Analgesic Drugs 11 to 20
Describe paracetamol metabolism.
Describe the mechanism of toxicity of Paracetamol.”]
Hepatotoxic metabolite in setting of glutathione depletion
Describe the metabolism of paracetamol?
Prompt: Does this change in toxic doses?
Rapidly absorbed, peak conc at 30-60 minutes
Slightly PP bound
Partially metabolised by hepatic MEs to paracetamol glucuronide and sulphate (inactive)
<5% excreted unchanged
Half-life is 2-3 hrs
Pass: 3 of 5
What is the toxic dose and how does this cause toxicity?
150-200mg/Kg or >7g in adult. Conjugation AAs (gluthathione in particular) used up, metabolised to toxic metabs NAPQI. Toxic to liver / kidneys.
Pass: Reasonable approximation. Must have reasonable understanding of how toxicity is caused
What are the clinical manifestations of toxicity?
GIT effects: Hepatic impairment. N/V, diarrhoea, abdo pain, dizzy, disorientation
Pass: Hepatic + one other
Describe the central nervous effects of Morphine.
• respiratory depression
• cough suppression
• truncal rigidity
• nausea / vomiting
Describe peripheral effects of Morphine.
• GI- constipation
Describe the clinically important pharmacological differences between morphine and fentanyl.
Prompt: Try dividing your response into the categories of receptor effects, absorption, and elimination.
1. Morphine (a phenanthrene) is naturally occurring. Fentanyl (a phenylpiperidine) is synthetic
2. RECEPTOR EFFECTS:
Both are strong agonists (all receptors), but potency fentanyl > morphine
Both morphine & fentanyl have low oral: parenteral potency ratios
elimination V/2 morphine > fentanyl
Pass: 2 of 3 differences
How does methadone differ from morphine and fentanyl?
PK: Methadone has a high oral:parenteral potency ratio
Elimination V/2 methadone >> morphine>fentanyl
Methadone has highly variable (between individuals) pharmacokinetics
Pass: Must know long V/2 and oral bioavailability.
What advantages and disadvantages might a drug like buprenorphine have in the treatment of heroin addiction, as compared to methadone?
1. Buprenorphine is a partial agonist at the µ (mu) receptor, and has a long duration of action due to slow dissociation from µ receptors. Said to be as effective as methadone in the detoxification and maintenance treatment of heroin addiction
2. Lower risk of overdose fatalities compared to methadone due to its partial agonist action
3. Slower receptor dissociation renders its effect resistant to naloxone reversal and preventions action of other narcotic analgesics (if needed)
Pass: Must describe what it does and that it is relatively safe.
Tell me about the pharmacokinetics of paracetamol.
1. Well absorbed orally with peak concentrations 30-60 mins
2 Hepatic metabolism Conjugated to sulphate and glucuronide which are inactive.
3 Renal excretion of conjugate. < 5% unchanged
4 Minor metabolite is toxic. N-acetyl-p-bemzoquinone. Detoxified by glutathione.
5. Elimination tY22-3 hrs
6. No plasma binding. VD 1L/kg (approx = TBW)
7. Activation of P450 system increases metabolism and toxic metabolite. Serum 150-200 mg/I normally 100 nrio/L if enhanced
1-3 to pass
How does n-acetylcysteine work in treatment of paracetamol overdose?
- serves as substrate for toxic metabolite to act on
- Glutathione substitute.
- SH donor early
1 to pass
What classes of local anaesthetics are used in the ED?
(Prompt for examples)
Amides: lignocaine, prilocaine, bupivacaine, ropivicaine
Esters: cocaine, benzocaine, procaine, tetracaine
Pass: 1 of each
What factors affect the systemic absorption of lignocaine after local infiltration?
Absorption: dose, site of injection, drug-tissue binding, tissue blood-flow, vasoconstrictors,
Pass: bold + 1
What are the toxic effects of lignocaine?
CNS: All can get: sleepiness, light-headed, visual, auditory disturbance, restlessness
Early tox: circumoral/tongue numbness, metallic taste
Serious/higher: Twitching, nystagmus, seizures
Direct neurotoxicity – radicular irritation with spinals
CVS: Na channel (depress abnormal pacemaker, excitability, conduction) v Ca channel effects
at high doses – decrease myocardial contractility, arteriolar dilatation, hypotension, with
bupivicaine can get idioventricular rhythm, broad QRS, EMD
Allergy: rare with amides as not metab’d to PABA
CNS: seizures and 1 other
Describe the pharmacokinetics of oxycodone.
PROMPT – Describe the pharmacokinetics of opiates.
- Oral commonly
- Good oral absorption
- High volume of distribution
- Low first pass metabolism compared with otehrs
- 10 morphine = 4.5mg oxycodone
- Duration 3-4 hours, longer if controlled release formulation.
- Hepatic metabolism.
Pass: 1 of each
What adverse effects might you anticipate?
- Respiratory depression
- Biliary colic
- Caution in renal failure
- 3 to pass
When prescribing oxycodone, what prescribing strategies may help in reducing the development of dependence?
- Smaller doses at longer intervals
- Establish goals at start of treatment
- Limit doses
- Use of other analgesics
- Frequent evaluation of ongoing need
- Use of modified controlled release formulations
- 2 to pass
What is the mechanism of action of morphine?
- Brain and spinal cord receptors: mu, delta, kappa (subtypes: 2 mu and delta, 3 kappa)
- Binding to receptor (particularly mu) -> reduction of neurotransmitter release from presynaptic nerve terminals (especially glutamate) and inhibit postsynaptic neurons (by opening K channels).
- Central thalamic action and activation of descending inhibitory pain neurons
- Must name mu and 1 other type of receptors
- 2 bold actions
How is morphine metabolised and excreted?
- Mostly liver conjugated to morphine-3-glucuronide which has neuroexcitatory properties
- 10% is metabolised to morphine-6-glucuronide with 4-6% increased analgesic potency
- Excreted renally
- Liver metabolism & metabolites are renally excreted
What are the possible acute adverse reactions with morphine?
PROMPT – Why are we more cautious in using morphine in renal failure patients?
- Sedation/respiratory depression
- Nausea and vomiting
- Hypotension if predisposed
- Histamine release
- Biliary colic
- In renal failure it can cause seizures or prolonged analgesia
- Bold and 2 more
What is drug potency?
- Dose or concentration to achieve 50% maximal effect (EC50 or ED50)
- Bold to pass
Draw and explain dose-response curves comparing morphine with fentanyl.
- Must graph dose or log dose (X axis) versus response (Y axis)
- Display differences and explain on graph
What are the pharmacokinetics of fentanyl?
- Highly lipid soluble
- Half-life 5 minutes
- Duration 1-1.5 hours
- Low bioavailability
- Hepatic metabolism
- 3/5 to pass
What is bioavailability?
- Fraction of unchanged drug reaching the systemic circulation following administration by any route
- Bold to pass
What factors affect bioavailability?
- Extent of absorption
- Too hydrophilic or too lipophilic – decreased absorption
- Reverse transporter associated with p-glycoprotein – pumps drug back to gut lumen – decreased absorption
- Gut wall metabolism – decreased absorption
- First pass metabolism
- Metabolism by liver before it reaches systemic circulation
- Small additional effect if drug has biliary excretion
- Rate of absorption
- Determined by site of administration and drug formation
- Bold with reasonable explanation of each
What is the bioavailability of ibuprofen?
- Weak organic acid
- Well absorbed rapidly
- Minimal first pass metabolism
- Bold to pass