Midodrine

Midodrine is an alpha₁ agonist belonging to antihypertensive agent.

Midodrine is an alpha-adrenergic agonist used to treat orthostatic hypotension.

Midodrine is rapidly absorbed. 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. The absolute bioavailability of midodrine (measured as desglymidodrine) is 93%. Renal elimination of midodrine is insignificant. The renal clearance of desglymidodrine is of the order of 385 mL/minute, most, about 80%, by active renal secretion. The actual mechanism of active secretion has not been studied, but it is possible that it occurs by the base-secreting pathway responsible for the secretion of several other drugs that are bases.

Midodrine shows common side effects like Numbness and tingling, scalp itching, goose bumps, Chills, frequent urination, urgent need to urinate, difficulty urinating, rash, stomach pain.

Midodrine is available in the form of an Oral Tablet.

Midodrine is available in India, US, France, South Africa, New Zealand, Canada, Japan, China, and Australia.

Midodrine belongs to the antihypertensive agent acts as an alpha₁ agonist.

Midodrine undergoes metabolism to form its pharmacologically active metabolite, desglymidodrine. Desglymidodrine acts as an agonist at the alpha₁-adrenergic receptors expressed in the arteriolar and venous vasculature. Activation of alpha₁-adrenergic receptor signaling pathways lead to an increase in the vascular tone and elevation of blood pressure. Desglymidodrine is reported to have negligible effect on the cardiac beta-adrenergic receptors.

The Data of onset of action of Midodrine is not available.

The duration of action of Midodrine is about 2-3 hours.

The Tmax of Midodrine is approximately 30 mins.

Midodrine is available in the form of Oral Tablet.

Midodrine tablets is taken orally, usually 3 times daily.

Midodrine is used for the treatment of orthostatic hypotension, a condition of low blood pressure that occurs when standing up quickly from sitting or lying position.

Midodrine is an alpha₁ agonist belonging to antihypertensive agent.

Midodrine, a direct-acting sympathomimetic amine, is a prodrug which forms an active metabolite, desglymidodrine. It selectively activates the α₁-adrenergic receptors of the arteriolar and venous vasculature, producing peripheral vasoconstriction and elevation of BP.

Midodrine is approved for use in the following clinical indications

Adult indication

• Hypotension, symptomatic orthostatic

Although not approved, there have been certain off-label indications. These include

• Ascites, cirrhotic, diuretic resistant or with hypotension
• Hemodialysis-induced hypotension, prevention
• Hepatorenal syndrome
• Hypotension in the ICU, vasopressor sparing
• Postural orthostatic tachycardia syndrome
• Syncope, vasovagal

Adult Dose

• Hypotension, symptomatic orthostatic

Oral: Initial: 2.5 mg 2 or 3 times daily during daytime hours (eg, every 3 to 4 hours) when patient is upright; titrate as needed based on response and tolerability up to a usual maximum dose of 10 mg 3 times daily. Avoid administering <4 hours before bedtime to minimize risk of supine hypertension.

• Ascites, cirrhotic, diuretic resistant or with hypotension

Oral: Initial: 5 to 7.5 mg 3 times daily; adjust dose in increments of 2.5 mg per dose (eg, increase from 5 mg 3 times daily to 7.5 mg 3 times daily) every 24 hours to achieve target mean arterial pressure; maximum dose: 17.5 mg 3 times daily.

• Haemodialysis-induced hypotension, prevention

Oral: Initial: 2.5 to 5 mg given 15 to 30 minutes prior to hemodialysis. If response is insufficient, may increase up to 10 mg given 15 to 30 minutes prior to the next hemodialysis session; if hypotension occurs near the end of hemodialysis, may give an additional 2.5 to 5 mg dose mid-dialysis provided it is administered ≥3 hours after pre-dialysis dose.

• Hepatorenal syndrome

Oral: Initial: 5 to 10 mg 3 times daily in combination with albumin and octreotide; adjust dose (eg, by 2.5 to 5 mg per dose) as needed after each 8-hour dosing interval, with an immediate goal of increasing mean arterial pressure by ~10 to 15 mm Hg; maximum dose: 15 mg 3 times daily.

• Hypotension in the ICU, vasopressor sparing

Oral: Initial: 5 to 10 mg every 8 hours; titrate based on response and tolerability; usual dose: 10 to 20 mg every 8 hours; maximum reported dose: 40 mg every 8 hours. When hemodynamically stable, taper and discontinue.

