Pharmacology

Question 1

Supraspinal anti nociception is mediated by _____1____ Brain regions involved in pain perception and emotion project to ____2______ Neurons of brainstem nuclei give rise to efferent pathways that project to the ______3_______

Answer 1

1) descending pathways from the brain
2) specific brainstem nuclei
3) spinal cord to modify afferent input

Question 2

Important brainstem regions in the anti nociception pathway include?

Answer 2

Periaqueductal grey matter (located in the midbrain)
Locus coeruleus (located in the pons)
Nucleus raphe magnus (located in the medulla)

Question 3

Describe the antinociception pathway?

Answer 3

Excitation of the PAG by electrical stimulation produces profound analgesia, activated PAG neurons projecting to the nucleus raphe magnus excite certain neurons which project to the dorsal horn resulting in suppression of nociceptive transmission
locus coeruleus noradrenergic neurons projecting to the dorsal horn are also excited and inhibit nociceptive transmission
activity of relay neurons can also be inhibited by local interneurons which release opioid peptides which directly inhibit relay neurons as well as activating brain stem areas PAG NRM and LC so indirectly causing inhibition of relay neurons

Question 4

Opioid action is mediated by __________

Answer 4

G protein coupled receptors

Question 5

What 3 things does activation of opioid GPCRs result in?

Answer 5

• inhibition of opening voltage activated Ca2+ channels (which suppresses excitatory NT release from nociceptor terminals) >PRESYNAPTIC EFFECT
• opening of K+ channels (suppresses excitation of projection neurons) > POSTSYNAPTIC EFFECT
• inhibition of adenylate cyclase (important in long term effects)

Question 6

3 classes of opioid receptor?

Answer 6

U > responsible for most analgesic action of opioids
delta > contribute to analgesia but are proconvulsant
K > contribute to analgesia at spinal and peripheral level

Question 7

Opioid agonists mainly cause analgesia through ______

Answer 7

prolonged activation of U opioid receptors

Question 8

List some examples of opioid agonists?

Answer 8

morphine, diamorphine, codeine, fentanyl, pethidine, buprenorphine, tramadol, methadone, etorphine

Question 9

What do opioid antagonists do?

Answer 9

Competitive antagonists at U receptors used to reverse opioid toxicity

Question 10

List some examples of opioid antagonists?

Answer 10

naloxone, naltrexone

Question 11

List some adverse effects of opioids?

Answer 11

Addictive potential
Apnoea
Orthostatic hypotension (decrease in BP standing vs sitting or supine)
Nausea, vomiting, constipation
Confusion, euphoria, dysphoria, hallucinations, dizziness, myoclonus, hyperalgesia

Question 12

List some actions of NSAIDs?

Answer 12

analgesic, antipyretic, anti-inflammatory

Question 13

Mechanism of action of NSAIDs?

Answer 13

Inhibition of synthesis and accumulation of prostaglandins by cyclo-oxygenase (COX) enzymes COX-1 and 2

Question 14

Inhibition of COX 1 or 2 has greater therapeutic benefit and why?

Answer 14

COX 2 because it is induced locally at sites of inflammation whereas COX 1 is active at low levels all the time

Question 15

Give 3 ways in which NSAIDs can act?

Answer 15

• suppress the decrease in activation threshold of the peripheral terminals of nociceptors that is caused by prostaglandins
• decrease recruitment of leukocytes that produce inflammatory mediators
• if they cross the BBB they can suppress production of pain producing prostaglandins in the dorsal horn of the spinal cord

Question 16

Explain why NSAIDs have limited analgesic efficacy?

Answer 16

Multiple signalling pathways, several of which don’t involve COX 1 and 2 cause nociceptor sensitisation

Question 17

Why is a paracetamol not classed as a NSAID? What is its mechanism of action?

Answer 17

It lacks anti-inflammatory activity and acts only centrally, the precise mechanism of action is still debated but may involve several of its metabolites

Question 18

Neuropathic pain does not respond to ________

Answer 18

NSAIDs and appears relatively insensitive to opioids (unless given in high doses)

Question 19

How do gabapentin and pregabalin reduce neuropathic pain?

Answer 19

Decrease NTs from central terminals of nociceptive neurons

Question 20

How do amitriptyline, nortyptiline and desipiramine reduce neuropathic pain?

Answer 20

Act centrally by decreasing the re-uptake of noradrenaline

Question 21

How does carbamazepine reduce neuropathic pain?

Answer 21

Blocks subtypes of voltage gated sodium channels that are unregulated in damaged nerve cells.