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Drug Interactions in the Treatment of ED, LUTS and BPH: Clinically Relevant Drug­-Drug Interactions

Posted by admin on December 27th, 2009 No Comments

Clinically Relevant Drug­-Drug Interactions With the 5-Alpha-Reductase Inhibitors

Neither dutasteride nor finasteride have any clinically significant pharmacodynamic or pharmacokinetic adverse drug interactions. Studies show that the 5-alpha-reductase inhibitors do not affect the CYP 450 enzyme system. However, agents that inhibit the CYP 450 3A4 may, in theory, interfere with metabolism of these medications. Therefore, until more data are available, cautious monitoring should follow the concurrent administration of a 5-alpha-reductase inhibitor with an agent known to alter the activity of the hepatic mixed function oxidase enzyme system.

Pharmacodynamic Drug-Drug Interactions With PDE-5 Inhibitors

Pharmacodynamic drug interactions leading to precipitous hypotension and MI are clinically relevant with PDE-5 inhibitors. All selective inhibitors of cyclic GMP-specific PDE-5 are prone to clinically significant pharmacodynamic interactions with agents that produce vasodilation. The concurrent use of nitrate preparations is a contraindication to treatment with selective inhibitors of cyclic GMP-specific PDE-5. The selective inhibitors of cyclic GMP-specific PDE-5 differ with regard to the warning against concurrent use of with alpha-1-adrenergic blockers. For example, sildenafil in doses above 25 mg should not be used within four hours after ingestion of an alpha-1-adrenergic blocker. Vardenafil is contraindicated in patients treated with alpha-1-adrenergic blockers. Tadalafil is contraindicated in patients receiving an alpha-1-adrenergic blocker, with the exception of those taking tamsulosin 0.4 mg once daily. Extreme caution should be employed when any PDE-5 inhibitors are used in patients receiving antihypertensive medications (e.g., nitroprusside, nitroglycerin, phentolamine, amyl nitrate, ACE inhibitors, angiotensin receptor blockers, hydralazine, and nitrates) because the vasoactive effects of the combination may be exaggerated. Lastly, the concurrent administration of PDE-5 inhibitors and opiates (e.g., dihydrocodeine) results in exaggerated release of cyclic GMP and has been reported to produce priapism. An increased risk of cardiac events has been suspected with these agents when given concurrently with vasoactive agents that may steal blood from the cardiac collateral circulation.

Pharmacokinetic Drug­-Drug Interactions With PDE-5 Inhibitors

There are increasing numbers of patients with ED who are taking concurrent medications that can affect the metabolism of PDE-5 inhibitors. Medications that inhibit CYP3A4 (e.g., protease inhibitors, azole antifungals, erythromycin, and grapefruit juice) will significantly alter the metabolism and raise the bioavailability of PDE-5 inhibitors. These clinically significant pharmacokinetic interactions require that the dose or dosage interval of the PDE-5 inhibitor be modified to prevent drug accumulation and precipitous hypotension. Table 4 lists the drugs that may produce potentially life-threatening drug­drug interactions if used concurrently with a PDE-5 inhibitor.Although medications that induce CYP3A4 may increase the metabolism of PDE-5 inhibitors, no specific dosage adjustments are required. Lastly, studies show that PDE-5 inhibitors may be given safely with theophylline, digoxin, warfarin, antacids, glyburide, tolbutamide, and ranitidine.

Table 4. Drugs that May Produce Clinically Significant Pharmacokinetic Drug­Drug Interactions With PDE-5 Inhibitors
Sildenafil plus Mechanism Effect
Cimetidine 800 mg CYP3A4 inhibition 56% increase in sildenafil’s Cp
Erythromycin 500 mg BID CYP3A4 inhibition 182% increase in sildenafil’s AUC
Saquinavir 1.2 g BID CYP3A4 inhibition 210% increase in sildenafil’s AUC
Indinavir 800 mg TID CYP3A4 inhibition 340% increase in sildenafil’s AUC
Ritonavir 500 mg BID CYP3A4 inhibition 1,000% increase in sildenafil’s AUC
Tadalafil plus Mechanism Effect
Ketoconazole 400 mg/d CYP3A4 inhibition 312% increase in tadalafil’s AUC
Ritonavir 200 mg BID CYP3A4 inhibition 124% increase in tadalafil’s AUC
Rifampin 600 mg/d CYP3A4 induction 88% reduction in tadalafil’s AUC
Theophylline CYP1A2 substrate Pharmacokinetics were unchanged
Vardenafil plus Mechanism Effect
Cimetidine 400 mg BID CYP3A4 inhibition No effect on vardenafil’s AUC
Erythromycin 500 mg BID CYP3A4 inhibition Fourfold increase in vardenafil’s AUC
Ketoconazole 200 mg/d CYP3A4 inhibition Tenfold increase in vardenafil’s AUC
Indinavir 800 mg TID CYP3A4 inhibition 16-fold increase in vardenafil’s AUC
Ritonavir 600 mg BID CYP3A4 inhibition 49-fold increase in vardenafil’s AUC

Conclusions

Currently, the scientific literature is skewed in its content of useful information regarding potential drug interactions with alpha-1-adrenergic blockers and PDE-5 inhibitors. Most of the information on drug­drug interactions is with the older non­prostate-selective alpha-1-adrenergic blockers. The limited data available with tamsulosin and alfuzosin show that these agents are less likely to have pharmacodynamic interactions with alpha-1-adrenergic blockers than doxazosin or terazosin. Regarding pharmacokinetic interactions, tamsulosin has the lowest potential for clinically significant interactions because it undergoes minimal hepatic metabolism and is primarily eliminated via the kidneys. Fortunately, neither dutasteride nor finasteride have any clinically significant pharmacodynamic or pharmacokinetic adverse drug interactions. Because clinicians see an increasing number of patients being prescribed PDE-5 inhibitors who also have cardiovascular disease, clinicians must be vigilant about the potential for clinically significant pharmacodynamic interactions with medications that produce vasodilation or increase the release of NO. Furthermore, PDE-5 inhibitors are prime targets for clinically important drug interactions with agents that inhibit CYP3A4. Currently, there is insufficient information with which to judge the pharmacodynamic drug interaction liability of alfuzosin and of tamsulosin relative to PDE-5 inhibitors. Until such data are available, patients receiving alfuzosin or tamsulosin should be advised about the potential dangers of concomitant therapy with any of the PDE-5 inhibitors.

