pathophysiological basis of acei, arbs and ccbs

Pathophysiological Basis of

ACEI, ARBs & CCB Drugs

Historical perspective

In 1898, Robert A. Tigerstedt,

Professor of Physiology at the

Karolinska Institute in Stockholm

and Per Gustav Bergman, a medical

student, concluded that the kidney

contained a pressor substance they

named renin

Basso N, Terragno NA. History about the discovery of the renin-angiotensin system. Hypertension. 2001 Dec 1;38(6):1246-9.

https://en.wikipedia.org/wiki/File:Robert_Tigerstedt_B08899.jpg

In 1934, pathologist Harry

Goldblatt established the first

animal model of hypertension. This

model provided researchers with

the tools to delineate the renin-

angiotensin system of blood

pressure control and, eventually,

to design enzyme inhibitors for the

treatment of chronic hypertension

Basso N, Terragno NA. History about the discovery of the renin-angiotensin system. Hypertension. 2001 Dec 1;38(6):1246-9.

Van Epps HL. Harry Goldblatt and the discovery of renin. J Exp Med. 2005 May 2;201(9):1351.

Simplified RAAS cascade

Tortora GJ, Derrickson B. Principles of anatomy and physiology. 14ed. John Wiley & Sons; 2014

The current view of the RAS also includes:

•A local (tissue) RAS,

•Alternative pathways for Ang-II synthesis (ACE

independent),

•Formation of other biologically active angiotensin peptides

(AngIII, AngIV, Ang[1–7]), and

•Additional angiotensin binding receptors (angiotensin

subtypes 1, 2, and 4 [AT1, AT2, AT4]; Mas)

Brunton L, Chabner B, Knollman B. Goodman and Gilman’s the pharmacological basis of therapeutics. 12ed. McGraw-Hill Medical; 2011

The heavy arrows show the classical pathway, and the light arrows indicate

alternative pathways

Vasodilatation Anti-proliferation Anti-inflammatory

Anti-oxidation Anti-fibrotic

AP, aminopeptidase; E, endopeptidases;IRAP, insulin-regulated aminopeptidases; PCP, prolylcarboxylpeptidase; PRR, (pro)renin receptor

Vasoconstriction Cell proliferation Pro-inflammatory

Pro-oxidation Pro-fibrotic


Renin and Prorenin

• Renin regulates the initial, rate-limiting step of the RAAS by cleaving the N-terminal portion of a large molecular weight globulin, angiotensinogen, to form the biologically inert decapeptide Ang-I

• Renin is synthesized as a preprohormone, and mature (active) renin is formed by proteolytic removal of a 43-amino-acid prosegment peptide from the N-terminus of prorenin

• Prorenin is no longer considered the inactive precursor of renin. Prorenin is capable of activating local (tissue) RAS and Ang-II dependent and independent events that may contribute to organ damage.

• The concentration of prorenin in the circulation is ~10-fold greater than that of the active enzyme.


MD,macula densa; PGI2/PGE2 prostaglandins I2 and E2; NSAIDs, nonsteroidal antiinflammatory drugs; Ang II, angiotensin II: ACE, angiotensin-converting enzyme. AT1 R, angiotensin subtype 1 receptor; NE/Epi, norepinephrine/epinephrine; JGCs, juxtaglomerular cells

Schematic portrayal of the three major physiological pathways regulating renin release, and effect of various drugs on Renin Secretion


Mechanisms by which the macula densa regulates renin release


• The binding of (pro)renin to PRR also induces Ang-II independent signaling events that include activation of ERK1/2, p38, tyrosine kinases, TGF-β gene expression, and plasminogen activator inhibitor type 1 (PAI-1).

• These signaling pathways are not blocked by ACE inhibitors or AT1 receptor antagonists and are reported to contribute to fibrosis, nephrosis, and organ damage


• PRR is abundant in the heart, brain, eye, adrenals, placenta, adipose tissue, liver, and kidneys.

