NSAIDs & Opioids

Question 1

Recognise the central role of arachidonic acid in prostanoid synthesis

Answer 1

Prostaglandins are synthesised from arachidonic acid
Arachidonic acid –> eicosanoids –> prostanoids (PGs, prostacyclines, thromboxanes)
COX enzymes synthesise PG
Cell membrane phospholipase -phospholipase A2-> arachidonic acid -COX1/2-> PG ‘G’ -COX1/2-> PG ‘H’ -enzymes-> PG D,E,F,I
*PG ‘E’ most important in mediating inflammatory response

Question 2

Understand the general pharmacology of NSAID action on COX1 and COX2 inhibition

Answer 2

Small, sharp, aspirin-like drugs can inhibit both COX1 and COX2
Big, blunt drugs can only inhibit COX2

Question 3

Understand prostaglandins pharmacology

Answer 3

PGs bind with GPCR
EP1 receptor Gq - peripheral nociception (increase C fibre activity)
EP2 receptor Gs - vasodilation (increase COX2 and PG ‘E’ synthesis), increased cytokines in dorsal root cell body
EP3 receptor Gi - pyrexia (increase PG ‘E’), increase heat production, decrease heat loss

Question 4

Describe the role of COX enzymes

Answer 4

COX1 - constitutively expressed, wide range of tissue types, tight
COX2 - induced by injurious stimuli, constitutively expressed in parts of brain and kidney, baggy

Question 5

Describe the cytoprotective role of prostaglandins

Answer 5

Cytoprotective role:
Gastric mucosa
Myocardium
Renal parenchyma
Short half life, constant synthesis 
Increased perfusion (less ischaemia)

Question 6

Understand therapeutics/ADRs in terms of action on COX1 and COX2

Answer 6

Therapeutics - NSAIDS competitively inhibit mainly COX2 –> anti-inflammatory, analgesia of mild to moderate pain
*aspirin irreversibly inhibits COX enzymes
ADRs:
GI - stomach pain, nausea, heart burn, gastric bleeding, ulceration
Renal - decreased perfusion, low GFR, hypertension
Vascular - increased bleeding, bruising
Hypersensitivity
Stevens Johnson syndrome

Question 7

List the uses of NSAIDS

Answer 7

Analgesia (mild–>moderate)
Anti-inflammatory
Antipyretic

Question 8

Describe NSAID pharmacokinetics

Answer 8

Oral/topical
Linear kinetics
Heavily bound to plasma proteins

Question 9

Describe the drug interactions associated with NSAIDs

Answer 9

Aspirin - compete with COX1
Sulphonylureas
Warfarin
Methotrexate

Question 10

Understand the mode of action of NSAIDs on platelet function exemplified by aspirin

Answer 10

Aspirin irreversibly binds to both COX enzymes

It irreversibly blocks the formation of thromboxane A2 in platelets –> inhibitory effect on platelet aggregation

Question 11

Appreciate the special case of paracetamol as an analgesic/antipyretic

Answer 11

Non NSAID, non opioid
Effective for mild–>moderate analgesia, fever
Therapeutic dose = 8x500mg daily
Weak COX1/2 inhibitor, primarily act in CNS? COX3?

Question 12

Explain paracetamol overdose and toxicity

Answer 12

Caution in alcoholics/those with compromised hepatic function
Overdose = increase in toxic NAPQI due to phase 2 metabolism saturation
Unconjugated NAPQI = very reactive nucleophile –> binds with cellular macromolecules/mitochondria
Treatment - oral activated charcoal (0-4hrs), IV NAC/methionine (0-36hrs)

Question 13

Be familiar with the general pathways involved in pain and opiate control

Answer 13

Nociceptor –> type A (myelinated), type C (non-myelinated) –> dorsal root of spinal cord –> thalamus and primary sensory cortex
Interneurones in substantia gelatinosa inhibit signals from dorsal root of spinal cord and can inhibit substance P/glutamate

Question 14

Know the general classification of endogenous and exogenous opioids

Answer 14

Endogenous - enkephalins, endorphins, dynorphins

Exogenous - morphine, tramadol, tapentadol, codeine

Question 15

Appreciate the different classes of opioid receptors and their mechanism of action

Answer 15

Mu (MOP) - increased efflux of K+ –> hyperpolarised –> decreased excitability
Delta (DOP) - decreased cAMP synthesis
Kappa (KOP) - decreased influx of Ca2+ via channels
Due to low Ca2+ there is decreased release of neurotransmitters such as substance P

Question 16

Recognise the key importance of opiate pharmacokinetics in therapeutic/toxic balance

Answer 16

Morphine - low oral bioavailability, not lipid soluble
Methadone - high oral bioavailability, can be taken as syrup
Codeine - high oral bioavailability
Measure metabolites in urine = screening

Question 17

Describe major therapeutic uses of opiates

Answer 17

Analgesia - terminal illness
Maintenance in dependence (methadone)
Anaesthetics (fentanyl)
Labour analgesia (pethidine)
Reverse respiratory depression, toxicity (naloxene)

Question 18

Recognise side effects of opiates and factors that predispose to ADRs

Answer 18

Dependence, tolerance, constipation
MOP - nausea, vomiting, drowsiness, miosis
KOP - dysphoria
Toxic levels can lead to hypotension, respiratory depression

Question 19

Describe the management of intentional or accidental opiate overdose

Answer 19

Opioid antagonist = IV naloxene

t1/2 = 1-1.5h, repeated doses

Question 20

Describe the medico-legal aspects of opiate prescription

Answer 20

Controlled drugs

Question 21

Describe how polymorphisms can affect opiate action

Answer 21

In some populations (Chinese), polymorphisms in CYP2D6 percent codeine from being converted to morphine
Codeine medication has no analgesic effect

Question 22

Appreciate the main features of Gate Theory

Answer 22

Non painful input closes the ‘gate’ to painful input which prevents painful stimuli travelling to the CNS
Pain submission –> substantia gelatinosa (dorsal horn, spinal cord)
Opioid drugs inhibit release of substance P from nerve terminals
Opioids mimic inhibitory descending pathways from higher centres in the brain