Novel therapeutics for hypertension AV Flashcards
(29 cards)
What are the types of current RAAS therapies
RAAM
Renin inhibitors
ACE inhibitors
ARBs (angiotensin II receptor blockers)
MRAs (mineralocorticoid receptor antagonists)
Mechanism effects and limitations of renin inhibitors
Mechanism: Directly inhibit renin, reducing conversion of angiotensinogen to angiotensin I.
Effects:
§ ↓ Plasma renin activity (PRA)
§ ↑ Plasma renin concentration (PRC) due to loss of negative feedback
§ ↓ Angiotensin I, II, and aldosterone
Limitations:
§ Very low oral bioavailability
§ Compensatory rise in renin concentration may reduce long-term efficacy
§ Limited clinical outcome benefit in trials compared to ACEi/ARBs
Mechanism effects and limitations of ACE inhibitors
Mechanism: Block conversion of angiotensin I to angiotensin II.
Effects:
§ ↑ PRA and PRC
§ ↑ Angiotensin I
§ ↓ Angiotensin II
§ Variable effects on aldosterone
Limitations:
§ Increased renin and angiotensin I production through feedback
§ Bradykinin accumulation can cause side effects (e.g. cough, angioedema)
§ Potential for aldosterone escape, where aldosterone levels rebound over time
Mechanism effects and limitations of angiotensin II receptor blockers (ARBs)
Mechanism: Block AT1 receptor, preventing angiotensin II from exerting its effects.
Effects:
§ ↑ PRA, PRC, Angiotensin I & II
§ ↓ Aldosterone initially
Limitations:
§ Aldosterone breakthrough occurs in ~30–40% of patients, returning levels to baseline
§ Compensatory increases in angiotensin II may activate non-AT1 receptors (e.g., AT2), with unknown long-term effects
Mechanism effects and limitations of mineralocorticoid receptor antagonists
Mechanism: Block aldosterone receptor effects in the kidney and heart.
Effects:
§ ↓ Sodium retention and fibrosis
§ Feedback: ↑ PRA, PRC, Ang I, Ang II, and aldosterone
Limitations:
§ Upregulation of the entire RAAS pathway
§ Risk of hyperkalemia and endocrine side effects (especially with spironolactone)
RAAS system pathway
1. Renin release
- Triggered by Low blood pressure, Low sodium levels, Sympathetic activation
→ Kidneys (juxtaglomerular cells) release renin.
2. Angiotensinogen → Angiotensin I
- Renin converts angiotensinogen (from the liver) into angiotensin I.
3. Angiotensin I → Angiotensin II
- ACE (Angiotensin-Converting Enzyme), mostly in the lungs, converts angiotensin I into angiotensin II.
4. Actions of Angiotensin II
- Vasoconstriction → Raises blood pressure
- Stimulates aldosterone release from adrenal cortex
- Stimulates ADH release from posterior pituitary
- Enhances sodium and water retention
5. Aldosterone effects
Acts on kidneys to reabsorb sodium and water, and excrete potassium
→ Increases blood volume and pressure
role of the ‘protective arm’ of RAAS in counterbalancing classical RAAS pathways
This arm counterbalances the classical pathway and is vasoprotective and anti-inflammatory.
Key Components:
○ ACE2: Converts Angiotensin II → Angiotensin-(1–7)
○ Angiotensin-(1–7): Binds to the Mas receptor
○ AT₂ Receptors: Also respond to Ang II but with protective effects
○ Angiotensin-(1–9): Formed from Ang I via ACE2, may have beneficial effects via AT₂R
Protective Effects:
○ Vasodilation
○ Natriuresis and diuresis
○ Anti-fibrotic, anti-proliferative, and anti-inflammatory
○ Improved endothelial function
○ Reduced oxidative stress
○ Cardioprotective and renoprotective roles
What are the emerging anti-hypertensive agents within RAAS
A MAABBA
A – AT₂ receptor agonists
M – Mas receptor agonists
A – ACE2 activators
A – Ang(1-7) bias at AT₁R
B – Brain RAAS modulation
B – Alamandine/MrgD axis
A – Angiotensinogen-targeting siRNA
Mechanism and limitations of AT2 receptor agonists
Mechanism:
§ Activate AT₂R → vasodilation, natriuresis, anti-inflammatory, anti-fibrotic effects.
§ Peptide analogues (e.g. β-Tyr⁴ and β-Ile⁵ Ang II; modified Ang III).
§ Non-peptide: C21 (Compound 21), selective AT₂R agonist; lowers BP in preclinical models.
Limitations/Controversies:
§ Peptide analogues often ineffective unless AT₁ is blocked (e.g. with candesartan).
§ Peptide instability, poor oral bioavailability.
§ Limited data in human trials; mostly preclinical evidence.
Mechanism and limitations of ACE2 activators
Mechanism:
§ Promote conversion of Ang II → Ang-(1–7), which acts via MasR → vasodilation, natriuresis.
§ Recombinant ACE2 (synthetic), small molecules (e.g. XNT), and repurposed drugs like DIZE.
Limitations/Controversies:
§ Recombinant ACE2 is expensive and not practical for long-term use.
§ Small molecule activators may lack selectivity, e.g. DIZE’s off-target effects.
§ Human trials are lacking, mechanisms not fully understood.
Mechanism and limitations of MasR agonists
Mechanism:
§ Mimic Ang-(1–7) action on MasR → vasodilation, natriuresis, diuresis.
§ AVE-0991, CGEN-856/857 (MasR-specific, non-peptides).
Limitations/Controversies:
§ AVE-0991 has high hydrophobicity → potential BBB penetration → halted development.
§ Clinical data sparse, mostly animal studies.
§ Unclear long-term effects of prolonged MasR activation.
