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used with some success in neonates with persistent pulmonary hypertension of the newborn (PPHN).

Phosphodiesterase type 5 inhibition has beneficial effects on hemodynamics and cardiac function in heart failure. In various experimental models of heart failure, PDE inhibitors prevent and reverse cardiac hypertrophy, reduce remodeling, and decrease

myocardial fibrosis.

of patients with severe heart failure, sildenafil treatment for 1 year

38,39

In a recent placebo-controlled clinical trial

improved ejection fraction, improved parameters of diastolic function, and reduced left atrial size while improving functional capacity and clinical status.

This study was not designed to determine whether sildenafil improves survival; larger studies are needed with longer-term follow-up to discern whether PDE5 inhibition provides survival benefit. Nevertheless, these orally available agents, which avoid the problem of tolerance encountered with the nitrovasodilators, have substantial promise in treating ventricular dysfunction.

Prostaglandins and Thromboxane Agonists and Antagonists

Release of lipids from the cell membrane upon receptor binding or mechanical stimulation is a major signaling event in mammalian cells. One major class of lipid metabolites is the prostanoids, which include the prostaglandins (PGs) and thromboxane. The pathway leading to formation of these lipids is illustrated in

Figure 6-5. They are formed from arachidonic acid, released from

membrane phospholipids via the action of phospholipase A The initial step in prostanoid synthesis is conversion of arachidonic acid to the endoperoxide prostaglandin H

(PGH2) by COX

enzymes. Prostaglandin H including various PG synthases and thromboxane synthases (see

is in turn a substrate for several enzymes

Fig. 6-5), which leads to formation of multiple PG metabolites

including PGE ane A

TxA2. Each of these has several G protein–linked receptors

that are widely distributed and modulate myriad physiological

, prostacyclin (PGI2), PGF2α, PGD2, and thrombox-

and pathophysiological responses that include inflammation, vasomotor tone, hemostasis, renal function, and blood pres-

41,42

sure.

Vascular response to the various prostanoids depends on the category of the heterotrimeric G-protein receptor to which it binds. Vasodilator prostanoids, including PGI G

, which leads to an increase in intracellular cAMP. The con-

tractile prostanoids, including TxA leads to increased intracellular calcium. There are both Gs and G

receptors for PGE2, which can therefore both vasodilate and

vasoconstrict.

and PGF2α, activate Gq, which

and PGD2, activate

There are two isoforms of the COX enzymes: COX-1 and COX-2. Cyclooxygenase-1 is constitutively expressed and exerts housekeeping functions in many cells, including vascular cells. Cyclooxygenase-2 is generally considered an inducible enzyme, and its levels increase in the settings of inflammation, in particular when inflammatory cells enter the affected tissue.

Cyclooxygenase-2 is also constitutively expressed in some cells, including ECs. The preferred substrate of COX-1 is arachidonic acid, but COX-2 can also produce unique antiinflammatory products from the endogenous cannabinoid 2-arachidonyl glycerol. activated by shear stress in the endothelium. products of COX are highly dependent on the cell type. In healthy

blood vessels, the predominant arachidonic acid metabolite is PGI

, whereas platelets predominantly produce TxA2. In a variety

Both COX-1 and COX-2 are

The downstream

Phospholipase A

Arachidonic Acid

COX

PGD

PGJ

HOOO

6-Keto-PGF

PGI

PGG

PGH

PGE

PGA

PGF

FIGURE 65 Arachidonic acid metabolic pathway. COX, cyclooxygenase; PG, prostaglandin; PGI2, prostacyclin; Tx, thromboxane.

TxA

TxB

of common cardiovascular diseases, however, vascular produc-

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tion of prostanoids can be shifted toward proinflammatory, procoagulant, and vasoconstrictor prostanoids. stimulates COX-2 expression and production of PGE and this response contributes to VSMC proliferation and migration

As an example, Ang-II

in VSMCs,

in response to this hormone.45 In several experimental models of hypertension, obesity, and aging, the endothelium begins to produce prostanoid-contracting factors including PGH ROS generated as byproducts of COX activity.

, TxA2, and

Cyclooxygenase Inhibitors

Cyclooxygenase inhibitors have been used since antiquity to alleviate pain and fever. Salicylic acid was purified from willow bark in the 18th and 19th centuries and was further modified to acetylsalicylic acid (ASA) in 1897. A large number of nonsteroidal antiinflammatory drugs (NSAIDs) have been developed to specifically inhibit COX enzymes, and together with ASA are the most commonly used drugs in the world. Drugs that specifically inhibit COX-2 were subsequently developed. These were intended to reduce gastrointestinal side effects and block inflammation caused by COX-2, although as mentioned later, they have unexpected and untoward effects that have reduced their popularity.

Aspirin has been studied extensively since the 1950s as a means

of reducing cardiovascular events.

Numerous large clinical trials performed in the 1980s supported the concept that aspirin decreases the occurrence of MI and stroke. A recent large metaanalysis showed that aspirin was effective in both primary and secondary prevention of total coronary events, ischemic stroke, and serious vascular events, with the greatest benefit observed in the case of secondary prevention.

Another recent meta-analysis of nine trials that included 90,000 patients showed that aspirin is effective for primary prevention of nonfatal MI and total cardiovascular events, but not for stroke, cardiovascular mortality, or allcause mortality. suggested that aspirin might not be useful for primary prevention of events in the diabetic population.

Of interest, several recent meta-analyses have

50,51

The beneficial effects of aspirin are generally considered a consequence of its antiplatelet effects and reduction of thrombosis. However, aspirin reduces levels of C-reactive protein (CRP) in patients with recent unstable coronary syndromes, experimental models of atherosclerosis, reduces atheroma burden, decreases inflammation, and improves endothelial function,

and in

53,54

suggesting that it might also have direct vascular effects.

Although aspirin has proven effective in reducing cardiovascular events, there are no clinical trials showing that other COX inhibitors convey similar cardiovascular benefit, and paradoxically, there is substantial evidence that these agents are harmful. The most striking example is that of the COX-2 inhibitor rofecoxib, which was withdrawn from the market because of increased thrombotic

events

; however, other COX inhibitors might also increase cardio-

vascular risk, depending upon the relative COX-2–to–COX-1 selec-

56,57

tivity.

The precise mechanisms underlying this increased risk remain undefined, and it is unclear why aspirin, which inhibits the same enzyme, albeit via different mechanisms, is beneficial. These differences might relate to inhibition of vascular PGI renal COX, which in turn could promote sodium retention and

and perhaps

blood pressure elevation and worsen cardiovascular outcome. As previously mentioned, the downstream products and their receptors are myriad, so the

in vivo actions of these agents are complex

and difficult to predict. Nevertheless, NSAIDs other than aspirin should be used sparingly in patients with known cardiovascular diseases and currently have no role in preventing cardiovascular events.

