ORAL AGENTS (PILLS)
Cialis (Tadalafil), Levitra (Vardenafil), Staxyn (Vardenafil), Stendra (Avandaifl), Viagra (Sildenafil)
Although Viagra® was the first oral agent with proven benefit in the treatment of erectile dysfunction, nowadays we have more oral products which differ in time to achieve erection, effects of food intake on activity, and daily or on demand use. This gives physician and patient more flexibility in choosing the best type of medication and dose to suit individual needs of patient. Early media coverage generated worldwide demand for medications for erection and brought sexual dysfunction into main stay media coverage and layman language. All available medications are effective and safe first line medication. What every physician and patient should know about the drugs follows.
Above medications are called inhibitors of phosphodiesterase type 5 (PDE5) and they all work by the same mechanism.
Medications in this group are inhibitors of an enzyme that is concentrated in penile erectile tissue (although it is present in some other tissues). This enzyme, known as phosphodiesterase type 5 (PDE5), turns off erection, therefore, PDE5I by blocking it promotes the development and maintenance of an erection. Sildenafil is rapidly absorbed, with maximal blood concentrations occurring within one hour after administration. Its effect last on average 4 hours, that is, after taking the medication, there is a 4-hour window in which to pursue sexual activity. In my experience there are some men in whom the effect may last as long as 8 hours. It is best taken on an empty stomach as fatty food interferes with its absorption. Therefore, patients are instructed to take the medication 2 1-2 hours after a meal and wait another hour before starting sexual stimulation. Stimulation is required for Viagra to work. There is also a suggestion that alcohol may interfere with the medication's absorption. Vardenafil has similar properties and its absorption is also affected by food intake. Staxyn is a form of vardenafil which is placed on the tongue to overcome interaction with food. Tadalafil (Cialis) is not affected by food and it can be taken with food or on empty stomach.
Tadalafil can be taken on demand – before sexual activity – at dose of 10 or 20 mg or it is approved for daily use of 5 mg. This is especially useful in younger men who may not necessary plan the sexual activity with same ease as married men or men in long –term relationships.
Treatment with any of PDE5 inhibitors allows approximately 65% of men to resume sexual intercourse. All medications in this group have been shown to be effective across a wide spectrum of medical conditions, although it is least effective in certain diabetics and early after radical prostatectomy. Headache, flushing, transient visual disturbances and dyspepsia are the most common side effects occurring in 6-18% of men using Viagra and Levitra. Headache and back ache are common side effects in men using Cialis.
The benefit of PDE5 inhibitors in men with angina or a history of heart attacks who have ED who are NOT taking nitrates has been shown to be similar to men without these conditions. From a safety standpoint, in carefully selected patients there is no evidence to show that use of PDE5 inhibitors are associated with heart attacks or an increased incidence of death. The overall incidence of cardiac side effects is approximately 5% for those with a history or compared to 3% in men without coronary artery disease. Prior to sexual activities men should be evaluated and stratified into 3 different risk category using Princeton III consensus conference criteria.
PDE5 inhibitors should not be used by certain patients: patients who are on any form of nitrate therapy (pill, spray, paste, or patch) as the combination of the 2 drugs has been shown to lower the blood pressure to a dangerous level. Men with significant cardiac disease are at higher risk of problems. These patients include: heart attack within the last 3 months; poorly controlled high blood pressure; poorly controlled angina (cardiac chest pain); stroke within the last 3 months; severe congestive heart failure; and heart valve disease. There is a group of men with cardiovascular disease who may benefit from a cardiologist's input prior to starting PDE5 inhibitors and these include: men with moderate angina; mild congestive heart failure; heart attack or stroke in the recent past (more than 3 months less than 6 months ago).
The advantage of medications in this group is the simplicity of their use. After thorough discussion of the potential side effects and review of medications, those patients who are considered safe candidates are simply given a prescription for six lower doses of respective medication. They are instructed to take only one dose per 24-hour period. For the first dose, the patient is instructed to take one pill one hour before planned intercourse. If this dose is ineffective on two different occasions, the patient doubles the dose. At the end of this home trial, the patient speaks with his or her doctor or a nurse for a refill of the minimum, effective dose. Patients who are not successful are asked to return to consider alternative forms of therapy.
