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POSSIBILITIES OF INFLUENCING RENIN- ANGIOTENZIN- ALDOSTERON SYSTEM prof. MUDr. J. Bultas, CSc.

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Presentation on theme: "POSSIBILITIES OF INFLUENCING RENIN- ANGIOTENZIN- ALDOSTERON SYSTEM prof. MUDr. J. Bultas, CSc."— Presentation transcript:

1 POSSIBILITIES OF INFLUENCING RENIN- ANGIOTENZIN- ALDOSTERON SYSTEM prof. MUDr. J. Bultas, CSc.

2 adapt. according to Anderson, Goodfriend, Phillips In: Hypertension Primer, 2003. Chronic hyper-activation of RAAS contributes to damage of vital organs stroke heart failure myoc. inf. renal failure Circulation collaps - death ↑ of aldosteron proteinuria Na + and water retention glomerulosclerosis atherogenesis and destabilization of plate vasoconstriction hypertrophy and remodelation proliferation of fibrous tissue endotelial dysfunction hypertrophy and remodelation inhib. of fibrinolysis fibrosis decay of cardiomyocytes hypertension ↑A II

3 Activation of RAA system adrenergic receptors  1 osmotic receptors chemorecept. baroreceptors renin

4 angiotensinogen angiotensin I angiotensin II ACE AT1 rec. vasoconstriction retention of Na + and water stimul. of aldosteron stimul. of inflammation oxid. stress Renin-angiotensin-aldosteron system renin

5 angiotensinogen angiotensin I angiotensin II ACE AT1 rec. AT2 rec. AT4 rec. vasoconstriction vasodilatation vasodilatation Na + and water retention (stimul. of NOS) (stimul. of NOS) stimul. of aldosteron inhib. of inflammation inhib. of fibrinolysis stimul. of inflammation oxid. stress Renin-angiotensin-aldosteron system renin

6 angiotensinogen angiotensin I angiotensin II ACE bradykinin degrad. products of bradykinin rec. AT1rec. AT2rec. AT4 vasoconstriction vasodilatation vasodilatation Na + and water retention (stimul. of NOS) (stimul. of NOS) stimul. of aldosterone inhib. of inflammation inhib. of fibrinolysis stimul. of inflammation oxid. stress Renin-angiotensin-aldosteron system natriuresis vasodilatation (stimul. of NOS) inhib. of inflammation renin

7 angiotensinogen angiotensin I angiotensin II ACE bradykinin degrad. products of bradykinin rec. AT1rec. AT2rec. AT4 vasoconstriction vasodilatation vasodilatation Na + and water retention (stimul. of NOS) (stimul. of NOS) stimul. of aldosterone inhib. of inflammation inh. of fibrinolysis stimul. of inflammation oxid. stress angiotensin 1-7 Mas rec. natriuresis vasodilatation (stimul. of NOS) inhib. of inflammation ACE2 Renin-angiotensin-aldosteron system natriuresis vasodilatation (stimul. of NOS) inhib. of inflammation renin

8 angiotensinogen angiotensin I angiotensin II ACE bradykinin degrad. products of bradykinin rec. AT1 rec. AT2rec. AT4 vasoconstriction vasodilatation vasodilatation Na + and H 2 O retention (stimul. of NOS) (stimul. of NOS) stimul. of aldosterone inhib. of inflammation inhib. of fibrinolysis stimul. of inflammation oxid. stress angiotensin 1-7 Mas rec. natriuresis vasodilatation (stimul. of NOS) inhib. of inflammation ACE2 Renin-angiotensin-aldosteron system natriuresis vasodilatation (stimul. of NOS) inhib. of inflammation renin proliferation PR rec.

9 LOX-1 VCAM ICAM according to: Jacoby DS, Arch Intern Med. 2003;163:1155-64. Activation of RAAS and atherotrombosis IL-6 PDGF NOSNOS PAI-1 TF TGF-  thrombosis activation of inflammation proliferation of fibrous tissue endothelial dysfunction oxidation of lipids adhesion of leucocytes AT 1 R hypertension angiotensin II

10 Indications of ACE inhibitors arterial hypertension prophylaxis of progression of nephropathy (especially diabetic) reduction of morbidity/mortality in patients with ischemic heart disease and after stroke chronic heart failure (opt. in combination with beta- blockers)

11 angiotensinogen angiotensin I angiotensin II ACE bradykinin degrad. products of bradykinin rec.AT1 rec.AT2rec.AT4 vasoconstriction vasodilatation vasodilatation retention of Na + and water (stimul. of NOS) (stimul. of NOS) stimul. of aldosterone inhib. of inflammation inhib. of fibrinolysis stimul. of inflammation oxid. stress angiotensin 1-7 Mas rec. natriuresis vasodilatation (stimul. of NOS) inhib. of inflammation ACE2 Systém renin-angiotensin-aldosteron natriuresis vasodilatation (stimul. of NOS) inhib. of inflammation renin proliferation PR rec. sartans

