7.8 (9.6) Non-opioid analgesics Flashcards
What are 2 major types of non opioid analgesics?
What 2 properties do they exhibit?
NSAIDs
acetaminophen
analgesic & antipyretic properties
List four advantages pertaining to the use of non opioid analgesics
effectiveness for mild pain conditions* ease of administration additive analgesia when combined with other analgesics familiarity to patients* wide availability* low cost*
List two major disadvantages of NSAIDs
ceiling effect for analgesia
risk of SE (GI, renal, hepatic, cardiovascular)
How are prostaglandins formed?
List 4 functions of prostaglandins
List 3 types of prostaglandins
PGs are lipid soluble molecules that are produced by the enzymatic breakdown of arachidonic acid (which is produced by cell membrane phospholipids)
Functions:
-mediate inflammation and pain
-protect gastric mucosa
-maintain normal renal function
-modulate platelet aggregation
FS:
1. Cell membrane produces arachnoid acid
2. COX enzymes breakdown arachnoid acid to PGs (PGE2, PGI2, TXA2)
List three factors which stimulate local production of COX2 enzyme
What are 3 subsequent effects of this?
Factors:
- tissue damage*
- inflammatory cytokines (IL-1, IL-6, TNF-alpha) *
- substance P*
- bradykinin
Effects:
- inflammation
- pain
- fever
How do NSAIDs produce their effects
inhibit COX1 and COX2 enzymes - therefore decrease PG production = decrease pain, inflammation, fever (also affect stomach, kidney, vasculature)
(Note coxibs inhibit COX2 to a greater degree)
FS:
Stomach: COX 1 -> PGE2 -> stomach protection
Kidney: COX1 + COX2 -> PGE2 -> kidney vasodilation + decrease Na and water
Vasculature:
COX1 -> TXA2 -> plt aggregation (+)
COX2 -> PGI2 -> plt -
How do NSAIDs cause renal toxicity?
COX-1 is also responsible for the synthesis of PGE2, which in addition to vasodilatation during inflammatory processes counteracts vasoconstriction in the kidneys.
Under normal physiological conditions, the PG synthesis activity in the kidney is low and its role in modifying renal blood flow (RBF) is minimal
However, if RBF is critically lowered, glomerular filtration rate (GFR) may be partly restored by vasodilatatory effects of PGE2.
If PGE2 production is reduced due to the use of NSAIDs, volume depletion of different aetiologies may aggravate the reduction of RBF.
Inhibition of PGs may also result in a higher extracellular concentration of electrolytes such as sodium, which may cause water retention and oedema.
FS:
1. NSAID inhibits cox 1 and 2 enzymes in kidney
2. Cox-inhibition decrease PGE2 production
3. Less PGE2 = decrease vasodilation in kidney to restore GFR (when renal blood flood is lowered)
3. Less PGE2 = na + water retention = edema
Where are NSAIDs absorbed?
What is their plasma protein binding like?
Where are they metabolized and by what process?
How are they eliminated?
absorbed in upper GI tract, stomach mucosa may also absorb substantial proportion of dose
highly protein bound 90-99%
metabolized by liver by CYP450 enzymes
eliminated by urine in free and conjugated forms, small amount in bile/fecal
Which NSAID has the shortest time to peak concentration? Which has the longest half life?
ibuprofen peak plasma concentration 15-30min*
longest t1/2
-meloxicam 24h*
-etoricoxib 20h-26h
- naproxen 14h*
List four GI side effects of NSAIDs
pain*
heartburn
nausea
Bleeding *
gastric erosion/ulceration*
perforation*
List four renal side effects of NSAIDs
water and Na retention*
Edema*
Kidney failure *
Hyper-K*
decreased effectiveness of antihypertensives and diuretics
List four CNS side effects of NSAIDs
HA confusion Dizzy vertigo depression
What is the benefit of COX-2 selective inhibition?
What is the impact of concurrent ASA use for cardioprotection?
