FACULTY OF PHYSICAL THERAPY

SINAI UNIVIRISITY

Activity (2)

Name: shereen hosney hassan mohammed

ID:201917037

Lecture: Saturday 11am& Sunday 11 am

Under supervision of: Dr.Hassan ElFayoumy

1
(2) A-digoxin
Pharmacokinetics: Digoxin is usually given orally, but can also
be given by IV injection in urgent situations (the IV injection
should be slow, and heart rhythm should be monitored). While IV
therapy may be better tolerated (less nausea), digoxin has a very
long distribution half-life into the cardiac tissue, which will delay
its onset of action by a number of hours. The half-life is about 36
hours for patients with normal renal function, digoxin is given
once daily, usually in 125 μg or 250 μg doses.[citation needed]
Digoxin elimination is mainly by renal excretion and involves P-
glycoprotein, which leads to significant clinical interactions with
P-glycoprotein inhibitor drugs. Examples commonly used in
patients with heart problems include spironolactone, verapamil and
amiodarone. In patients with decreased kidney function the half-
life is considerably longer, along with decrease in Vd (volume of
distribution), calling for a reduction in dose or a switch to a
different glycoside, such as digioxtin (not available in the United
States), which has a much longer elimination half-life of around
seven days and is eliminated by the liver.
Effective plasma levels vary depending on the medical indication.
For congestive heart failure, levels between 0.5 and 1.0 ng/ml are
recommended. This recommendation is based on post hoc analysis
of prospective trials, suggesting higher levels may be associated
with increased mortality rates. For heart rate control (atrial
fibrillation), plasma levels are less defined and are generally
titrated to a goal heart rate. Typically, digoxin levels are
considered therapeutic for heart rate control between 0.5 and 2.0
ng/ml (or 0.6 and 2.6 nmol/l). In suspected toxicity or
ineffectiveness, digoxin levels should be monitored. Plasma
potassium levels also need to be closely controlled (see side
effects, below).
Quinidine, verapamil, and amiodarone increase plasma levels of
digoxin (by displacing tissue binding sites and depressing renal
digoxin clearance), so plasma digoxin must be monitored carefully
when co administered.
A study which looked to see if digoxin affected men and women
differently found that digoxin did not reduce deaths overall, but did
result in less hospitalization. Women who took digoxin died "more
frequently" (33%) than women who took placebo (29%). Digoxin
increased the risk of death in women by 23%. There was no
difference in the death rate for men in the study.
Digoxin is also used as a standard control substance to test for P-
glycoprotein inhibition

