| Viagra:
Performance, Side Effects and Safe Alternatives
by Jim English and Ward Dean, MD, Nov.
1998
On March 27, 1998, the FDA approved the drug Viagra
(sildenafil citrate) as a treatment for male impotence. Aside from
the recent gyrations in the stock market, little else has generated
as much excitement as the response to the availability of this new
drug designed to deal with the common but embarrassing male problem
of erectile dysfunction.
Viagra was originally investigated as a potential anti-angina medication,
based on its ability to release nitric oxide and increase blood
flow to the heart. Although Viagra failed as a heart medication,
researchers in London became excited when many of the men in the
clinical trials reported the frequent occurrence of unaccustomed
erections and improved sexual performance. Following this serendipitous
finding (and five years of clinical trials), Viagra was finally
granted approval as a treatment for men suffering from difficulty
in achieving erections due to conditions such as diabetes, vascular
disease, spinal cord injury, and radical prostatectomy.
Viagra is a drug that lives up to all the hype,
lifting the hopes and self-esteem of up to 80 percent of men suffering
from non-organic impotence. Others with mild to moderate organic
impotence also respond to Viagra. Additionally, Viagra also seems
to enhance sexual performance and enjoyment and reduce the “latent
period” between erection even in men who have no dysfunction.
In the two months following its release, over
one million prescriptions were issued, making it one of the most
successful drugs ever introduced. As expected, the success of Viagra
also raised Pfizer’s profits and drove stock prices through
the roof.
Viagra is also quickly gaining a reputation with women. This makes
sense when one considers that the clitoris, structurally similar
to the penis, becomes engorged with blood during sexual arousal.
Viagra may provide similar benefits, enhancing the sexual sensation
and orgasmic enjoyment of women. In response to this growing demand
(and very lucrative market) Pfizer is now conducting clinical trials
of Viagra as a pill for sexual enhancement in women.
Vascular smooth muscle (VSM) cells surround arteries and arterioles,
contracting and relaxing the arteries to regulate blood pressure.
The given state of smooth muscle cells, and their effect on blood
pressure, understandably have a profound effect on the male sexual
organ. Let’s examine how this process works.
Normally, in the presence of sexual stimulation,
blood flow is directed into “pockets” known as the corpus
cavernosum, contained within the shaft of the penis. The resulting
inflow of blood leads to the enlargement and stiffening of the penis.
This engorgement is triggered by nitric oxide
(NO), a short-lived neurotransmitter. Nitric oxide, synthesized
from the oxidation of the amino acid arginine, activates an enzyme
that manufactures cyclic guanosine monophosphate (cGMP), a biochemical
signaling enzyme. Under normal circumstances, cGMP, directs the
smooth muscle cells to relax, leading to the dilation of penile
arteries.
However, immediately following release of NO and
production of cGMP; another enzyme, cGMP phosphodiesterase type
5 (PDE-5), is activated.
PDE-5’s main activity is to destroy cGMP
almost as fast as it is formed. The result of this breakdown of
cGMP by PDE-5 is a rapid decrease in smooth muscle relaxation and
a loss of blood flow to the penis. Subsequently, the penis returns
to its flaccid state.
Unfortunately, as we age, cellular concentrations of cGMP decrease.
Viagra works to achieve and maintain erections by (1) enhancing
the effects of nitric oxide, and (2) maintaining higher levels of
cGMP, the two key players in penile erection. The way Viagra does
this is to selectively inhibit the cGMP-destroying actions of PDE-5.
By blocking the actions of this enzyme system, cGMP is no longer
broken down. This leads to elevated cGMP levels in the corpus cavernosum.
This in turn prevents relaxation of the smooth muscle in the corpus
cavernosum, increases blood flow to the genitals, and leads to stronger
erections and intensified sensation.
The most common side effects of Viagra include headaches, facial
flushing, and indigestion. The FDA also noted that three percent
of men taking the little blue pill reported temporary changes in
their vision, including light sensitivity and a bluish tinge in
their vision.
In early May, the American Academy of Ophthalmology, meeting in
San Francisco, urged that the problem be taken more seriously. “FDA
clinical trials show that taking the medication, especially at higher
doses, can cause some retinal dysfunction, and affect the way we
see for a number of hours,” association spokesman Dr. Michael
F. Marmor said in a statement.
Marmor, a professor of ophthalmology at Stanford
University, said a clinical study showed that electrical measures
of retinal function dropped by 30 to 50 percent and lasted for at
least five hours after taking a large dose of Viagra.
