„„Hypertension”Hypertension”
Prof. Dr. János BorvendégProf. Dr. János BorvendégCHMP memberCHMP member
HungaryHungary
Definitions and Classification of Blood Definitions and Classification of Blood Pressure levels (mmHg)Pressure levels (mmHg)
CategoryCategory Systolic Systolic DiastolicDiastolic
OptimalOptimal 120 120 80 80
NormalNormal 120-129 120-129 80-84 80-84
High normal High normal 130-139 130-139 85-89 85-89
Grade 1 Hypertension 140-159Grade 1 Hypertension 140-159 90-99 90-99
-”- 2 -”- 160-179 100-109-”- 2 -”- 160-179 100-109
-”- 3 -”- -”- 3 -”- 180 180 110 110
Isolated SystolicIsolated Systolic
HypertensionHypertension 140 140 90 90
The significance of hypertensionThe significance of hypertension
The number of patients with The number of patients with hypertension is growing(!)hypertension is growing(!)1988-19911988-1991 43,2 mill/US43,2 mill/US1999-20001999-2000 60,0 mill/US60,0 mill/US
- the population ages - the population ages - obesity - obesity
- diabetes - diabetes HyHyppertension is the most common risk ertension is the most common risk
factor for heart attack and strokefactor for heart attack and stroke
The significance of hypertension: The significance of hypertension: (cont.)(cont.)
Only ≈ 34 % of patients with Only ≈ 34 % of patients with hypertension have their blood pressure hypertension have their blood pressure controlled.controlled.- the HBP remains asymptomatic for - the HBP remains asymptomatic for long long period of time period of time- lack of adherence with the therapy- lack of adherence with the therapy- side effects of the antihypertensive- side effects of the antihypertensive- poor access to medications- poor access to medications
Factors influencing the prognosisFactors influencing the prognosis
Risk Factors:Risk Factors:
S/D BP levels S/D BP levels 180/ 180/ 110 mmHg110 mmHg
Diabetes mellitusDiabetes mellitus
Age (M Age (M 55 y. F 55 y. F 66 y) 66 y)
DyslipidemiaDyslipidemia
Abdominal obesityAbdominal obesity
Metabolic syndromeMetabolic syndrome
SmokingSmoking
Snoring / sleep apnoeaSnoring / sleep apnoea
Obesity:Obesity: Body weightBody weight
Increased waist circumferenceIncreased waist circumference
M : M : 102 cm W: 102 cm W: 88 cm88 cm
Increased body mass indexIncreased body mass index
body weight (kg) / heightbody weight (kg) / height22(m)(m)
overweight overweight 25 kg/m 25 kg/m22
obesity obesity 30 kg/m 30 kg/m22
Complications:Complications:
heart failureheart failure Left ventricular hypertrophyLeft ventricular hypertrophy MIMI sudden cardiac deathsudden cardiac death strokestroke intracerebral haemorrhageintracerebral haemorrhage chronic renal insufficiency hypertensive chronic renal insufficiency hypertensive
nephrosclerosisnephrosclerosis retinopathyretinopathy
Laboratory InvestigationsLaboratory Investigations::
fasting plasma glucose/tolerance testfasting plasma glucose/tolerance test
se total cholesterolse total cholesterol
se LDLse LDL
se HDLse HDL
fasting se triglyceridesfasting se triglycerides
se uric acidse uric acid
se creatininese creatinine
creatinin clearancecreatinin clearance
Hgb/HtcHgb/Htc
urine analysis (quantitative microalbiminuria)urine analysis (quantitative microalbiminuria)
se electrolytesse electrolytes
Determinants of arterial pressureDeterminants of arterial pressure
Stroke volumenStroke volumen
CardiacCardiac
outputoutput
Heart rateHeart rate
Arterial pressureArterial pressure
Vascular structureVascular structure
Perip.Perip.
