Pharmacology

Question 1

What are the various mechanisms that analgesics use to reduce pain?

Answer 1

• act at site of injury to decrease nerve sensitisation
• suppress nerve conduction
• suppress synaptic transmission in dorsal horn
• activate descending inhibitory controls
• targeting ion channels upregulated in nerve damage

Question 2

How do NSAIDs reduce nociception and pain at the injury site?

Answer 2

• blocking synthesis of prostaglandins (PGE2 and PDE2)

- prostaglandins usually make afferent nerve terminal more sensitive to pain signals

Question 3

How do local anaesthetics suppress nerve conduction to reduce pain and nociception?

Answer 3

blocking/inactivating voltage-activated Na+ channels

Question 4

How do opioids and some anti-depressant drugs work to relieve pain and nociception?

Answer 4

• suppress synaptic transmission of nociceptive signals in dorsal horn of the spinal cord
• activate descending inhibitory controls

Question 5

What are the three levels on the WHO analgesic ladder and give an example of drugs in each level.

Answer 5

3) STRONG opioid (e.g. morphine, oxycodone, heroin, fentanyl)
2) WEAK opioid (e.g. codeine, tramadol)

1) NSAIDs (e.g. aspirin, diclofenac, ibuprofen, naproxen)
+ paracetamol

Question 6

What levels of the WHO ladder are appropriate to combine?

Answer 6

1+2
1+3

Don’t combine 2 and 3 as these act on ame receptors => combination makes little difference

Question 7

WHat is the difference between Opiates and Opioids?

Answer 7

Opiates - substances extracted from opium

Opioids - any agent acting on opioid receptors (including substances made in the body)

Question 8

What is Supraspinal anti-nociception?

Answer 8

Descending controls which are modifying th eperception of pain and nociception

Question 9

What areas of the brain are involved in Supraspinal anti-nociception?

Answer 9

• parts involved in pain perception and emotion
  => cortex, amygdala, thalamus, hypothalamus
  These project signals to specific brainstem nuclei

Question 10

WHat areas of the brainstem are involved in creating the efferent signals to the spinal cord (which will eventually modify afferent inputs)?

Answer 10

• the periaqueductal grey matter (PAG) (midbrain)
• locus ceruleus (pons)
• nucleus raphe magnus (NRM) (medulla)

Question 11

Excitation of the PAG in the brainstem by what two components has the potential to inhibit nociceptve transmission in the spinal cord?

Answer 11

Electrical signals from neurones or by opioids (these can even be endogeneous)

Question 12

After its own excitation, PAG excites the NRM in the medulla to send signals along what neurones?

Answer 12

serotonergic and enkephalinergic neurones (=> ones releasing serotonin (5HT) and enkephalins)

These project to the dorsal horn resulting in nociceptive suppression

Question 13

What type of receptor is the opioid receptor?

Answer 13

G protein-coupled receptors

signal to Gi or Go

Question 14

What are the main functions of binding to the opioid receptor?

Answer 14

• Prevent neurotransmitter release (less Ca2+ intake)

- hyperpolarise post synaptic terminal => less likely APs

Question 15

What are the main classifications of opioid receptor?

Answer 15

μ - responsible for most opioid analgesic action
- BUT these can have major adverse effects

δ - contributes to analgesia but can cause convulsion

κ - contributes to analgesia at spinal and peripheral level
- activation associated with sedation, dysphoria and hallucinations

Question 16

What is the main adverse effect of opioids?

Answer 16

Respiratory depression

Question 17

Morphine can be used for both acute severe pain and chronic pain. TRUE/FALSE?

Answer 17

TRUE

Question 18

Describe how morphine is metabolised?

Answer 18

• metabolised in the liver at positions 3 and 6 on molecule
• yields M3G that is inactive
• also yields M6G which retains analgesic activity and is excreted by the kidney

Question 19

Give an example of immediate and sustained release preparations of morphine

Answer 19

Immediate (e.g. Oramorph)
Sustained release (e.g. MST Continus)

Question 20

How long do sustained release morphine preparations usually last for?