Posted in Benign Prostatic Hyperplasia

Drug Interactions in the Treatment of ED, LUTS and BPH: Clinically Significant Drug­-Drug Interaction

Posted by admin on December 26th, 2009 No Comments

The English-language medical literature, from 1986 to the present, was searched via the computer-based Medline system of the National Library of Medicine. The search focused on drug interaction data for the following agents: alfuzosin, doxazosin, dutasteride, finasteride, sildenafil, tamsulosin, tadalafil, terazosin, and vardenafil. Data were limited to information derived from studies of human subjects or actual patients and included premarketing and postmarketing observations. Articles reviewed included original studies, meta-analyses, and systematic reviews. Drug interactions were grouped into either pharmacodynamic interaction or pharmacokinetic interaction based on the mechanism.

Pharmacodynamic Drug­-Drug Interactions With Selective Alpha-1-Adrenergic Receptor Blockers

As a class, these agents potentiate hypotension when given concurrently with other antihypertensive agents. However, tamsulosin and alfuzosin do not cause a greater hypotensive effect when given concurrently with antihypertensive agents because tamsulosin and alfuzosin are highly selective for alpha-1-adrenergic receptors in the prostate. To evaluate the safety of a highly selective alpha-1-adrenergic blocker, Lowe studied 36 hypertensive men ages 45 years or older whose blood pressure was being controlled with maintenance doses of nifedipine (study 1), enalapril (study 2), or atenolol (study 3). All 36 subjects were treated with placebo for five days, then randomly assigned to either placebo (control group) or tamsulosin therapy (0.4 mg/day for seven days followed by 0.8 mg/day for seven days) in addition to continuing their maintenance antihypertensive therapy. Blood pressure and pulse rate were monitored over a 24-hour period on study days 4, 11, and 19. Coadministration of tamsulosin in these small studies had no clinically significant effects on the pharmacodynamic action of nifedipine, enalapril, or atenolol. It produced no clinically significant differences in pulse rate and blood pressure, did not alter electrocardiographic or Holter monitoring results, and did not cause increased side effects. Lowe concluded that a highly selective alpha-1-adrenergic blocker can be safely coadministered with the three antihypertensive agents studied and produce a favorable safety profile without having to reduce the dosage of the preexisting regimens of nifedipine, enalapril, or atenolol in patients with benign prostatic hyperplasia (BPH).

Immediate-release alfuzosin has been shown to potentiate the negative chronotropic and the vasodilatory effects of atenolol. Administration of a single dose of atenolol 100 mg with a single dose of immediate-release alfuzosin 2.5 mg in eight healthy young male subjects increased both the maximum plasma concentration (Cmax) and AUC values by 28% and 21%, respectively. Alfuzosin increased atenolol Cmax and AUC values by 26% and 14%, respectively. The combination of alfuzosin with atenolol caused significant reductions in mean blood pressure and in mean heart rate in this study. However, the immediate-release preparation used in this study bears no pharmacokinetic resemblance to the extended-release that is commercially available in the United States.

Studies show that hypertension in the elderly can be safely controlled with low-dose diuretic therapy. According to Maruenda and colleagues, men with benign prostatic hyperplasia may benefit from peripheral alpha-blocking drugs. However, drugs such as doxazosin or terazosin may further lower blood pressure and at times may be associated with orthostatic hypotension, especially if diuretics are given concomitantly. The newer, highly selective alpha-1-adrenergic receptor blockers (i.e., tamsulosin and alfuzosin) achieve relaxation of the smooth muscle of the prostate, as do terazosin and doxazosin, but without provoking changes in blood pressure, particularly orthostatic hypotension. There appears to be no adverse interaction with any other antihypertensive medication or with low-dose diuretics. In summary, when compared to doxazosin and terazosin, tamsulosin and alfuzosin produce fewer vascular side effects including dizziness, vertigo, and orthostasis, and tamsulosin and alfuzosin may be coadministered with agents such as calcium channel blockers or angiotensin-converting enzyme (ACE) inhibitors without precipitating a hypotensive response. This level of enhanced tolerability with tamsulosin and alfuzosin is attributed to the specificity of these highly selective alpha-1-adrenergic blockers for prostatic alpha1A receptors.

Pharmacokinetic Drug­-Drug Interactions With Selective Alpha-1-Adrenergic Receptor Blockers

Because the alpha-1-adrenergic receptor blockers, irrespective of their prostate-receptor selectivity, are metabolized by the CYP 450 system, there is the always potential for pharmacokinetic drug interaction. For example, studies show that cimetidine decreases the clearance of tamsulosin by 26% and increases AUC by 44%, and repeated administration of ketoconazole 400 mg produced a threefold increase in the AUC following a 10-mg single dose of extended-release alfuzosin. Although alfuzosin is highly selective for prostate gland alpha-1-adrenergic receptors, the safety and selectivity of this medication may be overshadowed by the exaggerated increase in its AUC as the result of decreased drug clearance by coadministration of potent inhibitors of CYP3A4 (e.g., amiodarone, azole antifungals, protease inhibitors, and macrolide antibiotics). Diltiazem, a moderate inhibitor of CYP3A4, increased the alfuzosin AUC by 1.5-fold but did not produce any changes in blood pressure. As tamsulosin is primarily excreted via the kidney, inhibition of hepatic mixed function oxidase enzymes is less likely to produce clinically significant drug interactions. Neither tamsulosin nor alfuzosin affect the mixed function oxidase enzyme system in the liver, and these drugs may be given concurrently with warfarin or digoxin. The recommended oral dose of tamsulosin for the treatment of mild to moderate benign prostatic hyperplasia is 0.4 mg once daily. In patients who fail to respond to the 0.4-mg dose after two to four weeks of dosing, the dose may be increased to 0.8 mg once daily. Dosage escalation does not increase the risk of pharmacokinetic interactions.

