week 8- OTC pain meds Flashcards
inflammation in the body
- mediated by phospholipase A2, which uses phospholipids from the cell membrane to make arachidonic acid
- arachidonic acid is a substrate for COX, which catalyzes the synthesis of proinflammatory molecules at the site of tissue injury (prostaglandin E2/prostacyclin)
roles of PGE2/PGI2
uterine contraction, decreased secretion of acid, increased production of protective mucous, vasodilation, attracts immune cells, acts on neurons that detect pain to increase sensitivity to stimuli, increased body temp
COX- role in kidneys
catalyzes prostaglandin and prostacyclin synthesis, leading to vasodilation which supports renal blood flow
COX- role in platelets
promotes thromboxane synthesis, which leads to platelet aggregation
COX
- found throughout the entire body
- prostaglandins, prostacyclins and thromboxase work locally (only work where they were made)
types of COX
a) COX1
- good COX, found in all tissues
- protects gastric mucosa, supports kidney function, promotes platelet aggregation
b) COX2
- bad COX, found at sites of injury
- mediates inflammation and pain, fever, vasodilation, renal perfusion
COX inhibitors
- aspirin and related drugs
- used to reduce fever, relieve pain and decrease inflammation
inhibition of COX1
leads to harmful effects such as gastric erosion/ulceration, bleeding or renal impairment
inhibition of COX2
leads to beneficial effects such as suppression of inflammation, decreased pain and fever, protection against colon cancer
categories of COX inhibitors
a) with anti-inflammatory properties
- first and second generation NSAIDs
b) without anti-inflammatory properties
- acetaminophen
first-generation NSAIDs
nonselective inhibition of COX1 and COX2
ie. aspirin (salicylate family), ibuprofen, naproxen
second-generation NSAIDs
selective inhibition of COX2
ie. celecoxib
uses of first-gen NSAIDs
- treat osteoarthritis, rheumatoid arthritis and bursitis
- alleviate mild-moderate pain
- decrease fever
- relieve dysmenorrhea (uterine cramps)
aspirin MOA
- non-selective inhibition of COX
- most benefits from inhibiting COX2
- side effects come from inhibiting COX1
- irreversible binding to COX (ASA only)
aspirin pharmacokinetics
a) absorption
- rapidly in small intestine, slower with PR
b) distribution
- tightly bound to plasma albumin, delivered to entire body 9including CNS/breast milk/placenta)
c) metabolism
- short half-life, converts to salicylic acid quickly
- SA’s inactivation based on amount of drug present
d) excretion
- renal, dependent on urinary pH (more alkaline = faster excretion)
benefits of aspirin- analgesia
- mild-moderate pain
- not effective against visceral organ pain
- no tolerance or physical dependence
- inhibiting COX2 suppresses prostaglandins, which decreases pain receptors
benefits of aspirin- fever reduction
- only if febrile
- hypothalamus regulates fever and is triggered by prostaglandins, which is suppressed by COX2 inhibition
benefits of aspirin- dysmenorrhea
- inhibits prostaglandin synthesis in uterine smooth muscle
benefits of aspirin- inflammation
- COX2 inhibition prevents prostaglandins synthesis, which are innate to inflammatory response
ASA and heart health
- COX1 causes synthesis of TXA2, leading to platelet aggregation
- ASA causes irreversible inhibition of COX1 and platelets cannot synthesize new COX1 (takes 8 days for platelets to die)
- beneficial for patients at risk of coronary clotting (MI, angina, TIA, ischemic stroke)
ASA in cancer prevention
- COX2 can promote tumour growth, especially in the colon
- COX2 inhibition has shown to prevent tumour growth
- high and low-dose studies have shown efficacy
- in solid tumours, low-dose decreases risk of death
ASA side effects
a) GI- heartburn, nausea, ulcers
b) bleeding- inhibits platelet aggregation
c) renal impairment- inhibition of COX1 deprives kidneys of prostaglandins for normal function, we see decreased urine output/weight gain/rapid increase in serum creatinine
d) reyes syndrome- rare but leads to encephalopathy and fatty liver
e) salicylism- ASA levels just above therapeutic, tinnitus, sweating, headache, dizziness, acid-base imbalance
f) pregnancy- suppression of spontaneous uterine contractions, premature closing of ductus arteriosus
g) hypersensitivity- profuse, watery rhinorrea, generalized urticaria, bronchospasm, laryngeal edema
ASA contraindications
- people with bleeding disorders or on anticoagulants
- people with hypertension (at higher risk of hemorrhagic stroke)
- elective surgeries or childbirth, stop ASA for at least one week prior
- peptic ulcer disease
- caution for older adults, smokers, renal dysfunction, asthma, nasal polyps, EtOH misuse
ASA poisoning
- rarely fatal in adults (20-25g), fatal in children at 4g
signs: compensated respiratory alkalosis leading to respiratory acidosis, hyperthermia, diaphoresis, electrolyte imbalances, coma/death
treatment: mechanical ventilation, external cooling, fluids, bicarb infusion, dialysis
non-ASA first generation NSAIDS
- reduce fever, relieve pain, reduce inflammation
- reversibly inhibit COX1/2
- side effects occur with lower intensity
(GI ulcers, renal impairment, bleeding) - can increase risk of thrombotic events
second-generation NSAIDs
- used with inflammatory disorders
- only COX2 inhibition
- increased risk of stroke, allergic reactions in patients with sulfonamide allergy, GI symptoms remain
- contraindicated with warfarin, lithium, diuretics and ACEIs
ie. celecoxib
acetaminophen
- analgesic and anti-pyretic but not anti-inflammatory
- inhibits COX in CNS extensively but not periphery
- no effects on platelets, renal impairment or gastric ulceration
acetaminophen PK
- metabolized in liver, excreted in urine
- half-life of 2 hours
- two metabolic pathways (major pathway = non-toxic metabolites, minor pathway = oxidized into toxic metabolite but quickly gets converted to non-toxic form using glutathione)
acetaminophen and alcohol
- alcohol induces cytochrome P450 within minor pathway, leading to larger amounts of toxic intermediate
- alcohol also decreases the amount of glutathione available
- liver cannot clear alcohol and so detox stops and liver damage results
acetaminophen toxicity
- rare with therapeutic doses
- anaphylaxis also rare, hypersensitivity can occur (presents similarly)
- early signs of toxicity include nausea, vomiting, diarrhea, sweating, sweating, abdominal pain
- late signs of toxicity include liver failure (hepatomegaly, jaundice, visceral tenderness)
- treated with acetylcystiene, which substitutes depleted glutathione
polypharmacy concern
- daily maximum is 4g/d or 3g/d for hepatic failure
- many other drug compounds contain acetaminophen such as percocet, vicodin, tylenol cold and flu, robaxacet, excedrine, migraine
