IC13 analgesics

Question 1

what is the phospholipase a2 breakdown

Answer 1

phospholipase A2
= arachidonic acid
= cox, and lipoxygenase
cox
= 1) PGE2 (prostaglandins) = for pain and vascular permeability
= 2) PGI2 (prostacyclin) = for vasodilation and inhibiting platelet aggregation
= 3) TXA2 = for vasoconstriction and platelet aggregation

Question 2

what does corticosteroids and nsaids inhibit in the phospholipase a2 breakdown

Answer 2

steroids = inhibit phospholipase a2 directly

NSAIDs = cox

Question 3

mechanism of action of nsaids

Answer 3

block production of prostaglandins
role of prostaglandins is to increase the sensitisation of nociceptive fibres to stimulation by other inflammatory mediators.
*note that leukotrienes and bradykinin are also sensitisers…

also has additional analgesic actions in the CNS.

Question 4

mechanism of antipyretic action of aspirin

Answer 4

cox inhibition (and prostaglandin) in the hypothalamus of the brain = reducing body temperature

• note that it does not alter normal body temperature.

Question 5

what is the mechanism of aspirin ADRs?

Answer 5

low dose is due to cox inhibition,

high dose is due to salicylate toxicity.

Question 6

what are the aspirin side effects related to salicylate toxicity?

Answer 6

tinnitus
uricosuric
central hyperventilation
respiratory alkalosis
metabolic acidosis
respiratory alkalosis
fever, dehydration
hypothrombinaemia
vasomotor collapse
coma
respiratory and renal failure

Question 7

what is rare condition associated w aspirin and what increases risk

Answer 7

risk increases if aspirin taken by children with viral infections

causing reyes syndrome = swelling of brain (encephalitis) AND liver

sx ( vomiting, personality change, listlessness [no interest], delirium, convulsions, LOC)

Question 8

additional mechanisms and side effects of indomethacin?

Answer 8

strongly anti-inflammatory due to additional steroid-like phospholipase A inhibition

HOWEVER CNS effects: confusion, depression, psychosis, hallucinations.

Question 9

additional mechanisms of diclofenac (relate to side effects)?

Answer 9

short half-life in plasma (less GI risk)

longer half life in synovial fluid = useful in inf joint disease

Question 10

effects of prostaglandins on GI?

Answer 10

more specifically cox1
reduce gastric acid secretion
increase mucosal blood flow
increase secretion of mucus
increase secretion of bicarbonate

Question 11

GI related side effects of NSAIDs

Answer 11

dyspepsia, NV
ulcer formation
potential haemorrhage

increase risk of peptic ulcer if >5 days of use

Question 12

renal adverse effects of NSAIDs?

Answer 12

inhibition of PGE2 and PGI2

PGE2 inhibition:
- sodium (pge2 inhibits na+ reabsorption in TAL thick ascending limb) and water retention, peripheral edema, hypertension

PGI2 inhibition
- suppression of RAA
- hyperkalemia (pgi2 stimulates secretion of RAA; RAA involved in k+ excretion & na+ reabsorption; distal convoluted tubule DCT)
- acute renal failure

Question 13

risk factors for NSAIDs-induced AKI

Answer 13

1) increasing age >65yo), chronic HTN, atherosclerosis = narrowing of renal arterioles (reduced capacity for renal afferent dilation)

2) pre-existing glomerular disease or renal insufficiency = renal afferent dilation (to maintain GFR)

3) volume depletion
- true: gi/renal salt and water loss, blood loss, diuretic use
- effective: cirrhosis, heart failure
= stimulates AngII secretion

4) ACEi/ARB
= prevent efferent vasoconstriction to maintain GFR

5) triple whammy: acei/arb + diuretic + nsaid

Question 14

resp/derm side effects of NSAIDs and caution

Answer 14

psuedo-allergic side effects
- skin rash, swell, itching, nasal congestion, anaphylactic shock

asthma

caution in patients with asthma, chronic urticaria, nasal polyps

Question 15

mechanism of resp/derm SE of NSAIDs

Answer 15

cox inhibition = increased AA = increase leukotrienes = bronchospasm in asthmatics (LTD4) and allergic reaction like symptoms.

Question 16

heme side effect of NSAIDs (incl mechanism) and caution?

