- Drugs used to target RAS (Renin-Angiotensin-Aldosterone system)
1. Renin inhibitors
-Aliskiren (Not used in Australia)
-Dose dependent decrease in blood pressure with few adverse effects.
-More research needed on Renin inhibitors (1st and 2nd generation had poor bioavailability)
2.1 Mechanism of action: Inhibit the conversion of AngI to AngII. Pharmacological action and clinical effects arise from suppression of AngII synthesis.
-They reduce/weaken the response to ANG I but not ANG II (no effect on Ang II)
–Don’t directly interactly with other components of the RAS
‘ACE escape’ refers to the elevated levels of plasma aldosterone and AII in patients with an activated RAS brought upon by CHF despite treatment with ACE inhibitors (van de Wal et al., 2007).
- Rise in plasma AII levels may be brought upon by initial inhibition of the negative-feedback system of RAS when administered ACE inhibitors
- . Danser et al. (2007) proposed that ACE inhibition of AII conversion result in renin release as decreased levels of AII no longer suppress renin release.
- Consequently, AI generation will increase and thus activation of other non-ACE dependent AII conversion pathways. 90% of patients receiving ACE inhibitors would fully restore circulating AII levels after a 10-fold increase in renin levels.
- Moreover, human ACE plasma concentrations doubles over time during extended ACE inhibition, resulting in systematic pressor response increase to AI (Danser et al., 2007).
- Non-ACE dependent conversion of AI to AII pathways had been demonstrated in human myocardial tissue and in vitro studies (Petrie et al., 2001).
-Triple Whammy effect:
-combinations of diuretics, nonsteroidal anti-inflammatory drugs (NSAIDs), ACE inhibitors (ACEI) and/or diuretics used in the treatment of hypertension
-The term describes a phenomenon in which a combination these drugs results in impaired renal function or potentially leading to renal dysfunction.
-Two mechanisms are thought to primarily be involved in the pathogenesis of renal dysfunction and the “triple whammy” effect.
- Drugs that impact the renin-angiotensin system, as well as NSAIDs, decrease afferent arteriolar vasodilation. Diuretics decrease plasma volume. Synergistically, these mechanisms can lead to decreased renal blood flow and subsequent renal dysfunction.
- The elderly are thought to be more susceptible to the “triple whammy” effect due to a decreasing GFR, as well as decreased compensatory abilities (PGI, PGE production).
- Age and pre-existing renal impairment are the most likely factors to increase the risk of developing such adverse effects. Treatment considerations for this population may include the use of acetaminophen or opioids over NSAID for pain relief, low doses and slow titration of loop agents when diuresis is necessary, and cautious use of potassiumsparing diuretics in patients already receiving angiotensin agents in combination with NSAIDs.
2.2 Pharmacological aspects of ACE-inhibitors
-3 Basic structural groups:
(A) Sulfhydryl groups (SH)-Captopril (May cause skin rashes)
(B) Dicarboxyl containing-Enalapril, Lisinopril, Quinapril, Moexipril, Ramipril, Trandolapril, Perindopril, Benazepril
(C) Phosphorus containing-Fosinopril
Acronym: QPR, FML, CEBS (spirapril not in list above)
-Many of these ACE-inhibitors are ester-containing prodrugs with 100-1000 times less potent but more bioavailabile than the active.
-Potency, metabolite or not, pharmacokinetics all vary between ACE-inhibitors
*All have similar therapeutic indications, adverse effect profiles, contraindications
*With the exception of fosinopril and spirapril (eliminated via kidneys and liver), ACE inhibitors are eliminated mainly via kidneys
-Thus renal impaired people has a great reduction in clearance of most ACE inhibitors. Drug doses should be reduced in these patients.
2.3 Adverse effects: Due to the fact that ACE (enzyme) has many substrates. Thus, inhibition of ACE may induce unwanted side effects (not related to reducing levels of AngII)
1. ACE inhibitors increase bradykinin levels (resembles angiotensin I). Bradykinin stimulates prostaglandin biosynthesis –> Cough side effects
2. Bradykinin and/or prostaglandins may contribute to the pharmacological effect of ACE inhibitors.
3. ACE inhibitors interfere with negative feedback of renin release
4. ACE inhibitors thus increase renin levels (ACE escape?) and rate of formation of AngI.
5. Metabolism of AngI to AngII is blocked by ACE-inhibitors, Ang I is directed down other metabolic routes, resulting increased Ang (1-7)–>SIDE effects?