ACE inhibitors and angiotensin receptor blockers

This chapter is probably relevant to Section G8(iii)  of the 2017 CICM Primary Syllabus, which asks the exam candidate to "understand the pharmacology of anti-hypertensive drugs". It deals with ACE-inhibitors and ARBs. The back of the syllabus document attributes to these drugs a Level 1 Detail of Understanding Level, suggesting we aim for "detailed knowledge and comprehension of their class, pharmaceutics, pharmacodynamics, pharmacokinetics, relevant structure activity relationships and adverse effects", etc etc. From these strong words, we might surmise that an unquestioned mastery of the subject is expected. This is not supported by the historical representation of these drugs in the exam, which at the present moment is limited to Question 9(p.2) from the second paper of 2008.

In summary:

The most specific peer-reviewed articles available to cover the pharmacology of these drugs are Regulski et al (2015) and Miura et al (2011). For a specific answer to Question 9(p.2) from the second paper of 2008, which called for a discussion of the specific effects of ACE inhibitors and ARBs on congestive cardiac failure, the best resources were discussion section of Tai et al (2017), which was a meta-analysis of RCTs specifically dealing with this application, and Ferrario et al (2006), which was a review of their anti-inflammatory effects.

Available ACE-Is and ARBs

The list is ordered by the drug's year of market availability. For some reason, to the author this must have seemed more logical than alphabetical order, or organisation into some sort of functional groups. Moreover, though a few dozen possible molecules are listed as having anti-ACE activity, selfishly the author limited himself to what is commonly available in Australia. 

ACE-inhibitors and ARBs

Agent	Year it was approved for use
Angiotensin converting enzyme inhibitors
Captopril	1980
Enalapril	1984
Lisinopril	1987
Perindopril	1988
Ramipril	1989
Quinapril	1989
Fosinopril	1991
Angiotensin Receptor Blockers (ARBs)
Losartan	1995
Valsartan	1996
Irbesartan	1997
Candesartan	1997
Telmisartan	1999
Olmesartan	2002

Do you need to know this entire list? Every detail about each drug? Certainly not. Following the casual trend set by trainees who came before us, the general rule is "know the class and know the exceptions". Where possible, broad generalisations about these drugs and their exceptions will be identified in the text below.

Chemical structure

Nobody anywhere will ever ask any intensive care trainee to draw the chemical structure of lisinopril, and if they do, they will be first against the wall when the revolution comes. However, for the purposes of reference, links are provided here, as one cannot rule out the possibility that somebody at some stage might need this level of detail. For those unfortunates, Regulski et al (2015) cover the 'prils, and Miura et al (2011) cover the 'sartans. 

In brief point-form, for ACE-inhibitors:

• ACE  is a zinc metallopeptidase.
• The most important structure-function relationship of ACE-inhibitors is their ability to interact with that zinc component, i.e. the zinc-binding moiety of the drug molecule
• For that reason, people tend to sub-classify them according to the group that interacts with the zinc:
  • Sulfhydryl (-SH) group:
    • captopril
  • dicarboxylate (-COOH) group:
    • enalapril,
    • lisinopril
    • perindopril
    • quinapril
    • ramipril
  • phosphoryl (-PO₂) group:
    • fosinopril
• Chemically, these are all L-proline derivatives, which is probably where the -pril suffix comes from (though there is no real way to prove that, as the origins of the name appear to be lost in history).

Whereas for the ARBS,

• Structurally, most of these are imidazole analogues
• As they mimic the angiotensin II (octapeptide) molecule, most of these drugs have a similar molecular structure
• Their specificity for docking with the AT₁ receptor is a couple of salt bridges between side-chains which bind to the receptor site but do not activate the actual receptor, making them blockers rather than agonists. Angiotensin II binds via both these salt bridges as well as at a couple of other binding sites, which is what confers the activating effect.

Routes of administration

There is just one ACE-inhibitor (enalaprilat) which is commonly available for parenteral use. The others are administered orally or by NG. Captopril helpfully comes as a syrup, apparently in strawberry or mint flavour. 

Absorption, solubility and distribution

Again from the boundless reserves of Regulski et al (2015) and Miura et al (2011) comes this array of forgettable pharmacokinetic data. The pKa values are from Remko (2007), and ARB pharmacokinetic data came from Taylor et al (2011).

