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CHAPTER 15

Committee 14

Pharmacotherapy for Erectile Dysfunction


Chairs
H. PADMA-NATHAN (USA),
G.CHRIST (USA)
MEMBERS
G.ADAIKAN (SINGAPORE),
E. BECHER (ARGENTINA),
G. BROCK (CANADA),
S. CARRIER (CANADA),
C. CARSON (USA),
J. CORBIN (USA),
S. FRANCIS (USA),
R. DEBUSK (USA),
I. EARDLEY (U.K.),
H. HEDLUND (NORWAY),
A. HUTTER (USA),
G. JACKSON (U.K.),
R. KLONER (USA),
C. LIN (USA),
K. MCVARY (USA),
A. MCCULLOUGH (USA),
A. NEHRA (USA),
H. PORST (GERMANY),
C. SCHULMAN (BELGIUM),
A. SEFTEL (USA),
I. SHARLIP (USA),
C. STIEF (GERMANY),
C. TELOKEN (BRAZIL)

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CONTENTS

A. MECHANISM OF ACTION
AND BASIC SCIENCE OF ED 4. TOPICAL THERAPIES
PHARMACOTHERAPIES
I. INTRODUCTION GENERAL PRINCIPLES OF
TOPICAL AGENTS
CENTRALLY ACTING
1. 4.I. TOPICAL THERAPY FOR
DRUGS ERECTILE DYSFUNCTION
BACKGROUND
1.I. APOMORPHINE

1.II. MELANOCORTIN AGONIST: 4.II. TOPICAL PGE1


MELANOTAN II and PT-141

1.III. TRAZODONE 4.III. TOPICAL MINOXIDIL

1.IV. DELEQUAMINE
4.IV. TOPICAL PAPAVERINE
1.V. NALMEFENE

1.VI. NALTREXONE 4.V. TOPICAL NITROGLYCERIN

CENTRALLY AND PER-


2.
IPHERALLY ACTIVE
B. EVIDENCE-BASED REVIEW
2.I. YOHIMBINE OF ED PHARMCOTHERAPIES
2.II. PHENTOLAMINE

PERIPHERALLY I. INTRODUCTION
3.
ACTIVE
II. ORAL ED
3.I. PDE 5 INHIBITORS PHARMACOTHERAPIES
3.II. VASOACTIVE INTESTINAL
POLYPEPTIDE III. LOCAL ED THERAPIES
3.III. L-ARGININE
IV. HIGH AND INTERMEDIATE
3.IV. ALPROSTADIL (PGE1) LEVEL OF EVIDENCE CARDIO
VASCULAR PUBLICATIONS IN THE
3.V. PAPAVERINE FIELD OF ED PHARMACO-THERAPY
(graded by cardiologists on committeee)
3.VI. COMBINATIONS

504
Pharmacotherapy for Erectile Dysfunction
H. PADMA-NATHAN , G.CHRIST
G.ADAIKAN, E. BECHER, G. BROCK, S. CARRIER, C. CARSON, J. CORBIN, S. FRANCIS,
R. DEBUSK, I. EARDLEY, H. HEDLUND, A. HUTTER, G. JACKSON, R. KLONER, C. LIN,
K. MCVARY, A. MCCULLOUGH, A. NEHRA, H. PORST, C. SCHULMAN, A. SEFTEL,
I. SHARLIP, C. STIEF, C. TELOKEN

A. MECHANISM OF ACTION AND BASIC SCIENCE OF ED


PHARMACOTHERAPIES

INTRODUCTION

As is clear from the other chapters in this compendium, incredible advances have been made in the understan-
ding, diagnosis and treatment of sexual dysfunction/disorders. In the case of erectile dysfunction, this has led
to an improved understanding of the molecular and cellular mechanisms of action of nearly all of the current-
ly used drug therapies. In the sections that follow, the basic research underlying the putative mechanism of
action (MOA) of the available centrally and peripherally acting drugs is reviewed.
These reviews are accompanied by two summary figures (Figures 1, 2), that provide a conceptual framework
for understanding this field of medical therapy. In addition, a detailed summary table (Table 1) is given, which
outlines as much as possible, the specific MOA of these drugs. In the last MOA section, which deals with the
exciting developments in the PDE5 field, there are three additional figures (Figs. 3-5) and an additional Table
(Table 2), to provide an exquisite level of detail about the currently most explosive area of drug research and
development in erectile dysfunction.
We hope this material will assist the interested physician/health care provider in better understanding the
actions of currently available drugs, and in better educating their patients about the same.

505
506
Figure 1 : Schematic depiction of the general classification and putative sites of action of the currently used drugs for the treatment of erectile dysfunction.
507
Figure 2 : Schematic diagram showing the mechanism of action and impact of currently used drugs at the level of the corporal smooth muscle cell. +: denotes stimulatory pathway,
and -: denotes inhibitory pathway. Where PKA, PKC and PKG denote protein kinases A, C and G respectively, DAG denotes diacyl glycerol, MLC20 denotes myosin light chain,
SMPP denotes smooth muscle myosin phosphatase, Cam denotes calmodulin, MLCK denotes myosin light chain kinase, Rho A denotes Rho A kinase, and Gq and Gs denote the G
protein coupled to activation of Phospholipase C and adenylate cyclase enzymes, respectively.
Table 1 : Mechanism of action summary
(Legend: IC: Intracavernosal; IU: Intaurethral; EP: Prostaglandin receptor; VIP: vasoactive intestinal polypeptide; NTG: nitroglycerine)

508
and contains premotor neurones that project directly
CENTRALLY ACTING onto spinal autonomic preganglionic neurones. The
1. PVN plays a key role in the erectile response and
DRUGS
pharmacological or electrical stimulation of this small
hypothalamic nuclei results in seminal discharge in
unanaesthetised rats (Eaton, 1991) and erection and
1.I. APOMORPHINE ejaculation in anaesthetised rats (Chen et al., 1997).
Dopaminergic neurones belonging to the incertohypo-
Although the mechanisms underlying erectile func- thalamic dopamine system are the main components
tion are not fully understood, advances have been of the PVN. These dopaminergic neurones impinge on
oxytocin containing neurones (Bujis et al., 1984). The
made regarding the interplay of central and periphe-
PVN is believed to be the nucleus where apomorphi-
ral mechanisms. It is now widely agreed that central
ne acts as a dopaminergic substance. From the PVN,
disinhibition plays a crucial role in the induction of
signals are then transmitted to the brainstem nuclei
erectile responses and this has led to the develop-
(periaqueductal grey (PAG), nucleus paragigantocel-
ment of the central enhancer, the dopaminergic sub-
lularis (nPGi) and raphe nuclei) and then to the per-
stance apomorphine. Apomorphine acts in the para-
iphery of the erectile axis (Marson & McKenna, 1990,
ventricular nucleus of the hypothalamus as a dopa-
1992; Sancila et al., 2002).
mine (D2) receptor agonist. It works as a pro-erecti-
le conditioner at this level to increase the responses Dopamine is one among a number of important cen-
of the erectile pathway following appropriate sexual tral neurotransmitters involved in the initiation of
stimulation. Certainly, understanding the role of cen- erection. Dopamine is the main transmitter within the
tral pathways/mechanisms in the control of the erec- PVN (Eaton, 1991; Allard et al., 2002) that, as discus-
tile process is critical to elucidating the mechanism sed above, plays an important role in the central
of action of this newer class of orally active erecto- control of erection. Dopamine receptors are divided
genic agents. Chapters 10 & 11 in this volume deals into two main families D1 and D2-like receptors that
in great detail with this subject, and thus, only a brief are in turn further subdivided into D1 to D5 receptor
summary is given below. subtypes. Apomorphine has a higher affinity for the
D2-like receptors (Rampin et al., 2003) that are
Physiological erections are initiated, in large part, by thought to be the main site for the induction of erec-
central stimuli. Depending on the type of stimulus, tions in the PVN (Chen et al., 1999) Apomorphine is
various areas of the cortex are involved like the occi- therefore postulated to increase erectile responses by
pital region for visual, the rhinencephalic for olfacto- acting as a conditioner in the PVN, increasing the res-
ry, the thalamic for tactile and the limbic region for ponse to sexual stimuli resulting in enhanced erections
imaginative stimuli. There is good evidence that these induced in the periphery (Brien et al., 2002).
and other stimuli from higher centers are sending
inputs to hypothalamic nuclei (medial preoptic area In summary, apomorphine is an agonist of the D1-
(MPOA), paraventricular nucleus (PVN)). The and D2-receptor subtypes that are mainly located in
MPOA contains a high density of neurons that the paraventricular nucleus of the hypothalamus.
concentrate androgens and shows an extensive inter- Oxytocinergic neurons in this nucleus are responsive
connection to the limbic system and the lower autono- to the administration of apomorphine via activation
mic brain stem nuclei. The role of the MPOA is to of both the D1-and D2-receptor subtypes, which sub-
recognise sensory stimuli from the higher brain sequently induces a cascade of events that reach the
centres and integrate them with sexual motivation and periphery to elicit penile erection. It has been sug-
gested that nitric oxide acts as a cofactor at the level
copulatory motor programmes. The MPOA plays an
of the paraventricular nucleus of the hypothalamus
important role in the erectile response, and both phar-
with regards to the activation of the oxytocinergic
macological and electrical stimulation of the MPOA
neurons (Melis & Argiolas, 1996). In this scenario,
results in erection in anaesthetised rats (Giuliano et al.,
the presence of nitric oxide is thus mandatory in
1997: Sato & Christ, 2000; Sato et al., 2001). The
order to allow for the action of apomorphine. Apo-
MPOA is also involved in maternal behaviour
moprhine SL has recently been approved for marke-
(Numan, 1988) thermoregulation (Kanosue et al.,
ting in Europe at the doses of 2 and 3 mg. The erec-
1994) and thirst (Bourque et al., 1994).
togenic effects are usually seen within 20 minutes of
The PVN also seems to integrate the input from higher its administration; provided the presence of an ade-
centers (Melis & Argiolas, 2002; Melis et al., 2003) quate sexual stimulation.

509
Rampin, O., Jerome, N., Suaudeau, C.: Proerectile effects of
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Sancila, M., Giuliano, F., Rampin, O., Mailly, P., Brisorgueil,
MJ., Calas, A., Verge, D.: Evidence for a direct projection
Allard, J., Bernabe, J., Derdinger, F., Alexandre, L., McKen-
na, K. & Giuliano, F.: Selegiline enhances erectile activity from the paraventricular nucleus of the hypothalamus to puta-
induced by dopamine injection in the paraventricular nucleus tive serotoninergic neurons of the nucleus paragigantocellula-
of the hypothalamus in anesthestized rats. Int. J. Impotence ris involved in the control of erection in rats. Eur. J. Neuros-
Res. 14: 518-522, 2002. ci. 16: 1240-1248, 2002.
Bourque,C.W., Oliet,S.H. & Richard,D. Osmoreceptors, Sato, Y. & Christ, G.J.: Differential intracavernous pressure
osmoreception, and osmoregulation. Front Neuroendocrinol. (ICP) responses elicited by electrical stimulation of the
15, 231-274 (1994). medial preoptic area (MPOA). Am. J. Physiol. 268: H964-
H970, 2000.
Brien, S.E., Smallegange, B., Gofton, WT., Heaton, JPW. And
Adams, MA: Development of a rat model of sexual perfor- Sato, Y., Zhao, W., & Christ, G.J.: Central modulation of the
mance anxiety: effect of behavioural and pharmacological NO/cGMP pathway affects the MPOA-Induced intracaver-
hyperadrenergic stimulation on APO-induced erections. Int. nous pressure (ICP) response. Am. J. Physiol. 281: R269-
J. of Impotence Res. V.14 P.107-115 2002 R278, 2001.
Buijs,R.M., Geffard,M., Pool,C.W. & Hoorneman,E.M. The
dopaminergic innervation of the supraoptic and paraventricu- 1.II. MELANOCORTIN AGONIST:
lar nucleus. A light and electron microscopical study. Brain
Res. 323, 65-72 (1984).
MELANOTAN II and PT-141
Chen,K.K., Chan,J.Y. & Chang,L.S. Dopaminergic neuro-
Melanotan II is a synthetic nonselective analog of -
transmission at the paraventricular nucleus of hypothalamus
in central regulation of penile erection in the rat. J. Urol. 162, melanocytestimulating hormone (-MSH). -MSH
237-242 (1999). and adrenocorticotrophin, known as the melanocor-
Chen,K.K., Chan,S.H., Chang,L.S. & Chan,J.Y. Participation tins, are derived from proteolytic cleavage of the pre-
of paraventricular nucleus of hypothalamus in central regula- cursor, pro-opiomelanocortin. Melanocortins are
tion of penile erection in the rat. J. Urol. 158, 238-244 (1997). implicated in the regulation of sexual behaviour
Eaton, R.C. et al.: D2 receptors in the paraventricular nucleus including penile erection, sexual motivation and in
regulate genital responses and copulation in male rats. Phar- the female rat the secretion of sexual attractants from
macol. Biochem. Behav. 39, 177-181 (1991). the preputial gland (Thody AJ et al, 1981, van der
Giuliano, F., Bernabe, J., Brown, K, Drouphy, S., Benoit, G. Kraan et al, 1998). Through cloning techniques five
& Rampin, O.: Erectile response to hypothalamic stimulation types of melanocortin receptors (MC1, MC2, MC3,
in rats: role of peripheral nerves. Am. J. Physiol. 273: R1990-
MC4, and MC5) have been characterized (Wikberg
R1997, 1997.
et al, 2000).
Kanosue,K., Zhang,Y.H., Yanase-Fujiwara,M. & Hosono,T.
Hypothalamic network for thermoregulatory shivering. Am. Injection of -MSH into the rat hypothalamic per-
J. Physiol 267, R275-R282 (1994). iventricular region induces grooming, stretching,
Marson,L. & McKenna,K.E. A role for 5-hydroxytryptamine yawning and penile erection. Grooming, stretching
in descending inhibition of spinal sexual reflexes. Exp. Brain and yawning but not penile erection seem to be
Res. 88, 313-320 (1992).
mediated by MC4 receptors which are found almost
Marson,L. & McKenna,K.E. The identification of a brainstem
exclusively in the central nervous system especially
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515, 303-308 (1990). in the hypothalamus of the rat (Vergoni et al, 1998;
Melis, M.R., Succu, S. & Argiolas, A.: Dopamine agonists
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Neurosci. 8: 2056-2063, 1996. increases in the rabbit has been documented (Vemu-
Melis, M.R., Argiolas, A.: Reduction of drug-induced yaw- lapalli et al., 2001). Another recent study (Van der
ning and penile erection and of noncontact erections in male Ploeg et al., 2002) has provided strong support for an
rats by the activation of GABAA receptors in the paraventri- MC4-receptor-mediated proerectile response in spi-
cular nucleus: involvement of nitric oxide Eur. J. Neurosci.,
nal cord erectile centers, as well as at the level of the
15: 852-860, 2002.
somatosensory afferent nerve terminals in the mouse
Melis. M.R., Succu, S., Mascia, M.S., Cortis, L., Argiolas, A.:
Extra-cellular dopamine increases in the paraventricular
penis. Moreover, a similar distribution of the MC4
nucleus of male rats during sexual activity. Eur. J. Neurosci. receptor subtype has been found in the correspon-
17: 1266-1272, 2003. ding rat and human tissues. Therefore, while the
Numan, M.: Neural basis of maternal behavior in the rat. Psy- melanocortin receptor subtype(s) that mediate the
choneuroendocrinology, 13: 47-62, 1988. proerectile effects of Melanotan II/melanocortins

