Aspiring, NSAIDs, and Acetaminophen Flashcards
function of NSAIDs
inhibit COX-1 and COX-2
how does aspirin inhibit function of COX-1 and COX-2
it covalently modifies the enzyme
how does NSAIDs inhibit COX-1 and COX-2
competes for the active site of cyclooxygenase (competitive inhibitor)
how does Acetaminophen inhibit COX-1 and COX-2
- interfers with the oxidative state of cyclooxygenase site
- inhibition impaired by “peroxide tone”
acetaminophen metabolites can form a conjugation with arachidonate acid in the brain to yield
a neuroactive metabolite
-or inhibition of the nitric oxide pathway mediated by a variety of neurotransmitter receptors including N-methyl-D-aspartate and substance P
general properties of NSAIDs
- anti-inflammatory
- analgesia (inability to feel pain)
- antipyresis
- gastric erosion
- cause renal dysfunction, impair renal function
- variable effect on platelet aggregation; increase cardiovascular pathologic events due to COX-2 inhibition
side effects of NSAID therapy
- gastric and intestinal ulceration
- anemia from resultant blood loss
- local irritation from drugs (organic acids) plus removal of PGE2 and PGI2 cytoprotective effects (less mucous covering GI)
how should patients at risk of GI toxicity be managed
-given celecoxib or other NSAID co-administered with a proton pump inhibitor or the PGE1 analong misoprostol
All NSAIDs have what effect on the cardiovascular system
- prothrombotic effects that increase risk of stroke, TIA, symptomatic coronary artery disease
- symptomatic peripheral vascular disease (COX-2 inhibition)
All NSAIDs can exacerbate
hypertension
what is the safest NSAIDs
naproxen bc it has the lowest cardiovascular toxicity effects
what are the adverse effects of NSAIDs on the renal system
- decrease renal blood flow and GFR in patients with congestive heart failure, liver disease (ascites); chronic renal disease; or those who are hypovolemic or dehydrated
- promote salt and water retention by producing PG-induced inhibition of both the reabsorption of chloride and the action of ADH
- may cause increased intravascular volume/edema
- analgesic nephropathy
- idiosyncratic and dose-related hepatic injury
symptoms of aspirin “intolerance”
-vasomotor rhinitis, generalized urticaria (hives), and bronchospasm, laryngeal edema and bronchoconstriction, flushing, hypotension and shock
aspirin “intolerance” occurs in pts with
- nasal polyps, asthma, and chronic urticaria
- asthma may be induced or exacerbated in such patients
what is the mechanism of aspirin intolerance
- defect in mast cell histamine storage/shunting or arachidonic acid to lipoxygenase pathway
- nonimmunologic mechanism
effects of aspirin in pregnancy
- prolong labor
- promote premature closure of ductus arteriosus
common drug interactions of NSAIDs
- prolong bleeding time (warfarin; heparin)
- increase the ulcerogenic effects of glucocorticoids
- reduce effects of diuretics and other antihypertensive agents
- reduce lithium clearance; also methotrexate; cyclosporine; aminoglycosides
therapeutic uses of NSAID
- relief pain and inflammation
- reduce body temp in febrile states
- closure of ductus arterioles
- with antihistamines, in pts with systemic mastocytosis
- adjunct in cancer-related hypercalcemia
- Bartter’s syndrome
- moderate cutaneous rxns in pts receiving niacin
aspirin in a — dependent pharmacokinetics
dose
MAO of aspirin
acetylates COX
what type of inhibitor is aspirin (salicylic acid)
competitive inhibitor
dose-dependent therapeutic effects of aspirin
- anti-platelet effects
- analgesia; reduction in febrile responses
- anti-inflammatory
aspirin metabolism
- aspirin is metabolized in plasam to yield salicylic acid
- salicylic acid is biotransformed in liver and mitochondria
therapeutic uses of aspirin
-antipyretic, analgesic, anti-inflammatory
aspirin can be used as a prophlaxis of disease assocaited with
- platelet hyperaggreability (CAD; unstable angina; post_MI or stent; postoperative deep vein thrombosis; risk of stroke)
- pre-eclampsia and hypertension indued by pregnancy
adverse effects of aspirin
- gastric irritation, ulceration, erosion, hemorrhage
