eLFH - Inotropes and Vasopressors Flashcards
Inotrope definition
Drugs which increase myocardial contractility
Vasopressor definition
Drugs which cause peripheral arteriolar vasoconstriction
Mean arterial pressure equation
MAP = CO x SVR
= HR x SV x SVR
Systemic vascular resistance definition
Resistance to blood flow throughout the systemic peripheral vasculature
Systemic vascular resistance vs Afterload
Both often interchanged as SVR is the only part of afterload that can be manipulated
Afterload is a theoretical concept which includes SVR and LV outflow obstruction (e.g. aortic stenosis)
Determinants of Stroke volume
Preload
Contractility
Afterload
Preload definition
Measure of initial stretch on cardiac myocytes prior to contraction (i.e. end of diastole)
Amount of stretch determines number of myocardial cross bridges available to interact during contraction
Contractility definition
Intrinsic ability of cardiac muscle fibres to change the force of contraction independent of preload and afterload
Inotropy definition
Change in force of myocardial contraction
Afterload definition
Force required by the myocardium to eject the stroke volume during systole
Chronotropy definition
A change in the heart rate
Determinants of heart rate
Autonomic innervation - sympathetic and parasympathetic
Circulating catecholamines
Hormones (e.g. thyroxine)
Electrolytes
Starling’s law
Force of myocardial contraction is proportional to the initial fibre length, up to a certain point
Closest physiological variable that can represent preload
LV end diastolic volume
Closest physiological variable that can represent force of contraction
Stroke volume
Methods of assessing LVEDV
Cannot be routinely measured
Surrogate markers to assess it are:
- Echo
- Central venous pressure
- Pulmonary wedge pressures
Starling’s curve
Increasing preload causes increase in SV up to a certain point and then myocardial failure occurs
Effect of inotropes on Starling’s curve
Inotropes shift curve up and to left
Effect of increased afterload on Starling’s curve
Effect of sympathetic stimulation on cardiac output
Acts via beta 1 (and to lesser extent beta 2) adrenergic receptors in the heart
Causes positive inotropy and chronotropy
beta adrenergic receptor stimulation increases available cAMP intracellularly, which results in increased intracellular calcium
Overall common final pathway of all inotropic drugs
Increasing intracellular calcium to increase force of myocardial contraction
Mechanisms of action of inotropes
Beta 1 and Beta 2 adrenoreceptor stimulation (sympathomimetics)
Phosphodiesterase inhibition
Other mechanisms
Sympathomimetic inotrope examples
Adrenaline
Dopamine
Dobutamine
Isoprenaline
Dopexamine
Adrenaline as an inotrope
Non selective agonist of all adrenergic receptors
Low dose infusion has inotropic beta effects
Increasing adrenaline dose increases alpha adrenoreceptor agonism
Laeva isomers are 15x more potent than dextro isomers
Side effect of adrenaline as inotrope
Diastolic BP can drop due to beta 2 agonism linked to peripheral vasodilatation
Isoprenaline as inotrope
Potent beta 1 and beta 2 agonist
Increases CO but afterload / SVR can drop due to beta 2 agonism
Commonly used for bradyarrhythmia
Methods of administration of isoprenaline
Usually IV
can also be inhaled or PO
Dopamine as inotrope
Low dose infusion mainly beta 1 agonism
Higher doses increase alpha agonism
Does not cross blood brain barrier
Stimulates noradrenaline release
Side effect of dopamine as inotrope
Nausea and vomiting - acts on chemoreceptor trigger zone via D2 receptors
Inhibits prolactin secretion
Vasodilatation of renal and mesenteric beds by peripheral D1 receptor activation
Increases atrio-ventricular conduction and can cause tachycardia at higher doses
Dobutamine as inotrope
Structurally similar to isoprenaline
Mainly beta 1 agonism with some beta 2 and alpha 1 action
Half life 2 mins
Side effect of dobutamine as inotrope
