Due to the change of kidney function, it has an impact on drug metabolism, so when diabetic nephropathy patients use antihypertensive drugs to control blood pressure, they should also make corresponding changes to the dosage of drugs.
I. Angiotensin-converting enzyme inhibitors (ACEI)
The main pharmacological effect of ACEI is to inhibit angiotensin converting enzyme in plasma and tissues, reduce angiotensin II production, reduce vasoconstriction and secretion of aldosterone. During the course of administration, patients should be observed for changes in renal function and blood potassium, and patients with renal artery stenosis should be used with caution or prohibited. There are reports that the drug may be harmful to the fetus in early pregnancy (neonatal acute kidney injury, pulmonary toxic effects, congenital cardiovascular system malformations, central nervous system malformations, renal malformations, cranial hypoplasia, etc.).
Perindopril has no adverse metabolic effects in diabetic and hyperalgesic patients, but is cleared in dialysis. The dose should be adjusted according to changes in glomerular filtration rate in patients with moderate to severe renal impairment, with a starting dose of 2 mg/d and a maximum dose not exceeding 8 mg/d. Perindopril clearance in dialysis patients is the same as in patients with normal renal function.
Captopril should be used with caution in patients with severely decompensated renal function. The pharmacokinetics and bioavailability of benazepril are not affected in mild to moderate renal insufficiency, and dose reduction is required in patients with severe renal insufficiency. Dialysis has no effect on the concentration of benazepril, and no supplementation is required after dialysis. Ramipril requires dose reduction in patients with moderate renal insufficiency and should not be used in polyacrylonitrile or sodium methyl allyl sulfide high-flux membranes or hemodialysis. Fosinopril should be reduced or discontinued in patients with renal insufficiency; it is not cleared on dialysis but is more likely to cause anaphylactic-like reactions during hemodialysis with high-flux dialysis membranes. The half-life of lenopril in patients with severe renal insufficiency can be more than 40 hours, and it can accumulate in the body, and the accumulated prodrug can be removed in the dialysis.
II. Angiotensin II receptor antagonist (ARB)
ARB lowers blood pressure in a dual way, one of which is to block angiotensin II (Ang II) and angiotensin II
Type 1 receptor (AT1R) binding, thus directly or indirectly inhibiting vasoconstriction, reducing vasopressin and aldosterone release, and reducing renal water and sodium reabsorption; the second is to induce Ang II to bind to AT2R, causing vasodilation, inhibiting cell differentiation and growth, and inhibiting sodium and water reabsorption and sympathetic nerve activity. No dose adjustment is required for losartan in patients with renal insufficiency, and no dose adjustment is required for valsartan in most patients with decompensated renal function, but dosing experience in patients with severe renal insufficiency is inadequate and should be used with caution.
Telmisartan and candesartan do not require dosage adjustment in patients with mild to moderate renal insufficiency and are contraindicated in patients with severe renal insufficiency. Irbesartan may require dose adjustment in patients with renal insufficiency and hemodialysis.
1. Calcium antagonists (CCB)
The non-dihydropyridine calcium antagonists diltiazem and verapamil can reduce proteinuria; dihydropyridine calcium antagonists can maintain and increase renal blood flow and improve Ccr and GFR; they can inhibit the effects of endothelin on the kidney as well as prevent renal hypertrophy. The International Baysin Intervention Study Against Hypertension (INSIGHT) demonstrated that nifedipine gastrointestinal controlled release system significantly increased glomerular filtration rate and protected renal function compared with diuretics.
It is generally believed that the mechanism by which CCB slows the progression of renal function in hypertensive patients is mainly through lowering blood pressure which reduces the conduction of pressure within the glomerulus by the body circulation, thus improving the intra-glomerular hyperfiltration and hyperperfusion state. Long-acting calcium channel blockers do not require dose reduction in the presence of impaired renal function, and are particularly indicated in patients with combined coronary artery disease, renal artery stenosis, severe renal insufficiency, and the presence of contraindications to ACEI or ARB use.
CCB is one of the most common options for the treatment of CKD combined with hypertension, but if urine protein continues to increase, additional ACEI or ARB drugs are required to achieve the effect of protecting renal function. Some clinical studies have shown that the dihydropyridine CCB amlodipine combined with benazepril is superior to the combination of benazepril and thiazide diuretics in reducing cardiovascular events and delaying the progression of nephropathy in diabetic patients, and the non-dihydropyridine CCB drugs are significantly better than ACEI and β-blockers in reducing urinary protein levels and delaying the progression of nephropathy in diabetic nephropathy patients, and are not affected by blood pressure control.
