The central factor that determines potency is blood supply to the relevant tissues. In general, blood supply increases during sexual activity, leading to tumescence clearly in men and perhaps to a similar extent in women. Anything that interferes with this will compromise performance. Anything that improves this will enhance performance in men. Viagra, which has become the leading treatment for male potency problems, acts on just this issue.
One of the main controls on blood flow is the sympathetic system, and increases or decreases in blood flow can be brought about by stimulating or blocking a variety of receptors on which noradrenaline (norepinephrine) acts, either in the penis and vagina or in the brain.7 and 8
Many tricyclic antidepressants, as well as the selective noradrenaline (norepinephrine)-reuptake inhibitor reboxetine and a number of antipsychotics, produce erectile problems by this means. These effects may be transient or can be longer lasting in others – in both women and men. These effects on potency need to be distinguished from the effects on libido that antipsychotics and antidepressants can also produce. Many of these drugs can produce what was once termed ‘brewer’s droop’. This appears to come about because of an action on alpha-1 receptors that reduces blood supply to the sexual vasculature. The incidence of this problem with antipsychotics in general remains uncertain, although it was regarded as common on thioridazine when it was in wider use. A further problem possibly caused in the same way is retrograde ejaculation.
Noradrenergic inputs to sexual functioning are mediated through the sympathetic system. This system handles ‘psychogenic’ responses – lubrication or tumescence in response to sexual stimuli. There is also a parasympathetic system input, mediated by acetylcholine, which handles the rhythmic inputs to sexuality – the rhythmic increase and decrease in tumescence that takes place, usually unobtrusively, throughout the day and night. Tricyclic antidepressants and antipsychotics, with their anticholinergic effects, may affect either of these.
A great many compounds used for the control of blood pressure may lead to a reduction in noradrenaline (norepinephrine) output and hence to a reduced ability to vasodilate the sexual blood vessels. These include clonidine, guanethidine and methyldopa (Aldomet).
The effects of agents active on alpha-adrenergic receptors are generally antagonised by agents active on beta-adrenergic receptors. In this case one might expect beta-blockers, such as propranolol, to interfere with sexual potency, and there are some reports that this is the case, although it is unlikely to be a common effect, as there are far more alpha receptors in the sexual tissues than there are beta receptors.
The role of the cholinergic system in erectile and sexual functioning is at present less certain than that of the monoamine systems. A series of cases has been reported of sexual dysfunction precipitated by a range of different agents that has proved to be responsive to the addition of bethanechol (Myotonine), a cholinergic agonist. Bethanechol also appears to have a place in impotence or erectile failure stemming from back injuries. This may have something to do with the fact that the parasympathetic nerves to the sexual areas start from the sacral area of the spine. Bethanechol has also been reported in some cases to reverse problems produced by antidepressants or neuroleptics.
These hints of an effect with bethanechol raise the possibility that the anticholinergic drugs, which are widely used in clinical practice, might also produce sexual dysfunction. One effect that anticholinergic drugs are likely to have is a drying of secretory responses, such as the lubricant fluids produced by both men and women during arousal, making sexual interaction less comfortable.
The role of the cholinergic system may come into greater focus with the increasing use of cholinesterase inhibitors for cognitive dysfunction. While these agents are primarily used for dementing illness, and as such are used in a group of patients unlikely to report on the effects of these drugs on them, a number of other people can expect to be given them on a more experimental basis, to treat the effects of head injuries for instance, and these individuals are the ones who may be best placed to report on the effects. There are some reports from groups such as these that donepezil, rivastigmine and galantamine may be treatments for erectile dysfunction in men.
Ejaculatory and orgasmic effects
While erectile responses depend critically on the action of noradrenaline (norepinephrine) on its receptors, the dopamine and serotonergic systems appear to affect the threshold for ejaculatory or orgasmic responses. While not actually responsible for erections, effects on these systems may, however, make erectile and ejaculatory/orgasmic responses more or less likely.
