Drug treatment for schizophrenia is considered essential in managing acute, violent psychotic episodes and reducing their recurrence, while providing longterm stabilization of the condition. Firstgeneration, or typical, antipsychotic drugs for schizophrenia are limited by their predisposition to cause extrapyramidal symptoms (EPSs).
The emergence of second-generation, or atypical, antipsychotic drugs, beginning with clozapine, has provided relatively rapid-acting treatment for schizophrenia with far less risk of inducing effects associated with previous agents.
Although the specific correlation remains unclear, current wisdom implies that interfering with dopamine at D2 receptors, especially at times when these fluctuating sites are in a "high-affinity" mode, yields the best results. Interference with dopamine at these sites also contributes to the side effects associated with earlier therapies.
The first-generation treatments for schizophrenia (ie, haloperidol, chlorpromazine) are tightly bound to the D2 receptors, regardless of the amount of unbound dopamine present. This binding affects dopamine transmission at the basal ganglia, causing motor function disruption. This action gives rise to EPSs, including muscle stiffness and peripheral tremors that can evolve into tardive dyskinesia and uncontrolled, spasmodic, peripheral movements.
In general, a 65% binding capacity at the D2 receptors treats schizophrenia, whereas an 80% binding results in the development of EPSs. Older agents not only adhere more tightly to the D2 receptors, but they maintain their hold for longer durationsat least 1 to 2 days following an oral dose. The eventual accumulation of the drug almost ensures the development of EPSs, especially as doses are titrated upward.
Atypical antipsychotic agents such as clozapine also bind to the D2 receptors. Their binding, however, is described as "loose"meaning that they easily detach from the receptor and allow periodic, if reduced, transmission of dopamine to take place. In addition, whereas the 65% binding capacity is still necessary for effective treatment, studies indicate that this level is not required at all times. The net effect of this looser binding is to provide effective treatment while minimizing the EPSs.
Administration and Dosing
Clozapine is given orally. Food has no effect on absorption or clinical effect. Dosing for schizophrenia begins with 12.5 mg once or twice daily. If the drug is tolerated, the dosing is increased in 25-to 50-mg increments daily over a 2- week period, until a daily dose between 300 and 450 mg is reached. Gradual increases in dosing are necessary to prevent the possibility of hypotension, generalized seizures or myoclonic jerking, and sedation.
Subsequent increases in dosing should not be more often than once or twice weekly. Most patients respond to daily ranges of 300 to 600 mg; some may require daily dosing of 600 to 900 mg.
Because clozapine readily detaches from the D2 receptors, proper compliance with therapy is essential. If a patient misses just 1 or 2 daily doses, he or she can experience a rapid decompensation, or reemergence, of psychiatric symptoms. Discontinuation should be over a 1-to 2-week period, with careful observation for recurrence of psychotic symptoms.
Stress can pose another challenge. With increased dopamine present, clozapine will be more rapidly displaced, causing a drop from the minimal 65% binding needed for effectiveness. During such stressful episodes, an agent with greater D2 receptor affinity can be added only for the duration of the episodes and then removed. Increasing the dose of clozapine during these times can be effective but will increase the likelihood of unwanted side effects.
Clozapine has been used successfully in childhood-onset schizophrenia in a limited number of treatment-resistant situations, with a maximum daily dose of 525 mg. Its safety, however, has not been established in children or adolescents under the age of 16.
Side Effects and Drug Interactions
Contraindications to the use of clozapine include concurrent myeloproliferative disorders, preexisting bone marrow depression, or a history of clozapineinduced agranulocytosis.
Since its initial clinical trials, clozapine has been associated with potentially lifethreatening agranulocytosis. As a result, this drug is available only through distribution channels that ensure that periodic blood tests are given prior to the dispensing of each supply of medication, and that patients are registered in a single, national master database.
The supply of clozapine generally is limited to 1-week quantities. When a patient has a record of normal weekly white blood counts (WBCs) and absolute neutrophil counts (ANCs) for a 6-month period, however, the frequency of testing and the amount of drug dispensed may be changed to 2-week intervals. If, after 1 year, all remains normal, this interval may be further extended to 4 weeks.
In cases of moderate leukopenia (WBC between 2000 and 3500 cells/mm3), clozapine use is suspended while daily, then twice weekly, WBCs and ANCs are performed until blood counts reach normal levels. Clozapine dosing may then be reinstated, with weekly blood work for a year.