510
have not been unequivocally identified, a role for the
MC3/MC4 receptors seems likely. 1.IV. DELEQUAMINE
Melanotan II delivered subcutaneously has been
reported to initiate penile erection in normal men as Delequamine is a more specific and selective 2-
well as men with psychogenic and organic ED (Dorr adrenoceptor antagonist than yohimbine (Brown et
et al, 1996; Wessells et al, 1998, 2000). It is also al, 1993). 2-adrenoceptors are present on the nora-
noted to significantly increase sexual desire (Wes- drenergic cell bodies in the locus coeruleus and their
sells et al, 2000). The frequent side effects associated presynaptic terminals throughout the brain. The cen-
with melanotan II administration are nausea and tral effect of 2-adrenoceptor blockade by delequa-
stretching/yawning. mine is an increased noradrenaline level at the
synapse by blocking re-uptake leading to sexual
1.III. TRAZODONE arousal (Bancroft, 2000). In rat mating experiments,
delequamine dose dependently increased sexual
behaviour, but unlike yohimbine, it did not affect eja-
Trazodone, a serotonin reuptake inhibitor, is a non- culatory function, which is mediated via 5-HT-1A
tricyclic antidepressant that has been associated with
receptors (Tallentire et al, 1996)
prolonged erection and priapism when administered
orally in depressive patients. In human corpus cavernosum, norepinephrine (NE)
and epinephrine may activate postsynaptic 2-adre-
In healthy volunteers trazodone dose dependently
noceptor subtypes, in addition to activating 1-adre-
increased NPT following REM related erections and
noceptor subtypes, on smooth muscle cells, contribu-
blocked the detumescence phase of erection, which
ting to local control of human corpus cavernosum
is under sympathetic control, thereby prolonging the
smooth muscle tone in vivo (Traish et al, 1997).
erection (Saenz de Tejada et al, 1991). In vitro, tra-
zodone attenuated human corporal muscle contrac- A centrally mediated effect of delequamine in humans
tion elicited by both electrical stimulation of adre- is supported by the findings that intravenous infusion
nergic nerves and exogenous noradrenaline (Adaikan of low dose of the drug in the normal controls produ-
& Ratnam, 1988; Saenz de Tejada et al, 1991). Com- ced an increase in NPT during non-REM sleep, and
petitive radioligand binding studies indicate that tra- with the high dose, spontaneous erections occurred
zodone has high and moderate affinity for human just before sleep onset (Bancroft et al, 1995).
1- and 2-adrenoceptors, respectively (Krege et al, During the waking state, normal controls reported
2000). In contrast to trazodone, m-chlorophenylpipe- significantly higher subjective ratings of sexual arou-
razine (m-CPP) did not significantly affect caverno- sal before erotic stimulation and increased likelihood
sal contractions induced by electrical stimulation and of spontaneous erections or significant prolongation
exogenous noradrenaline (Saenz de Tejada et al, of erectile response to visual erotic stimuli following
1991). Thus, the proerectile action of trazodone is high dose of delequamine (Munoz et al, 1994).
likely to be related to the -adrenoceptor blocking
As with the putative 2adrenoceptor actions
property of trazodone in erectile tissue.
yohimbine (see Table 1), delequamine may also have
However, m-CPP, the main metabolite of trazodone, a dual MOA. Specifically, delequamine may serve as
is a serotonin agonist. m-CPP is capable of eliciting a conditioner in the CNS by blocking the prejunc-
an increase in spontaneous firing of the cavernous tional 2adrenoceptors and thereby increasing
nerve accompanied by an increase in cavernous pres- noradrenergic neurotransmission to enhance sexual
sure in the anaesthetized rat (Steers & de Groat, function. In addition, delequamine may also block
1989). distinct prejunctional 2adrenoceptors that are
Subcutaneous administration of m-CPP induces sympatholytic (blockade increases NO release; see
penile erection in rats. The proerectile property of m- discussion of yohimbine above). Finally, delequami-
CPP involves activation of 5-HT-2C receptors locali- ne may provide an additional sympatholytic compo-
zed in the lumbosacral spinal level of the rat (Millan nent via blockade of postsynaptic 2adrenoceptors
et al, 1997; Bancila et al, 1999). The neuro-modula- on smooth muscle cells (again, promoting relaxa-
tory role of m-CPP on penile erectile activity contri- tion; see Table 1). Obviously, clinical efficacy
buting to pharmacological action of trazodone in implies that the balance of the potential sympatho-
human is not clear. mimetic and sympatholytic actions favors the later.

511
Argiolas A, Melis MR, Murgia S, Schioth HB. ACTH- and
1.V. NALMEFENE alpha-MSH-induced grooming, stretching, yawning and peni-
le erection in male rats: site of action in the brain and role of
melanocortin receptors. Brain Res Bull 2000; 51(5): 425-31.
Nalmefene, derived from naltrexone, is a long-acting Bancila M, Verge D, Rampin O, Backstrom JR, Sanders-Bush
opioid receptor antagonist. Intravenous bolus admi- E, McKenna KE, Marson L, Calas A, Giuliano F. 5-Hydroxy-
nistration of nalmefene in male rhesus monkeys tryptamine2C receptors on spinal neurons controlling penile
leads to significant increases in plasma LH and tes- erection in the rat. Neuroscience 1999; 92(4): 1523-37.
tosterone levels with no change in LH or prolactin Bancroft J, Munoz M, Beard M, Shapiro C. The effects of a
pulse frequency or amplitude (Mello et al, 2000). new alpha-2 adrenoceptor antagonist on sleep and nocturnal
penile tumescence in normal male volunteers and men with
Nalmefene treatment in older impotent men also erectile dysfunction. Psychosom Med 1995; 57(4): 345-56.
increases the activity of the hypothalamic-pituitary-
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1.VI. NALTREXONE Brennemann W, Stitz B, Van Ahlen H, Brensing KA, Kling-
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Traish AM, Moreland RB, Huang YH, Goldstein I. Expres- thetic transmission (Molderings et al, 1989).
sion of functional alpha2-adrenergic receptor subtypes in
human corpus cavernosum and in cultured trabecular smooth
Yohimbine then, as a presynaptic 2-adrenoceptor
muscle cells. Recept Signal Transduct 1997; 7(1): 55-67. antagonist, is expected to increase sympathetic trans-
Van der Kraan M, Adan RA, Entwistle ML, Gispen WH, Bur- mission and promote smooth muscle contractility.
bach JP, Tatro JB. Expression of melanocortin-5 receptor in However, the occurrence of distinct pre-junctional
secretory epithelia supports a functional role in exocrine and 2-adrenoceptors in horse penile resistance arteries
endocrine glands. Endocrinology 1998; 139(5): 2348-55. has also been reported and stimulation of these
Van der Ploeg LH, Martin WJ, Howard AD, et. al. A role for receptors inhibit nitrergic transmitter release (Simon-
the melanocortin 4 receptor in sexual function. Proc. Natl. sen et al, 1997). Blocking these pre-junctional 2-
Acad. Sci. 99: 11381-11386, 2002. adrenoceptors would, therefore, effectively enhance
Vemulapalli R., Kurowski S., Salisbury B., Parker E., Davis NO release. As such, blockade of prejunctional 2
H.: Activation of central melanocortin receptors by MT-II
adrenoceptors can have both sympathomimetic and
increases cavernosal presure in rabbits by the neuronal
release of NO. Br. J. Pharmacol. 134; 1708-1710, 2001. sympatholytic effects at the end organ (peripheral)
Wessells H, Fuciarelli K, Hansen J, Hadley ME, Hruby VJ,
level; the balance of these actions presumably favors
Dorr R, Levine N. Synthetic melanotropic peptide initiates the latter. This might be one of the mechanisms by
erections in men with psychogenic erectile dysfunction: which yohimbine induces penile arterial relaxation.
double-blind, placebo controlled crossover study. J Urol Recent data also indicate that yohimbine may media-
1998; 160(2): 389-93. te relaxation of human and rabbit corpus cavernosum
Wessells H, Gralnek D, Dorr R, Hruby VJ, Hadley ME, Levi- via release of nitric oxide from endothelium, which
ne N. Effect of an alpha-melanocyte stimulating hormone is androgen dependent (Filippi et al, 2002). Finally,
analog on penile erection and sexual desire in men with orga-
nic erectile dysfunction. Urology 2000; 56(4): 641-6.
antagonism of post-junctional 2-adrenoceptors,
which mediate contractions of corpus cavernosum,
Wikberg JE, Muceniece R, Mandrika I, Prusis P, Lindblom J,
Post C, Skottner A. New aspects on the melanocortins and
by yohimbine may play a role in facilitating penile
their receptors. Pharmacol Res 2000; 42(5): 393-420. erection.
Wu FM, Noble RG. Opiate antagonists and copulatory beha- Experimental data show that central 2-adrenocep-
vior of male hamsters. Physiol Behav 1986; 38(6): 817-25 tors are implicated in the regulation of male sexual
behaviour (Sala et al, 1990). Clonidine, a selective
2-adrenoceptor agonist, administered intracerebro-
ventricularly or in the medial preoptic area of the

513
hypothalamus suppressed copulatory behaviour in adrenergic, endothelium-mediated mechanism sug-
male rats and yohimbine prevented the copulatory gesting nitric oxide synthase activation (Traish et al,
suppression induced by clonidine (Clark, 1991). 1998; Vemulapalli & Kurowski, 2001). The clinical
Yohimbine has also been demonstrated to increase utility of phentolamine is presumably a reflection of
sexual motivation in sexually experienced male rats the contribution of adrenergic neurotransmission to
and induce sexual activity in sexually nave or pre- the maintained rugosity of the penis, and thus, inhi-
viously inactive rats (Clark et al, 1984, 1985). In bition of -adrenoceptor activity alone may be suffi-
sexually exhausted intact rats, yohimbine is able to cient for erection to commence (Adaikan, 1979;
reestablish copulatory behavior whereas in rats Adaikan et al, 1986; see Chapter 10 for a full des-
administered a neurotoxin (DSP4, to cause a lesion cription of the role of the -adrenoceptor pathway in
in the central noradrenergic system), yohimbine, but penile erection and detumescence).
not naloxone (opioid antagonist) or 8-OH-DPAT
Oral/intracavernosal phentolamine therefore may
(5HT1A agonist) restored partially sexual perfor-
facilitate penile erection by inhibiting the functional
mance. These findings indicate that the integrity of
predominance of 1-adrenoceptor activity that main-
the central noradrenergic system is essential for
tains erectile tissues in a non-erect state. Attenuation
sexual behaviour (Rodriguez-Manzo & Fernandez-
of the opposing adrenergic contractile response
Guasti, 1995).
enhances NO-mediated corpus cavernosum relaxa-
The site of action of yohimbine in human as a pro- tion. Furthermore, phentolamine may delay detu-
erectile agent is not well defined. Yohimbine may act mescence, which is mediated by noradrenaline,
peripherally by dual mechanisms: contributing to the maintenance of penile erection.
1) a post-junctional 2-adrenoceptor antagonist,
although the predominant subtype of -adrenocep-
tors in penile tissue is of 1-subtype, and REFERENCES
2) By releasing relaxing factors such as nitric oxide.
The effect of intracavernous yohimbine has not been Adaikan PG, Kottegoda SR, Karim S, Ratnam SS. Adrenergic
determined, however, intracavernous injection of mechanism in penile erection. Asia Pac J Pharmacol 1986; 1:
another 2-adrenoceptor antagonist, idazoxan, had 141-43.
no erectogenic effect in man (Brindley, 1986). Adaikan PG. Pharmacology of human penis. MSc Thesis.
University of Singapore 1979: 1-213.
Yohimbine, as demonstrated in rats, may presumably
Brindley GS. Pilot experiments on the actions of drugs injec-
act through central 2-adrenoceptor increasing nora-
ted into the human corpus cavernosum penis. Br J Pharmacol
drenergic transmission to enhance sexual function in 1986; 87(3): 495-500.
human. Christ, G.J., Maayani, S., Melman, A. Pharmacological stu-
dies of human erectile tissue: Characteristics of spontaneous
contractions and alterations in a-adrenoceptor responsiveness
2.II. PHENTOLAMINE with age and disease in isolated tissues. Br.J.Pharmacol.
101:375-381, 1990.
Clark JT, Smith ER, Davidson JM. Enhancement of sexual
Phentolamine is a non-selective -adrenoceptor motivation in male rats by yohimbine. Science 1984;
antagonist with similar affinity for 1- and 2-adre- 225(4664): 847-9.
noceptors. Both post-junctional 1- and 2-adreno- Clark JT, Smith ER, Davidson JM. Evidence for the modula-
ceptors mediating contractions are present in corpus tion of sexual behavior by alpha-adrenoceptors in male rats.
cavernosum and penile vascular smooth muscle Neuroendocrinology 1985; 41(1): 36-43.
(Molderings et al, 1989; Christ et al, 1990; Traish et Clark JT. Suppression of copulatory behavior in male rats fol-
al., 1998; Simonsen et al, 1997). Pre-junctional 2- lowing central administration of clonidine. Neuropharmaco-
logy 1991; 30(4): 373-82.
adrenoceptors in the corpus cavernosum modulate
Filippi S, Luconi M, Granchi S, Natali A, Tozzi P, Forti G,
stimulus-evoked release of noradrenaline from sym-
Ledda F, Maggi M. Endothelium-dependency of yohimbine-
pathetic nerves in the erectile tissue (Molderings et induced corpus cavernosum relaxation. Int J Impot Res 2002;
al, 1989), whereas those in the horse penile resistan- 14(4): 295-307.
ce arteries regulate the release of nitrergic transmit- Molderings GJ, Gothert M, Van Ahlen H, Porst H. Noradre-
ter (Simonsen et al, 1997). naline release in human corpus cavernosum and its modula-
tion via presynaptic alpha 2-adrenoceptors. Fundam Clin
Phentolamine mesylate induced relaxation of corpus Pharmacol 1989; 3(5): 497-504.
cavernosum erectile tissue is thought to occur by Rodriguez-Manzo G, Fernandez-Guasti A. Participation of
direct antagonism of 1- and 2-adrenoceptors, as the central noradrenergic system in the reestablishment of
well as by indirect functional antagonism via a non- copulatory behavior of sexually exhausted rats by yohimbine,

514
naloxone, and 8-OH-DPAT. Brain Res Bull 1995; 38(4): 399-
404.
Sala M, Braida D, Leone MP, Calcaterra P, Monti S, Gori E.
Central effect of yohimbine on sexual behavior in the rat.
Physiol Behav 1990; 47(1): 165-73.
Simonsen U, Prieto D, Hernandez M, Saenz de Tejada I, Gar-
cia-Sacristan A. Prejunctional alpha 2-adrenoceptors inhibit
nitrergic neurotransmission in horse penile resistance arteries.
J Urol 1997; 157(6): 2356-60.
Traish A, Gupta S, Gallant C, Huang YH, Goldstein I. Phen-
tolamine mesylate relaxes penile corpus cavernosum tissue by
adrenergic and non-adrenergic mechanisms. Int J Impot Res
1998; 10(4): 215-23.
Traish A, Moreland RB, Huang YH, Goldstein I. Expression
of functional alpha2-adrenergic receptor subtypes in human
corpus cavernosum and in cultured trabecular smooth muscle
cells. Recept Signal Transduct 1997; 7(1): 55-67
Vemulapalli S, Kurowski S. Phentolamine mesylate relaxes
rabbit corpus cavernosum by a nonadrenergic, noncholinergic
Figure 3 : Molecular structures of sildenafil, vardenafil,
mechanism. Fundam Clin Pharmacol 2001; 15(1): 1-7.
and tadalafil as compared with those for caffeine and
cGMP. Arrows denote differences between structures of sil-
PERIPHERALLY denafil and vardenafil.
3.
ACTIVE
Part of the ring structure of sildenafil or vardenafil is
similar to that of caffeine (see dashed ovals). This
3.I. PDE 5 INHIBITORS same ring structure is similar to a ring structure in
cGMP. This is important since these drugs are com-
petitive inhibitors of cGMP for PDE5, and they pre-
Major research efforts have led to the production and sumably form some of the same molecular interac-
development of compounds that are selective and tions as cGMP forms with amino acids in PDE5
potent in inhibiting particular PDEs (Corbin and (hydrogen bonds, hydrophobic stacking interactions,
Francis, 2002; Ballard et al, 1998; Rotella DP, 2002; van der Waals contacts, ionic interactions, etc). Even
Hellstrom et al, 2002; Klotz et al, 2001; Lue 2000; though the tadalafil structure differs significantly
Montorsi et al, 2003; Padma-Nathan et al, 2001; from those of the other two inhibitors, its molecular
Padma-Nathan et al, 2002; Hellstrom et al, 2003). mechanism of action is believed to be similar.
The clinical success and public interest have resulted The normal pathway for penile erection (Fig. 4) is
in the generation of an enormous amount of infor- initiated by sexual arousal, which stimulates release
mation and data regarding the mechanism of action of nitric oxide at nerve endings in the penis. Another
of these groundbreaking treatments for erectile dys- source of nitric oxide is vascular endothelial cells. As
function. The salient aspects of this ever growing described elsewhere in this chapter, nitric oxide dif-
database are reviewed below. fuses into vascular smooth muscle cells in the penile
Sildenafil (Viagra) is the first commercialized corpus cavernosum to cause stimulation of guanylyl
compound in this class. This class has been recently cyclase and elevation of cGMP in these cells (Ignar-
joined by vardenafil (Levitra) and tadalafil (Cia- ro et al, 1990; Burnett et al, 1992). This leads to acti-
lis). Vardenafil has a similar structure to sildenafil vation of cGMP-dependent protein kinase (PKG),
but the structure of tadalafil is significantly different phosphorylation of several proteins, and lowering of
(Fig. 3). As will be discussed below, vardenafil is cell calcium, which results in smooth muscle relaxa-
more potent than sildenafil in vitro to inhibit PDE5, tion. The increased accumulation of blood in corpus
and this difference is explained by differences (see cavernosum caused by this relaxation is the under-
arrows) in molecular structures of these two com- lying basis for penile erection. The pathway shown
pounds. We should note that potency is an in vitro in Fig. 4 may not work properly if the cGMP level in
measure of a drug concentration that elicits an corpus cavernosum smooth muscle cells is not eleva-
action. It is not a direct measure of clinical efficacy. ted sufficiently or if relaxation of smooth muscle in
More potent does not necessarily mean more clini- this tissue is deficient/incomplete (Corbin and Fran-
cally efficient. cis, 1999; Jeremy et al., 1997).

