Q.

Outline the mech an ism of a cti on of non- stero ida l an ti-inf lamma to ry drugs and
their p ote nti al ad verse effect

Overview
•NSAIDS exert it pharamacological action via inhibition of prostaglandin synthesis
•Prostaglandin is synthisized from arachidonic acid metabolism

Arachidonic acid pathways

•arachidonic ---2 pathways-1.--lipooxygenase pathway and 2.---cyclooxygenase pathway

•prostaglandin is mediators ------------ variety of physiological effects;

•The prostaglandins together with the thromboxanes and prostacyclins form the prostanoid
class of fatty acid derivatives;

•prostanoid class ------------- subclass of eicosanoids

Cycloxygenase

•Cyclooxygenase (COX)

•responsible for formation of biological mediators ------------ prostanoids

•including prostaglandins, prostacyclin and thromboxane).

COX 1-

•constitutive enzyme, housekeeper enzyme.

•found in ---gastric mucosa, renal parenchyma, platelets

•slighly upregulated ---in resposne to inflammatory condition

function

•involve in homeostatic process-

•platelet aggregation

•renal function

•maintains normal gastric mucosa -gastrointestinal mucosal integrtity

•influences kidney function

drug action

•inhibition of COX-1 is therefore ---------undesirable

COX 2
•an inducible enzyme,

•inducible by inflammation

•undetectable in most normal tissues

•expressed ---at site of injury---in brain and kidney

Function
•becoming abundant in activated macrophages and other cells at sites of inflammation.

•mediate---inflammation , fever , pain , carconigenesis

•doesnt exert protective role in body

•may facilitate ---oncogenic process, angiogenesis , metastasis

Drug action

•inhibition of COX-2 ----------- desirable effect

•inducible enzyme -------- enzyme that is expressed only under conditions in which it is
clear of adaptive value, as opposed to a constitutive enzyme which is produced all the time

Prostaglandin

•prostaglandin ----------- lipid mediators

•act upon platelet, endothelium, uterine and mast cells that are derived enzymatically from
fatty acids

http://upload.wikimedia.org/wikipedia/commons/4/40/Eicosanoid_synthesis.svg

Type of NSAIDS and mechanism of action

•NSAIDS can be classified based on its action on COX
•there are non-specific and specific inhibitor of COX 2
•most of NSAIDS are non-specific inhibitor
•some NSAIDS---such as aspirin form irreversible inhibition of COX
 •non-specific inhibitor of COX-2IbuprofenNaproxenAspirin acetaminophen Ketorolac
•COX-2 selective inhibitorsCelecoxibRofecoxibValdecoxibParecoxib

Specific NSAIDS – Acetaminophen

•NSAIDS- such as acetominophen drug action has strong central inhibition of protaglandin
syntheis
•thus---confer antipyretic and and analgesic effect
•has modest peripheral inhibiting effect on prostaglandin synthesis

Specific NSAIDS- aspirin

Overview
•some NSAIDS---such as aspirin form irreversible inhibition of COX

Anti-inflammatory
•reduced synthesis: eicosanoid mediators
•interference: kallikrein system mediators
•inhibits granulocyte adherence to damaged vasculature
•stabilizes lysosomes
•inhibits polymorphonuclear leukocyte/macrophage migration to inflammation sites

Analgesic Effects
•Effective for management of mild to moderate pain
•Pain may arise from:
•musculature
•dental work
•vascular
•postpartum conditions
•arthritis
•bursitis
•Sites of action: peripherally -- sites of inflammation ---subcortical sites

Antipyretic Effects:
•"normal" temperature: slightly affected
•"elevated" temperature: reduced
•Mechanisms of Antipyretic Action:
•vasodilation (superficial vessels): heat dissipation
•Fever associated with infection: mechanism
•Prostaglandin production in the CNS: induced by bacterial pyrogens
•Interleukin 1: produces a hypothalamic effect which increases temperature
•Interleukin 1: produced by macrophages; released during inflammation; activates
lymphocytes
•Aspirin blocks:
•pyrogen-induced prostaglandin production
•CNS response to interleukin 1

