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. Isolated 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 „masked hypertension“ - false finding of normal blood pressure during the examination; opposite of white coat hypertension

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 % (Standard guidelines, 2nd edition)

6. According to: 2018 ESC/ESH Guidelines for the management of arterial hypertension

7. According to: 2018 ESC/ESH Guidelines for the management of arterial hypertension

8. 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

12. 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)

13. very important is the circadian rhythm of blood pressure! • physiological profound nocturnal decline, mostly around 4 a.m. ("dipping"), acts as a protection against pathological lesions of blood vessels, resp. reduces them • also hypertensive patients with significant nightime BP decrease have a more favorable prognosis ,as patients whose blood pressure at night compared to daytime values ​​doesn´t decrease (worse prognosis) • → according to it are patients diveded to „dippers“ versus „non-dippers“ • ≅ improvement of diagnosis ← broaderapplication of 24-hour blood pressure monitoring

14. Circadian rythm of BP (dippers vs. non-dippers)

15. Wegaininformationaboutpatientfrom • 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)

16. CVS Risk Factors • Hypertension • Dislipidemia • Diabetes Mellitus • Age • CVS anamnesis in family • Obesity • Smoking • Alcohol • Low physical activity All of these datas influence the prognosis 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

17. 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!

18. 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

21. Pharmacologic treatment Antihypertensives 1st choice drugs: 1. angiotensin-converting enzyme inhibitors (ACEI) angiotensin receptor blockers (ARB) 2. calcium channel blockers 3. diuretics 4. β-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

22. 4 major classes of antihypertensives A: ACEI,ARB B: beta-blockers C: CCB (Ca2+ channel blockers) D: diuretics

23. A1: ACEI (Angiotensin-converting enzyme inhibitors) • block the change of angiotensin I to angiotensin II and at the same time block inactivation of bradykinin in lungs • vazodilation in both resistant and capacitance vessels • Indication: • hypertonic people with heart failure • after myocardial infarction • hypertonic people with DM and different forms of diabetic • nephropathy starting with microalbuminuria (nephroprotective effect of ACEI)

24. Renin-angiotensin-aldosterone system

25. Main Benefits of ACE inhibition

26. A1: ACEI • block the change of angiotensin I to angiotensin II and at the same time block inactivation of bradykinin in lungs • they are administered as “prodrug“, to effective substance are changed in liver • vazodilation in both resistant and capacitance vessels • Indication: • hypertonic people with heart failure • after myocardial infarction • hypertonic people with DM and different forms of diabetic • nephropathy starting with microalbuminuria (nephroprotective effect of ACEI)

27. A1: ACEI • ADRs: impaired renal function, hyperkalemia, hypotension, dry cough, angioneurotic edema • excessive initial fall in BP → postural hypotension or syncope; treatment should be started in bed from the lowest doses • reaction of airways is often strong and irritating cough→ intollerance of the whole group → replacement to AT1 receptor blockers • Contraindications: pregnancy!, high concentration of potassium and creatinine, stenosis of a. renalis on both sides, severe aortal stenosis, angioneurotic edema in anamnesis

28. A1: ACEI - classification • division to hydrophilic (“blood“) and lipophilic (“tissue“) • hydrophilic act only inside vessels and in endothelium; lipophilic also on the outer side of vessels (on “adventicial“ angiotenzinconvertase) and in myocardial interstitium → probably more effectively at regression of left ventricule hypertrophy and vessel media • typical hydrophilic ACEI: • captopril (prototype substance – has SH-group; nowadays used only in hypertension crisis, Tensiomin) • enalapril (Enap, Ednyt) • lisinopril (Dapril, Diroton) • typical lipophilic ACEI: • perindopril (Vidotin, Stopress, Prestarium) • trandolapril (Actapril, Gopten) • quinapril (Quinpres, Accupro)

29. A2: ARB(Angiotensin receptor blockers) • the most often replacement of ACEI in case of cough • losartan • valsartan • candesartan • irbesartan

