Alfuzosin - a Selective Alpha1 Receptor Antagonist: Improving the Quality of Life
By - 07/23/2006
,
C.Vinodhini
Benign prostatic hyperplasia (BPH) is a very common non-neoplastic tumour
like enlargement of the prostate in men and considered by some as normal ageing
process[1].
Clinically BPH is characterized by lower urinary tract symptoms(urinary frequency,urgency,a
weak and intermittent stream, needing to strain, a sense of incomplete emptying
and nocturia)and can lead to complications including acute urinary retention.
The prevalence of BPH is more above the age of 50 years and its incidence
approaches 75-80% in men above 80 years [2]. The cause of BPH has
not fully established. It has been thought that the mechanism of lower urinary
tract symptoms in patient with BPH is related to both dynamic and static factors
affecting the bladder outlet.
Pharmacotherapy for BPH associated with overactive bladder symptoms[3,4,5] includes two classes of drugs.The first class are steroid 5-α reductase inhibitor (androgen receptor antagonist) like finasteride and dutasteride reduce prostate volume and symptoms scores,while increasing peak urinary flow rate.The main problem with these drugs are increases the incidence of ejaculation disorder and reduce the size of the prostate gland,thus decreasing urinary outflow obstruction but found with comparable efficacy with other classes.
The second class,the α adrenergic antagonist terazosin[6],doxazosin,alfuzosin
and tamsulosin can cause smooth muscle in the bladder and prostate to relax
resulting in an improvement in urinary flow and a reduction in symptoms of BPH.Currently
available α1 adrenoreceptor antagonist appear to possess very
similar clinical efficacy producing 15% to 25% increase in maximum flow rate
with a significant improvement in 30% to 40% of patients.The non-tissue selective
α1 blockers like prazosin, terazosin and doxazosin can elicit
postural symptoms related to orthostatic hypotension and they may cause episodes
of dizziness and somnolence as a result of distribution and action in the CNS.
The main objective of drug therapy is to reduce or alleviate lower urinary
tract symptoms to prevent complications and to minimize the adverse effects
of treatment.Uroselective α1 blockers like Alfuzosin hydrochloride
have been developed most recently to address the drawbacks of the non-selective
agents.
Alfuzosin hydrochloride acts on the dynamic components of BPH[7]
and causes significant increase in objective measures such as maximal urine
flow rate and drugs also improve semi objective symptoms.
Chemistry:
Alfuzosin a Prazosin analogue[8] having quinazoline derivative differs
from the non-tissue selective α1 blocker as a result of replacement
of the piperazine heterocycle in the latter with propylene diamine moiety in
the structure[3].It is chemically N-[3-(4-amino-6, 7-dimethoxy-2-quinazolinyl)
methyl amino] propyl] tetrahydro-2-furancarboxamide hydrochloride [7].
Its empirical
formula is C19H27N5O4.HCl
and the molecular weight
is 425.9. It is a white or almost white slightly hygroscopic crystalline powder,
Melting Point 225°C also reported as 235°C, freely soluble in water, sparingly
soluble in ethanol, practically insoluble in dichloromethane[9].
Its structural formula of alfuzosin is
Mechanism of Action:
The efficacy and importance of a1 adrenergic receptors antagonist
in the conservative treatment of benign prostatic hyperplasia are increasingly
being recognized. Alfuzosin HCl relaxes the tone of the prostate smooth muscle,
prostate capsule, bladder neck and proximal urethra. It competitively and selectively
binds to the post synaptic α1-adrenergic receptors in the lower
urinary tract. It also relaxes sympathetic nervous stimulation, reduces resting
urethral pressure and inhibits urethral hypertonia-induced sympathetic nervous
stimulation.
As an uroselective agent, alfuzosin preferentially binds to prostatic α1
receptors. Blockage of these receptors results in reduction of BPH symptoms,
improvement of urine flow and a decreased potential for hypertensive events
[10]. It dose dependently and selectively reduces urethral pressure with
a preferential relaxant activity on urethral tissues without effect on arterial
pressure [11].
Pharmacokinetics:
Absorption:
Alfuzosin is readily absorbed after oral administration and peak plasma concentrations
generally occur 0.5 to 3 hours after a dose. The bioavailability is about 64%.
The absolute bioavailability of the extended release Alfuzosin Hcl tablet is
49% following multiple dosing of 10mg extended release tablets under fed conditions,
the time to maximum concentration is 8 hours, Cmax 13.6 (SD=5.6) and AUC 0-24
(194-75) mg.h/ml. The extent of absorption is 50% lower under fasting conditions.The
oral absorption of alfuzosin is significantly aided by the presence of food,while
there is no relationship between peak plasma concentrations of alfuzosin ans
age,trough levels are positively correlated with age.The concentrations in subjects
75 and older are approximately 35% greater than in those below age 65[10,11].
