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Pharm Ch 21
Introduction
 Vascular tone (degree of contraction of vascular smooth muscle) determines adequacy of perfusion of tissues of
body; angina pectoris, hypertension, Raynaud’s phenomenon, and migraine headaches all associated with
dysregulated vascular tone
Physiology of Vascular Smooth Muscle Contraction and Relaxation
 Vascular tone – key regulator of tissue perfusion, which determines whether tissues receive sufficient O2 and
nutrients to meet their demands
 Myocardial O2 supply depends on tone of coronary arteries, while myocardial O2 demand depends on tone of
both systemic arterioles (resistance vessels) and veins (capacitance vessels)
o Major determinants of myocardial O2 demand are heart rate, contractility, and ventricular wall stress
 Wall stress equation σ = Pr/2h
where σ is wall stress, P is ventricular pressure, r is ventricular chamber radius, and h is
ventricular wall thickness
o Systolic ventricular wall stresses influenced by systemic arteriolar tone, and diastolic ventricular wall
stresses influenced by venous tone
 Arteriolar tone directly controls systemic vascular resistance, and arteriolar blood pressure
MAP = (SVR)(CO) where MAP is mean arterial pressure, SVR is systemic vascular resistance,
and CO is cardiac output
 During systole, intraventricular pressure must exceed arterial pressure in order for blood to be
ejected
 Afterload (systolic ventricular wall stress) is equivalent to resistance that ventricle must
overcome to eject its contents
 Assuming there is no obstruction between ventricle and aorta, systolic arterial blood pressure
approximates systolic ventricular wall stress (i.e., afterload)
o Resistance of arterial circulation is most important parameter determined by arteriolar tone
o Capacitance of venous circulation is most important parameter determined by venous tone
o Venous capacitance regulates volume of blood returning to heart, which is major determinant of enddiastolic volume of heart
 Preload (end-diastolic ventricular wall stress) – equivalent to stretch on ventricular fibers just
before contraction; approximated by end-diastolic volume or pressure
 Venous tone determines end-diastolic ventricular wall stress (i.e., preload)
o Hypoxia occurs when there is O2 deprivation despite adequate perfusion
o Ischemia occurs when decreased perfusion leads to O2 deficit
 Myocardial ischemia occurs when myocardial O2 supply and demand imbalanced such that
coronary blood flow cannot fully meet O2 needs of heart; most causes of myocardial ischemia
(especially coronary artery disease) involve some aspect of abnormal vascular tone
 Chest pain (angina pectoris) is common, though not always present, symptom of myocardial
ischemia; common treatment is nitroglycerin (decreases vascular tone and thereby ameliorates
mismatch between myocardial O2 supply and demand)
 Regulators of vascular tone act by influencing actin-myosin contractile apparatus of vascular smooth muscle
cells; actin-myosin interaction leads to contraction and is regulated by intracellular Ca2+ concentration
o Steep transmembrane gradient of Ca2+ concentration maintained by relative impermeability of PM to
Ca2+ and by membrane pumps that actively remove Ca2+ from cytoplasm
o Stimulation of vascular smooth muscle cells can increase cytoplasmic Ca2+ concentration by
 Ca2+ can enter cell by way of voltage-gated Ca2+-selective channels in sarcolemma
 Increases in cytoplasmic Ca2+ can be elicited by release of intracellular Ca2+ from sarcoplasmic
reticulum
o Vasoconstriction (contraction of vascular smooth muscle) commonly initiated by opening of voltagegated L-type Ca2+ channels in sarcolemma during PM depolarization
 Open Ca2+ channels mediate Ca2+ flux into cytoplasm and activation of cytoplasmic calmodulin
(CaM); Ca2+-CaM complex binds to and activates myosin light chain kinase, which
phosphorylates myosin-II light chains
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When light chain phosphorylated, myosin head can interact with actin filament, leading to
smooth muscle contraction
o Vasodilation occurs upon dephosphorylation of myosin light chain; dephosphorylation potentiated when
guanylyl cyclase activated inside smooth muscle cell
 Activated guanylyl cyclase increases production of cGMP, which stimulates cGMP-dependent
protein kinase, which then activates myosin light chain phosphatase
 Dephosphorylation of myosin light chain inhibits interaction of myosin head with actin, leading
to smooth muscle relaxation
Regulation of Vascular Tone
 Vascular endothelium – endothelial cells elaborate many signaling mediators and alter expression of many genes
in response to diverse stimuli
o Nitric Oxide – acetylcholine causes vasoconstriction when applied directly to de-endothelialized blood
