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Impotence Drugs and Obstructive Sleep Apnea
By Regina Patrick, RPSGT
Three drugs commonly used to treat impotence
are sildenafil (trade name, Viagra), vardenafil
(Levitra), and tadalafil (Cialis). These drugs inhibit
the actions of the enzyme phosphodiesterase-5
(PDE-5), resulting in vasodilation and increased
bloodflow in penile tissues and therefore
an erection. Men with impotence often have
obstructive sleep apnea (OSA), a disorder in which
a person stops breathing intermittently during
sleep due to obstruction of the upper airway.
OSA may contribute to erectile dysfunction, but
scientists are not sure how. As PDE-5 inhibitor
drug use increases, some scientists are beginning
to find that the medications that successfully
treat impotence may also worsen OSA.
This shifted scientific focus on using UK-92,480
to treat impotence. In 1996 Pfizer patented
sildenafil, and on March 27, 1998, sildenafil
became the first PDE-5 inhibitor drug approved
by the U.S. Food and Drug Administration (FDA)
for the treatment of impotence.5
PDE-5 & OSA
Inhibiting PDE-5 – while great for counteracting
a major cause of impotence (e.g., insufficient
blood flow in penile tissues) – has unintended
consequences in other tissues where it is found.
REGINA PATRICK,
For example, blocking PDE-5 in the respiratory
RPSGT
tract reduces the tone of respiratory muscles
and impairs immunological processes in the airways. These
factors can contribute to a worsening of OSA.
In OSA the upper airway collapses inwardly intermittently
Background
during sleep. Scientists are not fully sure why OSA occurs.
The nucleotide molecule cyclic guanosine
One thought is that the upper airway muscle tone in some
monophosphate (cGMP) relaxes smooth muscle tissues.
people with OSA is lower than normal.6 During sleep, upper
The enzyme PDE-5 degrades cGMP into guanosine
monophosphate (GMP). Once cGMP is degraded into GMP,
airway muscle tone further decreases. As a result, structures
the relaxing effect no longer occurs.
such as tonsils and adenoids that are supported by the
Currently, scientists know of 11 classes of PDE enzymes
muscles are easily drawn inward during inspirations to the
that are labelled PDE-1 through PDE-11. PDE-5 is found in
point that the structures can completely collapse into the
blood platelets (thereby playing a role in immunity), the
upper airway and block airflow. This then results in apnea
lungs, and vascular smooth muscle. Its role in vascular
(cessation of breathing).
smooth muscle tone has been of particular interest in
Some scientists suspect that an increase in cGMP due to
research studies.
PDE-5 inhibition may exacerbate relaxation of upper airway
muscles.6 For a person with OSA, this may mean an even
greater collapsibility of the upper airway and therefore
PDE Inhibitor Drugs
increased episodes of apnea during sleep.
In the 1980s, scientists were working to develop PDE
inhibitor drugs with the hope that such substances would
prevent the degradation of cGMP, thereby allowing it to exert
PDE-5 & Nitric Oxide
its vasodilating effect for a longer period of time. This would
Adding credence to this suspicion, a 1996 in vitro study
allow the prospective drug to be used to treat high blood
led by Ingolf Gath found that inhibiting PDE-5 resulted in
pressure and angina (thoracic pain resulting from insufficient
relaxation of diaphragm tissue samples from guinea pigs.7
blood flow to the heart). Initially, scientists focused on a
The Gath study focused on the molecule nitric oxide (NO),
molecule M&B 22,948 – now called zaprinast – which since
which plays a role in the synthesis of cGMP. The process
the 1970s had been investigated for its ability to reduce
begins with nitric oxide synthase II (NOS II), an enzyme
allergic reactions.1 By the 1980s, zaprinast had demonstrated
that synthesizes NO. Once NO is formed, it interacts with
another enzyme, guanylate cyclase, to synthesize cGMP.
an ability to lower blood pressure in anesthetized dogs2 and
Gath found that when the diaphragm tissue was bathed
dilate blood vessels in in vitro studies.3,4 It also was found
in the NOS II inhibitor L-NNA (NGnitro L-arginine) and then
to inhibit several classes of PDE enzymes, giving it a weak
electrically stimulated to induce contractions, the strength
vasodilating effect.2 Nevertheless, scientists worked to alter
of contraction was stronger than when the tissue was bathed
zaprinast’s chemical structure (which is very similar to cGMP)
in SNAP (S-nitroso-N-acetyl-D,L-penicillamine), a substance
in order to create a compound that would be more selective
that releases an NO molecule in chemical reactions.
for the PDE-5 class of enzymes and therefore have a stronger
Inhibiting the actions of NOS II reduces the amount of NO,
vasodilating effect.
which in effect lowers the production of cGMP. With less
In 1994 scientists at Pfizer laboratories in England had
cGMP available, the muscle sample could be contracted more
success with a compound named UK-92,480 (now known
easily. Increasing the amount of NO resulted in increased
as sildenafil). Despite its greater selectivity for PDE-5 and a
cGMP production. With increased amounts of cGMP, the
stronger vasodilator effect than zaprinast, clinical studies
muscle sample relaxed and was more difficult to contract.
proved it was ineffective as a treatment for high blood
Modulating NO synthesis indirectly demonstrated that cGMP
pressure or angina. However, during clinical studies subjects
can impact respiratory muscle tone.
had frequently reported improved erections as a side effect.
