ic13 analgesics Flashcards
(42 cards)
what are the types of analgesics
- NSAIDs
a) non selective NSAIDs
i) irreversible COX inhibitor: aspirin
ii) reversible COX inhibitor: naproxen, ibuprofen, diclofenac, mefenamic acid, idomethacin
b) selective NSAIDs (COX2 selective)
i) reversible COX2 inhibitor: celecoxib, parecoxib, etoricoxib - CNS selective COX inhibitor
i) reversible COX inhibitor: paracetamol - opioids/ narcotics: tramadol, codeine, morphine, oxycodone, fentanyl
where do each type of analgesic exert its action
i) brain: paracetamol acts by modulating how the brain is interpreting the pain signal
ii) spinal cord: opioids act by blocking the transmission of pain signals through the nerves of the spinothalamic tract (Adelta/C fibers)
iii) injury site: NSAIDs block the acute inflamm response at site of injury
what is “pain”
pain is the unpleasant sensory and emotional experience assoc with actual or potential tissue damage; pain is a subjective experience
what is “nociception”
process of detecting and signalling the presence of a noxious stimulus to the CNS
what occurs when there is damage to the cells
damage to the cells result in mobilisation of fragments of lipids in the phospholipid cell membrane and these phospholipids are acted on by phospholipase A2 to form arachidonic acid (AA) which are subsequently acted on by various enzymes to form eicosanoids which are lipoxins, prostanoids, leukotrienes
i) lipoxins are produced by 15-lipoxygenase
ii) prostanoids are produced by COX
iii) leukotrienes produced by 5-lipooxygenase
compare the types of inflamm related to prostanoids vs leukotrienes
prostanoids are more selective for acute inflamm response while leukotrienes are more selective in chronic inflamm and immune responses
compare the moa between steroids and NSAIDs
steroids: exert its action by blocking phospholipase A2 thus decreasing the production of eicosanoids
NSAIDs: exert its action by blocking COX thus decreasing the production of prostanoids which are more involved in acute inflamm; prostanoids include PGI2 (prostacyclin), PGE2 (prostaglandins), TXA2 (thromboxane)
relating to the moa of steroids, why is a common s/e of long term steroid use immunosuppression
steroids exert actions through blocking the activity of phospholipase A2 thus decreasing the production of eicosanoids which includes leukotrienes that is responsible for chronic inflamm and immune response (serves to activate the immune system) thus a decrease in leukotrienes results in immunosuppression
explain the rationale behind the clinical presentation of an injury or tissue damage
prostanoids produced by COX includes PGI2 (prostacyclin), PGE2 (prostaglandin), TXA2 (thromboxane)
PGI2 is responsible for
i) vasodilation (redness and heat)
ii) inhibition of PLT aggregation
PGE2 is responsible for
i) vasodilation (redness and heat); is technically a vasoconstrictor too but is mostly vasodilator
ii) increase vascular permeability (edema and swelling)
iii) pain
TXA2 is responsible for
i) vasconstriction
ii) promotes PLT aggregation
since different tissue types will have different ratio of various prostanoids produced (different extent of isomerases) thus different types of wounds will have slightly different presentations like open wound would try to produce more TXA2 vs closed wound would have more PGI2 production
explain how aspirin exerts its therapeutic effects
aspirin has anti-inflamm, analgesic and anti-pyretic and antiPLT effects
i) anti-inflamm: aspirin irreversibly inhibits COX which blocks the production of prostanoids (PGI2, PGE2, TXA2), and since prostanoids are more assoc with acute inflamm, blocking this acute inflamm suggests it blocks the vasodilation, vascular permeability and pain (vasodilation causes redness, heating and swelling; incr in vascular permeability causes edema and swelling; pain assoc w inflamm)
ii) analgesic: PGE2 sensitises the nociceptive fibers that transmit pain signals to activation by other inflamm mediators, thus aspirin blocking COX which reduces PGE2 production can help relieve pain (however note that since aspirin is blocking the sensitisation and not the direct nociceptive activation, aspirin has an analgesic ceiling)
iii) antipyretic: since aspirin blocks the production of prostanoids from COX and reduces acute inflamm response, it prevents activation of the immune system (neutrophils), as a result of tissue injury, infection and inflamm, in producing cytokines (IL1, TNFalpha, IL6) which typically signal the hypothalamus to incr the expression of PGE2 by COX which would raise the thermal set point of the body thus inducing a fever