Effects on Platelets
 •Reduced hemostasis;
•Mechanism of Action:
•Inhibition of platelet aggregation because of thromboxane synthesis inhibition

Analgesia/Anti-inflammatory Effects
•Commonly used for management of mild to moderate pain

Adverse effect of non-specific NSAIDS

Gastrointestinal Side Effects
•Gastric upset ----d/t---gastric mucosal irritation (undissolved tablet)
•inhibition of protective prostaglandins
•reduced/absent prostaglandin may make gastric mucosa more likely to be damaged

Gastric Bleeding:
•Upper GI bleeding
•associated with aspirin:----------- erosive gastritis
•fecal blood loss: slightly increased with aspirin (normal one ml- four mls)
•Management: ---------appropriate buffering (food; antacids)

Central Nervous System Effects:

•High doses: "Salicylism"
•tinnitus
•decreased hearing
•vertigo
•Higher doses: hyperpnea (increaset respiration rate)-- medullary effect
•low toxic salicylate levels: initial respiratory alkalosis (due to increased ventilation)
•accumulation of salicylic acid derivatives + respiratory depression ------acidosis
•can –cause headache, confusion , dizziness, can aggravate psychitric illness
•epilepsy

Renal effect
•aspirin doses < 2 grams/day: increase serum uric acid levels
•aspirin doses > 4 grams/day: ----decrease
 urate levels < 2.5 mg/dL
•mild, typically asymptomatic hepatitis--typically in patients with:
•systemic lupus erythematosus
•juvenile & adult rheumatoid arthritis
•reversible decrease in glomerular filtration rates (patients usually have underlying renal
dysfunction)

CVS effect
•Large doses: vascular dilation; depression of cardiac function
•Hypersensitivity reactions: -- leukotriene-mediated
•asthma patients
 •patients with nasal polyps
•associated: bronchoconstrictions/shock

Hematologic effect
•agranulocytosis----by inhibtion of neutrophil
•aplastic anemia---are
•hypoprothrombinemia by depression of vitamin K-clotting factor

cartilage effect
•excerbate cartilage erosion
•bony destruction of femoral head

pulmonary effect
•bronchocostriction
•airway oedema

Aspirin Overdosage Toxicity

•gastric lavage
•if patient hyperthermic: alcohol sponges/ice packs
•manage acid-based abnormality
•insure high urine volume
•urine alkalinization (sodium bicarbonate infusion) promotes salicylate excretion

Drug-Drug Interactions
Promote salicylate intoxication when ingested concurrently:
•acetazolamide
•ammonium chloride

increased bleeding:
•alcohol

Aspirin displaces drugs from protein binding sites:

•tolbutamide
•chlorpropamide
•nonsteroidal antiinflammatory drugs
•methotrexate
•phenytoin
•probenecid

Drug interaction
•aspirin reduces: spironolactone pharmacologic action
•aspirin --penicillin G competition for tubular secretion
•aspirin: inhibits uricosuric effect of: ----probenecid & sulfinpyrazone

Side effect of acetominophen

GIT
•no effect on gastric mucosa
 •doesnt produce---gastric irritation
•however may cause liver failure secondary to its metabolites

hematology effect
•not altering platelet aggregation

drug interaction
•not alter uricosuric drugs

inflammatory effect
•weak antiinflammatory effect

Side effect of specific inhibitor of COX 2

GIT
•minimal effect on GIT

hematology
•no antiplatelet activity

cartilage effect
•may have role in cartilage repair

pulmonary
•may reverse bronchoconstriction

Viva
•Why rofexoxib is withdrawn from market?
•How does it causes toxicity ?
•What are two main contraindication of rofexoxib IHD, RENAL FAILURE