Interaction of antihypertensivedrugs with mechanisms of blood
High blood pressure (BP) contributes substantially to cardiovascular compli-
cations such as cerebrovascular accidents and myocardial infarction. Periph-
eral vascular disease, heart failure and renal insufficiency have also beenidentified as major sequelae of the hypertensive process. Fortunately, many
studies have shown that adequate antihypertensive treatment will reducethe number of cardiovascular complications, with risk reductions of about40% for cerebrovascular events and approximately 20% for cardiac endpoints.
However, epidemiologic investigations such as the Framingham Study havealso shown that an elevated BP tends to cluster with other (metabolic) riskfactors, such as diabetes and hyperlipidaemia, which markedly enhance therisk carried by the increased pressure itself. It is essential, therefore, thatthe practising physician takes care of hypertension and other risk factors atthe same time.
Because antihypertensive treatment, once instituted, must be maintained for
many years, the decision to treat or not should not be taken lightly. Accordingto current guidelines and recommendations this requires the assessment ofoverall risk, which means that one tries to estimate the chance that a patientwill sustain a major cardiovascular event within a certain time frame. If overallrisk is low, it is justifiable to withhold treatment for a while and to keep thepatient under surveillance. However, when risk exceeds a certain (arbitrary)level the patient should be treated with antihypertensive drugs. Currently,the most important of these are diuretics, b-blockers, calcium antagonists,angiotensin converting enzyme inhibitors and angiotensin II type 1 receptorblockers, because of their favourable effect on long-term prognosis.It is notan easy task to choose among the various categories. In coming to a sound deci-sion, the physician may take several courses, approaching the problem from adrug-related or a patient-related perspective. In this chapter we will focus onthe mechanisms of BP regulation with which antihypertensive drugs caninterfere.
provides a simplified scheme of the most important systems that are
involved in blood-pressure control. Theoretically, all these systems are poten-
tial targets for therapeutic intervention. Haemodynamically, hypertension canbe considered as an increase in systolic and diastolic BP or mean arterial pres-sure (MAP), the latter representing a ‘static’ component of the circulation.
Alternatively, an increase in pulse pressure (‘dynamic’ component) can betaken as the most important haemodynamic abnormality in hypertension.
From a circulatory point of view, MAP is determined by cardiac output (CO)and systemic vascular resistance (SVR), while pulse pressure (PP) is largely
dependent upon ventricular ejection and the stiffness of the arterial tree. Theo-
retically, all these components are amenable to pharmacological modulation.
In the normal individual, BP is kept within certain limits by an extensive
array of stabilizing mechanisms, with the sympathetic nervous system andthe kidney as the most important regulators. Short-term changes in BP can be
effectively buffered by the baroreflex and the sympathetic nervous system,but in the long term it is the kidney that will determine at what level BP willbe maintained.This Guytonian concept of circulatory control thus predictsthat no intervention will be able to produce a sustained drop in BP unless
the renal volume–pressure relationship (pressure-natriuresis or renal function
Fig. 2.1 Simplified scheme of the mechanisms involved in the control of the circulation and the siteof action of various classes of drugs. CNS ¼ central nervous system; SNS ¼ sympathetic nervous
system; RAAS ¼ renin–angiotensin–aldosterone system.
Table 2.1 Main (primary) effect of various classes of antihypertensive agents
Antagonism of type 1 receptors for Ang II
Reduced intracellular calcium concentration
ACE¼angiotensin converting enzyme; Ang¼angiotensin; ARB¼angiotensin II type 1 receptor blocker
Basically, both the regulation of fluid volume balance and that of vascular
resistance can be attacked. In practice, however, most antihypertensive drugsact on multiple systems so that it is not always evident which mechanismsare actually responsible for a certain fall in BP. Moreover, any direct drug effect
may be compensated for by counterregulatory (and not necessarily renal) sys-
tems, which can even totally offset an initial decline in pressure. In the longterm, therefore, the efficacy of each antihypertensive agent is determined notonly by its primary pharmacological effect, but also by the efficiency of such
Based on current pathophysiological concepts, drugs have been designed
that can lower cardiac output or vascular resistance, increase urinary sodium
output or modulate vessel wall properties. In general, the primary pharmaco-logical action of available drugs is straightforward (), but the compen-
satory mechanisms that are elicited are not always obvious. Consequently, formost antihypertensive drugs the long-term actions have not been defined soclearly. However, since the kidney responds to a fall in pressure by retainingmore sodium, no antihypertensive drug can work effectively if sodium excre-tion is not facilitated, either directly or via modulation of neurohumoralsystems with a bearing on renal sodium handling.
While the aim of treatment has always been to lower systolic, diastolic and
mean arterial pressure, we are now increasingly aware that not only the ‘static’components of pressure, but also pulse pressure should be reduAn idealantihypertensive drug, therefore, not only lowers MAP but also PP. In the fol-lowing, the mechanisms by which various classes of antihypertensive drugsinterfere with BP regulatory systems will be discussed in more detail.
Since mean arterial pressure is the product of cardiac output and systemic vas-cular resistance, it follows that drugs that are to lower pressure must do so byaffecting either CO or SVR or both. The ways by which such haemodynamicchanges are accomplished may vary considerably however, and can involve
direct effects on the heart (e.g. b-blockers) or the vessels (e.g. so-called direct
vasodilators) or indirect actions. As both the sympathetic nervous system andthe renin–angiotensin system play a key role in regulating haemodynamics, itis not surprising that many antihypertensives act via one of these systems.
Alternatively, drugs may interfere directly with the vascular contraction pro-cess, for example by inhibiting the inflow of calcium ions or by blocking the
excitation–contraction coupling. In recent years there has been increasing inter-est in agents that, besides lowering vascular resistance, enhance the dynamicproperties of the vasculature (compliance, distensibility).
Although CO may be elevated in a subgroup of especially young patients,the
common finding in hypertension is a normal or slightly reduced At firstsight, therefore, there seems to be no point in reducing cardiac output any fur-ther. Yet, drugs that lower CO, such as b-blocking agents, have become a main-stay in the treatment of hypertension with a definite benefit on prognosis.Thus, a fall in CO is not a priori harmful.
