Session 7 - Pain pathways and NSAIDs

Question 1

What are the three main stages of pain perception?

Answer 1

1. Activation of Nociceptors
2. Transmission of pain information (Gate Theory)
3. Onward passage of pain information

Question 2

What causes activation of nociceptors?

Answer 2

Noxious thermal, chemical or mechanical stimuli can trigger firing of primary afferent fibres, (

Question 3

What are the two kinds of nociceptors and what do they do?

Answer 3

Sharp Stabbing Pain - A Fibres, Dull Nagging Pain C-Fibres through the activation of nociceptors

Question 4

What is the gate-control mechanism?

Answer 4

Transmission of pain information from the periphery to the dorsal horn of the spinal cord is inhibited or amplified by a combination of local (spinal) neuronal circuits and descending tracts from high brain centres.

Question 5

Where do primary afferent pain fibres synapse, and what substance do they release?

Answer 5

Synapse in lamina I, II and V of spinal cord dorsal horn (substantia gelatinosa). Release substance P (P for PAIN),

Question 6

What is the activity of the dorsal horn relay system moderated by?

Answer 6

Inhibitory inputs

• Local inhibitory interneurons which release opioid peptides
• Descending inhibitory noradrenergic fibres from the locus ceruleus of the brainstem
  
  • Activated by opioid peptides
• Descending inhibitory serotonergic gibres from the nucleus raphe magnus and PAG
  
  • Activated by opioid peptides

Question 7

Outline the process of prostaglandin synthesis

Answer 7

Cell membrane phospholipids —phospholipaseA2–> Arachidonic Acid –Cox1–> Prostaglandin G –Cox1–> Prostaglandin H –> PgE

Question 8

Give three ways in which cox can be inhibited

Answer 8

Irreversible inhibition (aspirin)
Competitive inhibition (ibuprofen)
Reversible, non-competitive inhibition (Paracetamol)

Question 9

What does Cox-1 do?

Answer 9

Expressed in most tissues (especially platelets, gastric mucosa and vasculature) and invovled in physiological cell signalling - major cytoprotective role in gastric mucosa, renal parenchyma and myocardium

Question 10

What are the adverse reactions of NSAIDs mostly due to?

Answer 10

Cox-1 inhibitors

Question 11

Where is Cox-2 produced?

Answer 11

Sites of inflammation

Question 12

What are the main therapeutic effects of NSAIDs due to?

Answer 12

 Analgesic and Anti-inflammatory (therapeutic) effects of NSAIDs are largely a result of inhibition of COX-2

Question 13

How do NSAIDs work?

Answer 13

In peripheral nerves, Prostaglandins increase neural sensitivity to bradykinins via Gq inhibition of K+ channels and increased Ca2+ levels increased Na+ channel sensitivity. These effects increase C-Fibre activity.

Question 14

What is inflammation?

Answer 14

Fundamental response of body to injurious simuli which is rapid, focussed and integrated. Signalling agents include bradykinins, cytokines, Nitric Oxide, histamine, Leukotrienes and neuropeptides. Eicosanoids (prostaglandins and thromboxanes) overlap with this response.

Question 15

How do cox inhibitors reduce inflammation?

Answer 15

Primarily reduce erythema, swelling and pain response associated with swelling, which comes about pathologically due to vasodilation and increased vascular permeability (although not directly the latter)

Question 16

How do cox inhibitors reduce fever?

Answer 16

Fever due to bacterial endotoxins trigger macrophage release of endogenous pyrogen IL-1. This stimulates hypothalamic production of Prostaglandin E that elevates the set point on central ‘thermostat’ via EP3 receptor, which is Gi tpe GPCR receptor. This causes decreased cAMP, increase in Ca2+ in temperature regulation and increases heat production and decreases heat loss. NSAIDs reduce PG-E synthesis.

Question 17

How do cox inhibitors reduce pain?

Answer 17

In peripheral nerves, Prostaglandins increase neural sensitivity to bradykinins via Gq inhibition of K+ channels and increased Ca2+ levels increased Na+ channel sensitivity. These effects increase C-Fibre activity.

Question 18

How are NSAIDs administered?

Answer 18

Typically given orally, but there also many topical preparation for local delivery

Question 19

What kind of kinetics do NSAIDs show?

Answer 19

First Order Elimination

Proceeds to zero order at >12 300mg tablets

Question 20

Name two of the main ADR associated with NSAIDs

Answer 20

GI

Renal

Question 21

What happens in NSAID GI ADRs?

Answer 21

o PGE2 is involved in protection of gastric mucosa
 Inhibition of PGE2 increases mucosal permeability and decreases mucosal blood flow and protection
 NSAIDs can cause damage to stomach directly on ingestion
o Ulceration, haemorrhage and even perforation seen with long term high dose elderly users

Question 22

How can NSAID GI ADRs be offset?

Answer 22

o GI ADRs can be offset (long term) with PPIs or Misoprostol (synthetic prostaglandins)

Question 23

Why do NSAIDs cause renal problems

Answer 23

o Prostaglandins responsible for vasodilation of afferent arteriole
o Reversible reduction in GFR occurs as a result of PGE2 and PGI2 inhibition
o Decreased renal perfusion can cause Na+/K+/Cl- and H20 retention.

