Non-opioid Analgesics Flashcards
Amine autocoids
histamine, serotonin
Lipid derived autocoids
prostaglandins, leukotrienes
Peptide hormones
bradykinin, angiotensin
Autocoids
amine, lipid-derived, peptide hormones and cytokines
NSAIDs
Salicylates, arylpropionic acids, arylacetic acids, enolic acids
Salicylates
aspirin
Arylpropionic acids
Ibuprofen, naproxen
Arylacetic acids
Indomethacin, diclofenac, ketorolac, etodolac
Enolic acids
Piroxicam (Feldene) and meloxicam (mobic)
p-Aminophenols
acetaminophen
Therapeutic applications of NSAIDs
analgesic, antipyretic, anti-inflammatory
Three phases of inflammation
Acute (vasodilation, increased permeability)
Subacute (infiltration)
Chronic (proliferation)
Mediators that recruit inflammatory cells
Arachidonic acid metabolites, prostaglandins, thromboxanes, leukotrienes, and cytokines
What kind of inhibitors are NSAIDs?
COX inhibitors
Inhibition of COX-1 leads to
a reduction in thromboxanes, causing reduced platelet aggregation - thus NSAIDs also function as a blood thinner
COX1 enzymes, prostaglandins and prostacyclins serve what kind of role in the GI tract?
a protective role
COX-1 constitutively expressed in
platelets, stomach and kidney
PGE2 and PGI2 are protective in
stomach; inhibit acid secretion, promote mucus secretion
Inhibition of PGE2 and PGI2 can lead to
stomach ulcers
What do prostacyclins do?
vasodilation and reduce platelet aggregation
What do thromboxins do?
synthesis induces platelet aggregation, vasoconstriction, and inhibitor functions as a blood thinner
COX-2 constitutively expressed in
brain and spinal cord
When is COX-2 induced?
induced in the setting of inflammation and induced by cytokines and inflammatory mediators
MOA of aspirin
irreversibly inhibits COX1/2 by acetylation; modifies COX2 activity; duration of effect corresponds to time required for new protein synthesis
MOA of other NSAIDs (besides aspirin)
competitive (reversible) inhibitors of COX 1/2; some arylacetic acids also inhibit leukotriene synthesis, contributing to anti-inflammatory effects
Absorption of salicylates
rapidly absorbed from stomach and jejunum
aspirin mainly absorbed in jejunum
passive diffusion of free acid
delayed by presence of food
Distribution of salicylates
throughout most tissues and fluids, readily crosses placenta, competes with many drugs for protein binding sites
Metabolism and excretion of salicylates
Active secretion and passive reabsorption in renal tubule, increased excretion with increased urinary pH
Absorption of non-salicylate NSAIDs
well absorbed from GI tract
Metabolism of non-salicylate NSAIDs
Little first pass metabolism; multiple routes of metabolism; therapeutic effect poorly related to plasma levels
Excretion of non-salicylate NSAIDs
drugs and metabolites excreted primarily as conjugates; active secretion of parent drug in renal tubule
Aspirin’s main use is for
anti-coagulation
MOA of ibuprofen and naproxen
potent reversible COX inhibitors
Safest to use in CAD
Naproxen
Excellent alternative to ibuprofen and naproxen
acetic acid derivatives
Acetic acid derivatives have an increased risk of what with prolonged use
increased risk of peptic ulcer and renal dysfunction with prolonged use
Indomethacin (Indocin)
One of the most potent reversible inhibitors of PG biosynthesis; high incidence and severity of side effects long-term
Indomethacin used for
acute gouty arthritis, ankylosing spondylitis and pericarditis
Enolic acids used to treat
arthritis; great joint penetration; one of the least GI side effects
At low doses, meloxicam is
COX-2 selective
Acetaminophen is highly effective as an
analgesic and antipyretic; weak inflammatory activity
Advantages to acetaminophen compared with NSAIDs
no GI toxicity; no effect on platelet aggregation; no correlation with Reye’s syndrome;
Disadvantages to acetaminophen compared with NSAIDs
little clinically useful anti-inflammatory activity; acute overdose may lead to fatal hepatic necrosis
Adverse affects of salicylates
gastrointestinal distress; treat with misoprostol
Overdose of salicylates
manifests as metabolic derangement, more specifically metabolic acidosis and respiratory alkalosis; order ABG/BMP
