analgesic pharmacology

Question 1

Aspirin
Outline the mechanism of action of aspirin

Answer 1

● Irreversible non selective cyclooxygenase inhibitor (COX 1 and 2)
● Inhibits platelet aggregation through reduction of thromboxane A2 (COX-1
inhibition), effect lasts for the life of the platelet (10 days)
● Inhibits prostaglandin synthesis in tissues (COX-2) resulting in the
anti-inflammatory, analgesic and antipyretic effects

Question 2

Describe the pharmacokinetics of aspirin

Answer 2

● Absorption: Rapid due to pKa of 3.5, hydrolysed to salicylic acid in the blood,
peak plasma level in 1-2 hours
● Distribution: Low protein binding, small volume of distribution
● Metabolism: Metabolised by esterases in tissues and plasma. Saturable
metabolism with increasing doses – switches from first order to zero order
kinetics. Half-life of 15 mins but clinical effects last longer due to irreversible
binding.
● Elimination: Metabolites cleared in the urine – increased elimination in more
alkaline urine

Question 3

Outline the adverse effects of aspirin

Answer 3

● GI—nausea & vomiting, GI bleeding from gastritis or peptic ulceration,
hepatotoxicity
● Hypersensitivity reactions – asthma, oedema, rash
● Bleeding – can be prolonged due to platelet inhibition
● CNS—headache, tinnitus, dizziness
● CVS—fluid retention, oedema
● Renal impairment

Question 4

Ibuprofen
Describe the pharmacodynamics of ibuprofen

Answer 4

● Ibuprofen is a NSAID
● Inhibition of prostaglandin biosynthesis via REVERSIBLE inhibition of COX
● Anti-inflammatory, antipyretic and analgesic effects

Question 5

Describe the pharmacokinetics of ibuprofen

Answer 5

● Absorption: Well absorbed orally
● Distribution: Highly protein bound, small volume of distribution
● Metabolism: in the liver by cytochrome P450 enzymes
● Elimination: renal, serum half life 1-3 hours

Question 6

Colchicine
Describe the mechanism of action of colchicine

Answer 6

● Anti inflammatory effect via binding to tubulin, inhibits WBC migration and
phagocytosis
● Inhibits formation of leukotrine B4
● No effect on uric acid metabolism

Question 7

What are the indications for colchicine?

Answer 7

● Treatment of acute episodes of gout
● Prophylaxis of recurrent episodes
● Can also be used in familial mediterranean fever
● Sometimes prescribed in pericarditis

Question 8

Paracetamol
Describe the pharmacokinetics of paracetamol

Answer 8

● Absorption: Rapid, bioavailability 70-90%, peak concentration at 30-60minutes.
Given PO, IV, PR
● Distribution: Low protein binding, widely distributed but not into fat
● Metabolism: Hepatic, first order kinetics. >95% undergoes glucoronidation and
sulfation, 5% undergoes metabolism via CYP450 mechanism (phase 1 reaction –
hydroxylation) to form NAPQI. NAPQI is toxic but is usually detoxified by
glutathione. Half life 2-3 hours
● Elimination: <5% is excreted unchanged in the urine

Question 9

What is the toxic dose of paracetamol?

Answer 9

150-200mg/kg in an adult

Question 10

Describe the mechanism by which paracetamol causes toxicity

Answer 10

● Paracetamol is usually conjugated with glucuronide and sulphate by transferase
enzymes
● This pathway becomes saturated in overdose, allowing increasing paracetamol to
be metabolised by the smaller pathway to NAPQI
● NAPQI is detoxified by glutathione, which becomes depleted, resulting in high
levels of the toxic metabolite

Question 11

What are the clinical features of paracetamol toxicity?

Answer 11

● Nausea, vomiting, abdominal pain
● HAGMA
● Liver failure
● Renal failure (acute tubular necrosis)
● In massive doses can cause decreased level of consciousness and coma

Question 12

How does N-acetyle-cysteine work in the treatment of paracetamol overdose?

Answer 12

4 mechanisms:

● Sulfhydryl group donor – restores hepatic reduced glutathione levels
● Acts as an alternative substrate for conjugation with toxic metabolite
● Provision of inorganic sulphate
● Reduction of NAPQI back to paracetamol

Question 13

What are the adverse effects of N-acetylcysteine?

