From the Guidelines
RAS blockers, including ACE inhibitors and ARBs, are recommended as part of BP-lowering treatment in patients with a history of aortic valve stenosis and/or regurgitation, or moderate-to-severe mitral valve regurgitation, as stated in the 2024 ESC guidelines for the management of elevated blood pressure and hypertension 1.
Key Points
- RAS blockers are used to treat conditions like hypertension, heart failure, and kidney disease by inhibiting the renin-angiotensin system.
- The typical starting dose for lisinopril is 10mg daily, while losartan usually begins at 50mg daily, with doses adjusted based on blood pressure response.
- These medications work by either preventing the formation of angiotensin II (ACE inhibitors) or blocking its receptor (ARBs), resulting in blood vessel relaxation and reduced blood pressure.
- Common side effects include dry cough (more common with ACE inhibitors), dizziness, and elevated potassium levels.
- RAS blockers are contraindicated during pregnancy and require monitoring of kidney function and potassium levels.
Benefits and Usage
- RAS blockers provide additional benefits beyond blood pressure control, including protection against heart failure progression, reduction in proteinuria, and preservation of kidney function in diabetic patients.
- They are first-line treatments for many cardiovascular and renal conditions, as recommended by the American Diabetes Association (ADA) and Kidney Disease: Improving Global Outcomes (KDIGO) 1.
- However, the combined use of ACE inhibitors and ARBs should be avoided due to higher adverse event rates, such as hyperkalemia and AKI, as shown in clinical trials 1.
Important Considerations
- RAS blockers should be used with caution in patients with kidney disease, and the maximum tolerated doses should be used to achieve optimal benefits, as demonstrated in clinical trials 1.
- In patients with normal urinary albumin excretion, RAS blockers may not be superior to alternative classes of antihypertensive therapy, such as thiazide-like diuretics and dihydropyridine calcium channel blockers 1.
From the Research
Ras Blocker
- A Ras blocker, also known as a farnesyltransferase inhibitor (FTI), is a type of drug that targets the Ras protein, which is involved in cell signaling pathways 2, 3.
- The Ras protein requires farnesylation, a post-translational modification, to be active and localize to the cell membrane 4, 5.
- FTIs, such as tipifarnib, work by inhibiting the enzyme farnesyltransferase, which is responsible for adding the farnesyl group to the Ras protein 2, 3.
- Tipifarnib has been shown to be effective in inhibiting the growth of cancer cells with HRAS mutations, which are dependent on farnesylation for their activity 4, 5.
- The combination of tipifarnib with other drugs, such as simvastatin, has been shown to have a synergistic effect in inducing apoptosis in leukemia cells by disrupting RAS membrane localization and ERK pathway inhibition 6.
Mechanism of Action
- FTIs, such as tipifarnib, inhibit the farnesylation of the Ras protein, which prevents its localization to the cell membrane and subsequent activation of downstream signaling pathways 2, 3.
- The inhibition of farnesylation leads to a decrease in the activity of the Ras protein and a subsequent decrease in cell growth and proliferation 4, 5.
- The combination of FTIs with other drugs can enhance their effectiveness by blocking alternative prenylation pathways, such as geranylgeranylation, which can bypass the effect of FTIs 6.
Clinical Applications
- FTIs, such as tipifarnib, have been investigated as a potential treatment for various types of cancer, including multiple myeloma, head and neck squamous cell carcinoma, and rhabdomyosarcoma 2, 4, 5.
- The use of FTIs in combination with other drugs has shown promise in clinical trials, particularly in patients with HRAS-mutant tumors 4, 5.
- Further research is needed to fully explore the potential of FTIs as a treatment for cancer and to identify the most effective combinations and dosing regimens 2, 3, 4, 5, 6.