Pinacidil- Antihypertensive agent- Investigational Drug
Drug Name:Pinacidil- Antihypertensive agent- Investigational Drug
List Of Brands:
Indication Type Description:
Drug Interaction
Adverse Reaction
Pharmacology/ Pharmacokinetics
Drug Interaction:
Hypertension
Summary-
Pinacidil appears to be promising alternative agent for the treatment of moderate to
severe hypertension. However, further studies are needed to clarify the drugs optimal
dosing schedule, long term side effects, and optimal drug combinations
FDAs Cardio-Renal Drugs Advisory Committee recommended approval of pinacidil on
May 28, 1987, with the stipulation that it be used concomittantly with diuretics.
The drug was approved by the FDA in December 1989, however Lily has no plans to market
at this time.
Adverse Reaction:
Side effects-
Pinacidil appears to be well tolerated. Only a few reports of mild side effects (eg.dizziness,
headache, and facial flushing) have been noted.
Edema has occured in 23.5% to 45.2% of patients on doses of pinacidil alone of 25mg to
50mg. Concomittant diuretics may be required in most patients
Two patients developed positive anti-nuclear antibody (ANA) titers while receiving
pinacidil. Neither had clinical manifestations of a lupus-like syndrome, and a direct
cause and effect relationship could not be linked to pinacidil.
Further studies are necessary to investigate the potential for pincaidil to cause d
drug-induced lupus syndrome
Pharmacology/ Pharmacokinetics:
Pharmacology-
Pinacidil is a vasodilator under investigation for use an antihypertensive agent.
Pinacidil acts at the level of the precapillary , arterioral (resistence) vessels
causing direct relaxation of the vascular smooth muscle. Its vasodilator effect is
not altered by blockade of Beta-adrenergic , cholinergic or histamine receptors,
or by the presence of prostaglandin inhibitors such as indomethicin
When compared to other vasodilators with similar sites of action, (eg minoxidil,
(Loniten) guancydine, diazoxide, (Hyperstat) ,pinacidil, at comparble levels of
blood pressure reduction, produces quantitatively identical increases in heart rate,
reflux sympathetic mediated cardiac contractility and cardiac output.
However, when compared to hydralyzine (another precapillary arterior vasodilator),
pinacidil at doses which produce equivalent reductions in total peripheral resistence,
is a more potent blood pressure lowering agent. Since blood pressure is a function of the
cardiac output multiplied by the total peripheral resistence , this difference may be
explained by the fact that hydralazine appears to have a direct (as well as the indirect)
cardiostimulatory effect which offsets some of the blood pressure reductions caused by
vasodilation.
As would be expected from differing effects of cardiac output, pinacidil produces less
of an increase in myocardial oxygen consumption than hydralyzine
There is a linear correlation between pinacidil drug levels and the fall in mean blood
pressure and total peripheral resistence, minimal therapeutic levels are 50ng/ml
Pharmacokinetics-
Absorption/distribution- Available data are complicated by the fact at least two different
formulations have been used in clinical trials. However the general bioavailability
approaches 100% after oral administration, with both peak serum levels and effect
occuring at 1 hour. Coadmininstration of food does not alter the bioavailability but slightly
delays absorption. Approximately 60% of a dose is protein bound.
Metabolism and Excretion- Pinacidil is metabolised in the liver to a number of metabolites,the most significant being the active metabolite, pinacidil N-oxide. Within the first 24 hours,55% to 60% of an administered dose appears in the urine as pinacidil or the N-oxide,20% to 30% is excreted in the urine as other other metabolite and 3% is recovered in the feces. The elimination half life (t 1/2) varies between 1.5 to 3 hours. average clearance values are 42+/- 5 L/hr
Although exact dosage guidelines have not been established patients with liver disease
should have therapy initiated slowly, at low doses and with careful blood pressure
monitoring.
Clinical trials-
Only a limited number of clinical studies each involving only a few patients have been
published. This may reflect that pinacidil is not considered to be first-or second line
drug for stepped-care approch.
Pinacidil has generally confined to patients with moderate to severe hypertension,
It is safe and effective, especially when added to a regimen of a diuretic and a
beta-blocker in patients who failed the initial combination regimen.
Pinacidil has been particularly efective in selected patients with renal impairment
( both dialysis and non-dialysis patients) with drug resistent, non-volume dependent
hypertension.
Although most studies have used doses of 10 to 100mg twice daily,some clinicians
feel the drug may require 3 times daily dosing. The most efective dose range appears
to be 12.5 or 25mg twice daily