Posted in Benign Prostatic Hyperplasia

Drug Interactions in the Treatment of ED, LUTS and BPH: Selective Cyclic GMP-Specific PDE-5 Inhibitors

Posted by admin on December 25th, 2009 No Comments

Pharmacodynamics

PDE-5 inhibitors are indicated for the treatment of erectile dysfunction (ED). The physiological mechanism of penile erections involves the release of nitric oxide (NO) during sexual stimulation. Nnitric oxide activates guanylate cyclase to release copious amounts of cyclic guanosine monophosphate (GMP). Subsequently, nitric oxide and cyclic GMP cause the smooth muscle of the corpus cavernosum to relax, and as the corpus cavernosum fills with blood, the penis becomes erect. Unfortunately, the cause of erectile dysfunction in many patients is an imbalance between contraction and relaxation of the smooth muscle of the corpus cavernosum. Competitive inhibition of PDE-5 enzymes increases the intracellular stores of cyclic guanosine monophosphate and enhances the vasodilatory effects of nitric oxide. Subsequently, cyclic GMP relaxes corpus cavernosal smooth muscle cells and increases blood flow into cavernosal spaces. These changes enhance blood flow into the corpus cavernosum and increase intracavernosal pressure to produce a firm erection during sexual stimulation.

Pharmacokinetics

PDE-5 enzyme inhibitors are rapidly absorbed after oral administration, and food has minimal effect on the absolute oral bioavailability. Fatty meals will reduce the rate of absorption of sildenafil and vardenafil. In contrast, rate and extent of absorption of tadalafil are not influenced by food. Despite the rate of absorption following a fatty meal, the wide therapeutic index and efficacy observed with these agents does not warrant caution with regard to taking either sildenafil or vardenafil with food. However, all agents have significant first-pass effect. Because PDE-5 inhibitors undergo extensive hepatic metabolism, they are prone to interactions with diseases or medications that affect hepatic function. For example, in volunteers with hepatic cirrhosis (Child-Pugh A and B), clearance of sildenafil was decreased, producing an 84% increase in area under the concentration-time curve (AUC) and a 47% increase in maximum serum concentration compared with age-matched volunteers with no hepatic impairment. Sildenafil is metabolized primarily via the CYP3A4 and to a minor extent by CYP2C9 hepatic microsomal isoenzymes. The N-desmethyl metabolite has 50% of the potency of the parent drug and accounts for 20% of sildenafil’s pharmacologic effects. Tadalafil undergoes hepatic metabolism and is primarily metabolized by the CYP 450 3A4 isoenzyme to inactive metabolites. However, patients with mild to moderate hepatic dysfunction do not experience a change in the AUC of tadalafil, and there are insufficient data to assess the effect of severe hepatic failure on the pharmacokinetics of tadalafil. Hepatic insufficiency significantly reduces the clearance of vardenafil. Vardenafil is primarily metabolized in the liver by CYP3A4, and to a lesser extent, CYP3A5 and CYP2C9 isozymes. The MI metabolite of vardenafil accounts for approximately 7% of the total pharmacologic activity. Moderate to severe renal insufficiency appears to increase the bioavailability of the PDE-5 inhibitors and may predispose to clinically significant pharmacokinetic drug interactions. For example, severe renal insufficiency (i.e., CrCl < 30 mL/minute) may double the AUC of sildenafil. Normal volunteers with CrCl values below 50 mL per minute saw a 20% to 30% increase in AUC following single-dose administration of vardenafil. With tadalafil, the AUC doubled in subjects with CrCls between 30 and 80 mL per minute, and the AUC increased twofold to fourfold in patients requiring hemodialysis. Table 3 lists the pharmacokinetic properties of the PDE-5 inhibitors.

Table 3. Pharmacokinetics of Type-V Cyclic GMP­PDE-5 Enzymes
Agent/

Formulation

 Bioavailability

(%)

Protein Binding (%) Half-Life Active Metabolites Elimination

(%)

Sildenafil

Immediate-release tablets

 40 94 3.5 h Yes Bile/feces: 80

Urine: 13
Tadalafil

Immediate-release tablets

 Not known 94 17.5 h No Bile/feces: 61

Urine: 36
Vardenafil

Immediate-release tablets

 15 95 14 ­ 15 h Yes Bile/feces: 93

Urine: 6
Posted in Benign Prostatic Hyperplasia

Drug Interactions in the Treatment of ED, LUTS and BPH: 5-Alpha-Reductase Inhibitors

Posted by admin on December 24th, 2009 No Comments

Pharmacodynamics

The deficiency of 5-alpha-reductase was discovered more than 30 years ago. At this time, the role of 5-alpha-reductase inhibitors was hypothesized to be beneficial for the treatment of androgen-related diseases. Dihydrotestosterone (DHT) is the main prostatic androgen and is approximately twice as potent as testosterone; DHT binds to androgen receptors to induce androgenic effects in the prostate gland, liver, and skin. The enzyme 5-alpha-reductase is necessary to catalyze the conversion of testosterone to dihydrotestosterone. Five-alpha-reductase acts upon circulating testosterone, which when reduced to DHT accumulates in the prostate. There are two isoenzymes of 5-alpha-reductase: type 1 and type 2. The function of type 1 5-alpha-reductase is unknown. It has been found most commonly in sebaceous glands and is present in most body tissues. Type 2 5-alpha-reductase plays a role in prostate development and in the androgenic effects on the hair follicle. Finasteride inhibits mostly type 2 isoenzymes and is used for the treatment of benign prostatic hyperplasia (BPH) and alopecia. Approximately 85% to 90% of dihydrotestosterone is suppressed by the inhibition of type 2 isozymes. The remaining DHT is hypothesized to be from type 1 5-alpha-reductase. Dutasteride inhibits both type 1 and type 2 5-alpha-reductase and is also indicated for the treatment of benign prostatic hyperplasia.

