pharmacology of pain

Question 1

What is the pain ladder?

Answer 1

Mild pain: non-opioid +/- adjuvant therapy.
Mild-moderate: weak opioid +/- non-opioid +/- adjuvant therapy.
Moderate-severe pain: strong opioid +/- non-opioid +/- adjuvant therapy

Question 2

What is the pain pathway?

Answer 2

• Stimulus activated receptor in periphery, sensory neurone goes to spinal cord, synapses onto spinothalamic neurone (goes to thalamus) transmitting stimulus from periphery to brain.
• Brain processes stimulus and sends inhibitory signal back to spinal cord to stop painful stimulus relaying up to brain.
• Inhibition changes depending on severity of painful stimulus

Question 3

What is difference between paracetomal and NSAID?

Answer 3

Both are antipyretic & analgesic, but only NSAIDs are anti-inflammatory

Question 4

Why doesn’t paracetamol work well in inflammation?

Answer 4

-Paracetamol inhibits peroxidase activity, but in inflammation many peroxides released so paracetamol cannot get to the peroxidase enzyme as they are acting on peroxides.

Question 5

What is effect of paracetamol & NSAIDs on anandamide (endogenous cannabis)?

Answer 5

Increase anandamide which acts on cannabinoid receptors stimulating increased inhibitory descending pathways - analgesic.

Question 6

What is effect of opioids on cellular level?

Answer 6

G-protein coupled receptors, inhibit adenylyl cyclase reducing levels of cAMP so cellular activity goes down.

• Reduces calcium influx (less exocytosis of ns), increases potassium efflux causing hyperpolarisation of neurone.
• Generally depressant at cellular level so will decreaese function/activity of that cell

Question 7

Where can opioiods act?

Answer 7

Receptors at stimulus, in spinal cord and in brain.

• When not in pain, descending pathway switched off (GABA inhibitory neurotransmitter acts on downward pathway keeping it switched off).
• Opioids inhibit GABA to get activation of descending pathway (disinhibition - switch off inhibition)

Question 8

What is needed for opioid to get into brain effectively?

Answer 8

Lipid solubility

Question 9

Which opioids have highest lipid solubility?

Answer 9

Heroin & codeine. Morphine has less

Question 10

After opioid is in brain what determines how they bind to opioid receptor? What are implications of this?

Answer 10

• Opioid receptor binding dependent on hydroxyl group at position 3 plus tertiary nitrogen.
• Morphine has 2 hydroxyl groups so binds well, codeine has 1 less hydroxyl group ad heroin has 2 less hydroxyl groups so they bind less well.
• Need to be converted into something that binds to the receptor (need to be metabolised before they can act)

Question 11

What can cause a build up of opioids in body?

Answer 11

Renal impairment (opoiods are renally cleared)

Question 12

What are signs of opioid overdose?

Answer 12

• Respiratory depression (cardio-resp depression) which is serious/can be fatal needs to be dealt with quickly.
• Cardiorespiratory centre in medulla is depressed by too much opioid.
• Constricted pupils diagnostic (opioids cause massive pupil constriction directly - usually when unconscious would be dilated & fixed, but here not)

Question 13

What is naloxone?

Answer 13

Opioid receptor antagonist. Possesses affinity (ability to bind) but no efficacy (doesn’t active it whilst bound)

Question 14

What is morphine?

Answer 14

Opioid receptor agonist (has both affinity and efficacy)

Question 15

What are similarities between structures of morphine & naloxone?

Answer 15

• Both have hydroxyl group at position 3 & tertiary nitrogen, so both can bind receptor.
• If side chain of tertiary nitrogen is short it is efficacious to activate receptor, if longer than 2 carbons lose efficacy.
• Naloxone has long side chain so cant fit properly on binding pocket (cant activate receptor, blocks it), whereas morphine has short side chin so activates receptor.

Question 16

What can codeine be metabolised into and how? Implications of this?

Answer 16

• Can be metabolised via P450 enzymes in liver to both norcodeine (inactive metabolite) via CYP3A4 quickly and into morphine via CYP2A6 slowly.
• If taken orally will go to liver first to metabolise into these 2, much more fast metabolism into norcodeine (inactive) which means that only about 10% of the codeine is metabolised into morphine and is active (codeine is weak opioid if given orally)

Question 17

Formula converting total dose of codeine to give?

Answer 17

• Total morphine a day / 0.1 = total codeine per day.
• Generally recommended that dose is reduced by 30% to reduce risk of overdose so total codeine x 0.7 should be given a day.
• But if don’t have underlying condition no reason have reduction, eg in old people can give 15 mg (codeine comes in 15mg, 30mg, 60mg)

Question 18

What is mechanism of paracetamol?

Answer 18

Not clear. Activation of descending serotonergic pathways possibly via 5HT3 receptor. Inhibits reuptake of endogenous endocannabinoids which would increase activation of cannabinoid receptors. Mild inhibition of COX

Question 19

What is drug target of paracetamol?

Answer 19

5HT3 receptors/cannabinoid reuptake/cox

Question 20

What are side effects of paracetamol?

Answer 20

Few. Overdose –> liver damage and less frequently renal damage. Nausea & vomiting (early), onset of right subcostal pain after 24h indicates hepatic necrosis

Question 21

What are some opioids?

Answer 21

Weak- codeine, tramadol. Strong - morphine, fentanyl (heroin)

Question 22

What is mechanism of opioids?

Answer 22

• Depressant effect on cellular activity.
• Multiple sites within pain pathway, activation of opioid receptors leads to decreased perception/increased tolerance to pain.
• Anti-tussive (coughing) effect due to decreased activation of afferent nerves relaying cough stimulus from airways to brain

Question 23

Target of opioids?

Answer 23

opioid receptors

Question 24

What are side effects of opioids?

Answer 24

Mild-nausea & vomiting (increase activity in chemoreceptor trigger zone) & constipation (opioid receptors in gut reduce gut mobility).
-Overdose leads to respiratory depression (direct & indirect inhibition of respiratory control centre)

Question 25

Mechanism of co-amoxiclav?

Answer 25

Amoxicillin binds to bacterial penicillin binding proteins, preventing transpeptidation (cross linking for bacterial wall synthesis).
Clavunalate is inhibitor of beta lactamase (bacterial enzyme that degrades beta lactam antibiotics & confers resistance to these antibiotics)

Question 26

Drug target of co-amoxiclav?

Answer 26

Amocillin to penicillin binding proteins. Clavulanate to beta lactamase

Question 27

Drug side effects of co-amoxiclav?

Answer 27

Nausea & diarrhoea. Hypersensitivity to penicillins common (rash or anaphylactic shock)

Question 28

what type of antibiotic is amoxicillin?

Answer 28

semi-synthetic antibiotic with broad spectrum against gram-positive & negative.

Question 29

What is mechanism of lactulose?

Answer 29

• Non-absorbable disaccharide, reaches large bowel unchanged, causes water retention via osmosis and easier to pass stool.
• Can be metabolised by colonic bacteria.
• Colonic metabolism of sugars has additional laxative effect

Question 30

What is drug target of lactulose?

Answer 30

no target

Question 31

Side effects of lactulose?

Answer 31

Abdominal pain, diarrhoea, flatulence, nausea

Question 32

What is lactulose used for? how long does it take to improve constipation?

Answer 32

constipation.
8-12 hours but maybe 2 days to improve constipation
(common side effect of opioids so often prescribed before starting opioids to improve side effect)