Drugs used to treat hypertension

2006

Hypertension
- risk factor for: ischemic heart disease, stroke, renal failure
and heart failure

Classification of BP
Category
Normal
High normal
Hypertension
Stage 1
Stage 2
Stage 3
Stage 4

Systolic
<130
<139

Diastolic
<85
<89

140-159
160-179
180-209
>210

90-99
100-109
110-119
>120

Arterial blood pressure (BP) is determined by cardiac output

(MV) and peripheral vascular resistance (PR).

BP = CO x PR

Cardiac output may be

increased in children or
young adults during the
earliest stages of essential
hypertension

Peripheral resistance is determined

by the caliber and total cross-sectional
area of the resistance vessels (small
arteries and arterioles) in the various
tissues.
- Influence of predisposing factors

Hypertension

Essential (primary)

Secondary

- most (90-95 %) patients with

persistent arterial hypertension
- genesis of hypertension unknown
- predisposing factors:

- is secondary to some
distinct disease:

susceptive
(obesity, stress, salt intake, lack of
Mg2+, K+, Ca2+, ethanol dose,
smoking)
non-susceptive
(positive family history, insulin
resistance, age, sex, defect of
local vasomotoric regualtion)

Renal + renovascular desease

(artery stenosis)
Hormonal defects
(Cushings syndrome,
phaeochromocytoma)
Mechanical defect
(coarctation of aorta)
Hypertension in pregnancy
Drug-induced hypertension
(sympatomimetics,
glucocorticoids)
Neurologic desease

1. Baroreceptors
- they are responsible for rapid adjustment in blood pressure

2. Kidney
- plays a key role in long-term control of blood pressure and in
the pathogenesis of hypertension
- excretion of salt and water controls intravascular volume,
which influences the force of contraction of the heart by the
Starling mechanism
- secretion of renin (1/3 of patients) increases production of
angiotensin II causes direct constriction of resistance
vessels and stimulation of aldosterone synthesis in the adrenal
cortex increases renal sodium absorption and intravascular
volume
- renal disease (vascular, parenchymal or obstructive) is a
cause of arterial hypertension

3. Non-renal mechanisms
neuronal mechanisms sympathetic nervous system
(continual background of vasoconstrictor tone), and
endocrine and autocrine/paracrine mechanisms
(NO vs, endothelin)

Clinically important consequences of hypertension (end

organ damage) include damage both to large and small
blood vessels as well as left-ventricular hypertrophy
(increased arterial pressure causes an increased risk of
arterial rupture and bleeding from a weak spot in the arterial
wall) !

THERAPY OF HYPERTENSION
Guidelines for management of hypertension: report of the fourth working party of the
British Hypertension Society 2004BHS IV. J Hum Hypertens 2004; 18: 13985.*

A. Non-pharmacological - lifestyle

- decrease of salt intake

- reduction of body weight
- restriction of smoking and drinking excessive
amounts of alcohol
- regular physical activity and relaxation, lack of stress
- increased intake of Mg2+, K+, Ca2+ - fruit, vegetables

*BNF 51th edition, 2006

The following thresholds for treatment are recommended:

Accelerated (malignant) hypertension (with papilloedema or fundal
haemorrhages and exudates) or acute cardiovascular complications, admit for
immediate treatment;
Where the initial blood pressure is systolic 220 mmHg or diastolic
120 mmHg, treat immediately;
Where the initial blood pressure is systolic 180219 mmHg or diastolic 110
119 mmHg, confirm over 12 weeks then treat if these values are sustained;
Where the initial blood pressure is systolic 160179 mmHg or diastolic 100
109 mmHg, and the patient has cardiovascular complications, target-organ
damage (e.g. left ventricular hypertrophy, renal impairment) or diabetes mellitus
(type 1 or 2), confirm over 34 weeks then treat if these values are sustained;
Where the initial blood pressure is systolic 160179 mmHg or diastolic 100
109 mmHg, but the patient has no cardiovascular complications, no target-organ
damage, or no diabetes, advise lifestyle changes, reassess weekly initially and
treat if these values are sustained on repeat measurements over 412 weeks;

*BNF 51th edition, 2006

 Where the initial blood pressure is systolic 140159 mmHg or diastolic 90

99 mmHg and the patient has cardiovascular complications, target-organ
damage or diabetes, confirm within 12 weeks and treat if these values are
sustained;
Where the initial blood pressure is systolic 140159 mmHg or diastolic 90
99 mmHg and no cardiovascular complications, no target-organ damage, or
no diabetes, advise lifestyle changes and reassess monthly; treat persistent
mild hypertension if the 10-year cardiovascular disease risk is 20%.

