Anti-inflammatory drugs: NSAIDS + Glucocorticoids Flashcards
Pain and inflammation results
Substance P, Bradykinin, Phospholipases, Prostaglandins, and serotonin all get released immediately
They all have an ability to bind and activate receptors on nerve endings
Prostaglandins and Inflammation
Injection of prostaglandins mimic aspects of the inflam response
Highly reactive oxidants also contribute to the inflammatory response and the formation of these compounds is inhibited by NSAIDS
All NSAIDS inhibit
Cyclooxygenase (COX)
If a drug does not inhibit COX
Does not have any anti- inflammatory activity
FEVER and PGE2
Immune cells respond to infections which produce cytokines (TNF, IL-6)
Cytokines release PGE2 by CNS vascular endothelial cells
PGE2 stimulates firing of HYPOTHALAMIC NEURONS, which raise the temp (fever)
NSAIDs + Fever
NSAIDS will lover fever but not lower body temp and have no impact on temp rising from exercise
Inhibitors of prostanoid Synthesis
phospholipase inhibitors corticosteroids
Lipoxygenase inhibitors
receptor antagonists
Colchicine
Acetyl Salicylic Acid
-Irreversible
Therapeautic Effects: Analgesia (reduces fever) and antipyretic within an hour
-non-selective COX 1/2 inhibitor
-anti-inflammatory effects after days (may take weeks for some conditions)
Theraputic effects of Acetyl Salictylic acid
Analgesia
-within an hour
-PGE2 sensitization of nociceptors
Antipyretic
-within an hour
-PGE2 in hypothalamus
Anti-inflammatory
-within says (could be weeks for some conditions)
-PGE2-mediated edema and leukocyte recruitment
Cardiac Protection: low dose therapy
-platelet thromboxane A2(reduce ability for platelets to be aggravated)
-although aspirin undergoes first-pass metabolism, the effect is on platelets in the bloodstream (portal vein has a lot of platelets)
What is Acetyl salicylic acid
Asprin
How is Acetyl salic acid metabolized?
Absorbed in the stomach and distributed throughout body tissues
-rapidly metabolized to salicylic acid. In GI cells, plasma and live.
-Further salicylate metabolism occurs in the liver (mostly Phase II)
-excreted by kidney
Undesired Effects of Aspirin
GI toxicity: dyspepsia, bleeding, ulceration, perforation. ADDITION of misoprostol (synthetic PGE) to NSAID formulation can be considered in patients at high risk of GI toxicity
Renal toxicity: inhibition of intrinsic PG system:hypovolemic patients at greatest risk
Salicylism: CNS toxicity (dizziness, headache, confusion)
platelet inhibition (can be deisred in lowering risk of cardiovascular disease)
Hepatotoxicity (liver toxicity)
Hypersensitivity reactions
PDR warning for…
Aspirin + all others NSAIDs
-can develop suddenly
-Serious GI toxicity such as bleeding, ulceration
-happens in people treated chronically with NSAIDS
RISK for NSAID induced GI complications
- Past complicated Ulcer
- Multiple NSAIDs
- High dose NSAID
- Anticoagulant
- Past uncomplicated ulcer
- Age > 70
- Steroids
Drug interactions
anticoagulants- combined activity
Alcohol- addictive irritant effect on gastric mucosa
Uricosuric Drugs- hyperuricemia at lower poses
Antihypertensive agents- generalized decrease in anti-hypertensice efficacy
diuretics- decreased effects of diuretic agents, increased risk of acute renal failure (particularly in the elderly who may already have reduced renal function// kidney damage)
How are the NSAIDS ibuprofen and Naproxen similar
-Cyclooxygenase inhibition (well-absorbed)
-hepatic metabolism
-adverse effects: GI, CNS, Renal toxicity, blood elements
-contraindications: hypersensitivity, peptic ulcer, hepatic disease
-less severe sside effects bc they are reversible inhibitors of COX 1/2
what are first line for mild pain and inflammation
Ibuprofen Naproxen
NSAID/PHARMACODNAMIC/HALFLIFE
Aspirin: COX 1/2 irreversible, half-life= 20 minutes but irreversible
Ibuprofen: COX 1/2 reversible: half-life 2 hours
Naproxen: COX 1/2 reversible: half-life 15 hours
COX-1 (from arachidonic acid)
constitutively expressed; Prostaglandins (Homeostatic Effects)
-Renal homeostasis
-Gastric mucosal protection
-Platelet function
From Physiologic stimulus comes through; the stomach, kidneys, intestine, platelets, endothelium all can be impacted. Things that come from COX-1 are: PGE2, TxA, PGI2: these things can impact physiologic functions
COX-2 (from arachidonic acid)
inducible; Prostaglandins (Inflammatory Effects)
-Pain
-Inflammation
-Fever
-Limited Homeostatic Effects
From Inflammatory stimuli; inflammatory sites (macrophages, synoviocytes) impacts: Inflammatory PGs, Proteases, O2: these things can impact inflammation
What is COX-2 selectively inhibited by
Celocoxib
In cox-2 there is a side pocked that was added; it fits into COX-2 side pocket
CELECOXIB
COX-2 Specific inhibitors
Benefits:
lower incidence of GI toxicity vs non-selective NSAIDS
Risks:
-inhibition may increase chance of thrombosis in patients at risk for this disease; it could be a key in generation of the prostacyclin. A PG that decreases platelet aggregation
- Rofecoxib (Vioxx): thrombotic cardiac events
-COX-2 active in kidneys, the recommended doses of COX-2 inhibitors causes renal toxicities similar to what is associated with traditional NSAIDs