• Circulating plasma concentrations of prorenin are 10-fold higher than renin in healthy subjects but are elevated to 100-fold in diabetic patients and are associated with increased risk of nephropathy, renal fibrosis, and retinopathy (Danser and Deinum, 2005; Nguyen and Danser, 2008).

• The interaction of prorenin with PRR has become a target for therapeutic interventions.

• Handle region peptide (HRP) is a (Pro)renin receptor antagonists drug which is currently being studied in animals.


Angiotensin-Converting

Enzyme Inhibitors

Patel VB, Parajuli N, Oudit GY. Role of angiotensin-converting enzyme 2 (ACE2) in diabetic cardiovascular complications. Clin Sci (Lond). 2014 Apr;126(7):471-82.

• ACEIs competitively block the action of ACE and thus the conversion of Ang I to Ang II, thereby reducing circulating and local levels of Ang II.

• Various trials to date have shown that the ACEIs control HTN, reverse left ventricular hypertrophy (LVH), prevent stroke, and reduce coronary artery disease to a degree similar to diuretics and beta blockers.

• ACEIs have been shown to reduce morbidity and mortality from congestive HF (CHF) especially after acute MI.

Ma TK, Kam KK, Yan BP, Lam YY. Renin-angiotensin-aldosterone system blockade for cardiovascular diseases: current status. Br J Pharmacol. 2010 Jul;160(6):1273-92.

Rao MS. Total renin-angiotensin aldosterone system (RAAS) blockade. Medicine update 2005. http://apiindia.org/pdf/medicine_update_2005/chapter_33.pdf

Dual role of angiotensin-converting enzyme (ACE) inhibitors, both preventing and treating cardiovascular disease

Opie LH, Gersh BJ. Drugs for the heart. 8ed. Elsevier; 2013

• ACEIs also decrease aldosterone and vasopressin secretion and sympathetic nerve activity

• Progression to chronic renal failure due to HTN, diabetes (DM) and primary glomerulonephritis is slowed down by ACEIs independent of their antihypertensive effects.

• ACEIs also have been shown to improve endothelial function.

• In the presence of both DM & HTN, ACEIs are the preferred initial drugs to treat HTN.



Actions of Bradykinin


• There are evidences, that over the long term ACE inhibition may be associated with a return of Ang II and aldosterone toward baseline levels (“ACE escape”)—perhaps, it is due to Ang II production through non-classical pathways (non-renin and non-ACE) not blocked by ACEIs.

• Bilateral renal artery stenosis, pregnancy and already existing hyperkalemia are absolute contraindications to ACEIs.

Atlas SA. The renin-angiotensin aldosterone system: pathophysiological role and pharmacologic inhibition. J Manag Care Pharm. 2007 Oct;13(8 Suppl B):9-20.


ACE2-Ang-(1–7)-Mas receptor

Axis

Ang I ACE 2 Ang 1-9

ACE ACE

Ang II ACE 2 Ang 1-7

AT1 receptor AT2 receptor MAS Receptor

•Ang II is the preferred substrate for ACE2 with 400-fold higher affinity than Ang I.

•ACE2 is not inhibited by the standard ACE inhibitors and has no effect on bradykinin.


A plethora of beneficial cardiovascular effects has been described for Ang-(1–7) in the past 2 decades, these include:

•protection against heart failure,

•natriuretric,

•antithrombotic,

•antihypertrophic,

•antifibrotic,

•antiarrhythmic effects,

•attenuation of plaque formation, and

•amelioration of metabolic syndrome-related vascular dysfunction

Te Riet L, van Esch JH, Roks AJ, van den Meiracker AH, Danser AH. Hypertension: renin-angiotensin-aldosterone system alterations. Circ Res. 2015 Mar 13;116(6):960-75.