Uses: -The most common indications for digoxin are atrial

fibrillation and atrial flutter with rapid ventricular response, though
beta blockers and/or calcium channel blockers may be preferred in
some patients, such as those without heart failure or hemodynamic
instability.
-Digoxin increases the risk of death, while another reported no
change in mortality. It has been suggested that the effect on
mortality seen in some studies was due to inappropriately high
doses of digoxin and that the low doses often used in practice
(levels <0.9 ng/ml) may not increase mortality. Cardiac
arrhythmias may also occur when patients are prescribed digoxin
alongside thiazides and loop diuretics.
-Digoxin is no longer the first choice for heart failure; it has fallen
out of favor in people with heart failure because it may increase the
risk of death. Currently, the recommendation for heart failure is a
triple therapy of ACE inhibitor, beta blocker and mineralocorticoid
antagonists. Digoxin is a third-line therapy.
-Digoxin is also used intrafetally or amniotically during abortions
in the late second trimester and third trimester of pregnancy. It
typically causes fetal demise (measured by cessation of cardiac
activity) within hours of administration.
Possible routes: oral, intravenous and intermuscular
Dose: oral solution
0.05mg/mL
injectable solution
0.1mg/mL
0.25mg/mL
tablet
0.0625mg (Lanoxin only)
0.125mg
0.1875mg (Lanoxin only)
0.25mg Atrial Fibrillation
Rapid digitalizing (loading-dose) regimen
IV: 8-12 mcg/kg (0.008-0.012 mg/kg) total loading dose;
administer 50% initially; then may cautiously give 1/4 the loading
dose q6-8hr twice; perform careful assessment of clinical response
and toxicity before each dose
PO: 10-15 mcg/kg total loading dose; administer 50% initially;
then may cautiously give 1/4 the loading dose q6-8hr twice;
perform careful assessment of clinical response and toxicity before
each dose
Maintenance
PO: 3.4-5.1 mcg/kg/day or 0.125-0.5 mg/day PO; may increase
dose every 2 weeks based on clinical response, serum drug levels,
and toxicity
IV/IM: 0.1-0.4 mg qDay; IM route not preferred due to severe
injection site reaction
Heart Failure
As per ACCF/AHA guidelines, a loading dose to initiate digoxin
therapy in patients with heart failure is not necessary
0.125-0.25 mg PO/IV qDay; higher doses including 0.375-0.5
mg/day rarely needed
Use lower end of dosing (0.125 mg/day) in patients with impaired
renal function or low lean body mass
B-losartan: Pharmacokinetics
Losartan is well absorbed following oral administration and
undergoes significant first-pass metabolism to produce the 5-
carboxylic acid metabolite, designated as EXP3174. About 14% of
an oral dosage is converted to this metabolite, which is long-acting
(6 to 8 hr) and a noncompetitive antagonist at the AT1 receptor,
contributing to the pharmacological effects of losartan. EXP3174
is 10-40 times more potent in blocking AT1 receptors than
losartan. In addition, the binding to the target enzyme is pH-
sensitive, and the negatively-charged tetrazole ring, which is
similar in size to the negative carboxylic acid derivative, may
contribute to the activity of the drug.Losartan's bioavailability is
about 33%.
Metabolism is primarily by cytochrome P450 isoenzymes CYP2C9
and CYP3A4. Peak plasma concentrations of losartan and
EXP3174 occur about one hour and three to four hours,
respectively, after an oral dose. Both losartan and EXP3174 are
more than 98% bound to plasma proteins. Losartan is excreted in
the urine, and in the feces via bile, as unchanged drug and
metabolites. About 4% of an oral dose is excreted unchanged in
urine, and about 6% is excreted in urine as the active metabolite.
The terminal elimination half-lives of losartan and EXP3174 are
about 1.5 to 2.5 hours and 3 to 9 hours, respectively.Losartan and
other angiotensin-receptor antagonists exhibit fetal toxicity and
should be avoided during pregnancy, particularly in the second and
third trimesters.
Uses: Losartan is used for hypertension, including in people with
left ventricular hypertrophy (enlarged heart muscle), and kidney
dysfunction among type II diabetics. It may also delay progression
of diabetic nephropathy. It is a suitable pharmacological agent for
the reduction of renal disease progression in patients with type 2
diabetes, hypertension, and microalbuminuria (>30 mg/24 hours)
or proteinuria (>900 mg/24 hours).
Although evidence shows calcium channel blockers and thiazide-
type diuretics are preferred first-line treatments for most people
(due to both efficacy[medical citation needed] and cost), an
angiotensin II receptor antagonist such as losartan is recommended
as first-line treatment in people under the age of 55 who cannot
tolerate an ACE inhibitor. One study demonstrated losartan was
superior to atenolol in the primary prevention of adverse
cardiovascular events (myocardial infarction or stroke), with a
reduction in cardiovascular morbidity and mortality for a
comparable reduction in blood pressure. The maximal effects on
blood pressure usually occur within 3–6 weeks of starting losartan
Mechanism of action: Losartan is a selective, competitive
