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„Hypertension”
Prof. Dr. János Borvendég
CHMP member
Hungary
Definitions and Classification of Blood
Pressure levels (mmHg)
Category
Optimal
Normal
High normal
Grade 1 Hypertension
-”2
-”-”3
-”Isolated Systolic
Hypertension
Systolic
 120
120-129
130-139
140-159
160-179
 180
 140
Diastolic
 80
80-84
85-89
90-99
100-109
 110
 90
The significance of hypertension
The number of patients with
hypertension is growing(!)
1988-1991
43,2 mill/US
1999-2000
60,0 mill/US
- the population ages 
- obesity 
- diabetes 
 Hypertension is the most common risk
factor for heart attack and stroke

The significance of hypertension:

(cont.)
Only ≈ 34 % of patients with
hypertension have their blood pressure
controlled.
- the HBP remains asymptomatic for long
period of time
- lack of adherence with the therapy
- side effects of the antihypertensive
- poor access to medications
Factors influencing the prognosis
Risk Factors:
S/D BP levels 180/ 110 mmHg
Diabetes mellitus
Age (M  55 y. F  66 y)
Dyslipidemia
Abdominal obesity
Metabolic syndrome
Smoking
Snoring / sleep apnoea
Obesity:

Body weight

Increased waist circumference
M : 102 cm W: 88 cm

Increased body mass index
body weight (kg) / height2(m)
overweight  25 kg/m2
obesity
 30 kg/m2
Complications:

heart failure

Left ventricular hypertrophy

MI

sudden cardiac death

stroke

intracerebral haemorrhage

chronic renal insufficiency hypertensive
nephrosclerosis

retinopathy
Laboratory Investigations:
fasting plasma glucose/tolerance test
se total cholesterol
se LDL
se HDL
fasting se triglycerides
se uric acid
se creatinine
creatinin clearance
Hgb/Htc
urine analysis (quantitative microalbiminuria)
se electrolytes
Determinants of arterial pressure
Stroke volumen
Cardiac
output
Heart rate
Arterial pressure
Vascular structure
Perip.
resistance
Vascular function
Essential (primary hypertension)
Pathogenesis:
 increased sympathetic neural activity,
with enhanced beta-adrenergic activity
 increased Angiotensin II. activity and
mineral corticoid excess
 genetic factors (≈ 30 %)
 reduced nephron mass
(genetic factors?
intra uterine developmental
disturbances)
Search for secondary hypertension
Measurement of:
renin
aldosterone, corticosteroids
catecholamines
arteriographies
renal / adrenal ultra sound
CT
MRI
Goals of Treatment:

Primary goal: to achieve maximum reduction in
the long-term total risk of cardiovascular
disease

BP should be reduced:
 140/90 mmHg (in all hypertensive patients)
 130/80 mmHg (in diabetics and
in high risk patients)

Antihypertensive th. should be initiated before
significant CV damage develops
Antihypertensive agents
Mechanism of Action of Antihypertensive Agents
Diuretics: (?)

Na+ excretion 

Plasma volume 

Smooth muscle Na+ conc. 
Outcome:
perif. resist. 
-blockers:

1/2 blocking

1 blocking

MSA (Membrane Stabilisig Activity)

ISA (Intrinsic Sympathetic Activity)
Outcome:
heart rate 
cardiac output 
plasma RA 
resetting of baro receptors
Mechanism of Action of Antihypertensive Agents (cont.)
Alfa antagonists
 Selective post synapticic
1 blockade
Outcome:
peripherial resist. 
preload 
Ca channel antagonists:
 Blockade of
voltage sensitive Ca channels
 Outcome:
peripherial. resist 
(relax the arterial smooth muscle)
Diuretics
thiazides
daily dose
HCTZ
6,25-50 mg
chlortalidone
other
indication
CHF
loop diuretics Furosemide
Ethacrynic
acid
aldosteron
spironoantagonists
lactone
40-80 mg
50-100 mg
CHF
renal failure
25-100 mg
CHF
hyper aldost.
K+ retaining
5-10 mg
50-100 mg
Amilorid
triamteren
Beta blockers
Non-selective:
Propranolol
Pindolol
Sotalol
Cardioselective
Atenolol
Metoprolol
Esmolol
Bisoprolol
Betaxolol
Combined /
Labetolol
Carvedilol
Celiprolol
Bucindolol
daily dose
other indication
40-160 mg
Angina ,
tachyarrhythmia
25-100 mg
25-100 mg
Angina,
CHF
tachyarrhythmia
200-800 mg
12,5-50 mg
Post.MI (?)
CHF
Alpha antagonists:
daily dose
other indication
Selective 1:
Prazosin
Doxazosin
Terazosin
Urapidil
2-20 mg
1-16 mg
1-10 mg
BPH
Sympatholytics
(2 agonists)
Clonidine
Guanfacin
Guanabenz
Moxonidine
-Methyldopa
0,1-0,6 mg
250-1000 mg
Ca antagonists
Dihydrophyridines
Nifedipine (longacting)
Amlodipine
Nimodipine
Nisoldipine
Nicardipine
Non-dihydropiridines
Verapamil
Diltiazem
daily dose
other indication
30-60 mg
angina
130-360 mg
180-240 mg
Supraventr. Tachycardia
angina
RAS (Renin-Angiotensin-System
Kidneys
beta blocking agents
renin
aliskiren
Angiotensinogen
Angiotensin I
ACEi
ACE
Angiotensin II
ARB
AR
aldosteron secretion
sympathic activity
Vasoconstriction
BP
The ACEi-s