An optimal target systolic blood pressure < 140 mmHg and diastolic blood
pressure < 85 mmHg is suggested.
In some individuals it may not be possible to reduce blood pressure below the
suggested targets despite the use of appropriate therapy.

*BNF 51th edition, 2006

Drug treatment of hypertension

No consistent or important differences have been found between the major
classes of antihypertensive drugs in terms of antihypertensive efficacy, sideeffects or changes to quality of life.
The choice of antihypertensive drug will depend on the relevant indications or
contra-indications for the individual patient:

1.
2.
3.
4.

Diuretics
Drugs influencing sympathetic nerves
Vasodilators
Angiotensin-converting enzyme inhibitors
(ACEI), blockers of AT1 receptor

*BNF 51th edition, 2006

Thiazides particularly indicated for hypertension in the elderly; a contraindication is gout;

Beta-blockers indications include myocardial infarction, angina; compelling
contra-indications include asthma, heart block;
ACE inhibitors indications include heart failure, left ventricular dysfunction
and diabetic nephropathy; contra-indications include renovascular disease and
pregnancy; when thiazides and beta-blockers are contra-indicated, not tolerated,
or fail to control blood pressure
Angiotensin-II receptor antagonists are alternatives for those who cannot
tolerate ACE inhibitors because of persistent dry cough, but they have the same
contra-indications as ACE inhibitors;
Calcium-channel blockers. a) Dihydropyridine calcium-channel blockers
are valuable in isolated systolic hypertension in the elderly when a low-dose
thiazide is contra-indicated or not tolerated. b) Rate-limiting calcium-channel
blockers (e.g. diltiazem, verapamil) may be valuable in angina; contraindications include heart failure and heart block;
Alpha-blockers a possible indication is prostatism; a contra-indication is
urinary incontinence.
*BNF 51th edition, 2006

A single antihypertensive drug is often not adequate and other antihypertensive

drugs are usually added in a step-wise manner until control is achieved. Unless
it is necessary to lower the blood pressure urgently, an interval of at least 4
weeks should be allowed to determine response.
Where two antihypertensive drugs are needed 1. an ACE inhibitor or an
angiotensin-II receptor antagonist or a beta-blocker may be combined with 2.
either a thiazide or a calcium-channel blocker.
If control is inadequate with 2 drugs, a thiazide and a calcium-channel blocker
may be added. In patients at high risk of diabetes it is best to avoid a
combination of a beta-blocker and a thiazide. In patients with primary
hyperaldosteronism, spironolactone is effective.

Response to drug treatment for hypertension may be affected by the patients

age and ethnic background. A beta-blocker or an ACE inhibitor may be the most
appropriate initial drug in younger Caucasians; Afro-Caribbean patients respond
less well to these drugs and a thiazide or a calcium-channel blocker may be
chosen for initial treatment.

*BNF 51th edition, 2006

1. DIURETICS

- drugs of first choice for treating patients with mild hypertension

- often combined with another drug in treatment of more severe
hypertension

THIAZIDES
hydrochlorothiazide, clopamid, chlorthalidone
indapamid, metipamid

- preferable (to loop diuretics) for the treatment of

uncomplicated hypertension
- given by mouth as a single morning dose
- begin to act within 1-2 hours and work for 12-24 hours
- treatment should be started using a low dose

Lumen
urine

Thiazides

Distal
convoluted
tubule

Interstitium blood

Mechanism of action:

= lower blood pressure by reduction of blood volume and by direct

vascular effect
- inhibition of sodium chloride transport in the early segment of the distal
convoluted tubule natriuresis, decrease in preload and cardiac
output - renal effect
- slow decrease of total peripheral resistance (raised initially) during
chronic treatment, suggesting an action on resistance vessels extrarenal effects
compensatory responses to pressor agents including angiotensin II and
noradrenaline are reduced during chronic treatment with thiazides
- used with loop diuretic - synergistic effect occurs

Adverse effects:
- Idiosyncratic reactions (rashes - may be photosensitiv, purpura)
- Increased plasma renin (which limits the magnitude of their effect on BP)
- Metabolic and electrolyte changes
Hyponatremia
Hypokalemia
(combine with potassium-sparing diuretics)