Prostacyclin Analogs as Therapeutic Agents

Given its potent vasodilator effects, there is enormous interest in therapeutic use of PGI been developed. The most commonly employed are epoprostenol,

and its analogs. Several preparations have

a freeze-dried synthetic preparation of PGI iloprost, treprostinil, and beraprost. These agents have become a

, and the PGI2 analogs

mainstay of treatment for PAH. Epoprostenol was initially approved for treatment of PAH following a 12-week trial in 81 patients prospectively randomized to either epoprostenol or conventional therapy.58 Among those treated with epoprostenol, there was improvement in exercise capacity and a decline in PAP. This was in contrast to those receiving conventional therapy, in whom walk time decreased and PAP increased. Patients treated with epoprostenol had greater symptomatic improvement, and most strikingly in this small study, eight patients died, all in the conventional therapy group. A second study showed that epoprostenol improved exercise duration and lowered PAP in patients with PH associated with scleroderma.

Interestingly, these subjects showed a trend toward improvement of digital ulcers, suggesting that systemic vasodilation caused by this drug might also be beneficial. Subsequent long-term follow-up in large registries have confirmed a beneficial effect of continuous intravenous epoprostenol in PAH.

A downside of epoprostenol therapy is that it requires chronic central line placement, which is accompanied by risk of infection that might be related in part to prostanoid-mediated immunosuppression. The drug also often requires up-titration to overcome tachyphylaxis and is expensive.

Owing to its short half-life, there is rebound PH that develops shortly after discontinuing the drug, which can have serious consequences. Common side effects include headaches, occasional cases of thyrotoxicosis, nausea, jaw pain, thrombocytopenia (in up to 34% of patients), flushing, skin rash, anorexia, arthralgias, and myalgias.

For the reasons mentioned, PGI

nil, beraprost) have been developed. These have longer half-lives

analogs (i.e., iloprost, treprosti-

and can be given intravenously, subcutaneously, via nebulizer, and in some cases orally. Numerous studies have shown that these improve exercise tolerance and quality of life, either alone or in combination with endothelin blockade and PDE5 inhibitors in patients with PAH. The subcutaneous and, intravenous forms of administration are frequently complicated by local pain, induration, and inflammation at injection sites. Inhaled forms avoid these complications but require frequent administration. Despite their limitations, these agents improve hemodynamics, increase exercise tolerance, and enhance quality of life.

Although these agents are potent vasodilators and have the potential to reduce pulmonary vascular resistance (PVR), it is actually unclear as to how they impart therapeutic benefit. Hemodynamic studies have shown that the decrease in pulmonary pressure following inhalation therapy is brief and unlikely to account for sustained benefit. Moreover, the pulmonary vasculature in these patients is often extensively occluded, questioning the potential benefit of vasodilation. These agents enhance RV performance, and they might decrease fibrosis and thrombosis within the pulmonary vasculature.

There is also lack of consensus on how to use these agents, which agents to use, and what dosing regimen is optimal.

As discussed elsewhere in this chapter, these agents are often used in conjunction with PDE5 inhibitors and endothelin-1 (ET-1) receptor antagonists, again without uniformity across various centers.

Sympathetic and Parasympathetic Nervous Systems

Abrupt changes in blood pressure are buffered by the sympathetic and parasympathetic nervous system ( flex response helps integrate blood pressure detection and CNS response, and impairment of this response produces profound orthostatic intolerance and inability to maintain upright posture. Increased blood pressure stimulates baroreceptors located in the carotid sinus and aortic arch, which transmit their signals to the nucleus tractus solitarius in the CNS. The transmitted signal inhibits sympathetic outflow from the rostral ventrolateral medulla (RVLM). Sympathetic efferent preganglionic axons extend to the

Fig. 6-6). The barore-

CH 6

VAsCulAR PHARmACology

NTS

Parasympathetic preganglionic fiber

Ach

Parasympathetic ganglia

Carotid sinus

and aortic arch

baroreceptors

RVLM

Sympathetic preganglionic fiber

Sympathetic ganglion

Ach

sympathetic ganglion, where acetylcholine serves as the principal neurotransmitter to postganglionic nicotinic receptors. Postganglionic sympathetic fibers extend to effector organs such as the heart and vasculature and release norepinephrine (NE) to produce vasoconstriction and increased contractility. The adrenal medulla is innervated directly by preganglionic sympathetic neurons and releases both NE and epinephrine into the circulation. At the same time, the reflex activates parasympathetic system and reduces heart rate via innervation of the cardiac conduction system. Therefore, the net effect of an abrupt increase in blood pressure is inhibition of the sympathetic system and activation of the parasympathetic nervous system.

Vascular Parasympathetic System

Postganglionic parasympathetic fibers release acetylcholine, which stimulates muscarinic and nicotinic receptors. Most blood vessels lack parasympathetic innervation, although some notable exceptions exist (e.g., coronary arteries), and the physiological role of endogenous acetylcholine in vasodilation is uncertain. The vasculature does contain muscarinic receptors and responds to exogenously administered acetylcholine or mimetics (e.g., methacholine). Exogenous acetylcholine dilates blood vessels by its actions on the vascular endothelium, but it produces vasoconstriction if the endothelial layer is injured or removed. This discovery demonstrated the importance of the endothelium as an active participant in vascular reactivity and eventually led to the discovery of endothelium-derived relaxing factors (e.g., NO, PGI2.63 Patients with cardiovascular disease exhibit an impaired vasodilatory response to acetylcholine (endothelial dysfunction) but often have a normal response to direct vasodilators such as nitroprusside. Impaired vascular reactivity in both the coronary and forearm vasculature predicts future cardiovascular events,

64,65

and the endothelium-dependent response may be improved with drug therapy, exercise, or risk factor modification (e.g., smoking cessation).

66–68

Ach

 receptors

,  receptors

FIGURE 66 Baroreceptors and the autonomic nervous system. Ach,

acetyl choline; M3, muscarinic acetylcholine receptor; NE, norepinephrine; NN, neuronal nicotinic acetylcholine receptor; NTS, nucleus tractus solitarius; RVLM, rostral ventrolateral medulla.

Sinus

node

Acetylcholine receptors (AchRs) are classified by their ability to respond to either muscarine (M Muscarinic receptors are classic G protein–coupled receptors (GPCRs), coupled to G AchRs are ligand-gated voltage channels. Vascular M

, which inhibits cAMP production. Nicotinic

receptors have been described and produce vasodilation via endothelial, or vasoconstriction via VSMC, receptors

) or nicotine (nAchR).