12 Indication of sartans arterial hypertension prophylaxis of progression of nephropathy (espec. diabetic) improved prognosis and reduced morbidity in patients with I.H.D. and in patients after stroke (telmisartan) chronic heart failure (if ACE-I are contraindicated)

13 Adverse effects and contraindications of sartans Adv. effects: the same as for inhib. of ACE, cough is not present! best tolerated group of antihypertensive agents hypotension, (espec. in the case of hypovolaemia) impairment of renal function (decrease of intraglom. pressure) higher levels of potassium (hyperkalaemia) angio-oedema (rarely) Contraindications: pregnancy (from 2. trimester)!!! bilat. stenosis of renal arteries, significant aortal stenosis and obstruct. cardiomyopathy

14 angiotensinogen angiotensin I angiotensin II ACE bradykinin degrad. products of bradykinin rec.AT1rec.AT2rec.AT4 vasoconstriction vasodilatation vasodilatation Na + and water retention (stimul. of NOS) (stimul. of NOS) stimul. of aldosterone inhib. of inflammation inhib. of fibrinolysis stimul. of inflammation oxid. stress angiotensin 1-7 Mas rec. natriuresis vasodilatation (stimul. of NOS) inhib. of inflammation ACE2 Renin-angiotensin-aldosteron system natriuresis vasodilatation (stimul. of NOS) inhib. of inflammation renin proliferation PR rec. inhib. of renin

15 Advantages of inhibition of RAAS in the treatment of hypertension favorable impact on prognosis cardioprotective influence (prevention of development of cardiac dilatation and reduction of mortality in patients with chronic heart failure and in patients after MI or stroke) beneficial metabolic effects (lipids and glycides) delay of progression of nephropathy prevention of loss of potassium during diuretic therapy beneficial combination with other antihypertensive agents

16 When is inhibiton of RAAS recommended? In the treatment of hypertension (ACE-I  sartans) For secondary prevention in patients with IHD (isch. heart disease) or after stroke or in patients with isch. disease of legs Prophylaxis of remodelation LV and heart failure Prophylaxis of diabetes mell. and diab. nephropathy

17 Inhibitors of aldosterone receptors aldosterone eplereron spironolacton

18 Axis renin-angiotensin-aldosterone angiotensinogen angiotensine I angiotensine II aldosterone ANP,BNP thirst resorption of Na + vasoconstriction RENIN rec. AT 1 ACE proliferation of fibroblasts retention of Na +

19 Cardiovascular diseases and role of aldosterone protrombotic effects Loss of potassium and magnesium inflammation and damage of vessels myocardial fibrosis central hypertensive effects endothelial dysfunction ventricular arrhytmia retention of natrium potentiation of effects of catecholamines cardiovascular diseases negative impact of increased level of aldosterone

20 aldosterone K+K+  Na + ACTH A I  AII Stimulation of secretion of aldosterone

21 aldosterone K+K+  Na + ACTH A I  AII ACE-I sartans blockers of aldost. rec. Possibilities of inhibition of aldosterone

22 Aldosterone receptors aldosterone rec. in dist. renal tubulus mineralocortic. effect (exchange Na + /K + ) aldosterone rec. in myocardium Stimulation of proliferation of fibroblasts aldosterone rec. in smooth muscle of vessels and endothel stimulation of proliferation of fibroblasts Inhibition of ACE and also blockade of AT1 rec. does not inhibit aldosterone rec. sufficiently – advantage of peripheral blockade of receptor

23 Na +, H 2 O H2OH2O Na + Cl - H2OH2O Na + K+K+ Blockers of aldosterone receptors Na + Cl - Site of effect of blockers of aldosterone receptors in kidney

24 SPIRONOLACTONE blockade of aldost. receptors in myocardium: inhib. of prolif. of fibroblasts (  dose 25 mg) in kidney: inhib. of Na/K pump in dist. tubulus with retention of potassium and natriuresis (  dose 50-300 mg/day) active metabolite with longer half-time (  15 h) blockade of degradation of andro-, estro- and gestagens (gynecomastia, menstrual cycle disorders) Caution: risk for hyperkalaemia (increased level of potassium)

25 effect on myocardium and kidney is the same as in the case of spironolactone Does not inhibit degradation of steroids better tolerated, expensive EPLERENON

26 Indications of antagonists of aldosterone receptors chronic heart failure (reduction of mortality of patients by a quarter), usage of sub-diuretic doses, main effect is prevention of hyperplasia of fibrous tissue in myocardium and in vascular wall, combination with ACE-I, betablockers, drugs that increase cardiac contraction and diuretics hypertension (espec. hypertension that is resistant) hyperaldosteronism (doses significantly higher) depletion of potassium and prevention of potassium depletion (middle doses)

27 Blockers of aldosterone rec. in chronic H.F. - clinical effect Improvement of LV function Improvement of life quality Improvement of prognosis - indication advanced heart failure (h.f.)