Acute administration of b-blocking drugs is associated with an immediate
fall in heart rate and CO, but BP does not change appreciably because SVR risesat the same time. However, with prolonged treatment this haemodynamic pic-
ture changes with SVR gradually falling to its initial level or even below.
At that time, BP also dropsMan in ’t Veld has summarized the acute andchronic haemodynamic effects of a variety of b-blocking agents in over 900
patients.This analysis yielded a fairly consistent pattern: cardiac output initi-ally falls, but less so when the drug possesses more partial agonistic activity. Inthe long term, peripheral resistance is invariably reduced. Prospective dataseem to confirm this sequence of evenUp to now, however, the causes ofthe secondary drop in resistance remain elusive. lists several poten-tial mechanisms, but none of these has been unequivocally proven to be thecause of the vasodilatory effect. One of the prevailing theories is that b-blockersinhibit the facilitation of noradrenaline release from nerve terminals by presyn-aptic b-adrenoceptors. As a consequence, a-mediated vasoconstriction wouldbe reduced. As attractive as this theory may appear, a fundamental problemis that the presynaptic b-adrenoceptor is a b2 receptor, while the most effective
b-blockers have a high degree of b1 selectivity. Alternatively, suppression ofrenin (via the b1 adrenoceptor) may be of importance, as conditions in which
Table 2.2 Potential mechanisms by which b-blockers may lower systemic vascular resistance
Inhibition of b-1 mediated renin releaseInhibition of central autonomic nervous systemResetting of the baroreflexIncrease in natriuretic peptidesEffect on prejunctional b-receptors: reduction in noradrenaline releaseReduction in venous toneReduction in plasma volumeAttenuation of the pressor effect of catecholaminesIncrease in vasodilator prostaglandins
renin is low have often been associated with lesser response to b-blockers.
Although this supposition has not been universally reproduced and, althoughthe hypotensive effect of b-blockers does not correlate well with changes in
renin, it is interesting that black people in whom renin is almost invariably sup-pressed consistently exhibit a reduced responsiveness to b-blockade.There
must also be a role, albeit a modest one, for prostaglandins, as non-steroidal
anti-inflammatory drugs that inhibit prostaglandin synthesis are able toattenuate the blood-pressure-lowering effect of b-blockers by a few mmHg.
In the past, several attempts have been made to define subgroups of patients
in whom b-blockers would be particularly useful, i.e. those with an elevatedcardiac output and/or high renin levels. While a few studies do, indeed, sup-port these claims, the number of exceptions is too great, presumably indicating
that we still do not know precisely how b-blockers lower pressure. Unfortu-nately, there are at present no distinct pathophysiological features that are ableto predict precisely the degree of responsiveness to b-blockade. The recent
claim that some b-blocking agents have effects on the prognosis of hyperten-sive patients that are less favourable than otseems premature and needs
confirmation. If this is found to be true, then this casts doubt on a uniform
While beta-adrenergic blockers primarily lessen heart rate and myocardial
contractility, they generally do not or only marginally lower stroke volume.
The latter may be diminished, however, by drugs which reduce venous return.
As well as nitrates and nitrate-like substances, diuretics, a-blockers, ACE inhi-bitors and centrally acting antihypertensives may induce venodilation anddiminish cardiac preload. Whether this is a favourable mechanism depends
on many factors, including the haemodynamic status of the patient. Thus,
under certain conditions a fall in stroke volume may help to lower pressure.
However, it is also possible that CO falls too much and that orthostatic intoler-
ance ensues. Therefore, drugs with high selectivity for the venous system with-out other beneficial effects have no significant role in the treatment of
Peripheral vasculature as the primary target
As, eventually, all forms of hypertension are related to an increase in SVR, itseems only logical to treat the disorder by lowering arteriolar tone. In fact, as ageneral rule, no drug will lower pressure unless it is able to elicit, directly or asa secondary phenomenon, a fall in vascular resistance. Vasodilation can beachieved in various ways. First of all, drugs may reduce the overall activity ofpressor systems (sympathetic nervous system, renin–angiotensin–aldosteronesystem (RAAS)). Secondly, drugs could interfere with specific receptors in thevascular wall that mediate the effects of these systems. Thirdly, drugs may mod-ulate voltage- or receptor responsive channels in the cell membrane that play arole in the initiation of the contraction of the vascular smooth muscle cell. Lastly,the contraction process in itself can be the target for interference.
Although it is a matter of semantics, drugs which lower SVR by modulating
‘extravascular’ mechanisms are not normally classified as vasodilators, eventhough their hypotensive potential may depend entirely upon the relaxationof precapillary arterioles (cf. the secondary fall in systemic vascular resistanceduring long-term b-blockade). These agents will be discussed elsewhere under
the appropriate headings (see below). The term (direct) vasodilator has been
reserved for drugs that activate intracellular guanylate cyclase. This conventionwill also be followed here. Sometimes, calcium antagonists are also classified asvasodilators, but this is less appropriate in view of their different mode of
Vasodilators may act on the arterial as well as the venous side of the circu-
lation. Probably, there are no drugs with an exclusive effect on either thearteries or the veins; there is always a mixture of arteriolar and venular effects.
It is the relative balance of pre- and postcapillary resistance reduction thatdetermines whether BP, heart rate and/or cardiac output will fall, remainunchanged or increase. Nitrates, for instance, predominantly dilate the venous
system, thereby reducing atrial pressure, stroke volume and cardiac output,
but at higher doses nitrates may also cause some dilation of resistance vessels
and a drop in systemic BP.Usually, the greatest changes are seen in sys-tolic pressure with no or very little alteration in diastolic pressure. The lattersuggests that nitrates act more on the large conduit arteries (improving compli-ance) than on arteriolar vessels. This alleged property makes nitrates an inter-esting tool for the treatment of patients with (isolated) systolic hypertension.
The mechanism by which nitrates dilate blood vessels involves the genera-
tion of nitric oxide (NO) from the drug molecules, although the precise stepsin this pathway are not well understood. NO is thought to stimulate cytosolic
guanylate cyclase, which, in turn, increases the intracellular concentration of
cyclic guanosine monophosphate (cGMP). The latter inhibits the inositol path-way and reduces intracellular calcium. As a result, the vascular smooth muscle
cell relaxes. Because the formation of NO is independent of the endothelium,nitrates still work when the vascular endothelium is damaged.
