Download CLINICAL Pharm_antihypertensives

Clinical Pharmacology of
Drugs for Controlling
Vascular Tone.
ANTIHYPERTENSIVE
DRUGS
ANTIHYPERTENSIVE DRUGS
I. DIURETICS
Bumetanide, furosemide, hydrochlorthiazide, spironolactone,
triamterene
II. -BLOCKERS
Atenolol, labetalol, metoprolol, propranolol, timolol
III. ACE INHIBITORS
Captopril, benazepril, enalapril, fosinopril, lisinopril, moexipril,
quinapril, ramipril
IV. ANGIOTENSIN II ANTAGONIST
Losartan
V. Ca++CHANNEL BLOCKERS
Amlodipine, diltiazem, felodipine, isradipine, nicardipine,
nifedipine, nisoldipine, verapamil
VI. -BLOCKERS
Doxazosin, prazosin, terazosin
VII. OTHER
Clonidine, diazoxide, hydralazine, -methyldopa, minoxidil,
sodium nitroprusside
TREATMENT STRATEGIES
Mild hypertension can often be controlled with a
single drug. More severe hypertension may
require treatment with several drugs that are
selected to minimize adverse effects of the
combined regimen. Treatment is initiated with
any of four drugs depending on the individual
patient: a diuretic, a -blocker, an ACE inhibitor,
or a calcium channel blocker. If blood pressure
is inadequately controlled, a second drug is
added. A -blocker is usually added if the initial
drug was a diuretic, or a diuretic is added if the
first drug was a -blocker. A vasodilator can be
added as a third step for those patients who still
fail to respond.
Treatment of arterial hypertension
Drugs of first row
-diuretics (furosemid, dichlothiazide, spironolacton)
-inhibitors of ACE (captopril, enalapril, ramipril)
-antagonists of angiotesine II receptors (АRА ІІ) (losartan)
-β-adrenoblockers (anaprilin, atenolol, thymolol)
-α-, β-adrenoblockers (labetolol, carvedilol)
-Ca ions antagonists (niphedipine, amlodipine, verapamil)
Drugs of second row :
-α-adrenoblockers (prasosine, terasosine)
-agonists of α2 –adrenoreceptors of central action (clopheline,
methyldopa)
-sympatholytics (reserpin, octadin)
-direct vasodilators (molsidomin, hydralasin)
New drugs:
-imidasolines (moxonidine, rilmenidine)
-serotonin receptors blockers (ketanserin)
-monateril (calcium antagonist, α2 -adrenoblocker)
Mechanism of action of thiaside diuretics
in case of arterial hypertension
Dychlothiaside
(hypothiaside)
Oxodolin
(chlortalidon, hygroton)
Thiaside
diuretics
Holding sodium and
water
Volume of circulating
blood
Peripheral vascular
resistance
Decreasing of arterial
pressure
Cardiac output
Hydrochlorothiazide+Losartan
Thiazide diuretics. Adverse effects:
Thiazide diuretics induce hypokalemia and
hyperuricemia in 70 % of patients, and hyperglycemia in
10 % of patients. Serum potassium levels should be
monitored closely on patients who are predisposed to
cardiac arrhythmias (with left ventricular hypertrophy,
ischemic heart disease, or chronic congestive heart
failure) (to prevent development of fatigue, cramps, and
arrhythmias) and who are concurrently being treated with
both thiazide diuretics and digitalis glycosides. Diuretics
should be avoided in the treatment of hypertensive
diabetics or patients with hyperlipidemia
Loop diuretics
The loop diuretics act promptly, even in
patients who have poor renal function or
who have not responded to thiazides or
other diuretics.
-blockers. Therapeutic uses
The -blockers are more effective for
treating hypertension in white young
patients. They are useful in treating
conditions that may coexist with
hypertension, such as
supraventricular tachyarrhythmia,
previous myocardial infarction,
angina pectoris,
glaucoma, and
migraine headache.
