Генле ішегінде әрекет ететін диуретиктер

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Бүйректегі Хенле ілмегі бойымен әрекет ететін диуретиктер

Ілмек диуретиктері – Хенле ілмегінің қалың өрлеу бөліміндегі жасушалардың люминальды мембранасында орналасқан Na-K-Cl котранспортерін басым бөлігі ингибиретін фармакологиялық заттар. Олар көбінесе жүрек жеткіліксіздігіне, бауыр циррозына немесе созылмалы бүйрек ауруына байланысты гипертония және ісінуді емдеу үшін қолданылады. Бүйрек функциясы қалыпты пациенттерде тиазид диуретиктері тиімдірек болса, бүйрек функциясы нашарлаған пациенттерде ілмек диуретиктері тиімдірек.

Әрекет ету механизмі

Бұрандалы диуретиктердің 90% ақуыздармен байланысады және органикалық анион тасымалдаушы 1 (OAT 1), OAT 2 және ABCC4 арқылы проксималды иілімді түтікшеге секрецияланады. Бұрандалы диуретиктер Хенле ілмегінің қалың өрлеуші бөліміндегі Na+ K+ 2Cl− симпортеріне (NKCC2) әсер ете отырып, натрий, хлорид және калийдің қайта сіңірілуін тежейді. Бұл Cl− байланысу орны үшін бәсекелесу арқылы жүзеге асырылады. Бұрандалы диуретиктер макула денсадағы NKCC2-нің жұмысын да тежейді, макула денса жасушаларына тасымалданатын натрий мөлшерін азайтады. Бұл рениннің бөлінуін стимуляциялайды, ол ренин-ангиотензин жүйесі арқылы денедегі сұйықтықты ұстап қалуды арттырады, гломеруланың перфузиясын жақсартады, соның салдарынан гломерулярлық сүзгілеу жылдамдығын (GFR) арттырады. Сонымен қатар, бұрандалы диуретиктер түтікшелік-гломерулярлық кері байланыс механизмын тежейді, осылайша макула денсаға жақын түтікшедегі тұздардың артуы GFR-ді төмендетпейді. Бұрандалы диуретиктер магний мен кальцийдің қалың өрлеуші бөлімде қайта сіңірілуін де тежейді. Магний мен кальцийдің сіңірілуі люмен жағындағы оң және интерстициалдық жағындағы азырақ оң кернеуге, 10 мВ трансепителиалды кернеу градиентіне байланысты. Бұл магний және кальций иондарының люмен жағынан интерстициалдық жаққа итерілуіне және сіңірілуіне көмектеседі. Екі жақтағы кернеу айырмашылығы бүйректің сыртқы қабықшалық калий арнасы арқылы калийдің қайта өңделуі арқылы құрылады. Калийдің қайта өңделуін тежеу арқылы кернеу градиенті жойылады және магний мен кальцийдің қайта сіңірілуі тежеледі. Бұл иондардың қайта сіңірілуін бұзу арқылы бұрандалы диуретиктер гипертониялық бүйрек миын қалыптастыруға кедері келтіреді. Мұндай шоғырланған мисыз су жинақтаушы түтікше жүйесінен шығу үшін азырақ осмостық күшке ие болады, нәтижесінде зәр өндірісі артады. Бұл механизм бүйрек қан ағынын азайтады. Бұл диурез қанға қайта сіңірілетін су мөлшерін азайтады, нәтижесінде қан көлемі төмендейді. Бұрандалы диуретиктердің қосалқы әсері – простагландиндердің өндірісін арттыру, бұл тамырлардың кеңеюіне және бүйрекке қанмен жабдықталудың жақсаруына әкеледі. Простагландинмен шақырылған прегломерулярлық афферентті артериолалардың кеңеюі гломерулярлық сүзгілеу жылдамдығын (GFR) арттырады және диурезді жеңілдетеді. Қан көлемінің төмендеуі мен тамырлардың кеңеюінің жиынтық әсері қан қысымын төмендетуге және ісінуді жеңілдетуге көмектеседі.

