Page 214 - Basic _ Clinical Pharmacology ( PDFDrive )

200 SECTION III Cardiovascular-Renal Drugs

This antidote for cyanide poisoning (inhaled amyl nitrite plus in ventricular fibrillation. Such patches should be removed before
intravenous sodium nitrite, followed by intravenous sodium thio- use of external defibrillation to prevent superficial burns.
cyanate and, if needed, methylene blue) is now being replaced by
hydroxocobalamin, a form of vitamin B , which also has a very B. Tolerance
12
high affinity for cyanide and combines with it to generate another With continuous exposure to nitrates, isolated smooth muscle
form of vitamin B . may develop complete tolerance (tachyphylaxis), and the intact
12
human becomes progressively more tolerant when long-acting
Toxicity & Tolerance preparations (oral, transdermal) or continuous intravenous infu-
sions are used for more than a few hours without interruption.
A. Acute Adverse Effects The mechanisms by which tolerance develops are not completely
The major acute toxicities of organic nitrates are direct extensions understood. As previously noted, diminished release of nitric
of therapeutic vasodilation: orthostatic hypotension, tachycardia, oxide resulting from reduced bioactivation may be partly respon-
and throbbing headache. Glaucoma, once thought to be a con- sible for tolerance to nitroglycerin. Supplementation of cysteine
traindication, does not worsen, and nitrates can be used safely may partially reverse tolerance, suggesting that reduced availability
in the presence of increased intraocular pressure. Nitrates are of sulfhydryl donors may play a role. Systemic compensation also
contraindicated, however, if intracranial pressure is elevated. plays a role in tolerance in the intact human. Initially, significant
Rarely, transdermal nitroglycerin patches have ignited when exter- sympathetic discharge occurs, and after 1 or more days of therapy
nal defibrillator electroshock was applied to the chest of patients with long-acting nitrates, retention of salt and water may partially

Drugs Used in the Treatment of Erectile Dysfunction

Erectile dysfunction in men has long been the subject of marketplace because it can be taken orally. However, sildenafil
research (by both amateur and professional scientists). Among is of little or no value in men with loss of potency due to cord
the substances used in the past and generally discredited are injury or other damage to innervation and in men lacking libido.
“Spanish Fly” (a bladder and urethral irritant), yohimbine (an α 2 Furthermore, sildenafil potentiates the action of nitrates used for
antagonist; see Chapter 10), nutmeg, and mixtures containing angina, and severe hypotension and a few myocardial infarctions
lead, arsenic, or strychnine. Substances currently favored by have been reported in men taking both drugs. It is recommended
practitioners of herbal medicine but of dubious value include that at least 6 hours pass between use of a nitrate and the inges-
ginseng and kava. tion of sildenafil. Sildenafil also has effects on color vision, caus-
Scientific studies of the process have shown that erection ing difficulty in blue-green discrimination. Three similar PDE-5
requires relaxation of the nonvascular smooth muscle of the inhibitors, tadalafil, vardenafil, and avanafil, are available. It is
corpora cavernosa. This relaxation permits inflow of blood at important to be aware that numerous nonprescription mail-order
nearly arterial pressure into the sinuses of the cavernosa, and it products that contain sildenafil analogs such as hydroxythio-
is the pressure of the blood that causes erection. (With regard to homosildenafil and sulfoaildenafil have been marketed as “male
other aspects of male sexual function, ejaculation requires intact enhancement” agents. These products are not approved by the
sympathetic motor function, while orgasm involves independent Food and Drug Administration (FDA) and incur the same risk of
superficial and deep sensory nerves.) Physiologic erection occurs dangerous interactions with nitrates as the approved agents.
in response to the release of nitric oxide from nonadrenergic-non- PDE-5 inhibitors have also been studied for possible use
cholinergic nerves (see Chapter 6) associated with parasympa- in other conditions. Clinical studies show distinct benefit in
thetic discharge. Thus, parasympathetic motor innervation must some patients with pulmonary arterial hypertension but not in
be intact and nitric oxide synthesis must be active. (It appears that patients with advanced idiopathic pulmonary fibrosis. The drugs
a similar process occurs in female erectile tissues.) Certain other have possible benefit in systemic hypertension, cystic fibrosis,
smooth muscle relaxants—eg, PGE 1 analogs or α-adrenoceptor and benign prostatic hyperplasia. Both sildenafil and tadalafil are
antagonists—if present in high enough concentration, can inde- currently approved for pulmonary hypertension. Preclinical stud-
pendently cause sufficient cavernosal relaxation to result in erec- ies suggest that sildenafil may be useful in preventing apoptosis
tion. As noted in the text, nitric oxide activates guanylyl cyclase, and cardiac remodeling after ischemia and reperfusion.
which increases the concentration of cGMP, and the latter second The drug most commonly used for erectile dysfunction in
messenger stimulates the dephosphorylation of myosin light patients who do not respond to sildenafil is alprostadil, a PGE 1
chains (Figure 12–2) and relaxation of the smooth muscle. Thus, analog (see Chapter 18) that can be injected directly into the cav-
any drug that increases cGMP might be of value in erectile dys- ernosa or placed in the urethra as a minisuppository, from which
function if normal innervation is present. Sildenafil (Viagra) acts it diffuses into the cavernosal tissue. Phentolamine can be used
to increase cGMP by inhibiting its breakdown by phosphodiester- by injection into the cavernosa. These drugs will cause erection
ase isoform 5 (PDE-5). The drug has been very successful in the in most men who do not respond to sildenafil.