analgesic pharmacology Flashcards
Aspirin
Outline the mechanism of action of aspirin
● 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
Describe the pharmacokinetics of aspirin
● 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
Outline the adverse effects of aspirin
● 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
Ibuprofen
Describe the pharmacodynamics of ibuprofen
● Ibuprofen is a NSAID
● Inhibition of prostaglandin biosynthesis via REVERSIBLE inhibition of COX
● Anti-inflammatory, antipyretic and analgesic effects
Describe the pharmacokinetics of ibuprofen
● 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
Colchicine
Describe the mechanism of action of colchicine
● Anti inflammatory effect via binding to tubulin, inhibits WBC migration and
phagocytosis
● Inhibits formation of leukotrine B4
● No effect on uric acid metabolism
What are the indications for colchicine?
● Treatment of acute episodes of gout
● Prophylaxis of recurrent episodes
● Can also be used in familial mediterranean fever
● Sometimes prescribed in pericarditis
Paracetamol
Describe the pharmacokinetics of paracetamol
● 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
What is the toxic dose of paracetamol?
150-200mg/kg in an adult
Describe the mechanism by which paracetamol causes toxicity
● 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
What are the clinical features of paracetamol toxicity?
● Nausea, vomiting, abdominal pain
● HAGMA
● Liver failure
● Renal failure (acute tubular necrosis)
● In massive doses can cause decreased level of consciousness and coma
How does N-acetyle-cysteine work in the treatment of paracetamol overdose?
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
What are the adverse effects of N-acetylcysteine?
Mild anaphylactoid reactions in 15-20% of people, causes flushing, rash and
angioedema
Fentanyl
Describe the mechanism of action of fentanyl
Synthetic opioid that acts as an agonist at the µ (mu) receptor
Describe the pharmacokinetics of fentanyl
● 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
What is the potency of fentanyl relative to morphine?
100 times more potent 0.1mg (or 100 micrograms) fentanyl equivalent to 10mg morphine
What are the adverse effects of fentanyl?
● Respiratory depression, cough, chest wall and laryngeal rigidity
● Nausea, vomiting, constipation
● Dysphoria
● Urticaria, itch
● Urinary retention
Morphine
What is the mechanism of action of morphine?
Acts on mu/delta/kappa receptors to reduce presynaptic and postsynaptic
neurotransmission.
Outline the pharmacokinetics of morphine
● 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.
What are the CNS effects of morphine?
● Analgesia
● Sedation
● Respiratory depression
● Euphoria
● Cough suppression
● Miosis
● Truncal rigidity
● Nausea/vomiting
Why do opiates cause respiratory depression?
Inhibition of brainstem respiratory controls, allowing less response to hypercapnoea
Outline the pharmacodynamics of oxycodone
Opioid agonist that acts on mu receptors in the brain and spinal cord.
Outline the pharmacokinetics of oxycodone
● 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
What strategies may be used when prescribing oxycodone to reduce the risk of
developing dependence?
● 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
Opiate dependence
What are some drugs that are used in the treatment of opioid dependence?
Outline the principles behind how these drugs work
● 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.
What problem can be associated with naloxone administration?
● Rapid precipitated withdrawal
● Re-sedation due to short half life
How can these problems be minimised?
● Using smaller, titrated doses
● Naloxone infusion