He suggested that people with retinal eye conditions
such as macular degeneration or retinitis pigmentosa use the drug
with caution, staying with the lowest dose possible. The recommended
dose level for most patients is 50 milligrams, according to the
FDA.
In addition to eye problems, both the FDA and Pfizer have warned
against taking Viagra with any nitrate-based cardiac medications
(i.e., sublingual nitroglycerin tablets, nitroglycerin patches,
etc.). Pfizer warned that heart patients should not be treated with
nitroglycerin if the patient has used Viagra in the previous 24
hours. Pfizer says there have been cases where patients who received
both drugs have died after developing irreversible hypotension (a
severe drop in blood pressure).
This is due to the drug’s action of enhancing
the smooth muscle relaxing effects of nitric oxide. Thus, a combination
of Viagra and a vasodilating drug like nitroglycerin might result
in a significant and potentially dangerous drop in blood pressure.
Perhaps the biggest drawback to using Viagra (aside from side effects)
is the high cost, which can range upwards of $10 per pill (or more)!
As noted earlier, Viagra works to increase both the levels and activity
of nitric oxide, leading to increased cGMP, increased blood flow
to the genitals, and more intense sensations. Fortunately, there
is a less expensive way to naturally increase the amount of nitric
oxide released during sexual stimulation. The key is supplemental
L-arginine, the direct precursor of nitric oxide.
In the 1990’s, scientists discovered that L-arginine, a non-essential
amino acid commonly found in the diet, is an oxidative precursor
of nitric oxide (NO). As mentioned previously, nitric oxide is required
for achieving and maintaining penile erection. Under conditions
in which nitric oxide is produced for a specific physiologic purpose,
the concentration of L-arginine (from which it is formed) can be
a limiting factor.
Researchers at New York University School of Medicine
gave L-arginine to a group of impotent men, and found that six out
of 15 men receiving the amino acid claimed an improved ability to
achieve erections, while none of the 15 men in the placebo group
reported any benefit.
Sexual arousal occurs not just in the genitals but in the whole
body and, especially, in the brain. For men, it actually begins
when the brain sends impulses down the spinal cord and out to the
nerves that serve the penis. These impulses trigger the production
of nitric oxide (NO), which causes penile arteries to dilate and
the spongy core of the penis to relax and become engorged with blood.
The neurotransmitter that carries the sexual message is acetylcholine
(ACh). ACh also seems to control sexual behavior through its activity
in the brain. For women, ACh is also a very important part of sexual
function.
Numerous studies confirm a key role for cholinergic
nerve transmission in sexual responses. Simply speaking, with too
little ACh, sexual activity goes down. Increase ACh levels, and
sexual activity goes up. ACh is involved in the build-up toward
orgasm and the urethral and vaginal contractions that occur during
orgasm as well as the subjective perception of orgasm intensity
and duration.
In addition to its direct role in the sexual response,
ACh is also the primary chemical the body uses to transmit signals
from nerves to skeletal muscles, the muscles that move the body.
You need this chemical for muscular control and proper muscle tone.
There is reason to believe that enhancing cholinergic neuromuscular
transmission will enhance your energy and stamina by raising your
ACh levels and that this can provide indirect sexual benefits by
allowing you to perform longer and with more energy.
While drugs can enhance the body’s cholinergic
activity, these drugs not only have unpleasant or even dangerous
side effects, but are available only by prescription. One way to
safely and effectively enhance ACh levels is to take supplements
of choline, along with vitamin B-5, so that the body will manufacture
more ACh.
Vitamin B-5, also known as pantothenic acid or
calcium pantothenate, actually seems to enhance endurance by two
routes. The first is its already-mentioned role in creating ACh
from choline. Second, is its role in the energy-producing Krebs
Cycle, which is vital for all living cells. An early indication
that vitamin B-5 might increase physical endurance came from a study
in which rats were placed into a tank filled with cool (64°F)
water and forced to swim until they became exhausted. Prior to their
swim, the rats’ diets had included either high, adequate,
or deficient levels of vitamin B-5. The high dose rats lasted more
than four times as long as those whose diet had been B-5 deficient.
In another experiment, pieces of frog muscle were stimulated electrically
to make them twitch. The stimulation continued until the muscle
became exhausted. Muscle tissue that was bathed in vitamin B-5 had
double the work output as the control muscle. [Ralli, 1953].
