1. Pharmacotherapy of hypertension

2. hormonal, kidney dysfunction, ...
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 %
• years old ... approximately 44 %
• years old ... approximately 54 %
• more than 70 years old ... ≥ 64 %
(Standard guidelines, 2nd edition)

6. Classification of hypertension
JNC 7
7th report of
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 ( /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 ← broader application 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
thiazide-like diuretics: effect also in vessel wall (↓ volume of Na and ↓
reactivity to norepinephrine; regression of media hypertrophy) !!
this effect is characteristic for indapamide and metipamide   (at administration increase of diuresis is negligible) →    also called "diuretics without diuretic effect"

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
ADRs - 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 lipophilic β-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; patients with existent ischaemic heart disease and mainly after myocardial infarction
• in our country are mainly prescribed :
metoprolol (Vasocardin) bisoprolol (Concor)
karvedilol (Talliton)
and according 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
! 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 verapamil 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. Ca2+ Channel Blockers (CCB)
Different chemical structures, with different haemodynamic and clinic effects
According to chemical structure divided to:
- dihydropyridins (amlodipine, felodipine, lacidipine, nifedipine, isradipine)
- phenylalkylamins (verapamil, gallopamil)
- benzothiazepins (diltiazem)

42. CCB – 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

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

44. 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

45. → 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 lower extremities
• 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

46. • nimodipine (1st generation) affinity to brain vasculature →
• 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)

47. Renin-angiotensin-aldosterone system

48. Pharmacologic Interference to AT Cascade

50. Inhibitors of AC enzyme
• block the change of angiotensin I to angiotensin II and at the same time block inactivation of bradykinin
• vazodilation in both resistant and capacitance vessels
• 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 airways is often strong and irritating cough
→ intollerance of the whole group → replacement to AT1 receptor blockers

51. • 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 to hydrophilic (“blood“) and lipophilic (“tissue“)
ACEI
• 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

52. enalapril (Enap, Ednyt), lisinopril (Dapril, Diroton)
• 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)
• ADRs:
impaired renal function, hyperkalemia, hypotension, dry cough, angioneurotic edema
• contraindications: pregnancy!, high concentration of potassium and creatinine, stenosis of a. renalis on both sides, severe aortal stenosis, angioneurotic edema in anamnesis

53. Main Benefits of ACE inhibition

54. AT1 receptor blockers α1-sympatholytics
• 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
• positively influence lipidogram
• strong 1st dose phenomenon! → postural hypotension, syncopes
• prazosin (prototype; Deprazolin), doxazosin (Cardura),
terazosin

55. α2-sympathomimetics
• central effect – stimulation of central α2 receptors
through negative feedback inhibit release of
norepinephrine on periphery → reflex BP reduction
• α-metyldopa (Dopegyt), clonidine
• ADR: central depression – sleepiness, bad dreams
• clonidine has significant rebound phenomenon
• α-metyldopa is advantageous during pregnancy –
doesn´t influence negatively blood circulation of
fetus

56. 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

57. Kallium channel openers
• opening of K+ channels on the top of myocytes → hyperpolarisation → induction of relaxation
minoxidil
• vazodilation in the area of arterioles
• retention of Na+, hirsutism, hypertrichosis → used in the treatment of alopecia
• expensive
diazoxide
• only short-term use – at hypertension crisis
• induces hyperglycemia – at short-term use not matters

58. 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, Moxostad, Cynt), rilmenidin (Rilmex, Tenaxum)
Other antihypertensives
• magnesium (MgSO4) – natural antagonist of calcium
• sodium nitroprusside – simple molecule releasing NO;
only i.v. at severe hypertension crisis, patient must lie,
cyanide is formed; max. lenth of therapy 3 days
• ketanserin – blocks S2 receptors for serotonin → prevents effect increase of catecholamines on symp. receptors

59. Direct renin inhibitors (PRI) • absolutely new group
• in many tissues is present own renin system
with individual 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 apparently decreases benefit of ACEI!
→ inhibition of the level of renin → ... better control
of the whole RAAS → ... possible better prevention
of organ damage

60. • indication in 2-combination aliskiren + ACEI or aliskirén + ARB
• first available peroral PRI
• ↓ plasmatic renin activity
• indication in 2-combination aliskiren + ACEI or aliskirén + ARB
→ dual inhibition of RAAS system
• product Rasilez
? - clinical results below expectations

61. 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.

62. recently is a growing trend to use combination of 2 antihypertensive drugs already in stage I hypertension
convincing evidence from relevant clinical trials →
combinations perindopril-amlodipine
perindopril-indapamide

64. 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

65. Other factors influencing selection of antihypertensives
Potentially negative effects:
tiazide diuretics at patients with gout and hyponatremia in anamnesis
βB at patients with asthma, allergic diseases of airways and with A-V blocks of 2nd and 3rd stage
ACEI and ARB should not be given at probability of getting pregnant, are contraindicated in pregnancy, ACEI at angioneurotic oedema
aldosterone antagonists and K-sparing diuretics can cause hyperkalemia