Pharmacokinetics

The pharmacokinetic properties of finasteride and dutasteride are well-defined. The agents have good oral bioavailability and undergo extensive hepatic metabolism. Both agents are extensively metabolized via hepatic CYP 450 3A4 enzymes. Bioavailability is approximately 60% and is not affected by food. The half-life of both agents increases with age; however, no dosage adjustments are necessary. Biliary/fecal elimination appears to be similar, but finasteride undergoes approximately 39% renal elimination, whereas dutasteride data suggests virtually no renal elimination. Although plasma metabolites of finasteride will be higher in patients with renal impairment, the metabolites display less than 20% of the activity of the parent drug; therefore, no dosage adjustment is necessary. The effect of hepatic impairment on either agent is unknown at this time. Table 2 compares selected pharmacokinetic properties between finasteride and dutasteride.

Table 2. Pharmacokinetic Parameters of 5-Alpha-Reductase Inhibitors
Agent/

Formulation

 Bioavailability Protein Binding Half-Life Metabolites Elimination
Finasteride

Film-coated tablets

 63% ~ 90% 6 ­ 15 h Two metabolites

with < 20% activity

 Biliary (57%)

Renal (39%)
Dutasteride

Soft gelatin capsules

 59% > 99.5% 5 weeks 6-beta-

hydroxydutasteride (active)

 Fecal (~ 45%)

Renal (~ 1%)
Posted in Benign Prostatic Hyperplasia

Drug Interactions in the Treatment of ED, LUTS and BPH: Selective Alpha-1-Adrenergic Receptor Blockers

Posted by admin on December 23rd, 2009 No Comments

Pharmacodynamics

Alpha1 receptors are located in nonvascular smooth muscles (e.g., bladder trigone and sphincters, gastrointestinal tract and sphincters, prostate adenoma and capsule, and ureters) and in nonmuscular tissues (e.g., central nervous system, liver, and kidneys). Symptoms of benign prostatic hyperplasia (BPH) are related to bladder outlet obstruction, comprised of underlying static and dynamic components. The static component is associated with an increase in prostate size caused by a proliferation of smooth muscle; however, the symptoms of benign prostatic hyperplasia and degree of urinary outlet obstruction do not correlate directly with prostate size. The dynamic component is associated with the increased smooth muscle tone in the prostate and bladder neck. Administration of the alpha1-receptor antagonist affects the dynamic component by decreasing urethral resistance, relaxing smooth muscle, and improving urine flow rates in the bladder neck and prostate. Few alpha1 receptors are in the bladder body; most are located on the prostate capsule and adenoma and the bladder trigone. Thus, blocking these receptors reduces bladder outlet obstruction without affecting bladder contractility.

At least three alpha1-adrenoceptor subtypes exist: alpha1A, alpha1B, and alpha1D. Approximately 70% of the alpha1 adrenoceptors located in the prostate are of the alpha1A subtype. Both doxazosin and terazosin are nonselective alpha1 antagonists, causing a decrease in blood pressure and urinary symptoms. Alfuzosin and tamsulosin are selective for the alpha1A adrenoceptor and are less likely to cause peripheral alpha-1-adrenergic blockade and hypotension.

Pharmacokinetics

Table 1 lists the pharmacokinetic properties of the alpha-1-adrenergic receptor blockers. The bioavailability of alfuzosin is improved with food, whereas the bioavailability of tamsulosin is 30% higher when it is administered in a fasting state compared with administration in a fed state. Tamsulosin pharmacokinetic properties do not differ whether the drug is taken with a light breakfast or a high-fat breakfast. All the agents have similar protein binding and once-daily dosing because of their long half-life or extended-release formulation. Tamsulosin is primarily eliminated in the urine, whereas alfuzosin, doxazosin, and terazosin are primarily eliminated in the bile or feces. No dosing changes are needed when tamsulosin is given to patients with renal impairment. Blood alfuzosin concentrations are significantly increased in the presence of moderate to severe liver failure (i.e., Childs-Pugh categories B and C) as well as in the presence of potent inhibitors of CYP3A4; these changes may predispose to alfuzosin toxicity. Severe renal insufficiency (creatine clearance [CrCl] < 30 mL/minute) may alter the elimination of alfuzosin and raise the serum drug concentration by 50%, but there are insufficient data to determine the clinical relevance of renal insufficiency on the kinetics of alfuzosin.table 1 summarizes the pharmacokinetics of the alpha1-receptor antagonists.

Table 1. Pharmacokinetics of Alpha1-Receptor Antagonists for BPH
Agent/
Formulation		 Bioavailability
(%)		 Protein Binding (%) Half-Life Active Metabolites Elimination (%)
Alfuzosin

Extended-release tablets

 49 (with food)

25 (fasted)

 88 10 h No Bile/feces: 69

Urine: 24
Doxazosin

Immediate-release tablets

 65 98 22 h Yes Bile/feces: 63

Urine: 9
Tamsulosin

Sustained-release capsules

 90 (fasted)

60 (with food)

 94 ­ 99 14 ­ 15 h No Bile/feces: 21

Urine: 76
Terazosin

Sustained-release tablets

 90 90 ­ 94 9 ­ 12 h No Bile/feces: 60

Urine: 40
Posted in Benign Prostatic Hyperplasia

The management of benign prostatic hyperplasia: Pharmacotherapy

Posted by admin on December 21st, 2009 No Comments

Recent developments in drug therapy have reduced the number of surgical procedures needed, although in men with severe symptoms, medications may delay but not prevent the need for surgery. Pharmacotherapy has been shown to result in clinically significant subjective improvement in symptoms with fewer side effects and is a viable initial option for all men. Alpha-blockers and 5-alpha-reductase inhibitors comprise the two classes of drugs used to treat benign prostatic hyperplasia (BPH). Table 2 summarizes the pharmacokinetics, dosing, and availability of the alpha-blockers and 5-alpha-reductase inhibitors for the management of BPH.

