Pharmacotherapy of hypertension

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Pharmacotherapy of hypertension
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• 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

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• 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

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Secondary hypertension
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• 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
• (tandardné terapeutické
  postupy, 2nd edition)

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Classification of hypertension
JNC 7

• 7th report of

Joint National Committee on Prevention,
Detection, Evaluation,
and Treatment of High Blood Pressure
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Classification of adults hypertension

• Previous classification of hypertension (JNC 6,
  WHO)

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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.

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Classification of adults hypertension

• New classification of hypertension according to
  JNC 7

Hypertenzia 3. tádia
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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

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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)

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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 doesnt know
  about their disease

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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

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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)

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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!

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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

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Pharmacologic treatment

• Antihypertensives
• 1st choice drugs
• 1. diuretics
• 2. ß-blockers
• 3. inhibitors of ACE (resp. blockers of
  AT1 receptors)
• 4. calcium channel blockers
• 2nd choice drugs mainly to drug combinations
• a1-sympatholytics a2-sympathomimetics
  direct
• vasodilators kallium channel openers
• agonists of I1 receptors in CNS other
  mechanisms of action

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Diuretics
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• 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

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• 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)
• the most is used hydrochlorothiazide
  daily dose
• 12,5 25 mg

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• 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

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Adrenergic receptor with agonist
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• ß-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 ?
  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)

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• ß-blockers possibilities of combinations
• diuretics, Ca2 blockers only
  dihydropyridines!, a1-
• sympatholytics, ACEI, vazodilators
• disadvantageous are metabolic adverse
  effects
• worsening of lipidogram
• tendency to bronchoconstriction and to
  vasokonstriction
• at periphery mainly at nonselective ßB
• they cant be combined with verapamilom a
  diltiazem!
• treatment cant be stopped abruptly
  rebound effect!

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Indication for self-medication pre ? ß-blokátormi
stage fright
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• 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

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• ? 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, ßB (only
  dihydropyridines), diuretics

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Renin-angiotensin-aldosterone system
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• 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

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• 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!

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• 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

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• AT1 receptor blockers
• the most often replacement of ACEI in case of
  cough
• losartan (prototype Cozaar), valsartan,
  kandesartan,
• irbesartan (Aprovel)
• a1-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

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• a2-sympathomimetics
• central effect stimulation of central a2
  receptors
• through negative feedback inhibit release of
  
• norepinephrine on periphery ? reflex BP
  reduction
• a-metyldopa (Dopegyt), clonidine
• ADR central depression sleepiness, bad
  dreams
• clonidine has significant rebound phenomenon
• a-metyldopa is advantageous during gravidity
  
• doesnt influence negatively blood
  circulation of
• fetus

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• 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

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• 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

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• 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

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• 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

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• Aliskiren
• first available peroral PRI
• ? plasmatic renin activity
• indication in 2-combination aliskiren ACEI
  or aliskirén ARB
• ? dual inhibition of RAAS system
• product Enviage

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Therapeutic algorithm of hypertension treatment
(JNC 7)
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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 (ßB), calcium
  channel blockers(Ca2B) 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.

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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

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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.

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Other factors influencing selection of
antihypertensives

• Potentially prosperous effects
• Tiazide diuretics slower the process of bone
  demineralisation at osteoporosis
• ßB can have positive influence at ventricular
  tachyarrhythmias and fibrilations, at migraine,
  short-termly at thyreotoxicosis, at essential
  tremor, perioperational hypertension
• Ca2B can be applied at Raynaud syndrome and some
  arrhythmias

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Other factors influencing selection of
antihypertensives

• Potentially negative effects
• tiazide diuretics at patients with gout
  and hyponatremia in anamnesis
• ßB 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

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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, ßB,
Ca2B, ACEI