vessels, but causes vasodilation when applied to normally endothelialized vessels
 Nitroglycerin (organic nitrate, NTG) metabolizes in body to NO, and NO causes relaxation of
vascular smooth muscle; NO released from endothelial cells and reacts with wide range of
biomolecules to elicit cellular responses
 Acetylcholine, shear stress, histamine, bradykinin, sphingosine 1-phosphate, serotonin,
substance P, and ATP can all elicit increased NO synthesis by vascular endothelial cells
 NO synthesized by family of Ca2+-CaM-activated NO synthases
 Endothelial isoform of nitric oxide synthase (eNOS) responsible for endothelial-c ell NO
synthesis; plays critical role in controlling vascular tone and platelet aggregation
 eNOS deficient mice are hypertensive
 NO may effect vasodilation not only by activating guanylyl cyclase, but also by activating Ca2+dependent K+ channels in vascular smooth muscle cells
 NO activates K+ channels directly via guanylyl cyclase-independent mechanism, leading
to hyperpolarization of cells and, subsequently, vasodilation
o Endothelin – vasoconstrictor peptide; most potent endogenous vasoconstrictor yet discovered;
endothelium-derived; has positive inotropic and chronotropic actions on heart, and it contributes to
remodeling within cardiovascular system; has 3 isoforms (ET-1, ET-2, and ET-3)
 ET-1 = isoform mainly involved in cardiovascular actions; produced by endothelial cells (and
vascular smooth muscle cells under inflammatory conditions); acts locally in paracrine or
autocrine fashion
 Local ET-1 concentration in vascular wall is more than 100x that in circulation because
ET-1 secreted chiefly on basal side of endothelial cells
 Preproendothelin cleaved into big endothelin, which is then cleaved by endothelin-converting
enzyme into endothelin
 2 receptor subtypes: ETA and ETB
 Both ETA and ETB are G protein-coupled receptors whose effectors involve
phospholipase C-modulated pathways
 ET-1 binds to ETA receptors on vascular smooth muscle cells as well as ETB receptors on
both endothelial cells and vascular smooth muscle cells
 ETA receptors on vascular smooth muscle cells mediate vasoconstriction
 ETB receptors located predominantly on vascular endothelial cells, where they mediate
vasodilation via release of prostacyclin and NO
 ETB receptors also found on vascular smooth muscle cells, where they mediate
vasoconstriction
 Autonomic nervous system – SNS important determinant of vascular tone; firing of certain sympathetic
postganglionic neurons releases norepinephrine from nerve terminals that end on vascular smooth muscle cells
o Activation of α1-adrenergic receptors on vascular smooth muscle cells causes vasoconstriction
o Activation of β2-adrenergic receptors on vascular smooth muscle cells induces vasodilation
o Effect of norepinephrine on α1 receptors typically greater than its effect at β2 receptors, especially in
organs that receive decreased blood flow during SNS responses
 Net effect of norepinephrine on vascular beds typically vasoconstrictive
o Because blood vessels not innervated by PNS fibers, PNS has little influence on vascular tone
 Neurohormonal mechanisms – circulating catecholamines from adrenal gland (i.e., epinephrine) can influence
vascular tone via α1-adrenergic and β2-adrenergic receptors on vascular smooth muscle cells
o Angiotensin II – stimulates angiotensin II receptor subtype 1 (AT1) to vasoconstrict arterioles and
increase intravascular volume
o Aldosterone – acts via mineralocorticoid receptor to increase intravascular volume
o Natriuretic peptides – promote renal natriuresis (sodium excretion) in situations of volume overlad and
cause vasodilation by stimulating guanylyl cyclase receptors on endothelial cells and vascular smooth
muscle cells
o Antidiuretic hormone/arginine vasopressin – stimulate arteriolar V1 receptors to constrict arterioles and
activate renal V2 receptors to increase intravascular volume
 Local mechanisms – autoregulation is homeostatic mechanism in which vascular smooth muscle cells respond to
increases or decreases in perfusion pressure by vasoconstriction or vasodilation, respectively, to preserve blood
flow at relatively constant level (flow = perfusion pressure/resistance)
o Vascular tone, and thus blood flow, governed by metabolites (H+, CO2, O2, adenosine, lactate, and K+)
produced in surrounding tissue
o Local mechanisms of vascular tone regulation predominate in vascular beds of essential organs (e.g.,
heart, brain, lung, kidney), so that blood flow, and thus O2 supply, can be adjusted quickly to meet
demands of local metabolism in these organs
Pharmacologic Classes and Agents
 Most vasodilators act by reducing contractility of actin-myosin complexes in vascular smooth muscle cells
o Pharmacologic donors of NO (such as organic nitrates and sodium nitroprusside) cause vasodilation by