As these results suggest, the primary sexual effect of treatment
with choline and vitamin B-5 or B-5 alone is reported to be increased
endurance. “I can generally have sex for about twice as long
as I can without it,” said a man in his 30s, who takes vitamin
B-5 by itself.
One woman, who uses choline plus vitamin B-5,
says they help her feel more relaxed during sex. “There’s
no muscle tightness,” she said. “It makes your body
feel smoother, especially if you tend to tense up while having an
orgasm.”
Experienced users recommend taking choline plus vitamin B-5 or B-5
by itself about 20 to 30 minutes before sex in order to get the
full effect right from the start. But, notes one user, “Don’t
worry if you start too soon, it’ll kick in as you’re
going.” He adds that, “Not everybody will notice it,
but if you set a clock, you’ll notice that you have the energy
to go longer. Pretty much everyone I’ve told about B-5 has
had that effect.”
Combinations that many people have found effective
include three times as much choline as B-5 (for example, 500 to
1,000 mg of B-5 in combination with 1,500 to 3,000 mg of choline).
It is probably wise to begin with lower doses in this same ratio,
and gradually increase the dose as tolerated.
Corynanthe yohimbe is the botanical name for a tree that grows in
West Africa. For centuries — perhaps millennia — the
folk medicine practiced by tribes in this region and the nearby
West Indies islands has included a tea distilled from the inner
bark of this tree. The brew is used to amplify male virility and
sexual prowess. It is the traditional fuel for intense tribal sex
ceremonies reported to last as long as half a month — rituals
which might never have been possible but for the power of this concoction.
Yohimbine’s primary path of action duplicates
a key biochemical role in male erection. Yohimbine acts upon a specific
network of nerve cells called the alpha-2 adrenergic system (a subsystem
of the adrenergic system, so named because its functions are closely
tied to the hormone adrenaline).
Yohimbine shuts down the alpha-2 adrenergic system
by blocking receptor sites for the neurotransmitters that stimulate
its activity. This is like putting tape over a light switch to prevent
the lights from being turned off.
A natural alpha-2 adrenergic blockade performed
by the body’s own chemicals is part of the normal physiology
of erection. Inhibition of the alpha-2 adrenergic system increases
the flow of blood through arteries into the penis, while at the
same time decreasing the flow of blood from the penis through veins.
It also results in higher levels of acetylcholine, the neurotransmitter
closely associated with male erection.
In addition to promoting erection, yohimbine’s
blockade of alpha-2 adrenergic receptors is the central means by
which this compound stimulates sex drive.
Yohimbine also increases blood levels of the neurotransmitter
norepinephrine by 66%. Norepinephrine stimulates the brain’s
sex center in the hypothalamus and is considered one of the body’s
natural prosexual chemicals.
Several controlled trials have been conducted to test the efficacy
of yohimbine in treating impotence. The proportion of men showing
a positive response to yohimbine therapy has consistently been in
the range of thirty-three to forty-six percent.
This level of success has qualified yohimbine
as an impotence treatment of only “modest effectiveness”
[Morales, 1987]. However, it is important to remember that impotence
occurs for a variety of reasons; it would be unrealistic to expect
one substance to be universally effective. Given the low incidence
of adverse reactions and the drawbacks of some other options (for
instance, surgical implants and drugs that must be injected into
the penis), yohimbine has been recommended as the “first line
of treatment” for this problem.
Several lines of evidence link activity of the neurotransmitter
dopamine in the brain with sexual behavior. Generally, it appears
that higher levels of dopamine are associated with more sexual interest
and vice versa. Increased brain dopamine activity caused by taking
the drug L-dopa is believed to be the cause of a “hypersexuality”
syndrome in people who take the drug for Parkinson’s disease.
L-dopa is a chemical precursor of dopamine (which
in turn is a precursor of norepinephrine). In other words, the body
uses L-dopa to make dopamine. L-dopa is available only by prescription,
but you can also increase your brain dopamine levels by taking the
nonprescription amino acids that the body uses to make L-dopa: tyrosine
and phenylalanine.
People who have lost interest in sex because they
are depressed may benefit from taking doses of 100 to 500 milligrams
of L-phenylalanine or L-tyrosine for two weeks. Supplements of vitamin
B-6, vitamin C, folic acid and copper in addition to the tyrosine
or phenylalanine, should help maximize the conversion of L-dopa
to dopamine. |