Table 2. Pharmacokinetics, Dosing and Availability of Agents Used in BPH Therapy
Nonselective Alpha-Blockers Selective Alpha1A-Blockers 5-alpha-Reductase Inhibitors
Doxazosin
(Cardura)
Pfizer		 Terazosin
(Hytrin)
Abbott		 Prazosin
(Minipress)
Pfizer		 Tamsulosin
(Flomax)
Boehringer
Ingelheim		 Alfuzosin
(Xatral)
Sanofi-
Synthelabo		 Finasteride
(Proscar)
Merck		 Dutasteride
(Avodart)
GSK
Pharma-cokinetics
tmax 1-2 hrs <1 hr 3 hrs 4-7 hrs 9 hrs 2-6 hours 2-3 hours
t/2 22 hrs 9.2-12 hrs 2-3 hrs 9-15 hrs 9.1 hrs 3-16 hrs 5-6 weeks
Elimination Hepatic Hepatic Hepatic Hepatic
(CYP-450 undetermined)		 Hepatic Hepatic
(CYP-3A3/4)		 Hepatic
(CYP-3A3/4)
Clinical onset of action Within days to weeks Within days to weeks Within days to weeks Within days to weeks Within days to weeks 3-6 months 3-12 months
Dosing
Starting dose 0.5-2 mg QD 1 mg HS 1 mg BID 0.4 mg QD 10 mg QD 5 mg QD 0.5 mg QD
Target dose for BPH 8 mg QD 10 mg QD 2 mg BID 0.4-0.8 mg QD 10 mg QD 5 mg QD 0.5 mg QD
Availability
Approved by the FDA Yes Yes Yes Yes No Yes Yes
Generic available Yes Yes Yes No No No No
Available dosage forms 1 mg, 2 mg, 4 mg, 8 mg tabs 1, 2, 5, 10 mg caps/tabs 1 mg, 2 mg, 5 mg caps 0.4 mg caps 10 mg prolonged-release tabs 5 mg tabs 0.5 mg caps

Alpha-Blockers

Alpha-blockers act to relax smooth muscles, particularly those in the urinary tract and prostate. Studies indicate they are most beneficial in men whose prostates are not significantly enlarged. These agents tend to have an immediate beneficial effect and have minimal effect on sexual drive. By relaxing the muscles in and around the prostate, alpha-blockers increase urinary flow and improve symptoms. Because these agents are short acting, symptoms tend to return once patients stop taking the medication. Alpha-blockers are not known to affect prostate specific antigen (PSA) levels.

The alpha1A-receptor subtype is found primarily in the bladder and urethral smooth muscle whereas other alpha-receptor subtypes, such as alpha1B and alpha1D are found in peripheral tissue. Therefore, alpha-blockers can be categorized as either nonselective, for the alpha1A-, alpha1B-, and alpha1D-receptor subtypes, or selective for the alpha1A-receptor subtype. Besides relaxing smooth muscles in the prostate, nonselective alpha-blockers also cause relaxation of blood vessels, which can lead to orthostatic hypotension. Nonselective alpha-blockers indicated for the treatment of symptomatic benign prostatic hyperplasia include quinazoline derivatives, such as terazosin and doxazosin. Prazosin is also a nonselective alpha-blocker; however, it is approved for hypertension and not BPH. Selective alpha-blockers, on the other hand, affect only the tissue around the prostate and have minimal effect on lowering blood pressure. Thus, it is important for clinicians to complete a full medical history and cardiovascular workup prior to determining the most appropriate alpha-blocker for their patients.

Doxazosin, terazosin, and prazosin undergo non-cytochrome (CY) P-450 hepatic metabolism; therefore CYP-450 drug interactions are not expected. Side effects associated with nonselective alpha-blockers include dizziness, headache, rapid heartbeat, and fatigue. The manufacturer of terazosin recommends that patients take the first dose at bedtime to minimize the risk of a severe first dose syncope effect. Subsequent doses may be administered once daily in the morning or nighttime. Although the manufacturer of doxazosin does not specifically recommend initiating the first dose at bedtime, advising patients to take the first dose at nighttime may help to minimize significant side effects.

There is some concern that because nonselective alpha-blockers are not first-line treatments for hypertension they may interfere with other medications being taken in men who are treated for high blood pressure. One large study using terazosin reported no danger from adding this drug to an antihypertensive regimen. Its greatest additive impact was with diuretics, but, in general, there was little difference in blood-pressure related side effects between men who took terazosin with other antihypertensive drugs and those who took the alpha-blocker alone.

Investigators of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) recently published the results of an interim analysis that showed cardiovascular risks involving doxazosin. Subjects who took doxazosin and chlorthalidone versus chlorthalidone alone had significantly greater risks for stroke (Relative Risk [RR] = 1.19; p=0.04), cardiovascular disease (RR = 1.25; p<0.001), and congestive heart failure by two-fold (RR = 2.04; p<0.001). Participants in this trial were hypertensive patients over the age of 55 years with at least one additional risk factor for coronary heart disease. Although some experts disagree that the ALLHAT results do not have implications in benign prostatic hyperplasia, clinicians must be aware of the patient characteristics of this trial that parallel those treated for BPH.