β-adrenoblockers
Used for mostly mild to moderate cases of AH
(frequently in combinations with other drugs)
Stable hypotensive response develops over
1-3 weeks
Titration the effective dose. The -blockers may
take several weeks to develop their full effects
Antihypertensive action is maintained over
24 hr after single daily dose
Contraindications: bronchial asthma, peripheral
vascular disease, diabetes
ACE-INHIBITORS
The angiotensin-converting enzyme (ACE)
inhibitors (captopril, enalapril, lisinopril,
perindopril) are recommended when the
preferred first-line agents (diuretics or blockers) are contraindicated or
ineffective.
MECHANISM OF ACTION OF
IACE
ANGIOTENSINOGEN
sympathetic
tone
Renin (kidneys)
ANGIOTENSIN
(inactive)
Decrease
angiotensine II
production
ACE
IACE
Decrease
aldosterone
production
peripheral
vessels tone
retention of
Na+ and H2O
bradicinine
Decrease of
arterial
pressure
Therapeutic uses
Like -blockers, ACE inhibitors are most
effective in hypertensive patients who are
white and young.
However, when used in combination with a
diuretic, the effectiveness of ACE inhibitors is
similar in white and black hypertensive patients.
ACE inhibitors are effective in the management
of patients with chronic congestive heart
failure.
ACE inhibitors are now a standard in the care of
a patient following a myocardial infarction.
Therapy is started 24 hours after the end of the
infarction.
ACE inhibitors adverse effects
Common side effects include
dry cough, rashes, fever, altered taste,
hypotension, and hyperkalemia.
Potassium levels must be monitored, and
potassium supplements or spironolactone are
contraindicated.
Because of the risk of angioedema and first
dose syncope, ACE inhibitors are first
administered in the physician’s office with close
observation.
Reversible renal failure can occur in patients
with severe renal artery stenosis.
ACE inhibitors are fetotoxic and should not be
used in pregnant women.
ANGIOTENSIN II ANTAGONISTS
Losartan (Cozaar®), Valsartan (Diovan®),
Irbesartan (Avapro®), Candesartan
(Atacand®).
The nanopeptide losartan, a highly
selective angiotensin II receptor blocker,
has recently been approved for
antihypertensive therapy. Its
pharmacologic effects are similar to ACE
inhibitors in that it produces vasodilation
and blocks aldosterone secretion. Its
adverse effects is improved over the ACE
inhibitors, although it is fetotoxic.
ANGIOTENSIN II ANTAGONISTS
CALCIUM CHANNEL BLOCKERS
– Calcium channel blockers are recommended when
the preferred first-line agents are contraindicated or
ineffective.
– Calcium channel antagonists block the inward
movement of calcium by binding to L-tipe calcium
channels in the heart and in the smooth-muscle of the
coronary and peripheral vasculature. This causes
vascular smooth muscle to relax, dilating mainly
arterioles.
– Calcium channel blockers have an intrinsic natriuretic
effect ; therefore, they do not usually require the
addition of a diuretic.
-ADRENERGIC BLOCKING AGENTS
Prazosin, doxazosin and terazosin produce a
competitive block of 1 adrenoreceptors. They decrease
peripheral vascular resistance and lower arterial blood
pressure by causing the relaxation of both arterial and
venous smooth muscle. These drugs cause only minimal
changes in cardiac output, renal blood flow, and
glomerular filtration rate. Postural hypotension may
occur in some individuals. Prazosin is used to treat
mild to moderate hypertension and is prescribed in
combination with propranolol or a diuretic for additive
effects
Prasosine
(α 1 –
–adrenoblocker
adrenoblocker))
CENTRALLY-ACTING
ADRENERGIC DRUGS
Clonidine – 2-agonist – diminishes central adrenergic
outflow. Clonidine does not decrease renal blood flow or
glomerular filtration and therefore is useful in the
treatment of hypertension complicated by renal disease.
Because it causes sodium and water retention, clonidine
is usually administered in combination with diuretic.
CENTRALLY-ACTING
ADRENERGIC DRUGS
Adverse effects are generally mild, but the
drug can produce sedation and drying of
nasal mucosa. Rebound hypertension
occurs following abrupt withdrawal of
clonidine. The dug therefore should be
withdrawal slowly if the clinician wishes to
change agents.
