14. Inotropes & Vasopressors Flashcards
What is a Vasoactive agent?
Endogenous compound or pharmacological drug which has an effect on blood vessels:
- Increase or decrease blood pressure
- Effect heart rate
Vasoactive agent
Inotropes – increase myocardial contractility (inotropy):
- Dobutamine, isoprenaline, digoxin
Vasopressors – cause vasoconstriction thereby increasing mean arterial pressure
- Noradrenaline, vasopressin
Inodilators – cause vasodilation thereby decrease mean arterial pressure
- Milrinone, levosimendan
Some agents don’t fit these categories
- Dopamine
Used in acute HF, sepsis or cariogenic shock
Inotropic agents
- Isoprenaline (beta1 & beta2)
- Dobutamine (beta1, beta2 - weak & alpha1 - selective)
+ Racemic mixture results in overall B1 agonism - Bind to 1 AR on cardiac myocytes
- Increase force of contraction through Gs – cAMP – PKA pathway
Vasopressor agents
- Noradrenaline
- Vasopressin (ADH) - Used as well as/or instead of NA in cardiac shock
- Cause vasoconstriction & thereby increase mean arterial pressure
Noradrenaline
- Mainly acts as an alpha1 & alpha2 agonist on vascular smooth muscle causing vasoconstriction
- Some beta1 agonism on ventricular cardiomyocytes to cause inotropy
Vasopressin (antidiuretic hormone)
Kidneys – act on collecting duct V2 receptors to increase water permeability
- cAMP mediated exocytosis
- More aquaporin-2 in the apical membrane
- Decreases urine due to water reabsorption
- Increases blood volume
- Increases cardiac output & MAP
Blood vessels – acts on V1 receptor (Gq) causes vasoconstriction
- Increases systemic vascular resistance
Inodilators
Agonists with inotropic effects that also cause vasodilation
- Decrease mean arterial pressure
- Decrease systemic vascular resistance
- Decrease pulmonary vascular resistance
- Milirinone
- Levosimendan
Milirione
- Phosphodiesterase inhibitor (PDEI)
- Inhibitor PDE3
- Cardiac muscle – inotrope
- Vascular smooth muscle – vasodilator
Levosimendan
- KATP channel activator
- Sensitisation of cardiac muscle to intracellular Ca2+ concentration to increase inotropy
+ Binds to troponin C in a Ca2+ dependent manner
+ No effect on intracellular Ca2+ levels - Acts on KATP channel in vascular smooth muscle to cause vasodilation
+ Opens KATP causing hyperpolarisation - Partially inhibit PDE3
- Increases inotropy & causes vasodilation
Dopamine
- Metabolic precursor of noradrenaline & adrenaline
- Dopamine given IV can act on dopamine receptors (D1 – D5)
OR - Adrenergic receptors
Mechanism of action varies depending on dose:
Low dose (1-5 µg/kg/min)
- Dopamine D1 receptor agonist – Gs/cAMP
- Vasodilation of capillary beds & renal blood vessels
Medium dose (6-10 µg/kg/min)
- B1 agonist
- Increase inotropy
High dose (11-12 µg/kg/min)
- a1 agonist
- Vasoconstriction – NO BENEFIT
Digoxin - MoA
- Inhibits sodium-potassium ATPase
+ Increases intracellular sodium
+ Sodium extruded through NCX
+ Increases intracellular Ca2+ - Increases inotropy – increases cardiac output
- Improved circulation leads to reduced sympathetic activity, which then reduces peripheral resistance with reduction in heart rate
- Slows down conduction velocity through the AV node, which accounts for its use in atrial fibrillation
Digoxin - clinical use
Heart failure:
- Increases cardiac output by increasing inotropy – 0.5-1 ng/mL
Atrial fibrillation:
- Slows down conduction velocity through the AV node – 0.5-2 ng/mL
- Narrow therapeutic index – 0.5-2 ng/mL
- Endpoint of therapy difficult to define & measure due to variability in serum digoxin concentration in different patients
- Incorrect dosage of digoxin occurs frequently & is due in most cases to relative over- or under- dosage - Digitalis toxicity
Digoxin - bioavailability
Factors affecting bioavailability
- Food – high fibre diet
- Drugs – antacids, cholestyramine, kaolin, metoclopramide, sulfasalazine & neomycin reduce bioavailability
Up to 40% of oral digoxin degraded by intestinal bacteria
- Varies patient to patient
- ~40% in 1 in 10 people
Digoxin - distribution
- Serum digoxin concentration – time curve follows 2-compartment model
- 25% protein bound in plasma
- Large volume of distribution 7L/kg
- Tissue distribution phase – 8-12 hours
- During the distribution phase digoxin in plasma is not equilibrium with digoxin in tissues
- Initial (fast) phase – plasma + highly perfused tissue – liver
- Second (slower) phase – peripheral deep tissue – skeletal muscle, kidneys, myocardium
- Clinical effect is not seen until sufficient drug accumulate at the target site of action
+ Hours after loading dose - Plasma drug concentration early after loading dose not representative of true drug concentration at site of action
- Inappropriate dosing – digitalis toxicity
Digoxin - toxicity
- Can also occur due to low potassium in the body
- Co-administration with diuretic agents – potassium sparing diuretic, spironolactone