- increased bleeding time (2X for 4-7 days)
- decreased renal function in patients at risk
- hepatic injury (usually with larger doses associated with treatment of RA)
low doses of aspirin inhibits
uric acid excretion
large doses of aspirin promotes
uric acid excretion
10 mg/dl of aspirin causes
analgesia, antipyretic, anti-platelet; gastric intolerance/bleeding, hypersensitivity
10-49 mg/dl of aspirin causes
anti-inflammatory, uricosuric
50-80 mg/dl of aspirin causes
mild intoxication; tinnitus, central hyperventilation
80-100 mg/dl causes
moderate intoxication; fever, dehydration, metabolic acidosis
110-160 mg/dl of aspirin causes
severe intoxication; hypoprothrombinemia, vasomotor instability; coma
> 160 mg/dl of aspirin causes
lethal blood levels; renal and respiratory failure
what is salicylism
aspirin overdose
effects of salicylism
-confusion; tinnitus, dizziness
how does salicylism affect respiration
- contributes to acid-base disturbances
- stimulation via uncoupling of oxidative phosphorylation
- direct stimulation of respiratory centre
- toxic doses suppress respiration
what metabolic effects does salicylism have
- increases uncoupling
- inhibit aerobic respiration
- release epinephrine
- reduces lipogenesis
- large doses stimulate glucocorticoid secretion
uncoupling of oxidative phosphorylation causes
increase of O2 consumption and CO2 production
toxic doses of aspirin inhibit aerobic respiration leading to
accumulation of pyretic, lactic and acetoacetic acids
aspirin promotes epinephrine release which promotes
hyperglycemia and depletes muscle and hepatic glycogen
aspirin reduces lipogenesis which causes
increase in oxidation of F/A
full therapeutic dose of aspirin produces respiratory alkalosis, how does compensation occur
-increase renal excretion of bicarbonate, accompanied by increased Na+ and K+ excretion
extreme metabolic acidosis is caused by
- salicylate accumulation
- renal dysfunction with accumulation of organic acids
- derangement of carbohydrate metabolism
what is Acetaminophen (Tylenol)
an effective antipyretic and analgesic
does Acetaminophen have anti-inflammatory effects
very little
Acetaminophen does not effect the — and —
GI tract
platelets
main toxicity of Acetaminophen is directed toward
liver
mechanism of action of Acetaminophen
-inhibits cyclooxygenase, by altering oxidate state of active site
ability of Acetaminophen to inhibit cylooxygengase is impaired in the presence of
peroxides (ie. inflammation)
ability of Acetaminophen to inhibit cylooxygenase is enhanced in the presence of
high [ ] of antioxidants (ie. brain)
experimental demonstration of novel metabolite of acetaminophen in
CNS which inhibits COX and stimulates TRPV1 receptor or possible interference with nitric oxide pathway and interface with central neurotransmitters
Large dose of Acetaminophen (>7.5 g) may cause
hepatotoxicity
hepatotoxicity of acetaminophen is mediated by
a metabolite formed by P450, which is normally inactived by glutathione
hepatotoxic dose may be substantially smaller in individuals with
preexisting liver disease or who consume alcohol regularly
acetaminophen over dose is the most common cause of
-acute liver failure
50% of adults
13% of pediatric cases
treatment of acetaminophen toxicity
N-Acetylcysteine
administration of N-Acetylcysteine is based on
a nonogram derived from time-dependent acetaminophen [ ] data generated in adults with a single, acute ingestions of drug who presented to medical centres with 24 h of the overdose
FDA issued manufactuers of TC pain delivers and fever reducers to revise their labelling to include warnings about potential safety risks. Products covered by the FDA action included
-acetaminophen (in a class by itself) NSAIDs -aspirin -ibuprofen -naproxen -ketoprofen
acetaminophen prescription products limited to
325 mg per dose
what were the changes in Aceaminophen dosing regulations and warnings
- require boxed warning highlighting the potential for liver injury, as well as allergic runs
- used in many combination products; label abbreviations are currently not standardized
