18A02: Exam Report
Compare and contrast the pharmacology of adrenaline and milrinone.
45% of candidates passed this question.
This question was best answered using a table. Better answers included: the mechanisms of action, the pharmacokinetics and pharmacodynamics, indications for use and adverse effects. To complete the answer, the two drugs should have been compared and contrasted. There are many areas which could be contrasted e.g. different indications, different mechanisms of action, different half-lives and duration of action, different metabolism and different
pharmacodynamic effects, in particular the effects on the cardiovascular system and the pulmonary circulation. Similarities should also have been highlighted.
G7i / 18A02: Compare and contrast the pharmacology of adrenaline and milrinone
Drugs
Adrenaline
Milrinone
They sound different, which is great in an emergency!
Chemical
Adrenaline
Naturally occurring catecholamine with mixed direct α & β activity, produced by adrenal medulla
The prototype sympathomimetic
Milrinone
Selective PDE III inhibitor → pipyridine derivative
Adrenergic & non adrenergic drugs
Use
Adrenaline
Inotropy
Cardiac arrest
Anaphylaxis
Vasoconstrictor
Milrinone
Cardiac failure (acute)
Adrenaline has multiple uses and is used in ALS, it is easily accessible and should be on every crash cart
Presentation
Adrenaline
Clear solution
100mcg – 1mg/mL
Brown ampoule → deteriorates on exposure to air/light
Excipients: sodium metabisulphite, sodium chloride, sodium hydroxide, hydrochloric acid, water
Milrinone
10mg/10ml ampoules, clear and colourless
Adrenaline is pre-formed for emergency administration in vials with specific concentrations
Milrinone is an ampoule which requires time to draw up
Dose
Adrenaline
Inotropy (IV)
- 1 – 2mcg/min = β2 receptors
- 2 – 6mcg/min = β1 & β2 receptors
- >10mcg/min = β & α receptors
Cardiac arrest = 1mg (IV)
Anaphylaxis = 100mcg – 1mg (IV)
Vasoconstriction = 1:200,000 diluted with lignocaine
Milrinone
Load: 50mcg/kg over 15 mins
Infusion: 0.5mcg/kg/min
Adrenaline has different doses according to what you are using it for
Adrenaline does not require a loading dose when used for inotropy
Milrinone requires a loading dose before infusion commencement
Route
Adrenaline
IV
ETT
Subcut
Epidural space
Milrinone
IV/PO
Milrinone tablets exist, however the ICU administration is IV via infusion
Adrenaline has multiple routes of administration
Onset
Adrenaline
immediate, effect lasting 1 – 5 mins
Milrinone
5 – 15 mins
Adrenaline has immediate onset & offset
DoA
Adrenaline
Offset immediate on cessation of infusion
Milrinone
t ½ 3 hrs
Milrinone requires a load and full effect is not reached immediately, it also has a longer half life.
MoA
Adrenaline
Agonist of adrenergic receptors; β2 > β1 > α1 = α2
- b2 → GS → activates AC → ↑cAMP
- Cardiac = ↑Ca++
- Smooth muscle = inhibits MLC CK
- Liver = activates glycogen phosphatase
- NB: MAST CELL stabilisation by β2 agonism of MC
- b 1 → GS → activates AC → ↑cAMP
- Cardiac = +ve inotropy, +ve chronotropy, +ve dromotropy
- Metabolic = lipolysis
- ↑RENIN → ↑AII → VC
- a1 → Gq → stimulates phospholipase C → ↑IP3 & DAG
- IP3: smooth muscle VC
- IP3: cardiac → weak +ve Inotropy
- DAG: metabolic → ↑BSL
- a 2 → Gi → inhibits AC → ↓cAMP
- CNS : ↓symp. outflow
- Peripheries : inhibits NA release by –ve feedback
- Platelets : ↓platelet aggregation
Milrinone
Competitive inhibition PDE III
- ↓hydrolysis of cAMP ∴↑cAMP of myocardium & smooth m.
Β1 receptor of heart = ↑Ca++
+ inotropy
+ chronotropy
+ dromotropy
Β2 receptor of heart = ↑Ca++
+ inotropy
Both have different mechanisms of action which allow them to be used synergistically, and for example minimize the adverse effects that would become by using larger doses
PK
Adrenaline
A
Slow after IM/SC injection
Good tracheal mucosal absorption
Inactivated PO
D
M
Metabolised by mitochondrial MAO
& COMT in liver, kidneys, blood
Metanephrine & VMA are
conjugated with glucuronic acid
E
Inactive metabolites excreted in urine
Milrinone
A
OBA 92% (IV only
preparations in Aus)
D
PPB 80%
VD 0.4L/kg
M
10% hepatically metabolized
E
Renally excreted
80% unchanged
renal dose adjustment
Comments
Milrinone requires renal dose adjustment w kidney impairment
PD
Adrenaline
CVS
+ INOTROPY, + CHRONOTROPY, + DRONOTROPY
↑CO
↑Myocardial O2 consumption
Coronary dilatation
VC peripherally
Resp
↑MV
Bronchodilation
↑PVR
Mast cell stabilisation
Renal
↑Bladder sphincter tone = difficulty voiding
↓Renal blood flow
Metabolic
↑BMR
↑Plasma glucose
Gluconeogenesis
↑FFA
CNS
Pupil dilatation
GI
↓Secretions & ↓ tone
Milrinone
CVS
- +ve inotropy
- Vasodilation
- Minimal effect on HR & myocardial O2 consumption
Comments
Milrinone has the benefit during cardiogenic shock of being a cardioselective drug
Adverse Effects
Adrenaline
Arrhythmias
Myocardial ischaemia
Cerebral bleed
Lactaemia (from aerobic glycolysis) ; ↑glycolysis, ↑glycogenolysis, ↑release of sk & lactate reserves ⇒ all for ENERGY
Tremor
Milrinone
↓SVR
Vasodilatory effect of milrinone often needs to be offset with a vasopressor
There are more side effects w adrenaline given it’s broader PD profile