1-M5

, M2, and M3

(Table 6-2) . Acetylcholine is a nonselective agonist; there are no clinically available subtype-selective agents, although a number of investigational drugs exist. Methacholine is frequently used in clinical research because of its longer half-life and stability. Atropine is a nonselective muscarinic antagonist used mainly to increase heart rate by its effects on cardiac M are also located on postsynaptic sympathetic nerve terminals

and M3 receptors. Muscarinic receptors

and inhibit NE release. Peripheral neuronal nicotinic AchRs (N transmit sympathetic impulses in autonomic ganglia and adrenal medulla to stimulate NE and epinephrine release. Trimethaphan inhibits N available, although it is no longer used, owing to resulting severe autonomic impairment and intolerable side effects.

and was one of the earliest antihypertensive agents

Adrenergic Receptors and Agonist Selectivity

Sympathetic postganglionic neurons richly innervate the vasculature and release NE, whereas the adrenal medulla secretes epinephrine in addition to NE. These catecholamines activate adrenergic receptors, which are classic seven-transmembrane receptors coupled to G proteins. They are further classified as either α (α subtypes have also been identified (α although no subtype-specific antagonists are available. Their physiological effects have been determined in part by the study of receptor knockout models. ulation of phospholipase C/D/A cyclase), and β-receptors to G

and α2) or β receptors (β1, β2, and β3) . α-Receptor

70,71

In general, α1 is coupled to Gq (stim-

(stimulation of adenylate cyclase).

, α1B, α1D, α2A, α2B, and α2C) ,

) , α2 to Gi (inhibition of adenylate

)

TABLE 6-2 Vascular Adrenergic and Muscarinic Receptor Actions

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RECEPTOR TISSUE ACTION AGONIST ANTAGONIST

VSMC Vasoconstriction Phenylephrine

Sympathetic nerve terminal Inhibition of NE release Clonidine

VSMC Placental vasculature

VSMC Adrenal medulla

Vasoconstriction Placental angiogenesis

Vasoconstriction Inhibition of NE/E release

Cardiac conduction system Increased heart rate Isoproterenol β-Blockers Cardiac myocytes

Coronary arteries

Increased contractility Vasodilation

Kidney: afferent arteriole Stimulation of renin release

EC, endothelial cell; NE, norepinephrine; VSMC, vascular smooth muscle cell.

VSMC Vasodilation Isoproterenol

Cardiac myocytes Vascular ECs

Vascular endothelium VSMC Sympathetic neurons

VSMC Sympathetic neurons Cardiac conduction system

Vascular endothelium VSMC Cardiac conduction system

Decreased contractility Vasodilation

Vasodilation Vasoconstriction Stimulate NE release

Vasoconstriction Inhibit NE release Slow conduction

Vasodilation Vasoconstriction Slow conduction

Sympathetic neurons Inhibit NE release Acetylcholine

Methoxamine Midodrine Amphetamine

α-Methyldopa Dexmedetomidine Guanabenz Guanfacine Tizanidine

Oxymetazoline Etomidate

Oxymetazoline

Dobutamine

Terbutaline Ritodrine

Acetylcholine Muscarine Methacholine Carbachol Arecoline Mc-N-A-343

Acetylcholine Muscarine Methacholine Carbachol Arecoline L-660,863

Acetylcholine Muscarine Methacholine Carbachol Arecoline

Muscarine Methacholine Carbachol Arecoline

Phenoxybenzamine Phentolamine Tolazoline α-Blockers Vasodilator β- blockers

Phentolamine Tolazoline Phenoxybenzamine Yohimbine Rauwolfia alkaloids Piperazine

β-Blockers

Atropine Pirenzepine Telenzepine

Atropine AF-DX-116 AQ-RA 741 Methoctramine BIBN 99

Atropine 4-DAMP p-F-HHSiD HHSiD

Atropine

CH 6

VAsCulAR PHARmACology

Distribution of tissue adrenergic receptors is a major determinant of the agonist response because they are relatively nonselective for epinephrine and NE (see

Table 6-2). Vascular smooth

stimulates lipolysis; β lation via β trol of vasodilation by vascular ECs.

receptors in cardiac myocytes and contribute to con-

receptors may counteract adrenergic stimu-

muscle cells (venous, arterial, and arteriolar) are richly innervated by sympathetic nerve terminals and possess adrenergic receptors (α

, α2, and β2). These receptors can have opposing actions

within the vasculature, as demonstrated by α-mediated vasoconstriction and β is determined by the relative activation of α1, α2, and β2 receptors. Vascular α aptic α

tors are expressed primarily within the cardiac conduction system

-mediated vasodilation, and the vascular response

receptors produce vasoconstriction, whereas presyn-

receptors suppress NE release. Cardiovascular β1 recep-

and cardiomyocytes, rather than in the vascular bed. However, vascular β and stimulate renin secretion in the renal juxtaglomerular apparatus.

receptors mediate vasodilation within coronary arteries

The β3 receptor is primarily expressed on adipocytes, where it

Pharmacological Interruption of Catecholamine Metabolism

Catecholamine metabolism is an important target of therapeutic drugs and other chemical agents. Catecholamines are produced locally within the sympathetic neurons by metabolism of tyrosine (

Fig. 6-7) to dopamine. Dopamine is concentrated into vesi-

cles via vesicular monoamine transporters. Once in the vesicles, dopamine is converted into NE. Norepinephrine is then secreted and activates adrenergic receptors, provides positive or negative feedback, or is taken back up into the cell via NE transporter (NET). Norepinephrine transporters and similar transporters also

Synaptic terminal



 Clonidine,

NE, E

Guanethidine

DH

Reserpine



DD TH

MAO-A/B

COMT

Dopa Tyrosine

NET

Cocaine, NET inhibitors

Metanephrines

Effector tissue

FIGURE 67 Norepinephrine (NE) release and reuptake. NE is released from the sympathetic nerve terminal and can signal via vascular α or β receptors. NE also provides positive and/or negative feedback. NE is rapidly taken back up into the nerve terminal via NE transporters (NETs) and can be recycled into granules or metabolized via monoamine oxidase (MAO). Metabolism and/or receptor signaling can be interrupted at multiple steps in the pathway. COMT, catechol-O-methyl transferase; DA, dopamine; DβH, dopamine β-hydroxylase; DD, dopamine decarboxylase; E, epinephrine; TH, tyrosine hydroxylase.

transport other neurotransmitters such as epinephrine, dopamine, and serotonin. Norepinephrine is metabolized via monoamine oxidases (MAO-A and MAO-B) after reuptake into the cell, or by catechol-O-methyltransferase (COMT) after diffusion into the circulation.

