Antihypertensives http://sk.tdmed.ru/uploads/posts/2015-01/gpotenzivn-preparati_121.jpeg •Definition : repeated increase of blood pressure (systolic-diastolic) 140/90 mmHg or higher in patients older than 18 years in at least two of three measurements in two different checks -The most often disease of cardiovascular system -AH + hyperlipidemia +DM + nicotine addiction premature atherosclerosis & ischemic heart disease • •prevalence in elderly 20-50 %, 35 % in CZ Definition of ARTERIAL HYPERTENSION ØEthiology Classification oPrimary – essential §App. 90 % of all patients with HT §Multifactorial disease without organic reason oPrimary – essential oSecondary ØEthiology Classification Secondary hypertension oPrimary – essential oSecondary §Nephropathy – the most often §Endocrine – suprarenal gland (hyperaldosteronismus) §Renovascular – renal arthery disease §Iatrogenic – long-term use of corticosteroids, NSA, sympatomimetics, HAT §Gestation – HT in pregnancy Treatment goals in hypertensive patients SBP < 140 mm Hg low- moderate CV risk diabetes previous stroke or TIA SBD between 150 and 140 mm Hg elderly < 80 years elderly > 80 years in good condition DBP < 90 mmg Hg always recommended, except diabetes ( < 85 mm Hg) Blood Pressure regulation Peripheral resistence (vasoconstriction/vasodilatation) § decrease / increase § decrease / increase Blood volume, cardiac output THERAPY OF ARTERIAL HYPERTENSION 1. NON-PHARMACOLOGICAL 2. PHAMACOLOGICAL decrease the risk of cardiovascular disease / target BP ↓ 140/90 mm Hg (high-risk 140/85 mm Hg) 2. PHARMACOLOGICAL oWHEN ? oWITH ? oMONOTHERAPY (app. 30 % of the patients) oCOMBINATION, lower doses /Fixed combination - better compliance, more problematic titration / o Next steps ü+ drug üIncrease the dose Changes - 4-6 weeks interval, urgent situation immediatelly Drug classes 1st line treatment •ACEi •AT-II inhibitors •CCB •Diuretics • BB 2nd line treatment •Central acting drugs •α1-lytics •Renin inhibitors • PHARMACOTHERAPY BLOOD PRESSURE Heart output Peripheral resistance •β-blockers •Ca2+ blockers •Central drugs •α1 blockers •Direct vasodilitans •ACE inhibitors •AT rcp antagonists •Renin inhibitors diuretics 1. ACEi 2. AT1-antagonists R-A-A-S Hyperactivation leads to ↑ TK ü↑ blood volume (aldosteron) + ü↑ peripheral resistence (A II) AT II actions include also… induction of growth, cell migration, mitosis of vascular smooth muscle cells, increased synthesis of collagen type I and III in fibroblasts, leading to thickening of the vascular wall and myocardium, and fibrosis. ljuxtaglomerular apparatus; as prorenin Physiology RENIN ØSignal from baroreceptors (decreased BP) ØSignal from chemoreceptors (decreased Na load) ØStimulation of β1 adrenergnic receptors Ø RENIN / PRORENIN are hormons Physiology RENIN PD effect vPROTEOLYTIC ENZYME endopeptidase acts on angiotensinogen splitting off a decapeptid angiotensin I inactive, but converted to AT II (potent vasoconstrictor) vNON-PROTEOLYTIC ACTIVITY induction of synthesis of TGF-β a PAI-1 ð fibroproduction and remodelation of tissues ð etiopathogenesis of CVD (!) PAI plazminogen aktivátor inhibitor RAAS R-A-AS Výsledek obrázku pro kininový systém + degradační produkty AIII a AIV Lokální zánětlivá reakce Agonisté potenciální léčiva?? Zvýšení exprese při vzniku zánětu – např. při aterosklerotickém postižení cévní stěny Protrombotický efet – inhibice fibrinolýzy TGF-β (13 AMK) R-A-AS - final step ALDOSTERON the main mineralocorticoid hormone