Nsaids

Front 1

List the products of the COX pathway.

Back 1

The COX pathway synthesises Prostanoids:

- Prostacyclin (PGI2)

- Prostaglandins (PGE2, PGD2, PGF2)

- Thromboxane (TXA2)

Front 2

Explain the role of prostanoids in the inflammatory response.

Back 2

- Prostacyclin (PGI2) causes:

1. vasodilation --> swelling, warmth redness at site

2. inhibition of platelet aggregation

- Prostaglandins (PGE2, PGD2, PGF2) cause

1. Vasodilation

2. Vasoconstriction

3. Increased vascular permeability --> swelling

4. pain

- Thromboxane (TXA2)

1. vasoconstriction

2. platelet aggregation

Front 3

Name some of the NSAIDs available.

Back 3

Aspirin

Naproxen

Indomethacin

Diclofenac

Front 4

What is the chemical name for aspirin?

Back 4

Acetylsalicylic acid.

Front 5

What is the mode of action (MOA) of NSAIDs?

Back 5

NSAIDs inhibit cyclooxygenase (COX), hence inhibiting the production of prostanoids i.e. prostacyclin (PGI2), prostaglandin (PGD2, PGE2, PGF2) and thromboxane (TXA2).

The following effects arise due to:

1. anti-inflammatory

Typical NSAIDs block:

i) Vasodilation (PGI2, PGs) --> reduce warmth, redness, swelling

ii) Increased vascular permeability (PG) - reduces swelling

iii) (PG) Pain associated with inflammation

2. analgesic

Typical NSAIDs block production of prostaglandins which sensitise nocireceptive fibres to stimulation by chemicals released during tissue injury e.g. bradykinin and leukotrienes which trigger transmission of signals along pain fibres

3. anti-pyretic

Infection, tissue damage and inflammation --> infiltration of neutrophils --> neutrophils release cytokines e.g. IL-1 --> stimulate COX in hypothalamus to produce PGE2 --> PGE2 raises the hypothalamus' thermostat --> results in rise in body temp.

NSAIDs inhibit COX in the hypothalamus --> block production of PGE2 --> prevent fever

4. anti-platelet

Aspirin is an irreversible COX inhibitor whereas the other NSAIDs are reversible COX inhibitors.

Platelets produce TXA2 via COX --> TXA2 promotes platelet aggregation. Aspirin irreversibly inhibits COX in platelets and hence inhibits platelet aggregation. Anti-platelet effects in aspirin last 7-10 days, until new platelets are synthesised.

(The inhibition of PGI2 production by endothelial cells, which removes the inhibition on platelet aggregation, can be restored within 4h after the synthesis of new COX enzymes.)

*PG refers to the classical prostaglandins PGD2, PGE2, PGF2

Front 6

What are 2 limitations of aspirin as a pain killer (analgesic)?

Back 6

1. Presence of analgesic ceiling - MOA of analgesia is by blocking sensitisation of nocireceptors to chemicals like bradykinin and leukotriene, rather than blocking direct activation of nocireception

- thus, once a certain limit is reached, additional administration of drug will not cause any increase in analgesic effects

- also, if there is too much bradykinin or leukotriene released by extensive tissue injury, NSAIDs have no/little analgesic effect. NSAIDs are only useful for mild to moderate pain.

2. Aspirin has serious adverse effects. (Paracetamol has replaced aspirin as a pain killer.)

Front 7

What is the most frequent clinical use of aspirin?

Back 7

Prescribed at low doses as an blood thinner (anti-platelet to prevent thrombosis) in those at risk of cardiovascular disease.

Front 8

What is a clinical use of naproxen?

Back 8

Dysmenorrhea.

Front 9

What is a clinical use of Diclofenac?

Back 9

Inflammatory joint disease.

Front 10

What are the adverse effects of NSAIDs?

Back 10

1. GI effects

Inhibition of prostaglandins produces:

- dyspepsia, nausea, vomitting

- ulcer formation, and potential hemorrhagic risk in chronic users

2. Renal effects

Inhibition of PGE2 production results in:

1. Na+ retention

2. Water retention

3. Peripheral oedema

4. Hypertension

Inhibition of PGI2 production results in:

1. Suppression of renin and aldosterone secretion

2. Hyperkalaemia

3. Acute renal failure

Pseudo-allergic reactions:

- skin rashes, swelling, itching, nasal congestion, anaphylactic shock

Asthma

- Can trigger bronchospasm in susceptible asthmatics due to excess leukotrienes/LTD4 (excess arachidonic acid is shunted towards leukotriene and lipoxin production due to inhibition on COX)

Bleeding

Failure of homeostasis, bruising

Reyes syndrome

- Very rare but threatening condition

- Swelling of brain (encephalitis) and liver

- Symptoms include vomiting, personality changes, listlessness, delirium, convulsions, loss of consciousness

- INCREASED RISK IF ASPIRIN IS TAKEN BY CHILDREN WITH VIRAL INFECTIONS. Thus aspirin is no longer in paediatric formulations

Front 11

Explain how NSAIDs can cause hypernatremia despite leading to inhibition of the renin-angiotensin II-aldosterone system (RAAS).