Pharmacological agents that affect this pathway are used clinically for treatment of hypertension, depression, and movement disorders. Reserpine blocks vesicular dopamine/NE transport and depletes NE from the nerve terminals. Guanethidine is an antihypertensive agent that is taken up into vesicles, displaces NE, and reduces NE release during long-term therapy. Many herbal, over-the-counter, or illicit medications act by stimulating NE release (e.g., amphetamine, pseudoephedrine), activat-

/ receptors

or stimulate release of catecholamines (indirect sympathomimetics).

73–75

Whereas epinephrine and NE are rapidly metabolized via COMT, many synthetic sympathomimetic drugs are resistant to this effect, and are therefore effective when ingested by mouth. Ephedra (or ma huang) is a sympathomimetic herbal extract used for asthma treatment, weight loss, and enhanced athletic performance. It can cause severe hypertension, cardiovascular events, and even death in young, apparently healthy individuals. Caffeine coadministration likely exacerbates ephedra-related complications.

Performance athletes or enthusiastic weight lifters may also take sympathomimetic supplements, which comprise many of the medications banned by the World Anti-Doping Agency.

ing adrenergic receptors (phenylephrine), or acting via mixed mechanisms (ephedrine). Cocaine and tricyclic antidepressants block NE reuptake into the cell and may transiently increase NE and produce hypertension. Antidepressant medications such as selective serotonin reuptake inhibitors (SSRIs) act similarly, and may also nonselectively block NET. Sibutramine is a nonselective serotonin reuptake/NET inhibitor previously used for appetite suppressant effects, but it has been withdrawn from the market because of increased risk of cardiovascular events. Monoamine oxidase inhibitors (MAOIs) are occasionally used to treat depression and can cause marked hypertension during ingestion of tyramine-containing foods, which stimulates NE release. COMT inhibitors and dopa are used to treat movement disorders and can cause orthostatic hypotension and blood pressure dysregulation.

Many weight-loss supplements, decongestant preparations, and

herbal supplements act as α1-agonists (direct sympathomimetics)

Adrenergic Agonists and Antagonists

Vascular α- and β-receptor agonists and antagonists are listed in

Table 6-2, and their vascular actions can generally be inferred from

the respective receptor actions. Physiological effects of endogenous and synthetic catecholamines are complex because they activate multiple receptors, exhibit dose-dependent responses, and activate compensatory reflexes.

Epinephrine is primarily secreted by the adrenal medulla, where it constitutes roughly 80% of total catecholamine content. Depending on the dose and route of administration, epinephrine may produce divergent vascular responses ( intravenous administration produces marked vasoconstriction, tachycardia, and elevated blood pressure. Continuous infusion or subcutaneous administration of epinephrine increases heart rate and cardiac contractility, systolic blood pressure, and mean

Table 6-3). Acute

TABLE 6-3 Receptor Activity and Hemodynamic Effects of Commonly Used Adrenergic Agonists

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RECEPTOR EPI NE DA* ISOPROTERENOL DOBUTAMINE PHENYLEPHRINE

Physiological Effects

HR ↑↑ ↓ ↑↑ ↑ ↑↑ ↔/↓ SBP ↑ ↑↑ ↑ ↔/↑ ↔/↓ ↑↑ MAP ↔/↑ ↑↑ ↑ ↓ ↔/↓ ↑↑ DBP ↑/↔/↓ ↑ ↑ ↓ ↔/↓ ↑↑ CO ↑↑ ↔/↓ ↑↑ ↑↑ ↔/↓ PVR ↔/↓ ↑↑ ↔/↑ ↓↓ ↓ ↑↑

Dopamine effects are dose-dependent. Effects at maximal dose are presented.

+ Indicates degree of receptor activation, and ↔ indicates minimal effect. CO, cardiac output; DA, dopamine; DBP, diastolic blood pressure; EPI, epinephrine; HR, heart rate; MAP, mean arterial pressure; NE, norepinephrine; PVR, peripheral vascular resistance; SBP, systolic blood pressure.

+++ ++ +++ + ↔ +++ +++ ++ ↔ + ↔ ↔ ++ ++ +++ +++ +++ ↔ ++ +/↔ + +++ +/↔ ↔

CH 6

VAsCulAR PHARmACology

arterial blood pressure. Diastolic blood pressure is affected to a lesser extent, resulting in a marked increase in pulse pressure. At lower doses, epinephrine reduces vascular resistance secondary to β

-receptor stimulation and vasodilation, which may reduce

blood pressure. Epinephrine is commonly used to treat anaphylactic reactions, bronchoconstriction, and refractory bradycardia and hypotension. Epinephrine is less often used than NE for treatment of septic shock because of tachycardia and concerns for worsened splanchnic ischemia compared to other agents.

Norepinephrine produces vasoconstriction with lesser direct

cardiac effects and β both blood pressure and peripheral vascular resistance. Heart

activity than epinephrine, which increases

rate decreases due to the baroreflex response. Norepinephrine is useful for treating hypotension refractory to fluid resuscitation (e.g., septic shock). Although there is debate regarding the optimal vasopressor in septic shock, NE has proven as effective as comparable agents, possibly with fewer complications.

77–81

Norepinephrine appears to produce less splanchnic vasoconstriction and intestinal ischemia than epinephrine or phenylephrine.

Isoproterenol is a nonselective β

used to increase heart rate for treatment of sinus bradycardia or

agonist that is commonly

1/β2

torsades de pointes. Although its predominant effect is to increase heart rate, vasodilation is also produced by vascular β Dobutamine is more β effects on cardiac contractility.

selective and is used for its relative selective

receptors.

a1-Antagonists

Most clinically available α-antagonists are α1-selective and produce vascular relaxation, vasodilation, and reduction in blood pressure ( treatment of urinary retention in prostatic hypertrophy because of their inhibitory actions on the prostatic urethra smooth muscle. They are therefore useful for hypertension treatment in patients with concomitant chronic urinary retention. Side effects are nasal congestion, fatigue, and those in common with other vasodilators (peripheral edema, reflex tachycardia, and postural hypotension). The major dose-limiting side effects are postural hypotension and fluid retention. α-Blockers have also been linked to the rare occurrence of “intraoperative floppy iris syndrome,” which may result in permanent vision loss after eye surgery. α-Blockers are not generally recommended as hypertension monotherapy, owing to side effects and increased occurrence of cardiovascular events, compared to the thiazide diuretic chlorthalidone in the Antihypertensive and Lipid-Lowering Treatement to Prevent Heart Attack Trial (ALLHAT) trial.

