Action And Clinical Pharmacology: Midodrine is a postsynaptic alpha adrenergic receptor stimulant with little effect on the beta-adrenergic receptors in the heart. The actions of midodrine on the cardiovascular and other organ systems are essentially identical with those of other alpha-adrenergic receptor stimulants, such as phenylephrine or methoxamine. The most prominent effects of midodrine are on the cardiovascular system, consisting of a rise in systolic and diastolic blood pressures, accompanied by a marked reflex bradycardia. The increase in blood pressure is due almost entirely to an increase in peripheral resistance. Midodrine slightly decreases cardiac output and renal blood flow; it increases the tone of the internal bladder sphincter and delays the emptying of the bladder.
Midodrine is a prodrug, i.e., the therapeutic effect of orally administered midodrine is due to and directly related to its conversion after absorption to desglymidodrine which differs chemically from methoxamine only by lacking in a methyl group on the side chain.
Pharmacokinetics: After oral administration, midodrine is rapidly and almost completely absorbed, with a mean absolute bioavailability (as desglymidodrine) of 93% for the oral tablets.
After the oral administration of 2.5 mg midodrine in a single dose to 12 volunteers, the mean peak concentration of unchanged midodrine is approximately 10 ng/mL and occur after 20 to 30 minutes, with a terminal plasma half-life of 0.4 to 0.5 hours. The mean plasma concentration of the active metabolite, desglymidodrine, peaks in approximately 1 hour, with a plasma half-life of approximately 3 hours after the oral administration of 2.5 mg midodrine.
Midodrine is poorly diffused across the blood-brain barrier. Both midodrine and desglymidodrine are quickly eliminated from the body, mostly by the kidneys. Approximately 91% of the administered dose is excreted in the urine in 24 hours. Of the urinary material, 50 to 60% is present as desglymidodrine and approximately 2%, as non-metabolized midodrine. Unidentified breakdown products do not exceed 3.9% of the urinary material.
Indications And Clinical Uses: Midodrine may be added to an established treatment regimen in order to attenuate symptoms in the primary neurogenic types of idiopathic orthostatic hypotension, that is in the Bradbury-Eggleston or Shy-Drager syndromes, in those cases when the response to the standard therapy is not adequate. The initiation of midodrine therapy should be undertaken under close medical supervision in a controlled clinical setting such as in hospital, in clinic or in the office.
Contra-Indications: In patients with severe organic heart disease, acute renal disease, urinary retention, pheochromocytoma, thyrotoxicosis or known hypersensitivity to midodrine.
Manufacturers’ Warnings In Clinical States: Supine Hypertension: The most serious and frequent (see Adverse Effects) adverse reaction to midodrine in patients suffering from primary neurogenic hypotension is the unacceptable elevation of supine arterial blood pressure (supine hypertension), which, if sustained, may cause stroke, myocardial infarction, congestive heart failure, renal insufficiency or similar disorders which individually or collectively may be fatal. Symptoms of supine hypertension are more frequently detected at the initiation of midodrine therapy and during the titration period.
Control of supine blood pressure has been obtained by an adjustment in midodrine dosage with or without a 45-degree elevation of the patient’s head. If supine hypertension persists, treatment with midodrine should be discontinued, and appropriate therapy (e.g., phentolamine, a specific antagonist of midodrine pressor activity) instituted immediately.
To minimize the incidence of supine hypertension, instruction how to initiate midodrine therapy should strictly be followed (see Dosage). Patients should be cautioned to report symptoms of supine hypertension immediately. Symptoms may include cardiac awareness, pounding in the ears, headache, blurred vision, etc. If these occur, the patient should discontinue the drug and consult with the prescribing physician.
Bradycardia: Bradycardia may occur after midodrine administration, primarily due to vagal reflex. Caution should be exercised when midodrine is used concomitantly with cardiac glycosides (such as digitalis), psychopharmacologic agents, beta blockers or other agents which directly or indirectly reduce heart rate. Patients who experience bradycardia should be told to report immediately any signs or symptoms suggesting bradycardia (pulse slowing, increased dizziness, syncope, cardiac awareness) and to take no more drug until they have consulted with the prescribing physician.
Midodrine should not be administered in the presence of uncorrected tachyarrhythmias or ventricular fibrillation.
Precautions: Urinary Retention: Midodrine may induce an increase in the tone of the internal sphincter of the urinary bladder which may lead to urinary retention. Midodrine also may effect the bladder trigone which may result in a delayed response to bladder filling. Initial signs of urinary retention are manifested clinically as hesitancy or change in frequency of micturition. Patients should be told to report promptly any indication of urinary retention (e.g., hesitancy or frequency of micturition) which may be a sign of urinary retention.