Mechanism of action Drug/ Compound Stage of development

Ang (1-7)/Mas receptor agonistsAng (1-7) Animal studies

AVE 0991 Animal studies

Mas receptor antagonists A-779 Animal studies

ACE2 analogues Recombinant hACE2(APN01) Animal studies

ACE2 inhibitors C16 Animal studies

Chamsi-Pasha M, Shao Z, Tang WH. Angiotensin-Converting Enzyme 2 as a Therapeutic Target for Heart Failure. Curr Heart Fail Rep. 2014 Mar; 11(1): 58–63.

Garg M, Angus PW, Burrell LM, Herath C, Gibson PR, Lubel JS. Review article: the pathophysiologicaAl roles of the renin-angiotensin system in the gastrointestinal tract. Aliment Pharmacol Ther. 2012 Feb;35(4):414-28.

Angiotensin Receptor

Blockers (ARBs)

• AT1 receptor mediates most of the known actions of Ang II that contribute to hypertension, volume dysregulation and cardiovascular damage

• ARBs have renoprotective and antiproteinuric effects similar to ACEIs

• ARBs also cause regression of LVH like ACEIs and are less hyperkalemic

• Effectiveness of ARBs in CHF and after MI has been well documented

• Pregnancy and bilateral renal artery stenosis remain strong contraindications for ARBs as with ACEIs


• ARBs specifcally block the AT1 receptor, while the AT2 receptor is not blocked

• In the case of ARBs, the increase in Ang I leads to a commensurate increase in Ang II, which is freely able to bind to AT2 or other receptor subtypes

• Studies have suggested that beyond AT1 receptor blockade, activation of the AT2 receptor might mediate additional beneficial actions on the vasculature, heart, and kidneys, in part via a bradykinin/NO/ cGMP pathway, an effect that would further distinguish ARBs from ACEIs


AT2 Receptor activation• AT2 receptor is abundant during fetal life in the brain, kidney, and

other sites, and its levels decrease markedly in the postnatal period

• Its presumed endogenous ligands are Ang II, Ang III, Ang IV, and Ang-(1–7) in order of highest to lowest affinity

• Despite low levels of expression in the adult, the AT2 receptor might mediate vasodilation and antiproliferative and apoptotic effects in vascular smooth muscle and inhibit growth and remodelling in the heart

• In the kidney, AT2 receptors may influence proximal tubule sodium reabsorption and stimulate the conversion of renal prostaglandin E2 to prostaglandin F2α



• AT2 receptors also stimulate neurite outgrowth, thereby facilitating pain• A recent clinical trial reported that after 3 weeks, AT2 receptor

antagonist reduced pain in patients with post-herpetic neuralgia

Mechanism of action Drug/ Compound Stage of development

AT2 receptor agonists CGP42112A In vitro studies

Compound 21 Animal studies

Compound 22 Animal studies

AT2 receptor antagonists

PD123319 In vitro studies

Saralasin Animal studies


Garg M, Angus PW, Burrell LM, Herath C, Gibson PR, Lubel JS. Review article: the pathophysiologicaAl roles of the renin-angiotensin system in the gastrointestinal tract. Aliment Pharmacol Ther. 2012 Feb;35(4):414-28.

Ang IV and AT4 receptor

• Ang IV, also called Ang(3–8), is formed from Ang III through the catalytic action of aminopeptidase M and has potent effects on memory and cognition

• Ang IV binding to AT4 receptors inhibits the catalytic activity of IRAPs (insulin- regulated amino peptidases) and enables accumulation of various neuropeptides linked to memory potentiation

• Other actions include renal vasodilation, natriuresis, neuronal differentiation, hypertrophy, inflammation, and extracellular matrix remodeling

• Analogs of angiotensin IV are being developed for their therapeutic potential in cognition in Alzheimer disease or head injury



Aldosterone blockade

• ACEI therapy only partially suppresses aldosterone production and ‘aldosterone escape’ occurs in upto 40% of patients with CHF.

