ANTIHYPERTENSIVE DRUGS

Antihypertensives are drugs that decrease the blood pressure through different
pharmacodynamic mechanisms. The high blood pressure (HBP) is an increase in systolic
blood pressure value that exceeds 140 mmHg and/or the diastolic one over 90 mmHg. In time
it can lead to severe complications, like stroke, heart failure, acute pulmonary edema or renal
failure. That is why an early diagnosis and a correct treatment of HBP are very important. The
target is to obtain a value of 140/90 mmHg, and in patients with diabetes and/or ischemic
heart disease even less, 130/80 mmHg.
The classification of high blood pressure, according to the blood pressure values:
● HBP stage I (mild): 140 – 159 / 90 - 99 mmHg
● HBP stage II (moderate): 160 – 179 / 100 – 109 mmHg
● HBP stage III (severe): more than 180 / 110 mmHg
The lifelong treatment in HBP is administered to decrease the blood pressure, to
maintain it as close as possible to the normal values and to prevent the complications. The
drug treatment should always be associated with some nonpharmacological measures: the
reduced salt and animal fat intake, smoking cessation, reducing overweight and the sedentary
behaviour.
The blood pressure is in direct relation with the cardiac output and the peripheral
vascular resistance. The physiological adjustment of blood pressure is made by:
● The vegetative nervous system: the sympathetic nervous system increases the blood
pressure by increasing the cardiac output and the peripheral vascular resistance. The
parasympathetic nervous system decreases the blood pressure by inducing
bradycardia, vasodilation and decreasing the cardiac output.
● The renin-angiotensin-aldosteron system (RAAS): renin, produced by the
juxtaglomerular cells in the kidney acts on angiotensinogen, resulting angiotensin I
(vasodilator), converted to angiotensin II, a strong vasoconstrictor and stimulator of
aldosteron secretion.
● The renal regulation of blood pressure: the renal artery perfusion pressure directly
regulates sodium excretion and influences the RAAS.
Classification
1. Diuretics
2. Renin-angiotensin-aldosteron system inhibitors
3. Sympatholytics
4. Calcium channel blockers
5. Direct vasodilators

DIURETICS

Diuretics are drugs that stimulate the renal elimination process of sodium and water,
decrease the plasmatic volume and the cardiac output, reducing the blood pressure values.
Classification. Diuretics are divided in 4 classes:
● Thiazides and related agents
▪ Benzothiadiazines
HYDROCHLOROTHIAZIDE
▪ Thaizid-like
CHLORTHALIDONE
INDAPAMIDE
● Loop diuretics
FUROSEMIDE ETHACRYNIC ACID
 BUMETANIDE PIRETANIDE
● Potassium sparing diuretics (antialdosteronics)
SPIRONOLACTONE AMILORIDE
EPLERENONE TRIAMTERENE
● Osmotic diuretics
MANNITOL
GLYCEROL
SORBITOL
Mechanism of action
The diuretics used in the treatment of HBP have different sites and mechanisms of
action (see the figure below)

THIAZID DIURETICS
The thaizid and loop diuretics are the most commonly prescribed diuretics in the
treatment of HBP.
Pharmacokinetics
● They are well absorbed after oral administration.
● They are renally eliminated and can produce active concentrations in the renal tubule,
acting on the luminal pole of the tubule cell.
● The duration of action for Hydrochlorothiazide is 12 hours and for Chlorthalidone 48-
72 hours.
Pharmacodynamics
● Thiazides have a mild diuretic action compared to loop diuretics.
● Lead to an increased water and electrolite (K +, Na+, Cl-) elimination, considered to be
hypokalemiant diuretics.
● Their antihypertensive action is mild to moderate, acting by decreasing the volemia,
cardiac output and taking sodium and water out of the vascular smooth muscle cells,
lowering the degree of vascular wall edema and vascular peripheral resistance.
Mechanism of action
● The thiazides act especially at the dilution segment of the contort distal tubule,
inhibiting the reabsorption and increase the elimination of water and electrolytes
(sodium, potassium, chloride, bicarbonate).
● In contrast to loop diuretics the calcium reabsorption is promoted.
 ● Administered in a high dose, they can inhibit the carbonic anhydrase.
Indications
● Mild or moderate HBP
● Heart failure
● Mild cardiac, hepatic or allergic edema
Adverse effects
● Hypokalemia (rare compared to Furosemid); can increase the risk of digitalis
intoxication.
● Hypomagnesemia, probably through the functional coupling between the elimination
of potassium and magnesium.
● Hypercalcemia (contrarily to loop diuretics).
● Hypochloremia, hypochloremic alcalosis.
● Reduced tolerance to glucose (hyperglycemia tendency) in predisposed patients.
● Metabolic: hyperuricemia, hyperglycemia and hypercholesterolemia; more intense
after Hydrochlorothiazide, less after Indapamide.