28 DIURETICS in the treatment of HYPERTENSION (diuretics in detail described also in part about treatment of heart failure)

29 DIURETICS Heterogeneous class of medicinal products, common effect is induction of increased diuresis and excretion of electrolytes Diuretics are indicated in the case of fluid retention (pulmonary congestion, oedema, ascites, hydrothorax) or in hypertension Diuretics applied in the treatment of hypertension reduce incidence of strokes and heart attacks, decrease mortality In the treatment of heart failure application of diuretics improves quality of life, but there is not enough information available about impact on prognosis

30 DIURETICS inhibition of spec. proteins that transport ionts in tubular renal system (loop and thiazide diuretics, potassium-sparing diuretics) Increase of glomerular filtration (osmotic diuretics, methylxantines) inhibition of effect of aldosterone (blockers of aldost. receptors) or effect of vasopressin (antidiuretic hormone) (blockers of vasopress. receptors – aquaretics, or alcohol)

31 DIURETICS – main groups  Loop diuretics (Henle´s loop)  diuretics acting in distal tubulus (thiazides)  potassium sparing diuretics  inhib. of aldosterone receptors  Aquaretic treatment (vaptans)  osmotic diuretics, inhib. of carbonic anhydrase

32 Na +, H 2 O H2OH2O Na + Cl - H2OH2O Na + K+K+ Inhibitors of carbonic anhydrase osmotic diuretics aquaretics blockers of aldosteron. receptors amiloride, triamteren Na + Cl - loop diuretics thiazides, indapamide Sites of action of diuretics osmotic diuretics, methylxantines

33 DIURETICS of HENLE´s LOOP inhibition of Na + /K + /2Cl - co-transport at loop of Henle (increase of excretion of ions Na, K, Mg, H and water) high diuretic effect fast and short-term effect effect maintained also in renal failure wide dosing spectrum advantageous when retention of fluids is present (pulmonary oedema, swellings,…) Not appropriate as antihypertensive agents (short term effect)

34 DIURETICS of HENLE´s LOOP furosemide: strong diuretic effect, rapid onset of action, short biol. half-time (1,5 hour), variable biol. availability in chr. heart failure, wide range of dosing 20 mg -2g, indicated in heart and renal failure Not suitable as anti-hypertensive drug (short-term effect) torasemide: more advantageous features, longer diuret. effect, stable availability, high cost, not available in Cz. Rep. bumetanide, ethacrynic acid – not used

35 DIURETICS of HENLE´s LOOP ADVERSE EFFECTS Depletion of potassium and hypokalaemia hyponatraemia, hypomagnesaemia, hypovolaemia - decrease of glomerul. filtration in hypovolaemia ototoxicity Increase of nephrotoxicity of many nephrotoxic drugs (e.g. ATB)

36 DIURETICS acting on the DISTAL TUBULE - THIAZIDES Inhibition of Na + /Cl - co-transport in distal tubulus Less effective diuretics, slow onset of action, long biol. half-time, stable biol. availability narrow therapeutic range cessation of diuretic effect, if GF is reduced (not effective in patients with renal insuficiency) Basic antihypertensive drugs Potentiation of loop diuretics (useful comb.) reduction of calcium excretion (treatment calciuria)

37 DIURETICS ACTING on the DIST. TUBULE - THIAZIDES hydrochlorothiazide (6-12 h, 6,25-25 mg), chlorthalidone (48-72h, 6,25-25 mg) - application 1x daily, or appl. every other day is possible - chlorthalidone is preferable because of longer effect indapamide : also vasodilatatory effect (16-36 h, 2,5 mg)

38 DIURETICS ACTING on the DIST. TUBULE - THIAZIDES ADVERSE EFFECTS depletion of potassium, hypokalaemia - increased exchange with natrium in the case of more natrium available in tubule hyponatraemia, hypovolaemia, hypotension metabol. effect in higher doses: - disorders of metabolism of carbohydrates and lipids, hyperuricaemia clear trend to use lower doses Use cautiously if patient is diabetic!