Selective alpha-blockers include tamsulosin, which was approved by the FDA in 1997, and alfuzosin, which is not currently approved for use in the U.S. These agents target only the smooth muscle of the prostate connective tissue. In general, studies have indicated that blood pressure reductions were similar in patients taking selective alpha-blockers compared to those taking placebo. Tamsulosin is administered 0.4 mg once a day. It should be taken 30 minutes following the same meal each day. If patients fail to respond to the 0.4 mg dose after two to four weeks of therapy, the dose may be increased to 0.8 mg once a day. Tamsulosin is a sulfonamide compound. We would consider a history of severe sulfonamide reaction as an absolute contraindication, although the manufacturer’s prescribing information does not list sulfonamides as a contraindication. Tamsulosin undergoes CYP-450 hepatic metabolism, however the specific isoenzyme system has not been well elucidated. Therefore, close monitoring of patients using polypharmacy is recommended. Side effects associated with selective alpha-blockers include fatigue, dizziness, sleepiness, runny nose, headache, sore throat, and weakness. Less common are nasal congestion and sexual dysfunction, which occurs in about 2% of cases. (It is important to be aware of look-alike/sound-alike similarities between terazosin and tamsulosin.)

5-Alpha-Reductase Inhibitors

These agents inhibit production of dihydrotestosterone. Finasteride has been on the market in the U.S. since 1992 for the treatment of symptomatic benign prostatic hyperplasia. Dutasteride, another agent in this class, was approved by the FDA in 2001 and is expected to be marketed in early 2003. These agents appear to be most useful in male patients with BPH whose prostates are very large (40 mL or larger), who have low urinary flow rates, and whose condition is related primarily to hormone-stimulated overgrowth of glandular tissue. A four-year study completed in 1998 found that finasteride reduced the need for surgery (5% for the finasteride group vs. 10% for the placebo group) and the incidence of urinary retention (3% vs. 7%) in men with enlarged prostate glands who had moderate to severe symptoms. This agent has not been shown to be as beneficial in men with normal or moderately enlarged prostate glands and whose BPH symptoms are caused primarily by muscle-cell overgrowth.Finasteride has been shown to be effective in reducing urinary tract bleeding, an occasional complication of benign prostatic hyperplasia.

The normal course for finasteride is once daily for up to six months, at which time lessening of symptoms should be clearly noted. Both finasteride and dutasteride are substrates for the CYP-3A3/-3A4 isoenzyme system and thus have the potential for drug­drug interactions with inhibitors of this pathway such as the “azole” antifungals, erythromycin, and cyclosporine. The effects of inhibition may lead to the worsening of adverse effects. The manufacturer has not reported any clinically significant untoward effects with finasteride on drug­drug interactions. Induction of this metabolic pathway with phenytoin or phenobarbital, for example, may lead to treatment failure. Finasteride has been associated with sexual dysfunction, including low sexual drive and impotence. Less common side effects include abdominal pain, back pain, decreased volume of ejaculate, diarrhea, dizziness, and headache.

Finasteride may reduce prostate specific antigen levels, which can mask the presence of prostate cancer. This was seen rather consistently in patients groups of various races. In one study, serum levels of free and total PSA were measured at baseline and for as long as nine months of treatment. In the finasteride group, mean total PSA levels declined from 3.0 ng/mL at baseline to 1.5 ng/mL after six months of treatment (50% decrease, p<0.01). In the placebo group, with similar baseline prostate specific antigen levels, no significant change was observed. Prostate specific antigen density declined significantly in finasteride-treated men (p<0.01), but not in patients on placebo. The mean percent free PSA (13% to 17% at baseline) was not significantly altered by finasteride or placebo. Patients taking finasteride should be advised that doubling their prostate specific antigen value would provide a more accurate number for assessing their cancer risk.

Finasteride has been shown to reduce the need for surgery in patients with moderate-to-severe symptoms. In one four-year study, patients on finasteride demonstrated a significant decrease in the need for surgery and in the incidence of acute urinary retention.

Other Agents

Gonadotropin-releasing hormones have been used in managing benign prostatic hyperplasia but have been associated with a reduction in sexual drive and are likely to cause impotence. Flutamide may be an alternative to surgery in certain patients with BPH who have physical or mental disorders. Patients with chronic conditions are often tempted to try alternative treatments, including herbs and other nontraditional therapies. These may be of benefit, but they should not be recommended without the patient first consulting with his physician. Until scientific studies determine actual benefits, proper doses, and side effects of unregulated herbal products, the patient is at risk for ineffective or even harmful treatment.

The berry of the plant Serenoa repens, commonly known as saw palmetto, contains certain chemicals that appear to improve benign prostatic hyperplasia symptoms. These chemicals appear to inhibit production of dihydrotestosterone, although there has been little scientific research conducted to validate this effect. Saw palmetto may aggravate chronic gastrointestinal diseases, such as peptic ulcers, gastroesophageal reflux disease, and ulcerative colitis. Until further research is conducted, pharmacists should be cautious in their recommendation of saw palmetto for patients with benign prostatic hyperplasia.

Combination Therapy

As new information comes to light, a growing area of interest is progression of BPH. Evidence is mounting that the combination of an alpha-blocker with a 5-alpha-reductase inhibitor in selected patients will significantly delay clinical progression of symptoms. The results of a multicenter National Institutes of Health clinical trial presented at the May 2002 American Urological Association meeting indicated that combination therapy may be more effective than monotherapy in managing BPH. The Medical Therapy of Prostatic Symptoms (MTOPS) Trial found that combining finasteride with doxazosin reduced the risk of benign prostatic hyperplasia progression by 67% vs. placebo. This compares favorably versus using each agent singularly, as finasteride alone reduced the rate of progression by 34% and doxazosin alone reduced the rate of progression by 39%.

MTOPS studied over 3,000 men with benign prostatic hyperplasia age 50 and over for an average of 4.5 years. Patients were divided into one of four treatment groups: those taking 5 mg of finasteride, those taking 4 mg or 8 mg of doxazosin, those taking both drugs, and those taking placebo. Endpoints for the trial included preventing BPH progression (defined as a >=4-point increase in symptom score), urinary tract infections, urinary retention, incontinence, and the need for invasive therapy.