A similar mechanism holds for sodium nitroprusside that has a more bal-
anced effect on arteriolar and venular tone. Due to venous dilatation, strokevolume falls. In comparison with nitrates, nitroprusside lowers BP and after-load more and slightly stimulates CO. Because the drug can only be adminis-tered intravenously, it is mainly used when BP needs to be lowered rapidlyas in conditions where rapid unloading of the heart is essential.
Other direct vasodilators acting via different mechanisms are hydralazine,
minoxidil and diazoxide. These agents primarily dilate arterioles while exert-ing little, if any, effect on the venous side of the circulation. Recent data suggestthat such drugs increase the intracellular concentration of cGMP, by acting aspotassium channel openers. ATP-dependent potassium channels in the sarco-lemmal membrane are believed to be involved in the maintenance of basal ves-sel wall tone in several vascular Opening of these channels causesefflux of potassium and membrane hyperpolarization. Subsequently, calciuminflux is reduced and the vascular smooth muscle cell relaxes.
Clinically, the use of direct vasodilators as monotherapy is greatly limited by
hyperadrenergic symptoms and marked fluid retention. These ‘side effects’ arerelated to enhanced sympathetic activity and fluid retention secondary toactivation of the RAAS. The rise in cardiac output that is observed duringtreatment with a direct vasodilator together with the expansion of the extracel-lular volume, may then completely offset the initial fall in BP. Nicorandil haspotassium channel opening and nitrate-like properties. It lowers both preloadand afterload with little effect on heart rate or cardiac output.
Despite a wealth of mechanisms that are involved in the regulation of cardiac
output and vascular tone, presently only the sympathetic nervous system andthe RAAS are of major clinical importance. In this part of our review, therefore,
we will restrict ourselves to a discussion of those drugs that interfere with these
systems. This is not to negate the role of, for example, prostaglandins, brady-kinin or other humoral factors, but to date these systems have not been the
primary target of the currently available antihypertensive drugs.
Sympathetic nervous system as the primary target
Pharmacologically, the sympathetic nervous system (SNS) can be ‘attacked’ atseveral levels: centrally, at the level of preganglionic or postganglionic neurons,and at the receptor level. Ganglion-blocking drugs interrupt the transmission of
sympathetic activity at the site where pre- and postganglionic nerve fibres com-municate. Although these agents are extremely potent as antihypertensives,
use should now be considered as obsolete (unless in very severe cases) becauseof intolerable side effects. Since both sympathetic and parasympathetic ganglia
are blocked, a wide array of physiological functions is disturbed, leading tosuch problems as orthostatic hypotension, constipation, impaired micturition
and loss of accommodation. Orthostatic hypotension and various other adverse
effects may also be seen with adrenergic neuron-blockers and reserpine, whichcause long-lasting depletion of noradrenaline stores in postganglionic sympa-thetic nerve endings. The limited use of these agents in the current treatment
of hypertension does not justify an extensive discussion of these drugs in this
chapter. Presently, only the centrally acting agents and the adrenoceptorblockers remain relevant for clinical practice.
Centrally acting drugs inhibit sympathetic outflow via stimulation of a2-adrenoceptors or type-1 imidazoline (I1) receptors. These receptors are locatedin the nucleus tractus solitarii and the rostral ventrolateral medulla respec-tively. Methyldopa is the classic example of an a2-agonist, while moxonidineand rilmenidine primarily stimulate I1-receptors and have much weaker affin-ity for a2-adrenoceptors. Clonidine has a mixed action and stimulates bothtypes of receptors. Although it is difficult to obtain direct evidence for a centralsympatholytic effect of these compounds in humans, a compelling observationwas made by Reid and coworkers in tetraplegic patients with physiologicallycomplete chronic cervical spinal cord transsection.In such patients, a singleoral dose of clonidine, 300 mg, which is effective in control subjects, did notlower BP, although heart rate still fell and ‘peripheral’ side effects stilloccurred. These data are at least consistent with a central mechanism of actionand suggest that the hypotensive effect of clonidine in humans is dependent onintact descending bulbospinal pathways. In patients with an intact sympatheticsystem clonidine also lowers resting plasma noradrenaline concentrations, aswould be expected if the drug reduces sympathetic activity. In fact, the fall inBP correlates well with the decline in plasma noradrenaline In addi-tion, the noradrenaline response to a cold pressor stimulus is reduceBesides a central action clonidine has also been shown to interact with a variety
of other receptors, including a1-adrenoceptors and histaminergic receptors as
well as with opioidergic mechaniBased on a number of animal experi-ments and the observation of clinical behaviour equivalent to that of clonidthe central action of methyldopa is also beyond dispute. For moxonidine and
rilmenidine, the evidence mainly rests on experimental data, although moxo-nidine has also been shown to reduce plasma noradrenaline levelIn
humans, cumbersome side effects, such as sedation and dry mouth, are lessfrequently seen with these drugs than with clonidine, presumably becausethese are related to the stimulation of a2-receptors and not the I1-receptors.
The haemodynamic profile of centrally acting antihypertensives is favour-
able: SVR falls with little change or sometimes a minute fall in heart rate
and/or CO. The bradycardic effect may be enhanced by simultaneous activa-
tion of the parasympathetic system. Importantly, levels of renin and aldoste-
rone are also reduced. Methyldopa has sometimes been found to lowervenous tone, but it is uncertain whether this plays a role in humans. With allagents, reversal of left ventricular hypertrophy has been observed duringlong-term treatment.