Nonselective α-antagonists (phenoxybenzamine and phentol-

amine) are used primarily for preoperative treatment of pheochromocytoma. Phenoxybenzamine is administered orally, produces irreversible inhibition, and has a long half-life, whereas phentolamine is given intravenously, acts competitively, and is

Table 6-4). These agents are most commonly used for

TABLE 6-4 α-Agonists and Antagonists

CLASS

Selective α

Nonselective α1-antagonist Phenoxybenzamine (Dibenzyline) 24 — 10-40 12-24

α2-Agonist Clonidine (Catapres) 4 — 0.3-0.9 6-8

L, liver failure; R, renal failure; T

-antagonist Alfuzosin (Uroxatral) 10 L, R 10 24

Doxazosin (Cardura) 22 L 1-8 24 Tamsulosin (Flomax) 15 — 0.4-0.8 24 Prazosin (Minipress) 2-4 L 3-15 8-12 Silodosin (Rapaflow) 24 L, R 4-8 24 Terazosin 12 — 1-20 24

Phentolamine (Regitine, OraVerse) 15-30 minutes — 5-20 2-4

Guanfacine (Tenex) 16 — 0.5-2 24 Guanabenz 10 L 4-32 12 Methyldopa (Aldomet) * R 250-3000 8-12

, half-life (includes active metabolites as appropriate).

1/2

DRUG

TRADE NAME

1/2

HOURS

DOSE

ADJUSTMENT

DOSE RANGE

TOTAL mg/ DAY

DOSING INTERVAL

HOURS

rapidly cleared. When used for treatment of pheochromocytoma, α-blockade should be achieved before starting β-blockers because of the risk of unopposed α-receptor activation during β-blocker monotherapy. Some β-blockers also have α-blocking effects (e.g., carvedilol, labetalol), but they should not be used for sole therapy of pheochromocytoma or cocaine overdose because of

the relatively low-potency α effects.

a1-Agonists

Activation of the α1 receptor stimulates vascular smooth muscle contraction and vasoconstriction. These agents are most commonly used in over-the-counter sinus preparations to treat nasal congestion. Phenylephrine is commonly used for treatment of hypotension in intensive care settings because of its relatively selective vascular effect without increasing heart rate.

a2-Agonists

Activation of the α2 receptor within the CNS provides negative feedback inhibition of sympathetic activity and NE release. Clonidine and other α thetic and increase parasympathetic activity by actions within the CNS. Evidence for the central effect is obtained from ies demonstrating no effect of clonidine after spinal cord transection. Clonidine can also produce vasoconstriction via activation of peripheral α intravenous administration or accidental overdose.

effect may be evident after oral clonidine administration in some patients with autonomic dysfunction. lized similarly to NE and acts as a false transmitter and α Methyldopa is commonly used in pregnancy for its history of safety, and also remains an effective alternative in resistant hypertension. Other α used for their sedative effects but may affect blood pressure regu-

-agonists, such as tizanidine and dexmedetomidine, are

lation as a side effect. Etomidate is a sedative with pressor effects that appear to be mediated via α

All α

-agonists can produce sedation, fatigue, dry mouth, bra-

dycardia, and orthostatic hypotension. Transdermal clonidine frequently produces localized skin irritation due to the adhesive, rather than a drug reaction. Methyldopa carries additional risks of hepatic dysfunction, hemolytic anemia, lupus-like syndrome, and thrombocytopenia. Long-term use of clonidine results in receptor hypersensitivity and rebound hypertension due to exaggerated sympathetic discharge after abrupt drug withdrawal. This syndrome is accompanied by sympathetic hyperactivity and can be minimized by gradual taper or treated with combined α- and

-agonists (see Table 6-4) suppress sympa-

receptors, although this usually only occurs after

Methyldopa is metabo-

However, this

in vivo stud-

-agonist.

β-blockade. Methyldopa is less likely to produce rebound, owing to the longer half-life of active metabolites, but caution should still be used when stopping this drug.

α2-Antagonists

Antagonists of α2-receptors are infrequently used in clinical practice but have a few specific clinical applications. Yohimbine is an

-antagonist that increases sympathetic activity in patients with

orthostatic hypotension and may also be useful for treatment of ED. Subtype-specific antagonists are not available. Although these drugs are not available commercially, herbal supplements with

-antagonist activity are commonly available.

b-Adrenergic Antagonists

Historically, β-adrenergic antagonists (β-blockers) have been classified by receptor subtype specificity and intrinsic sympathomimetic activity (ISA). In addition, some β-blockers also inhibit α receptors, producing a vasodilatory effect. Intrinsic sympathomimetic activity reflects the drug's ability to activate receptors when administered in the absence of any endogenous sympathetic activity (e.g., sympathetic denervation). This effect likely reflects the relative stabilization of the inactive/active receptor conformations as discussed in the pharmacodynamics section. Drugs with ISA tend to produce less bradycardia and may directly reduce vascular resistance, although evidence that this translates into hard clinical outcomes remains debatable. Analyses suggest that β-blockers with ISA do not reduce cardiovascular mortality and may actually worsen outcomes.

Drugs with β-blocking ability are summarized in Table 6-5. Propranolol was the first clinically available β-blocker, and is nonselective. Second-generation agents offer increased β Recently, vasodilatory β-blockers entered the market and produce additional blood pressure lowering effects via α possibly via β hypertension, acute MI, heart failure, angina, and supraventricu-

activation.86 β-Blockers are commonly used to treat

selectivity.

blockade and

lar arrhythmias. In acute MI, atenolol reduces in-hospital mortality by 15%, although benefit with prolonged therapy is less well established. Perioperative β-adrenergic blockade also reduces in-hospital mortality in patients with high cardiovascular risk.

In the past, β-blockers were withheld in patients with systolic heart failure, owing to concerns of worsening contractile function and intolerance. However, the observation that the sympathetic nervous system is activated in severe heart failure and predicted mortality supported the concept of sympathetic blockade in CHF.

Randomized clinical trials have definitively

TABLE 6-5 β-Blockers

CLASS

Nonselective

-antagonists

1/β2

Selective

β1-antagonists

Nonselective

β1/β2/α1-antagonists

"+"just refers to the presence and strength of intrinsic sympathomimetic activity.

Sotalol has additional potassium channel blocking effects.

ISA, intrinsic sympathomimetic activity; L, liver failure; R, renal failure; T

DRUG TRADE NAME

Propranolol (Inderal) — 3-6 L 20-240 8-12 Nadolol (Corgard) — 10-24 L, R 40-320 24 Pindolol (Visken) ++ 3-4 L, R 10-60 12 Penbutolol (Levatol) + 5 — 10-40 24 Sotalol* (Betapace) — 12 R 80-240 24

Acebutolol (Sectral) + 8-13 R 200-800 12 Atenolol (Tenormin) — 7 R 25-100 12-24 Betaxolol (Kerlone) — 14-22 L, R 5-20 24 Bisoprolol (Zebeta) — 9-12 R 2.5-20 24 Esmolol (Brevibloc) — 9 min — 150-300 μg/kg/min Continuous infusion Metoprolol (Toprol, Lopressor) — 3-8 L 25-400 12 Nebivolol (Bystolic) — 10-36 L, R 5-40 24

Carvedilol (Coreg) — 7-10 L 6.25-80 12 Labetalol (Normodyne, Trandate) + 6-8 — 200-800 12

, half-life (includes active metabolites as appropriate).