The development of the selective serotonin-reuptake inhibitors (SSRIs) and growing awareness of the changes in sexual functioning associated with their use have triggered renewed interest in this area and increased understanding of the various mechanisms involved. In brief, serotonin inhibits orgasmic functioning. In practice, S1 agonists, such as buspirone, and S2 antagonists, such as cyproheptadine and yohimbine, bring orgasm forward, whereas S1 antagonists and S2 agonists, such as LSD, delay it. There is a profound interplay between the sexual hormones and serotonin in this area, such that the sexual hormones mediate their effects by leading to increases or decreases in serotonin synthesis while serotonin in turn does not act other than in the presence of a normal hormonal milieu. 4
It is now estimated that SSRI drugs, and many other antidepressants with effects on serotonin reuptake such as imipramine and clomipramine, will lead to ejaculatory/orgasmic dysfunction in over 50% of people taking them.
However, the converse of this is that, according to company marketing estimates, up to a third of men suffer from premature ejaculation and these may benefit from an SSRI. The short-acting SSRI dapoxetine has been marketed for just this purpose. Cases of premature ejaculation may also be treated with paroxetine 10mg or clomipramine 10mg taken 1–2hours before sexual relations.
A further related effect of SSRIs is to produce penile or vaginal anaesthesia. This will be experienced as loss of normal sensation, which can be linked to an inhibition of ejaculatory or orgasmic function or to a change in the quality of any orgasm experienced.
Libido and arousal effects
SSRIs can also lead to a profound loss of libido. This may arise partly because of the close interplay between the serotonergic system and the dopamine system, whose role in libido is outlined next. It can be difficult to tease apart libido and arousal from potency and orgasmic functioning. A change in one will tend to affect the others. Initial research with these neurotransmitters suggested that serotonin was involved in ejaculation and orgasm, and noradrenaline (norepinephrine) and acetylcholine in potency, while dopamine was more linked to libido, but these considerations seem simplistic now.
Consistent with these ideas, however, cocaine, stimulants and dopamine agonists such as l-dopa, apomorphine, amantadine, pergolide and bromocriptine, all of which enhance dopaminergic functions, have been reported to bring about increases in libido. Conversely drugs that reduce the effects of dopamine in the brain, such as the antipsychotics, tend to antagonise sexual functioning, and decrease libido. Well over 50% of individuals taking antipsychotics may have some impairment of sexual functioning, in addition to a loss of libido. The loss of libido appears to be dose related, so that the higher the dose of an antipsychotic the more likely the sexual problem. One antipsychotic, benperidol, was in fact marketed for the management of hypersexuality, although there is little evidence to suggest that it has any more marked effects on libido and potency than any of the other antipsychotics.
The effects of dopamine antagonists are complex. There may be a direct action through the dopamine system, but dopamine blockade also leads to an increase in prolactin levels and increased prolactin levels can produce amenorrhoea and gynaecomastia and can reduce libido. The use of quetiapine, which has a much less marked effect on prolactin, may make it possible to tease apart these direct and indirect dopaminergic contributions.
The role of dopamine in libido and potency underpins an older use of apomorphine for potency and libido problems. Apomorphine is a dopamine agonist that leads to vomiting. In the 1960s it was used in an effort to ‘cure’ homosexuality; treatment involved exposing men to pictures with homosexual content and using apomorphine to produce vomiting in the hope that this would turn these men away from same-sex desire to heterosexual desire. The treatment never worked, partly perhaps because in the process it almost certainly produced arousal at the sight of the homosexual material. The treatment wheel has now swung full circle and low-dose apomorphine is being used as a treatment to enhance potency and libido.
Sex hormones
Another group of drugs that has effects on libido is the sex hormones, particularly testosterone. Testosterone may lead to increases in libido in both men and women, and, indeed, in women the androgens (male sex hormones) appear to be primarily responsible for libido. 5 A number of takers of contraceptive pills report a decrease in libido, which may stem from an alteration in the ratio of androgen to oestrogen, so that there are proportionately fewer androgens. The ratio of androgen to oestrogen, in both men and women, is likely to be the main determinant of the incidence of side effects from hormonal preparations. These can include excessive sexual interest and drive or ‘masculinisation’ – an increase in male secondary sexual characteristics, such as facial hair. There has been a clear use of testosterone for male potency and libido problems for some decades now, but in recent years this has been supplemented by the use of testosterone in women.
