Session 7 - Pain pathways and NSAIDs Flashcards Preview

Semester 5 - Farmocology > Session 7 - Pain pathways and NSAIDs > Flashcards

Flashcards in Session 7 - Pain pathways and NSAIDs Deck (39)
1

What are the three main stages of pain perception?

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

2

What causes activation of nociceptors?

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

3

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

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

4

What is the gate-control mechanism?

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.

5

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

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

6

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

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

7

Outline the process of prostaglandin synthesis

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

8

Give three ways in which cox can be inhibited

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

9

What does Cox-1 do?

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

10

What are the adverse reactions of NSAIDs mostly due to?

Cox-1 inhibitors

11

Where is Cox-2 produced?

Sites of inflammation

12

What are the main therapeutic effects of NSAIDs due to?

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

13

How do NSAIDs work?

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.

14

What is inflammation?

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.

15

How do cox inhibitors reduce inflammation?

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)

16

How do cox inhibitors reduce fever?

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.

17

How do cox inhibitors reduce pain?

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.

18

How are NSAIDs administered?

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

19

What kind of kinetics do NSAIDs show?

First Order Elimination
Proceeds to zero order at >12 300mg tablets

20

Name two of the main ADR associated with NSAIDs

GI
Renal

21

What happens in NSAID GI ADRs?

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

22

How can NSAID GI ADRs be offset?

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

23

Why do NSAIDs cause renal problems

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.

24

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

Neonates
Elderly
Patients with compromised HRH
Patients with reduced blood bolume

25

Give five ADRs other than prev stated concerning

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

26

What is the issue with selective Cox-2 inhibitors?

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.

27

Give four drug drug interactions of NSAIDs

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

28

What is unique about Aspirins pharmacokinetic profile?

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.

29

How does aspirin prevent coagulation?

Inhibits cox-1 activty, preventing thromboxane production

30

What is unique about paracetamol?

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

31

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

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).

32

Why is paracetamol an agent of choice in tackling pain?

Has fewer ADRs at standard dosage

33

Outline paracetamol metabolism at normal doses

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).

34

What happens if a toxic dose of paracetamol is taken?

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.

35

What is the treatment for paracetamol overdose?

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

36

Give three indications for NSAIDs

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

37

Give three contraindications for NSAIDs

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

38

What is the mech of action of NSAIDs?

 Inhibit Cyclooxygenase enzyme, preventing Prostaglandin synthesis

39

Give four drug-drug interactions of NSAIDs

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