N ON - STEROIDAL ANTI - INFLAMMATORY DRUGS

BY PROF. AZZA EL-MEDANY DR. OSAMA YOUSIF

OBJECTIVES At the end of the lecture the students should : Define NSAIDs Describe the classification of this group of drugs Describe the general mechanism of actions Define the following terms : Analgesic Antipyretics

O BJECTIVES ( CONTINUE ) Anti-inflammatory Anti-platelet o Describe the general pharmacological actions Describe the general therapeutic uses Describe the general adverse effects Describe the general contraindications Know some examples of each group of NSAIDs Know the difference between the selective & non-selective NSAIDs

Non-Selective COXs Inhibitor Selective COX2 Inhibitor

NON- SLECTIVE -NON -STEROIDAL ANTI-INFLAMMATORY DRUGS Group of drugs that sharing the capacity to induce the following pharmacological actions : Analgesic Antipyretic Anti-inflammatory Anti-platelet Effect on the kidney function

ANALGESIC Drug that relieve pain.

ANTIPYRETIC Drug that lower the elevated body temperature to normal.

P HARMACOKINETIC Oral administration Most NSAIDs are weak acid (absorbed well in stomach and intestinal mucosa) 95% bound to plasma-protein (high bioavailability) Most metabolized in liver (oxidation & conjugation)

DISCUSS

MECHANISM OF ACTION OF N-NSAIDS

G ENERAL M ECHANISM OF ACTION OF NS-NSAID S Reversible inhibition of both COX-1 & COX-2 enzymes EXCEPT Aspirin is the only NS-NSAID that irreversible inhibitor of both enzymes Resulting in inhibition of the synthesis of prostaglandins & thromboxane A2

M ECHANISM O F A CTION Analgesic Central inhibition of COX enzymes in CNS Antipyretic Central inhibition of COX enzymes in CNS Peripherally inhibition of interleukin-1 Anti-Inflam. Peripheral. inhibition of COX enzymes Antioxidant effect

( CONTINUE ) Effect on platelets Inhibit platelet aggregation through inhibition the synthesis of TXA2 ( inhibition of cox- 1)

E FFECT ON THE KIDNEY Inhibition of both COX-1& COX-2 enzymes (mainly COX-2) ( inhibit synthesis of PGE2 & PGI2 that are responsible for maintaining renal blood flow)  Salt &water retention & edema of lower limbs  Hyperkalemia  Interstitial nephritis 

THERAPEUTIC USES SHARED BY NS-NSAIDs

Antipyretic Analgesic ( Which type of pain?) Dull, mild, moderate e.g. Headache, Migraine, Dental pain,common cold

C ONTINUE Anti-inflammatory Rheumatic / Rheumatoid arthritis / myositis or other forms of inflammatory conditions. Dysmenorrhea

A DVERSE EFFECTS SHARED BY NS-NSAID S GIT upsets ( nausea, vomiting) GIT bleeding & ulceration Bleeding Hypersensitivity reaction Inhibition of uterine contraction Salt & water retention

C LINICAL USES OF A SPIRIN Acute rheumatic fever Low doses used as cardioprotective to reduce the incidence of myocardial infarction & unstable angina

( CONTINUE ) Large doses ( 5gm)used to treat chronic gouty arthritis Chronic use of small doses of aspirin used as protective to reduce the incidence of colorectal cancer

Adverse Effects Related to (A) Therapeutic Doses Of Aspirin Nausea & vomiting Hypersensitivity ( Aspirin asthma) Acute Gouty arthritis Reye's syndrome

( B) LARGE DOSES OR C HRONIC USE OF ASPIRIN Salicylism ( ringing of ear( tinnitus), vertigo) Hyperthermia Gastric ulceration & bleeding Respiratory depression

ADVERSE EFFECTS R ELATED TO H IGH DOSES

C ONTRAINDICATIONS Peptic ulcer Pregnancy Hemophilic patients Patients taking anticoagulants Children with viral infections Gout ( small doses )

PARACETAMOL IS commonly used as analgesic antipyretic

C ONDITIONS IN WHICH PARACETAMOL IS A SUITABLE DRUG

In patients with : Peptic or gastric ulcers. Bleeding tendency. Allergy to aspirin. Viral infections especially in children. o During Pregnancy.

A DVERSE E FFECTS Due to its active metabolite ( N-acetyl-p-benzoquinone) Therapeutic doses elevate liver enzymes Chronic administration causes kidney failure ( necrosis) Large doses cause Acute toxicity :{liver failure ( necrosis) } Treatment Of acute toxicity by : N- acetylcysteine ( SH- donor) to neutralize the toxic metabolite

DICLOFENAC ( accumulate in synovial fluid) Clinical uses o Rheumatoid arthritis, osteoarthritis & ankylosing spondylitis o Analgesic o Antipyretic o Acute gouty arthritis o Locally to prevent post-opthalmic inflammation

P REPARATIONS OF D ICLOFENAC Oral Oral with misoprostol to decrease upper gastrointestinal ulceration. 0.1% opthalmic ( eye drops) to decrease postoperative opthalmic inflammation. A topical gel 3%. Rectal suppository

C ONTINUE Oral mouth wash. Intramuscular preparations.

S ELECTIVE COX-2 INHIBITORS General advantages : o Potent anti-inflammatory o Antipyretic & analgesic o Lower incidence of gastric upset o ( recommneded in patients with a history of gastric ulceration )

C ONTINUE No effect on platelet aggregation ( have no inhibitory effect on (COX-1 enzyme) so can be given in hemophilic patients

G ENERAL ADVERSE EFFECTS Renal toxicity Dyspepsia & heartburn Allergy Increase incidence of myocardial infarction ( lack cardioprotective effect of NS-NSAIDs as they have no effect on COX-1 enzyme)

GENERAL CLINICAL USES Commonly used as antiinflammatory drugs Rheumatoid arthritis Osteoarthritis Acute gouty arthritis Acute musculoskeletal pain Ankylosing spondylitis Dysmenorrhea

E XAMPLE :C ELECOXIB Half-life 11 hours (twice/day) Food decrease its absorption Highly bound to plasma proteins

C LINICAL USES & A DVERSE EFFECTS Discussed before with general uses and general adverse effects of selective COX-2 inhibitors

D RUG INTERACTIONS With warfarin ( anticoagulant ) celecoxib inhibits warfarin metabolism so it potentiates its action resulting in bleeding.

S UMMARY NSAIDs are group of drugs that have analgesic, antipyretic, anti-platelet & anti-inflammatory effects. They are classified according to their action on COX-enzymes into non-selective that inhibit both COX-1 & COX-2 & selective that inhibit only COX-2 enzymes. They are sharing in common therapeutic uses as analgesic to relief mild to moderate pain not visceral pain, reducing high body temperature, preventing clot formation, so aspirin can be used as prophylaxis in ischemic heart disease.

S UMMARY ( C ONTINUE ) As anti-inflammatory in rheumatic, rheumatoid arthritis, desmenrrhea and other inflammatory conditions including muscles or bones. The common adverse effects includes : gastric upset ( nausea, vomiting,gastric ulceration or bleeding). Allergy Edema They are contraindicated mainly in patients with peptic ulcer, bleeding tendency or in pregnancy.

S UMMARY ( C ONTINUE ) Selective COX-2 inhibitors as celecoxib are potent anti-inflammatory & analgesic,but have no anti-platelet effect & less gastric upset. They can be used in patients with gastric ulcer, haemophilia. Their common adverse is mainly on kidney & cardiovascular system.

THANK YOU