Per Olov Lundberg
and effects of neurally active drugs
P O Lundberg MD, PhD, Authorized clinical sexologist NACS
of neuroscience. Neurology, Uppsala University, Uppsala, Sweden, Phone +46186115026,
+4618309397 (home), +46186115027 (fax), e-MAIL PO.Lundberg@neurologi.uu.se
Under the auspices of the WHO an international collaboration in monitoring adverse drug reactions (ADRs) was started. The prime intention was – and remains – to establish and maintain an effective method of detecting ADRs not revealed during clinical trials. This programme started 1968 and now includes 70 countries. The Swedish government assumed operational responsibility for the WHO programme in 1978 and the Uppsala Monitoring Centre for international Drug Monitoring was created in Uppsala. The centre has a review panel of some 30 scientists representing different specialities. I have been a member of this panel for some 20 year and have thus had access to the data base during this period. I have on a regular basis reviewed the data base for my particular interest, sexual adverse reactions (ADRs). I want to thank the Centre for giving me access to the data base and all national centres for their willingness to let me use data from them. However, the conclusions given in this lecture are my own. Since we are dealing with a living material, the number of reports is to-day 5 millions and new data are included on a regular basis no exact figures for each drug will be given.
Antihypertensive drugs is a group ot drugs that very often are reported to give sexual side-effects or sexual adverse reactions (sADRs).This is of course partly dependent upon the fact that they are so widely used, especially in elderly people. However, the mean age for this group of reports in the WHO data base is just over 50 years of age. Impotence is the most common adverse reaction among these. It has been reported with almost all types of antihypertensive drugs, such as betareceptor blockers, calcium channel blockers, ACE-antagonists, angiotensin II-antagonists as well as diuretic drugs. Aldosterone antagonists are the only exception. Here gynecomastia is the dominating sADR. The aldosterone antagonist spironolactone and/or its metabolites compete with androgens for intracellular receptors. This mechanism may also explain why digitalis has similar sADRs.
The only common mechanism explaining why these antihypertensive drugs are reported with impotence is that they are lowering the blood pressure and in such away may give a decrease in blood flow to the penis. Very often there are also in these patients arteriosclerotic changes in the blood vessels in question, as well as diabetes and smoking, thus acting in the same way on local blood flow. Decrease in sexual desire is the second most common sADR from antihypertensive drugs. The relation between the two types of sADRs is for almost all hypertensive drugs around 1:4. This indicates that there is no specific pharmacological mechanism explaining the combination of impotence and loss of libido. The mechanism behind is instead believed to be the fact that when a man looses his ability to perform sexually, the desire also goes done. The observation that there are almost no reports at all about sexual dysfunction in women in the form of vulvo-vaginal dryness – corresponding to the erection in the male - in women taking antihypertensive drugs also supports the mentioned mechanisms behind the sADRs. In women, decrease in blood flow in the genitalia does not seem play a significant role for normal sexual function.
Priapism is not an uncommon sADR but there are only a few antihypertensive drugs that are actually causing priapism. Here the mechanism is more well-known. Besides the nerve fibres initiating erection there are also sympathetic nerve fibres having an inhibitory effect. Among the antihypertensive drugs causing priapism we have the alpha-receptor blockers (prazosin, doxazosin, terazosin) but also a few antidepressive drugs, trazodone in particular and some neurolepic compounds (clozapine, risperidone, olanzapine). The drugs in question that also are alpha-adrenergic blocking agents are the drugs most often giving priapism...
Intracavernous injection of alpha-adrenergic antagonists (phenoxybenzamine and phentolamine) have in fact been used to treat impotence. Alpha-adrenergic agonists (pseudoephedrine, phenylpropanolamine and metaraminol) can instead be used to counteract priapism. Yohimbine, an extract from the yohimbe three, an old nature medicine. given orally against impotence is another example of an alpha-adrenergic blocker. Priapism may also result from an overdose of therapeutic drugs such as alprostadil, sildenafil, tadalafil or vardenafil.
A few of the antihypertensive drugs among the alpha-2-receptorblockers and ganglieblockers have also been reported to give ejaculation failure. This is probably dependent upon their capacity to block seminal emission and also to counteract the contractions of the internal urethral sphincter. The sphincter paresis results in a retrograde ejaculation which means that the ejaculate passes into the bladder. Certain alpha-adrenergic agonists given orally have been used to treat retrograde ejaculations.
