„„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)