Loop diuretics are 90% bonded to proteins and are secreted into the proximal convoluted tubule through organic anion transporter 1 (OAT 1), OAT 2, and ABCC4. Loop diuretics act on the Na+ K+ 2Cl− symporter (NKCC2) in the thick ascending limb of the loop of Henle to inhibit sodium, chloride and potassium reabsorption. This is achieved by competing for the Cl− binding site. Loop diuretics also inhibit NKCC2 at macula densa, reducing sodium transported into macula densa cells. This stimulates the release of renin, which through renin–angiotensin system, increases fluid retention in the body, increases the perfusion of glomerulus, thus increasing glomerular filtration rate (GFR). At the same time, loop diuretics inhibit the tubuloglomerular feedback mechanism so that increase in salts at the lumen near macula densa does not trigger a response that reduces the GFR. Loop diuretics also inhibit magnesium and calcium reabsorption in the thick ascending limb. Absorption of magnesium and calcium are dependent upon the positive voltage at the luminal side and less positive voltage at the interstitial side with transepithelial voltage gradient of 10 mV. This causes the magnesium and calcium ions to be repelled from luminal side to interstitial side, promoting their absorption. The difference in voltage in both sides is set up by potassium recycling through renal outer medullary potassium channel. By inhibiting the potassium recycling, the voltage gradient is abolished and magnesium and calcium reabsorption are inhibited. By disrupting the reabsorption of these ions, loop diuretics prevent the generation of a hypertonic renal medulla. Without such a concentrated medulla, water has less of an osmotic driving force to leave the collecting duct system, ultimately resulting in increased urine production. Loop diuretics cause a decrease in the renal blood flow by this mechanism. This diuresis leaves less water to be reabsorbed into the blood, resulting in a decrease in blood volume. A secondary effect of loop diuretics is to increase the production of prostaglandins, which results in vasodilation and increased blood supply to the kidney. Prostaglandin mediated vasodilation of preglomerular afferent arterioles increases the glomerular filtration rate (GFR) and facilitates diuresis. The collective effects of decreased blood volume and vasodilation help decrease blood pressure and ameliorate edema.

Фармакокинетика

Loop diuretics are highly protein bound and therefore have a low volume of distribution. The protein bound nature of the loop diuretic molecules causes it to be secreted via several transporter molecules along the luminal wall of the proximal convoluted tubules to be able to exert its function. The availability of furosemide is highly variable, ranging from 10% to 90%. The biological half-life of furosemide is limited by absorption from the gastrointestinal tract into the bloodstream. The apparent half-life of its excretion is higher than the apparent half-life of absorption via the oral route. Therefore, furosemide taken intravenously is twice as potent as an equivalent dose taken orally. Cerebral edema – intravenous furosemide can be combined with mannitol to initiate rapid diuresis. However, the optimum duration of such treatment remains unknown. Frequent fluid status monitoring is required to prevent intravascular volume depletion which leads to reduced cerebral perfusion. A bolus intravenous dose of 10 or 20 mg of furosemide can be administered and then followed by intravenous bolus of 2 or 3% hypertonic saline to increase the serum sodium level. Pulmonary edema – Slow intravenous bolus dose of 40 to 80 mg furosemide at 4 mg per minute is indicated for patients with fluid overload and pulmonary edema. Such dose can be repeated after 20 minutes. After the bolus, a continuous intravenous infusion can be given at 5 to 10 mg per hour. For those with underlying renal impairment or severe heart failure, up to 160 to 200 mg bolus dose can be given. Hypertension – A systematic review by the Cochrane Hypertension group assessing the anti-hypertensive effects of loop diuretics found only a modest reduction in blood pressure when compared to placebo. According to Joint National Committee (JNC 8) guidelines, the first-line treatment of hypertension is thiazide diuretics. The use of loop diuretics is not mentioned in this guideline. Meanwhile, according to 2013 European Society of Cardiology (ESC) guidelines, a loop diuretic can only replace thiazide type diuretics if there is renal impairment (Creatinine of more than 1.5 mg/dL or estimated glomerular filtration rate (eGFR) of less 30 mL/min/1.73 m2 due to lack of long-term cardiovascular outcome data and appropriate dosing regimen of its use. The 2012 KDIGO (Kidney Disease: Improving Global Outcomes) guidelines stated that diuretics should not be used to treat acute kidney injury, except for the management of volume overload. Diuretics have not shown any benefits of preventing or treating acute kidney injury. They are also sometimes used in the management of severe hypercalcemia in combination with adequate rehydration. The loss of magnesium as a result of loop diuretics has also been suggested as a possible cause of pseudogout (chondrocalcinosis). Infrequent ADRs include: dyslipidemia, increased serum creatinine concentration, hypocalcemia, rash. Metabolic alkalosis may also be seen with loop diuretic use. Ototoxicity (damage to the inner ear) is a serious, but rare ADR associated with use of loop diuretics. This may be limited to tinnitus and vertigo, but may result in deafness in serious cases. Loop diuretics may also precipitate kidney failure in patients concurrently taking an NSAID and an ACE inhibitor—the so-called "triple whammy" effect. Because furosemide, torsemide and bumetanide are technically sulfa drugs, there is a theoretical risk that patients sensitive to sulfonamides may be sensitive to these loop diuretics. This risk is stated on drug packaging inserts. However, the actual risk of crossreactivity is largely unknown and there are some sources that dispute the existence of such crossreactivity. In one study it was found that only 10% of patients with allergy to antibiotic sulfonamides were also allergic to diuretic sulfonamides, but it is unclear if this represents true crossreactivity or the nature of being prone to allergy. Ethacrynic acid is the only medication of this class that is not a sulfonamide. It has a distinct complication of being associated with gastrointestinal toxicity.

