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

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

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 %
(Standard guidelines, 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 adults
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 didnt bring expected
benefits.

Classification of adults
hypertension
New classification of hypertension according to
JNC 7

Hypertenzia 3. tdia

 in Europe partly remains classification of

hypertension to 3 stages

ESH a ESC (European Society of Hypertension /

E. S. of Cardiology) didnt adopt JNC 7
classification without comments

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 below 140/90 mm Hg is successful

among more and more patients, still their number (34%) is less than
intention (50%), 30% still doesnt know about their disease

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

- 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 doesnt 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

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

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. -blockers
3. inhibitors of ACE
4. blockers of AT1 receptors (ARB)
5. calcium channel blockers

2nd choice drugs mainly to drug combinations:

1-sympatholytics; 2-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 Henles loop
at treatment of hypertension is rarely used only
furosemide in low dosage if simultaneously is very
much reduced G filtration;
they arent 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 longlasting 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

Mechanism of Action of Thiazide Diuretics

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 of thiazide diuretics - hypokalemia, hypovolemia, hyperuricemia,

metabolic ADRs (impaired glucose tolerance and dyslipidemia - mostly
after high doses), erectile dysfunction

Adrenergic Receptor with Agonist

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

-blockers

preferenced are selective and hybrid substances before nonselective

dont 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, Egilok, Betaloc)
bisoprolol (Coronal, Bisogamma, Concor)
carvedilol (Dilatrend, Coryol, Talliton)
nebivolol (Nebilet)
and according to tradition nonselective metipranolol
(Trimepranol)

Main Effects of 1- a 2-blockade

 -blockers possibilities of combinations:

diuretics, Ca2+ blockers only dihydropyridines!, 1sympatholytics, ACEI, vazodilators

ADRs:
tendency to bronchoconstriction and to vasoconstriction
in the periphery mainly at non-selective B
metabolic ADR worsening of lipidogram; mask
symptoms of hypoglycemia and can impair glucose
tollerance more at non-selective B
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

! selectivity of action is only relative!

- at higher doses is dissapearing - even among 1selective agents appear 2-lytic effects

they cant be combined with verapamilom a diltiazem!

treatment cant be stopped abruptly rebound effect!

Indication for Self-medication with -blockers:

stage fright

Calcium Channel Blockers (CCB)

Classification:

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

Ca2+- channel L-type

Ca2+ Channel Blockers (CCB)

Different chemical structures, with different
haemodynamic and clinic effects
According to chemical structure divided to:
- dihydropyridins (amlodipine, felodipine, lacidipine,
nifedipine with slow release, isradipine)

- phenylalkylamins (verapamil)
- benzothiazepins (diltiazem)

Selectivity of CCB
Blood vessels
vasodilation of arterial
vasculature

Heart: decrease of
Heart
AV
rate
conduction

Strenght of
contraction

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

 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, B (only
dihydropyridines), diuretics
ADRs: headache, red face, perimalleolar edemas,
constipation, tachycardia (dihydrop.), severe bradycardia
(non-dihydropyridins), steal phenomen

 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)

Renin-angiotensin-aldosterone system

Pharmacologic Interference to AT Cascade

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

 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

typical hydrophilic ACEI:

captopril (prototype substance has SH-group; nowadays
only in hypertension crisis, Tensiomin)
enalapril (Enap, Ednyt),
lisinopril (Dapril, Diroton)
typical lipophilic ACEI:
perindopril (Vidotin, Stopress, Prestarium)
trandolapril (Actapril, Gopten)
quinapril (Quinpres, Accupro)

used

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

Main Benefits of ACE inhibition

AT1 receptor blockers

the most often replacement of ACEI in case of cough
losartan (prototype; Cozaar), valsartan, kandesartan,
irbesartan (Aprovel)
sometimes prescribed as 1st choice, even before ACEI
clinical studies indicate that they have among patients
with HT and DM 2 slightly better protective effects than
ACEI

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
moxonidine (Physiotens, Moxostad, Cynt), rilmenidine
(Rilmex, Tenaxum)

1-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
1-lytic only for the treatment of BPH, without vasodilating effects
tamsulosin

2-sympathomimetics
central effect stimulation of central 2 receptors
through negative feedback inhibit release of
norepinephrine on periphery reflex BP reduction
-metyldopa (Dopegyt), clonidine
ADR: central depression sleepiness, bad dreams
clonidine has significant rebound phenomenon
-metyldopa is advantageous during pregnancy
doesnt influence negatively blood circulation of
fetus

Direct vasodilators
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 hyperglycemia at short-term use not matters

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 aliskirn + ARB
dual inhibition of RAAS system
product Rasilez
? - clinical results below expectations

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 (B), 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 doesnt 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.

 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

Other factors influencing

selection of antihypertensives
Potentially prosperous effects:
Tiazide diuretics slower the process of bone
demineralisation at osteoporosis
B 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
B 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 doesnt prefer thiazide
diuretics so much, but recommends more or less equal
position of all 4 groups D, B, Ca2+B, ACEI