resistanceresistance Vascular Vascular
functionfunction
Essential (primary hypertension)Essential (primary hypertension)
Pathogenesis:Pathogenesis: increased sympathetic neural activity, increased sympathetic neural activity,
with enhanced beta-adrenergic activitywith enhanced beta-adrenergic activity increased Angiotensin II. activity and increased Angiotensin II. activity and
mineral corticoid excessmineral corticoid excess genetic factors (≈ 30 %)genetic factors (≈ 30 %) reduced nephron massreduced nephron mass
(genetic factors?(genetic factors? intra uterine developmental intra uterine developmental disturbances) disturbances)
Search for secondary hypertensionSearch for secondary hypertension
Measurement of:Measurement of:
reninrenin
aldosterone, corticosteroidsaldosterone, corticosteroids
catecholaminescatecholamines
arteriographiesarteriographies
renal / adrenal ultra soundrenal / adrenal ultra sound
CTCT
MRIMRI
Goals of Treatment:Goals of Treatment:
Primary goal: to achieve maximum reduction Primary goal: to achieve maximum reduction
in the long-term total risk of cardiovascular in the long-term total risk of cardiovascular
diseasedisease
BP should be reduced:BP should be reduced:
140/90 mmHg (in all hypertensive patients) 140/90 mmHg (in all hypertensive patients)
130/80 mmHg (in diabetics and 130/80 mmHg (in diabetics and
in high risk patients) in high risk patients)
Antihypertensive th. Antihypertensive th. should should be initiated be initiated
before significant CV damage developsbefore significant CV damage develops
Antihypertensive agentsAntihypertensive agents
Mechanism of Action of Antihypertensive AgentsMechanism of Action of Antihypertensive Agents Diuretics:Diuretics: (?) (?) NaNa++ excretion excretion Plasma volume Plasma volume Smooth muscle NaSmooth muscle Na++ conc. conc.
Outcome: Outcome: perif. resist. perif. resist. -blockers-blockers:: 11//22 blocking blocking 11 blockingblocking MSAMSA (Membrane Stabilisig Activity) (Membrane Stabilisig Activity) ISAISA (Intrinsic Sympathetic Activity) (Intrinsic Sympathetic Activity)
Outcome: Outcome: heart rateheart rate cardiac outputcardiac output plasma RAplasma RA resetting of barresetting of baroo receptors receptors
Mechanism of Action of Antihypertensive Agents Mechanism of Action of Antihypertensive Agents (cont.)(cont.)
Alfa antagonistsAlfa antagonists Selective post synapticSelective post synapticicic
11 blockade blockade
Outcome: Outcome: peripperipherial herial resist. resist. preload preload
Ca channel antagonistsCa channel antagonists:: Blockade of Blockade of
voltage sensitive Ca channelsvoltage sensitive Ca channels Outcome: Outcome: peripperipherialherial. resist. resist
(relax the arterial smooth (relax the arterial smooth muscle)muscle)
DiureticsDiuretics ddaily doseaily dose oother ther indicationindication
thiazidesthiazides HCTZHCTZchlortalidonchlortalidonee
6,25-50 mg6,25-50 mg CHFCHF
loop diureticsloop diuretics FurosemideFurosemide
Ethacrynic Ethacrynic acidacid
40-80 mg40-80 mg
50-100 mg50-100 mg
CHF CHF renal failurerenal failure
aldosteron aldosteron antagonistsantagonists
sspipirono-rono-lactonelactone
25-100 mg25-100 mg CHFCHFhyper aldost.hyper aldost.
