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

POSSIBILITIES OF INFLUENCING RENIN-

ANGIOTENZIN- ALDOSTERON SYSTEMprof. MUDr. J. Bultas, CSc.

adapt. according to Anderson, Goodfriend, Phillips In: Hypertension Primer, 2003.

Chronic hyper-activation of RAAS contributes

to damage of vital organs

stroke

heartfailure

myoc. inf.renal failure

Circulationcollaps- 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

Activation of RAA system

adrenergic receptors 1

osmotic receptors

chemorecept.

baroreceptorsrenin

angiotensinogen

angiotensin I

angiotensin II

ACE

AT1 rec.

vasoconstrictionretention of Na+ and water stimul. of aldosteron stimul. of inflammation oxid. stress

Renin-angiotensin-aldosteron system

renin

angiotensinogen

angiotensin I

angiotensin II

ACE

AT1 rec. AT2 rec. AT4 rec.

vasoconstriction vasodilatation vasodilatationNa+ and water retention (stimul. of NOS) (stimul. of NOS) stimul. of aldosteron inhib. of inflammation inhib. of fibrinolysis stimul. of inflammation oxid. stress


renin

angiotensinogen

angiotensin I

angiotensin II

ACE

bradykinin

degrad. productsof bradykinin

rec. AT1 rec. AT2 rec. AT4

vasoconstriction vasodilatation vasodilatationNa+ and water retention (stimul. of NOS) (stimul. of NOS) stimul. of aldosterone inhib. of inflammation inhib. of fibrinolysisstimul. of inflammation oxid. stress


natriuresisvasodilatation(stimul. of NOS)inhib. of inflammation

renin

angiotensinogen

angiotensin I

angiotensin II

ACE

bradykinin



vasoconstriction vasodilatation vasodilatationNa+ and water retention (stimul. of NOS) (stimul. of NOS) stimul. of aldosterone inhib. of inflammation inh. of fibrinolysisstimul. of inflammation oxid. stress

angiotensin 1-7

Mas rec.


ACE2



renin

angiotensinogen

angiotensin I

angiotensin II ACE

bradykinin



vasoconstriction vasodilatation vasodilatationNa+ and H2O retention (stimul. of NOS) (stimul. of NOS) stimul. of aldosterone inhib. of inflammation inhib. of fibrinolysisstimul. of inflammation oxid. stress

angiotensin 1-7

Mas rec.


ACE2



renin

proliferation

PR rec.

LOX-1

VCAM

ICAM

according to: Jacoby DS, Arch Intern Med. 2003;163:1155-64.

Activation of RAAS and atherotrombosis

IL-6

PDGF

NOS

PAI-1

TF

TGF-

thrombosis

activation of inflammation

proliferation of fibrous tissue

endothelial

dysfunction oxidation of lipids

adhesion of

leucocytesAT1R

hypertension

angiotensin II

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)

angiotensinogen

angiotensin I

angiotensin II

ACE

bradykinin


rec.AT1 rec.AT2 rec.AT4

vasoconstriction vasodilatation vasodilatationretention of Na+ and water (stimul. of NOS) (stimul. of NOS) stimul. of aldosterone inhib. of inflammation inhib. of fibrinolysisstimul. of inflammation oxid. stress

angiotensin 1-7

Mas rec.


ACE2

Systém renin-angiotensin-aldosteron


renin

proliferation

PR rec.

sartans

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)

Adverse effects and contraindications of sartansAdv. 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

angiotensinogen

angiotensin I

angiotensin II

ACE

bradykinin


rec.AT1 rec.AT2 rec.AT4

vasoconstriction vasodilatation vasodilatationNa+ and water retention (stimul. of NOS) (stimul. of NOS) stimul. of aldosterone inhib. of inflammation inhib. of fibrinolysisstimul. of inflammation oxid. stress

angiotensin 1-7

Mas rec.


ACE2



renin

proliferation

PR rec.

inhib. of renin

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

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

Inhibitors of aldosterone receptors

aldosterone

eplereronspironolacton

Axis renin-angiotensin-aldosterone

angiotensinogen

angiotensine I

angiotensine II

aldosterone

ANP,BNP thirst resorption of Na+ vasoconstriction

RENIN

rec. AT1

ACE

proliferationof fibroblasts

retention of Na+

Cardiovascular diseasesand

role of aldosterone

protrombotic effects Loss of potassium and magnesium

inflammation and damageof vessels

myocardialfibrosis

central hypertensive effects

endothelial dysfunction

ventricular arrhytmiaretention of natrium

potentiation of effectsof catecholamines

cardiovascular diseases

negative impact of

increased level of

aldosterone

aldosterone

K+

Na+

ACTH

A I AII

Stimulation of secretion of aldosterone

aldosterone

K+

Na+

ACTH

A I AII

ACE-I

sartans

blockers ofaldost. rec.

Possibilities of inhibition of aldosterone

Aldosterone receptorsaldosterone rec. in dist. renal tubulus

mineralocortic. effect (exchange Na+/K+)

aldosterone rec. in myocardiumStimulation of proliferation of fibroblasts

aldosterone rec. in smooth muscle of vessels and endothel

stimulation of proliferation of fibroblastsInhibition of ACE and also blockade of AT1 rec. does not inhibit

aldosterone rec. sufficiently – advantage of peripheral blockade of receptor

Na+, H2O

H2O

Na+

Cl-

H2O

Na+

Na+

K+

Blockers of aldosterone receptors

Na+

Cl-

Site of effect of blockers of aldosterone receptors in kidney

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)

• effect on myocardium and kidney is the same as in the case of spironolactone

• Does not inhibit degradation of steroids • better tolerated, expensive

EPLERENON

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)

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.)

DIURETICSin the treatment of HYPERTENSION

(diuretics in detail described also in part about

treatment of heart failure)

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

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)

DIURETICS – main groupsLoop 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

Na+, H2O

H2O

Na+

Cl-

H2O

Na+

Na+

K+Inhibitors of carbonic anhydrase

osmoticdiuretics aquaretics

blockers of

aldosteron.

receptors

amiloride, triamteren

Na+

Cl-

loop diuretics

thiazides,indapamide

Sites of action of diureticsosmoticdiuretics,methylxantines

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)

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

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)

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)

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)

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!

POTASSIUM SPARING DIURETICS inhibition of Na+ channel on collecting tubuleAmiloride, 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

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

Indications of diureticsloop diuretics

• acute and chron. heart failure

• massive retention of fluids or fluid retention during renal insuf.

thiazide diuretics

• antihypertensive agents of 1st 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

AQUARETICS - blockers of recept. for vasopressin, (vasopressin

increases expression of aquaporin)- studied in clin. trials

- diuresis without natriuresis- or increased excretion of potassium,

- rec. V1 : vasoconstriction,

- rec. V 2: excretion of water

indication: hyponatraemia with oedema

tolvaptam - inhib. of rec. V2 (vasoconstriction stimul. V1)

conivaptan - dual inhib. of rec. V1 +V 2

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

Choice of anti-hypertensive drug

according to associated disorders

Advantageous combinations of antihypertensivedrugs 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.+….

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, -methyldopaIt 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)

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

Smoking causes erectile

dysfunction!

What to do with smoker in bedroom?

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

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

Possibilities of abstinent therapy

• nicotine substitute therapy

• stimulation of acetylcholin-

nicotine receptors

• antidepressive treatment

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) for period of 8–12 weeks

• Suitable for combination with any form of NRT

Effect of bupropione is mediated by stimulation of two important centers

(release of dopamine and noradrenaline)

Thank you for attention

Documents

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