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. 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. in Europe partly remains classification of hypertension to 3 stages • ESH a ESC (European Society of Hypertension / E. S. of Cardiology) didn´t adopt JNC 7 classification without comments

12. 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

16. 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)

17. Effectivity of BP reduction • despite the fact that decreasing of BP below 140/90 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

18. Evaluation of patients 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

19. 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

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

21. 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)

22. 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!

23. 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

26. Pharmacologic treatment Antihypertensives 1st choice drugs: 1. diuretics 2. β-blockers 3. inhibitors of ACE 4. blockers of AT1 receptors (ARB) 5. 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

27. Diuretics

28. 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

29. 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) → this effect is characteristic for indapamid and metipamid (increase of diuresis is negligible) → also called „diuretics without diuretic effect“  • the most is used hydrochlorothiazide – daily dose 12,5 – 25 mg

30. Mechanism of Action of Thiazide Diuretics

31. 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) • xanthine • diuretics are suitable mainly for older patients and at simultaneous chronic heart failure • ADRsof thiazide diuretics - hypokalemia, hypovolemia, hyperuricemia, metabolic ADRs (impaired glucose tolerance and dyslipidemia - mostly after high doses), erectile dysfunction

32. Adrenergic Receptor with Agonist

33. β-blockers Classifications: 1. non-selective (β1- aj β2-effect – propranolol, metipranolol, ...); selective (β1-effect – metoprolol, bisoprolol, atenolol, ...); hybrid substances (beside β-effect have also other effects, additional, resp. β2-mimetic effect), through which they induce vazodilation – labetalol, carvedilol, nebivolol, ...) – the most important classification 2. β-blockers with ISA (intrinsic sympathomimetic activity – pindolol, acebutolol, ...; ≈ parcial agonists) and without ISA 3. hydrophilic (atenolol, celiprolol, ...) and lipophilicβ-blockers (propranolol, metoprolol, carvedilol, ...) 4. classification according to generations ....... and other different classifications....

34. 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 ↑ sympathicoadrenal 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, Egilok, Betaloc) bisoprolol (Coronal, Bisogamma, Concor) carvedilol (Dilatrend, Coryol, Talliton) nebivolol (Nebilet) andaccording to tradition nonselective metipranolol (Trimepranol)

35. Main Effects of β1- a β2-blockade

37. • β-blockers – possibilities of combinations: diuretics, Ca2+ blockers – only dihydropyridines!, α1- sympatholytics, ACEI, vazodilators • ADRs: • tendency to bronchoconstriction and to vasoconstriction in the periphery – mainly at non-selective βB • metabolic ADR – worsening of lipidogram; mask symptoms of hypoglycemia and can impair glucose tollerance – more at non-selective βB • sleep disturbances, bad dreams → ... depression • at very high doses can worsen heart failure; if indicated at chronic heart failure, dose should be increased step by step • erectile dysfunction

38. ! selectivity of action is only relative!- at higher doses is dissapearing - even among β1-selective agents appear β2-lytic effects • they can´t be combined with verapamilom a diltiazem! • treatment can´t be stopped abruptly – rebound effect!

39. Indication for Self-medication with  β-blockers: stage fright

40. Calcium Channel Blockers (CCB) Classification:

41. CCB – Mechanism of Action Blockinfluxofcalcium to cellthroughslowL-typechannels, loweritsintracellularconcentrationwhatcausesrelaxationofsmoothmuscle in vesselwall, decreaseofcontractility, decreaseofelectricalirritability and conductivity

42. Ca2+- channel – L-type

43. Ca2+ Channel Blockers (CCB) • Differentchemicalstructures, withdifferenthaemodynamic and cliniceffects • According to chemicalstructuredividedto: - dihydropyridins(amlodipine, felodipine, lacidipine, nifedipinewithslowrelease, isradipine) - phenylalkylamins(verapamil) - benzothiazepins(diltiazem)

44. Selectivity of CCB Blood vessels vasodilation of arterial vasculature Heart: decreaseof Heart rate AV conduction Strenght of contraction

45. 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 sympaticus with subsequent increase of BP and such a repeated BP fluctuation causes worse vessel damage as untreated hypertension → instead of mortality decrease its increase! • pharmacokinetic 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

46. → FDA approves as antihypertensives only drugs, that have T/P more than 50 % • this applies for the 2nd generation of dihydropyridines (isradipine, felodipine, nitrendipine) and 3rd generation of dihydropyridines (amlodipine,lacidipine, lercanidipine). • 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 • ADRs: headache, red face, perimalleolar edemas, constipation, tachycardia (dihydrop.), severe bradycardia (non-dihydropyridins), steal phenomen

47. •nimodipine (1st generation) affinity to brain vasculature → ... effectively relieves spasms of cerebral arteries → used at subarachnoid bleeding • lercanidipine has high T/P ratio • in our country for the treatment of hypertension are prescribed mainly following dihydropyridines: 2nd generation: felodipine (Presid, Plendil), isradipine (Lomir), nitrendipine (Nitresan, Lusopress) 3rd generation: amlodipine (Amlopin, Agen, Tenox, Norvasc), lacidipine (Lacipil), lercanidipine (Lercal)

48. Renin-angiotensin-aldosterone system

49. Pharmacologic Interference to AT Cascade