antiinflammatory drugs

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Inflammation =

Inflammatory mediators + Immune system

Inflammatory mediators

PG's, PAF, NO, BK, H, 5-HT, IL-1, cytokines, SOR, Lysosomal enzymes

The specific chemical mediators differ according to the type of

inflammatory process

Clinical Manifestations

1-Hotness: localized and Systemic 2-Redness (flare) 3-Edema (Swelling) ? 4-Pain 5-Loss of Function

Antiinflammatory Drugs

1-Non-steroidal Antiinflammatory Drugs(NSAID)2-Steroidal Antiinflammatory Drugs e.g. Glucocorticoids (immunosuppressants)3-Drugs for Rheumatoid Arthritis(DMARD: Disease-Modifying Antirheumatic Drugs)4-Drugs for Gout 5-Antihistamines

NSAID

Anti-inflammatory -modification of inflammatory reaction •Analgesic -reductionofcertainsortsofpain •Antipyretic -lowering a raised temperature Most commonly use do fall therapeutic drugs •for aches and pains •often taken without prescription (OTCdrugs)

NSAID: Mechanism of action

InhibitionofCOX1andCOX2:mostNSAIDSinhibitCOX1andCOX2 •someselectivelyinhibitCOX2 •less adverse effects on GIT, e.g. peptic ulcer •long term effects remain to be seen •Anti-inflammatory -due to reduction of vasodilatation, oedema and pain •Analgesic -due to reduced sensitisation of nociceptic nerve endings to bradykinin and 5-HT •Antipyretic -due to PGE-mediated hypothalamic set-point for temperature control •normal temperature is not affected by NSAIDS

Chemical Class Salicylates

Prototype Aspirin, st Analgesic st Antipyretic st Antiinflammatory

Chemical Class p-aminophenols

Prototype Paracetamol st Analgesic st Antipyretic +/- Antiinflammatory

Chemical Class Indoles

Prototype Indomethacin st Analgesic V.st Antipyretic st Antiinflammatory

Chemical Class Pyrrol acetic acid

Prototype Mefenamic acid, Tolmentin st Analgesic st Antipyretic st Antiinflammatory

Chemical Class Propionic acids

Prototype Ibuprofen, Naproxen V.st Analgesic st Antipyretic V.st Antiinflammatory

Chemical Class Enolic acids

Prototype Phenylbutazone, Piroxicam st Analgesic st Antipyretic V.st Antiinflammatory

Chemical Class Alkanones

Prototype Nabumetone med Analgesic med Antipyretic st Antiinflammatory

Chemical Class Sulfonamide

Prototype Celecoxib V.st Analgesic st Antipyretic V.st Antiinflammatory, new gen

9NSAID: Common Adverse effects

GIT -dyspepsia -nausea and vomiting -Peptic ulcer in chronic users •Skin reactions •Renal damage and nephropathy •Liver disorders and bone marrow depression •Aspirin Induced Asthma

Salicylates: Aspirin

several forms acetylsalicylic acid (ASA) aspirin, a wonder drug sodium salicylates: 2/3 of potency of aspirin methylsalicylate-topical use

Aspirin

Now, rarely used as anti-inflammatory ? Replaced with more effective & safer NSAID (Naproxen& Ibuprofen) PharmacokineticsWeak acid rapidly absorbed from stomach and upper small intestineAbsorbed as such and quickly hydrolyzed by body esterases25% excreted unchanged in urine (urine alkalinization ↑excretion)T1/2 = 3-5 h (600 mg/d) T1/2= 12-16 h (3.6 g/d)

Aspirin Mechanisms of action

A-AntiinflammatoryNonselective inhibitor of COX1 & COX2 Irreversibleacetylation of COXIn arthritis, it inhibits inflammation but does not arrest disease progression or induces remissionB-Analgesic↓PGE2Also suppress pain at subcortical sites (Thalamus and Hypothalamus)Mild to moderate pain due to inflammation (> opioids)Pain due to malignancy (NSAID + Opioids)C-AntipyreticInhibition of COX (↓PGE2) and IL-1Peripheral vasodilatation No effect on normal body temperature