515
There is where the PDE5 story comes into play. That PDE5 was discovered by Corbin and colleagues
is, PDE5 inhibitors enhance erectile function during (Lincoln et al, 1976; Francis et al, 1980). A cartoon
sexual stimulation by penetrating into smooth of the enzyme structure is shown in Fig. 5. Each of
muscle cells and inhibiting PDE5, which is an enzy- the two subunits of PDE5 has a catalytic domain and
me that degrades cGMP. This results in decreased a regulatory domain. The catalytic domain, but not
degradation of cGMP, which maintains higher cellu- the regulatory domain, is the target of PDE5 inhibi-
lar levels of cGMP in both corpus cavernosum and tors. The catalytic domain contains a single binding
the vessels supplying it. This increases relaxation of site for cGMP. When cGMP occupies this site the
the smooth muscle, which dilates the corporeal sinu- catalytic machinery (paired black structures), which
soids resulting in increased blood flow, allowing an is located very near the catalytic binding site, is
erection to occur. PDE5 inhibitors increase the cell brought into close proximity and breaks the cyclic
cGMP by competitively inhibiting PDE5, which trig- phosphate bond of cGMP to form linear 5-GMP.
gers penile erection. PDE5 inhibitors do not increase This dampens or terminates cGMP action. The cata-
the nitric oxide level, but they potentiate the nitric lytic machinery has been shown to utilize divalent
oxide effect to stimulate erection. Without sexual cations such as Zn++ (Francis et al, 1994). Because
arousal, which triggers the nerve-nitric oxide path- they have similar structures as cGMP, sildenafil or
way, these inhibitors are ineffective. The same type other PDE5 inhibitors can also occupy the catalytic
of synergistic effect between PDE5 inhibitors and site, thus blocking access to cGMP. In fact, sildena-
nitric oxide was found at the time of discovery of the fil occupies the site about 1000 times more avidly
caffeine inhibitory effect on PDEs more than forty than does the natural substrate, cGMP. However, the
years ago (Robison et al., 1971), whereby caffeine PDE5 inhibitors are not broken down by the cataly-
was shown to be synergistic with epinephrine to ele- tic machinery. Occupation of the catalytic site by
vate cAMP in dog liver. In other words, caffeine these inhibitors competitively inhibits cGMP break-
alone had little if any effect on metabolism of seve- down since cGMP cannot bind to gain access to the
ral isolated tissues, but when added together with a catalytic machinery. Inhibition of cGMP breakdown
stimulator (such as epinephrine or glucagon) of leads to elevation of cGMP in smooth muscle cells of
cAMP production, which also had minimal effect the penile corpus cavernosum, resulting in relaxation
when added alone, caffeine had a pronounced effect of the muscle and penile erection.
to increase cAMP as well as the tissue metabolic res-
Although the catalytic domain of PDE5 is the direct
ponse to cAMP. This same principle also applies to
target of PDE5 inhibitors, certain features of the
the combination of PDE5 inhibitor and nitric oxide
regulatory domain impact the PDE5 inhibitor actions
(sexual arousal) in the cGMP pathway that causes
on the enzyme (Corbin et al., 2000; Corbin et al,
penile erection.

Figure 4. Regulation of penile corpus cavernosum smooth Figure 5. Cartoon of PDE5 molecular structure showing
muscle relaxation and effect of PDE5 inhibitors. molecular effect of PDE5 inhibitor on the catalytic domain.
P = phosphate; NH2 = amino terminus.

516
2003). This domain contains allosteric cGMP-bin- beled PDE5 inhibitors to PDE5, and the value obtai-
ding sites (one or two per subunit) as well as a phos- ned by this method is termed KD instead of IC50
phorylation site for negative feedback regulation of (Corbin et al, 2003). As compared with IC50, mea-
the enzyme. PKG phosphorylates this site about 10 surement of KD is a more direct method of determi-
times faster than does PKA. When cGMP binds to ning potency. The KD of a PDE5 inhibitor obtained
the allosteric sites, cGMP is not degraded as it is in using this approach should approach the IC50 of the
the catalytic site, but PDE5 enzyme functions are same PDE5 inhibitor. In fact, our results show that
activated by the binding reaction. Phosphorylation the KD for sildenafil, vardenafil, or tadalafil approxi-
also activates PDE5 enzyme functions. However, mates the IC50 for each compound. The finding that
when PDE5 inhibitor is present, which causes cGMP the value of KD approaches the value of IC50 for
elevation and phosphorylation, PDE5 inhibitor bin- each inhibitor suggests that these compounds do not
ding at the catalytic site is expected to be stimulated. bind to an appreciable extent to sites on PDE5 other
This means that when cGMP is elevated in smooth than the catalytic domain. The approach of determi-
muscle cells after a patient takes a PDE5 inhibitor ning KD not only provides a new tool to measure
tablet, this should stimulate the catalytic site to bind PDE inhibitor potency but may also reveal new pro-
more of the inhibitor. That is, the PDE5 inhibitor sti- perties of PDE5 and PDE5 inhibitors which were not
mulates its own efficacy. For example, were it not for possible to study previously. These include the PDE5
this built-in enzyme mechanism, a 200-mg dose on-rates and off-rates of PDE5 inhibitors, which
rather than 100-mg dose of a particular PDE5 inhibi- should help to predict time of onset and duration of
tor might be required to induce penile erection in a inhibitor action in patients. The radiolabeled inhibi-
particular patient. tors could also be used to search for the presence of
non-PDE PDE5 inhibitor-binding proteins in body
Assuming all other factors are equal, the higher the
tissues, which might suggest the potential for side
affinity (potency) of a PDE5 inhibitor for PDE5, the
effects of a particular PDE5 inhibitor.
lower the expected dose of the inhibitor that will be
needed (Corbin and Francis, 2002). This concept of Based on comparative IC50 values, the potency of
potency can be assessed by measuring the concentra- sildenafil is about 1 million times higher than that of
tion of a particular PDE5 inhibitor in vitro that inhi- caffeine (Corbin and Francis, 1999). Other experi-
bits PDE5 activity by 50%, and is known as the mental PDE inhibitors have intermediate potencies.
IC50. Highly potent drugs are expected to have affi- According to literature values, the in vitro biochemi-
nities (IC50 values) in the nanomolar (nM) range. cal potencies of the three new commercial PDE5
However, as discussed below, factors such as phar- inhibitors are within the same range of each other,
macokinetics have strong impact on the dose requi- albeit vardenafil is more potent than the other two
red. Higher potency does not mean that a PDE5 inhi- inhibitors (Corbin and Francis, 2002). The in vitro
bitor has a greater clinical effect, but that less of it is potency of a PDE5 inhibitor is not the same as effi-
needed for the desired effect. For the PDE5 inhibi- cacy. As discussed below, efficacy is based on the
tors, less vardenafil is required than sildenafil or actual in vivo (clinical), effects of the inhibitor.
tadalafil to achieve the same degree of in vitro PDE5
The biochemical selectivity of an inhibitor for PDE5
inhibition. Vardenafil is therefore more biochemical-
is a key factor in determining its side-effect profile
ly potent than are sildenafil and tadalafil, although
(Corbin and Francis, 2002). Once a large enough
not necessarily more efficacious. Based on in vitro
separation exists between the affinity (IC50) of the
potencies, it would be predicted that a lower dosage
inhibitor for PDE5 and its affinity for non-target
of vardenafil than sildenafil would be required to
PDEs (or other proteins), the less likely it is that it
cause penile erection in men. This appears to be the
can achieve sufficient plasma concentrations to acti-
case since 5-20 mg doses of vardenafil are recom-
vate the non-target site at therapeutic doses. For
mended compared with 25-100 mg doses of sildena-
PDE5 inhibitors, selectivity is usually expressed in
fil. The recommended doses of tadalafil are also
terms of potency (IC50) to inhibit PDE5 as opposed
lower than those of sildenafil, but since these two
to inhibiting any others in the PDE family. The selec-
drugs have similar biochemical potencies, the expla-
tivity is computed by dividing the IC50s of the two
nation for lower dosage is not clear at this time.
compounds that are compared. The PDEs are com-
There are methods in addition to classical IC50 to prised of 11 families of enzymes that catalyze the ter-
measure potency of a drug. The Corbin group has mination of second messenger activity in cells by
recently measured the strength of binding of radiola- breaking the phosphodiester bond of either cAMP or

517
cGMP. Eleven distinct families have been identified Table 2 : Pharmacokinetic Parameters of the Selective
(PDE1 to PDE11) that are known or implicated in a PDE5 Inhibitors
broad range of cellular functions. Within some fami-
lies, more than a single gene exists, for a total of at
least 25 PDE genes, and some of these genes have
multiple products brought about by alternative
mRNA splicing, resulting in a grand total of more
than 50 PDE forms (Francis et al., 2001). PDE5,
which is cGMP-specific, exhibits only one gene,
although its mRNA can be spliced to yield at least
three isoforms. However, it should be noted that
these isoforms may not differ significantly in their
catalytic domains, which is the site of action of Patterson B et al. 4th Congress of ESSIR; 2001; Rome, Italy.
PDE5 inhibitors. PDE5 is present in high concentra- 2. Viagra USPI [package insert]. 2000. 3. Sasche et al.
tions in the smooth muscle of corpora cavernosa of AUA. 2001.
the penis (Gopal et al, 2001). Sildenafil and vardena-
fil cross-react slightly with PDE6, i.e., their IC50s
for PDE5 are only 4-10 fold lower than those for in less than 1 hour, the tadalafil Tmax occurs in 2
PDE6. PDE6 is expressed in the retina. This may hours), but the Cmax of vardenafil is significantly
explain the complaint of some patients that sildenafil lower than that for either of the other two inhibitors.
causes visual disturbances. Tadalafil cross reacts This might be expected based on the higher bioche-
with PDE11 to some extent, but the consequences of mical potency of vardenafil. The t1/2 of tadalafil is
this effect are unknown. PDE11 is expressed in testi- considerably longer than that of the other two PDE5
cular cells, cardiac muscle, smooth muscle and the inhibitors, which could be due to slower intestinal
pituitary. Neither of the three PDE11 inhibitors absorption and/or slower degradation of this drug by
cross-reacts to a large extent with any of the other the liver, or it could be due to other factors. The
PDEs except for PDE6 and PDE11, i.e., the IC50s of extended t1/2 of tadalafil provide a much longer the-
these compounds for PDE5 are more than 1000 times rapeutic effect (Porst et al 2003), which may be pre-
lower than those for most of the other PDEs. Except ferred for spontaneous sexual activity, but could
for visual disturbances, the other reported side expose the patient to greater risk of side effects.
effects of PDE5 inhibitors (headaches, flushing, PDE5 inhibitors are believed to be degraded in the
slight lowering of blood pressure, etc) are likely cau- liver. Therefore, since they are not degraded by
sed by PDE5 inhibition in smooth muscle tissues PDE5 or any other enzyme in smooth muscle cells of
outside the penile corpus cavernosum. corpus cavernosum, they must dissociate from
In addition to biochemical properties discussed above, PDE5, exit the smooth muscle cells and then be
pharmacokinetic properties of PDE5 inhibitors (inges- transported to the liver via the bloodstream before
tion, movement in the circulation, tissue uptake, eli- they can be degraded. The rate of exit of a PDE5
mination) have great impact on efficacy (Corbin and inhibitor from smooth muscle cells should be consi-
Francis, 2002). There are several common pharmaco- dered when comparing PDE5 inhibitors since this
kinetic parameters that can be measured and quanti- could affect its duration of action. Disappearance of
the inhibitor from plasma may imply, but does not
fied that describe bodily distribution of a PDE5 inhi-
prove, its disappearance, or clearance, from the cells
bitor (Table 2). The bioavailability, maximum plasma
in which it produces its effects. Since the inhibitor
concentration (Cmax), the time (Tmax) required for
binds tightly to PDE5 in these cells, this could signi-
attaining Cmax, and time (t1/2) required for elimina-
ficantly retard its exit from these cells and prolong
tion of one-half of the inhibitor from plasma are all
effects of PDE5 inhibitors in patients. It is concei-
important factors. The bioavailability, which is the
vable that PDE5 inhibitors with higher affinities for
percentage of ingested inhibitor that actually appears
PDE5 would dissociate from the enzyme more slow-
in the plasma, is about one-third as much for vardena-
ly, resulting in a more retarded clearance from corpus
fil (15%) as that for sildenafil (40%). The bioavaila-
cavernosum cells. Studies of clearance of PDE5 inhi-
bility for tadalafil is unknown at present. bitors from plasma are documented, but studies of
Sildenafil, vardenafil, and tadalafil have broadly clearance of these inhibitors from smooth muscle
similar Tmax (sildenafil and vardenafil Tmax occurs cells are rare.

518
patients: a RigiScan and pharmacokinetic study. World J Urol
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3.II. VASOACTIVE INTESTINAL
phorylation of phosphodiesterase-5 by cyclic nucleotide- POLYPEPTIDE
dependent protein kinase alters its catalytic and allosteric
cGMP-binding activities. Eur J Biochem 267:2760-2767. Vasoactive intestinal peptide (VIP) is a naturally
Francis SH, Colbran JL, McAllister-Lucas LM, and Corbin occurring neurotransmitter. VIPergic nerves are most
JD (1994) Zinc interactions and conserved motifs of the densely concentrated in the penis around the puden-
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that it is a zinc hydrolase. J Biol Chem 269:22477-22480.
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Francis SH, Lincoln TM and Corbin JD (1980) Characteriza-
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Francis SH, Turko IV and Corbin JD (2001) Cyclic nucleoti- tract suggests that this peptide neurotransmitter may
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Gopal VK, Francis SH and Corbin JD (2001) Allosteric sites
VIP co-localizes with NOS within the perivascular
of phosphodiesterase-5 (PDE5). A potential role in negative
feedback regulation of cGMP signaling in corpus caverno- and trabecular nerve fibres innervating the penis
sum. Eur. J. Biochem. 268:3304-3312. (Ehmke et al, 1995). Most of these NO- and VIP-
Hellstrom WJ, Gittelman M, Karlin G, et al.: Vardenafil for containing nerves appear to be cholinergic, since
treatment of men with erectile dysfunction: efficacy and safe- they also contain vesicular acetylcholine transporter,
ty in a randomized, double-blind, placebo-controlled trial. J a specific marker for cholinergic neurons (Hedlund
Androl 2002, 23:763-771. et al, 2000). Other VIP-related peptides such as
Hellstrom WJ, Gittelman M, Karlin G, et al.: Sustained effi- PHM, PACAP and helospectin (Hel-1) are also co-
cacy and tolerability of vardenafil, a highly potent selective localized with VIP in nerve structures within the
phosphodiesterase type 5 inhibitor, in men with erectile dys-
function: results of a randomized, double-blind, 26-week pla-
human cavernous tissue (Kirkeby et al, 1992, Hed-
cebo-controlled pivotal trial. Urology 2003, 61:8-14. lund et al, 1995). These peptides concentration-
Ignarro LJ, Bush PA, Buga GM, et al.: Nitric oxide and cyclic dependently relaxed corpus cavernosum and circum-
GMP formation upon electrical field stimulation cause relaxa- flex vein preparations in vitro. Their putative roles as
tion of corpus cavernosum smooth muscle. Biochem Biophys neurotransmitters and/or neuromodulators in the ner-
Res Commun 1990, 170:843-850. vous control of penile erection are yet to be clearly
Jeremy JY, Ballard SA, Naylor AM, Miller MA and Angelini established.
GD (1997) Effects of sildenafil, a type-5 cGMP phosphodies-
terase inhibitor, and papaverine on cyclic GMP and cyclic
Though VIP is a potent relaxant of both the corpus
AMP levels in the rabbit corpus cavernosum in vitro. Br J cavernosum and penile vascular smooth muscle in
Urol 79:958-963. vitro, the ineffectiveness of VIP-antiserum to inhibit
Klotz T, Sachse R, Heidrich A, et al.: Vardenafil increases the neurogenic relaxation in corpus cavernosum
penile rigidity and tumescence in erectile dysfunction strips suggests that VIP may not be released from the