Trazodone is an anti-depressant with the uncommon side-effect of prolonged erection (priapism). This occurs in approximately 1/10,000-20,000 users. It has been used for the treatment of erectile dysfunction without any clear evidence that it is truly effective. Its mechanism of action in promoting erection is not well known, but it is believed that it exerts its primary effect by stimulation of the serotonin receptors in the brain. The medication has been used at the dose of 50-200 mg by mouth each night at bed time (no relationship to intercourse timing). While some studies have cited trazodone’s effectiveness to be as high as 60%, the arrival of Viagra has decreased the use of this medication significantly. The side effects of trazodone include drowsiness in 31%, dry mouth in 1% and fatigue in 19%. At the Sexual Medicine Program the combination of trazodone and PDE5 inhibitors can only be used in men failing to initial therapy with maximum dose of PDE5 inhibitor.
Oral administration of the phentolamine, which blocks the action of adrenaline in the penis (the major inhibitor of erection) has been shown to result in erection in men with mild ED. Recently, this drug has received recognition as Vasomax® (Schering-Plough, NJ, USA) and has in some trials been shown to be better than placebo but because in most men with moderate to severe ED it was not beneficial it was never approved for use in USA.
This drug is derived from a tree bark and acts on receptors in the brain to stimulate area that are believed to be involved in sexual function. It has been used for many years, however, there is no good evidence to show that this drug is any better than placebo (sugar pill). Currently, its role as therapy in men with erectile dysfunction is minimal. It is associated with potentially serious side effects such as palpitations and high blood pressure, especially in patients with cardiovascular disease. Yohimbine can cause panic attacks in some patients and should only be taken in the morning.
Apomorphine has been used as a pharmacologic agent for over a century. Previously, it has been used primarily in Parkinson’s disease and is approved in a number of countries for this indication. The route of administration for this has been both by pill and injection with doses used up to 30 mg. It is a stimulator of dopamine receptors in an area of the brain (hypothalamus) that is key to the triggering of erection. TAP Pharmaceuticals licensed apomorphine for the treatment of erectile dysfunction in 1996 and the medication has been reformulated so that it can be delivered in under the tongue. The trade name for the drug is Uprima® and was available is Europe and Asia at 2mg and 3 mg doses but because of lack of effectiveness in treatment of erectile dysfunction. It was not approved in USA. It appears from trials that this agent is an effective drug in men who have some erectile function left (mild and moderate ED) and who have had ED for a short period of time (less than 2 years). The medication is rapidly-acting, causing erections to occur as quickly as 5 minutes after administration. In men who get erections in response to Uprima® about 70% get the erection within 20 minutes. Sexual stimulation is required for this medication to work. Because it is given under the tongue, it may be taken with food. The medication dissolves in about 10 minutes. It is a safe medication whose most common side effects include (at 3mg) nausea, headache, and dizziness (which occur in less than 5% of men). Apomorphine seems to be beneficial in men who have low sex drive but it is not approved for use for this indication.
INTRAURETHRAL AGENTS (SUPPOSITORIES)
Intra-urethral administration of alprostadil suppository (MUSE™, Vivus, Menlo Park, CA, USA) induces an erection sufficient for sexual intercourse in 30-40% of men. A pellet, the size of a grain of rice, is placed 1 inch into the urine channel following urination while the patient is standing. The reported side effects include pain and dizziness, albeit in less than 5% and 2% of men respectively. PGE1 has four dosage strengths (125, 250, 500, and 1000 mg), although the lower doses are not effective in the average man with ED. MUSE™ was introduced as a treatment for the impotent male in 1997. It bypassed the need for the direct injection of a drug into the penis. This factor alone has made it appealing to many physicians as well as patients. In the program's history experience, MUSE™ has an average overall success rate of 35% on office administration, as defined by the ability to obtain an erection sufficiently rigid for sex. It also showed that the at-home consistency rate was 55% in men with established in-office drug efficacy. No significant side effects have occurred in our patients. The incidence of priapism (prolonged erections) is negligible, with one study reporting 1,373 home administrations without the incidence of priapism or fainting, which is consistent with our experience.
Administration of intraurethral suppositories, while less intimidating than intracavernosal injection, is also somewhat complex. These medications should be given initially in the clinic, with instruction and demonstration of competence as well as effectiveness prior to dispensing a prescription for at-home use. In our experience, lack of effectiveness is the reason for patient drop-out with this route of administration. We currently use this medication in very small number of selected patients. A starting dose of 500 or 1000 mcg is used. The patient is instructed to void just prior to use of the medication. This lubricates the urethra and makes the administration of the suppository easier. To minimize venous leak and promote absorption, the patient is instructed to stand while the medication is absorbed. Gentle massage helps absorption. The effectiveness is assessed at 5, 10, and 30 minutes. Loss of erection is expected within one hour. Recently, the company has supplied a constriction device (ACTIS) that is placed at the base of the penis just prior to medication administration. This theoretically will increase intracavernosal concentrations and decrease systemic absorption. It may be worn during intercourse if desired. The effectiveness of MUSE™ in combination with the ACTIS device is under investigation.