angiotensin II receptor type 1 (AT1) antagonist, reducing the end
organ responses to angiotensin II. Losartan administration results
in a decrease in total peripheral resistance (afterload) and cardiac
venous return (preload). All of the physiological effects of
angiotensin II, including release of aldosterone, are antagonized in
the presence of losartan. Reduction in blood pressure occurs
independently of the status of the renin–angiotensin system. As a
result of losartan dosing, plasma renin activity increases due to
removal of the angiotensin II feedback. Renin is released from the
kidneys when there is reduced renal arterial pressure, sympathetic
activation, or increased sodium delivery to the distal renal tubule.
Renin then acts by converting angiotensinogen to angiotensin I;
angiotensin converting enzyme (ACE) converts angiotensin I to
angiotensin II; angiotensin II causes vasoconstriction and
aldosterone release. Aldosterone serves to retain sodium from the
distal renal tubule. Sodium retention ultimately results in increased
blood pressure. Therefore, the use of angiotensin II receptor
antagonists like losartan result in blocking the downstream effect
of renin, angiotensin II, and ultimately decreasing blood pressure.
Angiotensin II receptor antagonists include losartan, valsartan,
azilsartan, candesartan, eprosartan, irbesartan, olmesartan, and
telmisartan. They all have the same mechanism of action and
potentially inhibit the actions of angiotensin better than ACE
inhibitors, such as lisinopril, because there are other enzymes than
ACE that have the capability of producing angiotensin II.
Possible routes: Oral Administration
Dose: Hypertension
50 mg PO qDay initially; may increase to up to 100 mg/day
Patients with possible intravascular depletion or receiving diuretics
(eg, on diuretic therapy): 25 mg PO qDay initially
Hypertension with Left Ventricular Hypertrophy
Indicated to reduce risk of stroke in patients with hypertension and
left ventricular hypertrophy, but there is evidence that this benefit
does not apply to Black patients
50 mg PO qDay initially; may increase to up to 100 mg/day
Hydrochlorothiazide 12.5 mg PO qDay may be added in
combination; may increase to up to 25 mg/day
Nephropathy in Type 2 Diabetes
Indicated for diabetic nephropathy with an elevated serum
creatinine and proteinuria (urinary albumin to creatinine ratio ≥300
mg/g) in patients with type 2 diabetes and a history of hypertension
50 mg PO qDay initially; may increase to up to 100 mg/day
Dosage Modifications
Renal impairment
Mild, moderate, or severe: No dosage adjustment necessary, except
if the patient is volume depleted
Hepatic impairment
Mild-to-moderate: 25 mg PO qDay initially
C-Diltiazem
Pharmacokinetics: Diltiazem is well absorbed from the
gastrointestinal tract and is subject to an extensive first-pass effect,
giving an absolute bioavailability (compared to intravenous
dosing) of about 40%. CARDIZEM undergoes extensive
metabolism in which 2% to 4% of the unchanged drug appears in
the urine. In vitro binding studies show CARDIZEM is 70% to
80% bound to plasma proteins. Competitive in vitro ligand binding
studies have also shown CARDIZEM binding is not altered by
therapeutic concentrations of digoxin, hydrochlorothiazide,
phenylbutazone, propranolol, salicylic acid, or warfarin. The
plasma elimination half-life following single or multiple drug
administration is approximately 3.0 to 4.5 hours. Desacetyl
diltiazem is also present in the plasma at levels of 10% to 20% of
the parent drug and is 25% to50% as potent as a coronary
vasodilator as diltiazem. Minimum therapeutic plasma levels of
CARDIZEM appear to be in the range of 50 to 200 ng/mL. There
is a departure from linearity when dose strengths are increased. A
study that compared patients with normal hepatic function to
patients with cirrhosis found an increase in half-life and a 69%
increase in AUC (area-under-the-plasma concentration vs. time
curve) in the hepatically impaired patients. A single study in nine
patients with severely impaired renal functions showed no
difference in the pharmacokinetic profile of diltiazem as compared
to patients with normal renal function.
Uses: Diltiazem is indicated for:
Stable angina (exercise-induced) – diltiazem increases coronary
blood flow and decreases myocardial oxygen consumption,
secondary to decreased peripheral resistance, heart rate, and
contractility.
Variant angina – it is effective owing to its direct effects on
coronary dilation.
Unstable angina (preinfarction, crescendo) – diltiazem may be
particularly effective if the underlying mechanism is vasospasm.
Myocardial bridge
Dysmenorrhea
For supraventricular tachycardia (PSVT), diltiazem appears to be
as effective as verapamil in treating re-entrant supraventricular
tachycardia.
Atrial fibrillation or atrial flutter is another indication. The initial
bolus should be 0.25 mg/kg, intravenous (IV).
Because of its vasodilatory effects, diltiazem is useful for treating
hypertension. Calcium channel blockers are well tolerated, and
especially effective in treating low-renin hypertension.