activating guanylyl cyclase and thereby increasing dephosphorylation of myosin light chains
o cGMP phosphodiesterase type V (PDE5) inhibitors prevent cGMP hydrolysis and thereby promote
myosin light chain dephosphorylation, especially in smooth muscle of corpus cavernosum
o Ca2+-channel blockers cause vasodilation by reducing intracellular Ca2+ concentrations
o K+ channel openers induce vasodilation by opening ATP-sensitive K+ channels; resulting
hyperpolarization of cells prevents activation of voltage-gated Ca2+ channels necessary for Ca2+ influx
and vascular smooth muscle contraction
o Endothelin receptor antagonists block endothelin-mediated vasoconstriction
o α1-adrenergic antagonists inhibit vasoconstrictive action of endogenous epinephrine and
norepinephrine
o ACE inhibitors and AT1 antagonists inhibit vasoconstrictive effects of endogenous angiotensin II, either
by inhibiting angiotensin II formation (ACE inhibitors) or by blocking angiotensin II action at its cognate
receptor (AT1 antagonists)
Organic Nitrates, Inhaled Nitric Oxide, and Sodium Nitroprusside
 Indications for use of organic nitrates include stable angina pectoris, unstable angina, AMI, hypertension, and
acute and chronic heart failure
o Within body, organic nitrates chemically reduced to release NO (gas that can dissolve in biological fluids
and cellular membranes)
o NO may react directly with diverse biomolecules, including heme moiety in guanylyl cyclase
o NO can undergo chemical transformation to form S-nitrosothiol groups with cysteine (sulfhydryl)
residues in proteins or with low-molecular-weight intracellular thiols such as glutathione
o Metabolism of organic nitrates to NO can be catalyzed in tissues by specific enzymes such as
mitochondrial aldehyde dehydrogenase; enzymatic release of organic nitrates allows targeting of their
effects to specific vascular tissues
o Although NO can dilate both arteries and veins, venous dilation predominates at therapeutic doses
o NO-induced venodilation increases venous capacitance, leading to decrease in return of blood to right
side of heart and, consequently, decreased right ventricular and left ventricular end-diastolic pressure
and volume; decrease in preload reduces myocardial O2 demand
o At higher concentrations of organic nitrates, arterial vasodilation may also occur
o In absence of reflex tachycardia, arterial vasodilation leads to decrease in systemic vascular resistance,
which leads to decrease in systolic wall stress (afterload) and decrease in myocardial O2 demand
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In coronary circulation, NTG dilates predominantly large epicardial arteries; minimal effects on coronary
resistance vessels (i.e., coronary arterioles); preferential dilation of large epicardial arteries over smaller
coronary arterioles prevents development of coronary steal phenomenon (often encountered with
agents such as dipyridamole) that produce intense dilation of coronary resistance vessels
o Chronic myocardial O2 deficit in patients with coronary artery disease may (by autoregulatory
mechanism) cause maximal dilation of coronary arteries, such that vasodilators can provide no further
increase in coronary blood flow
o Stiffened, calcific atherosclerotic coronary arteries may remain noncompliant, even in face of coronary
artery vasodilators
o Administration of doses of organic nitrates sufficient to vasodilate large epicardial arteries can be
dangerous because such doses may also induce excessive peripheral arteriolar vasodilation and
refractory hypotension
 Excessive decrease in mean arterial pressure can lead to myocardial ischemia; because coronary
perfusion depends on pressure gradient between aorta and endocardium during diastole,
marked decrease in diastolic aortic pressure can lead to insufficient supply of O2 to heart
 Systemic hypotension can lead to reflex tachycardia, which also decreases myocardial O2 supply
by shortening diastole, and thus, myocardial perfusion time
 Reflex tachycardia typically observed when baroreceptors in aortic arch and carotid sinuses
sense decrease in blood pressure
 In patients with overt heart failure, reflex tachycardia is rare; nitrates can often be used to
decrease pulmonary congestion in patients with heart failure (by effecting venodilation and
decreasing end-diastolic pressure), without eliciting significant reflex tachycardia
o Several important adverse effects of nitrates are result of excessive vasodilation, including flushing
(caused by vasodilation of cutaneous vascular beds) and headache (Caused by vasodilation of cerebral
arteries)
o Inhaled NO gas can be used to selectively dilate pulmonary vasculature
 Because NO rapidly inactivated by binding to Hgb in blood, NO gas has little effect on systemic
blood pressure when administered by inhalation
 Therapy with inhaled NO has established efficacy in treatment of primary pulmonary