Virag and Brindley were the first authors to report the ability of penile injection to produce an erection, using papaverine and phenoxybenzamine, respectively. To date, a number of medications have been used for this purpose, most commonly papaverine, phentolamine and alprostadil. These medications have been administered in a variety of combinations with good effect. The success rate, defined by the production of an erection rigid enough for intercourse, has been in excess of 75%.
While all PDE5 inhibitors have become the most prescribed medication for the treatment of ED, injection therapy still represents a cornerstone of therapy. In a recent study patients were asked to compare penile injections to sildenafil with regard to hardness of erection, overall sexual satisfaction, and preference for future use. All patients, regardless of etiology of ED, reported a more rigid erection using injections versus sildenafil. The majority of patients chose to continue using injections as their preferred treatment.
The use of combination agents is preferred to single agents to minimize side effects and maximize effectiveness. For example, the combination of papaverine, phentolamine, and alprostadil was shown to be more effective than high dose alprostadil alone, but has a lower incidence of painful erections (due to the lower concentration of alprostadil). The advantage of intracavernosal agents compared to currently available oral agents, is that these medications induce erection even in the presence of only minimal stimulation. The disadvantages include more complex route of administration, potential for bleeding, bruising, and penile fibrosis, and a higher incidence of priapism (albeit all uncommon side effects).
It is mandatory that the patient receive detailed instructions on the use of this type of therapy and is administered his first dose in the clinic. In our clinic, each visit is an important combination of physician assessment, trial dose administration, and patient education. The patient is given instructions on cleaning the phallus. An alcohol swab is used to cleanse the intended area of injection. An insulin type syringe is then used to administer the medication. The injection is given at the ten or two o’clock position on the penis (away from the ventrally located urethra), away from visible veins, and never in the midline. To minimize the chance of scar formation, the sight is changed with each dose. The needle is aimed at a right angle to the skin and pushed in to the hub, ensuring delivery of the medication into the correct location. After administration of the medication, the patient holds direct pressure to the area of injection for a few minutes. Patients taking blood thinners are advised to continue pressure for 6 minutes. The staff gives the first dose with the patient watching. This is a very low dose (which varies depending on the choice of drug). Patients with pure nerve damage ED are started lower than those with suspected vascular ED. After administration and assessment of erectile response 5, 10, and 30 minutes later, the patient waits in the clinic until the erection goes away. With each visit the dose of medication is increased. The patient’s role in administration of the medication also progressively increases. The dosage goal is to produce an in-clinic erection of 60% maximum (barely adequate for penetration) that lasts less than one hour. It is presumed that at home with less anxiety, more appropriate stimulation, etc., the effect will be greater. Ultimately, the patient (or his partner) must also demonstrate the ability to draw up the drug and properly inject it with an aseptic technique without staff assistance. At this point, he is graduated from the clinic and given prescriptions for at-home use. As with all forms of medical therapy, the patient is given instructions to seek prompt medical attention for prolonged erections.
The potential side effects of scarring, priapism (see page on Priapism on this website), bleeding, bruising, can be thus minimized by using combination medications, carefully titrating to the correct dose in the clinic, and thoroughly educating the patient on injection technique. Scarring can occur as a nodule, plaque, or penile curvature. Patients in our clinic are instructed that prolonged erections constitute a medical emergency. If the patient has an erection that lasts longer than two hours that is not relieved by ejaculation, they are instructed to call the answering service for advice and should be in the Emergency Department by the fourth hour.
TOPICAL ADMINISTRATION (CREAMS AND GELS)
Two companies at present (Nexmed and Macrochem) are developing medications, in the form of gels that are applied to the penis that are absorbed into the erectile bodies and cause erection. These medications obviously have great appeal to patients given the absence of a needle and minimal side effects. It is unclear at this time, based on early trials, how effective these drugs will be in the general population of men with ED. As new information becomes available it will be posted on this website.
SIMPLIFIED APPROACH TO DRUG THERAPY FOR ED
ED is a common problem that affects men as they age. There are many effective forms of therapy available that should be offered to motivated patients. Consideration of the primary cause of ED is important in determining the likelihood of success with any given form of treatment. A history and physical examination are mandatory before the prescription of any form of erection-inducing medication. While the oral agents are currently the most popular first line medication, in patients who fail to respond to this agent, injection therapy should also be offered as second line therapy as it is easily the most effective treatment that exists. 5PDE inhibitors are absolutely contraindicated in patients who take nitrates of any kind but have proven to be safely used in combination with other blood pressure medications.
Darius A. Paduch, MD, PhD
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