ACE-inhibitors and ARBs: Pharmacokinetic Properties

Agent	Oral bioavailability	Administered as prodrug	Solubility (pKa)	Volume of distribution
Angiotensin converting enzyme inhibitors
Captopril	75%	No	9.8	2 L/kg
Enalapril	60%	Yes	3.0	Unknown!
Lisinopril	25%	No	2.5	1.7 L/kg
Perindopril	66%	Yes	3.8	0.2 L/kg
Ramipril	28%	Yes	3.7	0.1 L/kg
Quinapril	37%	Yes	3.7	3.6-7.8 L/kg
Fosinopril	32%	Yes	4.3	0.8-1.1 L/kg
Angiotensin Receptor Blockers (ARBs)
Losartan	33%	Yes	5.5	0.48 L/kg
Valsartan	23%	No	3.6	0.24 L/kg
Irbesartan	60-80%	No	4.1	0.7 L/kg
Candesartan	42%	Yes	6.0	0.14 L/kg
Telmisartan	43%	No	4.45	7 L/kg
Olmesartan	26%	Yes	4.9	0.24 L/kg

So:

• Most have relatively good oral bioavailability (which makes sense, as they were selected for the purpose of being marketed as tablets). Well, none of them has absolutely spectacular 100% bioavailability, but it is at least good enough that you could sell them as oral preparations with a straight face.
• Most have a relatively small volume of distribution, except for quinapril and telmisartan 
• All of them, other than fosinopril, have low lipophilicity
• Most ACE-inhibitors except for lisinopril and captopril are administered as pro-drugs. In contrast, only losartan candesartan and olmesartan are pro-drugs.

Metabolism, elimination and half-life

In short, most ACE inhibitors require activation by hepatic metabolism into some sort active diacid metabolite, with the exception of lisinopril which undergoes minimal metabolism. For the ARBs, the majority have high hepatic metabolism rates, but none are exclusively dependent on the liver apart from telmisartan.

ACE-inhibitors and ARBs: Pharmacokinetic Properties

Agent	Elimination (%)		Half-life
	Hepatic metabolism	Renal clearance (% excreted unchanged)
Angiotensin-converting enzyme inhibitors
Captopril	60%	40%	< 2hrs
Enalapril	60%	40%	11 hrs
Lisinopril	0%	100%	13 hrs
Perindopril	88%	12%	10 hrs
Ramipril	98%	2%	17 hrs
Quinapril	99.9%	0.1%	2 hrs
Fosinopril	50%	50%	11 hrs
Angiotensin Receptor Blockers (ARBs)
Losartan	70%	30%	~ 2-6 hrs
Valsartan	80%	20%	6 hrs
Irbesartan	75%	25%	11-15 hrs
Candesartan	40%	60%	9-12 hrs
Telmisartan	100%	0%	24 hrs
Olmesartan	60%	40%	14-16 hrs

Thus, you can see that:

• Only lisinopril has 100% renal excretion, with zero reliance on the liver
• Only telmisartan, ramipril and quinapril have close to 100% hepatic metabolism
• Captopril and quinapril are the drugs with the shortest half-life, whereas telmisartan and ramipril have the longest, but the half-life of these drugs is not very closely related to their duration of effect, which is mainly related to the rate of their dissociation from their target. For example, quinapril has a very short half-life but because of its dissociation kinetics it can be safely given as a single daily dose. In contrast, captopril usually needs to be given every 6 hours.

Target receptor and mechanism of action

The mechanism of action is where the money is, from the viewpoint of answering CICM questions. Judging by the (surprisingly extensive) college answer to Question 9(p.2) from the second paper of 2008, a fair amount of the answer would have to revisit the physiology of the renin-angiotensin-aldosterone system, which is discussed in the chapter dealing with humoral regulation of blood volume and flow.

• The renin-angiotensin-aldosterone system is a major system involved in the medium-term regulation of blood pressure and blood volume.
• Many of these regulatory effects are mediated by the activity of angiotensin-II on the AT₁ receptor
• The net effect of angiotensin II are:
  • Stimulation of the release of vasopressin
  • Stimulation of the release of aldosterone
  • Increased Na⁺/H⁺ exchange in the proximal tubules, thus sodium retention and acid excretion
  • Increased sensation of thirst
  • Increased sensitivity to catecholamines
• Thus, interference with angiotensin II synthesis or receptor binding would be expected to suppress these effects and to have a vasodilatory effect.
  • The ACE inhibitors get up into the zinc-filled heart of ACE and interfere with its activity, blocking the conversion of angiotensin I into angiotensin II
  • ARBs block the binding of angiotensin II to its AT₁ receptor

Even though their antihypertensive effects are of the greatest interest to the intensivist, what with our shortlived patient relationships, it is probably also important to know about other non-haemodynamic effects (like decreasing glomerular filtration or preventing harmful myocardial remodelling), which are detailed in the end section of this chapter.

Clinical effects of the ACE-I and ARB classes

There are a few common effects, and then there are a few effects which are unique to the ACE inhibitor class.