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• volume 17 • number 2
PSG Results
With this in mind, a 2006 Brazilian study headed by
Suely Roizenblatt investigated the effect of the drug
sildenafil on sleep and respiration in men with severe
OSA.6 This study was the first to demonstrate that
sildenafil can aggravate breathing problems in patients
who have severe OSA.
The study involved 14 subjects who did not have
hypertension, respiratory disease, cardiac disease, or
pulmonary hypertension (i.e., high pressure within the
pulmonary arteries). They were studied for three nights
with the first night being the baseline polysomnography
(PSG) night. On the second PSG night, the subjects selected
one of two envelopes – one containing a sildenafil pill or
the other containing a placebo pill. (The subject was blind
as to which envelope contained the actual drug.) On the
third PSG night one week later, the subject took the pill
contained in the second envelope.
The researchers found that on the night the subject took
the actual drug there was: 1) a significant increase in the
desaturation index (18 desaturation events/hour on both
baseline and placebo night vs. 30 events/hour on sildenafil
night); 2) a significant increase in the average duration
of a desaturation event from 8 seconds on baseline and
placebo night to 10 seconds on sildenafil night; and 3)
an increase in the apnea-hypopnea index (AHI) from 32
respiratory events/hour on both baseline and placebo
night to 48 events/hour on the sildenafil night. Roizenblatt
and colleagues concluded that the PDE-5 inhibitor drug
sildenafil could worsen OSA, and they suggest that the
drug may do this by prolonging the effects of NO in airway
tissues. However, they are unwilling to say that all PDE-5
inhibitor drugs worsen OSA.
Nasal congestion is a common side effect of PDE-5
inhibitor use that may contribute to a worsening of OSA.
Various researchers have found that when cGMP levels
rise due to PDE-5 inhibition, the excess cGMP triggers
NO levels to rise.6,8,9 The excessive NO level causes an
overproduction of eosinophils and mast cells in the airway.
Inflammation, swelling, and congestion result. These three
factors in the nasal passages can restrict airflow, which
in turn may contribute to the collapsibility of the upper
airway and worsen OSA.
Conclusions
Although the Roizenblatt study indicates that PDE-5
inhibitors worsen OSA, significantly more research is
needed to more clearly understand how PDE-5 inhibitor
drugs impact sleep-disordered breathing. The results of
the Roizenblatt study present these possible areas of
investigation for future research: 1) determining whether
there is a link between the severity of OSA and the risk
of upper airway collapse with PDE-5 inhibitor use; 2)
determining whether PDE-5 inhibitors impact gas exchange
in the lungs; 3) determining whether PDE-5 inhibitor use
can blunt one’s response to airway obstruction; and 4)
determining to what extent PDE-5 inhibitor drugs other
than sildenafil can worsen sleep-disordered breathing.
It has been estimated that 80% of men with OSA have
erectile difficulties.10 PDE-5 inhibitor drug therapy for
erectile difficulties may potentially set the stage for
continued erectile problems by worsening OSA. For this
reason, sildenafil and possibly other PDE-5 inhibitor drugs
may need to be used with caution in men with OSA.
References
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Burka JF, Eyre P. Modulation of the formation and
release of bovine SRS-A in vitro by several antianaphylactic drugs. Int Arch Allergy Appl Immunol
1975;49(6):774–781.
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Kling J. Viagra was discovered using a rational drug
design approach. Mod Drug Discov 1998;1(2):31-38.
Available at: http://pubs.acs.org/hotartcl/mdd/98/
novdec/disc.html. Accessed March 10, 2008.
3.
Shibata T, Ogawa K, Ito T et al. Role of cyclic
GMP of canine vascular smooth muscle in
relaxation by organic nitrates. Jpn Circ Journ
1986;50(11):1091–1099.
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Nakagawa H, Okumura K, Hashimoto H et al. Effects
of atrial natriuretic polypeptide and organic nitrates
on levels of relaxation and cyclic nucleotide of canine
coronary artery with and without endothelial injury.
Heart Vessels 1988;4(1):19–25.
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U.S. Department of Health and Human Services.
Food and Drug Administration. FDA Talk Paper.
FDA approves impotence pill, Viagra. March 27,
1998. Available at: http://www.fda.gov/bbs/topics/
ANSWERS/ANS00857.html. Accessed March 18, 2008.
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Roizenblatt S, Guilleminault C, Poyares D et al. A
double-blind, placebo-controlled, crossover study of
sildenafil in obstructive sleep apnea. Arch Intern Med
2006;166:1763–1767.
7.
Gath I, Closs EI, Godtelarmbrust U et al. Inducible
NO synthase II and neuronal NO synthase I are
constitutively expressed in different structures
of guinea pig skeletal muscle: implications for
contractile function. FASEB J 1996;10:1614–1620.
8.
Toward TJ, Smith N, Broadley KJ. Effect of
phosphodiesterase-5 inhibitor, sildenafil (Viagra), in
animal models of airways disease. Am J Respir Crit
Care Med 2004;169:227–234.
9.
Kiroglu AF, Bayrakli H, Yuca K. Nasal obstruction as a
common side-effect of sildenafil citrate. Tohoku J Exp
Med 2006;208(3):251–254.
10.
Teloken PE, Smith EB, Lowdosky C et al. Defining
association between sleep apnea syndrome and
erectile dysfunction. Urology 2006;67(5):1033–1037.
Regina Patrick, RPSGT, has been in the sleep field for 22
years, and she currently works as a sleep technologist at St.
Vincent Mercy Sleep Disorders Center in Toledo, Ohio.
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• volume 17 • number 2
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