LOOP DIURETICS
♦ Furosemide

Pharmacokinetics
● After IV administration, the diuretic effect appears rapidly, in the first 5 minutes.
● After oral administration it is well absorbed in the gastrointestinal tract.
● It binds to plasma proteins 99%.
● The T1/2 is aproximatively one hour.
● It is renally eliminated and can be found in active concentration in the renal tubule
lumen.
Pharmacodynamics
● The diuretic action is intense and rapid, lasts for 6-7 hours and consists of a large
elimination of water and electrolytes (K+, Na+, Cl-, Mg2+), useful in hypertensive crisis.
● Loop diuretics increase the renal plasma flow (because they increase prostaglandine
level and renin) and are useful in renal failure.
Mechanism of action
● The loop diuretics act on the ascending Henle loop, inhibiting the co-transport system
for sodium, potassium, chloride, with the elimination of great amounts of water and
this electrolytes.
Indications
● HBP crisis, because they decrease rapidly the plasma volume, the cardiac output,
decreasing the blood pressure.
● Acute pulmonary edema.
● Renal failure.
● Sever heart failure, because of reducing edema and pulmonary overload.
● Edema in liver cirrhosis or nephrotic syndrome.
Adverse effects
● Hypokalemia.
● Metabolic: hyperuricemia, hyperglycemia.
● Dehydration, especially in elderly.
● Temporary deafness.
Contraindications
● Hypovolemia or dehydration.
 ● Severe hypokalemia.
● Severe hyponatremia.
Drug interactions
● NSAIDs and glucocorticoids decrease the antihypertensive effect of Furosemide.
● The association with other antihypertensive drugs increases the risk of hypotension.

POTASSIUM SPARING DIURETICS (HYPERKALEMIANTS,

ANTIALDOSTERONICS)

♦ Spironolactone, Eplerenone

Pharmacokinetics
● They are well absorbed from the digestive tract, metabolised in the liver, renally and
digestive eliminated.
● The T1/2 for Spironolactone is 14 hours, for Eplerenone 3-5 hours.
● The latency is 24 hours, the effect lasts for 48 hours.
Mechanism of action
● Because of the similar structure to aldosterone, they will bind to the receptors in the
convoluted distal and collector tubule, decreasing the reabsorption of sodium, with
natriuretic effect, but retain potassium and hydrogen.
● They have a weak diuretic action.
Indications
● Heart failure.
● Primary or secondary hyperaldosteronism.
● Hypokalemia (arrhythmia, ileus, miastenia gravis)
● Edema, in association with loop diuretics (Furosemide).
Adverse effects
● Hyperkalemia.
● Endocrine disturbances: sexual impotence, gynecomastia in male patients, hirsutism
and amenorrhea in female patients. This effects are mild after the administration of
Eplerenone.
Contraindications
● Hyperkalemia.
● Acute renal failure, severe liver failure.
● Caution in chronic renal failure.
Drug interactions
● The association with other potassium sparing diuretics or potassium salts increase the
risk of hyperkalemia.
● The association with converting enzyme inhibitors needs potassium level monitoring.
● NSAIDs reduce the effect of Spironolactone.

OSMOTIC DIURETICS

♦ Mannitol, Glycerol, Sorbitol

Pharmacokinetics
● After IV administration, Mannitol is rapidly renally excreted, before it could have
been metabolised. Mannitol remains in the extracellular space. 80% of the IV
administered dose is renally eliminated in 3 hours.
Mechanism of action
● Administered IV, they increase the plasma osmolarity and actively mobilize the water
from tissues into the vessels, increasing the circulant volume. After glomerular
filtration, osmotic diuretics remain in the urin, were they retain the osmotic equivalent
of water, increasing the elimination.
Indications
● Prevention of anuria in the early phases of acute renal failure.
● Acute intoxications.
● Cerebral edema.
● Acute congestive glaucoma.
● Not to be used in the treatment of HBP.
Adverse effects
● Administered in high doses, they produce a circulatory overload, with an increase in
blood pressure and acute pulmonary edema.
Contraindications
● Edema in heart failure or acute pulmonary edema.
● Dehydration
● Intracranial bleeding
● Persistent oligo- or anuria after testing (5 minutes after the administration of 0,2 g/kg
Mannitol, diuresis should be at least 40-50 ml/hour)