Distribution:
Results of invitro studies indicate that alfuzosin is moderately, bound to
human plasma proteins i.e. 82% to 90%, with a linear binding over a wide concentration
range (5-5000mg/ml). The volume of distribution following intravenous administration
in healthing male middle aged volunteers was 3.2 lit/kg[11]..
Metabolism:
Alfuzosin undergoes extensive hepatic metabolism with 11% of the administered
dose excreted unchanged in the urine. The principal hepatic enzyme involved
is Cytochrome P450 Isoenzyme CYP3A4 in its
metabolism[11].
Excretion and Elimination:
Following oral administration of alfuzosin solution, it was found that it is 69% excreted in faeces and 24% in urine. The apparent elimination half – life is 10 hours [11]. Clearence of alfuzosin is reduced in patients with moderate or severe hepatic insufficiency(Child-Pugh categories B and C)leading to threshold to fourfold higher plasma concentration of the drug in these patients compare to healthy subjects[11].
Dose and Dosage Forms:
Dose:
In benign prostatic hyperplasia the usual dose 2.5 mg three times daily increased to 10mg once daily to be taken immediately after a meal .A modified release preparation may also used in a dose of 10mg once daily. Dose should be adjusted for those with mild hepatic insufficiency but no adjustment is needed for elderly patients or patients with renal insufficiency[10,11].At doses three to ten times higher than those required to induce significant urethral relaxation in animal models, alfuzosin shows the lowest and shortest testing hypotensive activity compared to doxazosin, tamsulosin and terazosin.
Dosage Forms:
1.UROXATRAL ® - NDA submitted
in December 2000 deemed approvable, final marketing clearance pending FDA review
of additional information requested from the manufacturer. Overseas trademark
for the 10 mg once daily formulation of alfuzosin for the treatment of BPH in
U.S.XATRAL 2.5 mg administered 3 times a day and XATRAL SR 5 mg administered
twice a day are also approved overseas but are not approved or available in
the U.S.
2.ALFUSIN – By Cipla each tablet contain 10 mg of extended release Alfuzosin
Hcl.
3.ALFOO - BY Dr.Reddy’s,each tablet contain 10 mg of extended
release Alfuzosin Hcl[11].
Adverse Effects:
Alfuzosin was well tolerated in clinical trials. The most commonly reported vasodilatorside effects include orthostatic hypotension, headache,
dizziness and tachycardia[10]. The following adverse effects are listed alphabetically by body system and by decreasing frequency within body system:
Body as a whole : Pain
Gastrointestinal System : Abdominal pain, dyspepsia, constipation, nausea.
Reproductive System : Impotence
Respiratory System : Bronchitis, sinusitis, pharyngitis.
Adverse effects have also been reported in post marketing experience such as
rash, tachycardia,chest pain,priapism[11] .
Drug Interactions:
However interactions may be expected, alfuzosin should not be used in combination
with other alpha blockers [10].
Ø The concominant use of potent CYP3A4 inhibitors (i.e.
Ketaconazole, Itraconazole and Ritonavir) can result in prolonged alfuzosin
exposure and is therefore contraindicated.
Ø With the administration of atenolol, the Cmax and AUC of alfuzosin
increases by 28% and 21% respectively.
Ø With Diltiazem, the Cmax and AUC of alfuzosin are elevated.
Ø Precautions should be taken when administered along with drugs that cause
changes in the QT interval.
Ø Both tadalafil and vardenafil are contraindicated for use with alfuzosin.
Storage:
Alfuzosin is stored at 25°C (77°F); excursions permitted to 15 to 30°C (59°
to 86°F) protected from light and moisture. Keep alfuzosin out of reach of children
[10].
Warnings and Precautions:
As with other α blockers, some patients may experience postural hypotension
or syncope. If symptoms of angina pectoris should appear or worsen, the use
of alfuzosin should be discontinued. Caution should be exercised when alfuzosin
is administered in patients with severe renal insufficiency. Consideration should
be given in deciding to prescibe alfuzosin for patients with a known QT prolongation
or who are taking medications known to prolong QT, although there has been no
signal of torsades de pointes in extensive post marketing experience with alfuzosin
outside the U.S[3].
Advantages:
No study reported ejaculatory dysfunction in men treated with alfuzosin, an
event linked to the use of tamsulosin and to a lesser extent to terazosin and
doxazosin. Rapid onset of action and avoidance of surgery.
Once-daily dosing regimens are ideal in that they further facilitate patient compliance and typically yield a more consistent plasma concentration over a 24 hr period than multiple dose regimens[13]..
Disadvantages:
Alfuzosin does not have the subtype selectivity as tamsulosin for the a1A
and a1D. It is found from the studies that tamsulosin 0.4 mg
have fewer cardiovascular effects than alfuzosin 10 mg.
