Antiinflammatory drugs

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Antiinflammatory drugs, Analgesics

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Anti-inflammatory Drugs:

Presented by:- Sonu M.Pharma P’Cology Ist year RBIP, Mohali, Punjab Anti-inflammatory Drugs

Anti-inflammatory Drugs:

Anti-inflammatory Drugs Nonsteroidal Anti-inflammatory Drugs (NSAIDs) Steroidal Anti-inflammatory Drugs Miscellaneous Drugs Pharmacological control of inflammation: Preventing the release of inflammatory mediators Inhibiting their actions Treating pathophysiologic responses to them

NSAIDs:

NSAIDs General characteristics Drugs that inhibit one or more steps in the metabolism of arachidonic acid (AA) Aspirin-like drugs or COX inhibitors Major action: inhibit Cyclooxygenase (COX) Pharmacological effects Suppress inflammation Relieve pain Reduce fever

Prostaglandins (PGs) are derived from arachidonic acid:

Prostaglandins (PGs) are derived from arachidonic acid Cell Membrane (phospholipids) phospholipase A 2 Arachidonic acid cyclooxygenase aspirin, indomethacin (COX1 & COX2) Cyclic endoperoxides (PGG 2 , PGH 2 ) prostacyclin prostaglandin thromboxane synthetase synthetase synthetase prostacyclin PGE 2 PGF 2  Thromboxane A 2 PDX, PGI 2 (vasodilator, (erythma (vasodilator (vasoconstriction antiaggregating) edema uterus contractor) platelet aggregation) pain, fever) Lipoxygenase (LOX) Leukotrienes

NSAIDs: Classifications based on chemistry:

NSAIDs: Classifications based on chemistry Salicylic acid derivatives Aspirin Para-aminophenol derivatives Acetaminophen Indole and indene acetic acids Indomethacin Pyranocarboxylic acids Etodolac Ketorolac Propionic acids Ibuprofen Naproxen Ketoprofen Carprofen Vedaprofen Fenamates Meclofenamic acid Tolfenamic acid Pyrazolones or enolic acids Phenylbutazone Dipyrone Oxicams Piroxicam Meloxicam Nicotinic acid derivatives Flunixin meglumine Hydroxamic acid derivatives Tepoxalin Coxib-class NSAIDs Deracoxib Firocoxib

NSAIDs: Cyclooxygenase:

NSAIDs: Cyclooxygenase Cyclooxygenase has 2 forms: COX-1 (good COX) : found in all tissues Mediates “housekeeping chores” Protect gastric mucosa Support renal function Promote platelet aggregation COX-2 (bad COX) : found at sites of tissue injury Mediates inflammation and sensitize receptors to painful stimuli Also present in brain- mediates fever and contributes to perception of pain Mediates a cytoprotective effect in damaged GI mucosa

NSAIDs: effect of COX inhibition:

NSAIDs: effect of COX inhibition COX-1 inhibition Results largely in harmful effects Gastric erosion and ulceration Bleeding tendencies Acute renal failure Results in some beneficial effects Protection against myocardial infarction COX-2 inhibition Results in beneficial effects Suppression of inflammation Alleviation of pain Reduction of fever

Classification of Cyclooxygenase Inhibitors:

Classification of Cyclooxygenase Inhibitors Drugs with anti-inflammatory properties NSAIDs— Nonsteroidal anti-inflammatory drugs: 2 types First generation (inhibit both COX1 and COX2) Non-selective COX inhibitors - aspirin Second generation (inhibit COX2 only) Preferential COX2 inhibitors (partial specificity for COX2) - celecoxib (human drug) - carprofen (canine drug) Selective COX2 inhibitors (full specificity for COX2) - rofecoxib (human drug) - deracoxib (canine drug) Drugs without inflammatory properties Acetaminophen

NSAIDs: mechanism of action:

NSAIDs: mechanism of action NSAIDs act to block the first step of prostaglandin synthesis by binding to and inhibiting cyclooxygenase Dose and drug dependent The major therapeutic, toxic, and potency of NSAIDs all relate to their ability to inhibit prostaglandin synthesis

Differential effect of NSAIDs on the COX isoforms:

Differential effect of NSAIDs on the COX isoforms Ratio of COX1 to COX2 (COX1:COX2 ratio) describes the amount of drug necessary to inhibit the respective isoform of the cyclooxygenase enzyme (IC 50 ) Calculation: COX1:COX2 ratio = IC 50 COX1 / IC 50 COX2 COX1 to COX2 ratio > 1 is desirable, or COX2 to COX1 ratio < 1 This means a drug can inhibit COX2 at lower conc, and is probably safer