It is used as topical application for Anal Fissures as it promotes
healing of fissures due to its vasodilatory property.
Mechanism of action: Diltiazem, also known as (2S,3S)-3-
acetoxy-5-[2-(dimethylamino)ethyl]-2,3-dihydro-2-(4-
methoxyphenyl)-1,5-benzothiazepin-4(5H)-one hydrochlorid has a
vasodilating activity attributed to the (2S,3S)-isomer.Diltiazem is a
potent vasodilator, increasing blood flow and variably decreasing
the heart rate via strong depression of A-V node conduction. It
binds to the alpha-1 subunit of L-type calcium channels in a
fashion somewhat similar to verapamil, another
nondihydropyridine (non-DHP) calcium channel blocker.It is a
potent and mild vasodilator of coronary and peripheral vessels,
respectively,which reduces peripheral resistance and afterload,
though not as potent as the dihydropyridine (DHP) calcium
channel blockers. This results in minimal reflexive sympathetic
changes.Diltiazem has been shown to increase exercise tolerance,
probably due to its ability to reduce myocardial oxygen demand.
This is accomplished via reductions in heart rate and blood
pressure at submaximal and maximal workloads. Diltiazem is a
potent dilator of coronary arteries, both epicardial and
subendocardial
Possible route: Oral route.
Dose: Angina
Conventional: 30 mg PO q6hr; increased every 1 or 2 days until
angina controlled (usually 180-360 mg/day PO divided q6-8hr);
not to exceed 360 mg/day
Cardizem CD, Cartia XT, Dilt-CD: 120-180 mg/day PO; titrate
over 7-14 days; maintenance range usually 120-320 mg/day; not to
exceed 480 mg/day
DilacorXR, Dilt-XR: 120 mg/day PO; titrate after 7-14 days;
maintenance range usually 120-320 mg/day; not to exceed 540
mg/day
Tiazac, Taztia XT: 120-180 mg/day PO; titrate after 7-14 days;
maintenance range usually 120-320 mg/day; not to exceed 540
mg/day
Cardizem LA, Matzim LA: 180 mg/day PO; titrate after 14 days;
maintenance range usually 120-320 mg/day; not to exceed 360
mg/day
Hypertension
Cardizem CD, Cartia XT, Dilt-CD: 180-240 mg/day PO; titrate
after 14 days; maintenance range usually 180-420 mg/day; not to
exceed 480 mg/day
Dilacor XR, Dilt-XR: 180-240 mg/day PO; titrate after 14 days;
maintenance range usually 180-420 mg/day; not to exceed 540
mg/day
Tiazac, Taztia XT: 120-240 mg/day PO; titrate after 14 days;
maintenance range usually 180-420 mg/day; not to exceed 540
mg/day
Cardizem LA, Matzim LA: 180-240 mg/day PO; titrate after 14
days; maintenance range usually 120-540 mg/day
Extended-release twice-daily dosing: 60-120 mg PO q12hr; may be
adjusted after 14 days; maintenance range usually 240-360 mg/day
Paroxysmal Supraventricular Tachycardia
0.25 mg/kg (average adult dose, 20 mg) direct IV over 2 minutes;
after 15 minutes, may repeat bolus by administering 0.35 mg/kg
actual body weight over 2 min (average adult dose, 25 mg) direct
IV if first dose tolerated but response inadequate; some clinicians
suggest additional doses q15min
Use weight-based dosing for lower-body-weight patients
Continuous infusion: 10 mg/hr IV initially; increased to no more
than 15 mg/hr for up to 24 hours
Atrial Fibrillation/Flutter
0.25 mg/kg (usual adult dose, 20 mg) direct IV over 2 minutes;
after 15 minutes, may repeat bolus by administering 0.35 mg/kg
actual body weight over 2 min (average adult dose, 25 mg) direct
IV if first dose tolerated but response inadequate; some clinicians
suggest additional doses q15min
Use weight-based dosing for lower-body-weight patients
Continuous infusion: 10 mg/hr IV initially; increased to no more
than 15 mg/hr for up to 24 hours.
D-Captopril
Pharmacokinetics:Angiotensin I-converting enzyme
inhibitorshave been shown to be effective antihypertensive drugs,
lowering blood pressure in animalsand in patients with
hypertension, especially when renovascular in origin Captopril, the
first orally active drug available in this group, induces a strong
converting enzyme inhibition, reduces plasma angiotensin II
andaldosterone levels, increases plasma renin activity and produces
a significant decrease in blood pressure in hypertensive patients.
However, the correlation between blood pressure reduction and
converting enzyme inhibition remains controversial .
Furthermore,because reliable plasma assay of captopril has forlong
not been available, the possible relationships between the drug's
pharmacokinetics, its effects on the renin-angiotensin-
aldosteronesystem and its antihypertensive properties have not yet
been studied simultaneously. Therefore,the recent advent of
appropriate methods for plasma captopril determination led us to
investigate these relationships after administration of a single oral
dose of captopril to moderate hypertensive patients and to
determine whether the relative bioavailability of the drug could be
predictive of hypertensive patients' potential responsiveness to
captopril's blood pressure lowering effects.
. To measure free or unchanged captopril concentrations, a
chemical stabiliser must be added to the biological samples to
prevent the formation of captopril disulphides ex vivo. In healthy
subjects given captopril intravenously, the body clearance of
captopril and steady-state volume of distribution were about 0.7
