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 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
• 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
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 doesn´t 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 ​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
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. 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
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
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 - hypokalemia, hypovolemia, hyperuricemia,
metabolic ADRs (impaired glucose tolerance and
dyslipidemia - mostly after high doses), erectile dysfunction
Adrenergic Receptor with Agonist
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....
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)
Main Effects of β1- a β2-blockade
• β-blockers – possibilities of combinations:
diuretics, Ca2+ blockers – only dihydropyridines!, α1sympatholytics, 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
! selectivity of action is only relative!
- at higher doses is dissapearing - even among β1selective agents appear β2-lytic effects
• they can´t be combined with verapamilom a diltiazem!
• treatment can´t be stopped abruptly – rebound effect!
Indication for Self-medication with  β-blockers:
stage fright
Calcium Channel Blockers (CCB)
Classification:
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)
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
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, βB (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
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
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)
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 pregnancy –
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 hyperglycemia – 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, 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
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 Rasilez
? - clinical results below expectations
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.
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.
• 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
• 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