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:
ACE-Inhibitors: Class Rules and their Exceptions
Domain Rule Exceptions Administration
& absorptionAll ACE-Is and ARBs are enterally administered
- Enalaprilat
All ACE-inhibitors are administered as a pro-drug which requires some metabolism to activate
- Captopril
- Lisinopril
Distribution Most of these dugs have a small volume of distribution
- Quinapril
- Telmisartan
Solubility Low lipophilicity (i.e.mainly water-soluble)
- Fosinopril
Metabolism All ACE-inhibitors undergo some (usually extensive) hepatic metabolism, except...
- Lisinopril
Clearance All ARBs undergo some renal elimination,
except...
- Telmisartan
Mechanism of action
- ACE:I: binding to zink moiety of ACE and inhibiting conversion of angiotensin I to angiotensin II
- ARBs: blocking the AT1 receptors, the main receptors which mediate the effects of angotensin II
- The effects of this are:
- Decreased catecholamine sensitivity
- Decreased aldosterone release
- Decreased vasopressin release
- Decreased Na+/H+ exchange in the proximal tubules, thus increased sodium excretion
- Decreased sensation of thirst
- Decreased myocardial remodelling and vascular smooth muscle hyperplasia
Clinical effects
- All ACE-Is and ARBs have the same positive effects on blood pressure and long term cardiovascular mortality, and the same negative effects on renal function in at-risk (eg. shocked) patients.
- Only ACE inhibitors have the adverse effects of chronic cough and occasional angioedema, which is related to the fact that ACE also degrades bradykinin.
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.
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.
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.
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:
Whereas for the ARBS,
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.
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).
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:
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.
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:
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.
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.
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:
Unique effects of ACE inhibitors:
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:
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Erdos, Ervin G. "The ACE and I: how ACE inhibitors came to be." The FASEB Journal 20.8 (2006): 1034-1038.
Regulski, Milosz, et al. "Chemistry and pharmacology of angiotensin-converting enzyme inhibitors." Current pharmaceutical design 21.13 (2015): 1764-1775.
Miura, Shin-ichiro, Sadashiva S. Karnik, and Keijiro Saku. "Angiotensin II type 1 receptor blockers: class effects versus molecular effects." Journal of the Renin-Angiotensin-Aldosterone System 12.1 (2011): 1-7.
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