RENIN-ANGIOTENSIN-ALDOSTERON SYSTEM (RAAS) INHIBITORS

Classification
● Angiotensin converting enzyme (ACE) inhibitors
BENAZEPRIL MOEXIPRIL
CAPTOPRIL PERINDOPRIL
CILAZAPRIL QUINAPRIL
ENALAPRIL RAMIPRIL
FOSINOPRIL SPIRAPRIL
LISINOPRIL TRANDOLAPRIL
● Angiotensin II receptor antagonists (sartans, AT1 receptor blockers)
LOSARTAN TELMISARTAN
VALSARTAN OLMESARTAN
EPROSARTAN CANDESARTAN
IRBESARTAN
● Direct renin inhibitors
ALISKIREN
Mechanism of action
RAAS inhibitors act at different levels of the RAAS (see the figure below).
ANGIOTENSIN-CONVERTING ENZYME INHIBITORS (ACE INHIBITORS)

ACE inhibitors are widely used in the therapy of HBP and heart failure, because the
RAAS is involved in their pathogenesis. They have several advantages: decrease the degree
of left ventricular hypertrophy, increase the life expectancy, do not develop tolerance, reflex
tachycardia or influence the metabolism.
Mechanism of action. Pharmacodynamics
● They inhibit the ACE, reducing the angiotensin II, substance with strong
vasoconstricting effect, causing vasodilation and reduction in peripheral resistance,
without modifying the cardiac output or heart rate.
● This drugs inhibit the myocardial fibrosis induced by angiotensin II, preventing and
reducing the ventricular hypertrophy, increasing the lifespan of this patients.
● They inhibit the remodelling after acute myocardial infarction (AMI).
● ACE inhibitors increase bradykinin levels (vasodilating effect) and prostaglandin
synthesis.
● Stimulate the prostaglandin E2 synthesis, with vasodilating and diuretic effect.
● Inhibit the aldosteron secretion, reducing renal sodium and water reabsorption.
● Increase sodium excretion through intrarenal mechanisms.
● Act through reducing the central sympathetic tone, modulation of baroreflexes,
decreasing the antidiuretic hormone production.
● Lower the biosynthesis and presynaptic release of Norepinephrine, plus increase its
reuptake in the periphery.
● Provides renoprotection in renal diseases, including diabetic nephropathy, through
proteinuria reduction.
Indications
● HBP, especially in left ventricular hypertrophy or after AMI.
● Chronic heart failure.
● Diabetic nephropathy.
Adverse effects
 ● Hypotension, especially in case of previous diuretic treatment, renal artery stenosis,
heart failure, hypovolemia (fever, vomiting) or low sodium diet. That is why the
treatment will be initiated with small doses and the diuretic administration will be
stopped for a short period, if needed.
● Renal failure, especially in case of bilateral renal artery stenosis, in single kidney
stenosis or in ischemic nephropathy, because normally the glomerular perfusion
pressure is determined by the afferent arteriolar vasodilation and the efferent
arteriolar vasoconstriction. The glomerular perfusion pressure may drop, with
concomitant signs of acute renal failure.
● Dry cough and bronchial spasm in 5-20% of the cases, because of bradikinin
accumulation.
● Angioneurotic edema.
● Allergic reactions, itching, exanthem.
● Loss of taste or metallic taste (rare, specific for Captopril).
Contraindications
● Angioedema.
● Pregnancy and lactation period.
● Bi- or unilateral renal artery stenosis.
● Advanced renal failure.
● Aortic stenosis, mitral stenosis, hypertrophic myopathy.
● Autoimmune diseases (colagenosis) and immunosuppressant therapy.
● Hypersensitivity reactions to the treatment.
Drug interactions
● Should not be associated with other ACE inhibitors.
● The risk of hypotension increases in case of association with other antihypertensive
drugs.
● There is a risk of leukopenia, in association with Allopurinol, glucocorticoids,
immunodepressants and anticancer drugs.
● NSAIDs inhibit prostaglandin synthesis, with sodium and water retention, which
reduces the antihypertensive effect of ACE inhibitors.
● The association with potassium, potassium sparing diuretics or Heparin, increases the
risk of hyperkalemia.
● ACE inhibitors increase the effects of Lithium salts.
● In case of patients treated with oral antidiabetic drugs or Insulin, a higher frequency of
hypoglycemia or glycemia fluctuations was detected.
● Alcohol consumption increase the risk of hypotension. Smoking lowers the effect of
ACE inhibitors.