Finally the opiates – heroin, morphine, pethidine, etc. – have been associated with a decrease in sexual libido. However, the acute use of opiates such as papaverine is associated with enhanced sexual performance and there are opiate receptors in the sexual tissues. The apparent contradiction can probably be best explained in terms of the reduction in libido that occurs as a consequence of long-term opiate use, leading to a more general impairment of health and nutritional status. It may also be partly a secondary impairment of libido rather than a primary impairment, in that the consuming focus of appetitive interest has become the getting and taking of opiate drugs, and this displaces sexual libido from its usual place in the emotional economy.
DRUG EFFECTS ON SEXUAL FUNCTION: FEMALES
The traditional headings under which female sexual functioning has been subsumed were dyspareunia and anorgasmia. These terms have been replaced by hypoactive sexual desire disorder, sexual arousal disorder, female orgasmic disorder and painful intercourse, which parallel the classification of male sexual disorders. 5 Women and men are supposedly the same.
However the medicalisation of what is now commonly referred to as female sexual dysfunction, or FSD, has been the subject of a vigorous and growing critique.91011 and 12 There is considerable evidence that pharmaceutical companies, in combination with experts interested in the medicalisation of this area, have been active in convening consensus conferences that represent one point of view exclusively, and in forming patient and other groups to lobby for the investigation of and the promotion of awareness of physical aspects of female sexual dysfunction. It is now possible to find sexual advice columns where young women with three young children who complain of loss of interest in sex are advised that they need their testosterone levels checked. The opposition to this new view has come from feminists and sexologists. While one drug has been approved for female sexual dysfunction, Intrinsa (low-dose testosterone), it is still in the balance as to whether FSD will become the pharmaceutical industry’s Vietnam/Iraq.
Just as in men, there is a complex set of functions involved in ejaculation and orgasm in women. While ejaculation itself is a peripheral act, in both men and women, it is linked intimately to a central event, orgasm, so that disruption of one set of functions tends to compromise the other. It is also difficult to disentangle this complex from general questions of libido. Drugs that reduce libido and tumescent responses can also be expected to interfere with orgasm and ejaculatory responses.7 and 8
While there are areas of overlap, there are also clear differences between erectile and orgasmic functions and these differences have become more apparent with the widespread use of the SSRIs. The commonest effect of the SSRIs on sexual functioning in both women and men is a delay of ejaculation. There is a separate but less often commented on change in the quality of orgasms. There are varying estimates of the frequency with which these effects happen and the severity of any problem that may result, but the data sheets for the agents involved suggest that up to 80% of individuals taking an SSRI or clomipramine may experience changes in sexual function.
When used in higher doses the SSRIs and clomipramine may lead to a failure of ejaculation in men and possibly in women, although this is less likely to be noticed in women, while they can also lead to anorgasmia in women and possibly in men, although this is less likely to be noticed in men.
In cases of drug-induced anorgasmia, a number of serotonergic antagonists such as cyproheptadine or trazodone may help, as may buspirone, which is a serotonergic agonist. Premature orgasm is something that may afflict women also, although the extent of the problem is unknown.
Discontinuing SSRIs may also lead to problems, with complaints of anorgasmia, for example, being replaced by problems with uncontrollable spontaneous orgasms. This appears to be more a case of spontaneous orgasms than spontaneous ejaculations; it has been reported primarily in women rather than men, although whether it is commoner in women is not known.
Spontaneous orgasm also appears to be a side effect of SSRIs in a small proportion of takers. This seems to happen because we are all ‘wired up’ slightly differently. Thus a few people given a beta-blocker, which slows heart rate in over 90% of cases, will find an increase in their heart rate. Again this increase in spontaneous orgasms on SSRIs has been reported in women rather than men, although what this means is less clear.
As regards loss of desire in women, there is an increasing resort to the use of either testosterone or apomorphine, and Intrinsa, a testosterone patch, is now licensed in Europe for hypoactive sexual desire disorder in post-menopausal women. The choice of testosterone may sound odd, but endogenous testosterone has a role in mediating sexual desire in women. It is increasingly common now to have blood tests of testosterone in women, even though at present normal ranges for testosterone in women remain uncertain. Treatment is sometimes instituted against a background of apparently low levels. It is not clear whether the risks of masculinisation are dependent on what the original testosterone levels were.