One other phenomenon has been consistently associated with the use of clo-
nidine, namely an immediate pressor effect when the drug is administeredintravenously. This is usually explained by a direct effect of the agent onperipheral, postsynaptic a2-adrenoceptors, leading to vasoconstricAt
higher doses of the drug this pressor effect even surpasses the BP lowering
effect. If the central and peripheral effects are both operative, either simulta-neously or sequentially, clonidine must produce a complex haemodynamic
pattern. This is evident, for instance, in the study by Mitchell and associates,who reported on the immediate haemodynamic responses following intrave-nous administration of a single dose of clonidine of about 300 mg in 28 normalvolunteers.Using impedance cardiography to measure cardiac output, theyobserved a profound fall in this variable that could be accounted for mostlyby a substantial reduction in stroke volume. Total peripheral vascular resis-tance showed a biphasic pattern with an immediate, short-lasting decline thatwas followed by a gradual increase. The initial reduction in vascular resistancewas explained by a vasodilatory action on the vascular wall (possibly involvingnitric oxide) while the secondary rise in resistance was thought to be the resultof baroreceptor-mediated reflex vasoconstriction. As attractive as theseexplanations may seem, there are other possibilities that need to be considered.
Indeed, in the dosage used, clonidine must have been able to stimulate presyn-aptic a2-adrenoceptors, the result of which is inhibition of noradrenaline releasefrom nerve terminals. This mechanism, together with an immediate centraleffect, could account for the early fall in vascular resistance. Additionally, itis difficult to see why primary vasodilation would not be associated withbaroreceptor-mediated increases in heart rate and cardiac output. It is verylikely, therefore, that clonidine exerted an immediate sympatholytic effect lead-ing to a decline in both cardiac output and vascular resistance. Morecomplicated pharmacological experiments employing various agonists andantagonists or such manoeuvres as orthostatic stress would be needed toelucidate whether the effect is primarily central or peripheral. Other explana-tions for the secondary rise in vascular resistance are also possible.
Earlier observations suggested that clonidine could ‘sensitize’ the arterial
baroreceptors, meaning that at a given level of BP afferent firing would be
increased.This would lead to greater inhibition of sympathetic outflow.
However, this sensitization occurs at relatively high dosages of the drug.
Probably more important is the observation that clonidine facilitates reflex
baroreceptor slowing. Indeed, clonidine-induced cardiac slowing is reducedfollowing baroreceptor denervation.What, then, could explain the vasocon-
striction? The most attractive hypothesis is probably the rise in vascular resis-
tance secondary to stimulation of postsynaptic a2-adrenoceptors. This wouldthen further stimulate the baroreceptor-mediated fall in cardiac output. Thus,most of the findings of Mitchell et al.could be explained entirely by an effect
of clonidine on pre- and postsynaptic a2-adrenoceptors. Nevertheless, it is note-worthy that such observations have not been made with the other centrally act-ing sympatholytics. This suggests that there are some more subtle differences
between the various representatives of this class.
In the periphery, only blockers of postsynaptic a- and b-adrenoceptors are rel-evant for the treatment of hypertension. As b-blockers have already been dis-
cussed (see above), we will confine ourselves here to a-adrenoceptor blocking
agents. Unfortunately, only a few drugs in this category are available. More-over, popularity has declined significantly, not only because of side effects,but also because of an alleged (and not totally well founded) adverse effect
on cardiovascular prognosis.In routine clinical practice, non-selective
a-adrenoceptor blocking drugs (e.g. phentolamine) have no place. Prazosinand doxazosin, on the other hand, are selective blockers of the a1-adrenoceptorand these agents are discussed here in greater detail. The mode of action seems
straightforward: competitive inhibition of noradrenaline at the postsynaptic
receptor. Drugs may differ, however, in relative potency for a variety of otherreceptors. These agents do not block the presynaptic a-adrenoceptor (of the
2-type) and, therefore, leave the presynaptic modulation of neurotransmitter
release (inhibition by a2-adrenoceptor stimulation) from nerve terminals intact.
Since a1-adrenoceptors are present in both resistance and capacitance vessels,the antagonists produce arterial as well as venous dilation. As a result, BP fallsby virtue of a drop in SVR without major changes in CO. Venous dilation may-contribute to the frequently observed orthostatic hypotension. As expected,volume depletion aggravates the postural response. Tachycardia may occurbut is usually mild. Although not very frequent, a troublesome side effectmay be sodium retention, which occurs despite the lack of significant activationof renin and aldosterone. There may be some increase in extracellular volumedue to enhanced renal sodium reabsorption, but this observation is disputed.
If true, however, this may contribute to the allegedly higher incidence of con-gestive heart failure that has been observed in clinical trials.
A few drugs combine a1-adrenoceptor blocking activity with other effects,
such as blockade of b-adrenoceptors (labetalol), central 5HT1A-serotonergicreceptors (urapidil) or 5HT2-serotonergic receptors (ketanserin).
Renin–angiotensin–aldosterone system as the primary target
The RAAS can be inhibited at several levels. Firstly, the secretion of renin canbe inhibited via blockade of b1-adrenoceptors. Since b-blockers have already
been discussed (see above), these drugs will not be dealt with here. Secondly,
the action of renin can be inhibited directly, thus producing a fall in the levelsof angiotensin I (Ang I) and angiotensin II (Ang II). In the past attempts todesign effective renin inhibitors have not been successful. Newer renin inhibi-
tors have potential.The third level to inhibit the RAAS is by blockingangiotensin converting enzyme (ACE), which converts Ang I into Ang II.
Finally, the action of Ang II can be antagonized at the level of its receptor bymeans of an angiotensin II type 1 receptor blocker (ARB). Specific blockers ofaldosterone also exist, but these agents leave the effects of Ang II on the circu-lation untouched. Only ACE inhibitors and ARBs are now clinically availableto antagonize the RAAS in hypertensive patients.
Superficially, the mode of action for ACE inhibitors is clear: diminished
activity of the enzyme will eliminate plasma Ang II and thereby reduce periph-
eral vasoconstriction. Indeed, acute administration of an ACE-inhibitor is asso-ciated with a fall in BP that correlates with the decrement in plasma Ang II.However, during continued treatment plasma Ang II and aldosterone tend torise again, sometimes to values that are not different from pre-treatmentvalues, even though BP remains reduced. Such observations make plasma
Ang II a less likely candidate to explain the hypotensive effect of ACE inhibi-tors. Accumulation of bradykinin (less degradation by ACE) and continuedsuppression of tissue ACE are among the most popular explanations for the
long-term efficacy of these drugs. An alternative possibility is enhanced forma-
tion of the vaso dilator y peptide Ang( 1–7 ). Regard less of the immedi ate inter-ruption of the RAAS by ACE inhibitors, Ang II has a number of indirect
effects and via these pathways an additional effect on BP can be achieved.
