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-angiotensin-aldosteron system
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
Renin-angiotensin-aldosteron system
natriuresisvasodilatation(stimul. of NOS)inhib. of inflammation
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 inh. of fibrinolysisstimul. of inflammation oxid. stress
angiotensin 1-7
Mas rec.
natriuresisvasodilatation(stimul. of NOS)inhib. of inflammation
ACE2
Renin-angiotensin-aldosteron system
natriuresisvasodilatation(stimul. of NOS)inhib. of inflammation
renin
angiotensinogen
angiotensin I
angiotensin II ACE
bradykinin
degrad. productsof bradykinin
rec. AT1 rec. AT2 rec. AT4
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.
natriuresisvasodilatation(stimul. of NOS)inhib. of inflammation
ACE2
Renin-angiotensin-aldosteron system
natriuresisvasodilatation(stimul. of NOS)inhib. of inflammation
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
degrad. productsof 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.
natriuresisvasodilatation(stimul. of NOS)inhib. of inflammation
ACE2
Systém renin-angiotensin-aldosteron
natriuresisvasodilatation(stimul. of NOS)inhib. of inflammation
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
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
angiotensin 1-7
Mas rec.
natriuresisvasodilatation(stimul. of NOS)inhib. of inflammation
ACE2
Renin-angiotensin-aldosteron system
natriuresisvasodilatation(stimul. of NOS)inhib. of inflammation
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
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