When midodrine is used concomitantly with other vasoconstrictor sympathomimetic pressor agents, monitoring of blood pressure is necessary.
Midodrine should be used with caution in patients with urinary tract outflow obstruction, neurogenic bladder or similar conditions, since midodrine is eliminated by the kidneys and accumulation may occur in such patients.
Laboratory Tests: Evaluation of the patient should include assessment of renal and hepatic function prior to initiation of therapy, and during treatment, when appropriate.
Pregnancy: No teratogenic effects have been observed in studies in animals. At very high doses (20 mg/kg/day) the drug was toxic to dams and fetal loss occurred. There are no data on the use of midodrine on pregnant women. Therefore, midodrine should be used during pregnancy only when the benefit to the mother exceeds the possible harm to the fetus.
Lactation: It is not known if midodrine is excreted in human milk. Caution should be exercised when midodrine is administered to nursing mothers.
Children: Safety and effectiveness in children have not been established.
Drug Interactions: When administered concomitantly with midodrine, cardiac glycosides may enhance or precipitate bradycardia, block or arrhythmia.
The use of drugs which stimulate alpha adrenergic receptors (e.g., phenylephrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of midodrine. Therefore, when midodrine is used concomitantly with vasoconstrictor sympathomimetic agents, use caution.
Patients on salt-retaining steroids (e.g., fludrocortisone), with or without salt supplementation, may experience an excessive pressor effect after midodrine therapy, especially in the supine posture. The possibility of hypertensive effects with midodrine can be minimized by either reducing the dose of fludrocortisone or decreasing the salt intake prior to initiation of treatment with midodrine.
Alpha adrenergic blocking agents antagonize the vasopressor effect of midodrine.
Adverse Reactions: In 305 patients treated with midodrine for primary neurogenic types of idiopathic orthostatic hypotension (Bradbury-Eggleston or Shy-Drager Syndrome), the overall adverse reaction rate was 34%, and the drop out rate due to adverse reactions was 6.9%. The most serious and frequent adverse reaction to midodrine is supine hypertension (17.5%). The other frequent adverse reaction to midodrine (>10%) is pruritus (11.5%).
Symptoms And Treatment Of Overdose: Symptoms and Treatment: We have had no reports of overdose with midodrine. However, symptoms of overdose could include piloerection (goose flesh), a sensation of coldness and urinary retention. The effects of midodrine can be treated with alpha sympatholytic drugs (e.g., phentolamine). In cutaneous hypersensitivity reactions, H1-antihistamines should be administered.
Dosage And Administration: Adults and Adolescents: Treatment with midodrine should be started under close medical supervision in a controlled clinical setting such as in hospital, in clinic, or in the office. Hourly measurements of blood pressure (supine and sitting or standing, if possible) should be made for 3 hours following the first dose and also the second dose of a three times daily dosage regimen.
It is recommended that treatment begin at the lowest level and be titrated at intervals of 3 to several days until the optimal response is obtained. Upon escalating the dosage, the supine and standing blood pressure should be closely monitored in hospital, in clinic or in the office as for the initiation of therapy, hourly for 3 hours following the first 2 doses.
The usual starting dose is 2.5 mg 3 times daily. Single doses of 2.5, 5 and 10 mg have been successfully employed. Most patients are controlled at or below 30 mg/day given in 3 or 4 divided doses. Midodrine can be given up to 6 times/day. Some patients require a morning dose that is higher than that taken later in the day. In some instances midodrine has been given on a 3 times/day schedule as follows: 1 to 2 hours before arising in the morning, mid-morning and mid-afternoon. In order to reduce the potential for supine hypertension, it may be recommended that midodrine doses not be given after the evening meal. The maximum recommended dose should not exceed 30 mg daily.
During the period of close medical supervision, the patient or a relative should be trained to measure blood pressures. Supine and sitting blood pressures should be measured daily for at least a month after initiation of treatment and twice per week afterwards.
The administration of midodrine should be stopped and the attending physician notified immediately, if the blood pressure in either position increases above 180/100 mmHg.
Children: In view of the lack of experience in children, this drug is not recommended for patients under 12 years of age.
Availability And Storage: 2.5 mg: Each oral, white tablet, scored on one side contains: midodrine HCl 2.5 mg. Nonmedicinal ingredients: colloidal anhydrous silica, magnesium stearate, maize starch, microcrystalline cellulose and talc. Glass bottles of 100 with plastic cap to cap LDPE closures.
5 mg: Each oral, orange tablet, scored on one side contains: midodrine HCl 5 mg. Nonmedicinal ingredients: colloidal anhydrous silica, magnesium stearate, maize starch, microcrystalline cellulose, sunset Yellow col. lake and talc. Glass bottles of 100 with plastic cap to cap LDPE closures.
AMATINE® Knoll Midodrine HCl Vasopressor