Classification of inotropes and vasopressors

This chapter is relevant to Section G8(i)  of the 2017 CICM Primary Syllabus, which asks the exam candidate to "Understand the detailed pharmacology of inotropes and vasopressors". Unsuprisingly, this ICU specialist training pathway dedicates a lot of assessment bandwidth to making sure the trainees are completely at home with the use of these substances. They are our most commonly used instruments, and some might say that the history of intensive care is really the history of vasopressors and inotropes. 

Questions about inotropes and vasopressors from past Part One papers include the following:

• Question 2 from the first paper of 2018 (adrenaline vs. milrinone)
• Question 15 from the second paper of 2017 (adrenaline and the "ideal" inotrope)
• Question 20 from the first paper of 2017 (vasopressin)
• Question 15 from the second paper of 2016 (noradrenaline vs. dobutamine)
• Question 1 from the second paper of 2014 (classification of inotropes)
• Question 10 from the second paper of 2013 (digoxin vs. levosimendan)
• Question 22 from the first paper of 2013 (vasopressin)
• Question 18 from the second paper of 2012 (adrenaline and the "ideal" inotrope)
• Question 8 from the first paper of 2012 (adrenaline vs. levosimendan)
• Question 14 from the second paper of 2011 (dobutamine vs. milrinone)
• Question 7 from the first paper of 2010 (classification of inotropes)
• Question 12 from the second paper of 2009 (noradrenaline)

As you can see, a couple of questions ask for a classification of these drugs. This is the main objective of this chapter. Unfortunately, there is no single widely-accepted classification system available, not in the same way that antiarrhythmics or antihypertensives might be classified. Moreover, it appears that every expert who is commisioned to write a review article on this subject had felt compelled to generate their own unique classification system.

What would CICM say? Examiner comments to Question 1 from the second paper of 2014 are an example of how to effectively demonstrate your contempt for the trainees through the careless laziness of your feedback. "The poorer answers suffered for want of a useful classification system", they said, and they said little else in their two-line "model answer". Logically, that is a fair statement, as this author also suffers for want of a useful classification system, there being none available anywhere.  Fortunately for trainees, an earlier group of college examiners very clearly outlined what they expected in their comments to Question 7 from the first paper of 2010. The classification system which follows is based on their detailed statement.

CICM classification system for inotropes and vasopressors

Let's try to reconstruct what they wanted when they said "this question required a classification based on chemical structure and class action". The question was about inotropes only, which actually makes it a little bit easier. From the way the college comments are structured, it appears they wanted a two-tiered system, with the first order occupied by pharmacological class.

Thus:

Classification of inotropes

Class	Mechanism
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.

Different approaches to classification of inotropes and vasopressors

There are lots of different ways to classify vasopressors and inotropes. The best one can do in this lawless chaos is arm the trainees with several different frameworks which they can reliably deploy depending on their circumstances.

Classifications based on organic chemistry

These are probably the least useful classification systems in medicine, because they usually tell you nothing about either the clinical effects, molecular mechanisms or even chemical properties of these drugs. There is literally no merit to this exercise, except that it generates headings to break up the columnar monotony of an unordered list. Observe:

• Phenylethylamines
  • Adrenaline
  • Noradrenaline
  • Dopamine
  • Dobutamine
  • Metaraminol
• Endogenous peptides
  • Vasopressin
  • Angiotensin
• Ions
  • Calcium
• Bipyridines
  • Milrinone
  • Amrinone
• Glycosides
  • Digoxin
• Pyridazinones
  • Levosimendan
  • Pimobendan
• Imidazole derivatives
  • Enoximone

Classification based on pharmacological drug class

Surely, we should expect more from our taxonomies. For example, you should at leas be able to have a guess as to what the drug will do, on the basis of how it is classified. On that basis, one could classify inotropes and vasopressors according to their pharmacological class:

• Sympathomimetics
  • Direct
    • Adrenaline
    • Noradrenaline
    • Dobutamine
  • Indirect
    • Metaraminol
    • Ephedrine
• Vasopressin receptor agonists
  • Vasopressin
  • Terlipressin
• Phosphodiesterase inhibitors
  • Milrinone
  • Inamrinone
• Cardiac glycosides
  • Digoxin
• Calcium sensitizers
  • Levosimendan

It seems what the college wanted in Question 7 from the first paper of 2010 was this system, lightly rolled in the previous chemistry-based system. Yes, this is a bit more informative than just a purely chemical classification, but it just seems to include an unnecessary extra step. Pharmacological class is itself based on the molecular mechanisms of drug effect; surely we could just skip to that instead?

Classifications based on the molecular mechanism of action

This would be a system that organises the available substances according to the manner by which they activate the intracellular mechanisms which lead to muscle contraction. For a good example of what that might look like, have a look at this system proposed by Feldman (1993), who was clearly taking a page out of Vaughan Williams' book:

• Class I: Agents that increase intracellular cyclic adenosine monophosphate
  • Beta-agonists
  • Phosphodiesterase inhibitors
• Class II: Agents that affect sarcolemmal ions pumps/channels
  • Digoxin
• Class III: Agents that modulate intracellular calcium mechanisms by either :
  • Release of sarcoplasmic reticulum calcium (IP3)
  • Increased sensitization of the conductile proteins to calcium
• Class IV: Drugs having multiple mechanism of action
  • Pimobendan
  • Vesnarinone

Unfortunately, the Feldman classification did not catch on, which is why you've never heard of anybody referring to levosimendan as a "Class III inotrope". Additionally, it does not incorporate vasopressors, and doesn't even include all inotropes (i.e. what about calcium chloride?)

