L19

Question 1

Nociceptive pain

Answer 1

protective; response to the detection of noxious stimuli that can potentially cause tissue injury

Question 2

Inflammatory pain

Answer 2

protective; caused by tissue damage; release of inflammatory mediators

Question 3

Pathological pain

Answer 3

neuropathic pain
* caused by damage to the nervous system; e.g., spinal cord injury, diabetic neuropathy, multiple sclerosis

Question 4

dysfunctional pain

Answer 4

• abnormal function of the nervous
  system in the absence of damage or
  inflammation

Question 5

Inflammatory pain sensitisation simple

Answer 5

Tissue injury
↓
Production & release of a chemical soup
↓
Peripheral sensitisation to pain
↓
Central processing and sensitisation (Spinal cord)
↓
Signal sent to brain for final processing

Question 6

What does PGE2 do with peripheral excitability

Answer 6

PGE2 increased peripheral excitability; evoked many action potentials,
* cAMP/PKA-dependent modulation of the tetrodotoxin-resistant sodium channel

Question 7

Cyclooxygenase and prostaglandin synthesis

Answer 7

Membrane phospholipids
↓ – Phospholipase A2
Arachidonic acid
↓ –cyclooxygenase activity (COX)
Prostaglandin G2
↓ –peroxidase activity (COX)
Prostaglandin H2
↓
Prostaglandin E2

Question 8

COX

Answer 8

Cyclooxygenase (COX)*

Question 9

COX-1 stomach

Answer 9

COX-1 synthesises cytoprotective PGs (e.g., PGI2)→ protection on mucosal epithelium→ protection from peptic ulcer

Question 10

Cox-1 Kidney

Answer 10

PGE2 production→ vasodilation and maintains renal blood flow

Question 11

Cox-1 Platelet

Answer 11

production of thromboxane A2- platelet aggregation

Question 12

COX1 CNS

Answer 12

distributed in neurons throughout the brain

Question 13

COX-2 - inflam and CNS

Answer 13

• Can be induced by stimuli that are associated with inflammation
• CNS: restricted to parts of the CNS, e.g., spinal cord, hippocampus

Question 14

What type of drugs inhibit COX

Answer 14

• steroids
• NSAID
• Diclofenac
• Aspirin

Question 15

Diclofenac and COX

Answer 15

• Drug inhibits COX
• Compete with arachidonic acid for cyclooxygenase active site thereby blocking it

Question 16

Aspirin and COX

Answer 16

• Unique MoA
• Acetyl group with acetylated the hydroxyl group serine → irreversible COX inhibition
• antiplatelet effects from inhibition of thromboxane A2 formation

Question 17

Aspirin in asthma

Answer 17

• bronchospasm in aspirin-sensitive asthmatics (leukotrienes - airway constriction)

Question 18

How aspirin produces leukotrienes

Answer 18

• Arachidonic acid
• 5-Lipoxygenase (5-LOX)
• 5-HPETE
• Leukotrienes
• bc aspirin irreversibly blocks prostaglandin formation

Question 19

Reye’s Syndrome

Answer 19

• affect children - use aspirin to treat fever after viral infection; first described in 1963
• vomiting, hyperventilation→ hepatic failure, encephalopathy
• high mortality

Question 20

Difference in structure of COX-1 and COX-2

Answer 20

• isoleucine to valine substitution at position 523 - a side pocket to accommodate bulkier substrates
• wider channel opening
• Only COX-2 has the side pocket not COX-1 which make it easier to make selective inhibitors

Question 21

-coxibs are what type of drug

Answer 21

COX-2 selective inhibitors that fit into the side pocket of COX-2

Question 22

Non-steroidal anti-inflammatory drugs uses

Answer 22

• analgesic effects - useful non-opioid analgesics
• anti-inflammatory effects - painful conditions with an inflammatory component
• anti-pyretic effects

Question 23

Effects of using Non-selective COX inhibitors

Answer 23

• GI tract adverse effects
• bleeding
• acute renal dysfunction - ↓ renal blood flow
• problems in the elderly

Question 24

Elderly patients and Non-selective COX inhibitors

Answer 24

• elderly patients
• history of previous GI ulcers
• patients with CV risk factors
• patients with renal risk factors
• make side effects worse

Question 25

Effects of using selective COX-inhibitor compared to non-selective

Answer 25

* lower GI adverse effects * reduced risk of bleeding * no bronchospasm in NSAID-sensitive asthmatics

Question 26

Paracetamol effects

Answer 26

* analgesic effects * anti-pyretic effects * lacks anti-inflammatory effects

Question 27

Paracetamol deacetylation

Answer 27

By P-aminophenol to AM404 enzyme is a fatty acid amide hydrolase

Question 28

Paracetamol MoA proposed

Answer 28

* COX-3 inhibition in dogs its different in humans * Interaction with the endocannabinoid system –AM404 inhibits endocannabinoid reuptake→ CB1 receptor activation → descending serotoninergic pathways→ inhibit pain sensitisation * Interaction with TRP (transient receptor potential) channels – Paracetamol and metabolites * Inhibition of NO formation – Inhibit NMDA receptor-mediated NO synthesis - NO conveys nociceptive information at the spinal level

Question 29

Paracetamol metabolites

Answer 29

* NAPQI * AM404

Question 30

Paracetamol inactive at what sites

Answer 30

* kidney - no renal impairment * GI tract - no peptic ulcer risk * lacks anti-inflammatory effect

Question 31

NAPQI is rapidly detoxified - how? (treatment of OD)

Answer 31

* intrinsic drug-induced liver injury- NAPQI accumulation * antidote: *N-acetylcysteine* to replenish glutathione

Question 32

What is antidote to Paracetamol OD

Answer 32

N-acetylcysteine