1/2

ISA

1/2

HOURS

DOSE

ADJUSTMENT

DOSE RANGE

TOTAL mg/ DAY

DOSING INTERVAL

HOURS

demonstrated that metoprolol, bisoprolol, and carvedilol improve

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systolic function and reduce mortality in CHF. These agents should be introduced gradually and titrated upwards as tolerated in patients with severe CHF.

All β-blockers can produce side effects related to their mecha-

nism of action (bradycardia, heart block, hypotension). β-Blockers can also worsen hyperglycemia (especially when combined with thiazide diuretics) or blunt the compensatory response to hypoglycemia. They should not be used as primary treatment for pheochromocytoma, cocaine intoxication, clonidine-withdrawal hypertension, or other hyperadrenergic crises, owing to the possibility of unopposed α-receptor activation. Sotalol is a unique β-blocker with antiarrhythmic effects due to potassium channel blocking activity, which requires close monitoring for QT prolongation and proarrhythmia.

Dopamine and Dopaminergic Agonists

Dopamine is endogenously produced in both peripheral and central neuronal cells and in the adrenal gland via the action of dopa decarboxylase on dopa (see one of 5 G protein–linked receptors, termed D1 through D5, which are further classified into two major groups termed D1 and D2. The D1 class of dopamine receptors, D1 and D5, are G receptors that activate adenylyl cyclase; the D2 class receptors are linked to G dopamine signaling in the CNS have been linked with a variety

and inhibit adenylyl cyclase. Perturbations of

αi/o

of disorders, including Parkinson's disease, Huntington's disease, Tourette's syndrome, schizophrenia, and major depression. In addition to CNS receptors, dopamine receptors are widely present in peripheral tissues including the kidney, gastrointestinal tract, heart, adrenal glands, and vasculature. Dopamine receptor signaling has recently been reviewed in depth.

The predominant clinical use of dopamine has been for circulatory support in critically ill patients in settings such as shock or the postoperative period. The clinical response to dopamine is complex and depends on the dose. At low doses (1-4 μg/kg/min), often referred to as “renal doses,” dopamine acts on D1-like receptors and β-adrenergic receptors to promote renal arterial vasodilation and improve renal blood flow. As the dose is increased, dopamine begins to exert greater effects at β- and α-adrenergic receptors, and the α-adrenergic effects begin to predominate at doses exceeding 10 μg/kg/min. There is also substantial variability in these responses, such that the precise effect of dopamine in an individual patient is difficult to predict. The potential increase renal blood flow, due to D1-like receptor activation, has not proven to have significant clinical benefit. Recent clinical trials have shown no benefit of dopamine over NE infusion in patients with septic shock, with substantially more cardiac arrhythmias and sinus tachycardia caused by dopamine.

Owing to the mixed effects of dopamine on multiple receptors, agonists have been developed that have greater specificity for D1-like receptors, and therefore would serve as potent vasodilators with limited off-target effects. Fenoldopam is such an agent that has been approved by the FDA for treatment of severe hypertension. This agent is a potent vasodilator with rapid onset of action that produces dose-dependent reductions in blood pressure when administered intravenously to patients with hypertension. It is devoid of the α- and β-adrenergic effects of dopamine, so less prone to cause offtarget effects. Early studies showed that it preferentially increased renal plasma flow, in keeping with preferential dilation of the renal vasculature, and dramatically enhanced renal sodium excretion.

Despite these potentially beneficial effects of fenoldopam, its clinical use in severe hypertension remains limited, largely because several other drugs are quite effective. In prior clinical trials, fenoldopam showed no benefit over sodium nitroprusside in lowering blood pressure,

and it is considerably more expensive.

Based on its ability to enhance renal perfusion and sodium excretion, fenoldopam has been used as a renal protectant in critically ill patients. A recent meta-analysis of 16 randomized

Fig. 6-7). Dopamine acts on

-linked

αs

89,90

trials involving 1290 patients indicated that fenoldopam reduced the need for renal replacement therapy, in-hospital mortality, and length of stay in the intensive care unit in postoperative or critically ill patients. analysis of patients undergoing cardiovascular surgery.

Similar results were obtained from a meta-

Such analyses can be flawed by publication bias, and prospective trials are needed to establish a benefit of fenoldopam in this setting.

There was initial enthusiasm for use of fenoldopam to prevent contrast-induced nephropathy. However, a rigorous randomized prospective trial showed no benefit of this agent in preventing changes in renal function in patients undergoing angiography procedures, Dopexamine, which is a combined D1-like and β agonist, has been studied in a variety of settings involving critically ill patients, but it has not proven beneficial in randomized prospective trials.

and its use in this setting is no longer recommended.

-adrenergic

95,96

Vascular Potassium and Calcium Channels

Direct vasodilators reduce blood pressure by acting on vascular smooth muscle and ultimately impair myosin light chain phosphorylation and contraction (see activates K calcium entry and contraction. presented in

channels, which hyperpolarizes the cell and prevents

ATP

Table 6-6.

Calcium channel blockers (CCBs) decrease intracellular calcium entry via the L-type calcium channels on the vasculature and cardiac conduction system. L-type calcium channels are located on cardiac myocytes, vascular smooth muscle, and the cardiac conduction system. Blockade of these channels reduces cardiac and vascular smooth muscle contraction and slows conduction. Calcium channel blockers can be classified broadly as dihydropyridines (DHP; e.g., amlodipine, nifedipine) and nondihydropyridines (verapamil and diltiazem). Dihydropyridines are more potent vasodilators than non-DHP, whereas verapamil and diltiazem also slow cardiac conduction.

Dihydropyridines produce relatively selective vascular effects in vivo and do not significantly slow cardiac conduction. In some patients, vasodilation may produce reflex tachycardia and vasodilatory edema. This may cause tachycardia and rarely precipitate angina, especially if given acutely. The rapid hypotensive effect of immediate-release nifedipine, particularly when given sublingually, can actually increase cardiovascular events and should be avoided by using only slow-release formulations. long-acting DHPs have a good safety profile and reduce hypertensive complications.

Because multiple other agents have proven effectiveness in CHF, and CCBs may worsen cardiac function, they should not be used in this class of patients. Vasodilatory edema during treatment with CCBs is typically refractory to diuretic treatment, but the incidence is reduced by concomitant treatment with an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB).