ANGIOTENSIN II RECEPTOR ANTAGONISTS (SARTANS)

This class was introduced in 1995 in the therapy of HBP and heart failure.
Pharmacokinetics
● After oral administration they are rapidly absorbed and have a different
bioavailability.
● Food lowers the Valsartan absorption by 40%.
● Losartan and Candesartan are considered to be prodrugs.
Mechanism of action and pharmacodynamics
 ● There are evidences that angiotensin II is produced by alternative routes, not involving
the converting enzyme (the most important, but not single way). Just inhibiting this
enzyme will not stop the secondary routes of producing angiotensin II. That is why a
new class of drugs, blocking of the angiotensin II receptors, was developed.
● They cause selective inhibition upon the angiotensin-II receptor type AT 1 (without
any effect on AT2 receptors), resulting in vasodilation.
● The hypotensive effect is a result of the reduction in peripheral resistance, without
modifying the cardiac output and heart beat.
● The nephroprotecting effect is done by decreasing the proteinuria, slowing down the
disease progression.
● Uricosuric effect.
Indications
● HBP.
● Heart failure (only Candesartan, Losartan and Valsartan).
● Diabetic nephropathy with or without renal failure.
Adverse effects
● Hyperkalemia.
● Dry cough, less common compared to ACE inhibitors.
● Orthostatic hypotension, especially in associated treatment with diuretics and
dehydration.
● Dizziness, headache.
● Fetal toxicity.
● After the prolonged administration of Olmesartan, a reversible enteropathy can
rarely occur.
Contraindications
● Pregnancy, breastfeeding.
● Liver failure or colestasis.
● Bilateral renal artery stenosis;

DIRECT RENIN INHIBITORS

♦ Aliskiren

Pharmacokinetics
● After oral administration, it has a low bioavailability and a T1/2 of 40 hours.
Mechanism of action
● Aliskiren is a direct renin inhibitor, inhibiting the angiotensin I and II synthesis,
producing vasodilation, decreasing the aldosteron secretion and blood pressure.
Indications
● HBP.
Adverse effects
● Diarrhea is the most frequent side effect.
Drug interactions
● The association of Aliskiren with Cyclosporin, Quinidine and Verapamil is forbidden.
● The association with other inhibitors of the RAAS is to be avoided.

SYMPATHOLYTICS
 This class includes the drugs that act as sympathetic inhibitors, central or peripheral,
and adrenergic receptor (alpha and beta) antagonists (see also the “Adrenergic drugs”
chapter).

Classification
● Beta-blockers
▪ Nonselective agents
PROPRANOLOL OXPRENOLOL
SOTALOL PINDOLOL
TIMOLOL CARTEOLOL
▪ Selective agents
ESMOLOL BETAXOLOL
ATENOLOL NEBIVOLOL
METOPROLOL ACEBUTOLOL
BISOPROLOL CELIPROLOL
▪ Alfa and beta blockers
LABETOLOL
CARVEDILOL
● Alfa-blockers
▪ Non-selective agents (α1 and α2):
PHENTOLAMINE
PHENOXYBENZAMINE
TOLAZOLINE
▪ Selective agents (α1):
PRAZOSIN
DOXAZOSIN
TERAZOSIN
● Sympathetic inhibitors with central action
METHYLDOPA GUANFACINE
CLONIDINE MOXONIDINE
GUANABENZ
● Sympathetic inhibitors with peripheral action
GUANETIDINE
GUANADREL
RESERPINE
● Sympathetic inhibitors with mixed action
URAPIDIL