produced by the zona glomerulosa of the adrenal gland by acting on the mineralocorticoid receptors in the distal tubules and collecting ducts of the nephron §Na+ + H2O reabsorption §Tubular secretion K+ (antiport Na-K) Stimulation of aldosteron production: §ACTH §AT II §↑ K+ ionts § Inhibition of production: §Negative feadback regulation lDifferent level… vBeta – blockers (inhibition of renin secretion) vRenin inhibitors (inhibition of conversion angiotensionogen to AT I) vACEi (inhibition of conversion of AT I to AT II) vsartans (antagonization of AT1-rcp) vAntagonisation of aldosteron receptor Inhibition of R-AA-S Výsledek obrázku pro kininový systém Betablockers Renin inhibitors ACE inhibitors Sartans aldosteron rcp antagonists Možnosti ovlivnění RAAS léčivy 1. ACEi MECHANISM OF ACTION 1. Reversible antagonisation of ACE (dipeptidase) 2. Block od bradykinine degradation ð prolongation of vasodilatation and natriuretic effect §↓peripheral resistence §↓ aldosteron § ↓ sensitivity of baroreceptors BP ↓ PK ACEi §Given orally §Bioavailability 50-75 % §Liver metabolisation (to the active metabolite) §Renal elimination /glomerular filtration/ §Variable half-life 13-36 hrs ramipril(ate) 30-120 hrs perindopril(ate) ACEi §Safe and effective drugs in monotherapy as well as combination § §Favorable profile on carbohydrates (diabetic patients) § §Cardioprotective effect § §Renoprotective effect (↓ albuminuria) ADVANTAGE Classification accoring to t1/2 : oShort-acting (3x/ per day) t1/2 = app. 2 hrs, effect app. 8 hrs CAPTOPRIL (not used) oIntermediatte (1-2x/ per day) t1/2 = app. 6-12 hrs, effect app. up to 24 hrs ENALAPRIL*, LISINOPRIL, FOSINOPRIL oLong-acting (1x/ per day) t1/2 = app. 13-36 hrs (perindopril 120 hrs) TRANDOLAPRILt, RAMIPRIL, PERINDOPRIL * i.v. (hypertensive crisis) t lowest onset of action ADVERSE EFFECTS ØDry irritant cough. The most common ↓ degradation of bradykinin ØHyperkalemia. (↓ aldosteron ð inhibition of Na/K antiport) lab monitoring K, urea and kreatinine level (mainly during the first period of tretament) ØAngiooedema. allergic/ hereditary angioedema Ø ØTeratogenity. KI in gravidity (second and third trimestr) Ø Ø (hypotension ) ACEi INDICATION §Arterial hypertension* /suitable in DM pts. / §Chronic Heart Failure* – /↓ LVF, remodelation and hypertrophy of left ventricule/ §Secondary prophylaxy of trombotic complication * (IM, stroke) §Diabetic /non-DM/ nephropathy ACEi Long-time administration of ACEI for clinical benefit * The best RR in RCT: PERINDOPRIL, RAMIPRIL §GRAVIDITY * §Hypercalemia §Bilateral stenosis of renal arteries with clinically significant ↓ GF (relative KI) §Angioedema in anamnesis §Primary hyperaldosteronism (non-responders) CONTRAINDICATION * All RAAS acting drugs ACEi Angiotenzinogen Angiotenzin I Angiotenzin II RENIN ACE catepsin t-PA üCAGE CAGE chymostatin sensitive AT-II generated enzyme (veins) t-PA – tissue plazminogen activator catepsin – serum protease ACEi Alternative synthesis of AT-II not inhibited by ACEi ↓ BP 2. AT1 RECEPTOR ANTAGONISTS – SARTANS (ARB) Non-competitive/competitive antagonisms of AT1 receptor (selective) MECHANISM OF ACTION ACE not affected – cough not present ð ↓ peripheral vascular resistance ð vazodilatation ð ↓ volume EPROSARTAN LOSARTAN - prodrug - CYP2C9 metabolisation. Drug interaction!! VALSARTAN – nephroprotective drug CANDESARTAN – EBM efficacy in CHF OLMESARTAN IRBESARTAN TELMISARTAN - long half-life Strong inhibitor of P-glp, hepatal