Few licensed drugs are currently available for the treatment of men with ED. Those that are available elicit their effect by one of two mechanisms. The agent boosts either the neuronal control mechanism or the local control mechanism (13). As we shall see, oral therapies can have their effect on either system, whereas the intracavernosal and intraurethral systems act locally to produce an erection.
First Line (Oral) Therapies
Oral agents used to treat ED should be reliable, have minimal side effects, and be simple to use (22). The oral therapies currently licensed for ED are the phosphodiesterase 5 inhibitors (PDE5 inhibitors), which have a peripheral mechanism of action, and apomorphine, which acts centrally. These agents require sexual stimulation to initiate the neuronal activation required to start the hemodynamic erectile response. This is in contrast to the PGE mediated response initiated by intracavernosal and intraurethral alprostadil administration that "forces" an erection (see later). Yohimbine is another oral agent that has been shown to have some efficacy, but this is currently unlicensed in the UK although available on prescription in the UK and US. There are several advantages of the oral agents. Because they are administered orally, they are noninvasive, unlike intracavernosal and intraurethral medications and surgery. Taking a tablet is also more discreet, which is an important characteristic because it restores some of the spontaneity of sexual activity and removes the need for interruptions. In addition, oral methods of drug delivery are not associated with fibrosis (a potential adverse effect when using intracavernosal injections), neither is there any penile or urethral pain that can occur with alprostadil use when given by injection or as the intraurethral pellet. As a consequence, oral therapies are now considered to be first line therapy.
Inhibitors of phosphodiesterase 5: As we have already seen, NO is required for normal erectile function (13). NO is a gas and is derived from L-arginine (an amino acid) and oxygen in the presence of the enzyme NOS. NO, interacts with soluble guanylate cyclase, which then dephosphorylates gua-nosine tri-phosphate (GTP) to produce the second messenger cyclic guanosine mono-phosphate (cGMP). It is the amount of cGMP present that determines the extent of relaxation in corporal smooth muscle by stimulating the reduction of intracellular calcium (23,24).
Phosphodiesterase (PDE) is a molecule that has many different isoforms, and is found in most mammalian tissue (24). PDE5 is the predominant isoenzyme found in the corpus cavernosum and is a cGMP-binding, cGMP specific PDE (24,25). Its role in the reversal of the penile erection is to decrease the levels of cGMP so that vasoconstriction and trabecular smooth muscle contraction take place. Theoretically, by blocking the action of PDE5, the erection should be maintained. This is the proposed mechanism of action of the PDE5 inhibitors.
PDE5 inhibitors are not suitable for all patients, and it may take several attempts at taking them before they have the desired effect (26). All PDE5 inhibitors are absolutely contraindicated for patients who are taking any form of nitrate, including sublingual sprays and nitrates used recreationally (e.g., amyl nitrate). There are currently three licensed PDE5 blocking drugs available in the UK and US: sildenafil (Viagra), vardenafil (Levitra), and tadalafil (Cialis).
Sildenafil (Viagra). Since its introduction in 1998, sildenafil has been the subject of many clinical trials on men within the age range of 19-87 years. It the most studied of the PDE5 inhibitors and currently the most widely used treatment for ED. Sildenafil has been shown to be effective and well tolerated by patients with various etiologies (22,27,28). Sildenafil has a molecular structure similar to that of cGMP [see Fig. 7.1 (24)] and is highly selective for PDE5, with some selectivity for PDE6 found in the retina, which would reasonably account for the transient [usually minutes (24)] visual disturbance that some men experience. In a complex interaction between the molecules, sildenafil increases its own binding affinity by a positive feedback mechanism, making more cGMP available (24). More cGMP means more NO available to relax smooth muscle, which results in improved erections.
Sildenafil is rapidly absorbed, and has a plasma half-life of ^4 h (25). Of the circulating sildenafil, 96% is bound to plasma proteins and therefore is not excreted in urine (24). When correctly taken just once daily, there is no significant accumulation of the drug in the body, as it takes just over 24 h to achieve total clearance. Clinical experience since its introduction has shown sildenafil
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