inhibition:
- the LVH (Left Ventricular Hypertrophy)
- the myocardial ischemia
- glomerular hypertrophy
- production of procollagen
mitigate/decrease:
- deposition of mesangial macromolecules
- impairment tubule-interstitial tissues
- the endothelial impairment
improve:
- the cardiac function
- the rheological properties of the blood
- the lipid profile
- endothelial function
- insulin sensitivity
Pharmacological effects of ARB-s
Blockade of AT1 receptors:
Outcome:

vasodilatation
- TPR (total Peripheral Resistance) 

aldosteron secretion: 
- Na reabsorption 
- H2O reabsorption 
- plasma volume 
- cardiac output 

intra glomerular pressure 

release of NA from the synapses 
- sympathetic tone, neurotransmission 

endothelin production 

production of A II and renin secretion 

stimulation of AT2 receptors (indirectly)
Pharmacological effects of ARB-s
(cont.)
Blockde of AT1 receptors:
Outcome:
 decrease/mitigate:
- LVH (Left Ventricular Hypertrophy)
- albuminuria (microalbuminuria!)
- progression of renal impairment
 protect (?)
- CHF
- diabetic nephropathy
- stroke
Pharmacological effects of ARB-s
(cont.)
Blockade of AT1 receptors:
Outcome:
 decrease/mitigate:
- LVH (Left Ventricular Hypertrophy)
- albuminuria (microalbuminuria!)
- progression of renal impairment
 protect (?)
- CHF
- diabetic nephropathy
- stroke
Blockers of RAAS
daily dose
other indication
25-200 mg
10-40 mg
2,5-20 mg
CHF
neprhopathy
ARB
Losartan
Valsartan
Candesartan
25-100 mg
80-320 mg
2-32 mg
CHF
nephropathy
Direct Renin Inhibitors
Aliskiren
150-300 mg
ACE-i
Captopril
Lisinopril
Ramipril
Perindopril
Trandolapril
Benazepril
Pharmacological effects of RI-s
Direct blockade of renin enzyme activity

PRA (Plasma Renin Activity) 
(tissue renin activity ?)

Plasma AT1/AT2 

Aldosterone secretion 

BP 

- PRC (plasma cc. of renin) 
Renin Inhibitors:
Outcome:
 vascular effects:
- neointima formation 
- thickening in carotid intima  (?)
 renal effects (specific uptake of the drug by
the kidney?)
- renal vascular resistance 
- renal blood flow 
- proteinuria 
 ccardiac effects:
- beneficial hemodynamic effects
(LV end diastolic pressure 
stroke volume 
systemic vascular resistance )
?
Effects of RI-s on target organ damage
Cardiac:
- preventive (cardio protective): LVH
- curative: CHF
Vascular:
- protective: endothelial dysfunction
against atherogenesis,
stroke
- improve the elasticity of the large arteries
Renal:
- nephroprotective
(in diabetic nephropathy)
Metabolic:
- improve: insulin sensitivity
dyslipidemy
Monotherapy versus Combination

Use of more than one agent is necessary to
achieve target BP in the majority of patients

Initial treatment can be monotherapy or
combination of two drugs (at low doses) with a
subsequent increase in doses

Combination of two drugs should be preferred
as first step treatment in patients with grade
2/3 range or with high CV risk

In patient with severe hypertension
combination of three or more drugs is required
Monotherapy versus Combination strategies
Mild/moderate
BP elevation
Single agent (low dose)
previous
switch to diff.
agent (full dose) agent (low dose)
two/three
drug combination  mono th.
(full dose)
(full dose)
Marked BP elevation
CV high risk
Two-drug combination (low dose)
Previous add a third
comb.(full dose) drug (low dose)
two /three drug
combination
(full dose)