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Midodrine or 2-amino-N- 2-(2,5 –
dimethoxyphenyl) -2 – hydroxy – ethyl – acetamide is an
antihypotensive agent which regulate or raise the reduced blood
pressure (1,2).
This vasopressor agent is widely available as Midodrine Hydrochloride
tablets for the patients of postural hypotension and autonomic
nervous system dysfunction. Significance of midodrine was first
reported in 1976 as a new alpha- adrenergic stimulating agent by a
Pittner et.al group (3,4).
The team was fascinated with midodrine’s longer time period
function with good efficacy upon oral administration, which then
contradicted its metabolite, an active alpha adrenergic receptor
stimulating agent but with shorter action period.

CHEMICAL STRUCTURE

Looking at its chemical name one
can derive its structure with characteristic phenyl ring with two
methoxy group and a long chain of hydroxyethylacetamide attached with
carbon 1 of phenyl ring (1).

A
B

But as a drug it is
available as :

chemspider.com

PubChemCID: 18340

?1-adrenergic receptor is the
G-protein coupled receptor(GPCR) which is primarily known to regulate
the smooth muscle contraction. Among all, the smooth muscle cells of
blood vessels are mostly benefited with the ?1 adrenergic receptors
and these receptors are vastly present in blood vessels of skin,
kidney, and brain (5,6).
During hypotension, the blood pressure falls due to delay in the
constriction of the blood vessels. The administration of midodrine
results to formation of desglymidodrine (an active metabolite) which
being alpha1 adrenergic receptor agonist activates the receptor
resulting to increase in the vascular tone and ultimately leading to
an increase in the blood pressure. The metabolite desglymidrodrine is
unable to stimulate cardiac ? adrenergic receptor and thus avoids
any chance of vasorelaxation, making midodrine a safe option for the
patients of orthostatic hypotension (7-9).

Orthostatic hypotension(OH)
patient treated with midodrine experiences rise in systolic and
diastolic blood pressure, bypass any relapse in blood pressure while
standing up from sitting or lying.

CLINICAL TRIALS:

Jankovic.et.al on 1993 conducted
Initial trials with midodrine with 97 patients of age group varying
from 22 to 86 yrs. Patients were administered with placebo and
midodrine (dosage 2.5mg, 5 mg and 10 mg) 3 times a day for a period
of 4 weeks. 2.5mg volume was regular dose level, 5mg and 10mg was
maintained as 2.5 mg for initiation and then an increase of 2.5mg
after an interval of a week until the designated dose is reached.
Improvement of systolic blood pressure at 1 hour post dose
administration and increase in standing systolic blood pressure by
22mmHg concluded midodrine to be effective and well tolerated
treatment with mild to moderate side effects for the patients with
moderate to severe orthostatic hypotension that too associated with
autonomic failure(10).
Contradicting studies by Kaufmann.et.al published in 1998 (11)
reported patients which preserves minimum autonomic cardiovascular
reflexes will show positive results to orthostatic hypotension upon
treatment with midodrine, but not those with deminished baroreceptor
activity will create depletion in extracellular fluid volume
resulting to worsening of orthostatic hypotension.

The property of midodrine to
regulate orthostatic hypotension also been useful on other aspects,
such is a case study by Hurst GC.et.al has emphasized upon the role
of midodrine into OH patients undergoing kidney/pancreas(KP) or only
Pancreas (PA) transplant.(12)
7 KP and 1 PA recipient with OH when administered with midodrine of
mean dose 18mg/day which later settled to 30mg/day, registered a
record improvement in systolic blood pressure highlighting a mean
orthostatic change of 27mmHg from 43mmHg pre midodrine state in
patients. Unchanged Serum creatinine (SrCr) level from 1.4 to 1.3
mg/Dl between pre and post midodrine treatment respectively too
collectively suggests midodrine therapy during KP/PA transplant as
safe and effective.

