G8i / 18A02: Compare and contrast the pharmacology of adrenaline and milrinone

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.

G8i / 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