Clinical effects which are common to both ACE-Is and ARBs:

• Vasodilation: Being classified as antihypertensives, one would be understandably surprised if they did not drop your blood pressure, which is indeed what they reliably do. This is also the most common adverse effect of ACE-inhibitors and ARBs, i.e. a dangerous extension of their desirable properties - too much of a good thing, etc. It is therefore unfortunate that the early drugs were initially launched to market with hilariously massive dose recommendations. Squibb recommended 400-1000mg per day for captopril, which is approximately ten times the normally accepted dose in the modern era. That nobody died is remarkable. 
  Anyway, this mechanism of action means these drugs mainly act by decreasing the systemic vascular resistance. Ferrari et al (2005), writing about perindopril, reports that some of the normal haemodynamic responses to vasodilation are also blunted (i.e. that these patients are not known to experience reflex tachycardia). This may be because the RAAS is closely tied to sympathetic sensitivity, and the inhibition of ACE ablates the autonomic efferent arcs of those reflexes (Grassi et al, 1997).
• Renal impairment: Some vulnerable kidneys (eg. those with reduced perfusion pressure) rely on efferent arteriolar vasoconstriction in the glomerulus to maintain some glomerular filtration (Schoolwerth et al, 2001). This postglomerular vasoconstriction is mediated by angiotensin II via AT₁ receptors. Ergo, ACE inhibitors and ARBs can decrease glomerular filtration and produce a sort of functional renal impairment by overriding this normal regulatory mechanism. This is well demonstrated in septic patients, who have a much higher risk of AKI if they get septic while on ACE-inhibitors (Suberviola et al, 2017), and in patients undergoing cardiopulmonary bypass (Arora et al, 2008). As such, these drugs are generally grouped with "nephrotoxins", even though they do not cause any tubular damage per se. 
• Long-term benefits on cardiovascular mortality: in a manner apparently unrelated to their meritorious and noble activities in blood pressure management, ACE inhibitors and ARBs seem to improve mortality in hypertensive patients by preventing various forms of cardiovascular deterioration. In this, ACE inhibitors still seem to have some sort of edge over the newer drugs (Salvador et al, 2017). Most of the benefit seems to be the result of preventing longterm myocardial and vascular remodelling.

Unique effects of ACE inhibitors:

• Angioedema:  they have been taking them for years, and then one day they have a completely unpredictable idiosyncratic reaction which results in life-threatening airway swelling and haemodynamic collapse. It is fortunately quite rare - Vleeming et al (1998) report an incidence of 0.1-0.2%. The mechanism appears to be the blockade of bradykinin breakdown, for which ACE is also responsible. Incidentally, ACE is also responsible for the breakdown of enkephalins, neurotensin, substance P and luteinising hormone-releasing hormone (though fortunately none of these lead to weird side effects). This reaction usually occurs early in the course of therapy, but one may be stable on ACE-inhibitors for years and then randomly develop angioedema for no good reason. The management is focused on the withdrawal of the drug, control of the swelling with adrenaline and potentially the replacement of ACE, eg. by the infusion of fresh frozen plasma.
• Cough: A chronic dry irritating cough is generally reported by patients on chronic ACE-inhibitor therapy and is also due to the aforementioned effects of bradykinin metabolism, i.e. it is an irritation of the sensitive mucosa by inflammatory mediators.

Effects of ACE inhibitors and ARBs in congestive cardiac failure

After approximately 2200 words, the author has suddenly realised that this chapter really does nothing to answer Question 9(p.2) from the second paper of 2008, which asked specifically to "outline the pathophysiological basis for the use of [these drugs] in congestive cardiac failure". 

In summary, the positive clinical effects in CCF from the blockade of Ang-II or its receptors are:

• Antihypertensive (afterload-reducing) effects: 
  • Decreased catecholamine sensitivity
  • Decreased vasopressin release
  • Thus, decreased systemic vascular resistance
  • Thus, decreased afterload and myocardial oxygen demand
• Preload-reducing effects:
  • Decreased vasopressin release
  • Decreased aldosterone release
  • Decreased Na⁺/H⁺ exchange in the proximal tubules
  • Thus increased sodium excretion and decreased water retention
  • Thus, potentiated effects of diuretics and decreased preload
• Long term non-antihypertensive effects:
  • By restraining the degradation of angiotensin 1:
    • Anti-inflammatory effect on vascular smooth muscle
    • Anti-fibroproliferative effect on vascular smooth muscle
    • Thus, decreased hyperplasia of vascular smooth muscle
    • Thus, a reduced rate of atherosclerosis
  • By reduced degradation of bradykinin:
    • Reduced proliferation of vascular endothelium
    • Reduced 
  • Anti-inflammatory effects:
    • Decreased upregulation of inflammatory receptors (VCAM-1, ICAM-1,  P-selectin) and downregulation of inflammatory mediator transcription
    • Thus, reduced endothelial inflammation
  • Decreased cardiac myocyte hypertrophy (indirectly, by suppression of aldosterone secretion)