• Ang II (increased after ARBs therapy) is a potent stimulant for aldosterone production

• Increased levels of K+ (after chronic ACEI therapy), also is a powerful secretagogue for aldosterone

• It is impossible to get rid of aldosterone by blocking ACE or AT-I

• Aldosterone-blockade by eplerenone (a selective aldosterone blocker) has a role in the treatment of essential HTN; it has a mild diuretic effect in addition


During a physiologic body sodium load (left side) aldosterone exerts benefcial effects such as maintaining sodium and potassium balance and countering excess renin-angiotensin system (RAS) activation by decreasing plasma renin and thus angiotensin II.

During pathologic sodium loading as in heart failure, aldosterone exerts negative effects such as increased left ventricular hypertrophy (LVH) and atrial fbrillation (Afb), worsening heart failure, and greater peripheral vascular resistance.


Vasopeptidase inhibitors

• These drugs inhibit ACE and the neutral endopeptidase (NEP) which

normally degrades numerous endogenous natriuretic peptides.

Thereby the effects of ACEI viz., decrease in Ang-II and increase in

bradykinin – are combined with increases in natriuretic peptides.

• The most widely studied

of these agents is

Omapatrilat. The others

in the investigative stage

are Fasidotril, Sampatrilat

and Ecadotril.Rao MS. Total renin-angiotensin aldosterone system (RAAS) blockade. Medicine update 2005. http://apiindia.org/pdf/medicine_update_2005/chapter_33.pdf

RAS Summary

Guimond M, Gallo-Payet N. The Angiotensin II Type 2 Receptor in Brain Functions: An Update. Int J Hypertens. 2012;2012:351758

Calcium channel blockers

Types

The voltage-gated calcium channel consists of 4 subunits, α1, α2-δ, β and γ. An α1 subunit is the dominant component of the calcium channels and constitutes pore structure for ion conduction. Ten different α1 subunits have been reported and each of them has specific distribution and ion conductance of its channels. These distinct subunits characterize the channel properties of L-, N-, T-, P-, Q- and R-type calcium channels.

Chandra KS, Ramesh G. The fourth-generation Calcium channel blocker: Cilnidipine. Indian Heart J. 2013 Dec; 65(6): 691–695..

Voltage-gated calcium channelsSnutch TP, Peloquin J, Mathews E, McRory JE. Molecular Properties of Voltage-Gated Calcium Channels. Madame Curie Bioscience Database.

Physiological role of L type calcium channel

Zamponi GW1, Striessnig J1, Koschak A1, Dolphin AC. The Physiology, Pathology, and Pharmacology of Voltage-Gated Calcium Channels and Their Future Therapeutic Potential. Pharmacol Rev. 2015 Oct;67(4):821-70.

Zamponi GW1, Striessnig J1, Koschak A1, Dolphin AC. The Physiology, Pathology, and Pharmacology of Voltage-Gated Calcium Channels and Their Future Therapeutic Potential. Pharmacol Rev. 2015 Oct;67(4):821-70.

• L-type calcium channels are the main targets of the CCB.

• Based on the chemical structure, CCBs are categorized into 3 subgroups

i) benzothiazepines (e.g., diltiazem and clenazem),

ii)phenylalkylamines (e.g., verapamil and gallopamil)

iii)dihydropyridines (e.g., nifedipine, nicardipine, felodipine, amlodipine, aranidipine, azelnidipine, cilnidipine, efonidipine, manidipine and nilvadipine).

Chandra KS, Ramesh G. The fourth-generation Calcium channel blocker: Cilnidipine. Indian Heart J. 2013 Dec; 65(6): 691–695..

CCBs: Some Relative Cardiovascular EffectsGeneric name

Vasodilation (coronary

flow)

Suppression of cardiac

contractility

Suppression of

automaticity (SA node)

Suppression of

conduction (AV node)

Amlodipine 5 1 1 0

Felodipine 5 1 1 0

Isradipine NR NR NR NR

Nicardipine 5 0 1 0

Nifidipine 5 1 1 0

Diltiazem 3 2 5 4

Verapamil 4 4 5 5

Relative effects are ranked from no effect (0) to prominent (5). NR, not ranked. Brunton L, Chabner B, Knollman B. Goodman and Gilman’s the pharmacological basis of therapeutics. 12ed. McGraw-Hill Medical; 2011

As a group, the dihydropyridines (DHPs) are more vascular selective, whereas the non-DHPs verapamil and diltiazem act equally on the heart and on the arterioles.


