Friday, March 6, 2009

MIDODRINE



Orthostatic Hypotension



Midodrine hydrochloride is used in the management of symptomatic orthostatic hypotension; the drug is designated an orphan drug by the US Food and Drug Administration (FDA) for such use. Midodrine should be used only after nondrug therapies (e.g., support hose, increased sodium intake, life-style modifications) and fluid expansion have failed. Clinical studies indicate that midodrine is more effective than placebo and at least as effective as ephedrine, fludrocortisone, or dihydroergotamine in the management of orthostatic hypotension. However, despite comparable increases in blood pressure, midodrine may be more effective than comparative drugs (e.g., ephedrine) in managing postural symptoms.Midodrine increases supine, sitting, and standing diastolic and systolic blood pressures, and may attenuate postural symptoms (e.g., dizziness, lightheadedness, syncope, impaired ability to stand). In several clinical studies, midodrine decreased supine and standing pulse rates in patients with orthostatic hypotension; however, the manufacturer states that clinically important changes in pulse rates generally do not occur in patients with impaired autonomic function receiving the drug. There is some evidence that efficacy of midodrine is related to autonomic function; patients with less severe autonomic dysfunction may benefit from midodrine therapy to a greater extent than those with severe autonomic dysfunction.The most potentially serious adverse effect of midodrine is supine hypertension (systolic blood pressure of 180 mm Hg or higher), reported in up to 25% of patients receiving the usual dosage (10 mg 3 times daily)of midodrine hydrochloride and in up to 50% of patients receiving 20-mg dosesof the drug in clinical studies. Patients should be advised to report promptly to their clinician symptoms of supine hypertension (e.g., cardiac awareness, pounding in the ears, headache, blurred vision). If supine hypertension occurs, the dosage of midodrine may be reduced;withdrawal of the drug may be necessary, particularly if supine hypertension persists. Sleeping with the head of the bed elevated may relieve supine hypertension in some patients.Concomitant use of midodrine and some vasoconstricting agents (e.g., phenylephrine, ephedrine, dihydroergotamine, phenylpropanolamine, pseudoephedrine) may cause an exaggerated hypertensive response. Patients receiving midodrine concomitantly with a vasoconstricting agent should be observed for possible additive hypertensive effects.Although midodrine used concomitantly with fludrocortisone (with or without sodium supplementation) appears to be well tolerated, patients should be monitored closely for supine hypertension during combination therapy.In addition, caution should be exercised in patients with ocular conditions when midodrine is used concomitantly with fludrocortisone (which can increase intraocular pressure and precipitate or aggravate glaucoma).Concomitant use of midodrine and agents that can cause bradycardia (e.g., cardiac glycosides, β-adrenergic blocking agents) may cause an exaggerated bradycardic response.Patients receiving midodrine concomitantly with such agents should be observed for possible additive bradycardic effects.The manufacturer states that midodrine also should be used with caution in patients with diabetes mellitus and in patients with a history of urinary retention.



Dosage and Administration



Administration

Midodrine hydrochloride is administered orally, usually in 3 equally divided doses daily. Since food does not appear to affect GI absorption of midodrine hydrochloride, the drug generally can be administered without regard to meals.


Dosage

Safety and efficacy of midodrine hydrochloride in children younger than 18 years of age have not been established. The manufacturer states that midodrine hydrochloride dosage adjustment based solely on age is not necessary in geriatric patients. Dosage adjustment based solely on gender also is not necessary.

Dosage in Renal and Hepatic Impairment

The manufacturer recommends that renal function be assessed prior to initiating midodrine therapy.Because the drug’s active metabolite (desglymidodrine) is eliminated by renal excretion and because safety and efficacy have not been studied systematically in patients with renal impairment to date, the manufacturer states that midodrine should be dosed cautiously in patients with abnormal renal function.The manufacturer recommends that midodrine hydrochloride therapy be initiated with 2.5-mg doses in such adults. Desglymidodrine is dialyzable.Midodrine has not been studied systematically in patients with hepatic impairment, and the effect of alterations in hepatic function on the disposition of the drug currently is not known.Therefore, while the manufacturer currently makes no specific recommendations for dosage adjustment in patients with hepatic impairment, midodrine should be used with caution in such patients.