BETA BLOCKERS

Beta-blockers are the cardiovascular drugs with the most indications. They
competitively block the beta adrenergic receptors, preventing their stimulation by
norepinephrine released from the vesicle storage or by circulant cathecolamines (epinehrine
and norepinephrine). This drugs are administered in younger patients with hyperreninemia.
Their cardioprotective effect after AMI and the beneficial effect in the treatment of heart
failure, consolidated their position as first line drugs in HBP therapy.
 Despite having the same mechanism of action, beta blockers are classified accroding
to the specific side effects, resulting from their cardioselectivity, the intrinsic
sympathomimetic activity or their liposolubility.
● Cardioselectivity is related to the blocking intensity of the beta 1 cardiac receptors, in
comparison to the beta 2 bronchial and vascular receptors.
● Intrinsic sympathomimetic activity (ISA) is the capacity of some beta blockers to
interact with beta receptors, producing a measurable agonist effect.
● Liposolubility differentiates them. Atenolol and Nadolol have a low liposolubility and
do not cross the blood-brain-barrier, have reduced adverse effects, are slowly
metabolized and have a prolonged pharmacodynamic activity. Propranolol,
Metoprolol and others have a high liposolubility.
Classification
● Non-selective agents (block the β1 and β2 receptors)
▪ Without ISA
PROPRANOLOL (liposoluble)
SOTALOL (hydrosoluble, potassium channel blocker)
TIMOLOL
▪ With ISA
OXPRENOLOL (liposoluble)
PINDOLOL
CARTEOLOL
● Selective agents (block the β1 receptors)
▪ Without ISA
ESMOLOL
ATENOLOL (hydrosoluble)
METOPROLOL
BISOPROLOL
BETAXOLOL (liposoluble)
NEBIVOLOL (liposoluble)
▪ With ISA
ACEBUTOLOL
CELIPROLOL
● Beta blockers with alpha blocking action
LABETOLOL
CARVEDILOL (liposoluble, with α1 blocking action)
Mechanism of action
● They block the β-adrenoceptors, decreasing the heart rate, contractility (decreased
myocardial oxygen demand), systolic blood pressure, the renin, angiotensin II and
aldosteron production.
● Carvedilol is a nonselective beta blocker with α 1 blocking action, useful in the
treatment of HBP and heart failure.
● Labetolol reduces the blood pressure because of the nonselective beta blocking
effect, selective alpha blocking action and ISA, with peripheral vasodilation and a low
decrease in the cardiac output, administered in mild/medium HBP and hypertensive
emergencies.
● They decrease the nocturnal melatonin release, causing sometimes sleep
disturbances.
 ● The mechanism of the favourable and paradoxal effect in patients with heart failure
is unknown.
Pharmacodynamic action
● Upon the heart they have a negative inotropic, chronotropic, dromotropic and
bathmotropic effect. The actions of beta blockers are:
▪ Antiarrhythmic, because they decrease the automatism, slow down
the conduction, increase the refractory period duration in the sinus
and atrioventricular node (the heart frequency is not influenced in
resting condition, but only in effort or sympathetic stimulation).
▪ Antianginal and coronarodilating effect, because they block the
stimulating sympathetic actions upon the heart, producing
bradycardia, lower contraction force, with a decreased cardiac output
and oxygen consumption. Bradycardia and the prolonged diastolic
period eases the blood redistribution to the subendocardic ischemic
areas.
▪ Antihypertensive, because they decrease the cardiac output through:
o Blocking the β1 cardiac receptors (inhibiting the
heartstimulating beta adrenergic influences), with bradycardia
and reduced inotropism.
o Blocking the central adrenergic β formation, reducing the
peripheral sympathetic tonus.
o Decreasing the renin secretion (because of blocking the β
receptors in the juxtaglomerular zone) and plasmatic renin
activity.
o Blocking of the presynaptic receptors and the release of
norepinephrine in the synaptic cleft.
● They decrease intraocular pressure by lowering aqueous umor secretion. Only
Timolol and Betaxolol have this antiglaucoma effect (administered as eye drops).
● The antianxiety effect, with reduced tremor and vegetative symptoms of emotions, is
observed in case of liposoluble beta blockers (Propranolol), which can reach the
brain. They are useful in anxiety. For example Propranolol is found in the drug
Distonocalm, together with other antianxiety substances.
Indications
● HBP
● Arrhythmias (Esmolol, Sotalol): supraventricular tachyarrhythmias,
sympathoaderenergic arrhythmias (hyperthyroidism), atrial flutter and fibrillation,
ventricular arrhythmias (after AMI, coronary disease).
● Angina, post AMI (Atenolol, Metoprolol, Propranolol).
● Heart failure (Bisoprolol, Carvedilol, Metoprolol, Nebivolol), starting with small doses,
increasing slowly (not to decompensate the patient with the negative inotropic effect
)
● Glaucoma (Betaxolol, Timolol) as eye drops.
● Anxiety (Propranolol).
● Migraine prophylaxis (Timolol, Propranolol).
Adverse effects
● Contraction of the bronchiolar smooth muscles (bronchospasm, dyspnea) worsening
bronchial asthma (nonselective beta blockers).
 ● Decreased myocardial contractility (negative inotropic effect).
● Decreased heart rate (bradycardia).
● Atrioventricular conduction disturbances (heart block).
● Peripheral ischemia, with cold extremities, up to Raynaud syndrome.
● Decreased glucose tolerance and masking the hypoglycemia symptoms in diabetic
patients.
● Rebound phenomena at sudden cease of treatment.
● Sexual dysfunction.
● Fatigue, insomnia, dizziness, strange dreams.
Contraindications
Absolute
● Heart block.
● Severe bradycardia.
● Severe bronchial asthma.
● Severe depression.
● Severe peripheral vasospastic diseases (necrosis, gangrene).
Relative
● COPD.
● Raynaud syndrome.
● HBP in pregnancy.
● Vasospastic angina.
● Diabetes mellitus.

