Session 7

Question 1

What are autacoids and give three examples.

Answer 1

They are local modular mediatorys and signalling agents. For example, bradykinins, histamine, cytokines, leukotrienes and nitric oxide.

Question 2

How are prostaglandins synthesised?

Answer 2

Arachidonic acid is converted via COX-1 and COX-2 to PG-H. This can then be converted to a range of prostaglandins, in particular PG-E. This is important in mediating the inflammatory response.

Question 3

What are the roles of prostaglandins?

Answer 3

Bind with GPCRs and have specific actions depending on the receptor type present.

Question 4

Describe the role of prostaglandins in sensitising afferent nociception.

Answer 4

Painful stimuli are carried by afferent ‘C’ fibres. PGE2 binds with ‘C’ fibre neuronal EP1 GPCRs. This inhibits potassium channels, increases sodium channel sensitivity and increases neuronal sensitivity to bradykinin.
This increases C-fibre activity.

Question 5

Describe the role of prostaglandins in sensitising central nociception.

Answer 5

Increased cytokine levels in the dorsal horn causes increased COX-2 and PGE2 synthesis. PGE2 then increases sensitivity of secondary interneurones, leading to increased pain reception.

Question 6

Describe the role of prostaglandins in pyrexia.

Answer 6

In infected/inflammatory states, bacterial endotoxins stimulate production of IL-1. This stimulates PGE2 synthesis, which results in both increased heat production and reduced heat loss via GPCRs.

Question 7

What is the role of COX-1?

Answer 7

Constitutively expressed, and PG synthesis involved in cytoprotective role of gastric mucosa, myocardium and renal parenchyma. Also ensures optimal local perfusion. PG has a half life on 10 mins so needs constant synthesis.

Question 8

What is the role of COX-2?

Answer 8

Expression induced by inflammatory mediators hence only expressed during injurious stimuli. .

Question 9

What causes the therapeutic and adverse effects of NSAIDs?

Answer 9

COX-1 inhibition = ADRs

COX-2 inhibition = therapeutic effects.

Question 10

Give three examples of NSAIDs ADRs.

Answer 10

Stomach ulceration and perforation, hypertension, bruising, risk of haemorrhage, skin rashes.

Question 11

Give 2 DDIs of NSAIDs.

Answer 11

Aspirin, warfarin, sulphonylurea, methotrexate.

Question 12

Describe the role of aspirin.

Answer 12

An NSAID that irreversibly inhibits COX enzymes by acetylation.

• Athero-thrombotic disease prevention
• GI cancer prophylaxis.

Question 13

Describe the pharmacokinetics of Aspirin.

Answer 13

Rapidly hydrolysed in the plasma to salicylate. This is dose dependent: at lower doses it is first order, at higher doses it is zero order.

Question 14

Describe the role of paracetamol.

Answer 14

No anti-inflammatory action (NOAD). It is a simple analgesic, and has antipyretic properties. Appears to selectively inhibit COX-1/2/3 activity in the CNS.

Question 15

What happens when high doses of paracetamol have been taken?

Answer 15

PK becomes zero order. Phase 2 metabolism becomes saturated, causing increase in NAPQI. This depletes the glutathione levels until there becomes an increase in unconjugated NAPQI. This causes hepatic cell death and renal failure.

Question 16

What is the treatment for paracetamol overdose?

Answer 16

Activated charcoal or N-acetylcysteine. This increases glutathione levels.

Question 17

Describe the pain pathway.

Answer 17

Nociceptor to afferent pain fibres, to dorsal root on spinal cord, to the substantia gelatinosa, to the thalamus and primary sensory cortex.

Question 18

What are the three main endogenous opioid peptides?

Answer 18

Enkephalins (from proenkephalin), Endorphins (from POMC) and dynorphins (from prodynorphin).

Question 19

Name the three opioid receptor classes.

Answer 19

• MOP (supraspinally)
• DOP (widely distributed)
• KOP (spinally)

Question 20

How do opiates work to reduce pain?

Answer 20

• Increase outward flow of potassium ions
• Decrease excitability of the neurone
• Decrease influx of calcium
• Reduce cAMP synthesis
• Reduced release of neurotransmitter.

Question 21

Name the four types of opioids and give an example of each.

Answer 21

1) Agonists: morphine, codeina, methadone (bind to MOP)
2) Partial agonists: buprenorphine
3) Agonist/antagonist: nalbuphine (antagonist at MOP, partial at KOP and agonist at DOP)
4) Antagonist: naloxone (binds to MOP).

Question 22

Describe the PKs of morphine.

Answer 22

25% oral bioavailability, 35% protein bound, half life of 1.3-6.7 hours. Glucuronidised to M6G and M3G, and M6G is the main active metabolite.

Question 23

What must happen to diamorphine for it to exert it’s therapeutic effects?

Answer 23

Acted on by pseudocholinesterases to convert it to morphine.

Question 24

What is used to maintain opioid dependence?

Answer 24

Methadone

Question 25

Why might codeine not work as well in 10% of Caucasian individuals?

Answer 25

Genetic polymorphism to CYP2DP enzymes, hence it is not broken down to morphine.

Question 26

Give two uses of opioids.

Answer 26

To relieve moderate to severe pain, care of terminally ill patients, anaesthetics and in labour.
Also to treat diarrhoea, heroin addition and following an MI.

Question 27

Which opioid can cross the placentra?

Answer 27

Pethidine.

Question 28

Give three ADRs of opioids.

Answer 28

Respiratory depression
Euphoria
Constipation
Hypotension
Vomiting and diarrhoea
Confusion, miosis and coma
Anaphylactic response.

Question 29

How do you resolve opioid overdose?

Answer 29

Give the opioid antagonist naloxone which reverses respiratory depression.

Question 30

What information is required to be noted when prescribing opiates?

Answer 30

Name and address
Form and strength of the preparation
Total volume in ml
The dose