COX1: COX2 ratios of NSAIDs:

COX1: COX2 ratios of NSAIDs Examples Aspirin 0.343 Carprofen (racemix mixture) 129 Carprofen (S isoform) 181 Carprofen (R isoform) 4.19 Etodolac 0.517 Flunixin meglumine 0.635 Ketoprofen 0.232 Meclofenamic acid 15.4 Meloxicam 2.9 Phenylbutazone 2.64

NSAIDs: Pharmacokinetics:

NSAIDs: Pharmacokinetics As weak acids, well absorbed after PO Small volume of distribution (10%) Highly protein binding (90%) Clearance: hepatic metabolism both phase I and II Conjugated metabolites -> urine

NSAIDs: Pharmacological effects:

NSAIDs: Pharmacological effects Analgesia, antipyresis, and control of inflammation Relative potency in lab animals and human Meclofenamic acid > indomethacin > naproxen > aspirin Relative potency in horses Flunixin meglumine > meclofenamic acid > phenylbutazone > naproxen > aspirin Aspirin -> permanent effect on platelet activity

NSAIDs: Adverse reactions:

NSAIDs: Adverse reactions Gastrointestinal system GI ulceration Hematopoietic system Bleeding dyscrasias All NSAIDs are able to impair platelet activity Platelet aggregation defects caused by aspirin can last up to 1 week Renal system Analgesic nephropathy In kidney, vasodilatory and tubuloactive prostaglandins are protective Both COX1 and COX2 mediate renal effects of prostaglandins

NSAIDs: GI ulceration:

NSAIDs: GI ulceration GI damage is the most common and serious side effect of NSAIDs Dogs – very sensitive Inhibition of COX1-stimulated PGE 2 -mediated bicarbonate and mucous secretion, epithelialization, and increased blood flow Direct irritation of acidic drugs Salicylates cause backdiffusion of acid -> injury to mucosal cells and submucosal capillaries

NSAIDs: Specific Drugs in Vet Med:

NSAIDs: Specific Drugs in Vet Med Non-Selective COX inhibitors Acetaminophen Aspirin Etodolac Flunixin Meglumine Ketorolac Naproxen Phenylbutazone Piroxicam Tolfenamic acid Vedaprofen Preferential COX-2 inhibitors (Partial specificity for COX-2) Carprofen (Rimadyl, Pfizer) Meloxicam Selective COX-2 inhibitors (no significant effect on COX-1) Deracoxib (Deramaxx, Novartis) Firocoxib (Previcox, Merial) Robenacoxib (Onsior, Novartis) Mavacoxib (Trocoxil, Pfizer) Dual COX and LOX inhibitors Tepoxalin Ketoprofen

NSAIDs: Non-selective COX inhibitors:

NSAIDs: Non-selective COX inhibitors Acetaminophen Aspirin X

NSAIDs: Non-selective COX inhibitors:

NSAIDs: Non-selective COX inhibitors Etodolac Ketololac Flunixin meglumine

NSAIDs: Non-selective COX inhibitors:

NSAIDs: Non-selective COX inhibitors Naproxen Phenylbutazone

NSAIDs: Non-selective COX inhibitors:

NSAIDs: Non-selective COX inhibitors Piroxicam Vedaprofen Tolfenamic acid

NSAIDs: Preferential COX2 inhibitors:

NSAIDs: Preferential COX2 inhibitors Carprofen Meloxicam

NSAIDs: Selective COX2 inhibitors:

NSAIDs: Selective COX2 inhibitors Deracoxib (Deramaxx) Firocoxib (Previcox) Robenacoxib (Onsior) Mavacoxib (Trocoxil)

Steroidal Anti-inflammatory Drugs (Glucocorticoids, Corticosteroids):

Steroidal Anti-inflammatory Drugs ( Glucocorticoids , Corticosteroids) Most frequently used and misused drugs in veterinary medicine Needs an understanding of their actions on all body systems

Control of endogenous glucocorticoid secretion:

Control of endogenous glucocorticoid secretion Corticotropin-releasing factor (CRF) Adrenocorticotropic hormone (ACTH)

Mechanism of action:

Mechanism of action

Mechanism of action:

Mechanism of action Glucocorticoid receptors Intracellular, 3 subtypes at least activated receptor-glucocorticoid complex -> binds to glucocorticoid responsive element -> modulate gene transcription Target proteins could be induced or inhibited result in pharmacologic effects of glucocorticoids Differential gene regulation by glucocorticoids in different cells The liver is the primary target Half-life of the activated complex is about 10 hours

Examples of proteins whose synthesis is targeted by glucocorticoid receptor regulation:

Examples of proteins whose synthesis is targeted by glucocorticoid receptor regulation Induced Inhibited Lipocortin-1 Cytokines Beta2-adrenoreceptor Natural killer receptor Angiotensin-converting enzyme Inducible nitric oxide synthase Neutral endopeptidase Cyclooxygenase Endotheslin Phospholipase Collagenase Stromelysin

Physiologic effects: Metabolism:

Physiologic effects: Metabolism Protect glucose-dependent tissues (brain, heart) Hyperglycemic effect Increase gluconeogenesis, insulin antagonism Increased breakdown of proteins Skeletal muscles and collagen Provides gluconeogenic precursors Result in muscle wasting, delayed wound healing, and thinning of the skin Promote lipolysis Redistribution of body fat

Physiologic effects: Hemolymphatic system:

Physiologic effects: Hemolymphatic system Increase the RBC content of the blood Retarding erythrophagocytosis Lymphopenia Eosinopenia Monocytopenia Neutrophilia Increased release from bone marrow This blood cell profile: Stress leukogram

Anti-inflammatory and Immunosuppressive effects:

Anti-inflammatory and Immunosuppressive effects Inhibit early and late phases of the inflammation Inhibit edema formation, fibrin deposition, leukocyte migration, phagocytic activity, collagen deposition, and capillary and fibroblast proliferation Inhibit enzyme phospholipase A 2 and COX-2 Inhibit release of TNF- , IL-2, and platelet activating factor Inhibit inducible nitric oxide synthase (iNOS) Inhibit the synthesis of IL-1 and IL-2 Immunosuppression is more pronounced on the CMI than humoral immunity

Pharmacokinetics:

Pharmacokinetics Absorption Several products are well absorbed orally Topical use -> well absorbed Long-term use - > systemic effect Metabolism Eliminated by oxidation or reduction, and followed by conjugation Excreted principally via kidneys

Glucocorticoid Preparations:

Glucocorticoid Preparations Duration of action Anti-Inflam potency Short acting (< 12 hr) Hydrocortisone (identical to cortisol) 1 Topical use Intermediate acting (12 – 36 hr) Prednisolone and Prednisone 4 Methylprednisolone (has lipid antioxidant activity) 5 Triamcinolone 5 Alternate day administration Long acting (48 hr) Dexamethasone 30 Betamethasone 30 Highly potent glucocorticoids

Hydrocortisone Preparations:

Hydrocortisone Preparations

Prednisolone Preparations:

Prednisolone Preparations

Triamcinolone Preparations:

Triamcinolone Preparations

Dexamethasone Preparations:

Dexamethasone Preparations

Therapeutic indications:

Therapeutic indications Autoimmune diseases affecting skin Pemphigus complex Systemic lupus erythematosus Discoid lupus erythematosus Canine atopy (allergic inhalant dermatitis) Otitis externa Bronchial asthma in cats CNS edema

Therapeutic indications (continued):

Therapeutic indications (continued) Selected musculoskeletal disorders Polymyositis, Eosinophilic myositis Osteoarthritis Low dose: chondroprotective High dose: chondrodestructive (steroid arthropathy) Inflammatory bowel disease Eosinophilic granuloma complex in cats Gingivitis and stomatitis in cats

Therapeutic indications (continued):

Therapeutic indications (continued) Neoplasia Lymphoma Multiple myeloma Mast cell tumors Noninfectious conjunctival, corneal, and anterior uveal inflammatory diseases Contraindicate in corneal ulcers Immune-mediated hemolytic anemia and thrombocytopenia Hypoadrenocorticism (Addison’s disease)

Adverse effects:

Adverse effects Iatrogenic adrenocortical insufficiency Iatrogenic hyperadrenocorticism Susceptibility to infection Glucocorticoid-induced polyphagia Muscle weakness and muscle atrophy (common in dogs) Reversible hepatopathy Polyuria and polydipsia Pulmonary thromboembolism Hypertension Diabetes mellitus and hyperlipidemia

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