In cases of severe leukopenia (WBC under 2000 cells/mm3) or agranulocytosis (ANC under 500 cells/mm3), clozapine is discontinued. The patient must be monitored daily, then twice weekly, and then weekly for at least 4 weeks after laboratory values return to normal.
Clozapine use during pregnancy, although prolactin-sparing, is considered unwise because of the (theoretical) possibility of agranulocytosis and seizure induction in the developing fetus.
Whereas newer, atypical antipsychotic drugs provide broad-spectrum treatment for schizophrenia with fewer side effects than earlier agents, the side effects they do produce may be equally severe and require careful monitoring.
Clozapine is available as 25-and 100- mg tablets from Caraco Pharmaceutical Laboratories, IVAX Laboratories Inc, Mylan Pharmaceuticals Inc, and UDL Laboratories Inc.
Benign prostatic hypertrophy (BPH) remains one of the most common medical conditions among men past the age of 70. BPH represents a collection of urinary symptoms including the sensation of an incompletely empty bladder, impairment of the urine stream, nocturia, and daytime frequency.
Research has identified a limited population of men with genetically low levels of testosterone-converting enzymes who have smaller prostate glands throughout life and never develop BPH. Regulating that enzyme in the rest of the population has become a method for treating the symptoms of BPH.
By obstructing the activity of the steroid enzyme type II 5-α reductase, finasteride inhibits the conversion of testosterone to dihydrotestosterone (DHT). DHT, a more potent androgen, is associated with hyperplasia of the prostate gland, with the additional pressure on the bladder and the urethra contributing to the symptoms of BPH. During treatment, finasteride reduces serum concentrations of DHT by ~70%, while average circulating testosterone levels increase from 10% to 20% (yet remain within physiologic parameters).
Finasteride is indicated for the improvement of symptoms associated with BPH, to reduce the risk for acute urinary retention, and to diminish the potential need for prostatectomy or transurethral resection of the prostate.
The dose for finasteride is 5 mg daily, with DHT suppression noted within 8 hours after the first dose. The product may be taken as a single-drug treatment for BPH, but it can work synergistically with the α-blocking agent doxazosin (urethral tone being modulated by aadrenergic receptors).
Whereas finasteride can result in a decrease in serum PSA of ~50%, this effect will occur even in the presence of prostate cancer. During treatment with finasteride, therefore, it is important to understand that the PSA values can be artificially low and that subsequent elevations should be inflated by a factor of 2, because this increase may be due to the presence of a less-benign prostatic condition. It also should be noted that the use of finasteride has no significant effect on the overall incidence of prostate cancer, nor does its use provide any clinical benefit in the treatment of prostate cancer.
During the first year of treatment with finasteride, sexual dysfunction (impotence and decrease in libido) appears to occur more often than in placebo groups used in comparative studies. It is interesting to note, however, that after the first year the active and the placebo groups describe the same frequency of dysfunction.
Pregnant or potentially pregnant women should not handle broken or crushed finasteride tablets because of the potential for transdermal drug absorption and the probability of risk to a developing male fetus.
The goal in treating BPH is to reduce urinary symptoms, prevent the progression of the condition, and improve the quality of life despite recommended lifestyle restrictionscutting back on fluid intake after 7 pm and limiting the overall use of salt, spices, caffeine, chocolate, and alcohol.
Finasteride is available in 5-mg tablets from Teva Pharmaceuticals.
The well-publicized shortcomings of cyclooxygenase-2 (COX-2) inhibitors have prompted clinicians to seek alternatives for providing pain relief to patients suffering from osteoarthritis or other inflammatory conditions. Meloxicam actually is classified as a COX-2 inhibitor in other countries. In the United States, however, it remains in the category of nonsteroidal anti-inflammatory drugs (NSAIDs), with its COX-2 inhibition being considered more "preferential" than "selective," when compared with conventional agents such as ibuprofen.
Meloxicam has analgesic, antipyretic, and anti-inflammatory properties. It provides only symptomatic relief for osteoarthritis and, like other NSAIDs, does not reverse the destruction of joint tissues as the disease progresses.
Meloxicam has a one-time daily dose of 7.5 to 15 mg, taken with or without food or milk. Doses above 15 mg have not been shown to have added benefit for pain relief. Children with juvenile rheumatoid arthritis are dosed by weight at 0.125 mg/kg, to a daily maximum of 7.5 mg.