Decreases LV end diastolic pressure via beta 2 agonism
Beta 2 linked vasodilatation reduces venous return and SVR
Dopexamine as inotrope
Analogue of dopamine
Action on beta 2 and D1 receptors
Minimal beta 1 action and no alpha 1 action
Causes inotropy via cardiac beta 2 agonism
Side effect of dopexamine as inotrope
Peripheral vasodilatation reduces SVR / afterload via peripheral beta 2
Phosphodiesterase inhibitor mechanism of action
Phosphodiesterases breakdown cyclic adenosine monophosphate (cAMP)
Inhibition of phosphodiesterase therefore increases intracellular cAMP and thus calcium levels
Predominant phosphodiesterase isoenzymes working in the myocardium
Phosphodiesterase types III and IV
Selective Phosphodiesterase III inhibitor examples
Enoximone
Milrinone
Non-selective phosphodiesterase inhibitor examples
Aminophylline
Therefore also has some positive inotropic effects
Administration of enoximone and milrinone
IV as infusion +/- loading dose
Cause peripheral vasodilatation - often require co-administration of vasopressor to maintain BP
Other mechanism inotrope examples (usually not first line)
Levosimendan
Digoxin
Glucagon
Calcium
Thyroxine (T3)
Levosimendan as inotrope
Increases myocyte sensitivity to calcium by binding to troponin C
Relaxes smooth muscle by opening ATP sensitive potassium channels causing peripheral vasodilatation
Used in severe acute cardiac failure
Digoxin as inotrope
Inhibits Na+/K+ ATPase pump, increasing myocyte intracellular Na+
Therefore decreases inward movement of sodium via Na+/Ca2+ exchanger pump
Therefore increases intracellular calcium
Used in chronic cardiac failure
Glucagon as inotrope
Glucagon receptors are Gs protein linked
Activation increases intracellular cAMP
Used in beta blocker OD
Calcium as inotrope
IV calcium transiently improves cardiac output and BP
Effect is short lived
Used in cardiac arrest secondary to hyperkalaemia or calcium channel antagonist overdose
Thyroxine (T3) as inotrope
Positively inotropic and chronotropic
Via intracellular Ca2+ ATPase pump (probably)
Not used for its inotropy
Use of vasopressors
Treat hypotension secondary to reduced SVR
Mechanisms of action of vasopressors
Alpha 1 adrenergic receptor agonism
Vasopressin receptor activation
Structure of adrenoreceptors
7 transmembrane G protein couples receptors
Site of alpha 1 adrenoreceptors
Smooth muscle of peripheral vasculature
Alpha 1 agonism vasopressor examples
Noradrenaline
Ephedrine
Metaraminol
Phenylephrine
Noradrenaline as vasopressor
Alpha 1 agonism with some beta 1 agonism
Minor inotropic action which is offset by baroreceptor reflex vagal response to increased BP causing drop in HR
Ephedrine as vasopressor
Mixed alpha and beta stimulation
Works directly and indirectly by displacing noradrenaline from storage granules
Also inhibits monoamine oxidase (MAO)
Crosses blood brain barrier and placenta
Function of Monoamine oxidase
Breaks down noradrenaline
Therefore MAO inhibitors (e.g. ephedrine and Parkinson’s medications) reduce noradrenaline break down and therefore lower doses of vasopressor required
Side effect of Ephedrine
Tachyphylaxis occurs as noradrenaline stores depleted
Administration of Ephedrine
IV
Can be PO
Phenylephrine as vasopressor
Potent alpha 1 agonist
No effect on beta receptors
Causes reflex bradycardia due to baroreceptor response
Metaraminol as vasopressor
Mainly alpha 1 with some beta action
Direct and indirect actions by causing noradrenaline release
Side effects of Metaraminol
Increases pulmonary vascular resistance
Tachyphylaxis as noradrenaline stores depleted
Vasopressin synonyms
Anti-diuretic hormone (ADH)
Arginine vasopressin (AVP)
Site of vasopressin receptors
Throughout body
Including vascular smooth muscle cells
Features of vasopressin receptors
Gq protein coupled
Stimulation of V1 receptors causes peripheral vasoconstriction
Use of vasopressin
Second line vasopressor for severe septic shock