Classifications based on ionised calcium

Looking closely at the mechanisms listed above, one comes to the conclusion that an increased interaction of calcium with contractile proteins is the end product of all inotrope function, and all vasopressor function for that matter. From this, it follows that inotropes and vasopressors could be classified in terms of how they affect calcium handling. Palmer & Pennefather (2009) presented this classification method; except they don't appear to be advancing this classification system as their own; rather, when it is presented, the presentation is nonchalant, as if it's always been like this. "Inotropes are classified according to their effects on intracellular Ca²⁺", they casually toss. Thus:

• Drugs which increase intracellular Ca2+
  • Calcium salts
  • Drugs which inhibit Na+,K+-ATPase
  • Drugs which increase cyclic adenosine monophosphate (cAMP) levels
    • β1-agonists
    • phosphodiesterase inhibitors
    • glucagon
• Drugs which increase affinity of troponin C for Ca²⁺.
• Drugs which increase response of the myofibrillar proteins to a given level of Ca²⁺

Even though they managed to find a spot for calcium salts, this is again imperfect. For example, levosimendan would end up in both of the latter two categories. Also, vasopressors are sorely neglected (whither angiotensin?). Lastly, these mechanism-based classification systems both have the same flaw - they are entirely divorced from clinical meaning, i.e. by looking at a drug's position within such a classification system, one really cannot determine how it works or what effect it might have on the patient.

Classifications based on clinical effect

A purely functional classification system has the advantage of telling you what the drug is expected to do, at a glance. And then you would be able to immediately determine what alternative drugs exist in the same functional class. Jentzer et al (2015) offer an example of such a system:

Not only does this readily expand to accommodate weird drugs with mixed effects, but it incorporates vasodilators with no inotropic effects, and is in the running for some sort of "periodic table of inotropes". Unfortunately, it cannot accommodate drugs with dose-dependent variations in activity (eg. dopamine), and for pathology-related effects (eg. where adrenaline acts as an inodilator in maximally vasoconstricted cardiogenic shock patients). Moreover, from looking at this classification, you would not be able to tell which agents will have a clearly synergistic effect, and which will interfere with each other by targeting the same receptor class. Also, there is no obvious place in this for agents which have a purely inotropic effect (eg. high dose insulin).

The "ideal" inotrope

For some reason, Question 15 from the second paper of 2017 and Question 18 from the second paper of 2012 asked the trainees to compare adrenaline to the properties of an "ideal" inotrope. 

Characteristics of an ideal inotrope, according to Eliott (2006), are:

• Lacks tolerance
• Does not cause vasoconstriction
• Does not cause changes in heart rate
• Predictable and easily titratable
• Redistributes blood flow to vital organs
• Direct acting (does not rely on release of endogenous amines)
• Compatible with other vasoactive substances
• Demonstrates lusitropy
• Energy neutral, energy sparing or inoprotective

To this, you could probably add:

• cheap
• stable with prolonged shelf storage
• easily available in resource-poor environments
• Rapid onset and offset (titratable)
• Safe in pregnancy
• Wide therapeutic index 

To arrange this into a structured exam answer which incorporates adrenaline without wasting time, one would have to use a table:

Properties of an Ideal Inotrope, and

How Adrenaline Compares

Property	Adrenaline
Pharmaceutics
Cheap and widely available	A box of 25 ampoules retails for $399.96
Long shelf life	Shelf life of glass ampoules is 2 years, provided they are stored out of direct sunlight
Compatible with other infusions	No, usually needs to run in its own lumen
Pharmacokinetics
Administered by a range of routes	IV, IM, subcutaneous, nebulised, topical, as eye drops and directly into the ETT during an arrest.
Rapid onset and offset	Onset of action within one circulation time; half life ~ 2-3 minutes; easily titratable
Cleared in a non-organ-dependent manner	Adrenaline is rapidly metabolised by COMT and MAO
Inactive and inert metabolites	Metabolic byproducts of adrenaline have no activity
Pharmacodynamics
Directly acting	Adrenaline directly acts on adrenergic receptors
Lacks tolerance or tachyphylaxis	No tolerance
Does not cause tachycardia	Causes plenty of tachycardia
Does not cause vasoconstriction	Causes plenty of vasoconstriction, in some vascular beds
Redistributes blood flow to vital organs	Yes, but only because it causes vasoconstriction in other organs
Demonstrates lusitropy	Adrenaline is lusitropic, but this is often concealed by the tachycardia
Energy-neutral	Significantly increases myocardial oxygen consumption
Safety
Safe in pregnancy	Category C
Wide therapeutic index	Significant complications occur with high doses, but these are 50-100 times larger than the low doses.