iv) antiPLT: aspirin has a greater inhibition of COX1 compared to COX2 which are expressed on PLTs and endothelial cells; PLTs are cell fragments without a nuclei while endothelial cells have nuclei; COX1 in PLTs produces TXA2 while COX1 in endothelial cells produces PGI2; PLTs are unable to regenerate a new COX enzyme and lifespan of PLTs are 7-10d but endothelial cells are able to within a few hrs; TXA2 promotes PLT aggregation while PGI2 inhibits PLT aggregation thus aspirin can serve as an antiPLT
what is the difference between COX1 and COX2 which supports the antiPLT effect of aspirin
COX1 is constitutively expressed in most mammalian cells while COX2 is inducible and mainly plays a role in inflamm
do NSAIDs have action in the CNS
yes
why does PGE2 sensitise nociceptive fibers (and relate this to the analgesic effect of aspirin)
typically when there is tissue injury, bradykinin and leukotrienes are produced, both of which are potent activators of nerve terminals and thus would signal action potential to cause pain response
but when there is an addition of PGE2 production resulting from the tissue injury, the pain signal is heightened and since NSAIDs block the production of PGE2 through inhibition of COX, it can help to reduce the pain by decreasing the pain signal
why does aspirin have an analgesic ceiling (relate this to the severity of the pain)
aspirin is only useful in mild to moderate pain because in severe pain, the amount of bradykinin and leukotrienes produced is much larger which would trigger the nerve terminals to a large extent and since aspirin only blocks the production PGE2, the effect on the nerve terminals by bradykinin and leukotrienes is not addressed
what are the s/e of aspirin
aspirin has s/e relating to its salicylate chemical structure (which is dose dependent) and the typical s/e resulting from NSAID moa
SALICYLATE CHEMICAL STRUCTURE S/E
i) s/e that occur even within therapeutic range: GI intolerance, bleeding, hypersensitivity
ii) s/e that occur as a result of salicylate toxicity: tinnitus, central hyperventilation, respiratory alkalosis, renal and respiratory failure, HA, metabolic acidosis, dehydration, fever, vasomotor collapse, coma, hyperprothrombinemia
iii) linked to reye’s syndrome (with incr risk in children with viral infection) thus it is c/i in children (but also theres no pediatric formulation also)
TYPICAL NSAID S/E
i) GI related s/e (N/V, dyspepsia, risk of GI ulcer or bleed if chronic use of >5d)
ii) renal related s/e due to role of PGE2 and PGI2 (Na retention, H2O retention, peripheral edema, HTN, suppressed aldosterone and renin secretion, hyper K, AKI)
iii) pseudoallergy rxns
iv) asthma
v) bleeding
vi) effects on ovulation
vii) premature closure of ductus arteriosus (thus c/i in third trimester of pregnancy)
viii) impairment of wound healing (possible stop first then restart after ulcer healed)
what is “reye’s syndrome” and what are the sx and why is it of higher risk in children with viral infection
reye’s syndrome is the swelling of the brain and the liver
sx incl vomiting, personality changes, listlessness, delirium, convulsion, loss of consciousness, death (if pressure in brain not alleviated)
during a viral infection, there is rapid accumulation of fats in the liver and the brain
what is the role of prostaglandins (PG) in GI
i) decr gastric acid secretion
ii) incr mucosal blood flow
iii) incr secretion of mucus
iv) incr secretion of bicarb
environment in the stomach is very aggressive and thus need these protective mechanisms to protect the stomach wall
what are the NSAID s/e and elaborate on the rationale behind the occurrence of these s/e
- GI related s/e
i) N/V, dyspepsia
ii) risk of GI ulcer and bleed (risk incr greatly if chronic use of NSAID of >5d) - renal related s/e: arises as inhibition of PGE2 and PGI2 will alter the renal blood flow dynamics which is important in setting up the gradient for glomerular filtration and electrolyte movements
i) inhibition of PGE2 secretion results in Na retention, H2O retention, peripheral edema and HTN
ii) inhibition of PGI2 secretion results in suppressed aldosterone and renin secretion, hyperK and acute renal failure (what are the RF?)