519
nerves during field stimulation (Adaikan et al,
1986a). Furthermore, the inability of VIP to induce 3.IV. ALPROSTADIL (PGE1)
penile rigidity adequate for intromission when injec-
ted intracavernously in potent (Adaikan et al, 1986a)
PGE1 produced relaxation of human corpus caver-
and impotent men (Roy et al, 1990) indicates that it
nosum smooth muscle and this relaxant activity was
is not likely to be the primary neurotransmitter
first described by Karim and Adaikan (1975) and
mediating penile erection.
Adaikan et al in 1983. This was followed by the
The effects of VIP are mediated by a specific mem- mechanism of action and use of PGE1 for the treat-
brane-bound receptor linked to adenylate cyclase via ment of erectile dysfunction (Adaikan et al, 1986b;
a stimulatory G-protein. VIP has been shown to ele- Ishii et al, 1986; Virag & Adaikan, 1987). Of note,
vate cAMP concentrations in cavernosal tissues
the first competitive Ginestie Prize by the ISIR was
without affecting cGMP levels (Miller et al, 1995;
awarded to PG Adaikan for identifying conventional
Hedlund et al, 1995).
receptors and the use of PGE1 for the treatment of
erectile dysfunction in 1986, 2nd World Meeting of
3.III. L-ARGININE Impotence, Prague.
PGE1 mediates relaxation of corpus cavernosum
smooth muscle via activation of EP prostaglandin
Nitric oxide, the NANC neurotransmitter of primary
importance in regulating corpus cavernosum smooth receptors (EP2/4) by increasing the intracellular
muscle relaxation, is derived from L-arginine by concentration of cAMP in corpus cavernosum smoo-
nitric oxide synthase (NOS). As L-arginine is also a th muscle (Palmer et al., 1994; Lin et al, 1995; Trai-
substrate of arginase, NO production is likely to be sh et al., 1997; Moreland et al., 2001). PGE1-indu-
linked to the regulation of both NOS and arginase. ced relaxation of human corpus cavernosum is asso-
The decreased NOS nerves and upregulated arginase ciated with activation of KCa channels, leading to
II expression/activity found in diabetic corpus caver- hyperpolarisation and alterations in transmembrane
nosum, which is accompanied by a decrease in erec- Ca2+ flux (Lee et al, 1999). PGE1 may also act by
tile function, suggests that decreased NO synthesis inhibiting the release of noradrenaline from sympa-
may play a role in diabetic erectile dysfunction thetic nerves (Molderings et al, 1992) and suppres-
(Bivalacqua et al, 2001). Alterations in the penile L- sing angiotensin II secretion in the cavernosal tissues
arginine-NO pathway observed in atherosclerotic (Kifor et al, 1997).
and hypercholesterolaemic penile vascular bed may PGE1 is metabolised by the 15-hydroxydehydroge-
also result in reduction in NO bioavailability leading nase present in the corpus cavernosum (Roy et al,
to ED. Recent studies show that L-arginine augments 1989). The ability of human corpus cavernosum to
endothelium-dependent vasodilation in hypercholes- degrade PGE1 probably aids in regulating the activi-
terolaemic rabbits and human (Girerd XJ et al, 1990; ty of PGE1 and reducing the risk of undesirable side
Creager et al, 1992). The rationale for L-arginine the- effects such as prolonged erection and priapism.
rapy is therefore related to the supposition that dieta-
ry supplementation with NO-precursor L-arginine PGE1 suppressed the induction of collagen synthesis
may normalize endothelium-dependent vasodilation by TGF-1 in cultured human corpus cavernosum
and as such could have a beneficial effect in the treat- suggesting that PGE1 and TGF-1 may play a key
ment of erectile dysfunction. Based on this rationale, role in modulation of collagen synthesis and in the
as with other combination therapies, it is conceivable regulation of fibrosis of the corpus cavernosum
that oral co-administration of L-arginine with yohim- (Moreland et al, 1995). This suppressant effect
bine may be effective in improving erectile function seems to correlate with the low incidence of local
in mild to moderate erectile dysfunction because of fibrotic lesions reported in PGE1 treated ED patients
the complementary actions of the 2-adrenoceptor (Porst, 1996) and the unaltered intracavernous struc-
antagonist and the NO releasing effects of yohimbi- tures in the 5 patients with biopsies performed only
ne. (see Lebret et al, 2002; see yohimbine discussion after intracavernous PGE1 injection (Wespes et al,
above). 2000).

520
ne of VIP and PGE1-induced relaxation (cAMP-
3.V. PAPAVERINE mediated) suggests a synergistic interaction while
the interaction between phentolamine and sildenafil
Intracavernosal papaverine injection was the first cli- (cGMP-mediated) appears to be additive (Kim et al,
nically effective pharmacological therapy for ED. 2000). The same investigators also show that silde-
Papaverine is a nonopiate derivative of poppy plant nafil and PGE1 has additive and synergistic effect
(Papaver somniferum). Papaverine is a smooth respectively with phentolamine-induced relaxation.
muscle relaxant. In vitro, papaverine evoked relaxa- Hence, in combination therapy employing phentola-
tion of isolated corpus cavernosum smooth strips, mine as an adjunct, reducing the predominance of
penile arteries, cavernous sinusoids and the penile adrenergic tone through the blockade of -adreno-
veins and attenuated contractions induced by stimu- ceptors, increases the efficacy of vasodilators that
lation of adrenergic nerves and exogenous noradre- initiate erection via other independent relaxatory
naline (Adaikan & Ratnam 1988; Kirkeby et al, pathways.
1990). In addition, in vivo studies in the rat model
documented that intracavernous injection of papave-
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Combination therapy is not only predictably more Impot Res 1995; 7(3): 147-56.
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based on sound pharmacological principles, it is also arginine augments endothelium-dependent vasodilation in
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associated with a reduction in incidence of side
Hedlund P, Alm P, Ekstrom P, Fahrenkrug J, Hannibal J, Hed-
effects and cost per dose. lund H, Larsson B, Andersson KE. Pituitary adenylate cycla-
In vitro studies on human and rabbit cavernosal se-activating polypeptide, helospectin, and vasoactive intesti-
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col 1995; 116(4): 2258-66.
potentiated relaxation induced by sildenafil, VIP and
Hedlund P, Ny L, Alm P, Andersson KE. Cholinergic nerves
PGE1. These vasodilators also significantly enhan- in human corpus cavernosum and spongiosum contain nitric
ced relaxation induced by phentolamine in the caver- oxide synthase and heme oxygenase. J Urol 2000; 164(3 Pt
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Iguchi M, Nakajima T, Hisada T, Sugimoto T, Kurachi Y. On Palmer, L., Valcic, M., Melman, A., Giraldi, A., Wagner, G.,
the mechanism of papaverine inhibition of the voltage-depen- Melman, A. & Christ, G.J.: Characterization of cAMP accu-
dent Ca++ current in isolated smooth muscle cells from the mulation in cultured human corpus cavernosum smooth
guinea pig trachea. J Pharmacol Exp Ther 1992 ; 263(1): 194- muscle cells. J. Urol. 152:1308-1314, 1994.
200. Polak JM, Gu J, Mina S, Bloom SR. Vipergic nerves in the
Ishii N, Watanabe H, Irisawa H, Kikuchi Y, Kawamura S, penis. Lancet 1981; 2(8240): 217-9.
Suzuki K, Chiba, R, Tokiwa, M, Shirai M. Studies on male Porst H. The rationale for prostaglandin E1 in erectile failure:
sexual impotence. Report 18. Therapeutic trial with prosta- a survey of worldwide experience. J Urol 1996; 155(3): 802-
glandin E1 for organic impotence. Nippon Hinyokika Gakki 15.
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Karim SMM, Adaikan PG. In: Physiological roles and phar- Melman, A., & Christ, G.J.: Diminished neurogenic-, but not
macological actions of prostaglandins in relation to human pharmacologic-induced intracavernous pressure responses in
reproduction. In Prostaglandins and Reproduction. Ed: SMM the 3 month Streptozotocin (STZ)-diabetic rat. Am. J. Phy-
Karim, MTP Press Ltd, Lancaster, 1975, p23-75. siol., 272: H1960-H1971, 1997.
Kifor I, Williams GH, Vickers MA, Sullivan MP, Jodbert P, Roy AC, Adaikan PG, Sen DK, Ratnam SS. Prostaglandin 15-
Dluhy RG. Tissue angiotensin II as a modulator of erectile hydroxydehydrogenase activity in human penile corpora
function. I. Angiotensin peptide content, secretion and effects cavernosa and its significance in prostaglandin-mediated
in the corpus cavernosum. J Urol 1997; 157(5): 1920-5. penile erection. Br J Urol 1989; 64(2): 180-2.
Kim NN, Goldstein I, Moreland RB, Traish AM. Alpha-adre- Roy JB, Petrone RL, Said SI. A clinical trial of intracavernous
nergic receptor blockade by phentolamine increases the effi- vasoactive intestinal peptide to induce penile erection. J Urol
cacy of vasodilators in penile corpus cavernosum. Int J Impot 1990; 143(2): 302-4.
Res 2000; 12 Suppl 1: S26-36. Traish, A.M., Moreland, R.B., Gallant, C., Huang, Y.H. &
Kirkeby HJ, Fahrenkrug J, Holmquist F, Ottesen B. Vasoacti- Goldstein, I.: G-protein-coupled receptor agonists augment
ve intestinal polypeptide (VIP) and peptide histidine methio- adenylyl cyclase activity induced by forskolin in human cor-
nine (PHM) in human penile corpus cavernosum tissue and pus cavernosum smooth muscle cells. Recept. Signal Trans-
circumflex veins: localization and in vitro effects. Eur J Clin duct. 7: 121-132, 1997.
Invest 1992; 22(1): 24-30. Virag R, Frydman D, Legman M, Virag H. Intracavernous
Kirkeby HJ, Forman A, Andersson KE. Comparison of the injection of papaverine as a diagnostic and therapeutic
papaverine effects on isolated human penile circumflex veins method in erectile failure. Angiology 1984; 35(2): 79-87.
and corpus cavernosum. Int J Impot Res 1990; 2: 49-54. Virag R, Adaikan PG. Effects of prostaglandin E1 on penile
Lebret T, Herve JM, Gorny P, Worcel M, Botto H. Efficacy erection and erectile failure. J Urol 1987; 139: 1010.
and safety of a novel combination of L-arginine glutamate Wespes E, Sattar AA, Noel JC, Schulman CC. Does prosta-
and yohimbine hydrochloride: a new oral therapy for erectile glandin E1 therapy modify the intracavernous musculature? J
dysfunction. Eur Urol 2002; 41(6): 608-13. Urol 2000; 163(2): 464-6.
Lee SW, Wang HZ, Zhao W, Ney P, Brink PR, Christ GJ.
Prostaglandin E1 activates the large-conductance KCa chan-
nel in human corporal smooth muscle cells. Int J Impot Res
1999; 11(4): 189-99.
4. TOPICAL THERAPIES
Lin JS, Lin YM, Jou YC, Cheng JT. Role of cyclic adenosine
monophosphate in prostaglandin E1-induced penile erection
in rabbits. Eur Urol 1995; 28(3): 259-65. Topical therapy for the treatment of ED has been
Miller MA, Morgan RJ, Thompson CS, Mikhailidis DP, Jere- proposed as one means to circumvent some of the
my JY. Effects of papaverine and vasointestinal polypeptide negative factors associated with ICI (intracavernous
on penile and vascular cAMP and cGMP in control and dia- injection) and IUS (intrurethral suppositories). These
betic animals: an in vitro study. Int J Impot Res 1995; 7(2):
91-100.
therapies have an intrinsic appeal to many patients.
Molderings GJ, van Ahlen H, Gothert M. Modulation of nora- Currently, topical therapies for the treatment of erec-
drenaline release in human corpus cavernosum by presynap- tile dysfunction remain in clinical trials and have yet
tic prostaglandin receptors. Int J Impot Res 1992; 4: 19-25. to be released for widespread use. However, topical
Moreland RB, Traish A, McMillin MA, Smith B, Goldstein I, applications have the potential to avoid the systemic
Saenz de Tejada I. PGE1 suppresses the induction of collagen effects noted with oral therapies while being percei-
synthesis by transforming growth factor-beta 1 in human cor- ved as minimally invasive in so far as it does not
pus cavernosum smooth muscle. J Urol 1995; 153(3Pt1):
require needles or intraurethral instrumentation.
826-34.
Moreland, R.B., Albadawi, H., Bratton, C., Patton, G., Gold-
Topical therapy may also provide benefit to patients
stein, I., Traish, A. and Watkins, M.T.: O2-dependent prosta- unresponsive to systemic therapy or who use medi-
noid synthesis activates functional PGE receptors on corpus cations which cannot be taken along with such oral
cavernosum smooth muscle. Am. J. Physiol. 281: H552- treatments (nitrate use). That is, the overall goal is
H558, 2001. the local treatment of a local problem.

522
With such an assortment of confounding factors one
GENERAL PRINCIPLES OF
wonders exactly how gel applied to the penis could
TOPICAL AGENTS ever induce an erection. One attractive possibility is
that gel applied to the glans is rapidly absorbed
A short introduction to the major concepts and com- through the porous skin of the glans into the venous
plications of using topical agents for the treatment of
vasculature of the corpora spongiosum. From that
erectile dysfunction seems prudent. The transdermal
location it could travel into the corpora cavernosa
route is a well established technology that provides
akin to the intraurethral delivery of drug (Wolfson et
durable and constant plasma levels of drugs such as
al., 1993; Padma-Nathan et al., 1997). The known
hormonal replacements, narcotics and vasodilators.
absorptive nature of the penile skin and glans make
When it comes to local penile therapy using direct
this a real possibility (Maibach et al., 1971). If this is
smooth muscle relaxants, previous experience
the case then delivery of drug to the shaft of the penis
concerning the duration and onset of action
would seem superfluous and possibly only contribu-
employed for these other indications may not provi-
te to penile skin discomfort. Alternatively, the drug
de useful attributes. Several issues, in particular, are
applied to the skin of the penis could theoretically be
worth mentioning:
absorbed through the skin, the tunica of the corporal
1) High systemic concentrations are undesirable as bodies and thus into the cavernous tissues. The large
they may result in an unacceptable level of adverse distance, multiple tissues layers and unknown per-
events. meability of the tunica makes this a formidable drug
2) Agents may be largely metabolized in the first delivery challenge. A third more remote possibility
pass through the lungs or liver. involves the systemic absorption, recirculation and
delivery of drug to the penile tissues. Systemic levels
3) The vasoactive agent(s) needs to reach the corpo- have been measured with the penile skin application
ra cavernosa in a timely fashion with the effective of papaverine and minoxidil proving that absorption
(highest) concentration. does occur. However, its presence in the systemic
Topical penile therapy, therefore, entails a unique set circulation does not prove its role in the erectile res-
of anatomic and physiologic considerations. There ponse (Kim et al., 1995; Clark et al., 1994). All of the
are several anatomic/fascial layers between the peni- above mentioned possibilities are expected to be
le skin and the corpus cavernosa. The tunica albugi- inefficient at transfer of active agents thus requiring
nea is presumed to be difficult to penetrate due to a large amount of drug to compensate the losses in
its thick layers of collagen. Therefore, topical treat- the pathway.
ment trials have emphasized exposure to the glans Most of the delivery systems currently in use for
penis as it has direct venous communication to the topical therapy are intended for slow and steady
corpora cavernosa (Becher et al., 1998; McVary et release of the medications such as those used in hor-
al., 1999). The skin itself is a relatively impermeable monal, analgesic or narcotic patches. This slower
tissue due to the stratum corneum. The horny cells at process is not effective as an erection initiator as the
the stratum corneum are bonded with a very tight drug flux is likely to be low. Investigators are cur-
intercellular lipid matrix bilayer that makes the pas- rently trying permeation enhancers to increase drug
sage of drugs challenging (Gurny et al., 1993). To
flux speed. In order to achieve a rapid and efficient
overcome this barrier investigators have used pene-
penetration the formulation needs to have sufficient
tration enhancers which permeate this layer and
penetration enhancer to help transfer (flux) the acti-
reach the subdermis. Fortunately, the penis and scro-
ve agent with good tolerance (no significant irrita-
tum are unique in that their stratum corneum is the
tion), and release the drug at the site of action (right
most permeable of all anatomic locations tested.
bondage).
Depending on the molecular structure of the agent
tested there can be nearly 100% absorption of topical Several transdermal enhancers incorporated as one
agents applied to these areas. Again, exposure to the of the excipients in topical formulations have been
glans affords a more easily breached layer. Other reported (Becher et al., 1998; McVary et al., 1999;
skin regions (e.g.. back and palms) are particularly Kim et al., 1995; Samour et al., 1989; Pelham et al.,
impermeable (Maibach et al., 1971). An additional 1995). The task of these enhancers is to: 1) Disrupt
factor confounding efficient delivery of drug is the the stratum corneum lipid bilayer, 2) Interact with
rich vasculature of the deep dermis which may the membrane keratin, 3) Produce a weak interaction
steal the drugs to the systemic circulation. with the drug molecule, and 4) Reverse all actions in

