Titel, Vorname, Name

Abteilung, Fachbereich oder Institut

Pharmacotherapy
Hypertension

Dr. Sarah Küchler

LMU Munich
Department for Pharmacy
Blood Pressure

2
Hypertension (USA, 1997)

3
Hypertension: Consequences
Damage of organs complications

macroangiopathy - Stenosis
cerebral - TIA (transient
ischemic attack)
- stroke
cardial - left-ventricular
hypertrophy
- CHD
- Myocardial infarct

peripher - peripheral artery

occlusive disease

microangiopathy - retinopathy
eye - Retina bleeding

kidney - nephropathy
- Renal failure

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Blood pressure (syst/diast mm Hg)

optimal < 120 / < 80

normal 120-129 / 80 - 84
high-normal 130-140 / 85-90
WHO 1999
Threshold hypertension: 140-149 / < 90
instable hypertension

Hypertension: > 140 / > 90 (160/100, 180/110)

cardiac output hypertension
hypertension due to vascular resistance
stroke / CHD / heart- / renal failure
Aim: < 140 / < 90 (85)

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Hypertension - Therapy

Change of the habits

quit smoking, reduce body weight, sport, (reduced consumption of
salt)

Monotherapy of artery hypertension

diuretic (mostly Thiazides)
ß-blockers
ACE inhibition
Calcium antagonists (especially for elder patients and if
incompatibilities with other therapies)

Aim: slow normalisation

(except for hypertensive urgency)

6
Hypertension- Therapy

Double combination

•diuretic +
ß-blocker or
ACE inhibitor or
Calcium antagonist

•Calcium antagonist +
ß-blocker or
ACE inhibitor

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Antihypertensive drugs: site of action

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Antihypertensive drugs: site of action

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diuretics

Thiazides and analogues

chlortalidone
clopamide
hydrochlorothiazide Drugs of the first choice if no
indapamide incompatibilities or
metolazone contraindication
xipamide

Loop diuretics
azosemide Side effects: hypokaliaemia,
bumetanide hypotonsion, hyperuricaemia and
furosemide glucose intolerance
piretanide
torasemide

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b-blockers

 b1-selective receptor blockers preferred

 Relative contraindication: diabetes
 No monotherapy for hypertensive patients older
than 60

atenolol
betaxolol absolute contraindications
bisoprolol
carvedilol Asthma bronchiale
celiprolol AV- block II° oder III°
metoprolol
nebivolol

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Renin-Angiotensin
Juxtaglomerular
System apparatus,
proteolytic
Angiotensinogen (plasma enzyme
globulin)  Angiotensin I
(decapeptide)  Angiotensin II
(octapeptide)

ACE: membran bound enzyme

on surface of endothelial cells,
but also in other vascular tissue
heart, brain, kidney etc.

Renin release upon: renal

perfusion pressure, glomerular
filtration, PGI2, renal
sympathetic activity, low blood
pressure

Release of aldosteron from 12

ACE inhibitors: mechanism of action

HO O
CH3
N
N
H OH
O
O
Captopril
Dicarboxyprotease
Aspartylprotease

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ACE inhibitors: mechanism of action

pleiotropy:
also chymase, CAGE, t-PA
 Efficacy 

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Conversion enzyme = kininase II

→
Dry cough
Angioedema
(Quincke‘s oedema)

Aktories et al.

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ACE inhibitors

prodrug active form

Aktories et al.

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ACE inhibitors: kinetic

drug BA (%) fb (%) t1/2 (h) elimination

captopril 70-75 30 2h 50%

(NI ) cystein-
conjugate
enalapril 53-73 55 1,3 / 11 70%
(prodrug) (rest: GI ACE- Enalaprilat
hydrol.) binding 

lisinopril 25 (6-60) low 12 renal

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ACE inhibitors

First choice for

Muscle hypertrophy  diabetes
nephro-protection especially in diabetes patients
Clinical use: hypertension, chronic cardiac insufficiency, diabetic
nephropathy, following myocardial infarction

Side effects: dry cough; seldom: dysgeusia, angioedema,

acute renal failure, fetotoxic

CI: renal artery stenosis, donated kidney, pregnancy, lactation

(immune mediated diseases, asthma bronchiale)

 Replacement of potassium-sparing diuretics – use of loop diuretics or

Thiazides

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sartanes: AT1 receptor antagonists

Losartan Candesartan- mucosa

liver Prodrug

Valsartan

AT1-receptor antagonist Candesartan

40x higher affinity

vasodilation, antiproliferative
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sartanes: kinetic

drug BA (%) fb (%) t1/2 (h) elimination

losartan 30 98,7 1,5-2 5-carboxylic-

50 mg 4-9 acid:
Metab CYP2C9
(CYP3A4)
telmisartan 42 99,5 24 renal
40 mg
eprosartan 13 99 6 glucuronide
600 mg (6-29) (20%)

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sartanes

Clinical use: like ACE inhibitors; eventually more

effective?

Side effects: angioedema, (dry cough)

contraindication: liver insufficiency, renal failure,

pregnancy, lactation

interactions: azoles: losartan activation 

rifampicin: losartan-metabolite degradation 
no combination with digoxine, azoles, macrolides

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 renin-inhibitor: aliskiren

Aliskiren
Aliskiren competitivly inhibits the active
center of renin. Thus, binding of the
native substrate angiotensinogen and
ist degradation into angiotensin I is
inhibited  no formation of the strong
vasoconstrictor angiotensin II.