ALPHA BLOCKERS

Classification
● Non-selective agents (α1 and α2):
PHENTOLAMINE
PHENOXYBENZAMINE
TOLAZOLINE
● Selective agents (α1):
PRAZOSIN
DOXAZOSIN
TERAZOSIN
Mechanism of action
● They cause inhibition of α1 adrenoceptor mediated vasoconstriction, thus reducing
peripheral resistance and venous pressure.
● They also lower plasma LDL cholesterol, VLDL and triglyceride levels and increase HDL
cholesterol levels.
Indications
● HBP episodes in pheochromocytoma (Phenoxybenzamine, Phentolamine IV).
● Rarely in HBP, because of the reflex tachycardia.
● Prostate hyperplasia (reduced bladder and prostate resistance).
● Coronary artery disease.
● Hyperlipemia.
Adverse effects
● Postural hypotension.
 ● Dizziness, headache, fatigue.
● Palpitations.
● Hydrosaline retention (a diuretic is needed).
● Nausea.

SYMPATHETIC INHIBITORS WITH CENTRAL ACTION

Mechanism of action
● They are α2-adrenoceptor agonists, causing activation of presynaptic α 2-
adrenoceptors (inhibition of noradrenaline release and vasodilation which is
dominating) and postsynaptic α2-adrenoceptors (vasoconstriction).
● They reduce the activity of the vasomotor centre in the brain, causing reduced
sympathetic activity, vasodilation, reduced heart rate and cardiac output.
Indications
▪ HBP, when first-line antihypertensive drugs are ineffective or contraindicated. They
are second- or third-line drugs in the treatment of HBP, administered orally.
Clonidine can be given by IV infusion.
▪ Methyldopa is safe for HBP in pregnancy, asthmatic patients and those with heart or
renal failure (it does not modify renal blood flow).
Adverse effects
▪ Orthostatic hypotension.
▪ Dry mouth.
▪ Decreased psychomotor performances.
▪ Male sexual dysfunction.
▪ Galactorrhea.
▪ Raynaud syndrome.
▪ Diffuse parenchymal liver injury, fever, hemolytic anemia (Methyldopa).
▪ Withdrawal HBP crisis on stopping treatment (Clonidine).
Contraindications
● Depression.
● Liver disease.
● Alcohol consumption.
● Pheochromocytoma.

SYMPATHETIC INHIBITORS WITH PERIPHERAL ACTION

Mechanism of action
● Guanadrel inhibits the function of peripheral postganglionic adrenergic neurons. It is
a false neurotransmitter, inactive at adrenergic receptors.
● Reserpine acts by blocking uptake of biogenic amines into synaptic vesicles, leading
to depletion of these neurotransmitters and vasodilation.
Indications
● Mild-moderate HBP.
Adverse effects
● Sedation.
● Depression, parkinsonism (Reserpine).
SYMPATHETIC INHIBITORS WITH MIXED ACTION

♦ Urapidil
Mechanism of action
● Urapidil acts by blocking the postsynaptic α1 receptors, reducing the peripheral
vascular resistance and blood pressure.
● It stimulates the serotoninergic (5-HT1A) receptors centrally, inhibiting the reactive
increase of the sympathetic tone.
Indications
● HBP, in association with other antihypertensives (orally).
● HBP emergency (IV), if nitrates and Nifedipine are not effective.
Contraindications
● Pregnancy and lactation period.

