1.16 - Pharmacology of pain

Question 1

What are some analgesic drug classes? (3 + 1)

Answer 1

• paracetamol
• opioids
  
  • weak - codeine, tramadol
  • strong - morphine, fentanyl, (heroin)
• co-amoxiclav
• lactulose (not an analgesic, prescribed prior to opiates to reduce constipation)

Question 2

What is the mechanism of action of paracetamol?

Answer 2

Still not totally clear:

• at peripheral sites, may inhibit a peroxidase enzyme which is involved in the conversion of arachidonic acid to prostaglandins (1st step in this pathway involves the enzyme cyclooxygenase, which NSAIDs inhibit not paracetamol)
  
  • the ability of paracetamol to inhibit peroxidase can be blocked if excessive levels of peroxidase build up (e.g. in inflammation)
• activation of descending serotonergic pathways possibly via 5HT3 receptor activation
• inhibits reuptake of endogenous endocannabinoids, which would increase activation of cannabinoid receptors - this may contribute to activation of descending pathways

Question 3

What is the drug target of paracetamol?

Answer 3

Unclear, may be:

• peroxidase
• 5HT3 receptors
• cannabinoid reuptake proteins

Question 4

What are the main side effects of paracetamol?

Answer 4

• relatively safe drug with few common side effects
• OVERDOSE can lead to:
  
  • liver damage and less frequently renal damage
  • nausea and vomiting are early features of poisoning (settle in 24h)
  • onset of right subcostal pain after 24h indicates hepatic necrosis

Question 5

What is some extra information about paracetamol? (3)

Answer 5

• analgesic and anti-pyretic
• NOT anti-inflammatory
• a number of medications contain paracetamol, so care must be taken to avoid accidental overdose

Question 6

What are some examples of weak (2) and strong (3) opioids?

Answer 6

• weak - codeine, tramadol
• strong - morphine, fentanyl, (heroin)

Question 7

What is the mechanism of action of opioids?

Answer 7

• over-arching mechanism at a cellular level is a depressant effect on cellular activity
• multiple sites within pain pathway, where activation of the opioid receptor leads to decreased perception or increased tolerance to pain
• anti-tussive (cough suppressant) effect due to decreased activation of afferent nerves relating cough stimulus from airways to brain

Question 8

What is the drug target for opioids?

Answer 8

Opioid receptor

Question 9

What are the main side effects of opioids?

Answer 9

• mild:
  
  • nausea and vomiting (increase in activity in chemoreceptor trigger zone)
  • constipation (opioid receptors in GIT can reduce gut motility)
• OVERDOSE - respiratory depression (direct and indirect inhibition of respiratory control centre)

Question 10

What is the mechanism of action of co-amoxiclav?

Answer 10

• amoxicillin (like all penicillin-like drugs) binds to bacterial penicillin-binding proteins
• this prevents transpeptidation (cross-linking process for bacterial cell wall synthesis)
• clavulanate is an inhibitor of beta lactamase (a bacterial enzyme that can degrade beta lactam antibiotics and thus confer resistance to them)

Question 11

What is the drug target of co-amoxiclav?

Answer 11

• amoxicillin = penicillin binding proteins
• clavulanate = beta-lactamase

Question 12

What are the main side effects of co-amoxiclav?

Answer 12

• amoxicillin is well tolerated
• most common side effects are nausea and diarrhoea

Question 13

What is some extra information about co-amoxiclav?

Answer 13

• amoxicillin is a semi-synthetic antibiotic with a broad spectrum of bactericidal activity against many gram-positive and gram-negative microorganisms
• hypersensitivity to penicillin is relatively common - usually associated with rash but can lead to anaphylactic reactions

Question 14

What is the primary mechanism of action of lactulose?

Answer 14

• non-absorbable disaccharide so reaches large bowel unchanged
• 1) causes water retention in bowel via osmosis and makes it easier to pass stool (loosens it)
• 2) can also be metabolised by colonic bacteria which has additional laxative effect

Question 15

What is the drug target of lactulose?

Answer 15

No drug target

Question 16

What are the main side effects of lactulose? (4)

Answer 16

• abdominal pain
• diarrhoea
• flatulence
• nausea

Question 17

What is some extra information about lactulose?

Answer 17

• begins working within 8-12 hours but may take up to 2 days to improve constipation
• constipation is a very common side effect of opioids - lactulose is often prescribed prior to commencement of opioid therapy to improve symptoms associated with constipation

Question 18

What are the therapeutic objectives if diagnosed with gastroenteritis?