L/h/kg and 0.8 L/kg, respectively. The elimination half-life of
unchanged captopril was approximately 2 hours. The primary route
of elimination of captopril is the kidney. The renal clearance of
unchanged captopril exceeds the glomerular filtration rate, due to
active tubular secretion of the drug. In healthy subjects, about 70 to
75% of an oral dose is absorbed and the bioavailability of captopril
is approximately 65%. Peak blood concentrations are reached
about 45 to 60 minutes after oral administration. The
bioavailability of captopril is not altered by age or concomitant
medications including diuretics, procainamide, allopurinol,
cimetidine or digoxin. However, the co-administration of food or
antacids, or probenecid with captopril has been shown to diminish
the bioavailability of the latter and decrease its clearance,
respectively. The decreased bioavailability of captopril when taken
with meals does not significantly alter clinical responses to the
drug. Over a wide range of oral (10 to 150 mg) and intravenous
doses (2.5 to 10 mg) captopril had linear kinetics in healthy
volunteers. In healthy subjects with normal renal function and
patients with congestive heart failure given captopril 3 times daily,
blood concentrations of total captopril accumulated, whereas those
of unchanged captopril did not. Severe renal insufficiency was
associated with an accumulation of both unchanged and total
captopril.
Uses:Captopril's main uses are based on its vasodilation and
inhibition of some renal function activities. These benefits are most
clearly seen in:
-Hypertension
-Cardiac conditions such as congestive heart failure and after
myocardial infarction
-Preservation of kidney function in diabetic nephropathy.
Additionally, it has shown mood-elevating properties in some
patients. This is consistent with the observation that animal
screening models indicate putative antidepressant activity for this
compound, although one study has been negative. Formal clinical
trials in depressed patients have not been reported.
It has also been investigated for use in the treatment of
cancer.Captopril stereoisomers were also reported to inhibit some
metallo-β-lactamases.
Mechanism of action:There are two isoforms of ACE: the somatic
isoform, which exists as a glycoprotein comprised of a single
polypeptide chain of 1277; and the testicular isoform, which has a
lower molecular mass and is thought to play a role in sperm
maturation and binding of sperm to the oviduct epithelium.
Somatic ACE has two functionally active domains, N and C, which
arise from tandem gene duplication. Although the two domains
have high sequence similarity, they play distinct physiological
roles. The C-domain is predominantly involved in blood pressure
regulation while the N-domain plays a role in hematopoietic stem
cell differentiation and proliferation. ACE inhibitors bind to and
inhibit the activity of both domains, but have much greater affinity
for and inhibitory activity against the C-domain. Captopril, one of
the few ACE inhibitors that is not a prodrug, competes with ATI
for binding to ACE and inhibits and enzymatic proteolysis of ATI
to ATII. Decreasing ATII levels in the body decreases blood
pressure by inhibiting the pressor effects of ATII as described in
the Pharmacology section above. Captopril also causes an increase
in plasma renin activity likely due to a loss of feedback inhibition
mediated by ATII on the release of renin and/or stimulation of
reflex mechanisms via baroreceptors. Captopril’s affinity for ACE
is approximately 30,000 times greater than that of ATI.
Possible routes:Oral administration
Dose:Acute Hypertension
12.5-25 mg PO; may repeat PRN
Hypertension (Alone or with Thiazide)
Initial: 25 mg PO q8-12hr, increase gradually based on response
(may start lower in some patients)
Maintenance: 25-150 mg PO q8-12hr
450 mg/day maximum
Congestive Heart Failure (With Diuretics and Digitalis)
Initial: 6.25-12.5 mg PO q8hr in conjunction with cardiac
glycoside and diuretic therapy
Target therapy: 50 mg q8hr
450 mg/day maximum
Left Ventricular Dysfunction After Myocardial Infarction
6.25 mg PO initially followed by 12.5 mg q8hr
Increase to 25 mg PO q8hr over next few days; THEN
Target dose: 50 mg PO q8hr
Diabetic Nephropathy
25 mg PO q8hr
E-Minoxidil:
Pharmacokinetics:Minimally absorbed following topical
application to intact scalp; 1.4% of a 2% topical solution may be
absorbed.Onset of hair regrowth is variable; however, 2 or ≥4
months usually required before evidence of regrowth is observed
following topical administration with 2 or 5% topical solutions,
respectively.Not known whether topical minoxidil crosses the
placenta or is distributed into milk.Not fully determined following
topical administration; however, intact stratum corneum may serve
as a barrier that inhibits substantial diffusion of topically applied
minoxidil into systemic circulation.Not fully determined following
topical administration; however, appears to be converted in the hair
follicle to an active metabolite, minoxidil sulfate, by minoxidil
sulfotransferase.Excreted principally in urine.