hypertension of newborn, but therapeutic value of inhaled NO in other conditions characterized
by elevated pulmonary artery pressure (including heart failure and various forms of lung
disease) remains to be established
Sodium nitroprusside – nitrate compound that effects vasodilation by release of NO
o Unlike organic nitrates, sodium nitroprusside liberates NO primarily through nonenzymatic process; as a
result, sodium nitroprusside’s action isn’t targeted to specific types of vessels, and consequently, drug
dilates both arteries and veins
o Used intravenously for powerful hemodynamic control in hypertensive emergencies and severe heart
failure
o Because of rapid onset of action, short duration of action, and high efficacy, sodium nitroprusside must
be infused with continuous blood pressure monitoring and careful titration of drug dose to drug effect
o Sodium nitroprusside spontaneously decomposes to liberate NO and cyanide; cyanide then converted to
thiocyanate in liver, and thiocyanate excreted by kidneys
o Excessive cyanide accumulation can lead to acid-base disturbances, cardiac arrhythmias, and even death
o Thiocyanate toxicity can also occur in patients with impaired renal function, causing disorientation,
psychosis, muscle spasms, and seizures
Pharmacokinetics of different nitrate preparations and formulations provide basis for preferential use in certain
settings; for example, rapid onset of action of sublingual nitrate preparations desirable for relief of acute angina
attacks, while longer-acting nitrates more valuable for angina prophylaxis in long-term management of coronary
artery disease
o Orally administered NTG and isosorbide dinitrate have low bioavailability because organic nitrate
reductases in liver rapidly metabolize drugs
o To circumvent first-pass effect and attain therapeutic blood levels within minutes, NTG or isosorbide
dintrate can be administered sublingually
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IV administration of NTG indicated when continuous titration of drug action necessary; for example, in
treatment of unstable angina or acute heart failure
o Slow release transdermal and buccal preparations of NTG provide therapeutic steady-state levels of NTG
that can be useful for angina prevention in patients with stable coronary artery disease
o Inhaled NO has very short half-life, and hemodynamic effects on pulmonary vasculature rapidly reversed
when NO inhalation therapy stopped
o NTG has short half-life (about 5 minutes) after which it is denitrated into biologically active glyceryl
dinitrate metabolites that have longer half-lives (about 40 minutes)
o Equivalent doses of isosorbide dinitrate can be more effective than NTG because isosorbide dinitrate has
longer half-life (about 1 hour)
o Partially denitrated metabolites of isosorbide dintrate (isosorbide 2-mononitrate [2 hours] and
isosorbide 5-mononitrate [4 hours]) have even longer half-lives
o Isosorbide 5-mononitrate has become popular therapeutic agent, not only because it has prolonged
therapeutic effects, but it is well absorbed from GI tract and not susceptible to extensive first-pass
metabolism in liver; bioavailability of orally administered isosorbide 5-mononitrate is nearly 100%,
allowing it to be significantly more effective than equivalent amounts of isosorbide dinitrate
o After denitration, organic nitrates typically glucuronidated in liver and excreted renally
Desirable effects of nitrates can be offset by compensatory SNS responses (e.g., reflex increase in SNS vascular
tone) and compensatory renal responses (e.g., increased salt and water retention) – physiologic tolerance
Pharmacologic tolerance to organic nitrates – Monday morning headaches in munitions workers (development
of tolerance to NTG over work week that allowed relief from headaches, and loss of tolerance to NTG over
weekend allowed headaches to recur upon workers’ return to work)
o Tolerance to antianginal effects of nitrates diminishes their clinical efficacy
o Tolerance to NTG doesn’t depend on route of administration
o It is possible to minimize development of tolerance by modulating dosing schedule to include daily
“nitrate-free intervals” (i.e., removal of transdermal patch at night)
o In cases of severe angina that require uninterrupted nitrate therapy to manage symptoms adequately,
patients may experience rebound angina during periods that are completely nitrate-free
Pharmacokinetic properties of oral isosorbide 5-mononitrate make it attractive solution to dilemma of balancing
nitrate tolerance and angina rebound – high bioavailability and long half-life produce periods of high-therapeutic
plasma concentrations followed by periods of low-therapeutic (rather than zero) nitrate levels
2 major hypotheses for pharmacologic tolerance
