Jim LambRe: " RETINAL DAMAGE AND VIAGRA " By Dr.Marmor, Stanford Univsity:
The latest research showing on potential retinal damage from long
term Viagra use.
April 1999 :
Sildenafil (Viagra) and Ophthalmology
Editorial,
by
Michael F. Marmor, MD, Professor,
Dept. of Ophthalmology ,
Stanford University.
ama-assn.org.
TA
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Editorial - April 1999
Sildenafil (Viagra) and Ophthalmology
Although the new and popular impotence drug sildenafil (Viagra; PfizerPharmaceuticals,
New York, NY) is prescribed for indications outside the field of ophthalmology, there
are several reasons why ophthalmologists need to be informed about the pharmacologic
characteristics of this agent and its potential side effects. The drug is intended primarily
for older men with vascular disease that impairs their ability to have an erection, and
many of
these individuals see ophthalmologists for ocular disorders of aging, such as macular
degeneration, or ocular vascular disease, such as diabetic retinopathy. A second point
of relevance is that the drug has a direct effect on the retina,[1] which probably accounts
for many of the visual side effects that have been reported. We must be able to reassure
patients (and our medical colleagues) about acceptable side effects while warning them
of potential toxic effects. A third concern is that because of the great demand for
sildenafil, some ophthalmologists may be asked by patients to prescribe the drug.
Finally, although the drug has been deemed safe by the Food and Drug Administration,
the long-term data on ocular safety are not as complete as they might be, especially
since this drug has a high potential for self-dosage at levels that are too high or too
frequent and many prospective patients have underlying retinal disease that could put
them at greater risk of toxic effects. A degree of caution about the ophthalmic risks
seems prudent until more clinical information has been gathered.
Sildenafil is a selective inhibitor of phosphodiesterase 5 (PDE-5) that is
active in the vascular smooth muscle of the corpora cavernosa in the penis.
Sexual stimulation causes a release of nitric oxide in the corpus cavernosum,
which activates guanylate cyclase to increase the level of cyclic guanine
monophosphate (cGMP), which relaxes the smooth muscle and allows an
inflow of blood. By blocking PDE-5, sildenafil greatly enhances the effects
of nitric oxide and enhances the patient's ability to have an erection. The
drug has relatively few systemic side effects (headache most prominently),
although there is some slight risk of systemic vasodilatory effects[2-4];
however, patients taking nitroglycerine or other agents that can increase
nitric oxide activity are at serious risk for a life-threatening drop in blood
pressure.
There is a small risk that these vascular effects might be reflected in the eye
with an increase in choroidal blood flow or choroidal congestion. A small
percentage of patients report flushing or nasal congestion, but no changes in
intraocular pressure have been observed.[2-4] There is also a definite risk of
retinal side effects because sildenafil acts directly on the phosphodiesterase
(PDE-6) in photoreceptor outer segments that modulates the transduction
cascade.[1,5] Although sildenafil was designed as a specific PDE-5
inhibitor, it is roughly 10% as effective in blocking PDE-6. That is enough to
modify the transduction process. The outer segments of rods and cones have
a high concentration of cGMP in the dark, which acts to hold open the
sodium channels in the cell membrane. When light is absorbed by rhodopsin
or cone pigment, it activates an intermediary protein called transducin, which
in turn activates PDE-6 to break down cGMP. The resultant fall in the
concentration of cGMP allows the sodium channels to close and the
photoreceptor to hyperpolarize. This negative voltage or "receptor potential"
is the initial neural event of vision. While fluctuating levels of cGMP are
physiologic (cGMP levels rise every night in the dark), there are also reasons
to be concerned about pharmacologically induced rises in cGMP
concentrations. Rats and dogs that have hereditary abnormalities in the
PDE6 gene have permanently high levels of cGMP, which cause the
photoreceptors to degenerate, and defects in the PDE6 gene cause a type
of autosomal recessive retinitis pigmentosa.
The preclinical experimental data on sildenafil have shown that the
electroretinogram in rats and dogs is relatively unaffected by sildenafil at
ordinary clinical doses but shows a loss of amplitude and a delayed response
when very high doses (up to 10 times the normal dose) are given.[1] The
manufacturer (Pfizer Pharmaceuticals) reported at an oral presentation at the
meeting of the Association for Research in Vision and Ophthalmology (May
13, 1998, Fort Lauderdale, Fla) that no retinal degeneration was observed,
even in rats or dogs given high daily doses for 1 year. These studies have not
been peer-reviewed or published, however, and no studies have been done
on animals with retinal diseases that simulate conditions such as retinitis
pigmentosa, macular degeneration, or diabetic retinopathy that will be
present in some of our patients taking the drug. Pfizer states that patients
with diabetic retinopathy have so far shown no difference in visual symptoms
from nondiabetic patients. A group of individuals who might be at particular
risk are unsuspecting heterozygote carriers of a PDE6 gene defect, for
whom the drug might have an accentuated retinal effect.