The addition of a blackbox warning from the FDA may have dampened some of the enthusiasm for meloxicam as a COX-2 alternative. The warning states that "NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease (CVD) or risk factors for CVD may be at greater risk." The risk for heart attacks from meloxicam, in fact, has been reported as higher than that of the discontinued COX-2 inhibitor rofecoxib (Vioxx).
Meloxicam also can result in hypertension or a worsening of hypertensive symptoms. It should be used with caution in patients with preexisting gastric ulcers or a history of gastric bleeding. It may contribute to renal dysfunction with prolonged use. The potential for increased gastrointestinal (GI) bleeding requires additional monitoring if the patient also is being treated with warfarin.
Patients should be educated on and advised to report signs of CV reactions (angina, dyspnea), GI bleeding, or hepatotoxicity (fatigue, jaundice, lethargy).
Because of these potential adverse effects, the lowest possible effective dose and the shortest possible duration of therapy to achieve treatment goals should be employed in using meloxicam.
The resurgence of interest in meloxicam as a COX-2 "selective" inhibitor alternative, along with the substantial cost savings from its generic form, may increase the popularity of this particular NSAID.
Meloxicam is available as 7.5-and 15- mg tablets from companies including Teva Pharmaceuticals, Mylan Pharmaceuticals, and Caraco Pharmaceuticals.
Metronidazole Vaginal Gel 0.75%
Bacterial vaginosis is a noninflammatory condition in which the normal vaginal flora (ie, Lactobacillus) is replaced by a synergistic mixture of Gardnerella vaginalis, various anaerobic bacteria, and Mycoplasma hominis. Up to 40% of women affected are asymptomatic. Thus the absence or presence of a vaginal discharge is an unreliable indicator of infection. Symptomatic bacterial vaginosis (amineodor discharge) should be treated, regardless of pregnancy status.
Metronidazole is a bactericidal treatment commonly employed to treat bacterial vaginosis. Five-day intravaginal therapy results in cure rates comparable with those of 7-day oral regimens.
Intravaginal use of metronidazole employs a 0.75% concentration of the drug, in gel form. Commercial preparations include a vaginal applicator, which dispenses approximately 37.5 mg of metronidazole with each 5 g of gel. For once-daily dosing, intravaginal administration should be done at bedtime for 5 consecutive days'. The drug also may be administered twice daily (morning and evening), also over 5 consecutive days.
Precautions and Adverse Effects
The most common adverse effects include vaginal discharge and localized irritation. Undiagnosed vaginal Candida infections may become prominently symptomatic during treatment with the product. This effect occurs in 6% to 10% of patients. Abdominal or pelvic discomfort also is possible, and darkened urine is a rare occurrence. Dizziness and headache have been reported 2% to 5% of the time. Leukopenia has been reported in less than 2% of patients.
Patients suffering from severe hepatic disease will have a slower rate of metronidazole metabolism, causing drug and metabolite accumulation. Although it is generally well-tolerated otherwise, the manufacturers recommend cautious use of metronidazole vaginal gel in the presence of hepatic impairment.
If the vaginal infection is caused by Trichomonas vaginalis, intravaginal treatment is less than half as effective as oral treatment. The reason is that vaginal applications produce subtherapeutic serum concentrations, and systemic effectiveness is necessary to control Trichomoniasis. Whereas combination therapy with oral metronidazole often is employed in refractory cases, evidence is lacking to demonstrate that concurrent oral and vaginal administration is more effective than oral therapy alone.
Women should be instructed not to engage in vaginal intercourse or to use douches during the entire course of therapy, because these activities reduce the effectiveness of the metronidazole gel.
Although systemic absorption is slight with the use of the vaginal preparation, the concurrent use of oral anticoagulants may still be affected. Similarly, whereas a disulfiram-like interaction would seem unlikely with the vaginal preparation of metronidazole, there has been at least one case of such a reaction following ingestion of alcohol during treatment.
Bacterial vaginosis is the most common form of infectious vaginitis, although it may often be asymptomatic. Among pregnant women, it has a prevalence rate of 12% to 50%, and it has been identified as a potential risk factor for premature delivery. Thus treatment of symptomatic cases is essential.
The bactericidal agent metronidazole is effective as an oral and intravaginal treatment for bacterial vaginosis. The intravaginal route offers a more rapid recovery with a lower likelihood of systemic adverse effects.
Metronidazole is available as an intravaginal gel in concentrations of 0.75% from Upsher-Smith Laboratories (Vandazole).
Mr. Middleton is an instructor of pharmacology at Kellogg Community College in Battle Creek, Mich.
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