For instance, the drop in aldosterone may increase natriuresis or at least pre-vent reactive sodium retention. In addition, the stimulating effect of Ang IIon the sympathetic nervous system will disappear during ACE inhibition.
The latter may be responsible for the lack of a baroreceptor-mediated rise insympathetic activity during ACE inhibition. Suppression of endothelin secre-tionand improvement in endothelial functionmay also contribute to a sus-tained reduction in pressure. ACE inhibitors have also been shown to improvearterial compliance, notably in the
Haemodynamically, ACE inhibitors produce a fall in SVR without signifi-
cant changes in heart rate or CO. Cardiac filling pressures also tend todecline,possibly as a result of ACE-inhibitor-mediated venodilation.These drugs, therefore, reduce preload and afterload, and thus exert a favour-able effect on the circulation, without orthostatic hypotension. ACE inhibitorshave important effects on regional vascular beds. For instance, in the coro-nary circulation these drugs improve flow reserve and in the cerebral vascu-lature shift the lower limit of autoregulation towards lower BP levels so thatcerebral blood flow is maintained even under conditions of a low perfusionFinally, in the kidney ACE inhibitors lower postglomerularresistance and intraglomerular pressure and by that mechanism may reduceproteinuria. Renal blood flow is usually maintained or increases to a variableextent.
Nowadays, ACE inhibitors have to compete with ARBs in the treatment of
hypertension. These receptor blockers interact with aminoacids in the trans-membrane domains of AT1 receptors and occupy space among the seven
helices, thereby preventing the binding of Ang The antagonist-receptor
complex is not internalized and hence does not influence the receptorpopulation on the cell surface. Differences between various ARBs observed inthe laboratory (e.g. surmountable versus insurmountable antagonism) seem
to be irrelevant in the clinical context. Overall, the effects of ARBs are similarto those of ACE inhibitors. The most conspicuous difference, however, lies in
their effect on Ang II levels. While these tend to be reduced during ACE inhi-
bition, they increase in response to ARB treatment. As ARBs only block theAT1 receptor, the AT2 receptor remains accessible to Ang II. Possibly (althoughthis has not been proven unequivocally), the AT2 receptor mediates several of
the advantageous effects of ARBs (such as vascular remodelling).
The haemodynamic effects of ARBs closely resemble those of ACE inhibi-
tors: BP and vascular resistance fall while cardiac output remains largely
unchAlso, the renal effects of these classes of drug are similar. It isuncertain whether it is useful to combine an ACE inhibitor and an ARB. Therationale for such an approach is that during ACE inhibitor treatment alone,
Ang II can still be formed via non-ACE pathways while during ARB treatmentalone elevated levels of Ang II may overcome receptor blockade. Although a
few attempts have been made to evaluate the combination, most studies have
not utilized full doses of the drugs. Therefore, the claim made by some thatthe combination produces additive effectsneeds further substantiation.
Clinically, it remains uncertain whether the combination confers more benefit
ACE inhibitors and ARBs have a favourable effect on the microcirculation.
That this effect may be responsible for or contribute to an improvement ininsulin sensitivity. As b-blockers and diuretics often have opposite effects
on the microcirculation, insulin sensitivity usually deteriorates during treat-
ment with those drugs. The different microcirculatory actions of the variousagents may well account for the different incidences of new-onset diabetes
mellitus observed in large-scale trials. The number of patients with new dia-betes is consistently lower when treatment is based on an ACE inhibitor or an
Calcium antagonists (CA) are drugs that inhibit the influx of calcium intovascular smooth muscle cells by blocking plasma membrane calcium channels.
Although some calcium antagonists may block T-type or N-type channels,these are less relevant for clinical practice. The CAs that are used for thetreatment of hypertension have the slow L-type voltage-gated channels astarget. These channels are present in vascular smooth muscle cells, in the myo-cardium and in atrioventricular nodal tissue. Three types of CAs have foundtheir way to the clinic: the phenylalkylamine verapamil, the benzothiazepinediltiazem and the large group of dihydropyridines. The common effect of thesedrugs is a decrease in the cytosolic calcium concentration, which leads to relax-ation of the smooth muscle cell. In addition, CAs mitigate the response to vaso-constrictor hormones such as endothelin, Ang II and noradrenaline. In chronictherapy, CAs may also exert positive effects on the structure of the vascularwall. An example of this effect has been demonstrated by Schiffrin and Dengwho investigated the effects of the CA nifedipine GITS and the b-blocker aten-olol on the structure and function of resistance arteries in normotensive and
hypertensive people.Vessel specimens were obtained from gluteal sub-
cutaneous biopsies. Their data show that hypertensive patients with well-controlled BP after treatment for more than 1 year with nifedipine GITS exhibitnormal structure and function of gluteal subcutaneous small arteries, whereas
similar patients with BP equally well controlled by the b-blocker atenolol havethicker small arteries with abnormal endothelium-dependent relaxation and
altered contractility. Whether this finding also applies to other vascular beds,could not be determined from this study.