Uses: Minoxidil, applied topically, is widely used for the treatment

of hair loss. It is effective in helping promote hair growth in people
with androgenic alopecia regardless of sex.Minoxidil must be used
indefinitely for continued support of existing hair follicles and the
maintenance of any experienced hair regrowth.Its effect in people
with alopecia areata is unclear.
Mechanism of action: The mechanism by which minoxidil
promotes hair growth is not fully understood. Minoxidil is an
adenosine 5'-triphosphate-sensitive potassium channel opener,
causing hyperpolarization of cell membranes. Theoretically, by
widening blood vessels and opening potassium channels, it allows
more oxygen, blood, and nutrients to the follicles. Moreover,
minoxidil contains a nitric oxide moiety and may act as a nitric
oxide agonist. This may cause follicles in the telogen phase to
shed, which are then replaced by thicker hairs in a new anagen
phase. Minoxidil is a prodrug that is converted by sulfation via the
sulfotransferase enzyme SULT1A1 to its active form, minoxidil
sulfate. The effect of minoxidil is mediated by adenosine, which
triggers intracellular signal transduction via both adenosine A1
receptors and two sub-types of adenosine A2 receptors (A2A and
A2B receptors).Minoxidil acts as an activator of the Kir6/SUR2
channel upon selective binding to SUR2.The expression of SUR2B
in dermal papilla cells might play a role in the production of
adenosine.Minoxidil induces cell growth factors such as VEGF,
HGF, IGF-1 and potentiates HGF and IGF-1 actions by the
activation of uncoupled sulfonylurea receptor on the plasma
membrane of dermal papilla cells.
A number of in vitro effects of minoxidil have been described in
monocultures of various skin and hair follicle cell types including
stimulation of cell proliferation, inhibition of collagen synthesis,
and stimulation of vascular endothelial growth factor,
prostaglandin synthesis and leukotriene B4 expression.

