Case two-continued>>>

Our patient decided to consult his family physician, who told him that his
problem(Erectile Dysfunction) may be related to his current medication
(Tenormin).

The family physician prescribed him Norvasc,and scheduled follow-up
visits.

Unfortunately,our patient's condition didn't improve.


The family physician prescribed Viagra,50mg, to be used 1 hour prior to
sexual intercourse.

The patient read the included pamphlet, and in the "side effects" section he
found that the drug may lead to hypotension and hearing loss.

The patient called his doctor immediately,he wondered if there is a possible
additive hypotensive effect of the two medications....

Questions:

Can you answer the patient's question?

Hint:
Norvasc is popular trade name for Amlodipine
Sildenafil is the active ingredient in Viagra.

Viagra

It is an extremely popular drug! It is known by lay people as "the blue pill"
and "Vitamin V" (الحبة الزرقاء)

It was developed and is being marketed by the pharmaceutical company Pfizer.

It is available in the Egyptian market as tablets 100,50 and 25 mg







Pfizer:

Pfizer is a major pharmaceutical company, which ranks number one in the world
in sales.The company is based in New York City.

Logo of the company:



Mechanism of action:

A. Physiology of Erection
Penile erection is accomplished by engorgement of cavernous spaces within the
corpora cavernosa under near-arterial pressures and involves:

1-dilation of arterial inflow
2-relaxation of corpora cavernosa smooth muscle
3-constriction of venous outflow.

The 1st and 2nd event occur as the following:

The relaxation of the penile arterial smooth muscle, the corporal smooth muscle,
and therefore erection is under the control ofthe autonomic nervous system.

The principal neural mediator of penile smooth muscle relaxation is nitric oxide (NO).

Note:
Three isoforms of NO synthase (NOS) that convert L-arginine to NO have been
identified: neuronal (nNOS; type I NOS), inducible(iNOS; type II NOS), and
endothelial (eNOS; type III NOS). Which one do you think is present in the
penile nerve endings?

Terminals containing nNOS densely innervate the corpus cavernosum and its arterial
supply.NO derived from the endothelium lining penile arteries and cavernosal
sinuses also participates in the erectile response.

Now, how does NO work?

-The arterial dilator actions of NO and its relaxant effect on the smooth muscle of
the corpus cavernosum are mediated by the activation of soluble guanylate
cyclase and production of cGMP, which acts as a second messenger.

-Accumulation of cGMP leads to smooth muscle relaxation.

-The degradation of cGMP into its inactive form, GMP, is catalyzed by
phosphodiesterase enzymes.
The predominant isoform of this enzyme in the corpus cavernosum is PDE5.

Inhibitors of the activity of this enzyme prevent the breakdown of cGMP,resulting in enhanced penile erection.

B.Mechanism of action of Sildenafil.

Sildenafil is a potent and selective inhibitor of cGMP specific phosphodiesterase type 5 (PDE5) which is responsible for degradation of cGMP
in the corpus cavernosum.

The molecular structure of sildenafil is similar to that of cGMP and acts as a
competitive binding agent of PDE5 in the corpus cavernosum, resulting in more
cGMP and better erections.

Indications:
1-Erectile Dysfunction.

2-Pulmonary Hypertension: (this fact was mentioned by the pediatric
cardiologist,Dr Ayman Sabry during one of clinical sessions)

Because PDE-5 is primarily distributed within the arterial wall smooth muscle
of the lungs and penis, PDE-5 inhibitors can be used in pulmonary hypertension.

It relaxes the arterial wall, leading to decreased pulmonary arterial resistance and pressure. This in turn reduces the workload of the right
ventricle improves symptoms of right-sided heart failure.

Side effects:
The side effect profile can be easily expected.
Most of them are related to vasodilator effect of the drug!!

1-Headache.
2-Flushing.
3-Nasal congestion.
4-Hypotension.
5-Priapism: is a potentially harmful and painful medical condition in which the
erect penis does not return to its flaccid state, despite the absence of both
physical and psychological stimulation, within four hours. Priapism is considered a medical emergency.

-Other side effects:
-Blurred vision,photophobia.
-Hearing loss.

Contraindications:
-In patients receiving organic nitrates (such as nitroglycerin).Use of
sildenafil at the same time can lead to profound hypotension.

-Impairment of hepatic or renal function.
-Hypotensive patients.

Dose:
The dose of sildenafil for erectile dysfunction is 25 mg to 100 mg taken not
more than once per day between 30 minutes and 4 hours prior to sexual intercourse.

Task:

Please search for the reason of this grave interaction between Organic
nitrates and sildenafil.