Pharmacotherapy of hypertension

1. Pharmacotherapy of hypertension

2. Systemic hypertension • long-lasting, usually permanent increase of systolic and diastolic blood pressure primary (essential) hypertension – unknown cause; usually coincidence of more factors – neural, hormonal, kidney dysfunction, ... secondary (symptomatic) hypertension – symptom (sign) of other disease

3. only systolic hypertension • increased systolic blood pressure at normal or decreased diastolic BP pseudohypertension← rigid arteries in old age “white coat hypertension “– induced by stress at physical examination

4. Secondary hypertension

5. essential hypertension – 90 to 95 % of high blood pressure prevalence: • children...about 4 %, mostly secondary • middle age ... 11-21 % • 50-59 yearsold ... approximately 44 % • 60-69 yearsold ... approximately 54 % • more than 70 years old ... ≥ 64 % (Štandardné terapeutické postupy, 2nd edition)

6. Classification of hypertension 7th report of JNC 7 Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure

7. Classification of adult´s hypertension • Previous classification of hypertension (JNC 6, WHO)

8. Reasons for actualisation of classification JNC 6 (1997): • Completing of more new clinical studies with substantial consequences for the treatment of hypertension. • Need for less complicated classification of hypertension. • Need for new and clear guidelines suitable for physicians. • Previous reports didn´t bring expected benefits.

10. Classification of adult´s hypertension • New classification of hypertension according to JNC 7 Hypertenzia 3. štádia

11. Risk of cardiovascular diseases • relationship between BP and CVD (cardiovascular disease) risk is continual, consistent and not dependent on other risk factors • the higher BP, the higher risk of heart failure, stroke, renal diseases • each increase of systolic BP by 20 and diastolic BP by 10 mm Hg doubles the risk of CVD

15. Benefit of BP reduction In clinical studies was during antihypertensive therapy recorded: • 35-40% incidence reduction of stroke • 20-25% incidence reduction of myocardial infarction • more than 50% share at incidence reduction of heart failure • it is assumed that among patients at first stage of hypertension (140-159/90-99 mm Hg) and with other cardiovascular risk factors, permanent reduction of BP by 12 mm Hg during 10 years prevents one death from 11 treated patients (when CVS disease or organ affection it is one from 9)

16. Effectivity of BP reduction • despite the fact that decreasing of BP below140/90 mm Hg is successful among more and more patients, still their number (34%) is less than intention (50%), 30% still doesn´t know about their disease

17. Evaluation of patients All of these datas influence the prognsis and therapy selection. Evaluation of patients with diagnosed hypertension has importance to: evaluate the way of living + reveal other CVS risk factors and/or associated diseases

18. We gain information about patient from : • anamnesis • physical examination (BP measurement, eyeground examination, BMI calculation, listening to murmurs at large arteries, detailed examination of heart, lungs, stomach, searching for enlarged kidneys, palpation of glandula thyroidea, resistency and abnormal pulsation of aorta, palpation of lower extremities to search for oedemas and pulsations, neurologic examination) • laboratory examinations (ECG, urine, blood glucose, haematokrit, kallium, calcium, creatin in serum, lipid spectrum of serum)

19. Treatment • The final goal of antihypertensive therapy is reduction of mortality and morbidity to CVS and renal diseases. • Primary goal is reduction of systolic BP. We wamt to reach BP less than 140/90 mm Hg (Torr), or less than 130/80 mm Hg among diabetic patients and patients with kidney diseases • Needed is also increased detection!

20. Nonpharmacological treatment Change of life-style: • intake of salt ... ≤ 5 – 6 g per day • prevention of obesity – dietetic modification • alcohol ... ≤ 30 g per day • smoking – stop • physical activity • psychical relaxation

23. Pharmacologic treatment Antihypertensives 1st choice drugs: 1. diuretics 2. β-blockers 3. inhibitors of ACE (resp. blockers of AT1 receptors) 4. calcium channel blockers 2nd choice drugs – mainly to drug combinations: α1-sympatholytics; α2-sympathomimetics; direct vasodilators; kallium channel openers; agonists of I1 receptors in CNS; other mechanisms of action

24. Diuretics

25. Diuretics • increase urination 1. carboanhydrase inhibitors (acetazolamid) – not used in the treatment of hypertension 2. loop diuretics (furosemide, etacrynic acid, bumetanide) – strong short-lasting effect; ability to excrete to 25 % of Na+ from filtrate • block active reabsorption of Na+, Cl-, K+ from ascending limb of Henle´s loop • at treatment of hypertension is rarely used only furosemide in low dosage – if simultaneously is very much reduced G filtration; they aren´t suitable for long-lasting application