Answer 16

bleeding risk (higher risk in cox 1 > cox 2)

caution in patients who are going for surgical procedures or are initiated on antiplatelet therapy

Question 17

advantage of cox2 over cox 1

Answer 17

cox 2 plays a more significant role in inflammation and analgesia(?)

cox 1 involved in housekeeping.

Question 18

where is cox2 expressed in?

Answer 18

CNS
renal
female reproductive tract
synovium

Question 19

what are some unwanted SE of cox2 inhibition? (and related contraindications)

Answer 19

1) renal toxicity

2) effects on ovulation - delayed follicular rupture.

3) premature closing of ductus arteriosus (fetal lung bypass) in late pregnancy

CONTRAINDICATED IN THIRD TRIMESTER OF PREGNANCY (last pregnancy)

Question 20

impact of cox2 inhibition on wound healing?

Answer 20

cox2 inhibitors impair wound healing and may exacerbate ulcers.

Question 21

impact of cox2 inhibition on heme?

Answer 21

selective inhibition causes a relative increase in TXA2 = increase in platelet aggregation = increased risk of thrombosis

Question 22

heme caution in nsaids? include mechanism

Answer 22

renal effect = hypertension
prothrombotic effect

= risk of heart attack and stroke.

caution
in elderly and
hx of Cardio/CerebroVD (CVD)

Question 23

overall contraindications for nsaids:

Answer 23

1) eGFR <30 (severe kidney impairment)
2) severe heart failure
3) active GIT ulcer or bleeding
4) bleeding disorders eg haemophilia
5) use of systemic corticosteroids /antiplatelets/ anticoagulants
6) multiple risk factors for toxicity eg elderly + history of bleeding
7) third trimester of pregnancy

Question 24

which are the cox 2 selective nsaids?

Answer 24

mefenamic acid
celecoxib
diclofenac
etoricoxib

Question 25

possible MOA for paracetamol

Answer 25

CNS selective cox inhibition
useful as an antipyretic

Question 26

disadvantages of paracetamol

Answer 26

weak anti-inflammatory
toxic doses can cause
- N/V and
- liver damage

Question 27

mechanism of paracetamol toxicity

Answer 27

chronic alcohol use or abuse

and overdose

causes an increase in toxic metabolites (minor pathway) = hepatotoxicity

glutathione METABOLISES toxic metabolite to non toxic, but is depleted by alcohol and paracetamol overdose

Question 28

how to reverse paracetamol toxicity

Answer 28

NAC helps to replenish glutathione.

Question 29

counselling for paracetamol,

Answer 29

caution (and dose reduction) in underweight, significant liver disease, cachectic (weakness/wasting), frial.

AVOID ALCOHOL

Question 30

overdose of paracetamol and relevant procedures?

Answer 30

if ≥10g/day = ED
if ≥4g per 24h = increase risk of harm

Question 31

paracetamol and nsaid combination?

Answer 31

alternating ibuprofen and paracetamol can have sustained antipyretic effect

but combining can have synergistic analgesic effect.

Question 32

additonal moa of tramadol

Answer 32

weak opiod + SNRI

Question 33

opioid analgesic side effects

Answer 33

GI: N/V consitpation
hormonal & respiratory effects
depression

falls and fractures
sedation or drowsiness

tolerance, physical dependence, addiction, withdrawal

opioid-induced hyperalgesia

Question 34

opioid risk factors

Answer 34

1) combination w cns depressants
2) mental health condition
3) renal/hepatic insuff
4) >65 yo
5) pregnant
6) history of substance abuse disorder

Question 35

MOA of orphenadrine

Answer 35

tertiary amine that cross BBB
muscarinic receptor antagonist
central muscle relaxant

additionally: h1, NMDA, NE, DA reuptake inhibitor, CCB

Question 36

adr of orphenadrine

Answer 36

common: N/V,
Anticholinergic: flushing, dilated pupils. dry mouth

high dose:
CV: tachycardia,
Motor: ataxia, nystagmus,
CNS: drowsiness, delirium, agitation, visual hallucinations

Question 36

drug drug interactions with orphenadrine

Answer 36

combination w cns sedatives/depressants = caution

may have additive DDI with 1st gen antihistamines, anticholinergics, and antiparkinsonian drugs.