Patients with symptomatic
hypotension and end stage renal disease need to undergo regular
hemodialysis, and due to hypotension the procedure of dialysis turns
up very critical. Cruz DN.et.al on 1977 published results of their
observation, where patients were administered with dose of 5 to 10mg
with mean of 5.5mg midodrine 30mins before dialysis for successive 10
dialysis sessions maintaining control (without midodrine). (13)
Observation indicated progress in intradialytic and post hemodialysis
blood pressure which too coincided with progress in symptoms which
were associated with dialysis hypotension, suggesting administration
of midodrine 30mins prior to dialysis as an effective therapy and
also recommended a follow up study with adequate patient numbers.
Later Heidi Hoeben.et.al from Yale University school of medicine
published their data supporting the benefit of midodrine treatment to
patients during hemodialysis. (14)
The trial involved treatment with cool dialysate and midodrine.
Conclusion was derived observing the Cardiac output (CO), Peripheral
Vascular resistance (PVR) and central blood volume (CBV) measurement
after 30 mins of initiation of hemodialysis and 30 mins before the
termination. The outcome of the trial on small number of 14 patients
suggests cool dialysate and midodrine both to improve intradialytic
hemodynamics in the patients with dialysis associated hypotension
mainly via preserving the CBV and CO.

Successively another study
published on 2003 by a group from Taiwan studied the effect of
midodrine undergoing hemodialysis with complication of chronic
hypotension. Only difference here is dose of 5mg midodrine was given
twice a day for 4 weeks. Result again complimented the previous study
with significant increase in mean arterial pressure ( from 79.5 +/-
4.9 to 85.0 +/- 5.1mmHg P<0.005) and total peripheral resistance (768+/- 37 to 1097 +/- 72 dyne/sec/cm-5 , P<0.01) (15). Supporting test published in 2009 by BergmanSM.et.al suggesting dialysis on poor heart condition patients become possible even while avoiding risk of heart failure. (16) Other trials were also followed on the same path i.e Midodrine via regulating symptomatic hypotension also have eased the heart failure therapy via optimizing the uptake of neurohormonal blocking agent (20). This was trial conducted by Ramzan z Zakir.et.al on 10 patients with advanced heart failure due to systolic dysfunction or symptomatic hypotension.(17) The midodrine therapy of 5mg to 10mg for the period of 6 months reflected improvement in blood pressure along with reduction in left ventricular end-diastolic diameter (LVEDD) and B-Type natriuretic peptide level. A new aspect of midodrine was tried on 185 Spinal cord injured (SCI) patients who had lost capability of ejaculation due to loss in blood pressure. (18-19)The patients even failed to respond to peniel vibratory stimulation, thus resorting to midodrine therapy 30 to 120 mins before new stimulation. Dosage was maintained from 7.5mg to 30mg in weekly basis. The trial ended up with moderately increasing mean arterial pressure in all the patients stimulating antigrade or retrograde ejaculation in 64.6% of patients. Midodrine has appeared to be safe and well tolerated therapy for older patients with orthistatic hypotension, vasovagal syncope and vasodepressor as daily dosage of 2.5mg(thrice/day) for 2.7yrs have reported 71% success rate. (21)At the same time midodrine has also been a remedy for children with Postural Orthostatic Trachycardia Syndrome (POTS). (22)The trial constitutes of 55 POTS patients were grouped into 3 groups, group 1 receiving midodrine + conventional therapy, group 2 metropolo + conventional therapy and last group 3 only conventional therapy. Patients treated for 3 to 6 months showed cure rate for group 1 (68.42% vs 42.11% vs 20%) when tested against metropol + conventional therapy and conventional therapy respectively. Despite being an effective therapeutic agent for chronic OH, midodrine with dosage 5mg have been unsuccessful in reduction of prevalence of OH for early postoperative mobilization cases which is crucial for rapid recovery from major surgery such as hip arthroplasty.(23) This report also suggested need for more trials with higher dose. But on positive note, Midodrine still retained to be an effective agent to regulate intravenous vasopressor and thus be helpful to patient in leaving ICU without any persistent hypotension, making the medical affair a cost effective for patients and the efficient for the hospital.(24) FDA Midodrine was first approved to be used for treatment of dysautonomia and orthostatic hypotension on 1996 by Food and Drug Administration with warnings of its role in elevation of supine blood pressure and to be used by only critical patients and have been refrained from regular usage. Although on August 2010, FDA proposed of withdrawing its approval due to failure of completing study by manufacturer Shire plc, but in September 2010 FDA reversed its decision.(2)