Midodrine

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

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

Only limited data is available on the long-term effects of administering midodrine. Stimulation of the α-adrenergic receptors of the bladder and the ureter increases the sphincter muscle tone.Desglymidodrine has no β-adrenergic effects.

Absorption

After oral administration, midodrine is rapidly absorbed. The 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 C_max increase proportionally to the doses in a dosage range of 2,5-22,5 mg. Administration with food increases the AUC by approximately 25%, and the C_max decreases by approximately 30%. The pharmacokinetics of desglymidodrine is not affected.

Distribution

Midodrine and desglymidodrine bind for less than 30% to plasma proteins. Studies on animals show that desglymidodrine is distributed in the target organs. Records are made of diffusion across the blood-brain barrier, the placenta and the human milk.

Biotransformation

Midodrine is partially hydrolised 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 oxidative metabolism, followed by (partial) conjugation.

Excretion

Midodrine (8%), desglymidodrine (40%), and their degradation products (55%) are excreted in the urine within 24 hours in conjugated or non-conjugated form. The plasma elimination half-life for midodrine 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.

Pharmacology safety studies and toxicity studies with animals did not show any indications of a safety risk for humans after repeated administration. Studies on animals are inadequate to determine the effects on the reproduction system.

In carcinogenic trials in rats an increased tumour incidence in the testicular interstitial cells was observed; the relevance of this for humans is however unclear. The results of the micronucleus tests in rats also show that genotoxicity of midodrine cannot be ruled out.