Aspirin Mechanisms of action 2

D-AntiplateletTXA2↑platelet aggregation while PGI2↓platelet aggregation Irreversibly inhibit COX in platelets (8-10 d) at doses 60-80mg/d and not in endothelial cells*Anticoagulant effect with prolonged bleeding timeE-Respiratory Therapeutic doses: (Alveoli) increases ventilationHigher doses: (Respiratory Centre) Hyperventilation and Respiratory AlkalosisToxic Dose: Central Respiratory Paralysis + Respiratory AcidosisF-GITPGI2inhibits gastric acid secretion PGE2& PGF2α+ synthesis of protective mucousAspirin (normal dose/chronic use) Gastric distress ulceration/hemorrhageEnteric G-KidneysAspirin inhibits COX ↓↓ PGE2& PGI2↓↓ Renal Blood flow (especially in presence of vasoconstrictors i.e. Renal/Cardiovascular disease or use of diuretics) sodium and water retention Edema and HyperkalemiaInterstitial Nephritis happens with all NSAID but not with Aspirin

Aspirin Therapeutic Uses

1-Analgesic, Antipyretic, and Anti-inflammatory In gout, rheumatoid arthritis, and rheumatic fever Analgesia: headache, migraine, arthralgia, myalgia Not effective for severe visceral pain 2-CV applications: decrease the incidence of transient ischemic attacks, unstable angina, coronary artery thrombosis 3-Prophylaxis from colon cancer: long term/small doses

Aspirin Adverse Reactions

ReactionsAt normal dose:Gastric upset/ N&V / microscopic GI bleeding/ Peptic ulcersHepatotoxicityAsthma (AIA)Hypersensitivity (bronchoconstriction, edema, Urticaria) 15% Renal Toxicity (less common)Reye's syndrome occurring in childrena liver damageand CNSdisturbance following an acute viral infection e.g. chickenpox

Aspirin Mild Salicylate Toxicity (Salicylism)

Nausea, Vomiting, Hyperventillation, Headache, dizziness, mental confusion, tinnitus (ringing or roaring in the ears)

Severe Salicylate Intoxication

All the above symptoms followed by:Restlessness, hallucination, convulsions, coma, respiratory and metabolic acidosis, and death (respiratory failure)10 g Aspirin is fatal in children

16Paracetamol (Acetaminophen)

Not a real NSAID Inhibits COX in the CNS (analgesic & antipyretic) and less effects on peripheral COX (weak anti-inflammatory) No effect on platelet aggregation or bleeding time Preferred antipyretic drug T1/2= 2-4 h

16Paracetamol therapeutic uses

-analgesic and antipyretic of choice for patients with gastric complaints or elongated bleeding time -Drug of choice for children with viral infection -Safe during pregnancy

16Paracetamol adverse effects

common adverse effects liver damage in acute toxicity (dose related) treated with iv acetylcysteineor oral methionine

COX2 selective NSAID

COX2 inhibitors have an advantage of a lower risk of development of GI bleeding No impact on platelet aggregation (COX1 mediated)However, they have the same range of adverse effects as other NSAIDs e.g. renal insufficiency Do not show improved efficacy over other NSAIDs

COX2 selective NSAIDs Rofecoxiband Valdecoxib

double the risk of heart attack and stroke (both withdrawn from the market)

COX2 selective NSAIDs Celecoxib

Skin rashes, similar side effects to other NSAID

COX2 selective NSAIDs Etoricoxib

2ndgeneration COX2 inhibitors, similar activity to traditional NSAID with low GI side effects

Rheumatoid arthritis

one of the commonest inflammatory conditions common cause of disability major factors: IL-1 and TNF-a