Answer 20

12-24 hours

Question 21

What opioids are agonists of the opioid receptor?

Answer 21

AGONISTS:
morphine
heroin
Codeine
Fentanyl
Pethidine
Buprenorphine
Tramadol
Methadone

Question 22

What opioids are antagonists of the opioid receptor?

Answer 22

Naloxone
Naltrexone (longer 1/2 life)

Question 23

What is diamorphine (heroin) used for clinically?

Answer 23

• more lipophilic than morphine
  => when administered IV it enters CNS rapidly
  => can be used for severe post-operative pain

Question 24

How is codeine metabolised and what is it metabolised to?

Answer 24

• hepatic metabolism to morphine
• completed by CYP2D6 and CYP3A4
  => if patients have low levels of these, they may struggle to metabolise the drug to the active form

Question 25

How is codeine normally delivered?

Answer 25

Orally

Question 26

What other functions can codeine have?

Answer 26

anti-diarrhoeal (opiates cause constipation) | antitussive activity => relieves cough

Question 27

When is fentanyl used?

Answer 27

- Given IV during some surgeries to reduce the amount of general anaesthetic required - Transdermal patches used in chronic pain

Question 28

How much more potent is fentanyl than morphine?

Answer 28

75-100 times more potent

Question 29

When is Pethidine used for pain, and how is it delivered?

Answer 29

- acute pain, particularly labour - short duration of action => not suitable for chronic pain - Given IV, IM, or SC

Question 30

What drug class should not be given in combination with Pethidine and why?

Answer 30

MAO inhibitors (powerful antidepressant) Combination causes excitement, convulsions, hyperthermia

Question 31

What is buprenorphine used for and how is it given?

Answer 31

- chronic pain with patient-controlled injection systems - may have slow onset, but used due to long duration of action - Given by injection or sublingually

Question 32

Tramadol should be avoided in what group of patients?

Answer 32

Epileptic patients

Question 33

What is methadone used for, and why is it helpful that the half life is long?

Answer 33

- assists in withdrawal from ‘strong opioids’ e.g. heroin - short acting opioids = more addictive => this helps patients to withdraw - given orally - long duration of action also useful in treating patients with chronic pain in terminal cancer

Question 34

Naloxone is an antagonist at which of the opioid receptors?

Answer 34

antagonist at μ-receptors

Question 35

When is naloxone used?

Answer 35

- reverse opioid toxicity associated with ‘strong opioid’ overdose - may be given to a newborn with opioid toxicity due to administration of pethidine to mother during labour

Question 36

Why is the short half life of naloxone impractical if a patient has opioid toxicity?

Answer 36

- may need frequent dosing of naloxone to completely reverse toxicity (=> dont leave patient) - beware of opioid addicts as short duration of naloxone may trigger a very acute withdrawal response

Question 37

What are the side effects of NSAIDs and COX-2 inhibitors?

Answer 37

NSAIDs - gastrointestinal damage | COX-2 - prothrombotic

Question 38

What conditions can cause neuropathic pain?

Answer 38

- trigeminal neuralgia - diabetic neuropathy - post-herpetic neuralgia - phantom limb pain

Question 39

How do neuropathic pain drugs such as Gabapentin and pregabalin act to reduce pain and nociception?

Answer 39

- reduce expression of a subunit (α2δ) of some voltage-gated Ca2+ channels - These channels are upregulated in damaged sensory neurones => release more neurotransmitter/signals => less upregulated channels = decrease of neurotransmitters (glutamate and substance P) from nociceptive neurones

Question 40

Hod do tricyclic antidepressants aim to deal with neuropathic pain?

Answer 40

- E.g. Amitriptyline, nortriptyline - act centrally by decreasing the reuptake of noradrenaline - duloxetine and venlafaxine also decrease reuptake of 5-HT

Question 41

What drug is used to control pain in trigeminal neuralga and how does it achieve this?

Answer 41

Carbemazepine - blocks subtypes of voltage-activated Na+ channel that are upregulated in damaged nerve cells - prevents number of attacks in TN