Description


Midodrine is a synthetic sympathomimetic amine that is structurally similar to methoxamine. Midodrine is a prodrug and has little pharmacologic activity until metabolized to desglymidodrine .Desglymidodrine is a relatively long-acting α1-selective adrenergic agonistthat acts almost exclusively by a direct effect on peripheral α-adrenergic receptors of the arterial and venous vasculature, increasing vascular tone.Total peripheral resistance is increased,resulting in increased systolic and diastolic blood pressure. Standing blood pressure is increased by about 10–30 mm Hg 1 hour after a 10-mg dose of midodrine hydrochloride in patients with orthostatic hypotension, with some effect persisting for 2–3 hours;a 10-mg dose of the drug produces only modest elevations in supine and standing blood pressure in healthy individuals. Some evidence suggests that midodrine’s efficacy in improving standing blood pressure also may result in part from increased body weight during therapy with the drug, presumably secondary to expansion of extracellular fluid volume.Unlike most vasopressors, midodrine has virtually no stimulant effect on β-adrenergic receptors, including those of the heart. In addition, because desglymidodrine crosses the blood-brain barrier poorly, the drug generally does not appear to produce appreciable CNS stimulation. Because midodrine stimulates the trigone and sphincter of the urinary bladder, symptoms of urinary urgency can occur.The drug also stimulates pilomotor muscles, resulting in pilomotor effects (e.g., goose bumps, sensation of hair standing on end),and contracts the radial muscle of the iris, resulting in pupillary dilation. For additional information on this drug until a more detailed monograph is developed and published, the manufacturer’s labeling should be consulted. It is essential that the labeling be consulted for detailed information on the usual cautions, precautions, and contraindications.


Adverse Effects List from First Databank




More Frequent

BURNING,ITCHING,PRICKLING OF SCALP, CHILLS, HYPERTENSION (severe), SUPINE HYPERTENSION (severe), URINARY FREQUENCY, URINARY RETENTION

Less Frequent

ANXIETY ,CONFUSION ,DRY MOUTH ,FACIAL FLUSHING ,,HEADACHE NERVOUSNESS ,SKIN RASH ,VASODILATION ,

Rare or Very Rare

BACKACHE ,BRADYCARDIA severe ,CANKER SORE ,DIZZINESS ,DROWSINESS ,DRY SKIN, FLATULENCE ,GASTROINTESTINAL DISTRESS ,HEARTBURN ,INSOMNIA ,LEG CRAMPS ,NAUSEA ,VISUAL FIELD DEFECT ,WEAKNESS


Drug Disease Contraindications from First DataBank

• Urinary Retention
• Acute Renal Disease
• Congestive Heart Failure
• Angina Pectoris
• Severe Uncontrolled Hypertension
• Thyrotoxicosis
• Pheochromocytoma
Lactation Precautions

PRECAUTION


• NO DATA AVAILABLE.
• EFFECT ON THE INFANT IS UNKNOWN

Pregnancy Precautions

ANIMAL STUDIES HAVE SHOWN ADVERSE EFFECT ON FETUS BUT NO WELL-CONTROLLED STUDIES IN HUMANS: POTENTIAL BENEFITS MAY WARRANT USE IN PREGNANT WOMEN DESPITE POTENTIAL RISKS; OR NO ANIMAL REPRODUCTION STUDIES AND NO ADEQUATE AND WELL-CONTROLLED STUDIES IN HUMANS.