K+ retainingK+ retaining AmiloridAmilorid
triamterentriamteren
5-10 mg5-10 mg
50-100 mg50-100 mg
Beta blockersBeta blockers daily dosedaily dose other indicationother indication
Non-selectiveNon-selective::PropranololPropranololPindololPindololSotalol Sotalol
40-160 mg40-160 mg
Angina ,Angina ,tachyarrhythmiatachyarrhythmia
CardioselectiveCardioselectiveAtenololAtenololMetoprololMetoprololEsmololEsmololBisoprolol Bisoprolol BetaxololBetaxolol
25-100 mg25-100 mg25-100 mg25-100 mg
Angina,Angina,CHFCHFtachyarrhythmiatachyarrhythmia
Combined Combined //LabetololLabetololCarvedilolCarvedilolCeliprololCeliprololBucindololBucindolol
200-800 mg200-800 mg12,5-50 mg12,5-50 mg
Post.MI (?)Post.MI (?)CHFCHF
Alpha antagonists:Alpha antagonists: daily dosedaily dose other indicationother indication
Selective Selective 11::PrazosinPrazosinDoxazosinDoxazosinTerazosinTerazosinUrapidil Urapidil
2-20 mg2-20 mg1-16 mg1-16 mg1-10 mg1-10 mg
BPHBPH
SympatholyticsSympatholytics((22 agonists) agonists)ClonidineClonidineGuanfacinGuanfacinGuanabenzGuanabenzMoxonidineMoxonidine-Methyldopa-Methyldopa
0,1-0,6 mg0,1-0,6 mg
250-1000 mg250-1000 mg
Ca antagonistsCa antagonists daily dosedaily dose other indicationother indication
DihydrophyridinesDihydrophyridinesNifedipine (longacting)Nifedipine (longacting)AmlodipineAmlodipineNimodipineNimodipineNisoldipineNisoldipineNicardipineNicardipine
30-60 mg30-60 mg anginaangina
Non-dihydropiridinesNon-dihydropiridinesVerapamilVerapamilDiltiazem Diltiazem
130-360 mg130-360 mg180-240 mg180-240 mg
Supraventr. Tachycardia Supraventr. Tachycardia anginaangina
RAS (Renin-Angiotensin-System RAS (Renin-Angiotensin-System KidneysKidneys
bbeta blocking eta blocking agagentsents
rreenninin
aaliskirenliskiren
AngiotensinogenAngiotensinogen
Angiotensin IAngiotensin I
ACEiACEi ACEACE
Angiotensin IIAngiotensin II
ARBARB
ARAR
aaldldoosteron secretionsteron secretion sympathic activitysympathic activity
VasoconstrictionVasoconstriction
BPBP
The ACEi-sThe ACEi-s inhibition:inhibition:
- the LVH (Left Ventricular Hypertrophy)- the LVH (Left Ventricular Hypertrophy)- the myocardial ischemia- the myocardial ischemia- glomerular hypertrophy- glomerular hypertrophy- production of procollagen- production of procollagen
mitigate/decrease:mitigate/decrease:- deposition of mesan- deposition of mesanggial macromoleculesial macromolecules- impairment tubule-interstitial tissues- impairment tubule-interstitial tissues- the endothelial impairment- the endothelial impairment
improve:improve:- the cardiac function- the cardiac function- the rheological properties of the blood - the rheological properties of the blood - the lipid profile- the lipid profile- endothelial function- endothelial function- insulin sensitivity- insulin sensitivity
Pharmacological effects of ARB-sPharmacological effects of ARB-s BlockBlockadeade of AT of AT11 receptors: receptors:Outcome:Outcome: vasodilatationvasodilatation
- TPR (total Peripheral Resistance) - TPR (total Peripheral Resistance) aldosteron secretion: aldosteron secretion:
- Na reabsorption - Na reabsorption - H2O reabsorption - H2O reabsorption - plasma volume - plasma volume - cardiac output - cardiac output
intra glomerular pressure intra glomerular pressure release of NA from the synapses release of NA from the synapses
- sympathetic tone, neurotransmission - sympathetic tone, neurotransmission endothelin production endothelin production production of A II and production of A II and rrenin secretion enin secretion stimulation of ATstimulation of AT22 receptors (indirectly receptors (indirectly))
Pharmacological effects of ARB-sPharmacological effects of ARB-s (cont.)(cont.)
BlockBlockdede of AT of AT11 receptors: receptors:
Outcome:Outcome: decrease/mitigate:decrease/mitigate:
- LVH (Left Ventricular Hypertrophy)- LVH (Left Ventricular Hypertrophy)- albuminuria (microalbuminuria!)- albuminuria (microalbuminuria!)- progression of renal impairment- progression of renal impairment
protect (?)protect (?)- CHF- CHF- diabetic nephropathy- diabetic nephropathy- stroke- stroke
Pharmacological effects of ARB-sPharmacological effects of ARB-s (cont.)(cont.)