CCB Approved by FDA for Elliott WJ, Ram CV. Calcium channel blockers. J Clin Hypertens (Greenwich). 2011 Sep;13(9):687-9.

Verapamil Hypertension, angina, atrial dysrhythmias

Diltiazem Hypertension, angina, atrial dysrhythmias

Nifedipine Hypertension, angina

Nicardipine Hypertension

Isradipine Hypertension

Felodipine Hypertension

Amlodipine Hypertension, angina

Nisoldipine Hypertension

Clevidipine Hypertensive emergencies

Nimodipine Subarachnoid haemorrhage

• L-type calcium channels prevail predominantly in the afferent

arteriole but are sparsely expressed in the efferent arteriole, L-

type CCBs tend to dilate the afferent arteriole preferentially and

thus might accelerate glomerular hypertension and proteinuria.

• N-type calcium channels are expressed in nerve terminals

innervating both afferent and efferent arterioles as well as

glomerular podocytes. L/N-type CCBs has been shown to provide

renal protection by decreasing the activity of the sympathetic

nervous system and the RAAS, resulting in vasodilation of both

arterioles, inhibition of podocyte injury and decrease in

proteinuria. Thamcharoen N, Susantitaphong P, Wongrakpanich S, Chongsathidkiet P, Tantrachoti P, Pitukweerakul S, et al. Effect of N- and T-type calcium channel blocker on proteinuria, blood pressure and kidney function in hypertensive patients: a meta-analysis. Hypertens Res. 2015 Dec;38(12):847-55.

Diagrammatic representation of L/N dual action of clinidipineChandra KS, Ramesh G. The fourth-generation Calcium channel blocker: Cilnidipine. Indian Heart J. 2013 Dec; 65(6): 691–695..

• T-type channels have an important role in the kidney, mediating

efferent arteriole tone, and combined T- and L-type CCBs might

have a therapeutic advantage over selective L-type CCBs by

providing renoprotection via a lower glomerular pressure and

filtration fraction.

• L/T- and L/N-type CCBs, azelnidipine and cilnidipine have been

shown to lower nocturnal and morning blood pressure, which

might result in antiproteinuric effect.

• L/N- and L/T-type CCBs are currently in use only in East Asian

countries (that is, Japan and China).Thamcharoen N, Susantitaphong P, Wongrakpanich S, Chongsathidkiet P, Tantrachoti P, Pitukweerakul S, et al. Effect of N- and T-type calcium channel blocker on proteinuria, blood pressure and kidney function in hypertensive patients: a meta-analysis. Hypertens Res. 2015 Dec;38(12):847-55.

• L/N- and L/T-type CCBs as add-on therapy to an ACEI or an ARB

reduce albuminuria and proteinuria and improve kidney function

compared with the use of an ACEI or ARB alone or in

combination with other antihypertensive agents. These benefits

were observed irrespective of blood pressure-lowering effect,

suggestive of a non-hemodynamic-mediated mechanism. The

potential long-term hemodynamic and non-hemodynamic

effects of L/N- and L/T-type CCBs on the kidneys in patients with

hypertension need to be further examined.

Thamcharoen N, Susantitaphong P, Wongrakpanich S, Chongsathidkiet P, Tantrachoti P, Pitukweerakul S, et al. Effect of N- and T-type calcium channel blocker on proteinuria, blood pressure and kidney function in hypertensive patients: a meta-analysis. Hypertens Res. 2015 Dec;38(12):847-55.

pathophysiological basis of acei, arbs and ccbs

Health & Medicine