The various CAs show clear-cut differences in haemodynamics. Verapamil,
for instance, has a greater affinity for cardiac than for vascular tissue andpairs vasodilation with a degree of negative inotropy/chronotropy. Heart
rate usually slows modestly, while myocardial contractility and atrioventricu-
lar conduction are more markedly depressed by this drug. Diltiazem has
about equal affinity for cardiac and vascular calcium channels, but has hae-modynamic actions that resemble those of verapamil. Dihydropyridines, incontrast, have far greater affinity for vascular tissue and primarily inducevasodilation. Some increases in heart rate and cardiac output may ensue,secondary to baroreceptor-mediated sympathetic activation, but these are
usually transient. A side effect frequently seen during treatment with a dihy-dropyridine is the development of oedema, which seems to be the result ofaltered haemodynamic forces in the microcirculation. Since these drugs
mainly dilate precapillary vessels, a relatively greater portion of systemic
pressure is transmitted into the capillary system. As a consequence, and evenin the face of a reduced systemic pressure, intracapillary pressure rises lead-
ing to extravasation of fluid. The same increase in transcapillary pressure,when it occurs in the kidney, may be responsible for a (transient) rise in albuminexcretion. The corollary of these changes is that the addition of a drug thatdilates the postcapillary vessels (e.g. an ACE inhibitor) should reduce the inci-dence of oedema. Indeed, this was observed in a large, double-blind trial on thecombination of a CA and an ACE inhibitor.The development of oedema doesnot seem to result from enhanced sodium retention; rather, CAs stimulate natri-uresis, at least in the early stage of therapy. The reason why CAs do so has notbeen fully elucidated, but may involve relative suppression of aldosterone. CAsare usually somewhat less effective in terms of BP lowering when the patient ison a low salt diet or simultaneously uses a diuretic. An explanation for this phe-nomenon may be that the natriuretic effect will be less pronounced when thepatient adheres to a low rather than to a high salt intake.
Finally, dihydropyridine calcium antagonists may activate the sympathetic
nervous system, although this effect is variable and drug-dependent. Withlong-acting agents that produce a gradual and sustained fall in BP, sympatheticactivation hardly occurs.
As stated earlier, the tendency of the kidney to retain sodium upon a fall inBP must be counteracted if the change in BP is to persist. Obviously,many of the compounds described above must act on the kidney, althoughthe mechanism is far from clear. Based on the principles of Guyton,
the renal function curve (pressure-natriuresis curve) must have shiftedleftwards. However, this does not necessarily have to be the case whendrugs are administered that force the kidney to excrete more sodium, as when
Like b-blockers, diuretics have been in the forefront of hypertension treat-
ment for many years. The increasing knowledge about their potential to
improve overall prognosis has, unfortunately, not been matched by concurrentinsight into mode of action. It is known that the different classes of diureticsinterfere with sodium reabsorption in the renal tubules. Loop diuretics, such
as furosemide, inhibit the Na-K-2Cl cotransporter in the ascending limb ofthe loop of Henle, while thiazides block the basolateral sodium-chloride cotran-sporter in the distal convoluted tubule. Amiloride and triamterene directly
inhibit sodium channels while aldosterone antagonists have a similar effectvia antagonism of the nuclear aldosterone receptor. Drugs that act in the proxi-mal tubule, such as the carbonic anhydrase inhibitors, are not generally used in
hypertension because of low efficacy.
Diuretic treatment is associated with a biphasic response. Initially, renal
sodium output increases leading to a fall in plasma and extracellular volume.
This phase is characterized by renal vasoconstriction, a modest decline in glo-merular filtration rate (GFR) and slight elevation of filtration Variouscounterregulatory mechanisms are then activated, among which is the RAAS.
These mechanisms are needed to limit the loss of body sodium. The adaptation
to diuretic treatment and the re-establishment of a steady state between intakeand output occur swiftly and may precede any fall in BP. After several weeksof treatment, cardiac output is reduced with the greatest effect occurring
after approximately 3 months.Although it is tempting to attribute the hypo-
tensive effect of diuretics to this decline in cardiac output, observations duringprolonged treatment as well as comparisons between responders and non-
responders argue against this notion. Indeed, with continued administrationof a thiazide diuretic, plasma volume is partially restored while cardiac output
rises again.Nevertheless, extracellular volume remains low.In this phaseof treatment, the fall in BP is due mainly to a reduction in systemic vascularresistance. The picture is even more compelling when responders and non-responders are compared. For instance, Van Brummelen and coworkers con-trasted the haemodynamic findings in responders (greater than 10% fall inmean arterial pressure) with those in non-responders (less than 10% fall) andobserved strikingly different patIn responders the initial fall incardiac output was followed by a return to pretreatment levels, whereas innon-responders it was permanently reduced. Consequently, total peripheralresistance was lowered only in responders. Non-responders also tended toshow a greater degree of plasma volume depletion and greater stimulationof renin and aldosterone. The latter may have contributed to the elevatedperipheral resistance. These data show that changes in cardiac output areunlikely to be of decisive importance in the ultimate reduction of BP inresponders to thiazide therapy. Thus, the secondary fall in SVR seems to bethe prime mechanism whereby diuretics lower the pressure. Why this vasor-elaxant effect occur has not been fully elucidated. In experiments with aorticand pulmonary artery rings from male Wistar rats, Abrahams and associatesfound various diuretic preparations to possess vasorelaxing propertiesthat were endothelium independent.This effect was expressed only when
plasma had been added to the bath. This suggests that diuretic compounds
need a cofactor from plasma in order to obtain vasodilatory potential. Onthe other hand, there is evidence to show that diuretics are able to activatepotassium channels in vascular smooth muscle cells leading to hyperpolariza-
tion and a reduction in intracellular calcium.
With continued treatment both renal blood flow and glomerular filtration
rate rise substantially, while renal vascular resistance and filtration fraction fall.
This sequence of events was observed in patients who were treated with arather high dose of hydrochlorothiazide (50 mg twice daily) and who had onlymild reductions in sodium intake. In contrast Scaglione and coworkers treated13 essential hypertensive patients who were maintained on a normal sodium
diet (150 mmol/day for 8 weeks with hydrochlorothiazide (25 mg once a
day)). Using somewhat less reliable methods to measure renal plasma flow
and glomerular filtration rate they showed a significant fall in renal vascularresistance without changes in flow, filtration rate and filtration fraction atthe end of the study perDespite differences in methodology betweenstudies, the various data by and large point in the same direction: long-termtreatment with a thiazide drug induces a favourable renal haemodynamic
response whereby renal function is maintained.
Today, many antihypertensive agents are at the disposal of the practising phy-
sician. Not infrequently, though, the prescribing doctor is more interested inthe clinical efficacy (i.e. the final drop in pressure) than in the mechanismswhereby drugs are exerting these effects. Still, detailed knowledge of thesemechanisms is essential to understand why a drug works or not. This knowl-edge will help to find either suitable alternatives or appropriate combinationsof drugs in patients who do not respond to the initial therapy.