(at the TAL, PGE2 is responsible for inhibiting the reabsorption of Na which accounts for approx 25% of Na thus inhibiting the production of PGE2 would result in reabsorption of Na at the TAL; at the DCT, PGI2 stimulates the secretion of aldosterone and renin to reabsorb 1-2% of Na but due to the suppressed secretion of aldosterone and renin, this reabsorption of Na does not occur but it is insufficient to correct the 25% Na reabsorption at the TAL) - pseudo allergic rxn (sx incl rashes, swelling, itching, nasal congestion, anaphylactic shock) bc inhibition of COX pathway leads to overflow of AA into the other two paths and thus it results in an increased production of LT such as LTD4 which can cause bronchospasm and allergic rxn like sx
- asthma due to bronchospasm
- bleeding (esp so for agents with COX1 > COX2 inhibition like aspirin) bc of failure of homeostasis
- s/e arising from COX2 inhibition (constitutive COX2i)
i) renal related s/e (as per above bc kidney has constitutive expression of both COX1 and COX2)
ii) effects on ovulation
iii) premature closing of ductus arteriosus
iv) impairment of wound healing
what is the caution and c/i for NSAIDs
i) urticaria, nasal polyps and asthma due to the incr risk of bronchospasm and pseudoallergic rxn
ii) caution for surgical procedures esp if pt is on blood thinners
iii) severe kidney impairment (eGFR <30)
iv) severe HF
v) active GI ulcer or bleed
vi) bleeding disorders (eg. hemophilia)
vii) use of systemic corticosteroids or antiPLT or anticoags
viii) multiple risk factors for NSAID toxicity (eg. elderly pt w hx of GI bleed)
ix) third trimester of pregnancy
how might you differentiate between a pseudo allergy and a true allergy
pseudo allergy would imply that there is similar rxn across drugs of the same class while a true allergy implies that the Ab for the true allergy would be against the chemical structure of that particular drug
what are the eg. of typical NSAIDs
naproxen, ibuprofen, diclofenac, indomethacin, mefenamic acid
compare the properties across the typical NSAIDs (eg. PK properties like F and halflife, indications, therapeutic effects, s/e, formulations)
NAPROXEN:
i) more effective in women and thus lower doses can be used (free fraction of drug is >40% greater in females = drug is less bound to plasma protein and more avail)
ii) long half life of 12-14hr allows it to have BD dosing (comparison to aspirin is q4-6hr)
iii) often used for dysmenorrhea
DICLOFENAC:
i) short plasma half life of <2hr but bc longer half life in synovial joint fluid, it is effective for inflamm joint diseases
ii) short plasma half life also decr the extent of GI s/e
iii) can be applied topically
INDOMETHACIN:
i) strongly anti-inflamm due to inhibition of phospholipase A that is similar to steroids
ii) but more CNS s/e like confusion, depression, psychosis, hallucinations
iii) thus used less commonly now and only for RA mostly
what are the risk factors for NSAID induced AKI
i) age (>65yo), chronic HTN, atherosclerosis: narrowing of renal arterioles which reduces its capacity for renal afferent dilatation
ii) pre existing glomerular disease or renal insufficiency: requires afferent vasodilation to maintain GFR but NSAIDs causes vasoconstriction of afferent arteriole due to inhibition of PGE2 and PGI2
iii) volume depletion (true or effective): true volume depletion causes incl GI or renal salt and water losses, blood loss, diuretic use; effective volume depletion causes incl HF, cirrhosis; volume depletion lowers afferent glomerular arteriolar pressure and stimulates the secretion of angiotensin II (which acts on the efferent arterioles and causes efferent arterioles to contract)
iv) ACEi/ARBs: ACEi inhibits the action of angiotensin II which acts at the efferent arteriole to cause vasoconstriction, thus there is vasodilation in the efferent arteriole (these agents prevents vasoconstriction of efferent arterioles important to maintaining GFR bc glomerular filtration rate is directly proportional to the pressure gradient in the glomerulus)
v) triple whammy of ACEi with diuretics with NSAIDs: diuretics leads to volume depletion thus it reduces renal blood flow, ACEi/ARBs inhibit angiotensin converting enzyme and causes vasoconstriction of efferent arteriole, NSAIDs inhibits COX1 and COX2 which affects PG and causes vasodilation of afferent arteriole
differentiate between COX1 and COX2 in terms of ints func and locations where it is mostly found at
COX1: constitutive and play a greater role in housekeeping and normal physiological function in cells and tissues, found in stomach, intestine, kidney, PLT
COX2: inducible COX2 more involved with inflamm response and tissue repair occuring after inflamm response, present in macrophages, leukocytes, fibroblasts, endothelial cells; constitutive COX2 also present in CNS, kidney, female reproductive tract, synovium
