indication

For the treatment of symptomatic orthostatic hypotension (OH).

pharmacology

Midodrine is a prodrug, i.e., the therapeutic effect of orally administered midodrine is due to the major metabolite desglymidodrine formed by deglycination of midodrine. Desglymidodrine diffuses poorly across the blood-brain barrier, and is therefore not associated with effects on the central nervous system. Administration of midodrine results in a rise in standing, sitting, and supine systolic and diastolic blood pressure in patients with orthostatic hypotension of various etiologies. Standing systolic blood pressure is elevated by approximately 15 to 30 mmHg at 1 hour after a 10-mg dose of midodrine, with some effect persisting for 2 to 3 hours. Midodrine has no clinically significant effect on standing or supine pulse rates in patients with autonomic failure.

mechanism of action

Midodrine forms an active metabolite, desglymidodrine, that is an alpha₁-agonist, and exerts its actions via activation of the alpha-adrenergic receptors of the arteriolar and venous vasculature, producing an increase in vascular tone and elevation of blood pressure. Desglymidodrine does not stimulate cardiac beta-adrenergic receptors.

toxicity

Symptoms of overdose could include hypertension, piloerection (goosebumps), a sensation of coldness and urinary retention. The single doses that would be associated with symptoms of overdosage or would be potentially life- threatening are unknown. The oral LD₅₀ is approximately 30 to 50 mg/kg in rats, 675 mg/kg in mice, and 125 to 160 mg/kg in dogs. Desglymidodrine is dialyzable.

biotransformation

Thorough metabolic studies have not been conducted, but it appears that deglycination of midodrine to desglymidodrine takes place in many tissues, and both compounds are metabolized in part by the liver.

absorption

Rapidly absorbed following oral administration. The absolute bioavailability of midodrine (measured as desglymidodrine) is 93% and is not affected by food.

half life

The plasma levels of the prodrug peak after about half an hour, and decline with a half-life of approximately 25 minutes, while the metabolite reaches peak blood concentrations about 1 to 2 hours after a dose of midodrine and has a half-life of about 3 to 4 hours.

drug interactions

Betamethasone: Increased arterial pressure

Cortisone acetate: Increased arterial pressure

Dexamethasone: Increased arterial pressure

Dobutamine: Increased arterial pressure

Dopamine: Increased arterial pressure

Ephedra: Increased arterial pressure

Ephedrine: Increased arterial pressure

Epinephrine: Increased arterial pressure

Fenoterol: Increased arterial pressure

Fludrocortisone: Increased arterial pressure

Hydrocortisone: Increased arterial pressure

Isocarboxazid: Possible hypertensive crisis with this combination

Isoproterenol: Increased arterial pressure

Mephentermine: Increased arterial pressure

Metaraminol: Increased arterial pressure

Methoxamine: Increased arterial pressure

Methylprednisolone: Increased arterial pressure

Norepinephrine: Increased arterial pressure

Orciprenaline: Increased arterial pressure

Paramethasone: Increased arterial pressure

Phenelzine: Possible hypertensive crisis with this combination

Phenylephrine: Increased arterial pressure

Phenylpropanolamine: Increased arterial pressure

Pirbuterol: Increased arterial pressure

Prednisolone: Increased arterial pressure

Prednisone: Increased arterial pressure

Procaterol: Increased arterial pressure

Pseudoephedrine: Increased arterial pressure

Rasagiline: Risk of hypertensive crisis.

Salbutamol: Increased arterial pressure

Terbutaline: Increased arterial pressure

Tranylcypromine: The MAO inhibitor, Tranylcypromine, may increase the vasopressor effect of the alpha1-agonist, Midodrine. Concomitant therapy should be avoided.

Triamcinolone: Increased arterial pressure

Trimipramine: Trimipramine may increase the vasopressor effect of the alpha1-agonist, Midodrine. Avoid combination if possible. Monitor sympathetic response to therapy if used concomitantly.