Answer 13

Mild anaphylactoid reactions in 15-20% of people, causes flushing, rash and
angioedema

Question 14

Fentanyl
Describe the mechanism of action of fentanyl

Answer 14

Synthetic opioid that acts as an agonist at the µ (mu) receptor

Question 15

Describe the pharmacokinetics of fentanyl

Answer 15

● Absorption: Can be given transdermal, IV, subcut, sublingual/buccal (lozenge),
transdermal patch and via epidural.
● Distribution: Highly lipid soluble, crosses the blood brain barrier
● Metabolism: High first pass metabolism, metabolised by P450 enzymes with no
active metabolites
● Elimination: Excreted in the urine with <5% unchanged. Elimination half life is 7
hours due to lipid solubility

Question 16

What is the potency of fentanyl relative to morphine?

Answer 16

100 times more potent 0.1mg (or 100 micrograms) fentanyl equivalent to 10mg morphine

Question 17

What are the adverse effects of fentanyl?

Answer 17

● Respiratory depression, cough, chest wall and laryngeal rigidity
● Nausea, vomiting, constipation
● Dysphoria
● Urticaria, itch
● Urinary retention

Question 18

Morphine
What is the mechanism of action of morphine?

Answer 18

Acts on mu/delta/kappa receptors to reduce presynaptic and postsynaptic
neurotransmission.

Question 19

Outline the pharmacokinetics of morphine

Answer 19

● Absorption: Can be given orally, or parenterally. Oral bioavailability is 80-100%
but it has a high first pass metabolism so PO doses are larger.
● Distribution: Volume of distribution 5L/kg
● Metabolism: Conjugated in the liver to mostly morphine-3-glucoronide. Small
amount (10%) is metabolised to morphine-6-glucoronide, which has an increased
analgesic potency
● Elimination: metabolites, via the kidneys. Half life of 2-3 hours.

Question 20

What are the CNS effects of morphine?

Answer 20

● Analgesia
● Sedation
● Respiratory depression
● Euphoria
● Cough suppression
● Miosis
● Truncal rigidity
● Nausea/vomiting

Question 21

Why do opiates cause respiratory depression?

Answer 21

Inhibition of brainstem respiratory controls, allowing less response to hypercapnoea

Question 22

Outline the pharmacodynamics of oxycodone

Answer 22

Opioid agonist that acts on mu receptors in the brain and spinal cord.

Question 23

Outline the pharmacokinetics of oxycodone

Answer 23

● Absorption: Good oral absorption
● Distribution: High volume of distribution
● Metabolism: Low first pass metabolism compared to morphine, duration of action
3-4 hours, metabolised by P450 enzymes
● Elimination: Metabolites excreted by the kidneys

Question 24

What strategies may be used when prescribing oxycodone to reduce the risk of
developing dependence?

Answer 24

● Establish goals of care at the start of treatment
● Combine with non-opioid analgesics
● Smaller doses at longer intervals
● Use of controlled release preparations
● Frequent re-evaluation of ongoing requirements

Question 25

Opiate dependence
What are some drugs that are used in the treatment of opioid dependence?

Outline the principles behind how these drugs work

Answer 25

● Methadone
● Buprenorphine
● Clonidine
● Naltrexone
● Naloxone

● Methadone – longer acting opiate agonist, orally active, used to stabilise and
gradually reduce over time given longer half life
● Buprenorphine- partial opioid agonist that can be given once daily. Low doses for
detox and higher doses for maintenance
● Clonidine – centrally acting sympatholytic agent that mitigates the sympathetic
overactivity seen in withdrawal
● Naltrexone – used after patient has detoxified as it is a long acting pure opiate
antagonist
● Naloxone – short acting opiate antagonist, used in overdose as a rescue
medication.

Question 26

What problem can be associated with naloxone administration?

Answer 26

● Rapid precipitated withdrawal
● Re-sedation due to short half life

Question 27

How can these problems be minimised?

Answer 27

● Using smaller, titrated doses
● Naloxone infusion