Stomach production of PG is COX1 activity —> COX2 selective inhibition drugs produce significantly less GI ulcers and ulcer complications
ASA reduce GI benefit of coxibs (while decreasing risk of stroke/MI)
28% reduction in GI ulcers of patients taking Coxib + ASA vs non-selective + ASA
Rank the following NSAIDs in order of the lowest risk of GI side effects to highest risk
Group 1:
ASA
Ketorolac
Group 2:
Indomethacin
Naproxen
Group 3:
Celecoxib
Ibuprofen
Diclofenac
celecoxib
ibuprofen (advil)
diclofenac (voltaren)
——
indomethacin
naproxen
——
ASA
ketoralac
No specific order in each group
List 3 key factors that may worsen an individual’s risk of GI toxicity from NSAIDs
List 3 comorbidities that would increase risk of GI toxicity
~~~
NSAID duration of use
NSAID dose (higher increases risk)
Comorbidities:
V - recent stomach ulceration/bleed
I - H pylori infection
N - stomach cancer
D - cardiovascular/renal/hepatic impairment, age > 65
I - Concurrent anticoagulants/ASA or corticosteroids, etoh, smoking
C
A
T
E - DM
What 2 meds can be used with NSAIDs to limit GI side effects?
Do they have a role with COX 2 inhibitors?
PPI or misoprostol
Yes can combine with COX2 inhibitors to reduce risk of bleeding further (28%)
What is the cause of NSAID prothrombotic effect? (Especially with COXIBs)
What complications can this result in (2 examples)
COX 1 facilitates TXA2 production = potent vasoconstrictor and promotes platelet aggregation
COX 2 facilitates PGI2 production = decrease platelet aggregation
When there is greater COX2 inhibition > COX1 inhibition = less PGI2 and more TXA2 activity = prothrombic effect (example:
Coxibs)
All NSAIDs may be prothrombotic because all have an inhibitory effect on COX-2
Complications:
-stroke
-MI
List 2 major contraindications and 2 relative contraindications to use of NSAIDs
Contraindications
◆ high risk of GI hemorrhage
or
◆ unlikely to cope with bleeding should it occur:
- hemorrhage within last year
- hx of peptic ulcer disease
- NSAID induced gastroduodenopathy
- advanced age
- severe medical frailty
- concurrent tx which inc risk (ex. corticosteroid)
Relative Contraindications:
◆ clinically significant renal insufficiency
◆ hepatic disease
◆ those predisposed to cardiovascular outcomes
- hx of symptomatic atherosclerotic disease (MI, stroke, angina, TIAs, symptomatic PVD),
- poorly controlled HTN
- hyperlipidemia
- smoking
◆ NSAID induced asthma
◆ inflammatory bowel disease
◆ drugs inc risk:
- anticoagulant therapy
◆ drug drug interactions
- lithium
- phenytoin
What is the mechanism of action of ASA’s antithrombotic effects?
What is the effect of ASA on platelets?
ASA IRREVERSIBLY inhibits both COX-1 and COX-2 (more so COX 1)
Platelets are particularly susceptible to ASA because they have limited capacity for protein synthesis (ie cannot regenerate COX enzymes). A single dose of ASA will thus irreversibly inhibit the COX enzymes for the lifetime of the platelets!
What is the mechanism of action of acetaminophen?
What is its site of action?
Mechanism of action is poorly understood - Cox inhibition in central nervous system to reduce pain, inflammation, fever (in a different way than NSAIDs)
site of action seems to be brain
Where is acetaminophen absorbed?
What is its plasma protein binding like?
How long until peak concentration reached?
Where is it metabolized and how?
Where is it eliminated?
rapidly and almost completely absorbed from GI tract
-gastric emptying rather than diffusion across GI membrane is the rate limited effect
small protein binding 5-20%
peak concentration 30-60min
metabolized in liver via oxidative reactions by p450 enzymes
After therapeutic doses, 90–100% of the drug may be recovered in urine within the first day, primarily after hepatic conjugation with glucuronic acid (about 60%), sulphuric acid (about 35%), or cysteine (about 3%); small amounts of hydroxylated and deacetylated metabolites also have been detected
What is the major side effect concern with acetaminophen?
How does it occur and how is it treated?
Liver toxicity
A small proportion of paracetamol undergoes P450-mediated N-hydroxylation to form N-acetyl-benzoquinoneimine, a highly reactive intermediate metabolite. This metabolite normally reacts with sulfhydryl groups in glutathione.
At large doses of paracetamol (usually considered in those without liver disease to be a single dose > 10 g), the metabolite is formed in sufficient amounts to deplete liver cells completely of glutathione, which seems to trigger hepatotoxicity
Intervention: N-acetyl-L-cysteine (NAC) replenishes glutathione stores
FS:
Portion of tylenol is metabolized into toxic metabolite -> deplete glutathione in liver cells -> toxic
Where do COX 1 and COX 2 enzymes work?
COX 1 works in stomach, kidney and vasculature (platelets)
COX 2 works in kidney and vasculature