The most important erectile neurotransmitters are dopamine D2 and D3. In the hypothalamus oxytocin, vasopressin and the melanocortins, derived from the proopiomelanocortin polypeptide are working together with the parasympathetic nervous system. When the nerve impulses reach the vessels in the cavernous bodies the enzyme NO-synthase catalysis the production of nitric oxide (NO) from l-arginine and oxygen in the vessel muscle cells. NO activates another enzyme, guanylcyclase. This enzyme accelerates the production of cGMP (cyclic guanosine monophosphate) from GTP (guanosine triphosphate). This opens the calcium channels in the muscle cells leading to an outflow of calcium. This gives a relaxation of the muscle cells. Through this relaxation an increase in intracavernouse pressure is achieved. The venous outflow from the cavernous bodies is further surprised through compression of the subtunical venules against the firm tunica albuginea resulting in an erection.
High levels of cAMP (cyclic adenosine monophosphat) are also important erectogen factors. Other neurotransmitters, such as VIP (vasoactive intestinal polypeptide) and PGE1 (prostaglandin E1) stimulates the production of cAMP from ATP (adenosine triphosphate) which enhances the erection.
The phosphodiesterase- 5 inhibitor sildenafil was from the beginning developed for treatment of pulmonary hypertension. However, it was soon discovered that the drug had and important sADR, it enhanced erection. Nowadays, this is the main clinical indication for this and a number of similar drugs.
The enzyme PDE5 (phosphodiesterase-5) degrades cGMP. This gives a contraction of the muscles in the penile vessels and the erection subsides. If the PDE5 is inhibited the level of cGMP-stays high and the erection continues if there is enough stimulation of the proerectile nerve paths from the brain and spinal cord.
The non-steroidal anti-inflammatory drugs (NSAID) have a series of important effects on the cells. There is a number of reports of impotence in combination with treatment with these drugs. The most probable mechanism seems to be antagonistic action against prostaglandins. Prostaglandins have an important function in the erection mechanism (see above). They are relaxing the muscles in the blood vessels in the cavernous bodies in penis to make it possible for these cavernous bodies to fill with blood.. Intracavernous injection of prostaglandin PGE 1 is one important way to treat impotence.
The corticosteroids for topical or general use may give dyspareunia and perianal pains as sADR. Systemic use may cause dyspareunia and perianal pain probably through decreased local resistance against infections...
Antidepressive drugs have rather complex mechanisms of action and are thus important for many different systems in the brain. This group of drugs have for many years being the group that counts for the highest number of all sADRs taken together. Since they have very different pharmacological profiles their effects on sexual functions are very different.
Nowadays the selective serotonin reuptake inhibitors (SSRI) are most often used. Belonging to this group are fluoxetine, sertraline, paroxetine, citalopram and fluvoxamine. The most important and characteristic sADR for this group is orgasmic problems in both sexes and ejaculatory failure in men. Almost as many cases of loss of sexual desire have been registered in the data base and impotence is also of high frequency. Interestingly there are also a large number of reports about increase in libido and also priapism. In women is galactorrhoea also common. The drugs in the SSRI group have very similar sADR profiles. This indicates a common mechanism, an antiserotonin effect in the cerebral centres for sexual desire and orgasm. The different drugs within the group have varying number of reports. However, it is not possible to draw any conclusions about the relative risk fro sADR since the actual number of patients taking the drug in question is not known
Quite an other sADR profile can be observed for the non-selective monoamine reuptake inhibitors such as amitryptiline, nortriptyline lofepramine, desipramine and maprotiline. Impotence is here the most often reported problem. Orgasmic problems and ejaculatory failure is reported with one of these drugs, clomipramine. This drug has also SSRI-properties
Trazodon and nefazodon belongs to a further group of antidepressive drugs Here the typical sADR is priapism. With trazodon priapism is reported 10 times more often as impotence. This lead the use of trazodon in the treatment of impotence during a period in the era before the phosphodiesterase inhibitors.
Some further antidepressive drugs, such as mirtazapin, moclobemid and mianserin have quite different pharmacological properties, So far, these drugs have not so often be reported in connections with sADRs.
The observation that the SSRI drugs can give ejaculatory failure have lead to the idea to use such drugs in the treatment of precocious ejaculation. Now a particular SSRI drug (dapoxetine hydrochloride) have been introduced. This drug gives vasovagal syncope as an ADR.
Persistent genital arousal disorder (PGAD) and persistent sexual arousal syndrome (PSAS) are one or probably several different sexual hyperfunctions in women. They have been described in several hundred patients. There is a kind of physiological sexual arousal persisting for longer periods, days up to months. The phenomena are not related to increased sexual desire and do not disappear after orgasm. It may result in the women having many, up to a hundred orgasms per day without reaching sexual satisfaction. The problem may at first appear as agreeable but soon lead to suffering and frustration. The mechanisms behind is not known but the fact that most of the women have suffered from depressions and have taken SSRI-preparations has lead to the hypothesis that the syndrome is caused by disturbed cerebral serotonin metabolism.