CALCIUM CHANNEL BLOCKERS

Calcium channel blockers were introduced into therapeutics in 1960 as antianginal

and antiaarrhythmic drugs. Their antihypertensive action has been prooved because of their
capacity of reducing the vascular tone, producing vasodilation and a lower peripheral
vascular resistance.
The benefits of using the calcium channel blockers in the treatment of HBP are: they
decrease the blood pressure values because of reduced peripheral vascular resistance,
control the blood pressure for 24 hours, with a neutral effect upon the metabolic risk
factors, a good tolerance, a protective effect upon the “target” organs and an
antiatherogenic action.
Classification
● Dihydropyridines
NIFEDIPINE NIMODIPINE
AMLODIPINE NISOLDIPINE
FELODIPINE NITRENDIPINE
LERCANIDIPINE
● Non-Dihydropyridines
o Benzothiazepines
DILTIAZEM
o Phenylalkylamines
VERAPAMIL
GALLOPAMIL
Mechanism of action
● The inhibition of L-type calcium channels in the smooth muscle produces a decrease
in the intracellular calcium concentration. Dihydropyridines act by blocking the
calcium channels in the vascular cells, non-dihydropyridines in the myocardial cells
and nodal tissue, each with significant effects upon their action site.
Pharmacodynamic action
● Vasodilation with a decrease in the peripheral vascular resistance and blood pressure
(especially for the dihydropyridines).
● Negativ inotropic effect (especially for Verapamil and Diltiazem), slowing down of
the heart rate and atrioventricular conduction, coronarodilation on coronary arteries
and collateral circulation (especially for the dihydropyridines).
 ● Other effects (dihydropyridines) are the prevention of a cerebral artery spasm after a
stroke and the increasing in renal blood flow (preferred in HBP with chronic renal
failure).
From the pharmacological point of view, calcium channel blockers have:
● An antianginal action, because they reduce the oxygen consumption and improve the
collateral circulation, by: decreasing the heart rate, the myocardial contractility, the
afterload and increasing the coronary blood flow (especially in the big coronaries).
● An antihypertensive action, because of arterial vasodilation (not venous) with an
increase of the big arteries compliance and decrease of peripheral vascular resistance.
The renal blood flow is improved with an increased diuresis. They produce an
inhibitory effect upon the heart, lowering the cardiac output.
● An antiarrhythmic effect (only Verapamil and Diltiazem), because they inhibit the
calcium influx in the myocardial cells with a slow action potential (sinoatrial and
atrioventricular node) and depress the myocardial contractility function. They decrease
the atrioventricular conduction velocity and the sinusal frequency. Nifedipine
increases the heart rate, but the other dihydropyridines have no significant influence
upon it.
● An antiatherogenic action, by inhibiting the atheroma plaque formation, the
accumulation of calcium and lipids in the arterial wall.
Indications
● Ischemic cardiopathy, especially in unstable angina. In effort induced angina, they are
associated with beta blockers.
● In mild HBP as monotherapy, especially dihydropyridines, but in severe HBP in
association with other antihypertensives.
● Verapamil and Diltiazem are administered in supraventricular tachyarrhythmias
(paroxysmal supraventricular tachycardia, atrial flutter or fibrillation).
● Raynaud syndrome (dihydropyridines).
● Cerebral vascular spasms after subarachnoidian bleeding (Nimodipine).
Adverse effects
● Bradycardia (Verapamil, Diltiazem).
● Heart block (Verapamil, Diltiazem).
● Hypotension, reflex tachycardia (Nifedipine).
● Peripheral edema, in 10% of the cases, because of vasodilation, which are not treated
with diuretics.
● Headache (up to 10% of the cases), dizziness, fatigue.
● Flushing.
● Constipation (Verapamil).
Contraindications
● Heart failure NYHA III and IV class.
● Heart block of II or III degree (Verapamil, Diltiazem).
● Sick sinus syndrome (Verapamil, Diltiazem).
● Aortic stenosis, obstructive hypertrophic cardiomyopathy (dihydropiridines).
● Systolic blood pressure under 90 mmHg, shock.
● Unstable angina, AMI, in the first 4 weeks.
● Pregnancy, lactation period.
Drug interactions
● The association between dihydropyridines and nitrates increase the hypotension and
reflex tachycardia risk.
● Verapamil/Diltiazem should not be associated with beta blockers.
 ● In case of Digoxin or Theophylline association, their plasmatic concentration is
increased.
● NSAIDs reduce the efficiency of calcium channel blockers in decreasing the blood
pressure.

