2018B10 Outline the mechanisms of action of the drugs, with examples, which increase myocardial contractility.

 

List:

·      Intro: contractility, adrenergic signalling

·      Drug table: class, example, mechanism of action

 

Intro:

Contractility

·  Those factors contributing to cardiac performance independent of preload, afterload and heart rate

·  ICF [Ca2+]

Adrenergic signalling

·  Adrenaline/noradrenaline binds β1 adrenoceptor, a Gs G protein coupled receptor (GPCR)

·  Activation of adenylyl cyclase -> ↑cAMP

·  Activation of PKA -> phosphorylation of:

o Myosin: ↑rate at which cross-bridge cycling can occur

o Membrane L-Ca2+ and sarcoplasmic reticular ryanodine-sensitive Ca2+ channel: ↑Ca2+ influx upon activation

o Troponin I and phospholamban: ↑rate of relaxation

 

Drugs:

Group

Example

Effect

Naturally occurring catecholamines

Adrenaline

Noradrenaline

Dopamine

Activate β1

Synthetic catecholamine

Isoprenaline

Dobutamine

Activate β1

Non-catecholamine β2 agonist

Salbutamol

Terbutaline

Activate cardiac β2 (same cascade as cardiac β1)

More effect on chronotropy and dromotropy than inotropy

Indirect β1 agonist

Ephedrine

Metaraminol

↑NAd release at adrenoceptors

PDE3 inhibitors

Milrinone

Amrinone

Aminophylline (non-selective)

↓cAMP breakdown

Ca2+ sensitizer

Levosimendan

Ca2+ sensitization

Stabilises Ca2+/troponin C

Other

Calcium

↑gradient for Ca2+ into ICF

Glucagon

Glucagon R: Gs GPCR -> ↑cAMP

Thyroxine

Permissive effect on catecholamines

Digoxin

Inhibit cardiac Na+K+ATPase

↑ICF Na+

↑Activity Na+/Ca2+ antiporter (3:1)

↑ICF [Ca2+]

Ketamine

↑SNS output from medulla -> ↑adrenaline, noradrenaline release

But direct effect neg inotropy (R-ketamine)

 

 

Feedback welcome at ketaminenightmares@gmail.com