The department of internal medicine, clinical

pharmacology and occupational diseases, BSMU,

Chernivtsi

Clinical Pharmacology of
Antihypertensives

Eugene I. Shorikov, associate prof., PhD

 Elevated arterial pressure causes pathological
changes in the vasculature and hypertrophy of
the left ventricle.
 As a consequence, hypertension is the principal
cause of stroke, is a major risk factor for
coronary artery disease and its attendant
complications: myocardial infarction and sudden
cardiac death, and is a major contributor to
cardiac failure, renal insufficiency, and dissecting
aneurysm of the aorta.
 Base of therapy
The decision to start
antihypertensive treatment shuold
be based on criteria:
 the level of systolic and diastolic
blood pressure
 the level of total cardiovascular
risk
Very High Risk Of Hypertension
Principles of Treatment
Goals of Treatment
 Classification of Antihypertensive Drugs by Their Primary
Site or Mechanism of Action
 Diuretics
1. Thiazides and related agents (hydrochlorothiazide,
chlorthalidone, etc.)
2. Loop diuretics (furosemide, bumetanide, torsemide, ethacrynic
acid)
3. K+-sparing diuretics (amiloride, triamterene, spironolactone)
 Sympatholytic drugs
1. beta Adrenergic antagonists (metoprolol, atenolol, etc.)
2. alpha Adrenergic antagonists (prazosin, terazosin, doxazosin,
phenoxybenzamine, phentolamine)
3. Mixed adrenergic antagonists (labetalol, carvedilol)
4. Centrally acting agents (methyldopa, clonidine, guanabenz,
guanfacine)
5. Adrenergic neuron blocking agents (guanadrel, reserpine)
 Classification of Antihypertensive Drugs by Their Primary
Site or Mechanism of Action

 Ca2+ channel blockers (verapamil, diltiazem,

nimodipine, felodipine, nicardipine, isradipine,
amlodipine)
 Angiotensin converting enzyme inhibitors (ACEI),
(captopril, enalapril, lisinopril, quinapril, ramipril,
benazepril, fosinopril, moexipril, perindopril,
trandolapril)
 Angiotensin II-receptor antagonists (losartan,
candesartan, irbesartan, valsartan, telmisartan,
eprosartan)
 Vasodilators
1. Arterial (hydralazine, minoxidil, diazoxide,
fenoldopam)
2. Arterial and venous (nitroprusside)
 Classification of Diuretics by Their Primary Site or
Mechanism of Action

 Inhibitors of carbonic anhydrase (primary site of

action is proximal tubule)
 Osmotic diuretics (primary site of action is loop of
Henle)
 Inhibitors of Na+-K+-2Cl- symport (primary site of
action is thick ascending limb)
 Inhibitors of Na+-Cl- symport (primary site of action
is distal convoluted tubule)
 Inhibitors of renal epithelial sodium channels (primary
site of action is late distal tubule and collecting duct)
 Antagonists of mineralocorticoid receptors (primary
site of action is late distal tubule and collecting duct)
Primary Site and Mechanism of Action of Diuretics
Main Effects of Diuretics
 These drugs decrease extracellular volume by interacting
with a thiazide-sensitive Na-Cl cotransporter in the kidney,
leading to a fall in cardiac output. However, the
hypotensive effect is maintained during long-term therapy
because of reduced vascular resistance; cardiac output
returns to pretreatment values and extracellular volume
returns almost to normal due to compensatory responses
such as activation of the renin-angiotensin system.
 Antihypertensive effects can be achieved in many patients
with as little as 12.5 mg of chlorthalidone (HYGROTON) or
hydrochlorothiazide (HYDRODIURIL) daily. Furthermore,
when used as monotherapy, the maximal daily dose of
thiazide-class diuretics usually should not exceed 25 mg of
hydrochlorothiazide or chlorthalidone (or equivalent).
Most patients will respond to thiazide diuretics with a
reduction in blood pressure within about 4 weeks, although
a minority will not achieve maximum reduction in arterial
pressure for up to 12 weeks on a given dose.
Therefore, doses should not be increased more often than
every 4 to 6 weeks. There is no way to predict the
antihypertensive response from the duration or severity of
the hypertension in a given patient, although diuretics are
unlikely to be effective as sole therapy in patients with
stage 2 hypertension. Since the effect of thiazide diuretics
is additive with that of other antihypertensive drugs,
combination regimens that include these diuretics are
common and rational. Diuretics also have the advantage of
minimizing the retention of salt and water that is commonly
caused by vasodilators and some sympatholytic drugs.
 Beta blockers
(β Receptor Antagonists )
 Antagonism of b adrenergic receptors affects the regulation
of the circulation through a number of mechanisms,
including a reduction in myocardial contractility, heart rate,
and cardiac output.
 An important consequence of using b adrenergic receptors is
blockade of the b receptors of the juxtaglomerular complex,
reducing renin secretion and thereby diminishing production
of circulating angiotensin II. This action likely contributes to
the antihypertensive action of this class of drugs, in concert
with the cardiac effects. b
 Adrenergic receptor antagonists may lower blood pressure
by other mechanisms, including alteration of the control of
the sympathetic nervous system at the level of the CNS,
altered baroreceptor sensitivity, altered peripheral adrenergic
neuron function, and increased prostacyclin biosynthesis.
 Pharmacological/Pharmacokinetic Properties of β Receptor Blocking Agents
MEMBRANE INTRINSIC EXTENT OF PROTEIN
LIPID ORAL PLASMA t
DRUG STABILIZING AGONIST ABSORPTION BINDING
SOLUBILITY BIOAVAILABILITY (%) 1/2 (hours)
ACTIVITY ACTIVITY (%) (%)