• Postural orthostatic tachycardia syndrome

Oral: Initial: 2.5 mg 3 times daily (eg, morning, midday, and late afternoon); may increase gradually (eg, every 3 to 4 days) in increments of 2.5 mg/dose (eg, may increase from 2.5 mg 3 times daily to 5 mg 3 times daily) to a maximum of 10 mg 3 times daily. Avoid administering <4 hours before bedtime to minimize risk of supine hypertension.

• Syncope, vasovagal

Midodrine is available in various strengths as 2.5mg, 5mg, and 10mg.

Midodrine is available in the form of Oral Tablet.

• Dosage Adjustment in Kidney Patient

eGFR ≥30 mL/minute/1.73m²: No dosage adjustment necessary.

eGFR <30 mL/minute/1.73m²: Initiate with a low dose (eg, 2.5 mg 1 to 3 times daily); increase to indication-specific dose as needed based on tolerability and response; use with caution.

Midodrine is contraindicated in patients with

• Midodrine is contraindicated in patients with severe organic heart disease, acute renal disease, urinary retention, pheochromocytoma or thyrotoxicosis.
• Midodrine should not be used in patients with persistent and excessive supine hypertension.

• Diabetes

Midodrine should be used with caution in patients with diabetes due to the increased risk of severe adverse effects. Close monitoring of blood glucose levels, appropriate dose adjustments, or replacement with a suitable alternative may be required in some cases based on the clinical condition.

• Vision problems

Midodrine should be used with caution in patients with vision disorders due to the increased risk of worsening of the patient's condition. Close monitoring of the clinical condition, appropriate dose adjustments, or replacement with a suitable alternative may be required in some cases based on the clinical condition.

• Driving and operating machinery

Use of Midodrine may cause symptoms such as dizziness, blurred vision, light-headedness, etc. in some patients. It is advised that you do not perform any activities that require high mental alertness such as driving a vehicle or operating machinery if you experience any of these symptoms during treatment with this medicine.

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Midodrine is administered to a nursing woman.

Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

Common Adverse effects

• Piloerection, pruritus, Dysuria, Paresthesia, Supine hypertension, Skin rash, Chills, abdominal pain.

Rare Adverse effects

• Erythema multiforme, xeroderma, Aphthous stomatitis, flatulence, gastrointestinal distress, heartburn, nausea, Dizziness, drowsiness, hyperesthesia, insomnia, Asthenia, back pain, lower limb cramp, Visual field defect.