Verapamil and diltiazem slow cardiac conduction in addition to their vasodilatory effect, and are frequently used for control or prevention of supraventricular arrhythmias. These agents also impair cardiac contractility and should be avoided in patients with impaired systolic function. Both drugs also inhibit CYP3A4, and attention to avoid significant drug interactions is needed. In particular, caution should be given to patients receiving statins, owing to increased risk of rhabdomyolysis. Vasodilatory edema occurs less often than with DHPs. All CCBs may produce constipation.

Because of their frequent side effects, minoxidil and hydralazine are direct vasodilators typically reserved for refractory hypertension. component of the K flux, hyperpolarizes the cell, and produces vasodilation. Although

100

Minoxidil acts on the sulfonylurea receptor-2 (SUR2)

channel in VSMCs, and in turn increases K+

ATP

sulfonylurea drugs (e.g., glibenclamide, glyburide, glipizide) stimulate insulin secretion via opposite effects on SUR1, evidence

Fig. 6-1). Minoxidil, for example,

97,98

Channel blocking agents are

In contrast,

CH 6

VAsCulAR PHARmACology

TABLE 6-6 Channel Blocking Agents

CLASS

CCB: DHPs Amlodipine (Norvasc) 40-50 L 2.5-10 24

Ca2+ CCB: non-DHPs Diltiazem (Cardizem, Dilacor, Tiazac) 3-5 L 120-480 24

openers Hydralazine (Apresoline) 2-8 R 10-300 8-12

ATP

Not available in the United States.

Ca2+ CCB, calcium channel blocker; DHP, dihydropyridine; K

DRUG TRADE NAME

Felodipine (Plendil) 11-16 L 30-120 12-24 Isradipine (DynaCirc) 8 R 2.5-10 12 Nicardipine (Cardene) 11.5 — 60-120 8 Nifedipine (Adalat, Procardia) 2-5 L 30-120 12-24 Nimodipine (Nimotop) 2.8 L 180-360 4 Nisoldipine (Sular) 15 L 20-60 24

Verapamil (Calan, Isoptin) 8-12 L, R 80-480 8-24

Minoxidil (Loniten) 4 R 2.5-80 Pinacidil* 12.5-150 12

, ATP-sensitive potassium channel; L, liver failure; R, renal failure; T

ATP

HOURS

1/2

ADJUSTMENT

DOSE

1/2

DOSE RANGE

TOTAL mg/ DAY

, half-life.

DOSING INTERVAL

HOURS

that they cause vasoconstriction via SUR2

in vivo is lacking.

Hydralazine is a direct vasodilator, although the exact mechanism of action is poorly understood. Minoxidil is more effective than hydralazine and can be effective in patients who have not responded to hydralazine. They must be administered with a ratecontrolling agent and diuretic to prevent reflex tachycardia and fluid retention, which limit their antihypertensive effectiveness. Minoxidil may worsen LV hypertrophy despite adequate hypertension control, in part because of these compensatory responses. During long-term use, excessive hair growth also occurs and is particularly worrisome to female patients. Hydralazine may also produce a lupus-like syndrome. Both drugs may also produce pericardial or pleural effusions. Reflex sympathetic activation may precipitate cardiac ischemia in some patients. Use of these agents in the setting of acute aortic dissection should be avoided because of reflex sympathetic activation. Hydralazine has been approved for treatment of heart failure in African Americans in combination with a nitrate, as discussed earlier.

Renin-Angiotensin-Aldosterone System

Regulation of the Renin-AngiotensinAldosterone System

The renin-angiotensin-aldosterone system (RAAS) is highly coordinated to maintain blood volume and blood pressure, and is of major importance during sodium and/or fluid depletion ( The RAAS is stimulated under pathological conditions that cause reduced renal perfusion, such as heart failure, aortic coarctation, or renal artery stenosis. In addition, this system is inappropriately activated in obesity and diabetes.

Renin secretion by renal juxtaglomerular cells, the rate-limiting step in the RAAS cascade, is stimulated by reduced sodium chloride delivery to the macula densa, reduced renal perfusion pressure, and sympathetic stimulation.

101

Upon release into the circulation, renin cleaves circulating angiotensinogen to angiotensin (Ang-I). Although Ang-I is inactive, it is rapidly converted into Ang-II by angiotensin-converting enzyme (ACE), which is abundantly expressed within the pulmonary vasculature and to a lesser extent in the peripheral circulation. In addition to the endothelial membrane-bound form, ACE also circulates in a soluble form. Angiotensin-II is a potent vasoconstrictor, acting directly on the Ang-II type 1 receptors (AT the kidney, Ang-II acts upon the renal afferent and efferent arte-

) on VSMCs. Within

riole, to a greater extent on the efferent arteriole. During periods of volume depletion, this efferent selectivity serves to preserve glomerular filtration by increasing intraglomerular pressure. Angiotensin-II also stimulates aldosterone secretion from the

Fig. 6-8).

adrenal gland. Aldosterone reinforces the vasoconstrictor effect of Angiotensin-II by increasing renal sodium reabsorption and expanding intravascular volume via the mineralocorticoid receptor (MR) in principal cells of the kidney and activation of the epithelial sodium channel (ENaC). Angiotensin-converting enzyme is the principal metabolizing enzyme for a number of

Angiotensinogen

Renin

Ang-I

ACE

Ang-II

Adrenal Vasculature

Aldosterone

FIGURE 68 The renin-angiotensin-aldosterone system (RAAS). ACE, angiotensin-I converting enzyme; Ang, angiotensin; AT1, angiotensin-II type 1 receptor; ENaC, epithelial sodium channel; MR, mineralocorticoid receptor.

MR Antagonists

Sodium/Fluid Reabsorption

ENaC

Aliskiren

ACE Inhibitors

Antagonists

Vasoconstriction

Amiloride Triamterene

Hypertension

other vasoactive peptides, notably bradykinin, which may con-

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fer some of the beneficial antihypertensive and antithrombotic effects observed during ACE inhibition.

Receptors and Novel Mediators in RAAS Signaling

The AT1 and AT2 receptors are the principal Ang-II receptors in humans and are widely expressed, including in areas important for blood pressure regulation (vascular smooth muscle, kidney, adrenal cortex, brain). AT GPCR that signals via G G protein–independent pathways. tensin receptor–associated protein (ATRAP) facilitates AT nalization and desensitization. effects including vasoconstriction, adrenal aldosterone secretion, and renal proximal tubule sodium reabsorption. In addition, Ang-II participates in a negative feedback loop in the kidney to inhibit renin secretion via AT tified, AT and mitogenic effects, although a single AT

and AT1b, with AT1a responsible for most of the pressor

humans.