26. 3. thiazide diuretics (hydrochlorothiazide, chlorthalidone, clopamide) • block reabsorption of Na+ and Cl- from distal tubulus • effect is weaker as at loop diuretics – they excrete about 5 % from Na+ filtrate • most suitable diuretics for long–lasting treatment of hypertension • effect also in vessel wall (↓ volume of Na and ↓ reactivity to norepinephrine; regression of media hypertrophy) • the most is used hydrochlorothiazide – daily dose 12,5 – 25 mg

27. 4.K-sparing diuretics (spironolactone (aldosterone antagonist), amiloride, triamterene) • at hypertension only assistant drugs to combinations – to correct hypokalemia 5. other diuretics • osmotic (mannitol, sorbitol) • vodné • xantínové • diuretics are suitable mainly for older patients and at simultaneous chronic heart failure

28. Adrenergic receptor with agonist

29. β-blockers • preferenced are selective and hybrid substances before nonselective • don´t differ very much in antihypertensive effect, selection according to adverse effect profile • suitable for younger patients with ↑ sympaticoadrenal activity, hyperkinetic circulation, patients under psychical stress; patientswith existent ischaemic heart disease and mainly after myocardial infarction • in our country are mainly prescribed : metoprolol (Vasocardin) bisoprolol (Concor) karvedilol (Talliton) andaccording to tradition nonselective metipranolol (Trimepranol)

31. • β-blockers – possibilities of combinations: diuretics, Ca2+ blockers – only dihydropyridines!, α1- sympatholytics, ACEI, vazodilators • disadvantageous are metabolic adverse effects – worsening of lipidogram; tendencyto bronchoconstriction andto vasokonstriction at periphery – mainly at nonselectiveβB • they can´t be combined with verapamil a diltiazem! • treatment can´t be stopped abruptly – rebound effect!

32. Indication for self-medication of  β-blockers: stage fright

33. Calcium channel blockers • at treatment of hypertension are mostly used dihydropyridines; verapamil only at present tachycardia • prototype short-acting DHP nifedipine is contraindicated! - it reduces BP too rapidly, so induces reflex activation of sympathicus with subsequent increase of BP and such a repeated BP fluctuation causes worse vessel damage as untreated hypertension → instead of mortality decrease its increase! • pharmacocinetic explanation: effect fluctuates for fluctuation of level in blood – has low T/P (trough to peak ratio) • for antihypertensive to reduce mortality and morbidity, it has to reduce BP slowly and successively, without reflex activation of sympathicus → more steady level and higher T/P

34. → FDA approves as antihypertensives only drugs, that have T/P more than 50 % • this applies for the 2nd and 3rd generation of dihydropyridines – isradipine (Lomir), felodipine (Plendil), amlodipine (Agen, Norvasc),lacidipine (Lacipil) • Ca2+ blockers are suitable to treat hypertonic patients with DM, metabolic syndrome, at ischaemic disease of lowerextremities • particularly advantageous are for isolated systolic hypertension • possibilities of combinations: ACEI, βB (only dihydropyridines), diuretics

35. Renin-angiotensin-aldosterone system

36. Inhibitors of AC enzyme • block the change of angiotensin I to angiotensin II and at the same time inactivation of bradykinin • vazodilation in both resistant andcapacityvessels • accented indication: - hypertonic people with heart failure (vasodilating therapy of cardial insuficiency), also after myocardial infarction - hypertonic people with DM and different forms of diabetic nephropathy starting with mikroalbuminuria (nephroprotective effect of ACEI) • excessive initial fall in BP → postural hypotension or syncope; treatment should be started in bed from the lowest doses • reaction of airwaysis often strong and irritating cough → intollerance of the whole group → replacement to AT1 receptor blockers

37. • they are administered as “prodrug“, to effective substance are changed in liver • effect to reduce BP is in the whole group similar; they differ only in pharmacokinetic dependent from structure → division tohydrophilic (“blood“) andlipophilic (“tissue“) ACEI • hydrophilic act only inside vessels and in endothelium; lipophilic also on the outer side of vessels (on“adventicial“ angiotenzinconvertase) andin myocardial interstitium → probably more effectively at regression of left ventricule hypertrophy andvessel media • all ACEI – are contraindicated in gravidity!