Hypomagnesemia
Hyperuricemia (most diuretics reduce urate clearance)
Hyperglycemia
Hypercalcemia
(thiazides reduce urinary calcium ion clearance precipitate
clinically significant hypercalcemia in hypertensive patients with
hyperparathyroidism)

Hypercholesterolemia (a small in plasma cholesterol concentration)

LOOP DIURETICS
furosemid
- useful in hypertensive patients with moderate or severe renal
impairment, or in patients with hypertensive heart failure.
- relatively short-acting (diuresis occurs over the 4 hours following a
dose) used in hypertension if response to thiazides is inadequate
Mechanism of action:
- they inhibit the co-transport of Na+, K+ and Cl- of Ca2+ and Mg2+ excretion
- they have useful pulmonary vasodilating effects (unknown mechanism)

Lumen
urine

Furosemide

Thick ascending
limb

Interstitium blood

Toxicity:
- hypokalemic metabolic alkalosis (increased excretion of K+)
- ototoxicity (dose dependent, reversible)
- decrease of Mg2+ plasma concentration (hypomagnesemia)
- hyperuricemia (competition with uric acid about tubular secretion)
- sulfonamide allergy
- risk of dehydration (> 4 L urine/ 24 h)

Imporatant drug interaction may occurs if loop diuretic is given

with Li+ (thymoprofylactic drug). Decrease of Na+ reabsorption
can lead to increase of Li+ reabsorption toxicity.

2. Drugs influencing sympathetic nerves

a) a -adrenoreceptor antagonists
Mechanism of action:
- vasodilatation (reduce vascular resistence) and decreased blood
pressure by antagonizing of tonic action of noradrenaline on a1
receptors (vascular smooth muscle)
competitive with:
a. short-term action:
a blockers with ISA - ergot alcaloids
a non-selective - phentolamine
a1 selective - prazosin, uradipil,
b. long-acting
a1 antagonists - doxazosin, terazosin
non-competitive with long-term action, non-selective - phenoxybenzamin

2. Drugs influencing sympathetic nerves

Toxicity:
the most important toxicities of the alpha-blockers are simple
extensions of their a-blocking effects type A adverse effects

- the main manifestations are:

- drowsiness, weakness, orthostatic hypotension (first dose
bedtime administration) - and for the nonselective agents, reflex
tachycardia - in patients with coronary disease, angina may be
precipitated by the tachycardia (less frequent in selective alpha1blockers)
- oral administration of any of these drugs can cause
nausea, vomiting, diarrhoea

- urinary incontinece
- priapism, nasal congestion

2. Drugs influencing sympathetic nerves

Phaeochromocytoma
Long-term management of phaeochromocytoma involves surgery.
Alpha-blockers are used in the short-term management of
hypertensive episodes in phaeochromocytoma. Once alpha blockade is
established, tachycardia can be controlled by the cautious addition
of a beta-blocker; a cardioselective beta-blocker is preferred.
Phenoxybenzamine, a powerful alpha-blocker, is effective in the
management of phaeochromocytoma but it has many side-effects.

Phentolamine is a short-acting alpha-blocker used mainly during

surgery of phaeochromocytoma; its use for the diagnosis of
phaeochromocytoma has been superseded by measurement of
catecholamines in blood and urine.

2. Drugs influencing sympathetic nerves

b) b -adrenoreceptor antagonists
Mechanism of action:
- the fall in cardiac output BP
- they reduce renin secretion
- CNS-effects ???
- additional mechanisms involve baroreceptors or other homeostatic
adaptations
Possible mechanisms include:
b-adrenoceptors located on sympathetic nerve terminals can promote
noradrenaline release, and this is prevented by b-receptor
antagonists
local generation of angiotensin II within vascular tissues is stimulated
by b2-agonists.

