Lecture 10: Over The Counter Medication (Analgesics) Flashcards
What is the pain pathway?
neurons that detect sensory information in the periphery (i.e. skin, GI tract) are called primary afferents
primary afferents take all types of sensory information from the periphery to the spinal cord
primary afferent synapse onto secondary afferents in the spinal cord which pass sensory information up to the brain
motor efferents take motor commands from the brain and send them to the periphery (i.e. muscles)
What are nociceptors in relation to the sensation of pain?
pain is detected by a specific class of primary afferents called nociceptors
detect many types of painful stimuli (thermal, mechanical, chemical, electrical) –> polymodal nociceptors
nociceptors densely innervate every surface of our body
different types of painful stimuli are detected by specific receptors expressed on polymodal nociceptors
What are transient receptor potential (TRP) channels?
are temperature sensitive ligand-gated ion channels
different types of TRP channels are tuned to respond to very specific temperatures
these receptors can also be activated by ligands (TRPV1 –> capsaicin, TRPM8 –> menthol)
What receptors respond to inflammatory molecules?
other receptors respond to inflammatory molecules (bradykinin, cytokines, prostaglandins)
these are released from surrounding immune cells following tissue injury or infection
inflammation = pain
What is arachidonic acid?
fatty acid present in phospholipids of cell membranes
arachidonic acid is freed from the phospholipid molecule by the enzyme phospholipase A2
it is a key inflammatory mediator (released in response to tissue injury or infection)
What do the enzymes cyclooxygenase-1 and -2 (COX1, COX2) metabolize?
metabolize prostaglandins (PG), and thromboxanes (Tx)
prostaglandins and thromboxanes have diverse functions in the body (inflammation, body temperature regulation, platelet aggregation, renal function, etc.)
Why is prostaglandin E2 (PGE2) important in inflammation?
potent vasodilators
pyrogenic (fever)
attract immune cells (leukotactic) and coordinate the immune response
PGE2 also involved in producing gastric mucous, maintain optimal gastric pH
What is thromboxane A2?
thromboxane A2 signals to platelets to form a clot
it also causes vasoconstriction (narrows blood vessels)
What do the COX1 and COX2 do in the inflammation response?
both COX1 and COX2 enzymes contribute to the formation of prostaglandins and thromboxanes
however expression of cyclooxygenase enzymes is tissue specific
COX1 is primarily expressed in non-inflammatory cells (blood vessels, platelets, gastric mucosa), whereas COX2 is expressed in inflammatory cells
enzyme activity is either constitutive (always on) or inducible (must be activated by stimulus)
What is Asprin and other Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
asprin and other non-selective NSAIDs inhibit both cyclooxygenase isoforms (COX1 and COX2)
this decreases prostaglandin production that inhibits inflammation and reduces pain
these inhibitors also suppress prostaglandin synthesis in the brain then is stimulated by pyrogens and reduce fever (antipyretic action)
daily NSAIDs use also used to prevent platelet aggregation in those at risk of stroke or heart attack
What do NSAIDs and Asprin inhibit?
most NSAIDs inhibit the catalytic site of the cyclooxygenase enzymes (where arachidonic acid binds)
acetylsalicyclic acid (asprin) is a non-competitive, irreversible inhibitor; covalently (permanent) binds to the catalytic site of COX1 and COX2
this explains the long half life of aspirin, particularly for inhibiting platelet aggregation (~96 hours) because platelets are anucleated and make new proteins very slowly
What are some negative side effects of NSAIDs and Asprin?
non-selective NSAIDs associated with gastric toxicity (due to inhibition of COX1 enzymes in gastric mucosa)
chronic use can result in gastric ulceration, upper G1 bleeding an renal failure
Ketoralac (Toradol) is a highly efficacious non-selective NSAID (analgesic efficacy comparable to morphine)
recommended for short term use (post-surgical); however, chronic use pervasive in the NHL, has produced long term gastric issues in players
to bypass the gastric toxicity, specific COX2 inhibitors have been developed (e.g., celecoxib)
specific COX2 inhibitors are also associated with higher risk of cardiovascular toxicity (not OTC)
What is acetaminophen?
acetaminophen has been used in humans since the 1800s, but the mechanism of action of acetaminophen was unknown until very recently
it is a weak and reversible COX1 and COX2 inhibitor, so doesn’t work like other NSAIDS
turns out, it inhibits a third COX isoform (COX3) found most abundantly in the cerebral cortex
acetaminophen is an analgesic and antipyretic agent; lacks anti-inflammatory effects
What are the negative side effects of acetaminophen?
acetaminophen has negligible toxicity at therapeutic doses
when taking by overdose or in patients with liver impairment, can lead to liver damage and death
What was the first local anesthetic?
the first local anesthetic discovered was cocaine, serendipitously discovered to have anesthetic properties in the late 19th century (but probably way before that by indigenous tribes)
when the German chemist, Albert Niemann, isolated cocaine from the coca leaves, he noted that it numbed his tongue
introduced as a topical anesthetic for ophthalmological surgery
