Analgesics - NSAIDs Flashcards
galenicals
- drugs derived from plants with no attempt to purify it –> use the whole plant (ex. tea is a galenical preparation of caffeine)
- both opioids and NSAIDs were originally galenicals
types of chemical messengers
hormones - peptides and steroids, widely distributed
paracrine - local action hormones (autocoids), somewhat spread but mostly localized
neuromodulators - from synapse
neurotransmitters - within the synapse, released from presynaptic neurons into synapse to postsynaptic neurons and stay localized there
types of autacoids at free nerve endings involved in pain
eicosinoids: derived from phospholipids (ex. prostaglandins)
peptides: from AAs (ex. bradykinin, substance P, CGRP)
histamines: modified AAs released from mast cells and WBCs
history of NSAIDs
- willow bark tea was used for a long time in folk medicine
- 18th century entered western medicine
- 19th century - pure salicin extract was extracted and then more grips were added to make it more long lasting to make the semisynthetic acetyl salicylic acid
- now we have made pure synthetics like tylenol
common types of NSAIDs
salicylates - acetylsalicylic acid or ASA (aspirin)
para-aminophenols - acetaminophen (Tylenol)*
phenylproprinoic acid derivatives - ibuprofen (Advil)
napthylpropionic acid derivatives - naproxen (aleve) phenyl acetic acids - diclofenac (voltaren)
*should technically not be included because it is not anti inflammatory
NSAID typical actions
- analgesic: stops mild pain, low ceiling, no tolerance, no abuse or addiction potential
- antipyretic: lower fever
- anti-inflammatory: stops redness, swelling, joint pain
- anti-clotting: helps to prevent stroke
- uricosuric: for gout
NSAID indications
- mild to moderate pain: arthritis, headache, muscle ache
- some people use them to sleep because it takes away pain which allows them to sleep but they’re not hypnotics
NSAID side effects
- stomach upsets (10-20%), ulcers, bruising, bleeding, tinnitus
- acetaminophen and coxs don’t cause GI issues
- acetaminophen does cause liver failure at high doses - more common cause of liver failure/drug OD in north america
NSAID mechanism of action
- inhibit enzyme cyclooxyrgenase (COX)/prostaglandin syntheses that converts arachidonic acid to endoperoxidase intermediates prostaglandins PGG2 and PGH2
- by blocking COX they block prostaglandin release
- don’t block main pain signal, only block sensitization of free nerve endings –> low ceiling effect
- takes place at free nerve endings that generate pain signals
- competition is non competitive for ASA and competitive for NSAIDs
- cyclooxyrgenase has 3 forms (1,2,3), humans only have 1 and 2 but most drugs bind all forms
What is non-competitive (covalent) and competitive binding? Which drugs use which binding pattern?
Non-competitive/covalent: ASA
- drug binds permanently
- kills receptors because they are occupied
- ASA permanently inactives COX1 and COX2 - analgesic effects last long because the body needs more time to synthesize more enzyme
competitive: all other NSAIDs
- bind weakly
- come on and off
what drugs block the conversion of phospholipids? arachidonic acid?
phospholipids
- steroids by blocking phospholipase A2
- steroids and glucocorticoids - main use in inflammation
arachidonic acid
- NSAIDs block COX 1 and COX2
challenges to the classic story of NSAID MOA
- acetaminophen only weakly inhibits COX1 and COX2
- NSAIDs may have actions in addition to their effects on COX
- may act centrally on brain to block signal there as well as peripherally
(we know they work peripherally because topical NSAIDs are effective)
what occurs at the site of injury?
- pain and inflammation (swelling, redness, heat)
- inflammation is mediated by autocoids - some can lower pain threshold
- they’re not the pain stimulus but they increase response to pain stimulus
paracrine at injury site that lower pain threshold and increase inflammation
- prostaglandins (eicosinoids synthesized from membranes)
- lower pain threshold for receptors (TRPs) and trigger inflammation
- touch becomes more painful
- receptors for prostaglandins are on free nerve endings - bradykinin (peptide from precursor in blood)
- dilates look vessels (part of inflammation)
- lowers pain thresholds on receptors on primary afferent on free nerve endings (TRPs)
- we used to think these were the one pain stimulus
paracrine at injury site that increase inflammation
- histamines (modified from AA histadine)
- triggers inflammatory response
- dilates blood vessels - substance P and CGRP (peptides released from primary afferents from both ends - free nerve ending and spinal cord)
- trigger inflammation at site of injury
- helps pain signal get through
5HT, ATP
these also lower pain threshold but not to the same extent