DMARD

Also known as SAARD (Slow-acting Antirheumatoid Drugs): reduce or prevent joint damageSlow the course of the disease and prevent further damage BUT can not repair existing damageLong onset of action (3-4 months)

Antirheumatoid Drugs

1-Methotrexate2-Chloroquine and Hydroxychloroquine3-Penicillamine4-Gold salts5-Sulfasalazine6-Anticytokines

Methotrexate

Immunosuppressant Onset: quicker than other DMARD (3-6 weeks) SE:mucosal ulceration and nausea Chronic administrationCytopenias, liver cirrhosis, acute pneumonia-like syndrome N.B. Taking Leucovorin (Folinic acid) a day after methotrexate reduces the severity of adverse effects

Chloroquine & Hydroxychloroquine

Antimalarial drugs reducing IL-1, lymphocyte proliferation and chemotaxis Not very effective (reduce symptoms but no evidence of affecting disease progression) SE:ocular & oto-toxicity, GI troubles, rashes, nightmares

Penicillamine

Metabolite of penicillin and analogue of cysteine amino acidact by decreasing IL-1 generationmetal-chelating effect (Wilson's disease)Severe side effects: dermatologic problems, nephritis, aplastic anemia, GI troublesOnly used after failure of gold salts and before the use of corticosteroids

Gold Salts

Suppress phagocytosis and lysosomal enzyme activityOral (auranofin) and IM (aurothioglucose& aurothiomalate)Use hindered by serious side effects and cost Side effects: rashes, stomatitis and metallic taste, hematological abnormalities, nephrotoxicity, aplastic anemiaAntirheumatoid

Sulfasalazine

combination of Sulfonamide and Salicylate -mode of action is unknown •toxic oxygen scanvenger? -GIT disturbances, reversible infertility in men, hemolytic anemia

Anticytokines (TNF-αblockers)

More effective when combined with methotrexate

Anticytokines Etanercept

Recombinant fusion protein human TNF-receptor p75 + IgG1 (Fc portion)Upon discontinuation the symptoms of arthritis return within a monthWell-tolerated (injection site reaction)

Anticytokines Infliximab

IV infusion Chimeric IgG κMAB (human + murine) binds specifically to TNF-α Rheumatoid Arthritis (moderate to severe conditions) Also used for treatment of Crohn's disease Adverse effects: predispose for infection (life-threatening)

Anticytokines Adalimumab

AdalimumabsubcutaneousFully human IgG1 anti-TNF MABAdverse effects: predispose for infection (rare reactivation of pneumonia or TB)

Gout

overproduction of purines ↑uric acid in blood (hyperuricemia) deposition of sodium urate in the kidney and jointslocal inflammation

Gout Treatment strategy:

Lowering the uric acid level below saturation point and thus preventing deposition of urate crystals 1-interfering with synthesis of uric acid (Allopurinol) 2-Increasing uric acid excretion (Uricosuric agents) 3-Inhibition of leukocyte entry into affected joint (Colchicine) 4-NSAID (Indomethacin in acute gout attacks) Aspirin is contraindicated

Anti-Gout Drugs Allopurinol

- decrease urates and uric acid by non-competitive inhibition of xanthine oxidase -Chronic gout (with high uric acid excretion) -ineffective in acute gout attacks

Anti-Gout Drugs Uricosuric Agents

Decrease the reabsorption of uric acid from proximal tubules Probenecid, Sulfinpyrazone, Large doses of Aspirin Chronic gout with normal uric acid excretion

Anti-Gout Drugs Colchicine

Prevention and relief of acute gouty attacks (replaced by NSAID)Binds Tubulin prevents formation of microtubules inhibits cell motility inhibits leukocyte migration and phagocytosis SE:N,V, Diarrhoea, Abdominal pain, aplastic anaemia, agranulocytosis, alopecia (8 mg/d can be fatal)Currently, Only for prophylaxis

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