DIRECT VASODILATORS

Direct vasodilators are antihypertensive drugs, which act directly upon the resistance
vessels, relaxing the arteriolar smooth muscle, with a significant decrease in the peripheral
vascular resistance and blood pressure.
Classification
● Oral vasodilators
HYDRALAZINE
MINOXIDIL
● Injectable vasodilators
DIAZOXID
SODIUM NITROPRUSSIDE
Mechanism of action
The peripheral vasodilation activates the baroreceptors in the reflexogenic areas,
leading to compensatory reflex phenomenon (tachycardia, increase of cardiac output) and
increase in renal artery pressure (with secondary hydrosaline retention). This limits the
hypotensive effect in monotherapy, with a compulsory association of diuretics and beta
blockers to direct vasodilators.

ORAL VASODILATORS

♦ HYDRALAZINE

Hydralazine is the oldest vasodilator and still in use.

Pharmacokinetics
● It suffers the first hepatic passage in a high degree.
Mechanism of action
● Hydralazine interferes with the action of inositol triphosphate in vascular smooth
muscle, reducing the peripheral resistance.
Pharmacodynamics
● It produces a stronger vasodilation in the coronarian, cerebral, splanchnic and renal
area, compared to the muscular and cutaneous region. Hydralazine produces a rather
low reducing of blood pressure in the long term treatment of HBP, because of the
compensatory mechanisms.
Indications
● Moderate and severe HBP, in triple therapy, orally, together with a diuretic and a
beta blocker.
● HBP emergencies, IV.
Contraindications
▪ Systemic lupus erythematosus;
▪ Tachycardia.
Adverse effects
 ● Common for the class: tachycardia, angina pectoris, sodium and fluid retention,
headache, facial erythema, nasal congestion.
● Specific for Hydralazine: polyneuritis (through pyridoxine deficiency), lupus
phenomenon, anemia, leucopenia.

♦ MINOXIDIL

Pharmacokinetics
● It has a more intense and prolonged action (24-72 hours), compared to Hydralazine.
Mechanism of action. Pharmacodynamics.
● Minoxidil activates vascular smooth muscle ATP-sensitive potassium channels,
resulting in hyperpolarization of the cell membrane, causing reduced calcium entry
through L-type channels and inhibition of smooth muscle contraction (vasodilation).
● It is the strongest vasodilator, but it needs the association with diuretics.
Indications
● Severe HBP (orally), resistant to other antihypertensive drugs. Because of its adverse
effects, it is the drug of last choice in the long-term treatment of HBP.
● Baldness (topical cream).
Adverse effects
● Common for the class (see Hydralazine).
● Specific for Minoxidil: reversible hirsutism (hypertrichosis) in 80% of the cases, in 3-6
weeks after the beginning of the treatment.
Contraindications
● Pheochromocytoma.
● Porphyria.

INJECTABLE VASODILATORS

They are administered IV in hypertensive emergencies (Hypertensive crisis,

hypertensive encephalopathy).
♦ DIAZOXID

Diazoxid is a structural derivative of Chlorothiazide.

Pharmacokinetics
● The hypotensive effect appears after 5-20 minutes and lasts for 4-24 hours.
Mechanism of action. Pharmacodynamics.
● It acts similar to Minoxidil, activating the potassium channels, causing vasodilation
(stronger arteriolar).
● Diazoxid has also a hyperglycemiant effect, through the inhibition of insulin secretion
(contraindicated in diabetes).
Indications
● In the past in HBP emergencies (IV) as second line drug.
● Symptomatic treatment of hypoglycemia in insular tumors.
Contraindications
● Diabetes mellitus.

♦ SODIUM NITROPRUSSIDE
Pharmacokinetics
● After IV infusion, the effect appears immediately, is brutal, and requires constant
monitoring.
Mechanism of action. Pharmacodynamics.
● It decomposes into “NO” inside smooth muscle cells, that activates guanylyl cyclase,
increasing intracellular cGMP levels and causing vasodilation (arterial and venous).
Indications
● HBP crises or controlled hypotension in surgery or heart failure, but in many
countries it has been withdrawn from the market.
Adverse effects
● Severe hypotension.
● Headache, dizziness.
Contraindications
● Severe hepatic impairment.
● Megaloblastic anemia.
● Nausea, abdominal pain.
● Palpitations.