CI: angioedema
Combination with other inhibitors of the
RAA system increases risk of
hyperkalaemia

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Direct vasodilators (1)
Musculatur of smaller vessels

Hydralazin / Dihydralazin
Kin: Acetylierung
side effects: sympathikus, RAA ;
pyridoxin , headache N
Mode of action unkown N
Ind: hypertensive urgencies and during pregnancy
HN
Nitroprusside sodium - infusion NH2
NO-drug hydralazine
side effects: rhodanide-intoxication (> 2 d)
Ind: emergency remedy, intensive care, operations

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 Minoxidile

P2X-receptor-agonist, K+-channel opener

long half-time (24-75 h)
Ind: therapy resistant hypertension (renal hypertension)
minoxidile
sulphate (Hyper-)
K+ Ca2+
polarisation
(SUR) + -

ADP

ATP

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Minoxidile

H2N
N
+
O N N

H2N

UDP-Gluc, UGT PAPS, ST

M-glucuronide Minoxidile-sulphate
Side effects: strong sympathicus activation and RAA ; reversible hypertrichosis;
pericardial effusion

Minoxidile + dihydralazine only for patients with therapy resistant hypertension

Only in combination with ß-receptor antagonist and loop diuretics

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Aims of Hypertensive Treatment

Yielded blood pressure for high risk patients ≤ 130/80 mm/Hg

High risk patients: diabetes mellitus, chronic kidney disease, cardiac insufficiency
with systolic dysfunction

 First choice: ACE-inhibitors/AT1-antagonists

If: patients with chronic kidney disease AND proteinuria of 1 g/day

yielded blood pressure ≤ 125/75 mm/Hg

(Mostly) combination therapy required (50-60 % response rate, only 1/3 patients
sufficient reduction in blood pressure with 1 drug)

Enhance patients’ compliance: only once per day (morning!)

Titel, Datum 26
Steps of treatment of hypertension
monotherapy: first choice, reduced cardiovascular mortality/morbidity

diuretics ACE inhibitors calcium

(thiazide) ß-blockers antagonists
AT1 receptor antagonists
Double combination:

diuretics dihydropyridine

ß-blocker ACE inhibitor/sartane ß-blocker

Triple combination
diuretic
calcium
ß-blocker antagonists

ACE inhibitor/sartane
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 Antihypertensive drugs: special
indications
suitable Not suitable

Age of patient; activity

>65 years Diuretics, calcium antagonists,
Slow reduction; cave:
orthostatic dysregulation
(alpha1-antagonists!)
younger patients ACE inhibitors, sartane, ß-
blocker

Sporty, active ACE inhibitors ß-blocker

person sartane verapamil,
Diuretics diltiazem
Dihydropyridine
a2-receptor
antagonists
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 Antihypertensive drugs: special
indications
Suitable Not suitable
Heart diseases
CHD ß-blocker dihydropyridins
ACE inhibitor, sartane (short duration of drug
calcium antagonists effect)

Myocardial Diuretics, ß-blocker, ACE

insufficiency inhibitors, sartane

bradycardia ACE inhibitor, sartane ß-blocker

dihydropyridine verapamil, diltiazem
a1-blocker a2-Agonists

tachycardia ß-blocker, verapamil, a1-blocker dihydropyridine

diltiazem, a2-agonists (Di-)hydralazine

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 Antihypertensive drugs: special
indications
Suitable Not suitable

kidney diseases
Renal Loop diuretics thiazide
insufficiency ACE inhibitors, sartane Potassium-sparing
diuretics

Renal artery ACE inhibitors,

stenosis sartane
Metabolic disorders
Diabetes mellitus ACE inhibitors, sartane, ß-blocker
thiazide (low dose)
Calcium antagonists

hyperuricaemia thiazide
Loop diuretics
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Antihypertensive drugs during
pregnancy

Hypertension during pregnancy:

perinatale mortality 
BUT: controversial discussions about fetal development
Ind. of hypertensive therapy: persistent values ≥170/110 mm/Hg, diabetes,
kidney disease, delivery

Slow reduction of blood pressure! (uteroplacental perfusion)

1. choice: methyldopa, ß1-blocker (atenolol, metoprolol), dihydralazine

(2. choice: nifedipin (not 1. trimenon), (verapamil, diuretics))

CI: diuretics, ACE inhibitors, sartane

(uteroplacental perfusion)
calcium antagonists (teratogenic 1. trimenon)

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hypertensive urgency

emergency: hypertensive encephalopathy,

cerebral hemorrhage, pulmonary edema, instable angina, aortic aneurysm,
myocardial infarction
Blood pressure diastolic ≥ 120 mm/Hg

Emergency procedures:
glyceroltrinitrate (spray or capsule which you break with the teeth) or nifedipin
oder urapidile, clonidine (i.v.)
clinic: additionally furosemid i.v. (if no volume reduction)

During pregnancy: dihydralazin (i.v.), urapidil (i.v.), magnesium sulfate (if

cramps i.v.)
No calcium antagonists!

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