7.8 (9.6) Non-opioid analgesics

Question 1

What are 2 major types of non opioid analgesics?

What 2 properties do they exhibit?

Answer 1

NSAIDs
acetaminophen

analgesic & antipyretic properties

Question 2

List four advantages pertaining to the use of non opioid analgesics

Answer 2

effectiveness for mild pain conditions*
ease of administration
additive analgesia when combined with other analgesics

familiarity to patients*
wide availability*
low cost*

Question 3

List two major disadvantages of NSAIDs

Answer 3

ceiling effect for analgesia

risk of SE (GI, renal, hepatic, cardiovascular)

Question 4

How are prostaglandins formed?

List 4 functions of prostaglandins

List 3 types of prostaglandins

Answer 4

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)

Question 5

List three factors which stimulate local production of COX2 enzyme

What are 3 subsequent effects of this?

Answer 5

Factors:
- tissue damage*
- inflammatory cytokines (IL-1, IL-6, TNF-alpha) *
- substance P*
- bradykinin

Effects:
- inflammation
- pain
- fever

Question 6

How do NSAIDs produce their effects

Answer 6

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 -

Question 7

How do NSAIDs cause renal toxicity?

Answer 7

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

Question 8

Where are NSAIDs absorbed?

What is their plasma protein binding like?

Where are they metabolized and by what process?

How are they eliminated?

Answer 8

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

Question 9

Which NSAID has the shortest time to peak concentration? Which has the longest half life?

Answer 9

ibuprofen peak plasma concentration 15-30min*

longest t1/2
-meloxicam 24h*
-etoricoxib 20h-26h
- naproxen 14h*

Question 10

List four GI side effects of NSAIDs

Answer 10

pain*
heartburn
nausea
Bleeding *
gastric erosion/ulceration*
perforation*

Question 11

List four renal side effects of NSAIDs

Answer 11

water and Na retention*
Edema*
Kidney failure *
Hyper-K*
decreased effectiveness of antihypertensives and diuretics

Question 12

List four CNS side effects of NSAIDs

Answer 12

HA
confusion
Dizzy 
vertigo
depression

Question 13

What is the benefit of COX-2 selective inhibition?

What is the impact of concurrent ASA use for cardioprotection?

Answer 13

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

Question 14

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

Answer 14

celecoxib
ibuprofen (advil)
diclofenac (voltaren)
——
indomethacin
naproxen
——
ASA
ketoralac

No specific order in each group

Question 15

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

Answer 15

~~~
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

Question 16

What 2 meds can be used with NSAIDs to limit GI side effects?

Do they have a role with COX 2 inhibitors?

Answer 16

PPI or misoprostol

Yes can combine with COX2 inhibitors to reduce risk of bleeding further (28%)

Question 17

What is the cause of NSAID prothrombotic effect? (Especially with COXIBs)

What complications can this result in (2 examples)

Answer 17

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

Question 18

List 2 major contraindications and 2 relative contraindications to use of NSAIDs

Answer 18

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

Question 19

What is the mechanism of action of ASA’s antithrombotic effects?

What is the effect of ASA on platelets?

Answer 19

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!

Question 20

What is the mechanism of action of acetaminophen?

What is its site of action?

Answer 20

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

Question 21

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?

Answer 21

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

Question 22

What is the major side effect concern with acetaminophen?

How does it occur and how is it treated?

Answer 22

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

Question 23

Where do COX 1 and COX 2 enzymes work?

Answer 23

COX 1 works in stomach, kidney and vasculature (platelets)

COX 2 works in kidney and vasculature