Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties
Pharmacotherapeutic group: Cardiac Therapy, Adrenergic and dopaminergic agents ATC-code: C01C A17


Midodrine hydrochloride is the rapidly absorbed pro-drug of the pharmacologically active constituent desglymidodrine. Desglymidodrine is a sympathomimetic agent with a direct and selective effect on the peripheral α1-adrenergic receptors. This α1- stimulative effect induces vasoconstriction of the venous system (causing a reduction in venous pooling). The α1-adrenergic effects of desglymidodrine are almost wholly attributable to the (-) enantiomer of desglymidodrine. After taking midodrine hydrochloride, which is a racemic mixture, (+) desglymidodrine is also present, though this contributes almost nothing to the desired effect.


Desglymidodrine increases the peripheral arterial resistance, resulting in an increase in arterial blood pressure.


Only limited data is available on the long-term effects of taking midodrine hydrochloride.


Stimulation of the α-adrenergic receptors of the bladder and the ureter increases the sphincter muscle tone.


Desglymidodrine has no β-adrenergic effects.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties
Absorption
After oral administration, midodrine hydrochloride is rapidly absorbed. Peak plasma concentrations are reached after approximately 30 minutes, and the plasma concentration of the active metabolite, desglymidodrine, peaks after approximately 1 hour.


AUC and Cmax increase proportionally to the dose across a dosage range of 2.5 – 22.5 mg. Administration with food increases the AUC by approximately 25%, and the
Cmax decreases by approximately 30%. The pharmacokinetics of desglymidodrine are not affected.


Distribution
Neither midodrine hydrochloride nor desgylmidodrine are bound to plasma proteins to any significant extent (less than 30%). Desglymidodrine diffuses poorly across the blood-brain barrier. Diffusion across the placenta has been reported. It is not known whether this drug is excreted in human milk.


Metabolism
Midodrine hydrochloride is partially hydrolysed before absorption (in the intestines), and partially after absorption (in plasma) by the separation of glycine, herewith generating the active metabolite, desglymidodrine. The elimination of desglymidodrine is primarily caused by an oxidating metabolism, followed by (partial) conjugation.


Excretion
Midodrine hydrochloride (8%), desglymidodrine (40%), and their degradation products (55%) are excreted in the urine by more than 90% within 24 hours in conjugated or non-conjugated forms. The plasma elimination half-life for Midodrine hydrochloride is approximately 30 minutes, and is approximately 3 hours for desglymidodrine. Elimination of the active (-) enantiomer of desglymidodrine is slower than the elimination of the inactive (+) enantiomer.