2. Drugs influencing sympathetic nerves

b-adrenoreceptor antagonists
cardio-selective:
b1 blockers
b1 blockers with ISA
b1 + a1 blockers

cardio non-selective:
b1 + b2 blockers
b1 + b2 blockers with ISA

atenolol, metoprolol
acebutol
labetalol, carvedilol

metiprolol, propranolol,
nadolol
pindolol, bopindolol

Note: Partial agonist activity (intrinsic sympathomimetic activity ISA) - may be an

advantage in treating patients with asthma because these drugs will cause
bronchodilation; they have moderate (lower) effect on lipid metabolism, cause lesser
vasospasms and negative inotropic effect

2. Drugs influencing sympathetic nerves

Adverse effects
Cardiovascular adverse effects, which are extension of the beta
blockade, include:
- bradycardia
- antrioventricular blockade
- congestive heart failure (unstable)
- asthmatic attacks (in patients with airway disease)
- premonitory symptoms of hypoglycemia from insulin overdosage
(eg, tachycardia, tremor and anxiety, may be marked)
- CNS adverse effects - sedation, fatigue, and sleep alterations.

2. Drugs influencing sympathetic nerves

c) Centrally acting drugs

a2-agonist actions
Methyldopa
false transmitter
Clonidine, Moxonidine
direct a2-agonist, imidazol receptor agonists

- limited use in the treatment of hypertension.

- methyldopa hypertension during pregnancy
- methyldopa causes symptoms of drowsiness and fatigue that are
intolerable to many adult patients in long-term use
- they are seldom used to treat essential hypertension
- clonidine is potent but poorly tolerated (rebound hypertension, if it is
discontinued abruptly, is an uncommon but severe problem)

2. Drugs influencing sympathetic nerves

Adverse effects:
- drowsiness, fatigue (esp. methyldopa), depression, nightmares
(methyldopa - rarely extrapyramidal features) driving!!
- nasal congestion, anticholinergic symptoms (constipation, bradycardia)
clonidine
- dry mouth
- hepatitis, drug fever (with methyldopa)
- sexual dysfunction, salt and water retention
- hypertensive rebound associated with anxiety, sweating, tachycardia
and extrasystoles (rarely hypertensive crisis)

3. Vasodilators
- drugs which dilate blood vessels (and decrease peripheral vascular
resistance) by acting on smooth muscle cells through non-autonomic
mechanisms:

* release of nitric oxide

(NO stimulates guanylyl cyclase and increase cGMP in smooth
muscles reduction of cytoplasmic Ca2+ by causing Ca2+
sequestration in the endoplasmic reticulum relaxation of both
arterioles and venous capacitance vessels, lowering peripheral
vascular resistance and reducing cardiac pre- as well as afterload)

* opening of potassium channels

(leads to hyperpolarization and relaxation of vascular smooth muscle)

* blockade of calcium channels

(reduce intracellular calcium concentration relax aretriolar smooth
muscle, reduce peripheral vascular resistance)

3. Vasodilators
- compensatory responses are preserved (may include salt retention
and tachycardia) suitable combination with diuretics or b-blockers
A) DIRECT ACTING
minoxidil, diazoxide, sodium nitroprusside, hydralazine

Minoxidil
- therapy of severe hypertension resistant to other drugs
- prodrug its metabolite (minoxidil sulfate) is a potassium channel
opener ( repolarization + relaxation of vascular smooth muscle)
- more effect on arterioles than on veins
- orally active

- Adverse: Na+ and water retention coadministration with betavlocker and diuretic is mandatory for this drug, oedemas,
hypertrichosis, breast tenderness

3. Vasodilators
Diazoxide
- given by rapid iv. injection (less than 30 seconds)* in hypertensive
emergencies
- potassium channel opener
- glucose intolerance due to reduced insulin secretion (used in
patients with inoperable insulinoma)
- adverse: Na+ and water retention, hyperglycaemia, hirsutism
Hydralazine
- rapidly and fairly absorbed after oral administration
- arteriolar resistance

- useful for hypertensive crisis during pregnancy

- AE: Na+ and water retention, systemic lupus erythematosus
suspected if there is unexplained weight loss, arthritis

*BNF 51th edition, 2006

3. Vasodilators
Sodium nitroprusside
- short-acting agent (few minutes) administrated by infusion in
hypertensive emergencies (hypertensive encephalopathy, shock,
cardiac dysfunction) for max 24 hours (risk of cumulation of
cyanide toxicity)

- Releases NO

+ NO

- the stock solution should be

diluted and covered with foil to

CN

prevent photodeactivation

CN
++
Fe

- adverse effects: too rapid

reduction of BP, nausea,

CN

CN

palpitation, dizziness
cyanide metabolite accumulation
tachycardia, hyperventilation, arrhythmias, acidosis

