Pharm 17 - NSAIDS

Question 1

Use of NSAIDS are associated with deaths involving which systems?

Answer 1

GI and CVS

Question 2

Which 3 properties of NSAIDS make them widely used?

Answer 2

1. Analgesic
2. Anti-pyretic
3. Anti-inflammatory

Question 3

Where is arachidonic acid derived from?

Answer 3

Phospholipid membranes

Question 4

What reaction does COX-1/2 mediate

Answer 4

Conversion of Arachidonic acid into prostaglandin H2

Question 5

NSAIDS inhibit what?

Answer 5

COX-1/2 - prevents Prostaglandin and Thromboxane A2 synthesis

Question 6

Prostanoid receptors have 2 actions,

Answer 6

1. Physiological
2. Pro-inflammatory (pathological)

There are 10 known prostanoid receptors

Question 7

PGE2 has 2 downstream mechanisms

Answer 7

1. Ca mobilisation/immobilisation

2. cAMP increase/decrease

Question 8

Which 4 receptors does PGE2 have?

Answer 8

EP1, EP2, EP3, EP4

Question 9

What are 6 unwanted actions of PGE2

Answer 9

1. Increased pain perception
2. Increased body temperature
3. Acute inflammatory response
4. Immune responses
5. Tumorigenesis
6. Inhibition of apoptosis

Question 10

Why may PGE2 analogues lower pain threshold

Answer 10

1. PG receptors are stimulated

2. Peripheral PG receptor stimulation sensitises the nociceptors

Question 11

Why might stimulation of PG receptors cause pain?

Answer 11

1. cAMP mediated
2. P2X3 nociceptors activated
3. Inflammation causes Epac pathway to be activated and more PGE2 to be produced
4. More activation of P2X3 nociceptors

Question 12

What other reasons for pain may there be via PG receptor activation?

Answer 12

1. EP1 /EP4 receptor activation (periphery and spine)
2. Endocannabinoids (neuromodulators in thalamus, spine and periphery)
3. Decreased beta-endorphins in the spine

Question 13

What do NSAIDS do in the spine

Answer 13

Increase beta-endorphin in the spine

Question 14

How does PGE2 have a pyrogenic effect?

Answer 14

PGE2 stimulates hypothalamic neurones - stimulates rise in temp

Question 15

PGE2 role in inflammation is extremely complex

Answer 15

y=Y

Question 16

What are desirable physiological actions of pGE2 and other prostanoids

Answer 16

1. Bronchodilation
2. Renal salt and water homeostasis
3. Gastroprotection
4. Vasoregulation

Question 17

Why should asthmatic patients avoid taking NSAIDS?

Answer 17

Because COX inhibition favours leukotriene production - leukotrienes = bronchoconstrictors

Question 18

How can NSAIDS cause renal toxicity

Answer 18

PGE2 (& other prostaglandins) increase renal blood flow.

NSAIDS:

1. Constrict afferent arteriole
2. Reduce renal artery flow
3. Reduce GFR

Question 19

What gastroprotective features does PGE2 have?

Answer 19

1. Downregulates HCl secretion

2. PGE2 stimulates mucus and bicarbonate secretion

Question 20

What gastric complication do NSAIDS increase the likelihood of?

Answer 20

Gastric ulceration

Question 21

What is the coxib family?

Answer 21

NSAIDS that selectively reversibly inhibit COX-2

e.g. Celecoxib (caused fewer ulcers than normal NSAIDS)

Question 22

Ibuprofen selectively inhibits which isoforms of COX?

Answer 22

Both - i.e. COX 1 and 2

Question 23

What are the unwanted CVS effects of NSAIDS

Answer 23

1. Vasoconstriction
2. Salt and water retention
3. Reduced effect of antihypertensives

can cause:

1. Hypertension
2. Stroke
3. MI

Question 24

Selective COX-2 inhibitors have what problem?

Answer 24

Pose higher risk of CVS disease than conventional NSAIDS

Question 25

Which prostaglandin causes vasodilation and decreases platelet aggregation

Answer 25

PGI2

Question 26

COX-1 selective NSAIDS increase what risk? COX-2 selective NSAIDS increase what risk?

Answer 26

COX -1 = gastric COX -2 = CVS

Question 27

How can GI side effects be reduced?

Answer 27

1. Topical application 2. Minimise use in GI ulceration patients 3. Treat H pylori if present 4. Coadminister with omeprazole or PPI 5. Minimise NSAID use in patients with other RFs e.g. alcohol consumption / anticoagulant/glucocorticoid use

Question 28

Aspirin is selective for which COX enzyme?

Answer 28

COX-1

Question 29

How does aspirin bind to COX enzymes?

Answer 29

ASPIRIN BINDS IRREVERSIBLY BINDS TO COX ENZYMES

Question 30

Aspirin also reduces platelet aggregation. How

Answer 30

1. COX-1 permanently inhibited (due to covalent bonding) which suppresses TxA2 production by platelets (TXA2 increases platelet aggregation) 2. Aspirin has low capacity to inhibit COX-2. 3. PGI2 is synthesised by both COX-1 and COX-2 in endothelial cells 4. Therefore, there is still PGI2 synthesis as COX-2 works 5. PGI2 decreases platelet aggregation.

Question 31

Platelets have no nucleus, so more platelets must be regenerated for TXA2 and platelet aggregation to occur (when aspirin is administered).

Answer 31

Y Endothelial cells that produce PGI2 have a nucleus so can produce COX1/2.

Question 32

Aspirin can cause gastric irritation, bronchospasm, excess bleeding, nephrotoxicity. These side effects are likely not because aspirin is selective for COX-1, but because they:

Answer 32

Inhibit COX covalently (i.e. irreversibly)

Question 33

Why is paracetamol not an NSAID

Answer 33

It has minimal anti-inflammatory effect | but it does have a anti-pyretic action

Question 34

Overdosing on paracetamol may cause?

Answer 34

Liver failure

Question 35

How can overdosing on paracetamol cause liver failure

Answer 35

1. Glutathione used to metabolise a toxic metabolite of paracetamol into an inactive reduced form 2. Depleted glutathione = toxic metabolite oxidises thiol groups 3. Thiol groups are crucial in key hepatic enzymes - hepatotoxicity results and cell death occurs Paracetamol depletes glutathione

Question 36

What is the antidote for paracetamol poisoning

Answer 36

1. Add compound with -SH groups (often IV acetylcysteine) | 2. (Occasionally oral methionine)