o Classic (sulfhydryl) hypothesis – tolerance results mainly from intracellular depletion of sulfhydrylcontaining groups, such as glutathione and/or other forms of cysteine, that are involved in formation of
NO form organic nitrates
 Tolerance could be attenuated or reversed by administering reduced thiol-containing
compounds such as N-acetylcysteine
o Free-radical (superoxide) hypothesis – cellular tolerance results from formation of peroxynitrite (highly
reactive metabolite of NO that inhibits guanylyl cyclase)
 Tolerance could be attenuated or reversed by agents that inhibit free-radical formation
Most effective means of preventing tolerance is use of dosing strategy that includes interval of low plasma
nitrate levels every day
Generation of NO from organic nitrates can cause relaxation of other types of smooth muscle (esophageal,
bronchial, biliary, intestinal, and genitourinary) in addition to vascular smooth muscle
o Ability of NTG to relieve angina-like chest pain of esophageal spasm can occasionally result in
misdiagnosis of coronary artery disease
o Actions of nitrates on nonvascular smooth muscle usually of limited clinical significance
NO generated from organic nitrates functions as antiplatelet agent as well as vascular smooth muscle relaxant;
NO-mediated increases in platelet cGMP inhibit platelet aggregation
o Nitrate-induced inhibition of platelet aggregation important in treatment of rest angina (chest pain that
occurs spontaneously at rest) because rest angina frequently results from formation of occlusive platelet
aggregates at site of atherosclerotic coronary artery lesions
o
Rest angina is unstable angina because thrombotic occlusions that cause it can evolve into complete
coronary occlusion and result in myocardial infarction
 Nitrates contraindicated in patients with hypotension and those with elevated intracranial pressure (NOmediated vasodilation of cerebral arteries could further elevate intracranial pressure)
o Not advised for angina pain associated with hypertrophic obstructive cardiomyopathy because
obstruction can be worsened by nitrate-mediated preload reduction
o Should be used with caution in patients with diastolic heart failure, who depend on elevated ventricular
preload for optimal cardiac output
o Don’t use with patients taking sildenafil or another PDE5 inhibitor for erectile dysfunction
Phosphodiesterase Inhibitors
 Prevent hydrolysis of cyclic nucleotides (cAMP, cGMP) to their monophosphate forms (AMP, GMP)
 Certain phosphodiesterase inhibitors (such as amrinone and milrinone) selective for isoforms of
phosphodiesterase found mainly in cardiac and vascular smooth muscle
 Sildenafil – highly selective for PDE5; PDE5 expressed mainly in smooth muscle of corpus cavernosum, but also
expressed in retina and vascular smooth muscle cells
 PDE5 inhibitors prescribed for erectile dysfunction, common in men with vascular disease
o In normal physiology, NO released from penile nerve terminals activates guanylyl cyclase in smooth
muscle of corpus cavernosum, leading to increased intracellular cGMP concentration, smooth muscle
relaxation, inflow of blood, and penile erection
o Because they inhibit cGMP phosphodiesterase in corpus cavernosum smooth muscle, sildenafil,
vardenafil, andtadalafil can potentiate effects of endogenous NO-cGMP singaling and thereby potentiate
penile erection
 PDE5 expressed in small amounts in systemic and pulmonary vasculature; although principal actions of PDE5
inhibitors localized to corpus cavernosum, drugs can attenuate cGMP hydrolysis in vasculature by inhibiting
small amounts of PDE5 present in systemic and pulmonary vascular beds
o High doses of sildenafil efficacious in treatment of pulmonary hypertension
 Adverse effects of PDE5 inhibitors result from drug-induced vasodilation in systemic vasculature
o Headache caused by vasodilation of cerebral vascular beds, and flushing by vasodilation of cutaneous
vascular beds
o Sildenafil-related MI and sudden cardiac death may be related to vasodilatory effects
o PD5 inhibitors have only nominal effect on blood pressure at doses commonly used to treat ED, and all
above adverse effects relatively rare because of small amounts of PDE5 in vascular smooth muscle
o In presence of excess NO (e.g., when organic nitrates used concomitantly with PDE5 inhibitors),
inhibition of cGMP degradation can markedly amplify vasodilatory effect
 Excessive vasodilation can lead to severe refractory hypotension
o Possible association of PDE5 inhibitors with transient or permanent vision loss due to condition termed
nonarteritic ischemic optic neuropathy
 Patients taking PDE5 inhibitors advised to be aware of this adverse effect, with specific caution
that patients with prior episodes of vision loss may be at increased risk from drug exposure
 Even though experiments show no blood pressure plummet if taking sildenafil and a Ca2+-channel blocker, all