523
a short time. The available evidence indicates that Many of these actions are presumably mediated by
such agents enhance skin penetration by altering the protein kinase A. PGE1 may also act by inhibiting
fluidity of lipids in the stratum corneum, without any the release of noradrenaline from sympathetic nerves
interaction with the chemical whose skin permeabili- (Molderings et al, 1992) and suppressing angiotensin
ty is enhanced. II secretion in the cavernosal tissues (Kifor et al,
1997).
4.I. TOPICAL THERAPY FOR The physiologic endpoint is dilation of the caverno-
ERECTILE DYSFUNCTION sal arteries, relaxation of the corporal smooth
BACKGROUND muscle, and therefore, is accompanied by increased
arterial inflow velocity and increased venous flow
Organic nitrate donors were the first topical agents to resistance. As a result, the lacunar spaces expand and
be used in the treatment of erectile dysfunction blood becomes entrapped secondary to compression
(Mudd, 1977). Case reports have demonstrated that of venules against the tunica albuginea. To achieve
blood flow to the penis and tumescence are increased adequate tumescence and rigidity the tunica albugi-
after application of a nitro based paste (Owen et al., nea must be sufficiently stiff to compress the pene-
1989; Nunez & Anderson, 1993). The local effects trating venules and thus block venous outflow. This
on penile blood flow appear to be crucial since appli- process is also referred to as the corporal veno-
cation of such gels elsewhere on the body do not occlusive mechanism. Alprostadil does not directly
induce erections. Topical minoxidil has also been effect ejaculation or orgasm.
reported in placebo controlled double masked trials
(Clark et al., 1994; Cavallini, 1991). In one study,
Cavallini reported 2% minoxidil as superior to 10% 4.III. TOPICAL MINOXIDIL
nitroglycerin cream in inducing improved penile
hemodynamics and with fewer side effects.
Topical minoxidil has been recently used as an inves-
tigational drug in the treatment of erectile dysfunc-
4.II. TOPICAL PGE1 tion. Although little can be said about its role in that
regard, there is an extensive literature on its use as an
antihypertensive and alopecia medication. Much of
Alprostadil is a natural occurring prostaglandin E1. the information regarding this drug is drawn from the
Alprostadil and other prostaglandins in the E series literature detailing its use in the former rather than
are naturally present in the seminal vesicles, the
latter circumstance.
cavernous tissues of males and in the placenta and
ductus arteriosus of the fetus. Various formulations Minoxidil is an antihypertensive agent while topical
and injection techniques, urethral suppositories and minoxidil (Rogaine) is used for alopecia. Due to its
gels using PGE-1 have been used in the treatment of potency and adverse reactions, oral minoxidil is used
erectile dysfunction over the past 15 years. mainly for patients with the severe drug resistant
forms of hypertension. Tolerance to a prolonged the-
Alprostadil relaxes smooth muscle of the corpus
rapy with oral minoxidil does not appear to be a pro-
cavernosum. As described elsewhere in this section,
blem. Subsequent to the oral dosage (approved by
several mechanisms of action have been proposed.
the FDA in 1979 for use in hypertension) topical for-
Undeniably, its effects are due to increasing the intra-
mulations were approved for the treatment of alope-
cellular concentrations of cAMP, via a stereospecific
cia in 1988. Investigation of topical formulations in
activation of the membrane bound receptors. In par-
the treatment of erectile dysfunction are limited and
ticular, PGE1 mediates relaxation of corpus caverno-
follow on the heels of its approval for alopecia.
sum smooth muscle via activation of the EP prosta-
glandin receptor (EP2/4) to increase the intracellular Minoxidil does not have a direct vasodilatory effect
concentration of cAMP in corpus cavernosum smoo- on arterial smooth muscle. Rather, it is converted to
th muscle (Palmer et al., 1994; Lin et al, 1995; Cahn minoxidil O-sulfate by the hepatic enzyme sulfo-
et al., 1996; Traish et al., 1997; Moreland et al., transferase (McCall et al., 1983). This metabolite
2001). PGE1-induced relaxation of human corpus does have a direct vasodilatory effect on arterial
cavernosum is associated with activation of KCa smooth muscle causing a reduction in peripheral
channels, leading to hyperpolarisation and altera- resistance and blood pressure. While the precise
tions in transmembrane Ca2+ flux (Lee et al, 1999). mechanism of action of minoxidil is not certain

524
(Quast et al., 1995; Russ et al., 2003), and moreover,
may vary among distinct smooth muscle cell types 4.IV. TOPICAL PAPAVERINE
(Buchheit et al., 2000; Davies et al., 1996), it clearly
appears to be a relatively weak corporal smooth
Since the introduction by Virag in the early 1980s,
muscle cell relaxant (Christ, 1995). In that regard,
injection of papaverine into the corporal bodies for
minoxidil is not known to inhibit the CNS or have
the treatment of sexual dysfunction has become a
adrenergic neuronal blocking effects. Minoxidil
widespread and well accepted method (Virag, 1982).
retains its activity despite adrenergic denervation.
The use of papaverine as a topical therapy has a
With respect to the mechanism of action, presumably
much shorter experience and one that has not moved
at least some aspects of minoxidil-induced relaxation
beyond preliminary clinical trials.
shares common features with other members of the
K channel modulator family (i.e., pinacidil, croma- The most characteristic effect of papaverine is
kalim, etc.). In fact, in both vascular and nonvascu- relaxation of smooth muscle, especially when it has
lar (including urogenital) smooth muscle, minoxidil been spasmodically contracted. Papaverine acts, in
and other K channel activators have been shown to large part, directly on the muscle itself. There may be
activate KATP channels in a glibenclamide-sensitive several possible mechanisms by which papaverine is
fashion (Newgreen et al., 1990; Khan et al., 1997; able to directly relax corporal smooth muscle, but the
Teramoto & Ito, 1999). In all these cases, activation most prominent is by inhibition of the oxidative
of the KATP channel subtype results in an increased phosphorylation mediated inactivation of cAMP (via
K+ efflux and cellular hyperpolarization. The net phosphodiesterase-PDE) which interferes with cal-
result is a physiological antagonism of transmembra- cium mobilization during muscle contraction. In
ne calcium flux through L-type voltage-dependent fact, papaverine is a nonspecific phosphodiesterase
calcium channels, a reduction in the free intracellular inhibitor that initiates an increase in intracellular
calcium concentration, and a corresponding smooth cAMP and cGMP leading to corporal smooth muscle
muscle cell relaxation. relaxation and penile erection; via prolongation of
the half-life of these cyclic nucleotides. Papaverine
With regards to the treatment of erectile dysfunction, may also regulate cavernosal smooth muscle tone via
it is assumed that the active metabolite acts via a inhibition of voltage-dependent L-type Ca2+ chan-
direct vasodilatory effect on corporal and arterial nels independent of cAMP as demonstrated in tra-
smooth muscle causing a reduction in peripheral cheal smooth muscle and by suppression of angio-
resistance and cavernosal muscle relaxation. Presu- tensin II secretion in cavernosal tissue (Iguchi et al,
mably this promotes the veno-occlusive mechanism 1992; Kifor et al, 1997)
and results in erection. Such an effect from topical
minoxidil is interesting when one considers that it is Serum papaverine levels after topical administration
have been measured in a single study (Kim et al.,
a prodrug that requires hepatic metabolism to beco-
1995) with a high performance liquid chromatogra-
me active (McCall et al., 1983). For this to be effec-
phy assay. At 60 minutes mean serum levels increa-
tive the topically absorbed minoxidil would have to
sed 50% suggesting that absorption did occur, but
be metabolized through the liver then recirculated to
not significantly over baseline values. The papaveri-
the penis to be active. This appears to be a substan-
ne levels in this study indicated that topical absorp-
tial task. Issues regarding the site and efficacy of
tion is less than 1% of a comparable intravenous
absorption have been addressed above.
dose indicating minimal systemic uptake after topi-
Topical administration of minoxidil solutions should cal administration to the genitalia. In contrast, papa-
only be applied to the skin of interest. Absorption is verine is present in the blood at levels of 335 to 761
best when the hair and the skin are dry. If applied ng/ml within 3 minutes of IC injection of 40 mg as
with finger tips the hands should be thoroughly measured by similar techniques (Tanaka et al.,
washed after applying. Systemic effects resulting 1990). The pharmacokinetics and bioavailability of
from topically administered Minoxidil are unlikely topical papaverine on animal models have been stu-
but theoretically could occur if the drug is overused. died in which 9-12.4% of the papaverine is detected
Skin abrasion or irritation such as excoriations, pso- in the serum. Why the marked differences between
riasis, or sun burn can increase the systemic absorp- animal models and clinical trials has been blamed on
tion of topical minoxidil. gel formulation (Shaaya et al., 1992).

525
nitroglycerine-induced relaxation. As indicated
4.V. TOPICAL NITROGLYCERIN above, one major consensus point seems to be the
important role played by K channel-mediated hyper-
polarizing currents in this process. Furthermore,
The use of topical nitroglycerin is a standard treat- disease (diabetes)-related changes in the responsivi-
ment for unstable angina pectoris because predic- ty of isolated human corporal smooth muscle strips
table blood levels can be achieved. The use of nitro- to nitroglycerine-induced relaxation may indicate
glycerin ointments, pastes, plasters or patches for the that this compound may have diminished utility in
treatment of erectile dysfunction has been tried in diabetic patients. Other contraindications to the use
several studies (see earlier sections in this chapter).
of topical nitroglycerin include those who have aller-
The putative mechanism of action is described
gic reactions to organic nitrates. These are extremely
below.
rare, but they do occur. Allergies to the adhesives
Relaxation of corporal and arterial smooth muscle is used within the nitroglycerin patches have also been
the principle pharmacologic action of nitroglycerin, reported.
and presumably is dependent on activation of the
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528
II. ORAL ED
B. EVIDENCE-BASED REVIEW PHARMACOTHERAPIES
OF ED PHARMCOTHERAPIES
1. PDE5 INHIBITORS: SILDENAFIL

1. GENERAL EFFICACY
I. INTRODUCTION Ten (10) level 1 publications [1-10],
three (3) level 2 publications [11-13],
and twenty two (22) level 3 publications [14-35].
Qualifications for review by the committee
2. SPECIAL POPULATION EFFICACY
Peer-reviewed scientific publications
Diabetic ED Patients
Over 700 papers reviewed and graded
Three (3) level 1 publications [36,37, 150],
Publications: 1995-2004 (first part of 2004) one (1) level 2 publications [38],
(in press included) and two (2) level 3 publication [24, 39].
Excluded: Patients with Cardiovascular Disease (CAD,
Abstracts hypertension) and ED

Case studies Two (2) level 1 [40]


and two (2) level 2 publications [41, 42].
Review articles
Post-Prostatectomy ED Patients
Papers in journal supplements
Seven (7) level 3 publications [43-49].
SSRI- Related ED Patients
1. GRADING THE LEVEL OF EVIDENCE One (1) level 1 [50],
High (level 1) one level 2 [51]
High quality RCT with high power and three (3) level 3 publications [52-54]
Depression-related ED Patients
Intermediate (level 2)
RCT with low power and/or less than 80% follow-up Two (2) level 1 [50, 55]
and retention and one (1) level 3 publications [56]
Good quality, non-randomized, prospective compa- Spinal Injury-related ED Patients
rative study Two (2) level 1 publications from a single trial
Low (level 3) [57, 58],
two (2) level 2 publications from a single trial
Uncontrolled studies
[59, 60]
Non-randomized comparative studies with historical and three (3) level 3 publications [61-63].
control
Radiation Therapy-related ED Patients
2. CATAGORIES FOR GROUPING OF PUBLICA- One (1) level 2 [64]
TION REVIEWS and eight (8) level 3 publications [65-72].
General Efficacy Spina Bifida ED Patients
Special Population Efficacy One (1) level 2 [73]
Intracavernosal Injection Therapy Failure
General and Class Specific Safety
Patients
Cardiovascular Investigations One (1) level 3 publication [74]
Psychiatric Outpatients with ED
One (1) level 3 publication [75]

529
Detailed review of important Sildenafil clinical publications

530
Detailed review of important Sildenafil clinical publications
EFD = Erectile Function Domain Score.
GAQ: Global Assessment Question : has the treatment you have been taking over the past 4 weeks improved
your erection ?

531
Detailed review of important Sildenafil clinical publications

Table 3 : Adverse events (AE) and Comments

532
Detailed review of important Sildenafil clinical publications

533
Parkinsons Disease ED Patients 1011-8
5. Tan HM, Moh CLC, Mendoza JB, Gana T Jr, Albano GJ,
One (1) level 2 [76] de la Cruz R, Chye PLH, Sam CCW, ASSESS-1 Study
and two (2) level 3 publications [77, 78] Group. Asian sildenafil efficacy and safety study
Psychotropic Medication Related ED Patients (ASSESS-1): A double-blind, placebo-controlled
flexible-dose study of oral sildenafil in Malaysian, Sin-
One (1) level 3 publication [79] gaporean, and Filipino men with erectile dysfunction.
Renal Failure Patients on Dialysis with ED Urology 2000;56:635-640
6. Christiansen E, Guirguis WR, Cox D, Osterloh IH for the
Six (6) level 3 publications [80-85] Sildenafil Multicenter Study Group. Long-term efficacy
The Elderly ED Patients and safety of oral VIAGRA (sildenafil citrate) in men
with erectile dysfunction and the effect of randomised
One (1) level 2 [86] treatment withdrawal. Int J Impot Res 2000;12:177-182.
and one (1) level 3 publication [21] 7. Olsson AM, Speakman MJ, Dinsmore WW, Giuliano F,
Gingell C, Maytom M, Smith MD, Osterloh I. Sildena-
Chemotherapy and Testosterone Treated ED fil citrate (VIAGRA) is effective and well tolerated for
Patient treating erectile dysfunction of psychogenic or mixed
aetiology. Int J Clin Pract 2000;54(9):561-566
One (1) level 3 publication [87]
8. Meuleman E, Cuzin B, Opsomer RJ, Hartmann U, Bai-
Post-radical Proctectomy related ED Patients ley MJ, Maytom MC, Smith MD, Osterloh IH. A dose-
escalation study to assess the efficacy and safety of
One (1) level 2 publications [88] sildenafil citrate in men with erectile dysfunction. BJU
Post-renal Transplant Patients with ED Int. 2001;87(1):75-81
9. Chen KK, Hsieh JT, Huang ST, Jiaan DBP, Lin JSN,
Two (2) level 3 publications [89, 90]. Wang CJ, for the Assess 3 Study Group. ASSESS-3: a
randomised, double-blind, flexible-dose clinical trial of
3. GENERAL AND CLASS SPECIFIC SAFETY ISSUES
the efficacy and safety of oral sildenafil in the treatment
Nineteen (19) level 1 [1-9, 36, 37, 40, 50, 55, 57, of men with erectile dysfunction in Taiwan. Int J Impot
91-93, 150], Res. 2001;13 :221-229
six (6) level 2 [13, 41, 51, 94-96], 10. Giuliano F, Pena BM, Mishra A, Smith MD. Efficacy
and twenty three (23) level 3 publications [14-17, results and quality-of-life measures in men receiving sil-
denafil citrate for the treatment of erectile dysfunction.
19-27, 31-35, 97-101]. Qual Life Res. 2001;10(4):359-369
This category includes studies related to ocular
11. Boolell M, Allen M, Ballard S, Gepi-Attee S, Muirhead
safety G, Naylor A, Osterloh I, Gingell C. Sildenafil: an orally
4. Cardiovascular Investigations active type 5 cyclic GMP-specific phosphodiesterase
inhibitor for the treatment of penile erectile dysfunction.
Int J Impot Res 1996;47-52
Thirty (30) level 1 [36, 40, 41, 94, 102-127],
12. Boolell M, Gepi-Attee S, Gingell C, Allen M. Sildena-
twenty three (23) level 2 [96, 128-149]
fil: a novel effective oral therapy for male erectile dys-
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gy 2002;23(6):763-71
5. Goldstein I, Young JM, Fischer J, Bangerter K, Segerson
T, Taylor T. Vardenafil, a New Phosphodiesterase Type 5
Inhibitor, in the Treatment of Erectile Dysfunction in Men
With Diabetes: A multicenter double-blind placebo-
controlled fixed-dose study. Diabetes Care 2003;26:777-
83.
6. Brock G, Lipshultz L, Karlin G, Gleave M, Seger M,
Padma-Nathan H. Safety and Efficacy of Vardenafil for
the Treatment of Men With Erectile Dysfunction Subse-
quent to Radical Retropubic Prostatectomy. J. Urology
2003;170:1278-1283.
7. Hellstrom W, Gittelman M, Karlin G, Segerson T, Thi-
bonnier M, Taylor T, Padma-Nathan H, on behalf of the

540
Detailed review of important Vardanafil clinical publications

541
Detailed review of important Vardanafil clinical publications

542
Detailed review of important Vardanafil clinical publications

VfS - Valid for safety


ITT - Intent-to-Treat Popu-

543
lation
VfE - Valid for Efficacy
VPP - Valid per protocol

MC - Multicenter
R= Randomized
DB = Double Blind
PlA = Placebo

IIEF- EF Domain (LOCF)


Intercourse success
GAQ - Global Assessment
question
SEP-2 (LOCF) - Diary
(Sexual Encounter Profile)
Question 2 - (Last Observa-
tion Carried Forward
SEP-3 (LOCF) - Diary
(Sexual Encounter Profile)
Question 3 - (Last Observa-
tion Carried Forward
3. PDE5 INHIBITORS: TADALAFIL
a) General Efficacy

Three (3) level 1 publications [1-3]

b) Special Population Efficacy

Diabetic ED Patients
One (1) level 1 publication [4].

c) General and Class Specific Safety Issues

Four (4) level 1 publications, including a sperm


assessment study [1-5].
One (1) level 2 publication (open label) [6]

d) Cardiovascular Investigations

One (1) level 1 publication [7].

