2021A Question 6
Compare and contrast the pharmacology of metaraminol and adrenaline (epinephrine).
Examiner Report
55% of candidates achieved a pass in this question.
The main domains assessed in this question were:
- Structure and classification
- Mechanism of action
- Pharmacokinetics
- Pharmacodynamics – with particular emphasis on cardiovascular system effects
Both metaraminol and adrenaline (epinephrine) are drugs commonly used by anaesthetists and therefore it was expected that candidates should have a thorough knowledge of their pharmacology to pass. Many candidates utilised a table format and this lent itself well to a comparison of the two drugs across the required domains
Common problems included:
- Lack of detail regarding mechanism of action (including adrenoreceptor selectivity)
- Little pharmacokinetic information provided
- Superficial mention of the cardiovascular effects of the drugs
- No mention of effects on other body systems
The intracellular details of G-protein coupled receptor activation was not required and did not receive marks.
Model Answer
Physicochemical
| Adrenaline | Metaraminol | |
|---|---|---|
| Structure |  |
 |
| Structure-activity | - Catecholamine: Direct, potent, sensitive to COMT - OH on β-carbon: Direct, alpha - No substitution on α-carbon: MAO sensitive - Larger amine: Β>α |
- Non-catecholamine: Resistant to COMT - OH on β-carbon: Direct, alpha - NH2 substitution on α-carbon: Indirect, MAO resistant - Smaller amine: Α>β |
| Presentation | 1mg in 1mL or 10mL (concentrated ++++) | 10mg in 1mL (concentrated++) |
| Tissue necrosis | High risk – CVC only | Low risk – PIVC ok |
Pharmacokinetic
| Adrenaline | Metaraminol | |
|---|---|---|
| Administration | - IV infusion: 1-30μg/min - IV bolus: 1mg in cardiac arrest - IM bolus: 500μg in anaphylaxis |
- IV bolus: 0.5-1mg (10-20μg/kg) PRN - IV infusion: Typically 0.5-5mg/h (20-200μg/kg/h) - S/C or IM |
| Time course | - Onset ≤1min - Duration 5 mins - Drug elimination rapid - Receptor effects prolonged |
- Onset 1-2 min - Duration: Stated 20-60mins, likely shorter |
| Absorption | Not orally bioavailable | Orally bioavailable, % unknown |
| Distribution | - VD 0.1-0.2L/kg - 12% protein bound - Should not cross blood-brain barrier |
- Poorly studied in humans - 45% protein bound - VD 4L/kg - Should not cross BBB |
| Metabolism | - By COMT and MAO → VMA - By COMT only → Normetadrenaline - t1/2β 2 mins |
- Poorly studied in humans; likely slow - Not susceptible to MAO or COMT - t1/2β 6 hours |
| Excretion | Metabolites → Urine | Unknown |
Pharmacodynamics
| Adrenaline | Metaraminol | |
|---|---|---|
| Receptor activity | - β1 > β2 > α1 - Direct |
- α1 >> β1 - Direct - Indirect (displaces noradrenaline from vesicles) |
| Use | - Anaphylaxis (↑ CO, ↑ SVR, stabilize mast cells) - Cardiogenic shock (↑ CO) - Cardiac arrest (↑ SVR → Vital organ perfusion) - Additive with local anaesthetic (↑ duration, ↓ LAST) |
- Peri-operative hypotension – GA and neuraxial - Unclear if equivalent to phenylephrine in obstetrics |
| Toxicity | - Safer with noradrenaline reuptake inhibitors (NRI) - Tachyphylaxis slow: Adrenoceptor downregulation |
- Dangerous with NRI e.g. MAOi (↑↑ NAd release) - Tachyphylaxis rapid: Catecholamine depletion |