than aspirin as analgesic and anti-inflammatory agent•no antipyretic properties ( enter the CNS Can not relieve FEVER)

Diflunisal:

Mechanism of action :

• The antipyretic and anti-inflammatory effects of the salicylates are due to primary to the blockade of prostaglandin synthesis at the thermoregulatory centers in the hypothalamus and at peripheral target sites

Actions :

• Anti-inflammatory actions • Aspirin inhibits inflammation in arthritis (Cox-inhib)

• Analgesic action :• By decreasing Prostaglandin E2 (PGE2) synthesis, aspirin and other NSAIDs repress the sensation of pain.• Management of pain of low to moderate

Antipyretic action :

• impending PGE2 synthesis and release.• resets the “ thermostat” toward normal and rapidly lowers the body temperature of febrile

patients by increasing heat dissipation as a result of peripheral vasodilation and sweating• no effect on normal body temperature

Respiratory actions :

• At therapeutic doses increases alveolar ventilation• At higher doses hyperventilation• At toxic levels central respiratory paralysis

Gastrointestinal effects :

• increase gastric acid secretion and diminished mucus protection may cause epigastric distress, ulceration, and or/hemorrhage

Effects on platelets :

• Aspirin platelet aggregation is reduced anticoagulant effects prolonged bleeding time

Actions on the kidney :

• ↓ synthesis of PG result in retention of sodium and water and edema and hyperkalemia

•Gout, RF, RA, headache, arthralgia, myalgia

Antipyretics and analgesics :

•Salicylic acid To treat calluses, epidermophytosis•Methyl salicylate is used externally as a cutaneous counterirritant in liniment

External applications :

•Low doses of aspirin are used prophylactically to decrease the incidence of ischemic attack, unstable angina, coronary artery thrombosis

Cardiovascular applications :

•Chronic use of aspirin reduces the incidence of colorectal cancerColon cancer

THERAPEUTIC USES

PHARMACOKINETICS

ADMINISTRATION AND DISTRIBUTION :

• Salicylates, esp Methyl salicylate are absorbed through intact skin. • Oral adm : salicylates absorbed from the stomach and the small intestine. • Rectal absorption slow and unreliable• Salicylates (except for diflunisal) cross both the BBB and placenta

DOSAGE :

• The salicylates exhibit analgesic activity at low doses, only at higher doses do these drugs show anti-inflammatory activity

FATE

• Salicylate is converted by the liver to water–soluble conjugates that are rapidly cleared by the kidney (T1/2: 3,5 hours)• At anti-inflammatory dosages ( > 4 g/day) T1/2 : >15 hours• At low doses of aspirin uric acid secretion • At high doses uric acid secretion (Alkalinization of the urine promotes excretion)

ADVERSE EFFECTS

GI : epigastric distress, nausea, vomitingBlood: a prolonged bleeding timeRespiration : In toxic doses respiratory depressionHypersensitivity : urticaria, bronchoconstriction

DRUGS INTERACTING WITH SALICYLATES

Antacids

• Reduced rate of aspirin absorption

Heparin or oral anticoagulants

• Hemorrhage

Probenecid, Sulfinpirazone

• Decreased urate excretion (contraindicated in patients with gout)

Bilirubin, Phenytoin, Naproxen, Sulfinpirazone, Thiopental

• Increased plasma conc leading to prolonged half-lives, therapeutic effects, and toxicity

PROPIONIC ACID DERIVATESIbuprofen, Naproxen,

Fenoprofen, Ketoprofen, Flurbiprofen, Oxaprozin

Anti-inflammatory, analgesic and antipyretic activity The chronic treatment of RA + OA

GI effects < than aspirin

Well absorbed on oral adm. hepatic metabolism

excreted : kidney

Side effects : dyspepsia, bleeding, headache, tinnitus,

dizziness

INDOLEACETIC ACIDS

• DRUGS :INDOMETHACINSULINDACETODOLAC

• All have anti-inflammatory, analgesic, antipyretic activity

• They act by reversibly inhibiting cyclooxygenase

INDOMETHACIN

More potent than aspirin as an anti-inflammatory agent

Therapeutic uses :- control of pain associated with uveitis and postoperative opthalmic procedures

