PHARM Y1 S2: Anti-Inflammatory Agents

Question 1

inflammatory mediators which induce and potentiate pain

Answer 1

• induce: histamine, bradykinin, 5-HT (serotonin)
• potentiate (amplify): eicosanoids (e.g. prostaglandins)

Question 2

prostacyclin (PGI2)
- where is it made
- what are its functions

Answer 2

• made in endothelium
• function: vasodilation, hyperalgesic, decreased platelet aggregation

Question 3

location and function of PGD2

Answer 3

• mast cells
• vasodilation
• decreased platelet aggregation
• GIT relaxation

Question 4

location and function of PGE2

Answer 4

• GIT
• vasodilator
• decreased gastric acid secretion
• fever
• hyperalgesia

Question 5

location and functions of PGF2a

Answer 5

• myometrium and lungs
• bronchoconstrictor
• myometrial contraction

Question 6

thromboxane (Txa2) location and function

Answer 6

• generated in platelets
• promotes thrombosis
• vasoconstriction

Question 7

what do NSAIDs target?

Answer 7

• inhibit cyclo-oxygenases which convert arachidonic acid into prostaglandins
• decreased prostaglandins = decreased inflammation

Question 8

function of COX-1 and what eicosanoids does it generate?

Answer 8

• “constitutive”, involved in housekeeping and homeostasis
• generates PGD2, PGE2, PGI2, thromboxane (TxA2), PGF2a,

Question 9

function of COX-2 and what eicosanoids does it generate?

Answer 9

• induced in inflammatory cells when activated = “inducible”
• generates PGD2, PGE2, PGI2 (NOT TxA2 or PGF2a - these are COX-1)

Question 10

side effects of non-selective COX inhibitors (i.e. target both COX-1 and COX-2)

Answer 10

• increased bleeding time b/c decreased TxA2 (COX-1) = decreased clotting
• peptic ulcers b/c decreased PGE2 (COX-1 and 2) = increased gastric acid secretion = GIT irritation
• exacerbation of asthma b/c arachidonic acid is instead converted into leukotrienes by lipoxygenase > bronchoconstrictors

Question 11

how are NSAIDs metabolised?

Answer 11

• by CYP-450 enzymes in liver

Question 12

aspirin: MOA and function

Answer 12

• @ low doses: selective IRREVERSIBLE COX-1 inhibitor > anti-clotting
• @ higher doses: non-selective COX inhibitor > anti-inflammatory, analgesic, antipyretic

Question 13

why is aspirin more readily absorbed in the stomach?

Answer 13

• aspirin is a weak acid
• therefore in acidic environments it becomes unionised and therefore more lipid soluble

Question 14

how does aspirin overdose work?
- Sx and Tx

Answer 14

• too much aspirin = saturate the enzymes that break it down into salicylic acid
• Sx: tinnitus, deafness, confusion, convulsions, coma, death
• Tx: CVS and resp support, then correct acid-base balance

Question 15

how to correct acid-base balance re: aspirin overdose

Answer 15

• activated charcoal: porous and binds to aspirin > prevent further absorption and promote excretion
• rid body of salicylic acid: forced alkaline diuresis using IV bicarbonate or haemodialysis (severe)

Question 16

ibuprofen AND diclofenac (voltaren)
- MOA
- functions
- side effects

Answer 16

• inhibits both COX-1 and COX-2
• anti-inflammatory, analgesic, antipyretic
• increased bleeding, peptic ulcers, renal effects

Question 17

celecoxib AND meloxicam
- MOA
- functions
- risks

Answer 17

• selective COX-2 inhibitor
• decreases inflammation w/ LESS GI effects
• analgesic, anti-inflammatory, antipyretic
• increase risk of AMI due to inhibition of PGI2 (anti-clot), allowing TxA2 (pro-clot) to dominate
• more sodium retained since PGE2 is inhibited = increased BP = risk of AMI

Question 18

paracetamol
- MOA
- function

Answer 18

• simple analgesic + antipyretic, unknown MOA
• no anti-inflammatory effect and avoids GI side effects b/c not impacting COX-1 and 2
• useful when aspirin is contraindicated e.g. peptic ulcer, coagulation disorder

Question 19

paracetamol overdose
- what happens?
- why might this occur?

