Groups of anti-inflammatory agents and mechanism of action:1) nonsteroidal anti-inflammatory drugs - NSAI2) glucocorticosteroids (GCS)

glucocorticosteroids LK+ -

PhospholipaseА2

Phospholipids

Arachidonic acid

Cyclic endoperoxydases

Prostaglandins Thromboxan

Inflammation Pain Fever Vasoconstriction

Increasing of platelets aggregation

-

+

- depressing effect

- stimulating effect

NSAID

-Cyclooxygenases(COG-1, COG-2, COG-3)

Large and chemically diverse group of drugs with the following properties:AnalgesicAntiinflammatoryAntipyretic

Activation of the arachidonic acid pathway causes:

pain headache fever inflammation

Gastro-intestinal tract

Peptic ulcers and multiple micro-erosions Esophagitis and stricturesErosive damaging of large and small intestines

Kidney Reversible acute kidney insufficiencyWater-electrolyte disordersChronic kidney insufficiency and interstitial fibrosisInterstitial nephritisNephritic syndrome

Cardio-vascular system

Increasing of arterial hypertensionIncreasing of static cardiac insufficiencyIncreasing of stenocardia

Liver Increasing of transaminases levelLife-threatening liver insufficiency

CNS Headache, somnolenceconfusion, disorders of behavior aseptic meningitis

Blood system

ThrombocytopeniaHemolytic anemiaGranulocytopenia and aplastic anemia

Bones, joints Disorders of cartilages and subchondral tissue

Other Increasing of asthma and polypus of nose, skin rash

1) Administer simultaneously with gastric protectors

sucralfat, misoprostol, ranitidin, famotidin, omeprasol

2) Create and introduce NSAIDs which selectively inhibit COG-2 meloxycam, nimesulid, rofecoxib,

celecoxib

Prevention of development of GI complications while

administering NSAIDs:

Directions of medical treatment Directions of medical treatment ofof rheumatoid diseasesrheumatoid diseases::

1)1)NSAIDsNSAIDs with the aim of depression of inflammatory process, pain, rigidness of muscles and joints, but don’t effect the currency of disease

2) 2) Basis drugsBasis drugs ((disease modifyingdisease modifying)) • Methotrexat, hydroxychloroquin, sulfasalazin, gold

containing drugs, penicillamin, • purin derivatives (asathioprin and mercaptopurin)• Alkilying drugs (chlorbutin and cyclophosphamid), • cyclosporin

3) 3) GCSGCS are administered if there’s a lack of effect of NSAIDs and basis drugs in case of very severe currency of inflammatory process

Analgesic (mild to moderate) Antigout Antiinflammatory Antipyretic Relief of vascular headaches Platelet inhibition (ASA)

Relief of mild to moderate pain Acute gout Various bone, joint, and muscle pain Osteoarthritis Rheumatoid arthritis Juvenile rheumatoid arthritis Dysmenorrhea Fever

salicylates (aspirin) More potent effect on platelet

aggregation and thermal regulatory center in the brainanalgesicantipyreticantiinflammatory

Antithrombotic effect: used in the treatment of MI and other thromboembolic disorders

phenylbutazone (Butazolidin) Greater effects on uric acid

production and excretion, in addition to antiinflammatory effects

More commonly used for treatment of gout

Gastrointestinal dyspepsia, heartburn, epigastric

distress, nausea**GI bleeding**mucosal lesions (erosions or ulcerations)

Misoprostol (Cytotec) can be used to reduce these dangerous effects.

Renal reductions in creatinine clearance acute tubular necrosis with renal

failure

Cardiovascular noncardiogenic pulmonary edema

Adults: tinnitus and hearing loss Children: hyperventilation and CNS

effects Effects arise when serum levels exceed

300g/mL. Metabolic acidosis and respiratory

alkalosis may be present.

Before beginning therapy, assess for conditions that may be contraindications to therapy, especially:GI lesions or peptic ulcer diseaseBleeding disorders

Assess also for conditions that require cautious use.

Perform lab studies as indicated (cardiac, renal, liver studies, CDC, platelet count).

Perform a medication history to assess for potential drug interactions.

Several serious drug interactions exist:alcoholheparinphenytoinoral anticoagulantssteroidssulfonamides

Salicylates are NOT to be given to children under age 12 because of the risk of Reye’s syndrome.

Because these agents generally cause GI distress, they are often better tolerated if taken with food, milk or an antacid to avoid GI irritation.

Explain to patients that therapeutic effects may not be seen for 3 to 4 weeks.

Educate patients about the various side effects of NSAIDs, and to notify their physician if these effects become severe

or if bleeding or GI pain occur. Patients should watch closely for the

occurrence of any unusual bleeding, such as in the stool.

Enteric-coated tablets should not be crushed or chewed.

Monitor for therapeutic effects, which vary according to the condition being treated:

decrease in swelling, pain, stiffness, and tenderness of a joint or muscle area

• Reduce inflammation and immune responsesReduce inflammation and immune responses

• In clinical practice since 1948In clinical practice since 1948

• $10,000,000,000./year market size in US$10,000,000,000./year market size in US

GLUCOCORTICOIDSGLUCOCORTICOIDS

Steroid Hormones: Derived from CholesterolSteroid Hormones: Derived from CholesterolLipid Soluble: Able Lipid Soluble: Able to cross plasma to cross plasma membrane by membrane by passive diffusionpassive diffusion

PHYSIOLOGICAL EFFECTS OF GLUCOCORTICOIDS

Regulation of carbohydrate, protein and lipid metabolism Maintenance of fluid and electrolyte balancePreservation of normal function of the cardiovascular system, the immune system, the kidney, skeletal muscle, the endocrine system and the nervous systemPreservation of organismal homeostasis

GRGR

GRGR

CELL TYPE FACTOR COMMENTS

Macrophages Prostaglandins, Inhibition of COX-2,Monocytes Leukotrienes Phospholipase A2

IL-1, IL-6. TNF Inhib. Transcript., Release

Endothelial Cells ICAM-1. ELAM-1 Inhib. Transcript., ReleaseIL-1, Prostagl., Leuko. As above

Basophils Histamine, Leukotriene Inhib. IgE Release

Lymphocytes IL-1, IL-2, IL-3, etc As above

Effects of Glucocorticoids on Components of Inflammatory/Immune Responses

The anti-inflammatory and immunosuppressive actions of glucocorticoids play an important role in preventing potential damaging effects of an unopposed inflammatory response and can be exploited therapeutically

Glucocorticoids: Side EffectsGlucocorticoids: Side Effects

The beneficial effects of systemic glucocorticoids to limit inflammation is counter-balanced by its many adverse side effectsThe broad anti-inflammatory actions of glucocorticoids are due primarily to transcriptional repression of many pro-inflammatory genes in multiple cell types by the glucocorticoid receptor.

From Glass and RosenfeldFrom Glass and Rosenfeld