patients taking PDE5 inhibitor with any antihypertensive medication should be regarded as at risk for potentially
dangerous hypotension
 Patient at even higher risk if taking PDE5 inhibitor in conjunction with both antihypertensive vasodilator and
drug that inhibits degradation of PDE5 inhibitor by P450 3A4
Ca2+ Channel Blockers
 Ca2+ channel blockers act on both vascular smooth muscle and myocardium
 While organic nitrates have mainly venodilatory activity, Ca2+ channel blockers predominantly arteriolar dilators
 Commonly used in treatment of hypertension, certain cardiac arrhythmias, and some forms of angina
 Different subtypes of voltage-gated Ca2+ channels differ in electrochemical and biophysical properties and in
their tissue distribution patterns
o Ca2+ influx through L-type channel important determinant of vascular tone and cardiac contractility
 Ca2+ channel blockers in current use all act by inhibiting Ca2+ entry through L-type channel, although different
members of drug class have markedly different pharmacodynamics and pharmacokinetic properties
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In smooth muscle cells, decreased Ca2+ entry through L-type channels keeps intracellular Ca2+
concentrations low, thereby reducing Ca2+-CaM-mediated activation of myosin light chain kinase, actinmyosin interaction, and smooth muscle contractility
Although Ca2+ channel blockers relax many different types of smooth muscle (e.g., bronchiolar and GI), they
have greatest effect on vascular smooth muscle
o Arterial smooth muscle more responsive than venous smooth muscle
o Vasodilation of resistance arterioles reduces systemic vascular resistance and lowers arterial blood
pressure, thereby decreasing ventricular systolic wall stress and myocardial O2 demand
o Drug-induced dilation of coronary arteries may increase myocardial O2 supply, further ameliorating O2
supply-demand mismatch in patients with angina
o In cardiac myocytes, reduced Ca2+ influx through L-type channels leads to decreases in myocardial
contractility, SA node pacemaker rate, and AV node conduction velocity
Skeletal muscle not significantly affected by Ca2+ channel blockers because skeletal muscle depends mainly on
intracellular pools of Ca2+ (i.e., Ca2+ from sarcoplasmic reticulum) to support excitation-contraction coupling, and
doesn’t rely on transmembrane Ca2+ influx through L-type channel
o Skeletal muscle relaxants block neurotransmission mediated by nicotinic acetylcholine receptor at
neuromuscular junction
3 chemical classes currently in clinical use; all block L-type Ca2+ channel, but each class has distinctive
pharmacologic effect
o Dihydropyridines – exemplified by nifedipine, amlodipine, and felodipine
 Nifedipine binds to N binding site
o Benzothiazepines – exemplified by diltiazem, which binds to D binding site
o Phenylakylamines – exemplified by verapamil, which binds to V binding site
o D and V binding sites overlap, but N is in different region of Ca2+ channel; thus diltiazem and verapamil
affect each other’s binding in complex ways
o Nifedipine and diltiazem bind synergistically, whereas nifedipine and verapamil reciprocally inhibit each
other’s binding
o Ca2+ channel blockers have different affinities for different conformational states of channel
o Drugs have differential tissue selectivity because different channel conformations favored in different
tissues
Dihydropyridines – cause significantly more arterial vasodilation; have relatively little effect on cardiac tissue
o Compared to diltiazem and verapamil, dihydropyridines cause less depression of myocardial contractility
and have minimal effects on SA node automaticity and AV node conduction velocity
o Amlodipine differs from nifedipine principally in its pharmacokinetic properties
 Amlodipine has pKa of 8.7, so it is predominantly in positively charged form at physiologic pH
 Positive charge allows amlodipine to bind to cell membranes (typically negatively charged) with
high affinity and contributes to drug’s late peak plasma concentration and slow hepatic
metabolism
o Clevidipine – available only in IV formulation; administered as continuous infusion for management of
hypertensive urgency and emergency
Compared to dihydropyridines, nondihydropyridine Ca2+ channel blockers diltiazem and verapamil have lower
ratio of vascular-to-cardiac selectivity
o In heart, both diltiazem and verapamil act as negative inotropes
o Verapamil has greater suppressive effect on cardiac contractility than diltiazem
o Because diltiazem and verapamil also slow rate of Ca2+ channel recovery, cardiac conduction (i.e.,
automaticity and conduction velocity) significantly decreased by these drugs
Ca2+ channel blockers typically administered in oral dosage forms, although IV formulations of diltiazem and
verapamil also available