Classical non-selective β blockers: First generation

Nadolol 0 0 Low 30 30-50 20-24 30

Penbutolol 0 + High ≈100 ~100 ~5 80-98

Pindolol + +++ Low >95 ~100 3-4 40

Propranolol ++ 0 High <90 30 3-5 90

Timolol 0 0 Low to Moderate 90 75 4 <10

β1-Selective β blockers: Second generation

Acebutolol + + Low 90 20-60 3-4 26

Atenolol 0 0 Low 90 50-60 6-7 6-16

Bisoprolol 0 0 Low ≤90 80 9-12 ~30

Esmolol 0 0 Low NA NA 0.15 55

Metoprolol +* 0 Moderate ~100 40-50 3-7 12

Non-selective β blockers with additional actions: Third generation

Carteolol 0 ++ Low 85 85 6 23-30

Carvedilol ++ 0 Moderate >90 ~30 7-10 98

Labetalol + + Low >90 ~33 3-4 ~50

β1-selective β blockers with additional actions: Third generation

Betaxolol + 0 Moderate >90 ~80 15 50

Celiprolol 0 + Low ~74 30-70 5 4-5

*Detectable only at doses much greater than required for β blockade.
 Third-Generation β Receptor Antagonists with Additional
Cardiovascular Actions: Proposed Mechanisms Contributing to
Vasodilation

Nitric α1 receptor K+ Antioxi-

β2 receptor Ca2+ entry
Oxyde anta- channel dant
agonism blockade
produc-tion gonism opening activity

Nebivolol Celiprolol Carvedilol Carvedilol Tilisolol Carvedilol

Celiprolol Carteolol Labetalol Betaxolol

Bopindolol Bopindolol Nipradilol Bevantolol

Nipradilol Bucindolol
 Adverse effects of beta blockers
Drugs should be avoided in patients with reactive airway disease (asthma) or
with sinoatrial or atrioventricular (AV) nodal dysfunction or in combination
with other drugs that inhibit AV conduction, such as verapamil. Patients with
insulin-dependent diabetes also are better treated with other drugs.
b Receptor antagonists without intrinsic sympathomimetic activity increase
concentrations of triglycerides in plasma and lower those of HDL cholesterol
without changing total cholesterol concentrations. b Adrenergic blocking
agents with intrinsic sympathomimetic activity have little or no effect on blood
lipids or increase HDL cholesterol. The long-term consequences of these
effects are unknown.
Sudden discontinuation of some b adrenergic blockers can produce a
withdrawal syndrome that is likely due to up-regulation of b receptors during
blockade, causing enhanced tissue sensitivity to endogenous catecholamines;
this can exacerbate the symptoms of coronary artery disease. The result,
especially in active patients, can be rebound hypertension. Thus, b adrenergic
blockers should not be discontinued abruptly except under close observation;
dosage should be tapered over 10 to 14 days prior to discontinuation.
Nonsteroidal antiinflammatory drugs such as indomethacin can blunt the
antihypertensive effect of propranolol and probably other b receptor
antagonists. This effect may be related to inhibition of vascular synthesis of
prostacyclin, as well as to retention of Na+
 Therapeutic uses
The b receptor antagonists provide effective therapy for all grades of
hypertension. Despite marked differences in their pharmacokinetic
properties, the antihypertensive effect of all the b blockers is of sufficient
duration to permit once or twice daily administration. Populations that tend
to have a lesser antihypertensive response to b-blocking agents include
the elderly and African-Americans. However, intraindividual differences in
antihypertensive efficacy are generally much larger than statistical
evidence of differences between racial or age-related groups.
Consequently, these observations should not discourage the use of these
drugs in individual patients in groups reported to be less responsive.