Back 11

Inhibition of PGI2 production results the suppression of RAAS. RAAS acts on the DCT to increase the reabsorption of Na+.

However, by the time the filtrate reaches the DCT, most of the Na+ would already have been reabsorbed. This is because most Na+ reabsorption occurs in the PCT. In addition, the inhibition of PGE2 removes the inhibition on Na+ reabsorption in the thick ascending limb of the LoH. Thus, inhibition on the RAAS by the inhibition on PGI2 production has little effect on Na+ balance.

Front 12

What is a contraindication of aspirin?

Back 12

Children with viral infections.

(increases the risk of Reye's syndrome)

Front 13

What toxicity is associated with Indomethacin?

Who are more susceptible to these effects?

Back 13

CNS effects - confusion or depression, psychosis and hallucinations.

The elderly are more susceptible to these effects.

Front 14

Which NSAID has a strong anti-inflammatory effect?

Why?

Back 14

Indomethacin.

Indomethacin has an additional steroid-like phospholipase A (PLA) inhibition.

Front 15

Which NSAID has a low GI risk?

Why?

Back 15

Diclofenac.

It has a short plasma half life (<2h).

Front 16

Classify the following drugs based on whether they selectively inhibit COX-1 or COX-2 more.

Back 16

Inhibit COX-1 more than COX-2 (worse for GI):

- indomethacin

- aspirin

- naproxen

- ibuprofen

Inhibit COX-2 more than COX-1(safer for GI):

- Diclofenac

Front 17

COX-1 is constitutively expressed whereas COX-2 was thought to be inducible. What are the limitations of COX-2 selectivity?

Back 17

COX-2 is constitutively expressed in some areas:

- CNS

- kidneys

- female reproductive tract

- synovium

Front 18

What are the unwanted effects of COX-2 selective inhibitors?

Back 18

1. Renal effects

- Renal toxicity due to constitutive expression of both COX-1 and COX-2 in kidneys

2. Fetal effects

- Premature closure of foetal ductus arteriosus in late pregnancy

3. Reproductive effects

- Effects on ovulation; delayed follicular rupture

4. Impairment of wound healing

- Expectation of complete GI sparing with COX-2 selective inhibitors not completely realised

- COX-2 inhibitors impair wound healing --> may exacerbate ulcers (thus ulcers can still persist after switching from predominantly COX-1 to COX-2 inhibitors)

*possible implications in patients with existing ulcers or other ulcer risk factors, and in post-surgical analgesia

5. Increased risk of thrombosis

COX-2 pathway results in the production of PGI2 and PGE2. COX-1 pathway results in the production of PGI2, PGE2 and TXA2. PGI2 inhibits platelet aggregation while TXA2 promotes platelet aggregation --> inhibition of COX-2 results in a relative increase in TXA2, which favours platelet aggregation --> increases risk of thrombosis.

Front 19

Which is safer for the GI - COX-1-predominant or COX-2 predominant inhibitors?

Back 19

COX-2 predominant inhibitors (ie. inhibit COX-2 more than COX-1).

However, complete GI sparing is not realised with COX-2 as COX-2 inhibitors impair wound healing --> may exacerbate ulcers (thus ulcers can still persist after switching from predominantly COX-1 to COX-2 inhibitors).

Front 20

What is an alternative to aspirin as a pain killer (but not an NSAID)?

Back 20

Paracetamol.

Front 21

What is the chemical name of paracetamol?

Back 21

Acetaminophen.

Front 22

What are the advantages of paracetamol?

Back 22

- good analgesic

- potent anti-pyretic

- spares GIT

- side effects are few and uncommon (safe for paediatrics)

- few drug-drug interactions

Front 23

What are the disadvantages of paracetamol, including its toxic effects?

Back 23

Weak anti-inflammatory effect.

Toxic doses cause:

- nausea

- vomiting

- liver damage (hepatotoxicity should not occur at therapeutic doses in otherwise healthy individuals, but may be exacerbated in chronic alcohol abuse/use)

- allergic skin reactions

Front 24

How does alcohol exacerbate hepatotoxicity in overdose of paracetamol?

Back 24

1. Metabolism of paracetamol by the minor pathway is induced by alcohol as alcohol induces CYP2E1

2. Alcohol also depletes glutathione which is needed to conjugate toxic metabolites (NAPQI) for them to be excreted (as mercapturic acid). Thus, NAPQI is shunted towards another pathway, resulting in hepatoceullular necrosis.

Front 25

How can paracetamol poisoning be treated?

Back 25

Administer N-acetyl-cysteine (NAC) --> replenish glutathione --> increase conc of glutathione to conjugate toxic metabolites (NAPQI) --> urinary excretion as mercapturic acid.

Front 26

What is an early sign of salicylic poisoning?

Back 26

Tinnitus.