Inotropes & Vasopressors — Inotrope Classification

• Inotrope: Agent that alters the force of contraction of a muscle
• Inotropes can be classified in an number of ways:
  • Negative or positive (the examiners did not want a discussion of negative inotropes on previous reports)
  • Naturally occurring: Eg Adrenalin, Noradrenalin, Dopamine 
    vs Synthetic: Dobutamine, dopexamine, isoprenalin, salbutamol

Classification by Mechanism of action is most effective

Postitive Inotropes

Class 1: Increase intracellular Calcium by a variety of mechanisms → ↑force of contraction

• Direct Adrenoceptor agonists (NA, Adren):
  • ↑ intracellular cAMP and ↑ Ca by Gs protein coupled mechanism
• Indirect adrenoceptor agonists (Ephedrine):
  • displacing NA from vesicles into cytoplasm 
  • ↑’s carrier-mediated diffusion into synaptic cleft 
  • ↑NA release at nerve terminal → ↑’d stimulation 
• Phosphodiesterase inhibitors (Theophyline, Milrinone):
  • inhibit PDE → ↓breakdown of cAMP (cGMP) → effective ↑cAMP
  • cAMP effects as per direct adrenoceptor agonists
• Glucagon
  • Bypasses adrenergic receptor to stimulate ↑cAMP
• Na/K atpase inhibitors (digoxin):
  • Inhibit Na+/K+-ATPase → ↑[Na+]i → Impair Na+/Ca2+ exchange pump → ↑[Ca2+]i

Class 2: Increase sensitivity of actin/myosin complex to calcium by action on troponin C 

• Levosimendin
  • ↑Ca interaction with troponin C → enhance contractility without ↑[Ca]i
  • Activate K_ATP channels on mitochondrial membrane → protect muscle from ischaemia leading to ischaemic preconditioning

Class 3: Act via metabolic or endocrine pathways (T3, Ca, Mg) 

Negative Inotropes

• Beta-blockers
  • Usually β1 blocking action
  • Inhibits the action of natural stimulation of Class 1 above
• Calcium-channel blockers are used for treating high blood pressure, chest pain, and irregular heart rhythm.
  • ↓ intracellular Ca via action on L-type calcium channels
  • nifedipine, amlodipine
• Centrally acting sympatholytics are used for treating high blood pressure.
  • Act centrally on α2 receptors to decrease sympathetic tone.
  • Clonidine

Gladwin 2016

Answer by Gladwin