REFERENCES
TADALAFIL

1. Brock GB, McMahon CG, Chen KK, Costigan T, Shen W,


Watkins V, Anglin G, Whitaker S.Efficacy and safety of
tadalafil for the treatment of erectile dysfunction:results of
integrated analyses. J Urol. 2002 Oct;168(4 Pt 1):1332-6.
2. Porst H, Padma-Nathan H, Giuliano F, Anglin G, Varane-
se L, Rosen R Efficacy of tadalafil for the treatment of
erectile dysfunction at 24 and 36 hours after dosing: a ran-
domized controlled trial. Urology. 2003 Jul;62(1):121-5
3. Padma-Nathan H, McMurray JG, Pullman WE, Whitaker
JS, Saoud JB, Ferguson KM,Rosen RC; IC351 On-
Demand Dosing Study Group. On-demand IC351 (Cialis)
enhances erectile function in patients with erectile dys-
function. Int J Impot Res. 2001 Feb;13(1):2-9.
4. Saenz de Tejada I, Anglin G, Knight JR, Emmick JT.
Effects of tadalafil on erectile dysfunction in men with dia-
betes. Diabetes Care. 2002 Dec;25(12):2159-64.
5. Hellstrom WJ, Overstreet JW, Yu A, Saikali K, Shen W,
Beasley CM Jr, Watkins VS Tadalafil has no detrimental
effect on human spermatogenesis or reproductive hor-
mones. J. Urol. 2003 Sept; 170(3) : 887-91
6. Montorsi F., Verheyden B., Meuleman E., Jnemann K-P,
Moncada I., Valiquette L., Casab A., Pacheco C., Denne
J., Knight J., Segal S., Watkins V.S. Long-term safety
tolerability of tadalafil in the treatment of erectile dys-
function. Eur. Urol 2004, 45: 339-345
7. Kloner RA, Hutter AM, Emmick JT, Mitchell MI, Denne
J, Jackson G. Time course of the interaction between tada-
lafil and nitrates. J Am Coll Cardiol. 2003 Nov
19;42(10):1855-60.

544
Detailed review of important Tadalafil clinical publications (To be completed)

545
Detailed review of important Tadalafil clinical publications (To be completed)

IIEF = International Index of Erectile Function

546
EF = Erectile Function
> Intercourse sucess = SEP 3
SEP3 = sexual encounter profile question 3 (which is a self - report of intercourse success)
GAQ = Global Assessment Question - did this drug or treatment impove your erection ?
4. ALPHA-BLOCKERS: PHENTOLAMINE 5. ALPHA-BLOCKERS: YOHIMBINE
a) General Efficacy a) General Efficacy

Four (4) level 2 [1-4] and one (1) level 3 Four (4) level 2 (one demonstrating efficacy [1]
publication [5] and three demonstrating non-efficacy) [2-4], and
one (1) level 3 publication [5]
b) Special Population Efficacy
b) Special Population Efficacy
Absence of a specific publication in this category
Absence of a specific publication in this category
c) General and Class Specific Safety Issues
c) General and Class Specific Safety Issues
Four (4) level 2 [1-4] and
Four (4) level 2 [1-4], and
one (1) level 3 publication [5]
one (1) level 3 publication [5]
d) Cardiovascular Investigations d) Cardiovascular Investigations

Absence of a specific publication in this category Absence of a ED specific publication in this category
YOHIMBINE REFERENCES
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4 Becker AJ. Stief CG. Machtens S. Schultheiss . Hartmann
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5. Padma-Nathan H, Goldstein I, Klimberg I, Coogan C,
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266-70., 2002.

547
6. OTHER ALPHA-BLOCKER COMBINATIONS 7. DOPAMINE AGONIST: APOMORPHINE SL
Yohimbine and L-Arginine
a) General Efficacy
One (1) level 2 publication [1]
and phase 2 development status Two (2) level 1 [1,2],
L-Arginine two (2) level 2 [3,4] and
One (1) level two publication. Non-effective [2] one (1) level 3 publication [5]
Trazodone b) Special Population Efficacy
Three (3) level 2 publications [3-6]
demonstrating non-efficacy and one (1) level 2 Two (2) level 2 studies not specifically designed for
publication that was over 5 years old demonstra- the subgroups [1,2]
ting some efficacy [7].
c) General and Class Specific Safety Issues
Trazodone and Yohimbine
One (1) level 2 publication [8]. Two (2) level 1 [1,2],
two (2) level 2 [3,4]
OTHER ALPHA-BLOCKER and one (1) level 3 publication [5].
REFERENCES
d) Cardiovascular Investigations
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cacy and safety of a novel combination of L-arginine glu- Two (2) level 2 publications [1,2]
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for erectile dysfunction. Eur Urol. 41(6): 608-13;2002.
2. Klotz T. Mathers MJ. Braun M. Bloch W. Engelmann U. APOMORPHINE SL
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548
Detailed review of important Apormorphine SL publications

549
8. OTHER CENTRALLY ACTING AGENTS Naltrexone
1. Brennemann W, Stitz B, Van Ahlen H, Brensing KA and
Melanocortin Agonists/ MTII
Klingmuller D: Treatment of idiopathic erectile dysfunc-
Three (3) level 2 publications. Phase II tion in men with the opiate antagonist naltrexone - a
development [1-3] double-blind study. J Androl. 14:407-10., 1993.

Delequamine 2. van Ahlen H, Piechota HJ, Kias HJ, Brennemann W and


Klingmuller D: Opiate antagonists in erectile dysfunction:
Three (3) level 2 publications [4-6]. a possible new treatment option? Results of a pilot study
Naltrexone with naltrexone. Eur Urol. 28: 246-50, 1995.

Two (2) level 2 publications [7-8]


Nalmefene
One (1) level 3 publication [9]

CENTRALLY ACTING AGENTS


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eight (8) level 2, [5-12] and
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9. Montorsi F, Guazzoni G, Barbieri L, Ferini-Strambi L,
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1. Padma-Nathan H, Hellstrom WJ, Kaiser FE, Labasky RF, the consistency of intraurethral prostaglandin E(1)
Lue TF, Nolten WE, Norwood PC, Peterson CA, Shab- (MUSE) during at-home use. Urology. 2001
sigh R, Tam PY. Treatment of men with erectile dysfunc- Aug;58(2):262-6.
tion with transurethral alprostadil. Medicated Urethral 14. Kim SC, Ahn TY, Choi HK, Choi NG, Chung TG, Chung
System for Erection (MUSE) Study Group. N Engl J WS, Hwang TK, Hyun JS, Jung GW, Kim CI, Kim JJ,
Med. 1997 Jan 2;336(1):1-7. Kim SW, Lee CH, Lee KS, Lee WH, Min KS, Moon KH,
2. Williams G, Abbou CC, Amar ET, Desvaux P, Flam TA, Paic JS, Park KS, Park NC, Park YK, Seo JK, Seo KK,
Lycklama a Nijeholt GA, Lynch SF, Morgan RJ, Muller Shin JS, Yoon YR, Lee WC. Multicenter study of the
SC, Porst H, Pryor JP, Ryan P, Witzsch UK, Hall MM, treatment of erectile dysfunction with transurethral
Place VA, Spivack AP, Gesundheit N. Efficacy and safe- alprostadil (MUSE) in Korea. Int J Impot Res. 2000
ty of transurethral alprostadil therapy in men with erecti- Apr;12(2):97-101.
le dysfunction. MUSE Study Group. Br J Urol. 1998 15. Khan MA, Raistrick M, Mikhailidis DP, Morgan RJ.
Jun;81(6):889-94. MUSE: clinical experience. Curr Med Res Opin.
3. Shabsigh R, Padma-Nathan H, Gittleman M, McMurray 2002;18(2):64-7.
J, Kaufman J, Goldstein I. Intracavernous alprostadil alfa-
dex is more efficacious, better tolerated, and preferred
over intraurethral alprostadil plus optional actis: a compa-
rative, randomized, crossover, multicenter study. Urology.
2000 Jan;55(1):109-13.
4. Williams G, Abbou CC, Amar ET, Desvaux P, Flam TA,
Lycklama a Nijeholt GA, Lynch SF, Morgan RJ, Muller
SC, Porst H, Pryor JP, Ryan P, Witzsch UK, Hall MM,
Place VA, Spivack AP, Todd LK, Gesundheit N. The
effect of transurethral alprostadil on the quality of life of
men with erectile dysfunction, and their partners. MUSE
Study Group. Br J Urol. 1998 Dec;82(6):847-54.
5. Costabile RA, Spevak M, Fishman IJ, Govier FE, Hell-
strom WJ, Shabsigh R, Nemo KJ, Rapport JL, Tam PY,
Weldon KL, Gesundheit N. Efficacy and safety of trans-
urethral alprostadil in patients with erectile dysfunction
following radical prostatectomy. J Urol. 1998
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553
3. TOPICAL THERAPIES 8. Kim ED, el-Rashidy R, McVary KT: Papaverine topical
gel for treatment of erectile dysfunction. J Urol, 153:361-
Alprostadil combined with a proprietary Per- 365; 1995
meation Enhancer 9. Cavallini, G.: Minoxidil versus nitroglycerin: a prospecti-
There are no Level I publications. ve double-blind controlled trial in transcutaneous erection
facilitation for organic impotence. J. Urol., 146: 50, 1991.
There are two (2) Level 2 [1, 2].
In addition 2 (1) level 2 publication exists for ano- 10. Radomski SB, Herschorn S, Rangaswamy S Topical
ther combination that are in Phase II development Minoxidil in the treatment of male erectile dysfunction . J
Urol. 1994 May;151(5):1225-6
[3,4] as well as one (1) level 2 publication [5] for
topical PGE1 gel alone. 11. Chancellor MB, Rivas DA, Panzer DE, Freedman MK,
In addition there is one (2) Level 3 publication for a Staas WE Jr. Prospective comparison of topical minoxidil
different formulation of PGE [6] as well as one (1) to vacuum constriction device and intracorporeal papave-
rine injection in treatment of erectile dysfunction due to
Level 3 publication [7] using a combination of spinal cord injury. Urology. 1994 Mar;43(3):365-9
PGE1 and papaverine.
12. Owen, J.A., Saunders, F., Harris, C., Fenemore, J., Reid,
Papaverine K., Surridge, D., Condra, M. and Morales, A.: Topical
nitroglycerin: a potential treatment for impotence. J.
There is one (1) level 2 publication [8]. Urol., 141: 546, 1989.
Experimental
13. Nunez BD, Anderson DC Jr: Nitroglycerin ointment in the
Minoxidil treatment of impotence. J Urol, 150:1241-1243; 1993.
There are three (3) level 2 publications [9-11]. 14. Gramkow J, Lendorf A, Zhu J, Meyhoff HH. Transcuta-
Experimental neous nitroglycerine in the treatment of erectile dysfunc-
tion: a placebo controlled clinical trial. Int J Impot Res.
Nitroglycerine 1999 Feb;11(1):35-9.
There is one (1) level 2 [12] and two (2) level 3
publications [13, 14].
Experimental

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ED. Int J Impot Res. 2003 Feb;15(1):10-7.
2. Steidle, Padma-Nathan et al. Topical alprostadil cream for
the treatment of ED: a combined analysis of the phase II
program Urology 60:1077-1082, 2002] publications for
one formulation which have completed Phase III studies.
3. McVary KT, Polepalle S, Riggi S, Pelham RW. Topical
prostaglandin E1 SEPA gel for the treatment of erectile
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4. Goldstein, Payton and Schechter . Double blind, Placebo
controlled efficacy and safety study of 1-% alprostadil
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5. Kim ED, McVary KT: Topical Prostaglandin-E1 for the
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6. Foldvari, Oguejiofor et al. Liposomal encapusaled PGE in
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7. Chiang Kao Sheu Papaverine and PGE1 Gel applications
for impotence. Ann Acad Med Singapore 1995: 24: 767-
769.

554
Hemodynamic effects of sildenafil in men with
IV. HIGH AND INTERMEDIATE
severe coronary artery disease.
LEVEL OF EVIDENCE CARDIO Hermann HC, Chang G, Klugherz BD, et al. N
VASCULAR PUBLICATIONS IN THE Engl J. Med 2000; 342:1622-1626.
FIELD OF ED
Note: Oral sildenafil given to men with CAD at time
PHARMACO-THERAPY
of catheterization. Small in systemic and pulmo-
(graded by cardiologists on committeee) nary artery pressure. No effect on pulmonary capil-
lary wedge pressure, right atrial pressure, heart rate,
Grouped following level of Evidence, year of publi- cardiac output. No change in coronary diameter or
cation and alphabetical order of first author
flow. No adverse CV effects. Slight increase in
coronary flow reserve.
I : High Level Publications Level of Evidence : High level.

1998 - 1999 Acute type 5 phosphodiesterase inhibition with sil-
denafil enhances flow-mediated vasodilation in
Clinical safety of oral sildenafil citrate (VIA- patients with chronic heart failure.
GRA) in the treatment of erectile dysfunction. Katz, SD, Balidemaj K, Homma S, et al. J Am Coll
Morales A, Gingell C, Collins M, et al. Internatio- Cardiol 2000; 36:845-851.
nal J. of Impotence Research 1998; 10:69-74. Note: Sildenafil increased endothelium - dependent
Note: Reports safety from a series of double blind flow mediated vasodilation (assessed by making
and open label studies of large # of patients (4274). transient arterial occlusions of the brachial artery and
No difference in incidence of serious CV adverse measuring reactive flow by ultrasound) in heart fai-
events (including myocardial infarction) between lure patients.
placebo or sildenafil. Level of Evidence : High level.
Level of Evidence :High level.
Effects of sildenafil citrate (Viagra) combined with
Sildenafil for treatment of erectile dysfunction in nitrate on the heart.
men with diabetes. A randomized controlled trial. Ishikura F, Beppu S, Hamada T, et al. Circulation
Rendell MS, Rajfer J, Wicker PA, et al. JAMA 2000; 102:2516-2521.
1999; 281:421-426. Note: Animal study. Sildenafil did not affect syste-
Note: Primarily an efficacy study - but it is rando- mic blood pressure or pulmonary arterial blood pres-
mized, double blind, placebo-controlled. They do sures. Caused vasodilation in normal coronary. Did
present CV adverse events. 3% in sildenfail and 5% not induce ischemia in artery with critical stenosis.
in placebo group had cardiovascular events. With nitrates systemic BP and coronary blood flow.
Level of Evidence : High level. Level of Evidence : High level.

2000 Cyclic nucleotide phosphodiesterase type 5 activity


limits blood flow to hypoperfused myocardium
Effect of sildenafil on coronary active and reactive during exercise.
hyperemia. Traverse JH, Chen YJ, Du R, et al. Circulation
Chen Y, Du R, Traverse JH, et al. Am J Physiol 2000; 102:2997-3002.
Heart Circ Physiol 2000; 279:H2319-2325. Note: Shows in an animal model that sildenafil
Note: Study done in chronically instrumented dogs. improves coronary artery blood flow in the setting of
Sildenafil mean aortic pressure, no change in HR, a stenosis.
LV systolic pressure or LV maximal first time deriva-
Level of Evidence : High level.
tive of LV pressure (a measure of LV contractility).
Sildenafil rest and exercise myocardial blood flow.
Level of Evidence : High Level.

555
Sildenafil citrate potentiates the hypotensive effects and -6 mmHg vs. placebo). in BP with long acting
of nitric oxide donor drugs in male patients with nitrates when patients standing.
stable angina. Level of Evidence : High level.
Webb DJ, Muirhead GJ, Wulff M, et al. J Am Coll
Cardiol 2000; 36:25-31.

Note: Men with stable angina on isosorbide mono- Sildenafil modulates hemodynamics and pulmona-
nitrate or glyceryl trinitrate given sildenafil or place- ry gas exchange.
bo. Sildenafil substantially potentiated hypotensive Kleinsasser A, Loeckinger A, Hoermann C, et al.
effect of nitrates. Am J Respir Crit Care Med 2001; 163: 339-343.

Level of Evidence : High level. Notes: Anesthetized pigs received control or silde-
nafil while hemodynamics were measured. Sildena-
fil intrapulmonary shunt flow with marked
Sildenafil is a pulmonary vasodilator in awake decreases in PaO2, increased cardiac index, pulmo-
lambs with acute pulmonary hypertension. nary artery pressure at high doses. The issue of
Welmann J, Ullrich R, Hromi J, et al. Anesthesio- decreased arterial O2 and increased cardiac index
logy 2000; 92:1702-1712. differs from the other studies.
Notes: Animal study. Awake lambs in which acute Level of Evidence : High level.
pulmonary hypertension is chemically induced.
Cumulative sildenafil doses resulted in a cumulative Effect of sildenafil in patients with erectile dys-
decrease in pulmonary artery pressure, pulmonary function taking antihypertensive therapy.
vascular resistance. Only small fall in systemic arte- Kloner RA, Brown M, Prisant LM, et al. Am J
rial pressure after the highest dose. Sildenafil did not Hypertension 2001; 14:70-73.
augment effect of iNO a finding that differs from
Note: No in adverse events related to sildenafil in
other studies.
men on antihypertensive meds (even if on 3 or more)
Level of Evidence : High level vs. those not on antihypertensive meds. Overall effi-
cacy of sildenafil in this group of patients with
hypertension ~70%.
Effect of sildenafil citrate on blood pressure and
Level of Evidence : High level.
heart rate in men with erectile dysfunction taking

concomitant antihypertensive medication.
Zusman RM, Prisant LM, Brown MJ. Journal of Efficacy and safety of sildenafil citrate for the treat-
Hypertension 2000; 18:1865-1869. ment of erectile dysfunction in men with cardiovas-
cular disease.
Note: In men taking a variety of antihypertensive
Ollson AM, Persson C-A. Int J Clin Pract 2001;
medicines, sildenafil blood pressure by -3.6/-1.9
55(3):171-176.
mmHg versus -0.8/-0.1 mmHg for those on placebo.
Conclusions were that short-term effects of oral sil- Note: Important study in that many of these patients
denafil on BP and HR in men with ED were small had CV disease at baseline including hypertension,
and not clinically significant in those on antihyper- previous MI, chronic ischemic heart disease, angina.
tensives. In men not on antihypertensives, sildenafil Sildenafil was highly effective (71% had improve-
decrease in blood pressure was -2.2/-2.0 mmHg. ment) and no treatment related adverse CV events.
Level of Evidence : High level. Level of Evidence : High Level of Evidence.

