Nonsteroidal Antiinflammatory Drugs (Nsaids)

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Non steroidal Anti inflammatory Drugs (NSAIDs)

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Aspirin (ASA)
Ibuprofen
Cox II inhibitors
Celecoxib
Acetaminophen

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Slow acting anti-rhumatic drugs (SAARD)
Disease modifying anti-rhumatic drugs (DMARDS)

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Traditional: (Found by accident)
Anti-malarials: chloroquine and hydroxychloroquine.
Penicillamine- Used to treat toxicity such as copper toxicity
Methotrezate: anti-cancer agent
Gold compounds: toxic
Biologic: (Found specifically)
Leflunomide (Arava)
Infliximab (Remicade)
Etanercept (Enbrel)
Anekinra (kineret)

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Drugs used to treat gout

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colchicine: old, unique drug. Used for gouty arthritis
allopurinol: Limits uric acid.
Probenecid: Promotes excretion of uric acid
*Uric acid overload causes the body to work against itself

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Clinical signs of the inflammatory process

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erythema (reddening), edema, tenderness, pain

Migration of leukocytes and phagocytes to site of injury. Release of histamines.

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The inflammatory Process

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Acute inflammation (transient), immune response (delayed, subacute phase), Chronic inflammation (chronic proliferative stage)

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Acute Inflammation

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Initial response to injury: local casodilation, increased capillary permeability. Caused by release of autocoids: PG;s, His, 5-HT, bradykinin, leukocytes.

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Immune Response

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Infiltration of leukocytes and phagocytic cells. Outcome beneficial (phagocytosis of foreign organisms) or deleterious (no resolution/becomes chronic)

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Endocrine Hormone:

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Released by gland. Act on receptors

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Autocrine Hormone:

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Released by a cell and act on same cell. acts on cell surface receptor.
Autocoids

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Paraquine Hormone:

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Act on cell right next to cell released from. Autocoids

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Chronic Inflammation (Chronic Proliferative Stage)

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Tissue degeneration and fibrosis. Structural damage of tissue. More autacoids: IL-1 (interlukin), IL-2, IL-3, GM-GM-CSF, TNF-alpha, interferons (endogenous molecules produces at site of infiltration), PDGH
Leukocytes release lysosomal enzymes
Best example: Chromic rheumatic arthritis: bone and cartilage pain and destruction.

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Rheumatoid Arthritis

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Pathogenesis unknown
autoimmune disease: overtime immune system recognizes parts of the body as foreign.
Cytokine release: IL-1, TNF-alpha (only glucocorticoids (controls anti-inflamitory state: better than NSAIDS because NSAIDS work on prostoglandins) block synthesis or actions), PGE2 (prosteglandins elevated in inflamed joints because COS is not present, COX-II is produced), elevated in inflamed joints due to inductionj of COX-II.

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Synthesis of Prostaglandins (PG's)

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Involves enzyme cyclooxygenase (COX), arachidonic acid (AA) used as substrate

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Mechanism of NSAID action

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Inhibition of COX to decrease PG formation. Two isoforms of COX:
COX-1: Constitutional (blood vessels, stomach, kidney)
COX-II: Inducible (during inflation), by cytokines, other mediators)
Aspirin: Irreversibly acetylates COX platelets cannot regenerate COX. (platelets have no nuclei and platelets no longer able to produce thromboxine (A2) takes a week for new platelets to be made.
Most NSAIDS: non-selective COX inhibitors and reversibly inhibit COX.
Acetile calicilic acid forms covalent bond with COX enzyme meaning COX will never act again.

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Most NSAIDS act by:

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tissue injure --> aracodinic acid --> protiglandins --> thromboxine A2 produced only in the platelets. Prosticyclin PGI2 --> produced in blood vessel walls. PGE2 --> produced in a variety of tissue, have a variety of effects.

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NSAIDS

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act indirectly, do not block PG receptros, no effect on previously formed PG's, most effective when given before tissue injure. Possible additional mechanisms: seggested but not confirmed.

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Shared pharmacologic actions of NSAIDS: Ibuprofen

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Therapeutic Effects: Analgesic, antipyretic, anti-inflammatory: highest doses needed to treat, other: treatment of primary dysmenorrhea: due to prostiglandins and close patient ductus arteriosus: found in newborns and normally closes by itself. endomethosin can be used to treat.
Side effeects:GI ulverations and intolerance: usually complain of stomach ache. BLockade of platelet aggregation (ASA most effective; basis for use in thromboebolic disease) Aspirin causes most anti-clotting problems. Tocolytic action: prolongs gestation, delays labor; complicates delivery with post-partum bleeding and hemorrhage. Uterine relaxation
NSAIDS induced renal toxicity (acute renal failure)- rare in healthy subjects. Vulnerable pts have impaired renal function and/or hemodynamic instability, reduced renal blood flow, GFR, and salt and water retention; hyperkalemia. Cardiovascular disease.Hypersensitivity reactions: vasomotor rhinitis, profuse watery secretions, angioneurotic edema, generalized urticaria, bronchial asthma, laryngeal edema, bronchoconstriction, hypotesnion, shock. 20-25% incidence in middle ages with asthma, nasal polyps or chronic urticaria. Rx caused by COX inhibition/non-immunoligical.

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Aspirin (& Salicylates)

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Absorption: Delayed by food; no effect of buffering. Dose dependent kinetics: t1/2= 3 hrs low dose
t1/2 = 12 hrs usual anti-inflammatory dose (higher doses)
t1/2 = 15-30 hrs high therapeutic doses. (Even higher doses)
Buffered aspirin can decrease stomach painm but reduce pain caused less awareness of potential stomach problems. Aspirin inhibits COX in stomach --> inhibits mucus --> mucous usually protects stomach irritation. Enteric form: can irritate stomach wall, cause is after aspirin has been diagnosed it inhibits prostiglanding production and prostiglandins protect against stomach acid in the stomach.
Therapeutic Drug Monitoring (TDM): useful to monitor therapy and toxicity. (Blood levels of salicilate are measured).
Plasma salicylate levels: Single ASA dose: <60 ug/ml, optimal anti-inflammatory in RA: 15-300ug/ml, peripherally induced nausea: <270u/ml, central nausea: >270ug/ml, hyperventilation: >350ug/ml.
Therapeutic agents: Aspirin, sodium salicylate, salicylsalicylic acid (salsalate), choline salicylate (oral liquid), magnesium salicylate (tabs), choline and magnesium salicylate mix (trilisate); methyl salicylate (topical)-- irritate s surface of skin which stiumlates blood flow and causes pain relief.