- antipyretic for Hodgkin’s disease - like aspirin, indomethacin can delay labor by

suppressing uterine contractions

DRUGS INTERACTION

Concurrent administration of indomethacin may decrease the antihypertensive effects of :

FurosemideThiazide diuretics

Beta-blocking drugsACE inhibitors

SULINDAC Inactive pro-drug active form Hepatic microsomal enzymes of the drug

Long duration of action Less potent than indomethacin Adverse effects are similar to but less severe than indomethacin

Therapeutic uses :RA, ankylosing spondylitis, OA, Acute gout

ETODOLAC

- Has effects similar to those of the other NSAIDs- Gastrointestinal problems <- Adverse effects : fluid retention, abnormal kidney and liver function

DRUGS INTERACTION : ↑ the serum levels and thus raise the risk of adverse

reactions caused by digoxin, lithium, methotrexate enhance the nephrotoxicity of cyclosporine

OXICAM DERIVATES• Therapeutic uses : RA, ankylosing

spondylitis, OA• Half-life : 50 hours adm : once a

day

FENAMATES• Have no advantages over the other

NSAIDs • SE : diarrhea, hemolytic anemia

AI, AG, AP act •Has powerful anti-inflammatory effect but weak analgesic and antipyretic activities

Therapeutic uses •Acute gout & acute RA (toxicity short-term therapy)•Use : up to 1 week only

PKs•PO / rectal rapidly and completely absorbed•Active Metabolite : oxyphenbutazone•Interac : warfarin, oral hypoglycemic agents, sulfonamides (Bound to PP displacement free drugs )

SE •Agranulocytosis, aplastic anemia, nausea, vomiting, skin rashes, epigastric discomfort, fluid and electrolyte retention, diarrhea, vertigo, insomnia, blurred vision, euphoria, nervousness, hematuria

PHENYLBUTAZONE

OTHER AGENTS

•More potent than indomethacin or naproxen•Therapeutic uses : RA, OA, Ankylosing spondilitis

DICLOFENAC :

•Route of drug adm : PO, IM (Post operative pain), Topically (allergic conjunctivitis)

KETOROLAC

•Potency = aspirin for adult or juvenile RA or OA•SE < aspirin

TOLMETIN AND NABUMETONE

NON-NARCOTIC ANALGESICS

ACETAMINOPHENPHENACETIN

• Have little or no anti-inflammatory activity• Do not cause physical dependence or tolerance

ACETAMINOPHEN & PHENACETIN

Act by inhibiting PG synthesis in CNS Antipyretic and Analgesic properties

Less effect on COX in peripheral tissues weak anti-inflammatory activity

Do not affect platelet function or increase blood clotting time

SE < Aspirin

Phenacetin potential renal toxicity

THERAPEUTIC USES :

• Analgesic-antipyretic of choice for children with viral infections or chicken pox• Gastric complaints

PHARMACOKINETICS :

• Rapidly absorbed from GIT• First pass metabolism in intestine & hepatocytes• Phenacetin Acetaminophen conjugated with glucoronic or sulfat / hydroxylated Excreted in urine

ADVERSE EFFECTS :

• Infrequently : skin rash , minor allergic reactions• Large doses : Hepatic necrosis & renal tubular necrosis Treatment : N-acetylcystein

THERAPEUTIC DISADVANTAGES OF THERAPEUTIC ADVANTAGES OF

SELECTED NSAIDs SELECTED NSAIDs

Salycylates :

Aspirin

Salicylate salts

Diflunisal

Pyrazoles :

Phenylbutazone

Indoleacetic acids :

Indomethacin

Sulindac

Tolmetin

Propionic acids :

Ibuprofen

Naproxen

Ketoprofen

Fenoprofen

Oxicam :

Piroxicam

Fenamates :

Mefenamic acid

Meclofenamic acid

Upper GI disturbances

No antipyretic effect

Very potent : should be used only after less toxic agents have proven ineffective

CNS disturbances common

Low cost ; long history of safety

Less GI irritationthan aspirin

Long half-life permits daily or twice daily dosing

Lower toxicity and better acceptance in some patients

TERIMAKASIH