30. Pharmacologic Interference to AT Cascade

31. C: CCB (Calcium Channel Blockers) - mechanism of action • Block influx of calcium to cell through slow L-type channels, lower its intracellular concentration what causes relaxation of smooth muscle in vessel wall, decrease of contractility, decrease of electrical irritability and conductivity

32. C: CCB - classification • DIHYDROPYRIDINES (amlodipine, felodipine, lacidipine, nifedipine, isradipine) • NON-DIHYDROPYRIDINES • phenylalkylamins(verapamil) • benzothiazepins(diltiazem)

33. C : CCB - classification

34. C: CCB – selectivity:arteries vs. conduction system of the heart

35. C: CCB • Ca2+ blockers are suitable to treat hypertonic patients • with DM, metabolic syndrome, at ischaemic disease of lower extremities • particularly advantageous are for isolated systolic hypertension • nimodipine (1st generation) affinity to brain vasculature → ... effectively relieves spasms of cerebral arteries→ used at subarachnoid bleeding • possibilities of combinations: • ACEI, BB (onlydihydropyridines), diuretics • ADRs • headache, flushing, perimalleolar edemas, constipation

36. C: CCB – T/P ratio (trough to peak ratio) → FDA approves as antihypertensives only drugs, that have T/P more than 50 % 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

37. C: CCB – T/P ratio • this applies for the 2nd generation of dihydropyridines(isradipine, felodipine, nitrendipine) and 3rd generation of dihydropyridines(amlodipine, lacidipine, lercanidipine)withlongereliminationhalf-lifes • prototype nifedipineis usedonly in prolonged-releasedosageforms • short-acting nifedipine (1st generation DHP) reduced BP too rapidly, so induced reflex activation ofsympaticus with subsequent increase of BP and such a repeated BP fluctuation causes worse vessel damage asuntreated hypertension → instead of mortality decrease its increase!

38. D: Diuretics - classification • Thiazideand thiaziderelateddiuretics(effect is weaker as at loop diuretics – they excrete about 5 % from Na+ filtrate; most suitablediureticsforlong–lastingtreatment of hypertension) • Loopdiuretics(strong short-lasting effect; ability to excrete to 25 % of Na+ from filtrate) • Potassium-sparingdiuretics • Osmoticdiuretics (glycerol, mannitol) • Carbonicanhydraseinhibitors (acetazolamid, dorzolamid) • Antidiuretichormoneantagonists/Vaptans (conivaptan)

39. Diuretics

40. D: thiazide and related diuretics • thiazide: hydrochlorothiazide • thiazide related diuretics (have different chemical structure, bud similar effects as thiazide): chlortalidone, indapamide, metolazone • DISTAL CONVOLUTED TUBULE

41. D: thiazide and related diuretics • mechanism of action: diuretic, natriuretic, vazodilation (exact mechanism of vazodilation not known) • in distal tubule inhibit Na+/Cl- co-transporter

42. Diuretics

43. Mechanism of Action of Thiazide Diuretics

44. D: thiazide and related diuretics • ADRs: occasionally hypokalaemia, increased levels of glucose, lipids and uric acid • Indications: hypertension, oedemas (heart failure, cirrhosis, nephrotic syndrome), nephrolithiasis (at hypercalciuria), nephrogenic diabetes insipisus

45. D: loop diuretics • sulfonamidederivatives: furosemide, torasemide, bumetanide • etacrylic acid

46. D: loop diuretics • mechanism of action: strong diuretic and natriuretic effect • IN THICK ASCENDING LIMB OF HENLE inhibit Na+/K+/2Cl- co-transporter

47. Diuretics

48. D: loop diuretics • ADRs: hypokalaemia, hypomagnesaemia a metabolická alkalóza, increased levels of glucose, lipids and uric acid, rarely ototoxicity • Indications: if needed intensive diuresis, at hypertension preferred thiazide diuretics

49. D: potassium-sparing diuretics • direct inhibitors of Na+/K+ pump: amiloride, triamterene • aldosterone antagonists: spironolactone, eplerenone (block aldosterone receptor) • COLLECTING DUCTS

50. Diuretics