CN

3. Vasodilators
B) INDIRECT ACTING - CALCIUM CHANNEL-BLOCKING AGENTS
1. dihydropyridine (nifedipine, nicardipine, amlodipine)
2. diltiazem, verapamil
- they block voltage-dependent L-type calcium channels relaxation
of smooth muscle vasodilation reduce peripheral vascular
resistance reduction of BP

- negatively inotropic drugs

- they differ in selectivity for calcium channels in vascular smooth
muscles and cardiac tissues
- orally active suitable for long-term use

NIFEDIPINE*
coronary arteries dill
++
peripheral arteries dill
++++
negative inotropic
+
slowing AV cond

heart rate

blood presure
++++
depression of SA

increase in cardiac
++
output

DILTIAZEM VERAPAMIL
++
++
++
+++
++
+++
+++
++++

++
+++
++
++

* and others dihydropyridines

= decrease
= increase
= without change

3. Vasodilators
DIHYDROPYRIDINES (nifedipine, nicardipine)
- evoke vasodilatation resulting in sympathetic reflex activation,
- relatively selective for vascular smooth muscle (arterial)
amlodipine, lacidipine, isradipine, felodipine 2nd generation
- longer duration of action once daily
- do not reduce myocardial contractility do not produce clinical
deterioration in heart failure
nimodipine preferentially acts on cerebral arteries prevention of
vascular spasm following aneurysmal subarachnoid haemorrhage
Indication: all grades of essential hypertension
- alone (nifedipine, amlodipine) in patients with mild hypertension for
patients in whom thiazide diuretics and b-blockers are contraindicated

- combinations
angina (with beta-blockers)

3. Vasodilators
verapamil, diltiazem

- effects on the voltage-dependent channels in cardiac conducting

tissue
- vasodilatation
- it also blocks Ca2+ entry in gastrointestinal smooth muscle and

consequently causes constipation

3. Vasodilators
Adverse effects of calcium channel-blocking agents

Drug

Effect on
heart rate

Adverse effects

Nifedipine

Headache, flushing, ankle swelling

Amlodipine

Ankle swelling

Nimodipine

Flushing, headache

Diltiazem

Generally mild

Verapamil

Constipation, marked negative

inotropic action

Calcium channel blockers do not affect concentrations of plasma cholesterol

or triglycerides, or extracellular calcium homeostasis.

4. Angiotensin-converting enzyme inhibitors (ACEI), blockers of AT1 rc.

ANGIOTENSIN-CONVERTING ENZYME INHIBITORS (ACEI)
Captopril, enalapril, quinapril, lisinopril, perindopril, ramipril
Indications
- hypertension where thiazide diuretics and beta-blockers are
contraindicated
- useful in hypertensive patients with heart failure (beneficial effect)
- can limit the size of myocardial infarction
- diabetic nephropathy

4. Angiotensin-converting enzyme inhibitors (ACEI), blockers of AT1 rc.

Mechanism of action
- ACEI regulates balance between bradykinin (vasodilatation,
natriuresis) and angiotensin II (vasoconstriction, Na+-retention)
- AT1 receptors - widely distributed in the body (lung - huge surface
area of endothelial cells, heart, kidney, striated muscle and brain) and
present on the luminal surface of vascular endothelial cells
Angiotensin II
- vasoconstriction
- noradrenaline release from sympathetic nerve terminals
- aldosterone secretion from the zona glomerulosa of the adrenal cortex
- ADH
- is a growth factor for vascular smooth muscle and some other cells =
remodelling

4. Angiotensin-converting enzyme inhibitors (ACEI), blockers of AT1 rc.

Angiotensin I
(inactive)

ACE
inhibitors

Bradykinin
(active vasodilator)

angiotensinconverting
enzyme

Angiotensin II
(active vasoconstrictor)

Inactive metabolites

4. Angiotensin-converting enzyme inhibitors (ACEI), blockers of AT1 rc.

Mechanism of action:
Converting enzyme inhibitors lower blood pressure by reducing
angiotensin II, and also by increasing vasodilator peptides
such as bradykinin.
Dilatation of arteriol reduction of peripheral vascular
resistance, blood pressure and afterload
Increase of Na+ and decrease of K+ excretion in kidney

Decrease noradrenaline release reduction of sympathetic

activity (use is not associated with reflex tachycardia
despite causing arterioral and venous dilatation)
Inhibition of aldosterone secretion from the zona glomerulosa
contributes to the antihypertensive effects of ACEI
Influence on the arteriolar and left ventricular remodelling that are
believed to be important in the pathogenesis of human essential
hypertension and post-infarction state