The b receptor antagonists do not usually cause retention of salt and

water, and administration of a diuretic is not necessary to avoid edema or
the development of tolerance. However, diuretics do have additive
antihypertensive effects when combined with b blockers. The combination
of a b receptor antagonist, a diuretic, and a vasodilator is effective for
patients who require a third drug. b Adrenergic receptor antagonists are
highly preferred drugs for hypertensive patients with conditions such as
myocardial infarction, ischemic heart disease, or congestive heart failure.
 Ca 2+ entry blockers
Voltage-sensitive Ca2+ channels (L-type or slow
channels) mediate the entry of extracellular Ca2+
into smooth muscle and cardiac myocytes and
sinoatrial (SA) and atrioventricular (AV) nodal cells
in response to electrical depolarization. In both
smooth muscle and cardiac myocytes, Ca2+ is a
trigger for contraction, albeit by different
mechanisms. Ca2+ channel antagonists, also called
Ca 2+ entry blockers, inhibit Ca2+ channel
function. In vascular smooth muscle, this leads to
relaxation, especially in arterial beds. These drugs
also may produce negative inotropic and
chronotropic effects in the heart.
 Ca 2+ entry blockers
The basis for their use in hypertension comes
from the understanding that hypertension is
generally the result of increased peripheral
vascular resistance. Since contraction of vascular
smooth muscle is dependent on the free
intracellular concentration of Ca2+, inhibition of
transmembrane movement of Ca2+ through
voltage-sensitive Ca2+ channels can decrease the
total amount of Ca2+ that reaches intracellular
sites. Ca2+-calmodulin-dependent activation of
myosin light chain kinase, resulting in
phosphorylation of myosin light chains, causes an
increase in actin-myosin ATPase activity and
contraction
 Ca 2+ entry blockers
Verapamil was the first clinically available calcium-
channel blocker; it is a congener of papaverine.
Many other calcium entry blockers with a wide
range of structures are now available. The largest
group, including amlodipine, felodipine, isradipine,
and nifedipine, are termed dihydropyridines.
Diltiazem is, with verapamil, the other non-
dihydropyridine available clinically. Interestingly,
these different structures lead to differences in
their sites and modes of action on calcium entry
for reasons that are not well understood.
 Classification of Ca2+blockers

 I generation – verapamile, diltiazem,

nifidipine
 IIa generation – long-term forms of these
drugs (slow release tabs, GITS, retard)
 IIb generation – galopamile, clentiazem,
isradipine, felodipine
 III generation – amlodipine, lacidipine,
lerkanydipine
 Ca 2+ entry blockers
Indeed, all of the Ca2+ channel blockers lower
blood pressure by relaxing arteriolar smooth
muscle and decreasing peripheral vascular
resistance. As a consequence of a decrease in
peripheral vascular resistance, the Ca2+ channel
blockers evoke a baroreceptor-mediated
sympathetic discharge. In the case of the
dihydropyridines, tachycardia may occur from the
adrenergic stimulation of the sinoatrial node; this
response is generally quite modest except when
the drug is administered rapidly. Tachycardia is
typically minimal to absent with verapamil and
diltiazem because of the direct negative
chronotropic effect of these two drugs.
 Ca 2+ entry blockers
The profile of adverse reactions to the Ca2+ channel blockers varies among
the drugs in this class. Patients receiving immediate-release capsules of
nifedipine develop headache, flushing, dizziness, and peripheral edema.
However, short-acting formulations of nifedipine are not appropriate in the
long-term treatment of hypertension. Dizziness and flushing are much less of a
problem with the sustained-release formulations and with the dihydropyridines
having a long half-life and relatively constant concentrations of drug in
plasma. The peripheral edema is not the result of generalized fluid retention; it
most likely results from increased hydrostatic pressure in the lower
extremities owing to precapillary dilation and reflex postcapillary constriction.
Some other adverse effects of these drugs are due to actions in nonvascular
smooth muscle. Contraction of the lower esophageal sphincter is inhibited by
the Ca2+ channel blockers. For example, Ca2+ channel blockers can cause or
aggravate gastroesophageal reflux. Constipation is a common side effect of
verapamil, but it occurs less frequently with other Ca2+ channel blockers.
Urinary retention is a rare adverse effect. Inhibition of sinoatrial node function
by diltiazem and verapamil can lead to bradycardia and even sinoatrial node
arrest, particularly in patients with sinoatrial node dysfunction.
 ACE-inhibitors
There is the pharmacokinetic classification of ACEI,
which includes some classes (by Opie, 1997):
Class I – lipophillic drugs: Captopril
Class II - ipophillic prodrugs:
group IIА – medications with kidney path of
elimination (> 60%): Perindopril, Quinapril,
Benazepril, Enalapril
group IIВ – medications with 2 ways of eliminatin:
Moexipril , Ramipril , Fosinopril ;
group IIС – medications with hepatic path of
elimination (> 60%): Trandolapril .
Class III – hydrophillic drugs: Lisinopril ,
Enalaprilat
 Adverse Effects of ACE
Inhibitors
 Hypotension
 Cough
 Hyperkalemia
 Acute Renal Failure
 Fetopathic Potential
 Skin Rash
 Proteinuria
 Angioedema
 Neutropenia
 Hepatotoxicity
Antihypertensive drugs of different
classes can be combined if:
1) they have different and complementary
mechanisms of action.
2) there is evidence that the antihypertensive effect
of the combination is greater than at of either
combination component.
3) the combination may have a favourable tolerance
profile, the complementary mechanisms of action
of the components minimizing their individual
side effects.
The following two-drug combinations have been
found to be effective and well tolerated, and
have been favourably used in randomized
efficacy trials.
Thank You