2.Diuretics
The GUARD clinical study showed that the combination of ACEI and hydrochlorothiazide was better than the combination of ACEI and CCB in reducing the urinary protein level of patients. The results of the ACCOMPLISH clinical study in patients with systolic hypertension showed that the combination of ACEI and hydrochlorothiazide was less effective than the combination of ACEI and CCB in slowing the decline in glomerular filtration rate in patients at high risk for diabetic hypertension.
Although it is controversial whether thiazide or tab diuretics are stronger than CCB as combination drugs, most patients with diabetic nephropathy combined with hypertension, especially those with blood pressure above 130/80 mmHg, need more than one drug to control blood pressure, so thiazide or tab diuretics are recommended as the choice of combination drugs.
Hydrochlorothiazide promotes potassium and sodium excretion, which can cause reflex renin and aldosterone secretion when hyponatremia is caused, and it has poor effect in patients with anuria or renal impairment.
3.β-blockers
Although ACEI is more advantageous than β-blockers in reducing proteinuria in diabetic patients, both drugs can slow down the decline of renal function in patients. The first group is non-selective beta-blockers, the main representative drug is propranolol, which is less frequently used now.
The second category mainly acts on β1 receptor, and the representative drugs are metoprolol and bisoprolol. Metoprolol is mainly metabolized by the liver, and 5% is excreted by the kidney as a prototype, so the dose does not need to be adjusted for renal impairment. Bisoprolol is metabolized by the liver to inactive metabolites and then excreted from the kidneys, while the remaining 50% is excreted from the kidneys in the form of prodrugs.
The daily dose does not exceed 10 mg when the GFR is <20 ml/min-1・1.73 m-2, and there is less experience in using it in renal dialysis patients. The third category mainly acts on β and α1 receptors, and the representative drugs are carvedilol and labetalol. Labetalol 55% - 60% of the original form of the drug and metabolites are excreted by urine, hemodialysis and peritoneal dialysis are not easy to remove, should be used with caution in renal insufficiency.
Third, other renin-angiotensin system (RAS) blocking agents
ACEI or ARB drugs can reduce the plasma aldosterone level, but a study found that 40% of patients taking the above drugs did not decrease their plasma aldosterone level, but increased to its pre-treatment concentration level, called the “aldosterone escape” phenomenon, which may be related to the progression of renal disease, the specific mechanism is not The exact mechanism is not clear.
Early short-term clinical studies have shown a benefit of ACEI/ARB in combination with aldosterone receptor antagonists (MRAs) in reducing urinary albumin levels in patients with type 1 diabetic nephropathy, but more clinical studies are needed to confirm this. Urinary albumin levels were significantly lower in the lenopril combined with spironolactone group compared with patients in the lenopril + placebo group. Because spironolactone may increase the risk of elevated blood potassium, monitoring of blood potassium is required at the time of application.
Inhibition of renin activity in patients with diabetic nephropathy significantly reduces their blood pressure and proteinuria levels. urinary protein was lower with the renin inhibitor aliskiren in combination with crosartan compared to crosartan alone in patients with type 2 diabetes. However, a recent clinical trial of aliskiren in patients with type 2 diabetes was terminated due to serious adverse events resulting from the combination of aliskiren with ACEI/ARB, including renal failure, hyperkalemia and hypotension. Therefore, the FDA continues to prohibit aliskiren in patients with diabetes who are already on ACEI/ARB.
IV. Combination of drugs
Patients with diabetic nephropathy may choose other antihypertensive drugs in combination with ACEI/ARB when their blood pressure is not well controlled. The results of some early small clinical studies have shown that ACEI combined with ARB has high tolerability and efficiency in patients with diabetic nephropathy, resulting in significant reduction of urinary protein levels and effective reduction of diastolic blood pressure in patients with diabetes.
However, newer studies have shown that the efficacy of the combination of ACEI and ARB is not superior to monotherapy, and there is no significant difference in serum creatinine levels, ESRD occurrence and mortality in diabetic patients after the combination of ARB and ACEI. Therefore, the combination of ACEI and ARB is not recommended, and if ACEI and ARB are already being used in combination, blood potassium and renal function need to be tested and followed up.