elimination Partial agonist of PPAR-γ receptor → better metabolic profile PHARMACOKINETICS Sartans Angiotensin receptor blockers ( ARB) most used ADVERSE EFFECT At the beginning and during the treatment lab monitoring – kalium, urea and creatinine § (hypotension) § Hyperkalemia § angioedema less common Sartans §Arterial Hypertension (ACEI a sartans, both effective) §Chronic Heart Failure (ACEi better, only for – pouze pro candesartan EBM data for ↓cardiovascular complications) §Diabetic nephropathy with proteinuria (data for telmisartan and valsartan) §Cough after ACEi §Pregnancy, lactation §Hyperkaemia §Angioedema in anamnesis §Bilateral stenosis of renál arteries (relative contraindication) INDICATION CONTRAINDICATION Sartans DRUG INTERACTION of RAAS drugs §LITHIUM ð ↑ plazmatic level of LITHIUM (based on PK) §NSAID, ASA (more than 3g/day) ð ↓ antihypertensive effect ð ↑risk of renal function ð ↑risk hyperkalemia (PD interaction) LOSARTAN + strong inhibitor of CYP2C9 (FLUCONAZOL) ð ↓ level of active metabolitace (50%) TELMISARTAN (strong inhibitor of P-glycoprotein) + DIGOXIN ð ↑digoxin level Combination - dual effect ARNI = Angiotenzin receptor blocker / neprilysin inhibitor VALSARTAN + SACUBITRIL prodrug NEPRILYSIN = enzyme catalysed degradation of endogenous vasodilatative natriuretic petides ð ↓ BP Entresto® neprilysine inhibition ð prolongation of effects skupina ARNI INDICATION: Hypertension + symptomatic chronic heart failure with ↓left ventricular fraction in adult patients CONTRAINDICATION: §Hypersensitivity §Concomitant therapy with ACE inhibitors §Angioedema §Concomitant therapy with renin inhibitors RENIN INHIBITORS MECHANISM OF ACTION Selective direct renin inhibitor Binds to active site of renin, changes its steric confirmation and inhibits its binding to angiotensinogen ð block conversion of angiotenzinogen to angiotensin I Second line treatment of hypertension ! DRUGS ALISKIREN Registered Oral form, non-peptide, LW Combination with diuretics, ARBs – additive effect PHARMACOKINETICS §Bioavalability 15%, effect is not influenced by food §long T1/2 (about 24 hrs) §First pass efect §Biliary excretion (78 %) and kidney excretion (< 10%) INDICATION Essential hypertension §Hypersensitivity, allergic reaction in anamnesis §Gravidity (mainly 2. a 3. trimester), lactation §Bilateral stenosis of arteria renalis §Severe nephropathy CONTRAINDICATION ADVERSE EFFECTS §diarhhoea (the most often) §veretigo §atralgia §Hyperkalemia §Oedema ( < 1%) § In combination with sartans ↑ stroke in older patients 3. Ca CHANNEL BLOCKERS Previous lecture For the treatment of hypertension: DIHYDROPYRIDINES -↓peripheral vascular resistance (vazodilatation) - vasoselective (relatively) 4. DIURETICS Next lecture 5. β blockers β sympatolytics) From previous lecture… Drugs for second line treatment of hypertension vCentral α2-agonists vImidazolin I1 receptor agonists vCentral α2-agonists + peripheral α1-antagonists CENTRAL ANTIHYPERTENSIVES α1-receptor antagonists VASODILATANS (direct) vNitrates vPDE-5 inhibitors vEndotelin-1 antagonists vSyntetic analogs of prostacyclines Previous lecture Poznámka Jitky: U tohoto slidu možno připomenout, že není jen arteriální hypertenze, ale i portální, plicní apod. Indirectly acting vasodilatators – the central control of sympathetically mediated vasoconstriction: §central α2 rcp. (brain stem) §imidazoline rcp. (ventrolateral medulla) ACTIVATION ð reducing sympathetis activity Peripheral activation: §peripheral presynaptic α2 rcp. ð ↓NA §Imidazolin receptors in kidney ð stimulation of Na+/H+ pump in proximal tubulus CENTRAL ANTIHYPERTENSIVES METHYLDOPA KLONIDIN MOXONIDIN RILMENIDIN vCentral α2 agonists CENTRAL ANTIHYPERTENSIVES METHYLDOPA MoA: §Activation of central α2 rcp. in brain stem and peripheral presynaptic α2 rcp. §indirect sympatholytic activity - false NRA precursor/ prodrug α –metyldopa → α –methylnorepinephrine → activation of α2 adrenergic receptors § CLONIDIN MoA: §Activation of central α2 rcp and imidazolin I2 receptors METHYLDOPA INDICATION: §Hypertension in pregnancy §Hypertension in patient with renal insufficiency § §Patients with anxiety §Without metabolic effect - in combination for patients with DM, HLP GF is not affected Disadvantages: Short half-life ð more time daily Sedation, nasal congestion, dry mouth, orthostatic hypotension ADVERSE EFFECT: Methyldopa combined with diuretics CLONIDIN INDICATION: Hypertensive crisis (ICU) – on request Essential hypertension - obsolent vCentral α2 agonists §rebound fenomen ADVERSE EFFECTS: vImidazoline I1 receptor agonists CENTRAL ANTIHYPERTENSIVES I1 receptor stimulation (medulla oblongata, kidney) §Inhibition of sympathetic stimulation of heart, veins and kidney §↓renin secretion §↓ vasopresin secretion MOXONIDIN, RILMENIDIN Mechanism of action: Selective agonists of I1 receptors ð minimal effect on α2 – rcp. ð §less AE Positive metabolic profile §Stimulation of Na excretion §↓ insulin resistence §↑glucose tolerance ADVERSE EFFECTS INDICATION: prevention of diabetic nephropathy CONTRAINDICATION: chronic heart failure I1 rcp agonists vCentral α2 –rcp agonists + peripheral α1 – rcp antagonists CENTRAL ANTIHYPERTENSIVES URAPIDIL MoA: Agonistic effect α2 a 5HT1A rcp. in CNS ð ↓peripheral resistence without reflex tachycardia §Significant antihypertensive effect §i.v. administration – rapid onset ↓ sympatic tonus vasodilatation Antagonistic effect α1 rcp. in vessels Dual action INDICATION: §Rezistant hypertension §Severe hypertension (stroke) §Emergent hypertension crisis (ICU) §Perioperative hypertension §Well titrated (i.v. infusion) §Rapid onset (maximal effect 2-5 minutes) AE: §Sedation (higher dosis) §Bradycardia CONTRAINDICATION: Pregnancy, lactation Liver insufficiency PERIPHERAL α1-receptor antagonists MoA Selective reversible antagonisation of peripheral α1 receptors – relaxation of vascular smooth muscle ð↓peripheral vascular resistence Slight increase of hert output TERAZOSIN DOXAZOSIN INDICATION §In combination – severe hypertension §Vasospasm (Raynaud fenomen) CONTRAINDICATION § heart failure ADVERSE EFFECTS §Ortostatic hypotension §Reflex tachycardia §Impotency §Oedema, cephalea, fatigue uroselective, blocks α1A TAMSULOSIN ALFUZOSIN INDICATION §BHP §Not used for hypertension COMBINATION OF DRUGS MONOTHERAPY - 30 % of the patients Combination - two or more drugs fixed combination ( 2 v 1) - better compliance HYPERTENSION IN GRAVIDITY HT: Systolic BP ≥ 140 mm Hg or diastolic BP ≥ 90 mm Hg If systolic BP ≥ 170 mm Hg or diastolic BP ≥ 110 mm Hg – emergent situation with hospitalisation ACEi and sartans are contraidicated ! Relative contraindication – thiazide diuretics §Pre-existing hypertension chronic medication, if not contraindicated §Gestational hypertension METHYLDOPA (1st line) Metoprolol, atenolol – third trimester Pre-eclampsia – diuretics not recommended Severe hypertension LABETALOL i.v. PHARMACOTHERAPY Thank you for your attention