Compared to placebo, the risk of urinary retention was reduced by 79% for patients on combination therapy, 67% for patients on finasteride alone, 31% on doxazosin alone, and 28% on placebo. The risk for necessary invasive therapy was reduced by 69% in patients on combination therapy, 64% in patients on finasteride, 8% in patients on doxazosin, and 6% in patients on placebo. The study results also clearly delineated which patients were at increased risk of progression and those most likely to benefit from treatment.

Conclusion

The trend today in managing mild to moderate benign prostatic hyperplasia is pharmacotherapy, with surgery reserved for men with the most severe symptoms. Nonselective alpha-blockers have been the prototype pharmacologic treatment modality; however, it may be prudent to avoid these agents in elderly patients at risk for cardiovascular disease. Selective alpha-blockers offer an effective alternative with more tolerable side effect profiles. The use of combination therapy with alpha-blockers and 5-alpha-reductase inhibitors has been shown to be beneficial in men with moderately to severely enlarged prostates and acute urinary retention.

Posted in Benign Prostatic Hyperplasia

The management of benign prostatic hyperplasia: Behavioral Modifications

Posted by admin on December 20th, 2009 No Comments

Certain lifestyle changes can help relieve symptoms and are particularly important for patients who choose to avoid surgery or drug therapy. It is important for patients with benign prostatic hyperplasia (BPH) to urinate on a regular basis and not just in response to an urge to void. Avoiding exposure to extreme cold reduces the urge to urinate. Immobility can be detrimental to voiding, and thus men should try to sit in aisle seats in planes and theaters and avoid prolonged stretches in cars or other means of transportation. Regular exercising may be useful to relieve stress.

Avoiding alcohol, coffee, and other fluids after the evening meal is recommended. Drinking green tea, which contains flavonoids, may be of benefit. Gensini, a chemical found in soy, has been associated with a reduction in prostate tissue. Indeed, there is speculation that zinc supplementation may be helpful in treating males with BPH whose prostate is zinc deficient.

Men with benign prostatic hyperplasia should avoid prolonged use of decongestants and anticholinergics. Oral decongestants that may exacerbate benign prostatic hyperplasia include ephedrine, phenylephrine, and pseudoephedrine. Anticholinergic agents that may exacerbate BPH include first generation antihistamines (chlorpheniramine and brompheniramine), tricyclic antidepressants, and typical antipsychotics. These agents may reduce urine flow or increase prostate size in patients with benign prostatic hyperplasia. It should be noted that patients on diuretics may need to reduce their dosage or switch to another agent.

Kegel, or pelvic floor muscle, exercises may be useful in helping to prevent urine leakage. They strengthen the muscles of the pelvic floor that both support the bladder and close the sphincter. The exercises consist of repeatedly tightening and releasing the pelvic muscle. Since the muscle is difficult to isolate, patients should best perform this exercise while urinating, contracting and then relaxing the muscle to stop and then release the flow of urine. Kegel exercises should be performed three to five times a day.

Posted in Benign Prostatic Hyperplasia

Trimethoprim-sulfamethoxazole in the treatment of chronic prostatitis. Part 3

Posted by admin on December 6th, 2009 No Comments

Results

Of the 40 patients who received trimethoprim-sulfamethoxazole for 6 weeks, 9 were classed as failures. These either had no response or relapsed during therapy or relapsed after therapy with unchanged severity of symptoms.

Eleven were considered improved on the basis of continued symptomatic improvement or because of a good initial response followed by relapse with symptoms less severe than before treatment. Included in the “improved” group are two patients who initially relapsed but who have since remained asymptomatic on long-term therapy.

The 20 patients who have had continued satisfactory relief of symptoms are classified as having good results.

Discussion

An earlier controlled study compared the results of treatment with sulfamethoxazole with those from the use of trimethoprim-sulfamethoxazole. Only after 6 weeks of treatment was a significant response obtained and this influenced the choice of 6 weeks as the treatment period. A longer period of treatment (12 weeks) produced better results when trimethoprim-sulfamethoxazole (TMP-SMX) was used after a course of sulfamethoxazole. The late results, however, showed no significant differences according to the sequence in which the agents were given. In this later survey a similar success rate was obtained, namely 50% in patients with the clinical manifestations of chronic prostatitis.

When we disregarded bacterial counts of less than 3000/ml, which is standard practice, only one of the patients was reported as having a growth of Escherichia coli. This is in contrast with the earlier report, in which meticulous bacteriologic investigation, including use of anaerobic culture, showed that 66% of patients had pathogens in their prostatic fluid.

It is concluded from our results in this small series that there is justification for use of trimethoprim-sulfamethoxazole in patients with chronic prostatitis where proof of bacterial etiology is lacking. The desirability of meticulous bacteriologic studies is not disputed.

Posted in Prostatitis

Trimethoprim-sulfamethoxazole in the treatment of chronic prostatitis. Part 2

Posted by admin on December 6th, 2009 No Comments

Treatment

Antibiotic therapy with appropriate agents, even in well documented infections, rarely proved successful in the past because the diffusion of most antibacterial drugs from plasma into prostatic fluid provided too low a concentration to be effective. Of many drugs tested for diffusion across the prostatic epithelium only the basic macrolides (erythromycin and oleandomycin) achieved significant concentrations in the prostatic fluid. These drugs are ineffective against the common gram-negative organisms cultured from prostatic fluid. Trimethoprim has been shown in both dogs and man to reach higher concentrations in the prostatic fluid than in serum at the normal pH of prostatic fluid. The concentrations attained in the diseased prostate may be lower, since in prostatitis the prostatic fluid pH may be elevated, but are probably still effective. When trimethoprim is combined with a sulfonamide, synergistic antibacterial activity results, with both a bactericidal effect and delayed emergence of resistant strains. Because of a similar half-life, sulfamethoxazole has been used in the combined drug. Sulfamethoxazole attains a concentration in the prostatic fluid that is only 10% of that in the serum, but this concentration is sufficient to bring about the synergistic effects of trimethoprim-sulfamethoxazole, which has a wide range of activity against both gram-negative and gram-positive organisms.

