Transcript 1st_tutorial_-_hypertension

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 8
8th report of
Joint National Committee on Prevention, Detection,
Evaluation, and Treatment of High Blood Pressure
ESH Classification of Hypertension
in Europe partly remains classification of hypertension to 3 stages
ESH/ESC BP Goals
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:
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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 (140159/90-99 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)
- 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 „nondippers“
- ≅ 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)
CVS Risk Factors
 Hypertension
 Dislipidemia
 Diabetes Mellitus
 Age
 CVS anamnesis in family
 Obesity
 Smoking
 Alcohol
 Low physical activity
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
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
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"
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 β1-selective agents
appear β2-lytic effects
• they can´t be combined with verapamil 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
in hypertension crisis, Tensiomin)
enalapril (Enap, Ednyt),
lisinopril (Dapril, Diroton)
• typical lipophilic ACEI:
perindopril (Vidotin, Stopress, Prestarium)
trandolapril (Actapril, Gopten)
quinapril (Quinpres, Accupro)
used only
• 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
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