Answer 19

• lots of paracetamol = saturate enzymes which make it water soluble in liver = instead converted to toxic metabolite NAPQI = liver damage
• can occur due to deliberate poisoning, accidental paediatric exposure, inadvertent repeated subtherapeutic ingestions

Question 20

treatment for paracetamol overdose

Answer 20

• N-acetylcysteine
• inactivates toxic metabolite NAPQI so it can be excreted

Question 21

breakdown of membrane phospholipid > prostaglandin production pathway

Answer 21

Question 22

analgesic ladder

Answer 22

• start w/ simple analgesics (paracetamol)
• then NSAIDs if inflammation present
• then weak opioids +/- simple analgesics
• then strong opioids +/- simple analgesics

Question 23

function of adrenal cortex

Answer 23

• zona glomerulosa (outermost layer): mineralocorticoids
• zona fasciculata: glucocorticoids
• zona reticularis: androgens (sex hormones)
• all have cholesterol as a precursor

Question 24

glucocorticoids function

Answer 24

• slow onset of action
• regulate CHO and protein metabolism (stress response)
• anti-inflammatory (can also address loss of function) and immunosuppressive

Question 25

mineralocorticoids function

Answer 25

- regulate water and electrolyte (Na/K) balance

Question 26

Addison's disease, Sx, Tx

Answer 26

- deficiency in synthesis of endogenous hydrocortisone due to sudden withdrawal of glucocorticoids - Sx: weakness, lethargy, dehydration, hypotension - Tx: hydrocortisone replacement therapy

Question 27

MOA of glucocorticoids

Answer 27

- enter cell and bind to glucocorticoid receptor in cytosol - moves to nucleus (NUCLEAR RECEPTORS) and decreases transcription of inflammatory cytokines OR increases anti-inflammatory proteins e.g. lipocortin-1 - this inhibits phospholipase A2 which converts membrane phospholipids into arachidonic acid (prevents synthesis of leukotrienes = prevent bronchoconstriction)

Question 28

endogenous vs synthetic glucocorticoids

Answer 28

- endogenous glucocorticoids possess mineralocorticoid activity which can lead to side effects - exogenous: no mineralocorticoid activity

Question 29

drug interactions w/ glucocorticoids

Answer 29

- increase activity of CYP3A4 enzyme in liver > increased metabolism of other drugs - more likely to have interactions if administered IV/IM compared to topical

Question 30

why are glucocorticoids useful in life threatening situations?

Answer 30

- can give a massive 'one-off' dose (harmless) b/c side effects like immunosuppression come from prolonged use - h/w sudden withdrawal can result in adrenal insufficiency (takes time to start producing endogenous glucocorticoids again) > Addison's disease

Question 31

what conditions can we use glucocorticoids for?

Answer 31

- eye inflammation - rheumatoid arthritis - allergies e.g. hayfever, dermatitis, bee stings, asthma

Question 32

2 stages of asthma and which stage do glucocorticoids target?

Answer 32

- immediate: bronchospasm - late: inflammatory reaction + mucus plug - glucocorticoids prevent late phase, NOT bronchospasm

Question 33

best way to administer glucocorticoids for asthma

Answer 33

- inhaled: goes straight to site of action - B agonists increase penetration and cause bronchodilation - can also give oral in short term but leads to systemic side effects

Question 34

side effects of glucocorticoids

Answer 34

- increased susceptibility to hyperglycaemia - growth suppression and muscle wasting in kids - osteoporosis (decreased Ca2+ absorption and increased renal excretion) - HTN - increased risk of infection (hidden symptoms)

Question 35

Cushing's syndrome

Answer 35

- opposite to Addison's syndrome, due to long-term corticosteroid exposure - Sx: easy bruising (purpura), increased abdominal fat, poor wound healing, thinning of skin, HTN, diabetes, thin bones, moon-shaped face

Question 36

examples of glucocorticoids

Answer 36

- prednisolone - dexamethasone: eye inflammation, fever - fluticasone: prevents asthma

Question 37

what do the new generation NSAIDs primarily target

Answer 37

- COX-2 only