In general, the actions of the AT of the AT this generalization.

receptor, although some effects are inconsistent with

in part via an increase in bradykinin and receptor heterodimerization with the bradykinin receptor. AT effect within renal tubules. However, AT press renin secretion. Although investigational agonists and antagonists for the AT available clinically. Therefore, the clinical implication of the AT receptor remains unproven. Angiotensin-II decreases during ACE inhibition but increases during AT receptor remains available for Ang-II activation during chronic AT

antagonism and may promote beneficial effects. This ratio-

nale has led some to argue the benefit of AT ACE inhibition.

Aldosterone and other corticosteroids activate the MR within principal cells in the cortical collecting duct. Angiotensin-II, aldosterone, and MR activation induce multiple proteins that coordinate to increase renal sodium and water reabsorption. MR is a classic nuclear receptor localized to the cytosol in its inactive form, which dimerizes and translocates to the nucleus and activates nuclear transcription when activated. Although aldosterone appears to be the critical physiological stimulus, cortisol, corticosterone, and other steroids have a similar affinity for the MR. However, within epithelial target tissues, 11-β-hydroxysteroid dehydrogenase type 2 (11βHSD2) inactivates these hormones and prevents inappropriate MR activation. Either inhibition of this enzyme by licorice or genetic deficiency produces unregulated MR activation and hypertension with metabolic alkalosis and hypokalemia. The MR is also expressed within vascular smooth muscle and ECs, where it may contribute to vascular injury via activation of NADPH oxidase, generation of ROS, and inflammation.

Greater complexity of the RAAS has emerged with the discovery of novel angiotensin peptides and receptors. Angiotensin-(1-7) is formed by cleavage of Ang-I by neprilysin or prolyl-endopeptidase or from cleavage of Ang-II by ACE2. the Mas receptor, a G protein–coupled cell-surface receptor generally opposing AT fer protection against Ang-II-mediated cardiovascular injury, and ACE2-deficient mice have accentuated Ang-II-induced injury. Angiotensin-II is also metabolized in vivo by aminopeptidase A to Ang-III and Ang-IV, which may have important physiological effects within the CNS.

Additional interest has focused on the (pro)-renin receptor (PRR), which binds either renin or prorenin. can exist as a full-length transmembrane protein, a soluble circulating form, or a truncated protein (transmembrane/

is a classic seven-transmembrane domain

and phospholipase C, as well as other

αq

. In mice, two AT1 receptors have been iden-

105,106

AT2 stimulation produces vasodilation,

receptor are available, these agents are not

effects.

103

102,103

Upon Ang-II binding, angio-

104

AT1 mediates the classic Ang-II

receptor is present in

receptor tend to oppose those

has an antinatriuretic

and AT1 similarly sup-

antagonism. However, the AT2

antagonism over

110

Angiotensin-(1-7) acts via

111

Angiotensin-(1-7) and ACE2 con-

107–109

113

The PRR

inter-

The

112

cytoplasmic portion). The full-length transmembrane PRR can bind and activate prorenin by inducing a conformational change that exposes the catalytic site. In addition, (pro)-renin activates PRR and cellular signaling events (e.g., mitogenactivated protein kinase [MAPK] pathways) independent of renin activity.

114

Prorenin circulates in marked excess of active renin, and the prorenin/renin ratio is further increased in diabetes, raising the possibility that (pro)renin-PRR signaling or PRR-induced activation of prorenin and local angiotensin production could contribute to cardiovascular injury.

Drugs That Inhibit the Renin-AngiotensinAldosterone System

The first ACE inhibitor was serendipitously discovered as a bradykinin-potentiating factor isolated from venom of the pit viper Bothrops jararaca. Subsequent studies demonstrated its activity against ACE, suggesting that this enzyme played a key role in regulating both the RAAS and the kallikrein-kinin systems. Isolation of the responsible peptide sequences led to development of captopril, one of the earliest examples of structure-based drug design. Captopril's success in treatment of cardiovascular disease was critical to the development of other drugs that block the RAAS (

Table 6-7). Drugs are now clinically available to block the RAAS

cascade at nearly every level (see

Direct renin inhibitors are the most recent class of RAAS blocking agents. Although renin is the rate-limiting enzyme in the RAAS pathway and a logical drug target, development of clinical renin inhibitors was hindered by poor potency, stability, and oral bioavailability.

116

Development of aliskiren overcame these issues, and other agents are in clinical studies. Aliskiren selectively inhibits renin activity and dose-dependently reduces Ang-I and Ang-II production and blood pressure. Renin secretion markedly increases during aliskiren therapy, and attention to the assay method is needed if plasma renin concentration is measured. Plasma renin activity (assessed by remains inhibited, and thus compensatory renin secretion does not appear to overcome the effect of aliskiren or increase blood pressure.

118

Aliskiren is well tolerated and has a low rate of side effects, which are principally gastrointestinal. Aliskiren effectively reduces blood pressure when used in alone or in combination with diuretic therapy, ACE inhibitors, or ARBs. of aliskiren to maximal-dose losartan reduced proteinuria compared to placebo in a population with diabetic proteinuira. Aliskiren provided similar LV mass reduction compared to losartan in a group of overweight subjects with hypertension but provided no additional benefit in combination. are needed to investigate hard cardiovascular endpoints.

Angiotensin-converting enzyme inhibitors are used to treat hypertension, diabetic nephropathy, CHF, and prior MI or stroke. Their antihypertensive effect is generally less effective in African Americans because of a higher prevalence of low-renin hypertension, but concurrent thiazide diuretic administration improves responsiveness. Many orally administered ACE inhibitors are given as a prodrug, which are rapidly metabolized into active metabolite via enteric metabolism (e.g., enalapril to enalaprilat). Enalaprilat is the active metabolite of enalapril and is available for intravenous administration. Most ACE inhibitors are renally excreted and require careful monitoring in patients with renal insufficiency.

Angiotensin-II can also be generated by enzymes other than ACE (e.g., chymase, cathepsin G), providing a rationale for combination therapy with ARBs and ACE inhibitors. Angiotensin-II type 1 receptor antagonists (ARBs) also provide an alternative treatment option for patients who are intolerant of ACE inhibitors. Early studies were done with saralasin, an intravenous peptide Ang-II analog, which demonstrated effectiveness of ARBs and led to the development of orally available agents.

124

developed and approved for hypertension treatment and prevention of cardiovascular complications (see receptor blockers are remarkably well tolerated and may even

Fig. 6-8).

in vitro Ang-I generation)

116,119–121

123

Further studies

Since then, multiple agents have been

Table 6-7). Angiotensin

115

117

Addition

122

CH 6

VAsCulAR PHARmACology

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