Minoxidil causes a redistribution of cellular iron through its

apparent capacity to bind this metal ion. By binding iron in a
Fenton-reactive form, intracellular hydroxyl radical production
would ensue, but hydroxyl would be immediately trapped and
scavenged by the minoxidil to generate a nitroxyl radical. It is
presumed that this nitroxyl radical will be capable of reduction by
glutathione to reform minoxidil. Such a process would cycle until
the minoxidil is otherwise metabolized and would result in rapid
glutathione depletion with glutathione disulphide formation and
therefore with concomitant consumption of NADPH/ NADH and
other reducing equivalents.Minoxidil inhibited PHD by interfering
with the normal function of ascorbate, a cofactor of the enzyme,
leading to a stabilization of HIF-1α protein and a subsequent
activation of HIF-1. In an in vivo angiogenesis assay, millimolar
minoxidil increased blood vessel formation in a VEGF-dependent
manner. Minoxidil inhibition of PHD occurs via interrupting
ascorbate binding to iron.The structural feature of positioning
amines adjacent to nitric oxide may confer the ability of millimolar
minoxidil to chelate iron, thereby inhibiting PHD. Minoxidil is
capable of tetrahydrobiopterin inhibition as a cofactor for nitric
oxide synthase.
Minoxidil stimulates prostaglandin E2 production by activating
COX-1and prostaglandin endoperoxide synthase-1 but inhibits
prostacyclin production. Additionally, expression of the
prostaglandin E2 receptor, the most upregulated target gene in the
β-catenin pathway of DP cells, was enhanced by minoxidil, which
may enable hair follicles to grow continuously and maintain the
anagen phase.
Due to anti-fibrotic activity of minoxidil inhibition of enzyme lysyl
hydroxylase present in fibroblast may result in synthesis of a
hydroxylysine-deficient collagen. Minoxidil can also potentially
stimulate elastogenesis in aortic smooth muscle cells, and in skin
fibroblasts in a dose-dependent manner. In hypertensive rats,
minoxidil increases elastin level in the mesenteric, abdominal, and
renal arteries by a decrease in "elastase" enzyme activity in these
tissues. In rats, potassium channel openers decrease calcium influx
which inhibits elastin gene transcription through extracellular
signal-regulated kinase ½ (ERK 1/2)-activator protein 1 signaling
pathway. ERK 1/2 increases, through elastin gene transcription,
adequately cross-linked elastic fiber content synthetized by smooth
muscle cells, and decreases the number of cells in the aorta.
Minoxidil possesses alpha 2-adrenoceptor agonist
activity,stimulates the peripheral sympathetic nervous system
(SNS) by way of carotid and aortic baroreceptor reflexes.
Minoxidil administration also brings an increase in plasma renin
activity, largely due to the aforementioned activation of the SNS.
This activation of the renin-angiotensin axis further prompts
increased biosynthesis of aldosterone; whereas plasma and urinary
aldosterone levels are increased early in the course of treatment
with minoxidil, over time these values tend to normalize
presumably because of accelerated metabolic clearance of
aldosterone in association with hepatic vasodilation.
Minoxidil may be involved in the inhibition of serotonergic (5-
HT2) receptors.
Minoxidil might increase blood-tumor barrier permeability in a
time-dependent manner by down-regulating tight junction protein
expression and this effect could be related to
ROS/RhoA/PI3K/PKB signal pathway.Minoxidil significantly
increases ROS concentration when compared to untreated cells.
In vitro Minoxidil treatment resulted in a 0.22 fold change for 5α-
R2 (p < 0.0001). This antiandrogenic effect of minoxidil, shown by
significant downregulation of 5α-R2 gene expression in HaCaT
cells, may be one of its mechanisms of action in alopecia.
Possible route:Oral administration,topical administration
Dose:Usual Adult Dose for Hypertension
Initial dose: 5 mg orally once a day
Maintenance dose: 10 to 40 mg per day
Maximum dose: 100 mg per day
Usual Pediatric Dose for Hypertension
Less than 12 years:
-Initial dose: 0.2 mg/kg orally once a day
-Maintenance 0.25 to 1 mg/kg/day
-Maximum dose: 50 mg per day
Over 12 years:
-Initial dose: 5 mg orally once a day
-Maintenance dose: 10 to 40 mg per day
-Maximum dose: 100 mg per day
Androgenetic Alopecia
Male: Apply 1 mL of 2% or 5% solution to affected areas of scalp
q12hr (qAM & qHS); no more than 2 mL in 24 hours
Female: Apply 1 mL of 2% solution or 5% foam to affected areas
of scalp q12hr (qAM & qHS)
Hair growth may require 4 months of therapy