4. Angiotensin-converting enzyme inhibitors (ACEI), blockers of AT1 rc.

Pharmacokinetics:
- active when administered orally
- most of ACEIs are highly polar, eliminated in the urine, without CNS
penetration
fosinopril - metabolized by the liver
captopril, lisinopril - active per se
enalapril, quinapril - prodrugs require metabolic conversion to
active metabolites
enalapril, quinapril and lisinopril - given once daily
captopril - administered twice daily

However, ACE inhibitors are effective in many patients with low renin as
well as those with high renin hypertension and there is only a poor
correlation between inhibition of plasma-converting enzyme and chronic
antihypertensive effect, possibly because of the importance of
converting enzyme in various key tissues rather than in the plasma.

4. Angiotensin-converting enzyme inhibitors (ACEI), blockers of AT1 rc.

ACE inhibitors
Drug

Duration of
effect (hours)

Short-acting:

captopril

Medially-acting:

enalapril

6-8
12

quinapril
perindopril
Long-acting:

lisinopril
spirapril
ramipril

24

4. Angiotensin-converting enzyme inhibitors (ACEI), blockers of AT1 rc.

Adverse effects and contraindications of ACEI:
-are generally well tolerated. Adverse effects include:

First dose hypotension - particularly in those receiving diuretic

therapy; the first dose should preferably be given at bedtime.

Dry cough
- the most frequent (5-30%) symptom; could be reduced by treatment
with sulindac (inhibits prostaglandin biosynthesis)

Urticaria and angioneurotic edema

- kinin concentrations urticarial reactions and angioneurotic

edema)

Functional renal failure

- occurs predictably in patients with hemodynamically bilateral renal
artery stenosis, and in patients with renal artery stenosis in the vessel
supplying a single functional kidney (though they protect the diabetic
kidney) - !!! renovascular disease !!!

Fetal injury
- results in oligohydramnios, craniofacial malformations
- contraindication in pregnancy

4. Angiotensin-converting enzyme inhibitors (ACEI), blockers of AT1 rc.

Hyperkalemia monitor !!
- ACEIs cause a modest increase in plasma potassium as a
result of reduced aldosterone secretion. This may usefully
counter the small reduction in potassium ion concentration
caused by thiazide diuretics.
Potassium accumulation may be marked, especially if the
patient is consuming high-potassium diet and/or potasssiumsparing diuretics. Under these circumstances, potassium
concentrations may reach toxic levels (hazardous in patients
with renal impairment).

Therapeutic combination:
- useful interaction ACEIs with diuretics: Converting enzyme inhibitors interrupt
by diuretics increased plasma renin activity (and the consequent activation of
angiotensin II and aldosterone) and enhance the antihypertensive efficacy of
diuretics, as well as reducing thiazide-induced hypokalemia.
- adverse interaction ACE inhibitors with potassium-sparing diuretics and
potassium supplements, leading to hyperkalemia especially in patients with renal
impairment !!! NSAID renal damage

4. Angiotensin-converting enzyme inhibitors (ACEI), blockers of AT1 rc.

B) BLOCKERS OF AT1 RECEPTOR

losartan, valosartan, irbesartan

- the receptor blockers - competitively inhibit angiotensin II at its AT1

receptor site

most of the effects of angiotensin II - including vasoconstriction

and aldosterone release - are mediated by the AT1 receptor
AT1-blockers do not block AT2 receptor, which is exposed to
high concentration of angiotensin II during treatment with AT1blockers
they influence RAS more effective because of selective blockade
(angiotensin II synthesis in tissue is not completely dependent only
on renin release, e.g. in heart, but could be promote by serinprotease - stronger influence on the myocard remodelling)

angiotensinogen
renin
angiotensin I
chymase
CAGE

ACE
angiotensin II

nonrenin proteases
cathepsin
t-PA

- these drugs lower blood pressure as the ACE inhibitors and have the
advantage of much lower incidence of adverse effects resulting from
accumulation of bradykinin (cough, angioneurotic oedema)
- they cause fetal renal toxicity (like that of the ACE inhibitors)
- these drugs reduce aldosterone levels and cause potassium
accumulation (attainment of toxic levels - hazardous in patients
with renal impairment).