Question 24

Name four groups of patients with increased risk of NSAID renal ADR?

Answer 24

Neonates
Elderly
Patients with compromised HRH
Patients with reduced blood bolume

Question 25

Give five ADRs other than prev stated concerning

Answer 25

o Skin reactions (15% for some NSAIDs) o Steven Johnson Syndrome, immune complex mediated hypersensitivity disorder o Asthmatic bronchospasm (10% incidence) o Allergic response o Prolongation of bleeding time (platelet inhibition) o Aspirin is associated with risk of the post-viral Reye’s Syndrome (brain and liver injury) in children

Question 26

What is the issue with selective Cox-2 inhibitors?

Answer 26

Since most NSAID ADRs are due to COX-1 inhibition, drugs have been developed that only inhibit COX-2. Unfortunately their use was associated with an increased risk of hypertension and cardiac and renal failure. Still prescribed but short-term use only.

Question 27

Give four drug drug interactions of NSAIDs

Answer 27

o Aspirin is highly plasma protein bound and can displace other drugs, increasing their active free concentration. Competitive displacement of these drugs may require dose adjustment to avoid changes in PK and PDs.  Warfarin -  Concentration   Bleeding  Methotrexate -  Concentration  Wide ranging, serious ADRs  Sulphonylureas -  Concentration  Hypoglycaemia o NSAIDs can interact with ACE inhibitors and attenuate their action, blocking the production of vasodilating prostaglandins

Question 28

What is unique about Aspirins pharmacokinetic profile?

Answer 28

It is the only NSAID to irreversibly inhibit COX enzymes, via acetylation. It also has a unique pharmacokinetic profile, as its t½ is less than 30 minutes – it is rapidly hydrolysed in plasma to salicylate, which has it s own t½ of ~4 hours.

Question 29

How does aspirin prevent coagulation?

Answer 29

Inhibits cox-1 activty, preventing thromboxane production

Question 30

What is unique about paracetamol?

Answer 30

Paracetamol is a unique ‘non-NSAID’, as it has virtually no anti-inflammatory action. It is very effective for mild/moderate analgesia and fever.

Question 31

What is the mechanism of action of parecatamol (suspected?)

Answer 31

Paracetamol has a free-radical trapping action that interferes with the production of hydroperoxidases, which are believed to have essential role in cyclooxygenase activity (weakly Cox-1, Cox-2 and Cox-3 inhibitng).

Question 32

Why is paracetamol an agent of choice in tackling pain?

Answer 32

Has fewer ADRs at standard dosage

Question 33

Outline paracetamol metabolism at normal doses

Answer 33

At therapeutic levels, Paracetamol has Linear Pharmacokinetics, and is conjugated with Glucuronide (60%) or Sulphate (30%) in Phase II Drug Metabolism. A small amount also undergoes Phase 1 Oxidation, to produce the toxic metabolite N-acetyl-p-benzo-quinone imine (NAPQI).

Question 34

What happens if a toxic dose of paracetamol is taken?

Answer 34

If a toxic dose of Paracetamol is taken the Phase II pathways quickly become saturated and much more Paracetamol undergoes Phase I metabolism (Zero Order Kinetics), producing more NAPQI. Not only is NAPQI toxic to hepatocytes but it also undergoes Phase II conjugation with Glutathione, which is an important anti-oxidant, resulting in further damage from reactive oxygen species. Liver failure occurs over a period of several days. Unconjugated NAPQI is highly is highly reactive and binds with cellular macromolecules/mitochondria. Precipitous loss of function primarily leads to necrotic hepatic cell death. A single dose of over 10g (20 tablets) is potentially fatal.

Question 35

What is the treatment for paracetamol overdose?

Answer 35

Paracetamol overdose must be treated as soon as possible and guided by blood levels of the drug. Treatment is time dependent, as delayed hepatotoxic effects peak at 72-96 hours post ingestion. o Within 0-4 hours  Activated Charcoal orally  Reduces uptake by 50-90% o Within 0-36 hrs  Start N-Acetylcysteine  Methionine by mouth if N-Acetylcysteine cannot be given promptly

Question 36

Give three indications for NSAIDs

Answer 36

 Musculoskeletal and joint disease  Analgesia for mild to moderate pain  Symptomatic relief in fever

Question 37

Give three contraindications for NSAIDs

Answer 37

 Gastrointestinal ulceration or bleeding  Previous hypersensitivity to any NSAID  Caution in asthma and when renal function is impaired

Question 38

What is the mech of action of NSAIDs?

Answer 38

 Inhibit Cyclooxygenase enzyme, preventing Prostaglandin synthesis

Question 39

Give four drug-drug interactions of NSAIDs

Answer 39

 Warfarin (protein binding reaction)  Methotrexate (protein binding reaction)  Sulphonylureas (protein binding reaction)  ACE inhibitors – Attenuate action