"How it works" series: Midodrine

Midodrine is a peripherally-acting selective alpha1 receptor agonist.  Let's take that sentence apart to see what we should expect from this medication.  Being an alpha1 agonist, this means that it binds to the alpha1 receptor and activates it, causing it to perform the function that it would usually perform if its endogenous catecholamine (ie. norepinephrine) were to bind to it. 
Unlike norepinephrine, midodrine does not cause any direct cardiac effects because it has selectivity for the alpha1 receptor.  It is also different from norepinephrine in that it does not cross the blood-brain barrier (peripherally-acting) and therefore does not have any CNS effects.

The alpha1 receptor is a G protein coupled receptor.  If you look in the above image, you will see that activating this causes a chain of events (activates phospholipase C → release of IP3 and DAG → release of calcium stores) that increases calcium in the cytoplasm of the cell.  The effect of this varies by what organ system we're talking about.  All clinical indications for midodrine have to do with the cardiovascular system.  In the vascular beds, midodrine causes vasoconstriction of both the arterial and venous vasculature.  This respectively means more arterial resistance and less venous capacitance (because less venous blood pooling = more venous return).  In a healthy person, suddenly increasing vascular tone will result in a baroreceptor-mediated increase in vagal tone (ie. slowing of the heart rate (up to 20%)).  This means that if a person has impaired baroreceptor function, they will not have the compensatory drop in heart rate and will have an exaggerated increase in blood pressure. We can use this to our advantage in patients with autonomic dysfunction who need blood pressure support.  Examples of these patients include those with diabetes, multiple system atrophy, and end stage renal disease during dialysis.

Other notable features

• Rapidly and completely absorbed in the GI tract
• Excretion of midodrine and its active metabolites is primarily renal
• In normal renal function, the half-life of active metabolite is 3 hours
• Some studies show orthostatic symptoms improve even at doses lower than those that raise standing blood pressure
• Systolic blood pressure shown to increase up to 43 mm Hg with 20 mg dose
• Generally dosed three times a day
• Most common side effects
• Pilomotor reaction (like goose bumps)
• Scalp pruritus or tingling
• Urinary urgency
• Headache
• Supine hypertension (8%)

References
Cruz DN. Midodrine: a selective alpha-adrenergic agonist for orthostatic hypotension and dialysis hypotension. Exp Opin Pharmacother  2000;1(4):835-840.
Katzung chapter 9
Biaggioni I, Robertson D.  Adrenoceptor agonists and sympathomimetic drugs.  In: Basic and Clinical Pharmacology, 11th edition. Katzung BG et al. 2009

image adapted from Veronicago7