Trimethoprim-sulfamethoxazole has previously been shown to be effective in treating chronic prostatitis. The present study was a further clinical assessment of the usefulness of this combination in clinically diagnosed chronic prostatitis.

Methods and materials

The 40 subjects in this study were patients who satisfied the criteria of clinical diagnosis, who completed a 6-week course of trimethoprim-sulfamethoxazole (two tablets twice daily) and were available for review at 6 months or later. Clinical data on these patients are set forth in Table 2. All cultures of midstream urines and cultures for tubercle bacilli were negative. Serum acid phosphatase values were normal in all. Intravenous urograms were normal and no patient had a significant amount of residual urine. Those examined by cystourethroscopy showed only changes compatible with chronic prostatitis. None of the needle biopsies of the prostate was significantly abnormal.

Table 2 — Clinical data on 40 patients with chronic prostatitis
Average age, 37.9 years. Range, 22 to 65 years
Average length of history, 2.4 years. Range 6 months to 15 years
Manifestations:

Pain

36
  • Perineum

9

  • Groin

10

  • Testis

13

  • Suprapubic

7

  • Back

12

  • Penis

11

Urinary symptoms

32
Prostatic signs

35
Previous epididymitis

7

Patients were reviewed 2 weeks after completion of treatment and again at 6 months or later. Routine bacteriologic examination of midstream urines, expressed prostatic fluid (when obtained) and postmassage urines was carried out.

Assessment was based on clinical signs and symptoms and the appraisal was made by one observer.

Posted in Prostatitis

Trimethoprim-sulfamethoxazole in the treatment of chronic prostatitis. Part 1

Posted by admin on December 6th, 2009 No Comments

Chronic prostatitis is a common condition occurring in younger men which presents problems of diagnosis and treatment. In some patients a bacterial population of known pathogens can be identified in the prostatic fluid. In many others proof of bacterial etiology is lacking. There has therefore been an acceptance of two common forms of the disease, namely chronic bacterial prostatitis and a condition that has been variously termed chronic abacterial prostatitis, nonspecific prostatitis, prostatosis and prostatic neurosis. Despite the refinements of methods of collection and bacteriologic processing of prostatic fluid, certainty of bacterial recovery cannot be assumed. The sample obtained may fail to include fluid from all parts of the gland or, in particular, from the inflamed parts of the gland. The inconsistency of recovery of bacteria from known cases of bacterial prostatitis lends support to this thesis and suggests that the segregation of chronic prostatitis into bacterial and nonbacterial groups is by no means certain. Where episodes of recurrent genitourinary infection such as cystitis, epididymitis and, less commonly, pyelonephritis occur, bacterial etiology is more likely to be established but otherwise the distinction between differing clinical entities is not obvious.

Diagnosis

The common clinical features of chronic prostatitis are summarized in Table 1. A variety of complaints, singly or in various combinations, may be elicited, the most common being urinary symptoms and discomfort and pain in various sites. Less common symptoms include hemospermia, perineal discomfort or pain after ejaculation. Others relating to sexual function are sometimes emphasized but are probably coincidental. There is considerable variation between patients in severity of symptoms but the clinical pattern appears to be consistent for individual patients.

Table 1 — Signs and symptoms of chronic prostatitis
1. Urinary

  • Irritative: dysuria, frequency, urgency
  • Obstructive: slowness, dribbling
  • Urethral discharge
2. Pain at various sites (see Table 2)
3. Prostatic changes

  • Changes in consistence
  • Irregularity
  • Tenderness

Changes are commonly detectable on rectal examination of the prostate although normal palpatory findings may be encountered. These changes include variations in:

(1) size;

(2) consistence, such as areas of softening or bogginess with or without areas of induration;

(3) contour, with irregularity of the surface; and

(4) amount of discomfort or pain on palpation.

Assessment of these changes lacks the precision of bacteriologic quantitation but, provided the limitations are recognized, may still be valuable in diagnosis and assessment of therapy in chronic prostatitis.

The number of pus cells in prostatic fluid shows such variation from day to day in individual patients, unrelated to clinical course, that this feature lacks value in diagnosis or review.

Cystourethroscopy may show typical changes in the prostatic urethra but the importance of these has been largely discounted because to a minor degree they may be seen in asymptomatic patients. Apart from illustrating some typical prostatic changes, this examination is useful in excluding other pathologic conditions of the prostate and bladder. Trabeculation of the bladder in young men with prostatitis is seen frequently enough to suggest a relationship with dysfunctional voiding.

Radiologic studies including intravenous urograms serve to exclude other causes of urinary tract infection. Prostatic calculi may be demonstrated.

Needle biopsy of the prostate has been generally unrewarding either in demonstrating pathological changes or in isolating bacteria.

Bacteriologic diagnosis in chronic prostatitis was considerably advanced by the refined techniques introduced by Meares and Stamey. Their studies indicated the value of taking samples of urine from the first voided specimen (VB1), from a midstream specimen (VB2) and a voided specimen immediately after prostatic massage (VB3). Prostatic massage usually produces a specimen of prostatic fluid (EPS) for bacteriologic examination. Localization of the source of the infection may therefore be possible, although it must be remembered that all urine sampled passes through the prostatic urethra. In using these methods very sensitive bacteriologic culture techniques must be used to ensure counting of as few as 10 organisms per ml, because in chronic prostatitis there are often only small numbers of bacteria in the prostatic secretion (EPS) or urine after massage (VB3). This is the reason that routine bacteriologic studies of prostatic fluid or postmassage urine rarely show positive results.

Etiologic factors in chronic prostatitis are rarely obvious but include urethral stricture, previous urethritis (gonococcal or nonspecific), previous instrumentation or catheterization and previous episodes of acute prostatitis.

Posted in Prostatitis
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