2001 Effect of sildenafil citrate upon myocardial ische-


mia in patients with chronic stable angina in thera-
Cardiovascular safety of sublingual apomorphine py with beta-blockers.
in patients on stable doses of oral antihypertensive Patrizi R, Leonardo F, Pelliccia F, et al. Ital Heart
agents and nitrates. J 2001; 2(11):841-844.
Fagan TC, Buttler S, Marbury T, et al. Am J Car- Note: Sildenafil did not worsen ischemia during
diol 2001; 88:760-766. exercise test.
Note: > orthostatic decrease in BP when SL apomor- Level of Evidence : High level.
phine given with blockers and Ca++ blockers (-10

556
Sildenafil citrate (Viagra) does not exacerbate myo-
2002
cardial ischemia in canine models of coronary arte-
ry stenosis.
Cardiovascular effects of sildenafil during exercise
Przyklenk K, Kloner RA. J Am Coll Cardiol 2001;
in men with known or probable coronary artery
37:286-292.
disease.
Note: Experimental animal study. Sildenafil did not Arruda-Olson AM, Mahoney DW, Nehra A, et al.
exacerbate ischemia in a model of coronary stenosis. JAMA 2002; 287:719-725.
It did render platelets refractory to the inhibiting
Notes: Randomized, double blind, placebo control-
effects of adenosine receptor stimulation.
led study of patients with ED and known or highly
Level of Evidence : High level. suspected CAD. Symptom limited supine bicycle
echocardiogram exercise tests with sildenafil or pla-
cebo. Sildenafil had no effect on symptom, exercise
Cardiovascular events in users of sildenafil: results duration, exercise induced ischemic wall motion
from first phase of prescription event monitoring in abnormalities. Exercise BP and heart rates were
England. similar. 4 - 5 Mets reached (similar to intercourse).
Shakir SA, Wilton LV, Boshier A, et al. BMJ 2001; Level of Evidence : High level.
322:651-652.

Note: The very important PEM study of over 5000
men in United Kingdom. Compared those on silde- Sildenafil effects on exercise, neurohormonal acti-
nafil vs. general population. Showed no increase in vation, and erectile dysfunction in congestive heart
fatal MI or ischemic heart disease. As this was not a failure.
placebo controlled study might be intermediate level, Bocchi EA, Guimares G, Mocelin A, et al. Circu-
but high n value makes this an important study. lation 2002; 106:1097-1103.
Notes: Carefully performed double blind, randomi-
Level of Evidence : High level. zed, placebo controlled study showing that sildenafil
was well tolerated and effective in CHF patients
(mostly class II); improved exercise capacity, redu-
Cardiac electrophysiologic and hemodynamic
ced BP and HR with exercise, improved peak VO2
effects of sildenafil, a PDE5 inhibitor, in anestheti-
and exercise times.
zed dogs.
Sugiyama A, Satoh Y, Shiina H, et al. Journal of Level of Evidence : High level
Cardiovascular Pharmacology 2001; 38:940-946.
Note: Anesthetized closed chest dogs. IV sildenafil Effects of sildenafil on cardiac repolarization.
at various sub supratherapeutic doses did not Chiang C-E, Luk H-N, Wang T-M, Ding P Y-A.
affect monophasic action potential duration or effec- Cardiovascular Res 2002; 55:290-299.
tive refractory period. Sildenafil decreased periphe- Notes: In-vitro study of isolated guinea pig papilla-
ral resistance; some reflex tachycardia at high dose. ry muscles and canine Purkinje fibers, whole-cell
Level of Evidence : High level. patch clamp techniques in guinea pig ventricular
myocytes, in-vivo ECG recordings of guinea pigs.

Action potential duration not affected by therapeutic
Sildenafil inhibits hypoxia-induced pulmonary range of sildenafil. At high concentration sildenafil
hypertension. shortened action potential duration; QTc was not
lengthened by sildenafil, in fact it was shortened in
Zhao L, Mason NA, Morrell NW, et al. Circulation
guinea pigs.
2001; 104:424-428.
Level of Evidence : High level.
Note: Randomized, double blind study, placebo
controlled. Sildenafil attenuated hypoxia induced
pulmonary hypertension in normal volunteers as Acute and prolonged effects of sildenafil on bra-
well as mice. chial artery flow-mediated dilatation in type 2 dia-
Level of Evidence : High level. betes.
Desouza C, Parulkar A, Lumpkin D, et al. Diabetes
Care 2002; 25:1336-1339.

557
Notes: Sildenafil acutely and after two weeks of the- brachial artery dilation technique sildenafil prolon-
rapy improved brachial - artery flow mediated dila- ged the duration of hyperemia. Isosorbide dinitrate
tation and it persisted for at least 24 hours after the improved myocardial ischemia during exercise tes-
low dose. Suggests it may improve endothelial func- ting whereas sildenafils response was intermediate
tion in diabetic patient. between placebo and nitrate.
Level of Evidence : High level. Level of Evidence : High level.

Sildenafil for treatment of lung fibrosis and pulmo- Effect of sildenafil on the acute pulmonary vasodi-
nary hypertension: a randomised controlled trial. lator response to inhaled nitric oxide in adults with
Ghofrani HA, Wiedemann R, Rose F, et al. Lancet primary pulmonary hypertension.
2002; 360:895-900. Lepore JJ, Maroo A, Pereira NL. Am J Cardiol
2002; 90:677-680.
Note:16 patients with pulmonary hypertension
secondary to pulmonary fibrosis. Sildenafil reduced Notes: In nine patients with primary pulmonary
pulmonary vascular resistance. Sildenafil improved hypertension, sildenafil caused pulmonary vasodila-
arterial partial pressure of 02. tion and improved cardiac index. When given with
inhaled NO it augmented and prolonged the pulmo-
Level of Evidence : High level. nary vasodilator effects of NO and prevented
rebound vasoconstriction.
Level of Evidence : High level.
Combination therapy with oral sildenafil and inha-
led iloprost for severe pulmonary hypertension.
Ghofrani HA, Wiedemann R, Rose F, et al. Ann Oral sildenafil is an effective and specific pulmo-
Intern Med. 2002; 136:515-522. nary vasodilator in patients with pulmonary arte-
rial hypertension.
Notes: Thirty patients with pulmonary hypertension Michelakis E, Tymchak W, Lien D, et al. Circula-
in an ICU setting received inhaled NO and iloprost tion 2002; 105:2398-2403.
and were then randomized to 12.5 mg sildenafil, 50
mg of sildenafil, 12.5 mg of sildenafil plus inhaled Notes: Thirteen patients with pulmonary hyperten-
iloprost, or 50 mg sildenafil plus inhaled iloprost. sion had hemodynamic measures with inhaled NO,
Best combination was 50 mg sildenafil plus iloprost sildenafil or both. Sildenafil decreased pulmonary
for reducing pulmonary vascular resistance and vascular resistance and there was an additive effect
increasing cardiac index. Iloprost alone plus 50 mg with iNO. Sildenafil improved cardiac index whe-
sildenafil alone were equally effective but less potent reas iNO alone did not.
than the combination. Level of Evidence :High level.
Level of Evidence :High level.
Sildenafil (Viagra) induces powerful cardioprotec-
The effect of sildenafil on human vascular func- tive effect via opening of mitochondrial KATP
tion, platelet activation, and myocardial ischemia. channels in rabbits.
Halcox JPJ, Nour KRA, Zalos G, et al. J Am Coll Ockaili R, Salloum F, Hawkins J, et al. Am J Phy-
Cardiol 2002; 40:1232-1240. siol Heart Circ Physiol 2002; 283:H1263-H1269.
Notes: Study of acute effects of sildenafil in patients Notes: In a rabbit model of myocardial infarction
undergoing cardiac catheterization with normal coro- sildenafil decrease blood pressure transiently, mar-
naries as well as patients with coronary artery disea- kedly reduced myocardial infarct size when given
se. Sildenafil dilated epicardial coronaries by ~ 7%. acutely before coronary occlusion or 24 hours befo-
Response to acetycholine and cold pressor tests re coronary occlusion. Reasonable study but weve
improved with sildenafil > in the CAD patients sug- been unable to reproduce these results in our lab.
gesting that sildenafil improves endothelial function. Level of Evidence : High level.
Platelet IIb/IIIa receptor activation was inhibited by

sildenafil. In tests of endothelial dysfunction using

558
Intravenous sildenafil lowers pulmonary vascular cise time, or first awareness of angina. Vardenafil
resistance in a model of neonatal pulmonary hyper- significantly prolonged time to ischemic threshold.
tension. Vardenafil did not alter blood pressure, heart rate, or
Shekerdemian L, Ravn HB, Penny DJ. Am J Res- rate - pressure - product.
pir Crit Care Med 2002; 165:1098-1102.
Level of Evidence : High level.
Notes: Animal study. Eighteen piglets in which pul-
monary hypertension 2 to meconium aspiration is
mimicked (as a cause of pulmonary hypertension in Effects of sildenafil citrate (Viagra) on blood pressu-
neonates). IV sildenafil completely reversed the re in normotensive and hypertensive men.
increase in pulmonary vascular resistance with no Vardi Y, Klein L, Nassar S, et al. Urology 2002;
effect on systemic hemodynamics. 59:747-752.
Level of Evidence : High level. Notes: Sildenafil given to 22 hypertensive and 27
normotensive men while ambulatory blood pressure

was monitored. Overall sildenafil decreased systolic
The effect of vardenafil, a potent and highly selec- by 6 mmHg and diastolic BP by -4.5 mmHg with no
tive Phosphodiesterase-5 inhibitor for the treatment difference in response between normotensive and
of erectile dysfunction, on the cardiovascular res- hypertensive men. All men tolerated sildenafil well
ponse to exercise in patients with coronary artery without hypotensive symptoms event though 22.7%
disease. of hypertensive men and 4% of normotensive men
Thadani U, Smith W, Nash S et al. Journal of the had a decrease in systolic BP of 20 mmHg or more.
American College of Cardiology 2002;40(11): Level of Evidence : High level.
2002-2012.

Note: In this double-blind crossover, single-dose
multicentre study, 41 men with reproducible stable 2003
exertional angina due to ischaemic CAD received
vardenafil 10 mg or placebo, followed by ETT (5 to Immediate and long-term hemodynamic and clini-
10 metabolic equivalents [METS], Bruce protocol) 1 cal effects of sildenafil in patients with pulmonary
hour postdose. At peak exercise, vardenafil 10 mg arterial hypertension receiving vasodilator therapy.
did not alter blood pressure, heart rate, or rate pres- Bhatia S, Frantz RP, Severson CJ et al. May Clinic
sure product relative to placebo. Vardenafil 10 mg Proceedings 2003;78(10):1207-13.
did not impair the ability of patients with stable CAD
to exercise at levels equivalent or greater than that Note: Sildenafil has an immediate pulmonary vaso-
attained during sexual intercourse (average of 2.5 to dilator effect in 13 patients already receiving vasodi-
3.3 METS). lators for pulmonary arterial hypertension but its
long-term effects on right heart function and functio-
Level of Evidence: High level nal status are equivocal.
Level of Evidence: High level
The effect of vardenafil, a potent and highly selec-
tive phosphodiesterase-5 inhibitor for the treatment
of erectile dysfunction, on the cardiovascular res- Effects of sildenafil (viagra) on human myocardial
ponse to exercise in patients with coronary artery contractility, in vitro arrhythmias and tension of
disease. internal mammaria arteries and saphenous veins.
Thadani U, Smith W, Nash S, et al. J Am Coll Car- Cremers B, Scheler M, Maack C et al. Journal of
diol 2002; 40:2006-2012. Cardiovascular Pharmacology 2003;41(5)734-43.
Supports: Addresses Question #5. CV safety of Note: Sildenafil exerts potent vasodilatory actions
vardenafil. but has no direct influence on human myocardial
contractility or proarrhythmic effects in vitro.
Notes: Double-blind, crossover, placebo controlled
study of 41 men with stable exertional angina due to Level of Evidence: High level
CAD who had exercise treadmill testing on a Bruce
protocol (5 - 10 Mets). Vardenafil did not alter exer-

559
The effects of sildenafil on the cardiovascular res- Effects of sildenafil on myocardial infarct size,
ponse in men with spinal cord injury at or above the microvascular function, and acute ischaemic left
sixth thoracic level. ventricular dilation.
Ethans KD, Casey AR, Schryvers OI et al. The Reffelmann T, Kloner RA. Cardiovascular Resear-
Journal of Spinal Cord Medicine 2003;26:222-226. ch 2003;59(2)441-9.
Note: Large double blind placebo controlled crosso- Note: Open-chest rabbit study. Sildenafil reduced
ver trial of sildenafil 50 and 100 mg. Sildenafil cardiac pre- and afterload, and parameters of left
induces significant hypotension in people with cervi- ventricular contractility. Myocardial necrosis and
cal-level injuries-more so than in thoracic-level inju- microvascular dysfunction were neither exacerbated
ries- and can cause dizziness in both populations. It nor attenuated.
should be prescribed with caution and informed
Level of Evidence: High level
consent from the patient.
Level of Evidence: High level
Vascular effects of sildenafil in hypertensive car-
diac transplant recipients.
Sildenafil citrate does not reduce exercise tolerance
Schofield RS, Edwards DG, Schuler BT et al. Ame-
in men with erectile dysfunction and chronic stable
rican Journal of Hypertension 2003;16(10):874-7.
angina.
Fox KM, Thadani U, Ma PT et al. European Heart Note: 15 patient study. Sildenafil (50 mg) is well
Journal 2003;24(24):2206-12. tolerated in hypertensive cardiac transplant reci-
Note: Large study. Sildenafil was well tolerated and pients and improves BP, aortic augmentation index
did not adversely affect any exercise parameter in and endothelial function reducing left ventricular
men with coronary artery disease and ED. Favou- afterload and systolic stress.
rable trends in total exercise duration and times to Level of Evidence: High level
onset of angina and limiting angina were recorded
with sildenafil use. 2004
Level of Evidence: High level
Evaluation of the safety of sildenafil for male erec-

tile dysfunction: experience gained in general prac-
Timecourse of the interaction between tadalafil and tice use in England in 1999.
nitrates. Boshier A, Wilton LV, Shakir SAW. British Journal
Kloner Ra, Hutter Am, Emmick JT et al. Journal of Urology 2004;93:796-801.
of the American College of Cardiology 2003;
Note: Large study of 22,471 men identifying the
42(10):1855-60.
safety profile of sildenafil as used in the community,
Note: Large cross-over study demonstrating the hae- showing no unexpected events. The standardized
modynamic interaction between tadalafil and sublin- mortality ratio analysis of deaths from IH provided
gual nitroglycerin lasted 24 h, but was not seen at 48 no evidence to suggest a higher incidence of deaths
h and beyond. Similar to other PDE5 inhibitors, tada- in the study cohort than in the male population in
lafil should not be administered in combination with England.
organic nitrates.
Level of Evidence: High level
Level of Evidence: High level

Efficacy and safety of sildenafil citrate in men with
Clinical trials of sildenafil citrate (Viagra) demons- erectile dysfunction and stable coronary artery
trate no increase in risk of myocardial infarction disease.
and cardiovascular death compared with placebo. DeBusk RF, Pepine CJ, Glasser DB et al. Ameri-
Mittleman MA, Glasser DB, Orazem J. International can Journal of Cardiology 2004;93(2):147-53.
Journal of Clinical Practice 2003;57(7):597-600. Note: Large study, placebo-controlled. Sildenafil is
Note: Meta-analysis of over 120 trials. The use of sil- an effective and well-tolerated treatment for ED in
denafil was not associated with an increase in the risk men with CAD with no additional safety risks in this
of MI or cardiovascular death (Pfizer sponsored). patient population.
Level of Evidence: High level Level of Evidence: High level

560
Clinical efficacy of sildenafil in primary pulmona-
ry hypertension. A randomised, placebo-controlled, II : Intermediate Level Publications
double-blind cross-over study.
Sastry BKS, Narassimhan DM, Krishna Reddy N et
al. Journal of the American College of Cardiology 2000
2004;43(7):1149-53.
Note: Randomised cross-over trial of sildenafil 25 to Hypotensive interaction of sildenafil and nicorndil
100 mg tds versus placebo. Sildenafil significantly in rats through the cGMP pathway but not by
improves exercise tolerance, cardiac index and QOL KATP channel activation.
in patients with primary pulmonary hypertension. Ishizuka N, Saito K, Akima M, et al. Jpn. J. Phar-
macol 2000; 84:316-324.
Level of Evidence: High level
Notes: Combination of sildenafil plus nicorandil or

sildenafil with nitrates potentiates hypotension in
Use of sildenafil for safe improvement of erectile pentobarbital anesthetized rats.
function and quality of life in men with New York Level of Evidence : Intermediate level.
Heart Association classes II and III congestive
heart failure: a prospective, placebo-controlled,
double-blind crossover trial. Effects of sildenafil on human penile blood vessels.
Webster LJ, Michelakis ED, Davis T et al. Archives Medina P, Segarra G, Vila JM, et al. Urology 2000;
of Internal Medicine 2004;164(5):514-20. 56:539-543.
Note: Large crossover trial of 35 patients. Sildenafil Note: Uses isolated penile dorsal arteries and deep
is a safe and effective treatment for ED in men with dorsal veins from 14 multi-organ donors. Sildenafil
New York Heart Association classes II and III CHF caused contraction dependent relaxation and ampli-
and provides relief of depressive symptoms, explai- fied relaxation to sodium nitroprusside. Relaxation
ning an improvement in the perception of quality of was unaffected by inhibitor of NO synthase.
life.
Level of Evidence : Intermediate level.
Level of Evidence: High level


Relaxation induced by cGMP phosphodiesterase
inhibitors sildenafil and zaprinast in human ves-
sels.
Medina P, Segarra G, Martinez-Leon JB, et al.
Ann Thorac Surg 2000; 70:1327-1331.
Note: In vitro study of human coronary, internal
mammary, radial arteries, and forearm veins showing
that sildenafil caused concentration dependent
relaxation in theses vessels. Sildenafil amplified the
effect of sodium nitroprusside.
Level of Evidence : Intermediate level.