39 POTASSIUM SPARING DIURETICS inhibition of Na + channel on collecting tubule  Amiloride, triamterene minor diuretic effect, advantage is retention of potassium I: prophylaxis of depletion of potassium during treatment with loop or thiazide diuretics, combination of loop diuretics with potassium sparing diuretics results in improvement of prognosis nemocných (reduction of sudden deaths) if compared to the treatment with loop diuretics alone AE: hyperkalaemia

40 POTASSIUM SPARING DIURETICS amiloride: minor diuret. effect, slow onset of action, long biol. half-time (days), appropriate for combinations with diuretics (loop diuretics and thiazides) indications – antihypertensive drugs suitable also for treatment of heart failure triamterene: less advantageous, shorter diuretic effect

41 Indications of diuretics loop diuretics acute and chron. heart failure massive retention of fluids or fluid retention during renal insuf. thiazide diuretics antihypertensive agents of 1 st line in combination with loop diuretics in tha case of low diuretic response potassium sparing diuretics in combination with diuretics (loop diuretics, thiazides) depletion of potassium

42 AQUARETICS - blockers of recept. for vasopressin, (vasopressin increases expression of aquaporin) - studied in clin. trials -  diuresis without natriuresis- or increased excretion of potassium, - rec. V 1 : vasoconstriction, - rec. V 2 : excretion of water indication: hyponatraemia with oedema tolvaptam - inhib. of rec. V 2 (vasoconstriction stimul. V 1 ) conivaptan - dual inhib. of rec. V 1 +V 2

43 Rational and not rational (unreasonable) combinations Choose comb. of drugs with different mechanism of action: -  -block. + diuretics, CCB, alternatively ACE-I, sartans - diuretics +  -blockers, ACE-I, sartans, CCB - CCB +  -block., diuretics, ACE-I, sartans - ACE-I, sartans + diuretics, CCB, or  -block., - do not combine ACE-I with sartans

44 Choice of anti- hypertensive drug according to associated disorders

45 Advantageous combinations of antihypertensive drugs according to associated diseases Ischemic Heart Disease:  -blockers + CCB + ACE-I HEART FAILURE:  -block. ( ,  )+ACE-I+diuretics DIABETES: sartans or ACE-I, possibly CCB Ischemic Disease of Legs: ACE-I, sartans or CCB NEPHROPATHY: sartans or ACE-I with CCB GRAVIDITY:  -block., CCB, not ACE-I, not sartans!!! HYPERTR. OF PROSTATE GLAND:  -block.+….

46 How to treat hypertension in gravidity? It is necessary to avoid use of drugs with teratogenic potential and we exclude also prescription of medicinal products that activate regulatory systems in an unappropriate manner suitable: CCB and  -blockers or ,  -blocker - carvedilol,  -methyldopa It is possible to continue in therapy with: diuretics, if the treatment of woman with diuretics was maintained for longtime it is possible to continue with diuretic treatment, otherwise start of treatment with diuretics is not recommended. Contra-indicated: inhib. of ACE, sartans (espec. from 2. trim. because of teratogenic potential)

47 Treatment of hypertensive crisis hypertensive crisis is acute condition (situation) leading to injury of CNS (hypertensive encephalopathy) and circulation collapse We choose anti-hypertensive drugs with rapid onset of action for treatment ACE-I – captopril (onset of action till 30 min.), enalapril also possible CCB – isradipine (not retarded, onset of action is apparent till 30 min.)  -block. – esmolol (after i.v. appl. effect is immediate) or metoprolol (intravenous appl. is optimal) diuretics – furosemide i.v., alternatively furosemide in tablets onset of action is evident in tens of minutes Nitrates: nitroprusside or isosorbide nitrate in infus. for acute conditions

48 Smoking causes erectile dysfunction! What to do with smoker in bedroom?

49 Pharmacotherapy focused on help smokers when they try to stop smoking...can increase probability of successful abstinence from nicotine abuse twofold or threefold... …but cooperation of patient is necessary

50 SCHEME of TREATMENT Premise = smoker wishes to stop smoking psychosocial addiction : - social life with cigarette - in advance prepared alternate solutions - change of daily stereotype physical (drug) dependance: - determine D-day - pharmacological treatment for supression of withdrawal symptoms

51 Possibilities of abstinent therapy nicotine substitute therapy stimulation of acetylcholin- nicotine receptors antidepressive treatment

52 Bupropion (Zyban, Wellbutrin) Reduces incidence of withdrawal symptoms Decreases psychosocial dependance dosage: - first week 150 mg (1 tbl) each morning - then we titrate to recommended and maximal dose 300 mg/day (150 mg twice daily, > 8 hours between particular doses) f or period of 8–12 weeks Suitable for combination with any form of NRT

53 Effect of bupropione is mediated by stimulation of two important centers (release of dopamine and noradrenaline)

54 Thank you for attention


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