A significant percentage of men taking sildenafil have reported a bluish tinge
or haze to their vision and some increased light sensitivity.[2-4] These visual
symptoms are reported to occur in only 3% of men taking low doses of the
drug (25-50 mg) but in 11% of men taking 100 mg (the highest
recommended dose) and approximately 50% of men taking more than 100
mg.[6] Although the highest recommended dose is 100 mg, in studies in
which men have had a supply of pills at their disposal, some users have
taken the drug more frequently or at higher doses than recommended. The
visual symptoms usually peak an hour or 2 after taking the drug and
disappear 3 or 4 hours later. So far, no long-term symptoms have been
documented by Pfizer, nor has the frequency of these symptoms increased
with the duration of sildenafil usage. At the higher dose levels of sildenafil
(100-200 mg), mild abnormalities in color vision have been documented
with Farnsworth-Munsell 100-hue testing, but again, no long-term or
persistent abnormalities were found.[7-9] Visual acuity and contrast
sensitivity were not affected. On the other hand, Pfizer conducted only one
inconclusive, short-term electroretinogram study on sildenafil usage in
humans[9] and did not do any long-term electroretinogram studies to rule
out retinal damage. While visual symptoms and psychophysical tests can be
subtle indicators of some types of retinotoxic effects, they do not always
correlate precisely with the degree of physical damage.
For example, some
patients with retinitis pigmentosa lose 80% to 90% of their retinal function
before complaining of visual symptoms. With this new drug it would seem
circumspect to have objective as well as subjective data about long-term
retinal effects.
Since there is no clear or present evidence of retinal toxic effects, it does not
seem necessary to advise against the use of sildenafil by ophthalmologic
patients, including those with retinal disease; however, ophthalmologists
should make sure that their patients are fully informed about the potential
risks. Patients and general physicians need to understand that this drug
cross-reacts with a critical enzyme in the retina, and that the symptoms of
blue vision and light sensitivity represent a direct effect on the eye. Patients
with retinal degenerations, such as retinitis pigmentosa, should be especially
cautious about this agent (a warning to this effect is contained in the package
insert). The drug is new, and while preclinical safety studies were
encouraging, there are always risks of unexpected side effects with new
drugs, as society has learned from agents like thalidomide and fen/phen
(fenfluramine and phentermine). Ophthalmologists need to be aware of the
likelihood of visual symptoms (such as blue vision and light sensitivity) in
sildenafil users and should urge patients to take the lowest recommended
doses and avoid use of this drug at levels beyond the manufacturer's
recommendations. They should also be alert to any unexpected or persistent
visual symptoms and to any vascular events in the eye that seem to
accompany sildenafil usage, so that, over time, a more secure base of
knowledge about the safety and risks of this new drug will be developed.
Michael F. Marmor, MD
Stanford, Calif
Accepted for publication December 1, 1998.
Corresponding author: Michael F. Marmor, MD, Department of
Ophthalmology, Room A-157, Stanford University Medical Center,
Stanford, CA 94305-5308 (e-mail: marmor@stanford.edu).
References
1. Center for Drug Evaluation and Research. Viagra Tablets (Sildenafil
Citrate): Review and Evaluation of Pharmacology and Toxicology
Data for NDA-20-895. Washington, DC: Division of Cardio-renal Drug
Products, Center for Drug Evaluation and Research, Food and Drug
Administration; 1998:19-21.
2. Center for Drug Evaluation and Research. Viagra (Sildenafil): Joint
Clinical Review for NDA-20-895. Washington, DC: Center for Drug
Evaluation and Research, Food and Drug Administration; 1998.
3. Viagra [package insert]. New York, NY: Pfizer Pharmaceuticals; 1998.
4. Goldstein I, Lue TF, Padma-Nathan H, et al, for the Sildenafil Study
Group. Oral sildenafil in the treatment of erectile dysfunction. N Engl J Med.
1998;338:1397-1404.
5. Center for Drug Evaluation and Research. Animal pharmacology:
mechanism of action: section 4.2. In: Viagra (Sildenafil); Joint Clincal
Review for NDA-20-895. Washington, DC: Center for Drug Evaluation and
Research, Food and Drug Administration; 1998.
6. Center for Drug Evaluation and Research. Phase I investigator-blind,
placebo-controlled, evaluation of safety, toleration, and pharmocaokinetics
of sildenafil following escalating single oral doses in healthy male volunteers:
study 148-004. In: Viagra (Sildenafil): Joint Clinical Review for
NDA-20-895. Washington, DC: Center for Drug Evaluation and Research,
Food and Drug Administration; 1998.
7. Center for Drug Evaluation and Research. A double-blind, randomized,
placebo-controlled, four-period crossover study to assess the effect of orally
administered sildenafil (50, 100, and 200 mg) on visual function in healthy
male volunteers: study 148-223. In: Viagra (Sildenafil): Joint Clinical
Review for NDA-20-895. Washington, DC: Center for Drug Evaluation and
Reseach, Food and Drug Administration; 1998.
8. Center for Drug Evaluation and Research. A randomized, double-blind,
placebo-controlled, crossover pilot study to investigate the effects of a single
oral tablet dose of sildenafil (200 mg) on visual function (electroretinogram,
photostress, visual field and color discrimination tests) in healthy male
volunteers and patients with diabetic retinopathy: study 148-232. In: Viagra
(Sildenafil): Joint Clinical Review for NDA-20-895. Washington, DC:
Center for Drug Evaluation and Research, Food and Drug Administration;
1998.
9. Center for Drug Evaluation and Research. Amendment to Clinical Review
of 22 January 1998: Effects of Sildenafil on the Electroretinogram in Study
148-232. Memorandum issued on May 8, 1998, by Norman Stockbridge,
MD, PhD, Division of Cardio-renal Drug Products, Center for Drug
Evaluation and Research, Rockville, Md. Available at:
fda.gov.
(Arch Ophthalmol. 1999;117:518-519])
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