Mild effects of salicylism/aspirin poisoning
vertigo, tinnitus, and hearing impairment
CNS effects of salicylism/aspirin poisoning
nausea, vomiting, sweating fever, stimulation followed by depression, delirium, psychosis, stupor coma
Treatment of salicylism/aspirin poisoning
reduce salicylate load; charcoal, correct metabolic imbalance
Adverse effects of non-salicylate NSAIDs
GI intolerance/ulceration; renal function; transient inhibition of platelet aggregation; inhibition of uterine motility
At high doses or in the presence of alcohol, acetaminophen is metabolized into
NAPQI which is a toxic metabolite
NAPQI can be conjugated with
glutathione, depletion of which will further increase NAPQI levels
Adverse effects of acetaminophen
renal toxicity, papillary necrosis; dose-dependent potentially fatal hepatic necrosis
Non-selective COX1/2 inhibitors
aspirin, acetaminophen, non-salycilate NSAIDs
Selective COX2 inhibitors
Rofecoxib (Vioxx)
Why was Vioxx withdrawn
due to high chance of blood clots, strokes and heart attacks
NSAIDs should be avoided in
chronic kidney disease, peptic ulcer disease, history of GI blood
All NSAIDs when used in high doses can interfere with
bone healing
All NSAIDs carry what kind of risk
cardiovascular risk in patients with coronary heart disease in the short term, but this risk is highest in diclofenac and lowest in naproxen
Antiproliferative agents
methotrexate, cyclophosphamide, azathioprine
suppress B and T cell proliferation and function
leflunomide
inhibits T cell proliferation and B cell autoantibody production
IL-1 blocking agents
Anakinra (Kineret)
recombinant human IL-1 receptor antagonist
TNF-alpha blocking agents
Etanercept (Enbrel), infliximab (Remicade), adalimumab (Humira)
TNF-alpha agents used to treat
rheumatoid arthritis, Crohn’s, ulcerative colotis
All DMARDs can cause
fatal toxicities
Anti-gout drugs for acute gout
Colchicine and NSAIDs
MOA of colchicine
binds to tubulin, interferes with mitotic spindle function, causes depolymerization of microtubule
Anti-gout drugs for chronic gout
Allopurinol, Febuxostat, Probenecid
Allopurinol
inhibitor of xanthine oxidase
Febuxostat
new non-purine inhibitor of xanthine oxidase; more effective at reducing serum uric acid and tophus area than allopurinol
Probenecid
competes for renal tubular anion transporter; blocks active reabsorption of urate in proximal tubules; increases uric acid excretion
Ion channels that play an important role in the initiation and propagation of pain signals from the periphery
TRP, Nav and Cav channels - they can be targeted to provide analgesia
Blocking sodium channels prevents
hypopolarization/depolarization and thus blocks action potentials
Gain of function mutations of the sodium Nav1.7 channel causes
patients severe pain
Loss of function mutations of the sodium Nav1.7 channel causes
loss of pain sensation
Topical anesthetics
lidocaine, benzocaine, and oxybuprocaine (ophthalmology)
Sodium channel blockers
Lamotrigine (Lamictal), Amitryptilline (Elavil), and Carbamezipine (Tegretol)
Lamotrigine (Lamictal)
off label peripheral neuropathy, migraine
Stevens Johnson syndrome
Amitryptiline (Elavil)
post-herpetic neuralgia, polyneuropathy, fibromyalgia, visceral pain
Carbamezipine (Tegretol)
trigeminal neuralgia, bipolar disorder, seizures
teratogenic
Nortryptilic
metabolite of amitryptiline
Oxcarbazepine
fewer side effects than carbamezipine, excreted in breast milk
Sodium channel blockers with SNRI’s functionality
Duloxetine (Cymbalta), Venlafaxine (Effexor)
Duloxetine (Cymbalta)
SNRI; diabetic pain, fibromyalgia, and peripheral neuropathy
Venlafaxine (Effexor)
off label diabetic neuropathic pain; SNRI;non-selective opiod effects
SNRIs lacking sodium channel functionality
Milnacipran (SNRI, fibromyalgia); Tapentadol (NRI and MOR agonist, diabetic neuropathic pain)
SSRIs for pain associated depression
fluoxetine, paroxetine, setraline, escitalopram, citalopram
Major function of calcium channel blockers
heart rate, blood pressure
Calcium channel blockers
gabapentin, pregabalin, ziconotide, levetiracetam
