Biomedical Engineering Reference
In-Depth Information
Analogs of Nifedipine. Following the introduction of nifedipine into the market,
a number of analogs were prepared starting from its structure, which were
characterized by a short duration of pharmacological action. All of these belong
to the first generation dihydropyridines. Among these, felodipine, isradepine,
nimodepine, nisoldipine, amlodipine, lercanidipine and manidipine have emerged
as novel therapeutic agents.
Felodipine. Felodipine is a very potent calcium antagonist, which reduces both
systolic and diastolic blood pressures in a dose-related manner. The activity is
exerted through a specific binding to the dihydropyridine site. It increases the
secretion of potassium, calcium, and magnesium. Since this drug is mainly
metabolized by the liver, patients under therapy with felodipine should avoid
cytochrome P450 3A4 and 1A2 isoform inhibitors, such as grapefruit juice,
which induce interference with the hepatic metabolism of felodipine. Concerning
the structural characteristics, in this analog the
ortho
- nitro group in the aryl moiety
has been replaced by 1, 2-dichloro group (Fig.
3
).
Isradipine. It is used either alone or in combination with diuretics in the
treatment of hypertension. It presents high calcium antagonist activity together
with oral bioavailability (90-95%). However, the hepatic first-pass effect reduces
it to 15-24%. Although isradipine showed antiatheromatic activity in a number of
experimental models, clinical studies in patients failed to confirm these findings
(Fig.
3
).
Nimodipine (
S
). It is an asymmetric structural analog of nifedipine. The phar-
macological activity is exerted through its ability to bind to the
1 subunit of the
L
-type calcium channel. Nimodipine is lipophilic, which enables it to cross the
blood-brain barrier and achieve effective drug concentration. It shows a preferen-
tial binding activity at the cerebral vessels. Thus, it has been widely used for the
treatment of neurological disorders such as stroke of the subarachnoid hemorrhagic
type (Fig.
3
).
Nisoldipine. This nifedipine analog is at least five to ten times more potent than
the “parent” molecule on arterial smooth muscle and it can be used for the treatment
of hypertension. Due to its massive hepatic metabolism, it is currently used for once
daily administration (Fig.
3
).
Amlodipine. It presents a long kinetic half-life and thus is characterized as a
long-acting blocker. Its hepatic first pass is less than that of the other analogs.
Another interesting aspect is its antiatheromatic properties, which can be further
increased by combination with statins (Fig.
3
).
Lercanidipine. It is a molecule with high lipophilicity, which explains its long
duration of action. It is used in the treatment of hypertension and angina, and it is
especially indicated in elderly patients. It is one of the last dihydropyridines
introduced into the market (Fig.
3
).
Manidipine. It is a potent and selective analog toward the renal vasculature,
making it particularly helpful for the therapy of renovascular hypertension (Fig.
3
).
Dihydropyridines appeared as both blockers and activators of
L
-type calcium
ions channels [
35
]. They possess significant selectivity toward vascular versus
myocardial cells and therefore have a greater vasodilatory effect with respect to
a