• Alpha1-Blockers: May diminish the vasoconstricting effect of Alpha1-Agonists. Similarly, Alpha1-Agonists may antagonize Alpha1-Blocker vasodilation.
• Atomoxetine: May enhance the hypertensive effect of Sympathomimetics. Atomoxetine may enhance the tachycardic effect of Sympathomimetics.
• Benzylpenicilloyl Polylysine: Alpha1-Agonists may diminish the diagnostic effect of Benzylpenicilloyl Polylysine. Management: Consider delaying skin testing until alpha1-agonists are no longer required, or use of a histamine skin test as a positive control to assess a patient's ability to mount a wheal and flare response.
• Bradycardia-Causing Agents: Midodrine may enhance the bradycardic effect of Bradycardia-Causing Agents.
• Bromocriptine: May enhance the hypertensive effect of Alpha1-Agonists. Management: Consider alternatives to this combination when possible. If combined, monitor for hypertension and tachycardia, and do not coadminister these agents for more than 10 days.
• Cannabinoid-Containing Products: May enhance the tachycardic effect of Sympathomimetics.
• Cocaine (Topical): May enhance the hypertensive effect of Sympathomimetics. Management: Consider alternatives to use of this combination when possible. Monitor closely for substantially increased blood pressure or heart rate and for any evidence of myocardial ischemia with concurrent use.
• Doxofylline: Sympathomimetics may enhance the adverse/toxic effect of Doxofylline.
• Droxidopa: Midodrine may enhance the hypertensive effect of Droxidopa.
• Ergot Derivatives (Vasoconstrictive CYP3A4 Substrates): May enhance the vasoconstricting effect of Alpha1-Agonists.
• Guanethidine: May enhance the arrhythmogenic effect of Sympathomimetics. Guanethidine may enhance the hypertensive effect of Sympathomimetics.
• Iobenguane Radiopharmaceutical Products: Alpha1-Agonists may diminish the therapeutic effect of Iobenguane Radiopharmaceutical Products. Management: Discontinue all drugs that may inhibit or interfere with catecholamine transport or uptake for at least 5 biological half-lives before iobenguane administration. Do not administer these drugs until at least 7 days after each iobenguane dose.
• Kratom: May enhance the adverse/toxic effect of Sympathomimetics.
• Linezolid: May enhance the hypertensive effect of Sympathomimetics. Management: Reduce initial doses of sympathomimetic agents, and closely monitor for enhanced pressor response, in patients receiving linezolid. Specific dose adjustment recommendations are not presently available.
• Lisuride: May enhance the hypertensive effect of Alpha1-Agonists.
• Monoamine Oxidase Inhibitors: May enhance the hypertensive effect of Alpha1-Agonists. While linezolid is expected to interact via this mechanism, management recommendations differ from other monoamine oxidase inhibitors. Refer to linezolid specific monographs for details.
• Ozanimod: May enhance the hypertensive effect of Sympathomimetics.
• Pergolide: May enhance the hypertensive effect of Alpha1-Agonists.
• Solriamfetol: Sympathomimetics may enhance the hypertensive effect of Solriamfetol. Sympathomimetics may enhance the tachycardic effect of Solriamfetol.
• Sympathomimetics: May enhance the adverse/toxic effect of other Sympathomimetics.
• Tedizolid: May enhance the hypertensive effect of Sympathomimetics. Tedizolid may enhance the tachycardic effect of Sympathomimetics.
• Tricyclic Antidepressants: May enhance the therapeutic effect of Alpha1-Agonists. Tricyclic Antidepressants may diminish the therapeutic effect of Alpha1-Agonists.

The common side effects of Midodrine include the following

Common

● Numbness and tingling, scalp itching, goose bumps, Chills, frequent urination, urgent need to urinate, difficulty urinating, rash, stomach pain.

Rare

● Slow heartbeat, dizziness, fainting.

• Pregnancy

Pregnancy Category C

Midodrine increased the rate of embryo resorption, reduced fetal body weight in rats and rabbits, and decreased fetal survival in rabbits when given in doses 13 (rat) and 7 (rabbit) times the maximum human dose based on body surface area (mg/m²). There are no adequate and well-controlled studies in pregnant women. Midodrine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. No teratogenic effects have been observed in studies in rats and rabbits.

• Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Midodrine is administered to a nursing woman.

• Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

• Geriatric Use

Information is not available.

• Symptoms of overdose could include hypertension, piloerection (goosebumps), a sensation of coldness and urinary retention. There are 2 reported cases of over dosage with Midodrine, both in young males. One patient ingested Midodrine drops, 250 mg, experienced systolic blood pressure greater than 200 mmHg, was treated with an IV injection of 20 mg of phentolamine, and was discharged the same night without any complaints. The other patient ingested 205 mg of Midodrine (41 5-mg tablets), and was found lethargic and unable to talk, unresponsive to voice but responsive to painful stimuli, hypertensive and bradycardic. Gastric lavage was performed, and the patient recovered fully by the next day without sequelae.
• 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.
• Recommended general treatment, based on the pharmacology of the drug, includes induced emesis and administration of alpha-sympatholytic drugs (e.g., phentolamine).

Pharmacodynamic

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. 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.

Pharmacokinetics

• Absorption

Midodrine is rapidly absorbed. 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. The absolute bioavailability of midodrine (measured as desglymidodrine) is 93%. The bioavailability of desglymidodrine is not affected by food.

• Distribution

Neither midodrine nor desglymidodrine is bound to plasma proteins to any significant extent.

• Metabolism and Excretion

Thorough metabolic studies have not been conducted, but it appears that deglycation of midodrine to desglymidodrine takes place in many tissues, and both compounds are metabolized in part by the liver. Neither midodrine nor desglymidodrine is a substrate for monoamine oxidase. Renal elimination of midodrine is insignificant. The renal clearance of desglymidodrine is of the order of 385 mL/minute, most, about 80%, by active renal secretion. The actual mechanism of active secretion has not been studied, but it is possible that it occurs by the base-secreting pathway responsible for the secretion of several other drugs that are bases.

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