Inotropes
Last updated 24th April 2020 - Tom Heaton
Inotropy refers to myocardial contraction.
Inotropes are medications that increase the force of myocardial contractility (although the term negative inotropy may be used to describe the opposite effect)..
Having a good understanding of cardiovascular physiology is important to understand these drugs, and is covered elsewhere.
This is a nice introductory video to inotropes (although a little outdated now and also covers some vasopressors): https://www.youtube.com/watch?v=nw_WIl89LWo
Key inotropes include:
Inotropes are medications that increase the force of myocardial contractility (although the term negative inotropy may be used to describe the opposite effect)..
Having a good understanding of cardiovascular physiology is important to understand these drugs, and is covered elsewhere.
This is a nice introductory video to inotropes (although a little outdated now and also covers some vasopressors): https://www.youtube.com/watch?v=nw_WIl89LWo
Key inotropes include:
- Sympathomimetic
- Dobutamine (synthetic)
- Adrenaline
- Dopamine
- Dobutamine (synthetic)
- Phosphodiesterase inhibitors
- Milrinone
- Enoximone
- Milrinone
- Levosimendan
Dobutamine
This is a nice quick review of dobutamine: https://www.youtube.com/watch?v=JIOiZgPlseU
Dobutamine is a direct acting synthetic sympathomimetic.
It is a derivative of isoprenaline.
Actually a racemic mixture of dextro and levo isomers.
PD
Its sympathetic effect is relatively limited to beta-1 adrenergic receptors, although it does have a small beta-2 effect.
It is also described as having a small alpha-1 effect, which may offset some of the vasodilatation.
This results in the following effects:
PK
It is rapidly metabolised by COMT to inactive metabolites.
These metabolites undergo conjugation and subsequent renal excretion.
The plasma half life is around 2 minutes.
Dose
It is used in doses of 0.5-20 mcg/kg/min.
It is only administered intravenously.
Indications
Contraindications/cautions
Dobutamine is a direct acting synthetic sympathomimetic.
It is a derivative of isoprenaline.
Actually a racemic mixture of dextro and levo isomers.
PD
Its sympathetic effect is relatively limited to beta-1 adrenergic receptors, although it does have a small beta-2 effect.
It is also described as having a small alpha-1 effect, which may offset some of the vasodilatation.
This results in the following effects:
- Cardiovascular
- Increased cardiac contractility
- Positive chronotropy
- Increased myocardial oxygen demands (but increased delivery)
- Small reduction in SVR
- Increased BP (usual despite SVR reduction)
- Arrhythmogenic risk
- Renal
- Small increase in urine output due to CVS effects
- CNS
- Headaches
- Tremors
- Anxiety
PK
It is rapidly metabolised by COMT to inactive metabolites.
These metabolites undergo conjugation and subsequent renal excretion.
The plasma half life is around 2 minutes.
Dose
It is used in doses of 0.5-20 mcg/kg/min.
It is only administered intravenously.
Indications
- Cardiogenic shock
- IHD
- Sepsis
- Cardiomyopathy
- Dobutamine stress echo
- Perioperatively for cardiac surgery
Contraindications/cautions
- Cardiac outflow obstruction e.g. aortic stenosis.
- Arrhythmias
Dopamine
Dopamine is an important endogenous neurotransmitter that also has CVS effects.
It is part of the catecholamine pathway.
PD
It has its effects through stimulation of alpha and beta adrenoreceptors, as well as dopaminergic receptors (D1 and D2).
This results in:
CVS - dose dependent
PK
It is administered IV, preferably centrally due to the risk of necrosis with extravasation.
Onset is within 5 minutes and has a duration of action of 10 minutes.
The plasma half life is 3 minutes.
It is metabolised by MAO and COMT throughout the body (liver, kidneys and plasma) to inactive products and homovanillic acid (HVA) which undergo renal clearance.
Dose
The effects at different doses are described above.