Mechanism and limitations of 4. Ang-(1–7) Bias at AT₁R
Mechanism:
§ Ang-(1–7) binding to AT₁R favors β-arrestin signaling over G-protein → lowers BP.
§ Ang-(1–7) also activates MasR.
Limitations/Controversies:
§ Still a theoretical mechanism; translation to clinical use unclear.
§ Need for more selective agonists or biased ligands.
§ Complex signaling makes dose-responsiveness difficult to predict.
Mechanism and limitations of Alamandine/MrgD axis
Mechanism:
§ Alamandine activates MrgD receptor → vasodilation.
§ May be produced via ACE2-dependent pathways.
Limitations/Controversies:
§ Early-stage research, mostly preclinical.
§ Unclear if endogenous levels are sufficient for therapeutic benefit.
§ Human safety and efficacy data lacking.
Mechanism and limitations of brain RAAS Modulation
Mechanism:
§ Local RAAS in the brain controls sympathetic tone, vasopressin, water retention.
§ Targets:
□ APA inhibitors (EC33, Firibastat)
□ APN inhibitors (PC18)
□ Mineralocorticoid receptor (MR) antagonists
Limitations/Controversies:
§ Firibastat: Despite early promise, Phase 3 trials failed to show BP-lowering efficacy.
§ EC33: Does not cross BBB, limiting use.
§ PC18: Increases BP when given alone; needs AT₁ blockade to see natriuretic effect.
§ MR antagonists:
□ Spironolactone has anti-androgenic side effects (gynecomastia, menstrual irregularities).
□ Newer agents (e.g. finerenone, esaxerenone) are better tolerated but long-term data limited.
Mechanism and limitations of Angiotensinogen-targeting siRNA
Mechanism:
§ Silences angiotensinogen gene, suppressing entire RAAS cascade upstream.
Limitations/Controversies:
§ Promising BP reduction in Phase 1 and 2.
§ However, serious adverse events (including death) reported.
§ Still under clinical evaluation; concerns about safety and off-target effects.
§ Long-term impact on compensatory RAAS components remains uncertain.
Describe the role of sGC in mediating vascular tone and blood pressure
Core Mechanism:
○ Nitric Oxide (NO) activates soluble guanylyl cyclase (sGC) → converts GTP to cGMP.
○ cGMP activates Protein Kinase G (PKG), which leads to vascular smooth muscle relaxation and blood pressure reduction via multiple mechanisms:
PKG-Mediated Effects on Smooth Muscle Cells:
- ↓ Intracellular Ca²⁺ Availability:
§ Sequestration into sarcoplasmic reticulum via SERCA pump stimulation.
§ Extrusion from the cell through activation of PMCA (plasma membrane Ca²⁺ ATPase).
§ Reduced Ca²⁺ influx by phosphorylation and inhibition of voltage-gated calcium channels. - Membrane Hyperpolarization:
§ Activation of BK_Ca channels (large conductance calcium-activated potassium channels).
§ Causes K⁺ efflux, hyperpolarization, and closure of Ca²⁺ channels, reinforcing relaxation. - Direct Relaxation of Contractile Machinery:
§ Phosphorylation of myosin light chain phosphatase (MLCP) → dephosphorylation of myosin light chains → smooth muscle relaxation.
Termination of the Signal: ○ cGMP is broken down by phosphodiesterases (PDEs) into GMP → ends the vasodilatory signal.
○ PDE5 is a key enzyme here (targeted by drugs like sildenafil).
Renal Effects of sGC Activation:
○ Increased renal blood flow due to vasodilation.
○ Reduced sodium reabsorption in the nephron.
○ Relaxation of vasa recta (medullary circulation).
○ Results in ↑ natriuresis and ↑ diuresis, supporting BP reduction.
Mechanism of the sGC stimulators and activators
sGC (soluble guanylyl cyclase) is activated by NO, converting GTP to cGMP → smooth muscle relaxation and BP reduction.
sGC modulators work independently or synergistically with NO by stabilizing or activating sGC directly.
MoA, outcome and limitations of Riociguat
Riociguat - sGC stimulator
MoA:
□ Sensitizes sGC to NO by binding to Fe²⁺-heme group
□ Stimulates sGC directly when NO is low
□ Prevents heme oxidation and degradation
Outcome: ↑ cGMP → vasodilation → ↓ BP
Limitations: Contraindicated with nitrates and PDE inhibitors due to hypotension risk
MoA, outcome and limitations of Cinaciguat
Cinaciguat - sGC activator
MoA:
□ Binds oxidized/heme-free sGC
□ Activates NO-independent pathway
Outcome: theoretical benefit in oxidative stress
Limitations: Failed clinical trials – hypotension and safety concerns
MoA, outcome and limitations of Aticiguat
Aticiguat - sGC activator
MoA:
□ Inhibits phenylephrine-induced contraction (rat models)
Outcome: ↓ vasoconstriction
Limitations: Failed to show clinical efficacy
MoA, outcome and limitations of Runcaciguat
Runcaciguat - sGC activator
MoA:
□ Cardioprotective and renoprotective effects in low doses
Outcome: no significant BP reduction
Limitations: lacks robust antihypertensive effect
What is the MoA of natriuretic peptides
Promote vasodilation, natriuresis, lipolysis, inhibit cardiac fibrosis.
Act via NPR-A and NPR-B → ↑ cGMP levels → lower BP.
Neprilysin degrades NPs, reducing their beneficial effects.
What is the target effect and limitations of Candoxatril
neprilysin inhibitor
prevents NP degradation
did not lower BP despite ↑ NP levels
What is the target effect and limitations of Omapatrilat
ACEi and neprilysin
potent BP lowering
↑ risk of angioedema due to excess bradykinin