1. Neal B, MacMahon S, Chapman N. Effects of ACE inhibitors, calcium antagonists, and other
blood-pressure-lowering drugs: results of prospectively designed overviews of randomisedtrials. Blood Pressure Lowering Treatment Trialists’ Collaboration. Lancet 2000;356: 1955–1964.
2. Safar ME. Mechanical factors predicting cardiovascular risk and drug treatment of
hypertension. J Hypertens 2002;20:349–352.
3. Guyton AC, Hall JE, Coleman TG, et al. The dominant role of the kidneys in long-term
arterial pressure regulation in normal and hypertensive states. In: Laragh JH, Brenner BM,eds. Hypertension. Pathophysiology, Diagnosis, and Management. New York: Raven Press; 1995.
4. Julius S, Krause L, Schork NJ, et al. Hyperkinetic borderline hypertension in Tecumseh,
Michigan. J Hypertens 1991;9:77–84.
5. Birkenha¨ger WH, De Leeuw PW, Schalekamp MADH. Control mechanisms in essential
hypertension. Amsterdam: Elsevier Biomedical Press; 1982.
6. van den Meiracker AH, Man in ’t Veld AJ, van Eck HJ, et al. Hemodynamic and hormonal
adaptations to beta-adrenoceptor blockade. A 24-hour study of acebutolol, atenolol, pindolol,and propranolol in hypertensive patients. Circulation 1988;78:957–968.
7. Man in ’t Veld AJ, Van den Meiracker AH, Schalekamp MADH. Do b-blockers really
increase peripheral vascular resistance? Review of the literature and new observations underbasal conditions. Am J Hypertens 1988;1:91–96.
8. Frishman WH. Clinical Pharmacology of the Beta-Adrenoceptor Blocking Drugs. Norwalk. CT:
9. Saunders E, Weir MR, Kong BW, et al. A comparison of the efficacy and safety of a
beta-blocker, a calcium channel blocker, and a converting enzyme inhibitor in hypertensiveblacks. Arch Intern Med 1990;150:1707–1713.
10. De Leeuw PW. Nonsteroidal anti-inflammatory drugs and hypertension. The risks in
perspective. Drugs 1996;51:179–187.
11. Carlberg B, Samuelsson O, Lindholm LH. Atenolol in hypertension: is it a wise choice?
12. Kawakami H, Sumimoto T, Hamada M, et al. Acute effect of glyceryl trinitrate on systolic
blood pressure and other hemodynamic variables. Angiology 1995;46:151–156.
13. Pannier BM, Kando T, Safarian AA, et al. Altered hemodynamic response to isosorbide
dinitrate in essential hypertension. J Clin Pharmacol 1990;30:127–132.
14. Safar ME, London GM. Therapeutic studies and arterial stiffness in hypertension:
recommendations of the European Society of Hypertension. The Clinical Committee ofArterial Structure and Function. Working Group on Vascular Structure and Function of theEuropean Society of Hypertension. J Hypertens 2000;18:1527–1535.
15. Pollesello P, Mebazaa A. ATP-dependent potassium channels as a key target for the
treatment of myocardial and vascular dysfunction. Curr Opin Crit Care 2004;10:436–441.
16. Purcell H, Patel D, Mulcahy D, et al. In: Messerli FH, Cardiovascular Drug Therapy,
Philadelphia: WB Saunders Company; 1996. pp. 1638–1645.
17. Reid JL, Wing LM, Mathias CJ, et al. The central hypotensive effect of clonidine. Studies in
tetraplegic subjects. Clin Pharmacol Ther 1977;21:375–381.
18. Struthers AD, Brown MJ, Adams EF, Dollery CT. The plasma noradrenaline and growth
hormone response to alpha-methyldopa and clonidine in hypertensive subjects. Br J ClinPharmacol 1985;19:311–317.
19. Koshiji M, Ito H, Minatoguchi S, et al. A comparison of guanfacine, bunazosin, atenolol and
nadolol on blood pressure and plasma noradrenaline responses to cold pressor testing. ClinExp Pharmacol Physiol 1992;19:481–488.
20. Jarrott B. Clonidine and related compounds. In: Doyle AE, Clinical Pharmacology of
Antihypertensive Drugs. Amsterdam: Elsevier Science Publishers BV; 1988. pp. 125–186.
21. Mitrovic V, Patyna W, Huting J, Schlepper M. Hemodynamic and neurohumoral effects of
moxonidine in patients with essential hypertension. Cardiovasc Drugs Ther 1991;5:967–972.
22. Kirch W, Hutt HJ, Planitz V. Pharmacodynamic action and pharmacokinetics of moxonidine
after single oral administration in hypertension patients. J Clin Pharmacol 1990;30:1088–1095.
23. Prichard BN. Principles and practice of a-antiadrenergic therapy. In: Messerli FH,
Cardiovascular Drug Therapy. Philadelphia: WB Saunders Company; 1996. pp. 601–616.
24. Mitchell A, Buhrmann S, Opazo Saez A, et al. Clonidine lowers blood pressure by reducing
vascular resistance and cardiac output in young healthy males. Cardiovasc Drugs Ther 2005;19(1):49–55.
25. Aars H. Effects of clonidine on aortic diameter and aortic baroreceptor activity. Eur J
26. Shaw J, Hunyor SN, Korner PI. The peripheral circulatory effects of clonidine and their role
in the production of arterial hypotension. Eur J Pharmacol 1971;14:101–111.
27. Sica DA. Doxazosin and congestive heart failure. Congest Heart Fail 2002;8:178–184.
28. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group.
Major cardiovascular events in hypertensive patients randomized to doxazosin vschlorthalidone: the antihypertensive and lipid-lowering treatment to prevent heart attacktrial (ALLHAT). JAMA 2000;283:1967–1975.
29. Azizi M, Menard J, Bissery A, et al. Pharmacologic demonstration of the synergistic effects
of a combination of the renin inhibitor aliskiren and the AT1 receptor antagonist valsartan onthe angiotensin II-renin feedback interruption. J Am Soc Nephrol 2004;15:3126–3133.