The concept of ‘low dose/renal dose’ dopamine has generally been debunked.
A starting dose will commonly be 5mcg/kg/min.
Use
It is now rarely used because of the poor evidence of benefit and the higher rate of adverse effects.
Other agents have the effects at less risk.
It is part of the catecholamine pathway.
PD
It has its effects through stimulation of alpha and beta adrenoreceptors, as well as dopaminergic receptors (D1 and D2).
This results in:
CVS - dose dependent
- Low dose (1-5mcg/kg/min) dopaminergic effects predominate
- Mesenteric vasodilation
- Mesenteric vasodilation
- Middle dose (up to 10mcg/kg/min) beta-1 effects predominate
- Increased chronotropy
- Increased inotropy
- Increased coronary blood flow
- Increased chronotropy
- High dose (above 10mcg/kg/min) alpha effects predominate
- Increased SVR
- Increased venous return
- Increased SVR
- Arrhythmias (less than adrenaline)
- Attenuation of carotid body to hypoxia
- Pulmonary vasoconstriction
- Vasodilation of mesenteric vessels (D1 effect)
- Increased gastric transit time
- Emetogenic
- Extrapyramidal effects
- Prolactin release
- Increased urine output (may be from CVS changes)
- Natriuresis
- Immune dysregulation
PK
It is administered IV, preferably centrally due to the risk of necrosis with extravasation.
Onset is within 5 minutes and has a duration of action of 10 minutes.
The plasma half life is 3 minutes.
It is metabolised by MAO and COMT throughout the body (liver, kidneys and plasma) to inactive products and homovanillic acid (HVA) which undergo renal clearance.
Dose
The effects at different doses are described above.
The concept of ‘low dose/renal dose’ dopamine has generally been debunked.
A starting dose will commonly be 5mcg/kg/min.
Use
It is now rarely used because of the poor evidence of benefit and the higher rate of adverse effects.
Other agents have the effects at less risk.
Adrenaline
This is an endogenous catecholamine.
It has a mixture of effects at the adrenergic receptors of the SNS, with some variation depending on the dose.
The B1 effects are more prevalent at lower doses, leading to increased inotropy and chronotropy.
B2 effects are also present, with their bronchodilatory effects.
A1 effects are seen, and predominate at higher doses, with the effect of peripheral vasoconstriction, preserving coronary and cerebral blood.
Effects
CVS
PK
It is rapidly metabolised by COMT and MAO at nerve endings and hepatically (also kidneys and blood).
Half life is short: 2-3 minutes.
Caution is needed with MAO-I which can affect this metabolism.
Inactive products (vanillylmandelic acid (VMA) and metadrenaline) are excreted in the urine.
Dose
Infusion (CVC): 0.05mcg/kg/min - titrated up
Cardiac arrest - 10mcg/kg in children (1mg dose in adults)
Use
It is well recognised as the go to drug in cardiac arrest or severe peri arrest situations.
The profile is also very favourable in anaphylaxis, where it counters the adverse effects of histamine.
Key studies:
CAT 2009: https://www.thebottomline.org.uk/summaries/icm/cats/
This demonstrated no major differences in outcome compared to NA in septic shock.
It has a mixture of effects at the adrenergic receptors of the SNS, with some variation depending on the dose.
The B1 effects are more prevalent at lower doses, leading to increased inotropy and chronotropy.
B2 effects are also present, with their bronchodilatory effects.
A1 effects are seen, and predominate at higher doses, with the effect of peripheral vasoconstriction, preserving coronary and cerebral blood.
Effects
CVS
- Increased HR
- Increased contractility
- Increased vasoconstriction
- Increased myocardial oxygen consumption
- Bronchodilation
- Pulmonary artery vasoconstriction
- Hyperglycaemia
- Lactatemia
- Ketogenesis
- Hypokalaemia
- Raises MAC
- Raises pain threshold peripherally
PK
It is rapidly metabolised by COMT and MAO at nerve endings and hepatically (also kidneys and blood).