Clinical Trials:
Buzelin JM et al ,found in two placebo-controlled studies involving 588 patients
(292 receiving alfuzosin 5mg twice daily and 296 a placebo) were pooled. 51%
of the patients were more than or 65 years of age. It is found that the incidence
of withdrawal due to adverse events was lower (3.4%) in SR alfuzosin than with
placebo (5.7%) [8].
The most frequent adverse events being the gastrointestinal symptoms, respiratory
symptoms and dizziness, headache, vasodilation [8, 11, 12]. No first
day effect was observed. Symptomatic events related to vasodilation were reported
for one patient in each treatment group.
The cumulative incidence of asymptomatic orthostatic hypotension measured
during the first month of treatment was not statistically different between
SR alfuzosin and placebo. However in the 3 month study, the incidence of asymptomatic
orthostatic hypotension recorded was in favour of SR alfuzosin [8].
The use of SR alfuzosin significantly improved lower urinary tract symptoms
from the first month of treatment (pooled analysis). 42% of patients treated
with SR alfuzosin had symptoms of improvement in comparison with 32% in placebo
group. In the patients treated with SR alfuzosin, the improvements in lower
urinary tract symptoms and Cmax[11] were
maximal after 3 months of treatment and significant in comparison with
placebo.
S.Leto di priolo et al, has reported an open dose titration study of alfuzosin.
After a three week run in placebo period,12 patients with essential hypertension
received alfuzosin 5 mg oral b.d and then the dose was doubled every week, upto
a maximum of 20 mg q.i.d if the supine B.P was more than 90mmHg.The study lasted
for four weeks. Supine B.P was decreased from 160/102(day0) to 148/89 mmHg and
upright B.P from 151/102(day 0) to 137/84 mmHg. Alfuzosin did not cause any
significant change in supine or upright heart rate.
A weak but significant correlation was observed between the hypotensive effect
12 hour after drug intake and the plasma concentration of the drug at that time.
A 10% decrease in supine diastolic B.P was found at a drug plasma concentration
higher than 7ng/ml.
9 of the 1 patients reached the endpoint (supine diastolic B.P less than or
equal to 90 mmHg) at the end of 28 days:1 at the dose of 5 mg b.d,6 at 10 mg
b.d and 2 at 20 mg q.i.d.At the high dose they both complained of palpitations.
Two other patients complained of mild and transient palpitations at lower doses.
Conclusion:
The use of a1 antagonist has improved the quality of life by avoiding
the surgery in the case of urine outflow obstruction due to BPH. Hence alfuzosin
significantly improves the voiding symptoms and the urinary flow rates in patients
with BPH. Alfuzosin is found to be as effective as its other congeners (a1
antagonists) with lesser adverse events related to vasodilatory properties.
References:
1) Text book of Pathology, Harsh Mohan, Japee Brothers (P) Ltd,
5th edn; New Delhi, Medical Publishers;2005; p.743-4.
2) Lepor H. Non Operative Management of Benign Prostatic hypertrophy.
J. Urol 1989; 14; 1283-9.
3) U.S.Pharmacist, copyright 2000-2006.Jobson Publishing L.L.C.
4) Susan W. Miller, Joseph G. Ouslander, Drug therapy in overactive bladder.
Supplement B 2003,The Consultant
Pharmacist,21-28.
5) Knutson T, Edlund C, Fall M et al, BPH with coexisting overactive bladder
dysfunction-an everyday urological dilemma . Neurourol urodyn,2001;20;237-47.
6) Honkanen E,Pipuri A,Kairisalo P,Nove P,J.Med.Chem,1983;26;143.
7) Jardin A, Bansadoun H, Delanche-Carallier Mc. Attali P and the BPH-ALF Group.
Alfuzosin for treatment of benigns prostatic hypertrophy – Lancet 1991; 337
: 1457-61
8) Jargon A,Lancet, Alfuzosin a prazosin analogue and an α1
adrenoceptor antagonist especially used in urinary obstruction caused by BPH,1991;337;1457-59.
9) Clarke's Analysis of Drugs and Poisons, Anthony C Moffat, M David osselton
and Brain Widdop; 3rd edn;, London, UK Pharmaceutical Press; 2004;
2 : 598-9
10) Current Index Of Medical Sciences,91, Oct 2005[update-4],16.
11) American Journal of Health – System Pharmacy, Vol 60, Issue 14, 1426-1439.
12) Buzelin JM et al; M.C. Delanche-Carallier; S.Roth, Uroselectivity-evidence
from patients treated with slow release alfuzosin for symptomatic benign
prostatic obstruction, Br J Urol; 1997; 79; 898-906.
13) www.urotoday.com.
About Authors
C.Vinodhini, M.Pharm
*Author for Corresspondence
Lecturer, Sri Ramachandra College of Pharmacy, Sri Ramachandra Medical
College &Research Institute (D.U), Porur, Chennai-600 116.
M.V.Ramana M.Pharm
Bhupendra Shrestha M.Pharm
Dr. K.Chitra