30. Gradman AH, Schmieder RE, Lins RL, et al. Aliskiren, a novel orally effective renin inhibitor,
provides dose-dependent antihypertensive efficacy and placebo-like tolerability inhypertensive patients. Circulation 2005;111:1012–1018.
31. Brunner HR, Waeber B, Nussberger J. Angiotensin-converting enzyme inhibitors. In:
Messerli FG, Cardiovascular Drug Therapy. Philadelphia: WB Saunders Company; 1996.
32. Brunner F, Kukovetz WR. Postischemic antiarrhythmic effects of angiotensin-converting
enzyme inhibitors. Role of suppression of endogenous endothelin secretion. Circulation1996;94:1752–1761.
33. Mancini GB, Henry GC, Macaya C, et al. Angiotensin-converting enzyme inhibition with
quinapril improves endothelial vasomotor dysfunction in patients with coronary arterydisease. The TREND (Trial on Reversing ENdothelial Dysfunction) Study. Circulation1996;94:258–265.
34. Topouchian J, Brisac AM, Pannier B, et al. Assessment of the acute arterial effects of
converting enzyme inhibition in essential hypertension: a double-blind, comparative andcrossover study. J Hum Hypertens 1998;12:181–187.
35. Zarnke KB, Feldman RD. Direct angiotensin converting enzyme inhibitor-mediated
venodilation. Clin Pharmacol Ther 1996;59:559–568.
36. Dyker AG, Grosset DG, Lees K. Perindopril reduces blood pressure but not cerebral blood
flow in patients with recent cerebral ischemic stroke. Stroke 1997;28:580–583.
37. Lartaud I, Makki T, Bray-des-Boscs L, et al. Effect of chronic ANG I-converting enzyme
inhibition on aging processes. IV. Cerebral blood flow regulation. Am J Physiol 1994;267:
38. Motz W, Strauer BE. Improvement of coronary flow reserve after long-term therapy with
enalapril. Hypertension 1996;27:1031–1038.
39. Goodfriend TL, Elliott ME, Catt KJ. Angiotensin receptors and their antagonists. N Engl
40. Bauer JH, Reams GP. The angiotensin II type 1 receptor antagonists. A new class of
antihypertensive drugs. Arch Intern Med 1995;155:1361–1368.
41. Azizi M, Guyene TT, Chatellier G, et al. Additive effects of losartan and enalapril on blood
pressure and plasma active renin. Hypertension 1997;29:634–640.
42. Mogensen CE, Neldam S, Tikkanen I, et al. Randomised controlled trial of dual blockade of
renin-angiotensin system in patients with hypertension, microalbuminuria, and non-insulin
dependent diabetes: the candesartan and lisinopril microalbuminuria (CALM) study. BMJ2000;321:1440–1444.
43. Stergiou GS, Skeva II, Baibas NM, et al. Additive hypotensive effect of angiotensin-
converting enzyme inhibition and angiotensin-receptor antagonism in essentialhypertension. J Cardiovasc Pharmacol 2000;35:937–941.
44. Dahlof B, Devereux RB, Kjeldsen SE, et al. Cardiovascular morbidity and mortality in the
Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised
trial against atenolol. Lancet 2002;359:995–1003.
45. Julius S, Kjeldsen SE, Weber M, et al. Outcomes in hypertensive patients at high
cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUErandomised trial. Lancet 2004;363:2022–2031.
46. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group.
Major outcomes in high-risk hypertensive patients randomized to angiotensin-convertingenzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-
Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002;288:2981–2997.
47. Schiffrin EL, Deng LY. Structure and function of resistance arteries of hypertensive patients
treated with a beta-blocker or a calcium channel antagonist. J Hypertens 1996;14:1247–1255.
48. Messerli FH, Oparil S, Feng Z. Comparison of efficacy and side effects of combination
therapy of angiotensin-converting enzyme inhibitor (benazepril) with calcium antagonist(either nifedipine or amlodipine) versus high-dose calcium antagonist monotherapy forsystemic hypertension. Am J Cardiol 2000;86:1182–1187.
49. Ruzicka M, Leenen FH. Relevance of 24 h blood pressure profile and sympathetic activity for
outcome on short- versus long-acting 1,4-dihydropyridines. Am J Hypertens 1996;9:86–94.
50. Van Brummelen P, Woerlee M, Schalekamp MA. Long-term versus short-term effects of
hydrochlorothiazide on renal haemodynamics in essential hypertension. Clin Sci (Lond)1979;56:463–469.
51. Van Brummelen P, Man in ’t Veld AJ, Schalekamp MA. Haemodynamics during long-term
thiazide treatment in essential hypertension: differences between responders and non-responders. Clin Sci (Lond) 1979;57 Suppl 5:359s–362s.
52. Conway J, Lauwers P. Hemodynamic and hypotensive effects of long-term therapy with
chlorothiazide. Circulation 1960;21:21–27.
53. Van Brummelen P, Schalekamp MA. Body fluid volumes and the response of renin and
aldosterone to short- and long-term thiazide therapy of essential hypertension. Acta MedScand 1980;207:259–264.
54. Van Brummelen P, Man in ’t Veld AJ, Schalekamp MA. Hemodynamic changes during
long-term thiazide treatment of essential hypertension in responders and nonresponders.
Clin Pharmacol Ther 1980;27:328–336.
55. Abrahams Z, Tan LL, Pang MY, et al. Demonstration of an in vitro direct vascular relaxant
effect of diuretics in the presence of plasma. J Hypertens 1996;14:381–388.
56. Calder JA, Schachter M, Sever PS. Direct vascular actions of hydrochlorothiazide and
indapamide in isolated small vessels. Eur J Pharmacol 1992;220:19–26.
57. Pickkers P, Hughes AD, Russel FG, et al. Thiazide-induced vasodilation in humans is
mediated by potassium channel activation. Hypertension 1998;32:1071–1076.
58. Scaglione R, Indovina A, Parrinello G, et al. Antihypertensive efficacy and effects of
nitrendipine on cardiac and renal hemodynamics in mild to moderate hypertensive patients:randomized controlled trial versus hydrochlorothiazide. Cardiovasc Drugs Ther1992;6:141–146.
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