Nifedipine and verapamil excreted by kidney; diltiazem excreted by liver
Bioavailability of oral formulations of nifedipine, diltiazem, and verapamil lowered by significant first-pass
metabolism in gut and liver
o Oral nifedipine has rapid onset of action and can cause brisk, precipitous fall in blood pressure; druginduced hypotension can activate severe reflex tachycardia, which can worsen myocardial ischemia by
increasing myocardial O2 demand and decreasing myocardial O2 supply by decreasing diastolic filling
time; short half-life of oral nifedipine (about 4 hours) requires it to be administered frequently
o Amlodipine and nifedipine share similar pharmacodynamic profiles, but differ significantly in
pharmacokinetic profiles
 Amlodipine’s high bioavailability permits it to be effective at lower dosages because greater
proportion of administered drug reaches systemic circulation unchanged
 Amlodipine’s late peak plasma concentration and slow onset of action may be reason that,
compared to nifedipine, amlodipine causes significantly less reflex tachycardia
 Slow hepatic degradation of amlodipine contributes to long plasma half-life (about 40 hours)
and duration of action, which enable once-daily dosing
2+
 Toxicities of Ca channel blockers mainly mechanism-based and are typically extensions of their actions
o Flushing (common adverse effect of nifedipine) caused by excessive smooth muscle relaxation in
cutaneous vasculature, and constipation (common adverse effect of verapamil) caused by excessive
smooth muscle relaxation in GI tract
o In excess, negative chronotropic and negative inotropic effects of verapamil and diltiazem can lead to
bradycardia, AV block, and heart failure
 Patients taking β-adrenergic blockers (also negative inotropes) advised not to use diltiazem or
verapamil concomitantly because of increased likelihood of excessive cardiac depression
2+
o Ca channel blockers may increase risk of mortality in patients with heart failure, and Ca2+ channel
blockers contraindicated in management of heart failure
o Nifedipine associated with increased risk of myocardial ischemia and infarction, by virtue of its tendency
to disturb myocardial O2 supply-demand balance
K+ Channel Openers
 Cause direct arterial vasodilation by opening ATP-modulated K+ channels (K+ATP channels) in PM of vascular
smooth muscle cells
 K+ATP channel openers are powerful family of drugs that can be used to treat hypertension refractory to other
antihypertensive therapeutics
 Opening K+ATP channels hyperpolarizes membrane; if sufficient number of channels open at same time, normal
excitatory stimuli not able to promote membrane depolarization
o In absence of depolarization, voltage-gated Ca2+ channels don’t open, and Ca2+ influx and smooth muscle
contraction inhibited
+
 K ATP channel openers include minoxidil, cromakalim, pinacidil, and nicorandil
o Act primarily on arterial smooth muscle cells, and therefore decrease arterial blood pressure
 Adverse effects of K+ATP channel openers include headache (caused by excessive dilation of cerebral arteries) and
flushing (caused by excessive dilation of cutaneous arteries)
 When arterial vasodilators (e.g., Ca2+ channel blockers or K+ATP channel openers) used as monotherapy, decrease
in arterial pressure often elicits reflex SNS discharge, leading to tachycardia and increased cardiac work
o Reflex SNS discharge can upset balance between myocardial O2 supply and demand, precipitating
myocardial ischemia – particularly concerning in patients with preexisting coronary artery disease
o Use of β-blockers in combination with arterial vasodilators can help block effects of reflex SNS activity,
and thereby preserve therapeutic utility of arterial vasodilators
Endothelin Receptor Antagonists
 Bosentan – competitive antagonist at ETA and ETB receptors; approved for use in treatment of pulmonary
hypertension; significantly improves 6-minute walk-test for patients with severe dyspnea related to pulmonary
hypertension; decreases pulmonary vascular resistance
o Major adverse effect is elevation in serum transaminase levels (10% of patients having elevations that
exceed 3x upper limit of normal)
o Necessary to monitor liver function tests monthly
 Ambrisentan – endothelin receptor antagonist with relative specificity for ETA receptor
o Patients with pulmonary hypertension have improved 6-minute walk-test distance and increased
functional status when taking medication
o May have less hepatotoxicity than bosentan
Other Drugs that Modulate Vascular Tone
 Hydralazine – orally administered arteriolar vasodilator sometimes used in treatment of hypertension and, in
combination with isosorbide dinitrate, in treatment of heart failure
o Membrane hyperpolarization, K+ATP channel opening, and inhibition of IP3-induced Ca2+ released from