Preparations


Midodrine Hydrochlorider
Oral
ProAmatine® (scored),Tablets
2.5 mg, 5 mg

Thursday, July 31, 2008

Complications of Transjugular Intrahepatic Portosystemic Shunt

Complications of Transjugular Intrahepatic Portosystemic Shunt

Procedural complications are generally seen in 10% or fewer patients after TIPS.Severe life-threatening bleeding has been reported in 1% to 2% of cases because of either puncture of the liver capsule with resulting hemoperitoneum or inadvertent puncture of the biliary tree with resulting hemobilia. Other major complications include contrast medium induced renal failure, heart failure, stent migration, fever, infection, transient arrhythmias, and inadvertent puncture of the gallbladder or other organs adjacent to the liver. Hemolysis, which is typically self-limited and mild, is not uncommon after TIPS.
Although procedural complications are relatively infrequent, hepatic encephalopathy is a common complication after TIPS, with a frequency in the range of 20% to 30%. This figure is not unexpected: TIPS represents a side-to-side portosystemic shunt that often results in complete diversion of portal flow, as well as a proportion of hepatic arterial blood flow, into the shunt (hepatofugal flow).

Related to post-TIPS encephalopathy, but much more ominous, is the development of accelerated liver failure after TIPS as a result of a critical loss of hepatic perfusion. A retrospective study at the University of California, San Francisco, noted clinically significant increases in serum bilirubin or alanine aminotransferase levels or prolongation of the prothrombin time in over one fourth of patients after TIPS.This deterioration in liver function is typically transient, but in a minority (about 5%) of patients progressive liver failure develops leading to expedited liver transplantation or death. Determining the natural history of liver function after TIPS will be an important challenge in the years to come and will be important for the understanding of the long-term utility of TIPS as well as for optimal patient selection.


The 30-day mortality rate after TIPS varies from 3% to 44% but is typically in the range of 10% to 15%.Appropriate patient selection is the key to reducing the mortality rate after TIPS. Death after TIPS is usually related to decompensated hepatic function and is caused by liver failure, infection, renal insufficiency, or multisystem organ failure. The paradox is that patients in whom TIPS is most clearly indicated for refractory bleeding or ascites often have advanced liver disease and are at greatest risk of dying after the procedure. Identification of specific prognostic factors that will help identify patients at greatest risk of death after TIPS has therefore been undertaken in a number of studies. Independent prognostic variables identified in these studies have been used to formulate models and nomograms that can be used to calculate risk scores and the probability of short-term mortality after TIPS.Although this approach is clearly valuable, none of the predictive models published to date has been validated independently and prospectively. They are best used currently to complement clinical judgment and to counsel patients and their families accordingly. Another major problem that has limited the utility of TIPS is occlusion or stenosis of the shunt. Narrowing or occlusion of TIPS stents may occur as an early event secondary to thrombosis or more chronically over a period of weeks or months as a result of pseudointimal hyperplasia. The latter occurrence is the much more common cause of significant shunt insufficiency after TIPS. From 30% to 50% of cases of shunt insufficiency present with recurrent variceal hemorrhage or ascites; the remainder are discovered during routine monitoring, a practice necessitated by the high frequency of shunt dysfunction.The actuarial frequency of shunt insufficiency ranges from 30% to 50% at 12 months and 47% to 68% at 24 months.[The higher frequencies of shunt insufficiency reported by some centers reflect, in part, a more aggressive approach to monitoring of TIPS patency with frequent venography, as well as classification of any narrowing as an abnormality. A more conservative and practical approach is to monitor shunt patency every 3 to 4 months by Doppler ultrasound, with venography performed when a suggestive ultrasonographic abnormality is found.Such abnormalities include a reduction in mean peak flow velocity in the TIPS below 0.5 m/second, reversal of previous hepatofugal flow to hepatopetal flow, and reversal of flow in the stented hepatic vein. Useful venographic criteria for shunt insufficiency include narrowing of the lumen by 75% or more or a pressure gradient across the shunt of 15 mm Hg or higher.

The development of strategies to prevent shunt stenosis is the focus of active research. Potential strategies include pharmacologic approaches to reduce shunt intimal hyperplasia, the primary cause of stenosis, and engineering and testing of stents covered by selectively permeable materials like polytetrafluoroethylene.