pharmacology

Direct sympathomimetics

• Endogenous

  • Adrenaline

  • Noradrenaline

  • Dopamine

• Synthetic

  • Dobutamine

  • Isoprenaline

• Bind to beta-1 receptors

• Activate G-portein coupled adenylyl cyclase

• Increase cAMP production

• This leads to increased calcium availability inside the cardiac myocytes, and therefore increased contractility and pacemaker automaticity

Indirect sympathomimetics

• Ephedrine

• Act as "false neurotransmitters"; displace catecholamines from presynaptic storage vesicles

• The resulting catecholamine release produces direct catecholamine effects

Phosphodiesterase inhibitors

• Milrinone

• Inamrinone

• Enoximone

• Inhibit phosphodiesterase 3, which is responsible for cAMP catabolism.

• Thus, increases cyclic AMP

• Thus, increases calcium availability by increased voltage 

• Selective for vascular smooth muscle and cardiac muscle.

Calcium sensitisers

• Levosimendan

• Pimobendan

• Bind to troponin C and stabilise its open state

• This allows muscle contraction.

• Thus increased trop C / calcium complex stability increases contractility.

Cardiac glycosides

• Digoxin

• Inhibits Na+/K+ ATPase

• Thus, increases intracellular sodium

• This increses sodium-calcium exchange by the Na+/Ca2+ exchanger (INCX) during Phase 1 of the cardiac action potential.

• The resulting increase in intracellular calcum promotes inotropy. 

Class

Vasopressor

Chemistry

Catecholamine

Routes of administration

IV

Absorption

Basically zero oral availabilty due to destruction by brush border enzymes in the gut (COMT and MAO)

Solubility

pKa = 8.85; water-soluble

Distribution

VOD = 0.12 L/kg, i.e. essentially confined to the circulating volume; 25% protein-bound

Target receptor

Noradrenaline is highly selective for the alpha-1 receptor

Metabolism

Metabolised rapidly and completely by COMT and MAO

Elimination

Metabolites are renally excreted. Half-life is ~2 minutes

Time course of action

Very short acting, very rapid onset of effect

Mechanism of action

By binding to the alpha-1 receptor, noradrenaline increases the release of a secondary messenger (inositol triphosphate, IP3) which results in the release of calcium into the cytosol, and thus enhanced smooth muscle contractility.

Clinical effects

Increased peripheral resistance, increased afterload, increased blood pressure; redistribution of blood flow from splanchnic circulation and skeletal muscle.