CENTRALLY-ACTING
ADRENERGIC DRUGS
-Methyldopa. This 2-agonist is converted to
methylnorepinephrine centrally to diminish the
adrenergic outflow from the CNS, leading to
reduced total peripheral resistance and a
decreased blood pressure. Because blood flow
to the kidney is not diminished by its use, methyldopa is especially valuable in treating
hypertensive patients with renal insufficiency.
The most common side effects of -methyldopa
are sedation and drowsiness.
VASODILATORS
The direct-acting smooth muscle relaxants, such
as hydralazine and minoxidil, have traditionally
not been used as primary drugs to treat
hypertension. They act by producing relaxation
of vascular smooth muscle, which decreases
resistance and therefore decreases blood
pressure. These agents produce reflex
stimulation of the heart. They may prompt
angina pectoris, myocardial infarction, or cardiac
failure in predisposed individuals.
VASODILATORS
Mechanisms of Action of Vasodilators.
Mechanism
Examples
Release of nitric oxide from drug or endothelium
Nitroprusside, hydralazine, nitrates,
histamine, acetylcholine
Reduction of calcium influx
Verapamil, diltiazem, nifedipine
Hyperpolarization of smooth muscle membrane
through opening of potassium channels
Minoxidil, diazoxide
Activation of dopamine receptors
Fenoldopam
PRINCIPLES OF THERAPY
Therapeutic Regimens
Once the diagnosis of hypertension is established, a
therapeutic regimen must be designed and
implemented. The goal of management for most
clients is to achieve and maintain normal blood
pressure range (below 140/90 mm Hg). If this goal
cannot be achieved, lowering blood pressure to any
extent is still considered beneficial in decreasing the
incidence of coronary artery disease and stroke.
PRINCIPLES OF THERAPY
(cont’d)
If the initial drug (and dose) does not produce the
desired blood pressure, options for further
management include increasing the drug dose,
substituting another drug, or adding a second drug
from a different group. If the response is still
inadequate, a second or third drug may be added,
including a diuretic if not previously prescribed.
When current management is ineffective, reassess
the client’s compliance with lifestyle modifications
and drug therapy. In addition, review other factors
that may decrease the therapeutic response,such as
over-the-counter appetite suppressants, dietary or
herbal supplements, or nasal decongestants, which
raise blood pressure.
HYPERTENSIVE EMERGENCY
– is a life-threatening situation in which the
diastolic blood pressure is either over 150
mm Hg (with systolic blood pressure
greater than 210 mm Hg) in an otherwise
healthy person, or 130 mm Hg in an
individual with preexisting complications,
such as encephalopathy, cerebral
hemorrhage, left ventricular failure, or
aortic stenosis. The therapeutic goal is to
rapidly reduce blood pressure.
MANAGEMENT OF HYPERTENSIVE EMERGENCY (intravenously)
Drug
Sodium
nitroprussid
Dose
0,5-10 mcg/kg/min (dropply)
Nitroglycerinum
5-10 mcg/kg (dropply)
Onset
immediately
Side effects
nausea, vomiting,
muscles, sweating
2-5 min
tachicardia,
vomiting,
fibrillation of
flushing,
headache,
Diazoxidum
50-100 mg (quickly)
300 mg (during 10 min)
2-4 min
nausea,
vomiting,,
hypotension,
tachicardia, flushing, redness of skin,
chest pain
Apressinum
10-20 mg
10 min
flushing, redness of skin, headache,
vomiting
Furosemidum
20-60-100 mg during 10-15 sec
2-3 min
hypotension, fatigue
Clophelinum
0,5-1 ml 0,01 % solution (in 15-20 ml
0,9 % solution NaCI slowly)
15-20 min
somnolence
Anaprilinum
5 ml 0,1 % solution (in 20 ml 0,9 % NaCI
solution slowly)
20-30 min
bradicardia
Magnesium
sulfas
5-10-20 ml 25 % solution (i. v. very slowly
or dropply)
15-20 min
redness of skin
Labetololum
20-80 mg (slowly – 10 min) or 2 mg/kg
(dropply); the whole dose – 50-300 mg
5-10 min
nausea,
dizzeness
vomiting,,
hypotension,
REFERENCES
http://www.escardio.org
http://www.cardiosmart.org
http://www.medscape.com/cardiology