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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• 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

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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
• (Standard guidelines, 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. štádia
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• 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

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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 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

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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

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• 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

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Circadian rythm of BP (dippers vs. non-dippers)
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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
• 4. blockers of AT1 receptors (ARB)
• 5. 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)
• ? 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

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Mechanism of Action of Thiazide Diuretics
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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)
• 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

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Adrenergic Receptor with Agonist
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ß-blockers

• Classifications
• 1. non-selective (ß1- aj ß2-effect
  propranolol, metipranolol, ...)
• selective (ß1-effect metoprolol,
  bisoprolol, atenolol, ...)
• hybrid substances (beside ß-effect have also
  other effects, additional, resp. ß2-mimetic
  effect), through which they induce vazodilation
  labetalol, carvedilol, nebivolol, ...)
• the most important classification
• 2. ß-blockers with ISA (intrinsic
  sympathomimetic activity pindolol, acebutolol,
  ... parcial agonists) and without ISA
• 3. hydrophilic (atenolol, celiprolol, ...) and
  lipophilic ß-blockers
• (propranolol, metoprolol, carvedilol, ...)
• 4. classification according to generations
• ....... and other different
  classifications....

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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 ?
  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)

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Main Effects of ß1- a ß2-blockade
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• ß-blockers possibilities of combinations
• diuretics, Ca2 blockers only
  dihydropyridines!, a1-
• sympatholytics, ACEI, vazodilators
• ADRs
• tendency to bronchoconstriction and to
  vasoconstriction in the periphery mainly at
  non-selective ßB
• metabolic ADR worsening of lipidogram
  mask symptoms of hypoglycemia and can impair
  glucose tollerance more at non-selective ßB
• 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

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• ! selectivity of action is only relative!- at
  higher doses is dissapearing - even among
  ß1-selective agents appear ß2-lytic effects
• they cant be combined with verapamilom a
  diltiazem!
• treatment cant be stopped abruptly rebound
  effect!

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Indication for Self-medication with ? ß-blockers
stage fright
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Calcium Channel Blockers (CCB)
Classification
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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

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Ca2- channel L-type
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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)

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Selectivity of CCB
Blood vessels vasodilation of arterial vasculature
Heart decrease of
Heart rate
AV conduction
Strenght of contraction
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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!
• 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

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

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• 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)

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Renin-angiotensin-aldosterone system
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Pharmacologic Interference to AT Cascade
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• 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

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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

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• 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

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Main Benefits of ACE inhibition
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• 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

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

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• 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
• a1-lytic only for the treatment of BPH, without
  vasodilating effects ? tamsulosin

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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 pregnancy
  
• doesnt influence negatively blood
  circulation of
• fetus

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• 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

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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 hyperglycemia at short-term use
  not matters

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• 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 Rasilez
• ? - clinical results below expectations

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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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• 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-indapami
  de

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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