38. •typical hydrophilic ACEI: captopril (prototype substance – has SH-group; Tensiomin) enalapril (Enap, Ednyt), lisinopril (Dapril, Diroton) • typical lipophilic ACEI: perindopril (Prestarium) trandolapril (Gopten) quinapril (Accupro) • traditionally the most prescribed in our country is enalapril (Enap) – must be administered 2 x per day

39. AT1 receptor blockers • the most often replacement of ACEI in case of cough • losartan (prototype; Cozaar), valsartan, kandesartan, irbesartan (Aprovel) α1-sympatholytics • beside BP reduction they reduce benign prostatic hyperplasia → indication mainly older man with simultaneous BPH • in combination at severe resistant hypertension • positivelyinfluence lipidogram • strong 1st dose phenomenon! → postural hypotension, syncopes • prazosin (prototype; Deprazolin), doxazosin (Cardura), terazosin

40. α2-sympathomimetics • central effect – stimulation of central α2 receptors,n through negativefeedback inhibit release of norepinephrine on periphery → reflex BP reduction • α-metyldopa (Dopegyt), clonidine • ADR: central depression – sleepiness, baddreams • clonidinehas significant rebound phenomenon • α-metyldopa isadvantageous during gravidity – doesn´t influence negatively blood circulation of fetus

41. Direct vazodilators hydralazines • specific mechanism of action is unknown; probably directly influence contractile system of vessel wall myocytes • ADR: tachycardia, palpitations, fluid retention → necessary combinations dihydralazine, hydralazine • suitable in pregnancy • hydralazine – genet. polymorphism of biotransformation → at slow acetylators can develop as syndrome similar to lupus erythematodes

42. Kallium channel openers • opening of K+ channels on the top of myocytes → hyperpolarisation → inductionof relaxation minoxidil • vazodilation in the areaof arterioles • retention of Na+, hirsutism, hypertrichosis → used in the treatment of alopecia • expensive diazoxide • only short-term use – at hypertensioncrisis • induces hyperglycaemia – at short-term use not matters

43. Central I1 receptor agonists • I1 – imidazoline receptors type 1 in medulla oblongata • stimulation → reflectory decrease of peripheral resistency • without serious hemodynamic, metabolic ADR; are metabolically neutral → promising to future moxonidin (Physiotens), rilmenidin (Tenaxum) Other antihypertensives • magnesium (MgSO4) – natural antagonist ofcalcium • sodium nitroprusside – simple molecule releasing NO; only i.v. at severe hypertensioncrisis, patient must lie, cyanide is formed; max. lenth of therapy 3 days • ketanserin – blocks S2 receptors for serotonin → prevents effect increase ofcatecholamineson symp. receptors

44. Direct renin inhibitors (PRI) • absolutely new group • in many tissues is present own renin system withindividual receptors → (pro)renin is bind to cell surfaces; system acts pressorically and proliferatively • it is activated when stimulation of AT1 receptors decreases → negative feedback • this signal way apparentlydecreases benefit of ACEI! → inhibition of the level of renin → ... bettercontrol of the whole RAAS → ... possible better prevention of organ damage

45. Aliskiren • first available peroral PRI • ↓ plasmatic renin activity • indication in 2-combination aliskiren + ACEI or aliskiren + ARB → dual inhibitionof RAAS system • product Enviage

46. Therapeutic algorithm of hypertension treatment (JNC 7)

47. Selection of pharmacotherapy • Results gained in clinical studies show that BP reduction with using following antihypertensives – inhibitors of angiotensin converting enzyme(ACEI), blockers of angiotensin receptors(ARB), betablockers (βB), calcium channel blockers(Ca2+B) and diuretics, can reduce complications of hypertension. • Base of medicament treatment of uncomplicated hypertension in the first stage should be according to JNC 7 thiazide diuretics alone, or in combination with other antihypertensives in the second stage of hypertension.

48. Advantages of thiazide diuretics • according to more studies thiazide diuretics are considerably the most effective • they increase antihypertensive effectivity of combined treatment • they proved to reach BP normalisation • are less expensive than other antihypertensives

49. Reaching BP improvement at specific patients • Among most patients is necessary combination of 2 and more antihypertensives. • Adminastration of other drug should start when monotherapy in required dose doesn´t reduce BP to intended value. • If the BP is by 20/10 mm Hg higher than intended value, therapy should be started with combination of 2 antihypertensives.

50. Other factors influencing selection of antihypertensives Potentially prosperous effects: • Tiazide diuretics slower the process of bone demineralisation at osteoporosis • βB can have positive influence at ventricular tachyarrhythmias and fibrilations, at migraine, short-termly at thyreotoxicosis, at essential tremor, perioperational hypertension • Ca2+B can be applied at Raynaud syndrome and some arrhythmias