Clinical pharmacology of
hypertension
Hypertension in the elderly
Benefit from antihypertensive therapy is evident up to at least 80 years of age, but
it is probably inappropriate to apply a strict age limit when deciding on drug therapy.
Elderly individuals who have a good outlook for longevity should have their blood
pressure lowered if they are hypertensive.
The thresholds for treatment are diastolic pressure averaging 90 mmHg or
systolic pressure averaging 160 mmHg over 3 to 6 months observation
(despite appropriate non-drug treatment).

A low dose of a thiazide is the clear drug of first choice, with addition of another
antihypertensive drug when necessary.

Isolated systolic hypertension

Isolated systolic hypertension (systolic pressure 160 mmHg, diastolic pressure
< 90 mmHg) is associated with an increased cardiovascular disease risk,
particularly in those aged over 60 years. Systolic blood pressure averaging
160 mmHg or higher over 3 to 6 months (despite appropriate non-drug
treatment) should be lowered in those over 60 years, even if diastolic hypertension
is absent.
Treatment with a low dose of a thiazide, with addition of a beta-blocker when
necessary is effective; a long-acting dihydropyridine calcium-channel blocker is
recommended when a thiazide is contra-indicated or not tolerated.

Patients with severe postural hypotension should not receive blood pressure
lowering drugs.
Isolated systolic hypertension in younger patients is uncommon but treatment
may be indicated in those with a threshold systolic pressure of 160 mmHg (or less if
at increased risk of cardiovascular disease).

Hypertension in diabetes
For patients with diabetes, the aim should be to maintain systolic pressure
< 130 mmHg and diastolic pressure < 80 mmHg. However, in some individuals,
it may not be possible to achieve this level of control despite appropriate therapy.
Low-dose thiazides, beta-blockers, ACE inhibitors (or angiotensin-II receptor
antagonists) and long-acting dihydropyridine calcium-channel blockers are all
beneficial. Most patients require a combination of antihypertensive drugs.

Hypertension is common in type 2 (non-insulin-dependent) diabetes and

antihypertensive treatment prevents macrovascular and microvascular
complications.
In type 1 (insulin-dependent) diabetes, hypertension usually indicates the presence
of diabetic nephropathy. An ACE inhibitor (or an angiotensin-II receptor
antagonist) may have a specific role in the management of diabetic nephropathy;
In patients with type 2 diabetes, an ACE inhibitor (or an angiotensin-II receptor
antagonist) can delay progression of microalbuminuria to nephropathy.

Hypertension in renal disease

The threshold for antihypertensive treatment in patients with renal impairment
or persistent proteinuria is a systolic blood pressure 140 mmHg or a
diastolic blood pressure 90 mmHg.

Optimal blood pressure is a systolic blood pressure < 130 mmHg and a
diastolic pressure < 80 mmHg, or lower if proteinuria exceeds 1 g in 24 hours.
Thiazides may be ineffective and high doses of loop diuretics may be
required. Specific cautions apply to the use of ACE inhibitors in renal
impairment, but ACE inhibitors may be effective. Dihydropyridine calciumchannel blockers may be added.

Hypertension in pregnancy
Methyldopa is safe in pregnancy.
Beta-blockers are effective and safe in the third trimester. Modified-release
preparations of nifedipine [unlicensed] are also used for hypertension in
pregnancy.
Intravenous administration of labetalol can be used to control hypertensive
crises; alternatively, hydralazine may be used by the intravenous route.
Magnesium sulphate in pre-eclampsia and eclampsia

Accelerated or very severe hypertension

Accelerated (or malignant) hypertension or very severe hypertension (e.g.
diastolic blood pressure > 140 mmHg) requires urgent treatment in hospital,
but it is not an indication for parenteral antihypertensive therapy.
Normally treatment should be by mouth with a beta-blocker (atenolol or
labetalol) or a long-acting calcium-channel blocker (e.g. amlodipine or
modified-release nifedipine).
Within the first 24 hours the diastolic blood pressure should be reduced to 100
110 mmHg. Over the next 2 or 3 days blood pressure should be normalised by
using beta-blockers, calcium-channel blockers, diuretics, vasodilators, or ACE
inhibitors.
Very rapid reduction in blood pressure can reduce organ perfusion leading to
cerebral infarction and blindness, deterioration in renal function, and
myocardial ischaemia.
Parenteral antihypertensive drugs are rarely necessary; sodium
nitroprusside by infusion is the drug of choice on the rare occasions when
parenteral treatment is necessary.