But there are ambiguities in using testosterone in women that may go beyond the issue of female endocrinology and the risk of features of masculinisation such as hirsutism. Testosterone appears to increase desire in men but, while desiring a sexual partner may be an issue for women, desiring to be desired is also a component of female libido, and it is not clear what effect testosterone or altering the balance of oestrogens to androgen is likely to have on this.
The effect of apomorphine to increase libido and desire in men may have some counterpart in women, although there has been no convincing evidence of benefit for women in general from this group of drugs.
Before proceeding to aphrodisiacs in general and phosphodiesterase inhibitors in particular, it is worth making one further point. The marketing of Viagra and its congeners brought in its wake vigorous efforts to ‘sort out women’, whom it was suggested essentially have the same mechanics as men, leading to the differentiation into the four types of sexual dysfunction outlined above. Efforts to develop a pink Viagra have, however, failed, casting doubt on this mechanical exercise, with suggestions that women are much more complex. 13 Another option, however, may be that even men are less simple than previously thought and that, for instance, there are distinctions between ejaculation and orgasm that warrant further investigation.
APHRODISIACS
For millennia there has been a search for agents that will reliably enhance sexual functioning. 14 In general, this has tended to mean agents that increase male potency, although some agents such as cocaine may increase sexual interest quite separately from any effect on potency (see below). Among the agents quoted most consistently as being aphrodisiac is ginseng, especially powdered ginseng root, which probably acts to increase noradrenaline (norepinephrine) release.
Another widely cited aphrodisiac is cantharides, also called Spanish fly, which is composed of the dried and ground parts of the Cantharis vesicatoria beetle. This can be sprinkled on the penis and leads to erections by virtue of being an irritant. It can also be taken orally and, when excreted through the kidneys, leads to irritation of the genitourinary passages, which in turn makes erections more likely or prolonged. As it is a frank irritant, the effects are unpleasant.
A wide range of other herbs and vegetables have been cited as aphrodisiac, including garlic, leeks, khat (quat; Abyssinian tea), liquorice and seafood, especially oysters. In Japan, the puffer fish or fugu is used. Shark fin is sought after elsewhere in the Orient, while eels enjoyed the same reputation in the Occident, and the conch in the West Indies. This large variety of agents has been rapidly supplanted by Viagra; it remains to be seen which of the traditional methods may contain traces of phosphodiesterase inhibitors, the active ingredient in Viagra.
Yohimbine
While ginseng and cantharides are better-known aphrodisiacs, the agent for which the best evidence of effects on sexual functioning was available, before the advent of the SSRIs and sildenafil (Viagra), was yohimbine. This compound, which is derived from the bark of the yohimbe tree, has a long-standing reputation as an aphrodisiac. Its use was discouraged, however, because of doubts about its efficacy and a concern about possible side effects. However, recent studies appear to have laid these concerns to rest, showing that about two-thirds of men with erectile difficulties respond to it, without troublesome side effects.15 and 16 The theoretical side effects are an increase in blood pressure or in anxiety. These can happen but appear to be infrequent. The response seems better in cases where there appears to be a psychogenic component to the problem but is not absent in straightforward cases of organic impairment.
In the case of yohimbine, it seems likely that benefits are brought about by a combination of actions on receptors for noradrenaline (norepinephrine) and serotonin. It is both an alpha-2-adrenergic antagonist and an S2 antagonist. Both of these systems appear to affect the threshold for erectile and ejaculatory responses so that, while not actually responsible for erections, effects on these systems may make erectile responses more or less likely.
Trazodone and cyproheptadine
A compound with a very similar receptor profile to yohimbine, which is more widely available, is trazodone. This has been used as an antidepressant. One of its notable side effects has been priapism (sustained erections). While this side effect has been widely publicised, what has been less touted is the fact that a great number of people, male and female, show an enhancement of sexual interest while taking trazodone.Priapism, which can be a complication of psychotropic drug treatment, involves erections that fail to reduce over several hours. At present, it is considered that any erections lasting longer than 8–12hours warrant medical attention. If such erections are not reduced, there is a risk of damage to the penis owing to a compression of the blood supply to its component tissues; this can lead to cell death. The reduction of priapism involves aspirating blood from the penis by syringe, usually accompanied by the injection of drugs, which leads to vasoconstriction (closing down) of the blood vessels in the area.
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