Pharmacotherapy of

hypertension
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
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
Secondary hypertension
essential hypertension – 90 to 95 % of high
blood pressure

prevalence:
• children...about 4 %, mostly secondary
• middle age ... 11-21 %
• 50-59 years old ... approximately 44 %
• 60-69 years old ... approximately 54 %
• more than 70 years old ... ≥ 64 %

(Štandardné terapeutické postupy, 2nd edition)

Classification of hypertension

JNC 7
7th report of

Joint National Committee on Prevention, Detection,

Evaluation, and Treatment of High Blood
Pressure
 Classification of adult´s
hypertension
• Previous classification of hypertension (JNC 6, WHO)
 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.
 Classification of adult´s
hypertension
• New classification of hypertension according
to JNC 7

Hypertenzia 3. štádia
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
 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)
 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
 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
 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)
 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!
 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
 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
Diuretics
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
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
 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
Adrenergic receptor with agonist
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; 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)
• β-blockers – possibilities of combinations:
diuretics, Ca2+ blockers – only dihydropyridines!, α1-
sympatholytics, ACEI, vazodilators

• disadvantageous are metabolic adverse effects –

worsening of lipidogram;
tendency to bronchoconstriction and to vasokonstriction
at periphery – mainly at nonselective βB

• they can´t be combined with verapamilom a diltiazem!

• treatment can´t be stopped abruptly – rebound effect!

Indication for self-medication pre  β-blokátormi:

stage fright
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!
• pharmacocinetic explanation: effect fluctuates for fluctuation
of level in blood – has low T/P (time 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
→ 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 lower
extremities
• particularly advantageous are for isolated systolic
hypertension
• possibilities of combinations: ACEI, βB (only
dihydropyridines), diuretics
Renin-angiotensin-aldosterone system
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 and capacity 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
 • 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
• all ACEI – are contraindicated in gravidity!
• 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
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
• positively influence lipidogram
• strong 1st dose phenomenon! → postural hypotension,
syncopes
• prazosin (prototype; Deprazolin), doxazosin (Cardura),
terazosin
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 gravidity –
doesn´t influence negatively blood circulation of
fetus
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
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 hyperglycaemia – at short-term use not matters
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 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
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
Aliskiren

• first available peroral PRI

• ↓ plasmatic renin activity

• indication in 2-combination aliskiren + ACEI or aliskirén +

ARB
→ dual inhibition of RAAS system

• product Enviage
Therapeutic algorithm of hypertension treatment
(JNC 7)
 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) a 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.
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
 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.
 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
 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
 different views (conflict ):

JNC

versus

European Society of Hypertension (ESH)

ESH – as the drug of 1st choice doesn´t prefer thiazide

diuretics so much, but recommends more or less equal
position of all 4 groups – D, βB, Ca2+B, ACEI