BlockBlockadeade of AT of AT11 receptors: receptors:
Outcome:Outcome: decrease/mitigate:decrease/mitigate:
- LVH (Left Ventricular Hypertrophy)- LVH (Left Ventricular Hypertrophy)- albuminuria (microalbuminuria!)- albuminuria (microalbuminuria!)- progression of renal impairment- progression of renal impairment
protect (?)protect (?)- CHF- CHF- diabetic nephropathy- diabetic nephropathy- stroke- stroke
Blockers of RAASBlockers of RAAS daily dosedaily dose other indicationother indication
ACE-iACE-iCaptoprilCaptoprilLisinoprilLisinoprilRamiprilRamiprilPerindoprilPerindoprilTrandolaprilTrandolaprilBenazepril Benazepril
25-200 mg25-200 mg10-40 mg10-40 mg2,5-20 mg2,5-20 mg
CHFCHFneprhopathyneprhopathy
ARBARBLosartanLosartanValsartanValsartanCandesartan Candesartan
25-100 mg25-100 mg80-320 mg80-320 mg2-32 mg2-32 mg
CHF CHF nephropathynephropathy
Direct Renin InhibitorsDirect Renin InhibitorsAliskiren Aliskiren 150-300 mg150-300 mg
Pharmacological effects of Pharmacological effects of RIRI-s-s
Direct blockade of renin enzyme activityDirect blockade of renin enzyme activity
PRA (Plasma Renin Activity) PRA (Plasma Renin Activity) ((tissue renin activity ?)tissue renin activity ?)
Plasma ATPlasma AT11/AT/AT22
Aldosterone secretion Aldosterone secretion BP BP - PRC (plasma cc. of renin) - PRC (plasma cc. of renin)
Renin Inhibitors:Renin Inhibitors: Outcome:Outcome: vascular effectsvascular effects::
- neointima formation - neointima formation - thickening in carotid intima- thickening in carotid intima (?)(?)
rrenal effectsenal effects (specific uptake of the drug by (specific uptake of the drug by the kidney?)the kidney?)- renal vascular resistance - renal vascular resistance - renal blood flow - renal blood flow - proteinuria - proteinuria
cccardiac effectscardiac effects::- beneficial hemodynamic effects- beneficial hemodynamic effects(LV end diastolic pressure (LV end diastolic pressure stroke volume stroke volume systemic vascular resistance systemic vascular resistance ))
??Effects of RI-s on target organ damageEffects of RI-s on target organ damage
Cardiac:Cardiac:- preventive (cardio protective): LVH- preventive (cardio protective): LVH- curative: CHF- curative: CHF
Vascular: Vascular: - protective: endothelial dysfu- protective: endothelial dysfunnctionction
against atherogenesis, against atherogenesis, stroke stroke
- improve the elasticity of the large arteries- improve the elasticity of the large arteriesRenal: Renal:
- nephroprotective- nephroprotective (in diabetic nephropathy) (in diabetic nephropathy)
Metabolic:Metabolic:- improve: insulin sensitivity- improve: insulin sensitivity
dyslipidemy dyslipidemy
Monotherapy versus CombinationMonotherapy versus Combination
Use of more than one agent is necessary to Use of more than one agent is necessary to achieve target BP in the majority of patientsachieve target BP in the majority of patients
Initial treatment can be monothInitial treatment can be monotherapyerapy or or combination of two drugs (at low doses) with a combination of two drugs (at low doses) with a subsequent increase in dosessubsequent increase in doses
Combination of two drugs should be preferred Combination of two drugs should be preferred as first step treatment in patients with grade as first step treatment in patients with grade 2/3 range or with high CV risk2/3 range or with high CV risk
In patient with severe hypertension In patient with severe hypertension combination of three or more drugs is requiredcombination of three or more drugs is required
Monotherapy versus Combination strategiesMonotherapy versus Combination strategiesMild/moderateMild/moderate Marked BP elevationMarked BP elevationBP elevationBP elevation CV high riskCV high risk
Single agent (low dose)Single agent (low dose) Two-drug combination (low dose)Two-drug combination (low dose)
previousprevious switch to diff. switch to diff. Previous add a thirdPrevious add a thirdagent (full dose) agent (low dose) comb.(full dose) drug (low agent (full dose) agent (low dose) comb.(full dose) drug (low
dose)dose)
two/threetwo/threedrug combination drug combination mono th. mono th.(full dose) (full dose)(full dose) (full dose) two /three drug two /three drug combinationcombination
(full dose)(full dose)
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