Half life is short: 2-3 minutes.
Caution is needed with MAO-I which can affect this metabolism.
Inactive products (vanillylmandelic acid (VMA) and metadrenaline) are excreted in the urine.
Dose
Infusion (CVC): 0.05mcg/kg/min - titrated up
Cardiac arrest - 10mcg/kg in children (1mg dose in adults)
Use
It is well recognised as the go to drug in cardiac arrest or severe peri arrest situations.
The profile is also very favourable in anaphylaxis, where it counters the adverse effects of histamine.
Key studies:
CAT 2009: https://www.thebottomline.org.uk/summaries/icm/cats/
This demonstrated no major differences in outcome compared to NA in septic shock.
Phosphodiesterase Inhibitors
These include milrinone and enoximone.
Physiology
The physiology of the signalling pathway is important to understand how phosphodiesterase inhibitors work.
Phosphodiesterase is a widespread enzyme in the body that catalyses the hydrolysis of phosphodiester bonds.
They are responsible for the breakdown of cyclic AMP and cyclic GMP which have a number of important intracellular effects.
There are a range of different phosphodiesterase isoenzyme subtypes, of which some are cardiac specific.
The inotropic effect relates to the interaction with the cardiac contraction processes.
This is ultimately related to calcium release from the sarcoplasmic reticulum triggering actin-myosin coupling.
Phosphodiesterase is a widespread enzyme in the body that catalyses the hydrolysis of phosphodiester bonds.
They are responsible for the breakdown of cyclic AMP and cyclic GMP which have a number of important intracellular effects.
There are a range of different phosphodiesterase isoenzyme subtypes, of which some are cardiac specific.
The inotropic effect relates to the interaction with the cardiac contraction processes.
This is ultimately related to calcium release from the sarcoplasmic reticulum triggering actin-myosin coupling.
Milrinone
Milrinone is a bipyridine and acts as a phosphodiesterase inhibitor at PDE-3.
It is termed an inodilator, because of the CVS effects.
There is often a requirement for concurrent vasopressor use (noradrenaline) when commencing it.
CVS
General
PK
Primarily excreted renally with minimal metabolism.
It has a half life of 2-3 hours.
This may be doubled in renal failure.
Dose
Loading: 50mcg/kg
Infusion 0.375-0.75mcg/kg/min
Uses
The PROMISE trial suggested an increase in mortality when used for chronic heart failure.
It is termed an inodilator, because of the CVS effects.
There is often a requirement for concurrent vasopressor use (noradrenaline) when commencing it.
CVS
- Positive inotropy
- Reduced SVR
- Reduced pulmonary vascular resistance
- Increased cardiac output
- Low arrhythmia rate
General
- Thrombocytopenia
- Hepatic dysfunction
PK
Primarily excreted renally with minimal metabolism.
It has a half life of 2-3 hours.
This may be doubled in renal failure.
Dose
Loading: 50mcg/kg
Infusion 0.375-0.75mcg/kg/min
Uses
The PROMISE trial suggested an increase in mortality when used for chronic heart failure.
Enoximone
This is an imidazole derivative, and also a selective PDE3 inhibitor.
Effects
CVS
PK
Given by IV infusion - extensive first pass metabolism via oral route.
A loading dose can be given initially.
It can take 30 minutes to have an effect.
Hepatically metabolised.
Metabolite has about 10% of activity and is renally cleared - half life 7.5 hours.
Small amount excreted unchanged renally.
Highly protein bound (70%)
Dose:
Uses
Has been used around cardiac surgery to assist in cases of low cardiac output.
Effects
CVS
- Positive inotropy
- Reduced SVR - BP may drop or remain the same
- Reduced pulmonary vascular resistance
- Increased cardiac output
- Low arrhythmia rate
- Can increase HR
- May cause agranulocytosis
PK
Given by IV infusion - extensive first pass metabolism via oral route.