Loop diuretics are highly protein bound and therefore have a low volume of distribution. The protein bound nature of the loop diuretic molecules causes it to be secreted via several transporter molecules along the luminal wall of the proximal convoluted tubules to be able to exert its function. The availability of furosemide is highly variable, ranging from 10% to 90%. The biological half life of furosemide is limited by absorption from the gastrointestinal tract into the bloodstream. The apparent half life of its excretion is higher than the apparent half life of absorption via the oral route. Therefore, furosemide taken intravenously is twice as potent as an equivalent dose taken orally. Cerebral edema intravenous furosemide can be combined with mannitol to initiate rapid diuresis. However, the optimum duration of such treatment remains unknown. Frequent fluid status monitoring is required to prevent intravascular volume depletion which leads to reduced cerebral perfusion. A bolus intravenous dose of 10 or 20 mg of furosemide can be administered and then followed by intravenous bolus of 2 or 3% hypertonic saline to increase the serum sodium level. Pulmonary edema Slow intravenous bolus dose of 40 to 80 mg furosemide at 4 mg per minute is indicated for patients with fluid overload and pulmonary edema. Such dose can be repeated after 20 minutes. After the bolus, a continuous intravenous infusion can be given at 5 to 10 mg per hour. For those with underlying renal impairment or severe heart failure, up to 160 to 200 mg bolus dose can be given. Hypertension A systematic review by the Cochrane Hypertension group assessing the anti hypertensive effects of loop diuretics found only a modest reduction in blood pressure when compared to placebo. According to Joint National Committee (JNC 8) guidelines, the first line treatment of hypertension is thiazide diuretics. The use of loop diuretics is not mentioned in this guideline. Meanwhile, according to 2013 European Society of Cardiology (ESC) guidelines, a loop diuretic can only replace thiazide type diuretics if there is renal impairment (Creatinine of more than 1.5 mg/dL or estimated glomerular filtration rate (eGFR) of less 30 mL/min/1.73 m2 due to lack of long term cardiovascular outcome data and appropriate dosing regimen of its use. The 2012 KDIGO (Kidney Disease: Improving Global Outcomes) guidelines stated that diuretics should not be used to treat acute kidney injury, except for the management of volume overload. Diuretics has not shown any benefits of preventing or treating acute kidney injury. They are also sometimes used in the management of severe hypercalcemia in combination with adequate rehydration. The loss of magnesium as a result of loop diuretics has also been suggested as a possible cause of pseudogout (chondrocalcinosis). Infrequent ADRs include: dyslipidemia, increased serum creatinine concentration, hypocalcemia, rash. Metabolic alkalosis may also be seen with loop diuretic use. Ototoxicity (damage to the inner ear) is a serious, but rare ADR associated with use of loop diuretics. This may be limited to tinnitus and vertigo, but may result in deafness in serious cases. Loop diuretics may also precipitate kidney failure in patients concurrently taking an NSAID and an ACE inhibitor—the so called "triple whammy" effect. Because furosemide, torsemide and bumetanide are technically sulfa drugs, there is a theoretical risk that patients sensitive to sulfonamides may be sensitive to these loop diuretics. This risk is stated on drug packaging inserts. However, the actual risk of crossreactivity is largely unknown and there are some sources that dispute the existence of such cross reactivity. In one study it was found that only 10% of patients with allergy to antibiotic sulfonamides were also allergic to diuretic sulfonamides, but it is unclear if this represents true cross reactivity or the nature of being prone to allergy. Ethacrynic acid is the only medication of this class that is not a sulfonamide. It has a distinct complication of being associated with gastrointestinal toxicity.