Answer 18

• oral rehydration - can manage oral fluids, but at risk of dehydration due to consistent diarrhoea and vomiting
• analgesia - complaining of abdominal pain, OTC paracetamol is fine
• most patients can manage gastroenteritis at home

Question 19

Describe the WHO pain ladder.

Answer 19

1. mild pain: non-opioid +/- adjuvant therapy
2. mild to moderate pain: ‘weak’ opioid +/- non-opioid +/- adjuvant therapy
3. moderate to severe pain: ‘strong’ opioid +/- non-opioid +/- adjuvant therapy

Paracetamol/NSAIDs –> codeine/tramadol –> morphine/fentanyl/heroin

Question 20

Describe the pain pathway.

Answer 20

1. transduction via nociceptors
2. transmission via peripheral sensory nerves –> spinothalamic neurones
3. perception - thalamus –> cerebral cortex (how intense is the pain?)
4. modulation - descending inhibitory pathways - cerebral cortex decides how much inhibition there will be - how much pain needs to be felt? modulation of inhibitory pathways in SC then transmits this up spinothalamic neurones again and you get this feedback of how much pain is inhibited

Question 21

Why are NSAIDs anti-inflammatory while paracetamol is not?

Answer 21

• NSAIDs inhibit COX (analgesic, anti-pyretic, anti-inflammatory)
• paracetamol inhibits peroxidase (analgesic, anti-pyretic)

Question 22

What are the therapeutic objectives for acute appendicitis?

Answer 22

• surgery - open laparoscopy
• hydration (would need to be NBM) - IV crystalloids
• analgesia - move up the pain ladder as pain more intense
• antibiotics - obstructed appendix could lead to bacterial overgrowth, plus risk of post-surgical infection

Question 23

How does morphine/opioids have a depressant effect on cellular activity? (from tutorial)

Answer 23

• ATP–>cAMP is catalysed by adenylate cyclase
  
  • Morphine inhibits adenylate cyclase, inhibiting production of cyclic AMP
  • This downregulates the activity of the cell (as it acts on many things like kinases etc)
• Morphine inhibits Ca2+ - this can impact vesicle exocytosis
  
  • Ca2+ is vital to numerous cell processes - excretion of NTs and muscle contraction
  • Inhibiting calcium entry leads to reduced exocytosis of neurotransmitters
• Morphine enhances K+ efflux
  
  • K+ efflux increases hyperpolarisation of the neuron, which decreases depolarisation
  • Not able to generate an action potential –> decreased nerve activity
• All three of these things downregulate the activity of the nerve
• Opioids have an overall depressant effect on cellular and nerve activity
• Morphine activates (disinhibits) descending inhibitory pathways - inhibits inhibition of inhibitory pathways (more or less inhibition of inhibitory pathways is how the pathway is regulated, morphine inhibits this inhibition so you put the brake back on) i.e. do not feel the pain
• Brake (no pain), inhibitory pathway takes brake off (pain), morphine comes and puts brake back on (no pain)

To summarise:

• affects nociceptor nerve endings and reduces ability to send APs to SC
• inhibits transmission of APs between C-fibres and spinothalamic nerve
• increases the inhibitory descending pathway, thus modifying and reducing ascending transmission of pain

Question 24

What is a key sign of opioid overdose?

Answer 24

Pinprick pupils

Question 25

Morphine is an opioid receptor agonist. Naloxone is an opioid receptor antagonist. Agonists possess affinity and efficacy for a receptor. Antagonists only possess affinity for a receptor. Compare the chemical structure of morphine and naloxone. Which structural component do you think is important for efficacy? (Tutorial)

Answer 25

• Both have OH and terminal N
• N-CH3 (efficacy is short side chain) - anything longer than 2C will not be effective
• Naloxone is very good at affinity but very poor at efficacy as the carbon chain is longer than 2C
• OH - affinity

Question 26

Codeine can be metabolized to both norcodeine (inactive metabolite) AND morphine (active metabolite). In the liver, cytochrome P450 enzymes are responsible for this metabolism. CYP3A4 is responsible for ‘fast’ metabolism of codeine to norcodeine and CYP2A6 is responsible for ‘slow’ metabolism of codeine to morphine.
What do you think is the significance of this? (Tutorial)

Answer 26

• more codeine metabolised to norcodeine per unit time
• more inactive metabolite per unit time (only 10% of codeine dose metabolised to morphine)
• takes longer to OD on codeine than morphine as less availability of active metabolite