A loading dose can be given initially.
It can take 30 minutes to have an effect.
Hepatically metabolised.
Metabolite has about 10% of activity and is renally cleared - half life 7.5 hours.
Small amount excreted unchanged renally.
Highly protein bound (70%)
Dose:
- Loading: 0.5mg/kg (may be repeated up to 3)
- Infusion: 5-20 mcg/kg/min
Uses
Has been used around cardiac surgery to assist in cases of low cardiac output.
Levosimendan
This is a calcium sensitiser, and is also classed as an inodilator.
It works by binding to cardiac troponin C and thus increasing the sensitivity of the myocytes to calcium, improving inotropy.
Relaxation is not adversely affected.
It also has some vasodilatory properties, which can contribute to the positive effect on cardiac output, although with an impact on BP.
This is through activation of ATP-dependent K+ channels, with vascular smooth muscle relaxation.
PK
Highly protein bound.
Undergoes hepatic metabolism
The metabolites exert a similar clinical effect which can persist for several days (half life 70h).
Cleared in urine and faeces.
Dose
Loading: 6-24mcg/kg (over 10 mins)
Infusion (CVC): 0.05-0.2mcg/kg/min
Use
No evidence of benefit over dobutamine - SURVIVE study.
It is notably expensive which affects its use.
It works by binding to cardiac troponin C and thus increasing the sensitivity of the myocytes to calcium, improving inotropy.
Relaxation is not adversely affected.
It also has some vasodilatory properties, which can contribute to the positive effect on cardiac output, although with an impact on BP.
This is through activation of ATP-dependent K+ channels, with vascular smooth muscle relaxation.
PK
Highly protein bound.
Undergoes hepatic metabolism
The metabolites exert a similar clinical effect which can persist for several days (half life 70h).
Cleared in urine and faeces.
Dose
Loading: 6-24mcg/kg (over 10 mins)
Infusion (CVC): 0.05-0.2mcg/kg/min
Use
- Cardiac failure
- Septic cardiac dysfunction
- Pre-op optimisation in cardiomyopathy
No evidence of benefit over dobutamine - SURVIVE study.
It is notably expensive which affects its use.
Links & References
- IUCriticalCare. Vasopressors in ICU. 2012. Youtube. https://www.youtube.com/watch?v=nw_WIl89LWo
- Master Your Medics Geoff Murphy. Mastering Dobutamine. 2016. Youtube. https://www.youtube.com/watch?v=JIOiZgPlseU
- Peck, T. Hill, S. Williams, M. Pharmacology for anaesthesia and intensive care (3rd ed). 2008. Cambridge University Press.
- Lockwood, G. Inotropes and vasoconstrictors. e-LFH. 2017.
- Bewley, J. Vasoactive agents (Inotropes). e-LFH. 2016
- Nickson, C. Inotropes, vasopressors and other vasoactive agents.LITFL. 2017. https://lifeinthefastlane.com/ccc/inotropes-vasopressors-and-other-vasoactive-agents/
- Feneck, R. Phosphodiesterase inhibitors and the cardiovascular system. CEACCP. 2007. 7(6):203-207. https://academic.oup.com/bjaed/article/7/6/203/508160
- Slessor, D. CATS. The Bottom Line. 2014. https://www.thebottomline.org.uk/summaries/icm/cats/
- Nickson, C. Levosimendan. LITFL. 2019. https://litfl.com/levosimendan/
- Nickson, C. Milrinone. LITFL. 2019. https://litfl.com/milrinone/
- Nickson, C. Dopamine. LITFL. 2019. https://litfl.com/dopamine/
- Nickson, C. Dobutamine. LITFL. 2019. https://litfl.com/dobutamine/
- Nickson, C. Adrenaline. LITFL. 2019. https://litfl.com/adrenaline/
- Lyness, D. Understanding inotropes. Propofology. 2016. https://www.propofology.com/infographs/understanding-inotropes