Sympathetic activation by sildenafil.
Phillips BG, Kato M, Pesek CA, et al. Circulation
2000; 102:3068-3073.
Note: Fourteen normal volunteers received sildena-
fil vs. placebo. Sildenafil did not change HR, BP but
did increase muscle sympathetic activity and plas-
ma norepinephrine levels and sympathetic nerve
traffic during stress.
Level of Evidence : Intermediate evidence.

561
Nebulized sildenafil is a selective pulmonary vaso-
2001
dilator in lambs with acute pulmonary hyperten-
sion.
Cardiovascular effects of sildenafil citrate
Ichinose, F, Erana-Garcia J, Hromi J, et al. Crit.
(Viagra): A naturalistic cross-over study.
Care Med. 2001 Vol. 29 5:1000-1005.
Agelink MW, Schmitz T, Rembrink K, et al. Eur J
Med Res 2001 6:459-564. Note: Pulmonary hypertension induced by infusion
of thromboxane analogue. Nebulized sildenafil
Note: Shows sildenafil resting BP (blood pressu-
pulmonary artery pressures and had an additive
re), reflex in HR (heart rate), No change in ECG,
effect with inhaled NO.
HR variability. Suggests sildenafil does not affect
cardiac autonomic nervous system function. Level of Evidence : Intermediate level.
Level of Evidence : Intermediate level.

Effect of sildenafil on blood pressure and arterial
Modulation of human platelet aggregation by the wave reflection in treated hypertensive men.
phosphodiesterase Type 5 inhibitor sildenafil. Mahmud A, Hennessy M, and Feely J. Journal of
Berkels R, Klotz T, Sticht G, et al. Journal of Car- Human Hypertension 2001; 15:707-713.
diovascular Pharmacology 2001; 37:413-421.
Note: Sildenafil given to eight men with well
Note: 100 mg oral sildenafil increased bleeding time controlled hypertension reduced brachial blood pres-
at one hour after dose but bleeding time returned to sure and reduced arterial wave reflection.
baseline at four hours. 50 mg dose had no effect. In
vitro study showed that sildenafil 50 mg or 100 mg Level of Evidence : Intermediate level.
did not inhibit ADP induced aggregation but colla-
gen induced aggregation was reduced (note: differs
from data shown in Pfizer AJC supplement). Potentiation of sildenafil-induced hypotension is
minimal with nitrates generating a radical interme-
Level of Evidence : Intermediate level. diate.
Schwemmer M, Bassenge E, Stoeter M, et al. Jour-
The effect of sildenafil on nitric oxide-mediated nal of Cardiovascular Pharmacology 2001; 38:149-
vasodilation in healthy men. 155.
Dishy V, Sofowora G, Harris PA, et al. Clin Phar- Note: Chronically instrumented canine study. Twen-
macol Ther 2001; 70-270-279. ty-four hour infusion of three types of nitrates and
Note: In healthy men sildenafil increased sensitivi- then sildenafil. During glyceryl trinitrate sildenafil
ty to nitroglycerin 4 x but did not affect endothelium BP 21 13 mmHg; during ISDN -18 mmHg; during
- dependent vasodilation in hand vein or forearm pentaerythritol tetranitrate -6 mmHg.
arterial vasculature. No data on men with endo- Level of Evidence : Intermediate level.
thelial function at baseline.
Level of Evidence : Intermediate level.
Cardiac phosphodiesterase 5 (cGMP-specific)
Cardiovascular safety of sublingual apomorphine modulates -adrenergic signaling in vivo and is
in patients on stable doses of oral antihypertensive down-regulated in heart failure.
agents and nitrates. Senzaki H, Smith CJ, Juang GJ, et al. FASEB
Fagan TC, Buttler S, Marbury T, Taylor A, 2001; 15:1718-1726.
Edmonds A; SL APO Study Group. Am J Cardiol Notes: This agent was used in conscious dog models
2001 Oct 1;88(7):760-6. including a heart failure model. They claim that
Note: examined the pharmacodynamic interactions PDE5 is expressed in myocardial cells. PDE5A
between apomorphine SL and commonly used car- regulation of cGMP is altered in heart failure and
diovascular medications in a double-blind, crossover may blunt the beta adrenergic response.
study involving 162 men (mean age, 61 years) who Level of Evidence : Intermediate level.
had been stable on therapeutic doses of ACE inhibi-

tors, beta blockers, 1 blockers, calcium channel
blockers, diuretics, or nitrates for at least four weeks.
Level of Evidence : Intermediate level.

562
Assessment of the efficacy and safety of Viagra Relaxation and cGMP formation in response to sil-
(sildenafil citrate) in men with erectile dysfunction denafil and sodium nitroprusside in saphenous
during long-term treatment. veins from normotensive and hypertensive patients.
Steers W, Guay AT, Leriche A, et al. International Medina P, Segarra G, Martinez-Leon JB, et al. Am
Journal of Impotence Research 2001; 13:261-267. J Hypertens 2002; 15:798-802.
Note: Open label study of sildenafil for efficacy (n = Notes: Study of saphenous vein rings (in vitro) from
1008); not placebo controlled. Patients followed for hypertensive and normotensive individuals. Sildena-
36 or 52 weeks. Treatment related CV adverse events fil caused venorelaxation that was greater in normo-
( BP, tachycardia, palpitations, angina) < 1%. tensives but had a synergistic effect with sodium
Level of Evidence : Intermediate level. nitroprusside greater in veins of hypertensives. Sil-
denafil cGMP levels.

Level of Evidence : Intermediate level.
Effect of inhaled iloprost plus oral sildenafil in
patients with primary pulmonary hypertension.
Potential for use of pulse wave analysis in determi-
Wilkens H, Guth A, Knig J, et al. Circulation
ning the interaction between sildenafil and glyceryl
2001; 104:1218-1222.
trinitrate.
Note: Small nonrandomized study showing that sil- ORourke MF, Nichols WW. Clin. Cardiol. 2002;
denafil reduces pulmonary artery pressure in patients 25:295-299.
with primary pulmonary hypertension and that this
Notes: Central aortic wave form measured noninva-
effect is additive with iloprost.
sively. Oral sildenafil augmented fall in aortic sys-
Level of Evidence : Intermediate level. tolic pressure in healthy volunteers. There was a fall
in augmentation index and pulse pressure.
Level of Evidence : Intermediate level.
2002
Effect of Sildenafil on rennin secretion in human Sildenafil and T-1032, phosphodiesterase type 5
subjects. inhibitors, showed a different vasorelaxant proper-
Chiu YJ, Reid IA. Exp Bio Med 2002; 227:620- ty in the isolated rat aorta.
625. Mochida H, Inoue H, Takagi M, et al. European J.
of Pharmacology 2002; 440:45-52.
Notes: Ten healthy human volunteers had unrestric-
ted sodium intake; another 10 had restricted sodium Notes: Study done in isolated rat aorta (in-vitro).
intake. Sildenafil had only minor CV effects. Plas- Sildenafil caused vasodilation by both an in cGMP
ma rennin activity was associated with a fall after levels as well as an inhibition of external calcium
placebo but no fall after sildenafil. Results regarding dependent cascade.
renin similar between two groups. Significance of Level of Evidence : Intermediate level.
this study is not clear.

Level of Evidence : Intermediate level.
Effects of sildenafil citrate (Viagra) on cardiac
repolarizaton and on autonomic control in subjects
Intracavernous injections for erectile dysfunction with chronic heart failure.
in patients with cardiovascular diseases and failure Piccirrillo G, Nocco M, Lionetti M, et al. Am Heart
or contraindications for sildenafil citrate. J 2002; 143:703-710.
Israilov S, Niv E, Livne PM, et al. International Notes: In men with heart failure sildenafil decreased
Journal of Impotence Research 2002; 14:38-43. vagal modulations plus sympathetic modulations
Notes: Success rate was 94% with injection therapy. which may have been secondary to reflex vasodilator
Follow-up BPs in office did not show changes in bra- effect. Sildenafil had no direct effect on QT interval
chial blood pressure or deterioration of CV health or or dispersion. Nevertheless, authors conclude that
change in cardiac meds. autonomic system changes could alter QT dynamic
and favor arrhythmias.
Level of Evidence :Intermediate level. Level of Evidence : Intermediate level.

563
Interactions of sildenafil with various coronary
2003
vasodilators in isolated porcine coronary artery.
Sakuma I, Akaishi Y, Tomioka H, et al. European Sildenafil citrate does not affect QT intervals and
Journal of Pharmacology 2002; 437:155.163. QT dispersion: An important observation for drug
safety.
Notes: Study of isolated porcine coronary arteries in
Alpaslan M, Onrat E, Samli M et al. A.N.E.
which interaction of sildenafil with various coronary
2003;8(1):14-17.
vasodilators was studied. Sildenafil potentiated
relaxation of arteries to drugs that were NO donors.
Note: Sildenafil does not prolong QT intervals or
Level of Evidence : Intermediate level. increase QT dispersion in 36 patients with erectile
dysfunction.

Sildenafil-nitric oxide donor combination promotes Level of Evidence: Intermediate level


ventricular tachyarrhythmias in the swine right
ventricle.
Swissa M, Ohara T, Lee M-H, et al. Am J Physiol Oral sildenafil as long-term adjunct therapy to
Heart Circ Physiol 2002; 282:H1787-1792. inhaled iloprost in severe pulmonary arterial
hypertension.
Notes: Eight isolated swine right ventricles vulne- Ghofrani HA, Rose F, Schermuly RT et al. Journal
rability to VT/VF tested by rapid pacing. No increa- of the American College of Cardiology 2003; 42
se with sildenafil alone or NO donor alone, but com- (1):158-64.
bination increased incidence of VT/VF.
Level of Evidence : Intermediate level. Note: In 14 patients with severe pulmonary arterial
hypertension deteriorating despite ongoing prosta-
noid treatment, long-term adjunct oral sildenafil
Sildenafil reverses O2 constriction of the rabbit improves exercise capacity and pulmonary haemo-
ductus arteriosus by inhibiting type 5 phosphodies- dynamics at 9-12 months.
terase and activating BKCa Channels.
Thbaud B, Michelakis E, Wu X-C, et al. Pediatric Level of Evidence: Intermediate level
Research 2002; 52:19-24.
Notes: Fetal rabbit ductus arteriosus rings studied Sildenafil for long-term treatment of nonoperable
in-vitro. Sildenafil induced dose-dependent relaxa- chronic thromboembolic pulmonary hypertension.
tion of the rings and might be an alternative or use- Ghofrani HA, Schermuly RT, Rose F et al. Ameri-
ful adjunct to prostaglandin E1. can Journal of Respiratory 2003;167(8):1139-41.
Level of Evidence : Intermediate level. Note: Chronic oral dosing at 6 months improved pul-
monary haemodynamic and exercise capacity in 12
patients. Possible important treatment option.
Sildenafil (Viagra) augments sodium nitroprussi- Level of Evidence: Intermediate level
de-induced but not nitroglycerin-induced hypoten-
sion in dogs.
Yoo KY, Kim HS, Moon J-D, et al. Anesth Analog
2002; 94:1505-1509. Haemodynamic effects of sildenafil in patients with
stable ischaemic heart disease.
Notes: Anesthetized canine preparation. Sodium Manfroi WC, Caramori PR, Zago AJ et al. Interna-
nitroprusside or nitroglycerin induced dose-depen- tional Journal of Cardiology 2003;90(2-3):153-7.
dent decreases in mean arterial blood pressure Note: A single oral dose of sildenafil had no signifi-
without affecting heart rate. Sildenafil augmented cant haemodynamic effect in 12 supine patients with
this effect with sodium nitroprusside but not nitro- stable angina. Isolated administration of sildenafil
glycerin. Results differ from other findings - perhaps does not appear to be associated to adverse cardio-
anesthesia with thiopental blunted the effect. vascular effects.
Level of Evidence : Intermediate level. Level of Evidence: Intermediate level

564
Effects of sildenafil on cardiopulmonary responses Hemodynamic response to sildenafil, nitric oxide,
during stress. and iloprost in primary pulmonary hypertension.
Stanopoulos I, Hatzichristou D, Tryfon S et al. Leuchte HH, Schwaiblmair M, Baumgartner RA et
Journal of Urology 2003;169(4):1417-21. al. Chest 2004;125(2):580-6.

Note: Haemodynamic changes were minimal but Note: Small comparative study of 10 patients. All of
more in older patients with vasculogenic ED. 41 the three substances, iNO, iloprost aerosol, and oral
patient study. sildenafil, significantly improved pulmonary haemo-
Level of Evidence: Intermediate level dynamics in patients with PPH. The most prominent
haemodynamic effects and improvement of oxyge-

nation were observed with iloprost aerosol.
Effects of sildenafil citrate (Viagra) on hemodyna-
mic parameters during exercise testing and occur- Level of Evidence: Intermediate level
rence of ventricular arrhythmias in patients with
erectile dysfunction and cardiovascular disease.
Clinical and haemodynamic effects of sildenafil in
Vardi Y, Bulus M, Reisner S et al. European Uro-
pulmonary hypertension: acute and mid-term
logy 2003;43(5)544-51.
effects. Mikhail GW, Prasad SK, Li W et al Euro-
pean Heart Journal 2004;25:431-6.
Note: Sildenafil does not alter haemodynamic res-
ponse to exercise or change incidence of ventricular
Note: Small study of 10 patients. Acute right heart
arrhythmias in men with CVD and ED and should be
and repeat study after 3 months of oral 50 mg tds.
safe for most patients with both these conditions.
Pulmonary haemodynamics improved and quality of
life by questionnaire.
Level of Evidence: Intermediate
Level of Evidence: Intermediate level

2004
Sustained efficacy and tolerability with vardenafil
Erectile dysfunction in essential arterial hyperten- over 2 years of treatment in men with erectile dys-
sion and effects of sildenafil: results of a Spanish function.
National Study. Stief C, Porst H, Saenz De Tejada I et al. Interna-
Aranda P, Ruilope LM, Calvo C et al. American tional Journal of Clinical Practice 2004;58:230-9.
Journal of Hypertension 2004;17:139-145.
Note: Large study of 566 men with no cardiovascu-
Note: An observational study of 2130 men with lar safety concerns.
essential hypertension. Sildenafil showed an excel-
lent response and safety profile. Level of Evidence: Intermediate level

Level of Evidence: Intermediate level

Acute effects of sildenafil in patients with primary
pulmonary hypertension receiving epoprostenol.
Kuhn KP, Wickersham NE, Robbins IM, Byrne
DW. Experimental Lung Research 2004; 30
(2):135-145.

Note: Small study of 8 patients showing sildenafil


has greater acute haemodynamic effects than nitric
oxide and that it can further reduce pulmonary vas-
cular resistance in patients already demonstrating a
benefit from chronic epoprostenol.

Level of Evidence: Intermediate level


565
566