sarcoplasmic reticulum in vascular smooth muscle cells contribute to mechanism
o Prevents development of nitrate tolerance by inhibiting vascular superoxide production
o Combination pill containing isosorbide dinitrate and hydralazine reduces morbidity and mortality in
black Americans with advanced heart failure
o Use limited because it was initially thought frequent dosing required for sustained BP control and rapid
development of tachyphylaxis to antihypertensive effects made chronic use impractical
 As benefits for combination therapy for hypertension and heart failure becoming better
appreciated, it may be possible for hydralazine to be used more effectively, especially in
patients for whom other vasodilators (e.g., ACE inhibitors) are contraindicated
o Typically has low bioavailability because of extensive first-pass hepatic metabolism
 Rate of metabolism depends on whether patient is slow or fast acetylator
 In slow acetylators, hydralazine has slower rate of hepatic degradation and thus, higher
bioavailability and higher plasma concentrations
o Rare adverse effect is development of reversible lupus erythematosus-like syndrome; effect occurs
chiefly in slow acetylators
 α1-adrenergic antagonists – α1-adrenergic receptor is G protein-coupled receptor that associates with
heterotrimeric G protein Gq, which activates phospholipase C to generate inositol trisphosphate and
diacylglycerol; α1-adrenergic antagonists (such as prazosin) block α1-adrenergic receptors in arterioles and
venules, leading to vasodilation
o Effect is greater in arterioles than venules
o α1-adrenergic antagonists useful in treatment of hypertension
o Initiation of therapy can be associated with orthostatic hypotension
o Cause retention of salt and water
o β-adrenergic blockers and diuretics may be used together with α1-adrenergic antagonists to mitigate
compensatory responses
o Some α1-adrenergic antagonists, such as terazosin, used principally to inhibit contraction of nonvascular
smooth muscle (e.g., prostatic smooth muscle), but they also have some effect on vasculature
 β-adrenergic antagonists – increased intracellular cAMP induced by β2-receptor stimulation may cause smooth
muscle relaxation by accelerating inactivation of myosin light chain kinase and increasing extrusion of Ca2+ from
cell; activation of β2-adrenergic receptors on endothelial cells leads to vasodilation through activation of
endothelial NO synthase
o β-adrenergic antagonists are of major clinical importance in treatment of hypertension, angina, cardiac
arrhythmias, and other conditions
o Acting at cardiac β1-adrenergic receptors, β-adrenergic antagonists have negative inotropic and
chronotropic effects on heart; reduce cardiac output, which is important determinant of both
myocardial O2 demand and blood pressure
 Hypotensive effect reflects combined negative inotropic effect (leading to decrease in cardiac
output), inhibition of renin secretion, and CNS effects of β-blockers
 Inhibition of renin-angiotensin system results in significant vasorelaxation
o Hypotensive effect of ACE inhibitors may be caused in part by decreased catabolism of bradykinin
(vasorelaxant released in response to inflammatory stimuli)
o Antagonists at AT1 receptor (selectively inhibits angiotensin II-mediated vasoconstriction at level of
target organ) has more direct effect
o ACE inhibitors and AT1 receptor antagonists are balanced vasodilators because they affect both arterial
and venous tone
o Both classes of drugs effective in treatment of hypertension and heart failure
Conclusion and Future Directions
 Vasoconstriction occurs when increase in intracellular Ca2+ activates Ca2+-CaM-dependent myosin light chain
kinase (MLCK), which phosphorylates myosin light chains and allows formation of actin-myosin cross-bridges
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
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Vascular smooth muscle relaxes when intracellular Ca2+ concentrations returns to basal levels and myosin light
chains dephosphorylated, terminating formation of actin-myosin cross-bridges
Vascular tone influenced by state of vascular smooth muscle cells and overlying endothelial cells, by SNS
innervation, and by neurohormonal and local regulators
New class of drug, exemplified by ranolazine, appears to have minimal direct effects on cardiac contractility or
vascular tone, but has efficacy in treatment of angina
o Exerts principal therapeutic effects on cardiovascular system by affecting metabolic pathways in target
tissues
Nebivolol – recently approved β-blocker, has interesting property that it is both β1-adrenergic antagonist and β3adrenergic antagonist
o As efficacious as other β-blockers in treatment of hypertension
o Combines with cardiac-selective β1-adrenergic blockade with stimulation of β3 receptors, which activate
NO synthase in vasculature