Drugs used to treat hypertension

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Drugs used to treat hypertension
2006
2

• 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 Diastolic
• lt130 lt85
• lt139 lt89
• 140-159 90-99
• 160-179 100-109
• 180-209 110-119
• gt210 gt120

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Arterial blood pressure (BP) is determined by
cardiac output (MV) and peripheral vascular
resistance (PR).
BP CO x PR
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
Cardiac output may be increased in children or
young adults during the earliest stages of
essential hypertension
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Hypertension

• Essential (primary)
• - most (90-95 ) patients with persistent
  arterial hypertension
• genesis of hypertension unknown
• predisposing factors

• Secondary
• is secondary to some
• distinct disease
• 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

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)
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• Baroreceptors
• - they are responsible for rapid adjustment
  in blood pressure
• 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

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• 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) !

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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.

• 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
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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
110119 mmHg, confirm over 12 weeks then treat
if these values are sustained Where the initial
blood pressure is systolic 160179 mmHg or
diastolic 100109 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
100109 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
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• Where the initial blood pressure is systolic
  140159 mmHg or diastolic 9099 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 9099 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
  lt 140 mmHg and diastolic blood pressure lt 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
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Drug treatment of hypertension No consistent or
important differences have been found between the
major classes of antihypertensive drugs in terms
of antihypertensive efficacy, side-effects 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. Diuretics 2. Drugs influencing sympathetic
nerves 3. Vasodilators 4. Angiotensin-convertin
g enzyme inhibitors (ACEI), blockers of
AT1 receptor
BNF 51th edition, 2006
11
Thiazides particularly indicated for
hypertension in the elderly a contra-indication
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
contra-indications include heart failure and
heart block Alpha-blockers a possible
indication is prostatism a contra-indication is
urinary incontinence.
BNF 51th edition, 2006
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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
13
- 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
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
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Lumen urine
Distal convoluted tubule
Interstitium - blood
Thiazides
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• 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

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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) Hypercholest
erolemia (a small ? in plasma cholesterol
concentration)
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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)

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Lumen urine
Thick ascending limb
Interstitium - blood
Furosemide
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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 (gt 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.
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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
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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 alpha1-blockers)
• - oral administration of any of these drugs can
  cause nausea, vomiting, diarrhoea
• - urinary incontinece
• - priapism, nasal congestion

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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.
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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.

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2. Drugs influencing sympathetic nerves
b-adrenoreceptor antagonists
cardio-selective b1 blockers atenolol,
metoprolol b1 blockers with ISA acebutol
b1 a1 blockers labetalol, carvedilol
cardio non-selective b1 b2
blockers metiprolol, propranolol,
nadolol b1 b2 blockers with
ISA 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
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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.

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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)
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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)
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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)

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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 beta-vlocker and diuretic
is mandatory for this drug, oedemas,
hypertrichosis, breast tenderness
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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
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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 - the stock solution
should be diluted and covered with foil to
prevent photodeactivation - adverse effects too
rapid reduction of BP, nausea, palpitation,
dizziness cyanide metabolite accumulation
tachycardia, hyperventilation, arrhythmias,
acidosis
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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

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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)

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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

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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.
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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

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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

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4. Angiotensin-converting enzyme inhibitors
(ACEI), blockers of AT1 rc.
ACE inhibitors
40
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
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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.

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4. Angiotensin-converting enzyme inhibitors
(ACEI), blockers of AT1 rc.
ACE inhibitors
Drug Duration of effect (hours)
Short-acting captopril 6-8
Medially-acting enalapril 12
Medially-acting quinapril 12
Long-acting perindopril 24
Long-acting lisinopril 24
Long-acting spirapril 24
Long-acting ramipril 24
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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

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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 potasssium-
sparing 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
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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
  AT1- blockers
• 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 serin-
• protease - stronger influence on the myocard
  remodelling)

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angiotensinogen
renin
nonrenin proteases cathepsin t-PA
angiotensin I
chymase CAGE
ACE
angiotensin II
47
- 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).
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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.
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Isolated systolic hypertension Isolated systolic
hypertension (systolic pressure  160  mmHg,
diastolic pressure lt 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).
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Hypertension in diabetes For patients with
diabetes, the aim should be to maintain systolic
pressure lt 130 mmHg and diastolic pressure
lt 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.
51
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 lt 130 mmHg
and a diastolic pressure lt 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 calcium-channel 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
52
Accelerated or very severe hypertension Accelerat
ed (or malignant) hypertension or very severe
hypertension (e.g. diastolic blood pressure
gt 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 100110 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.