It is quite obvious that serotonin plays an important role in the regulation of sexual function. Why this regulation sometimes is is going in one, let us call it positive direction, and sometimes is going in the opposite, let us call it negative direction is not known. One explanation may be the following. Two of the most studied molecules involved in regulating the levels of serotonin are the serotonin transporter (5HTT) which transports serotonin from the extracellular space into the cells and monoamino oxidase A (MAOA), the key enzyme responsible for degrading serotonin the genes encoding these proteins harbour genetic polymorphism that may affect the transcriptional activity. This might also explain the difference in women compared to men.
Ordinary use of benzodiazepines and most anxiolytics is rarely reported to give sADRS. However, abuse of these drugs may result in severe problems in sexual behaviour. Benzodiazepines have been used in treatment of decrease of sexual interest. Buspirone, an anxiolytic drug how is a serotonin antagonist with serotoninagonistic effect; have in animal experiments showed increase in sexual behaviour. In a few cases also positive effects on sexual fucntions has been reported.
Neuroleptic drugs can give serious sADRS. The phenothiazines, the largest group, give impotence or priapism, a decrease or increase in sexual desire and rather often also problems with ejaculation. Retarded ejaculation or anejaculation is common. However, spontaneous ejaculations and/or painful ejaculations may also occur. Priapism is more common than impotence. The profile priapism and retarded ejaculation probably is explained by the fact that some of the phenothiaziens have alpha-adrenergic antagonists (see above).
Most reports of ejaculatory failure come from thioridazin. Thus, for that reason this drug was used to treat precocious ejaculations in the era before the SSRIs. However, there does not seem to be any reports of anorgamia in women taking phenothiazines. A decrease in sexual desire may be explained by the fact that many of these drugs also are dopamineantagonists and giving hyperprolactinemia. If the drug in question has both dopamineantagonistic and serotoninantagonistic effects the problems are more difficult to explain.
The new types of neuroleptics have other sADR profiles. Some examples: Haloperidol may give galactorrhoéa and amenorrhoéa in women and impotence or priapism in men. Clozapine may give problems with ejaculation but also priapism and in a few cases impotence in men. Olanzapine does not seem to cause problems with ejaculation but instead priapism. Sulpiride causes amenorrhoéa and especially galactorrhoéa. Risperidone gives often galactorrhoéa and amenorrhoéa in women and ejaculatory problems and impotence or priapism in men It should be recognised that in schizophrenia and paranoid psychoses, which are the principal clinical indications for these type of drugs, disturbances of sexual behaviour and dysfunctions are very common in it self.
Patients with focal epilepsy from the temporal lobe do often suffer from impotence and decrease in sexual desire interictally. Priapism may occur. This results probably from the brain damage in itself. Such problems can be enhanced by certain antiepileptic drugs, phenytoin, carbamazepine and valproat in particular. Modern antiepileptic drugs can be tried instead to avoid these problems.
Many antiepileptic drugs have hormonal effects such as galactorrhoea, amenorrhoea, gynecomastia and hypertrichosis. Some antiepileptic drugs may interact with the anticonceptive drugs because they increases the protein binding of both synthetic and natural steroids.
There are many observations indicating that dopamine is a transmitter in the nerve tracts who are active where an increase in sexual desire is achieved. Dopaminergic drugs (L-dopa, bromocriptine, pergolid and the MAO-B-inhibitor selegilin) may give increase in sexual desire as a sADR. These drugs constitute the only group of drugs where increase in sexual desire is reported more often than decrease in sexual desire. Observations of this type are particularly common among parkinsonian patients. The effects is hardly to be described as hypersexuality, but instead more as a normalisation of the sexual desire in the elderly Parkinsonian patient. He so to say recovers some of his young capacity. However, this may cause problems if the treatment results are not so good as regards the movement disorder in it self. Apomorfine, which is a short-acting dopamine agonist is registered for treatment of impotence. Quinelorane, a selective D2-agonist, have been used to treat decrease in sexual desire. In a large study of the dopamine transporter gene (DAT 1) in patients with premature ejaculation has shown an association between polymorphism in this gene and the complaint. In animal studies it has been shown that the neuronal activity in the paraventricular nucleus in the hypothalamus stimulated by apomorphine administration varies with the oestrus cycle. Thus, the effect of a pharmaceutical drug on sexual function can be influenced both by internal hormonal variations and genetic polymorphisms.
It is very rare that sexual problems are reported in patients treated with antibiotics, one exception is tetracyclines and some other broad spectrum antibiotics that may destroy the normal flora in the vagina/vulva and under the fore-skin. This may lead to growth of Candida albicans and other fungi resulting in dyspareunia.
Also the antimycotic drugs may, irrespective of the fact that they may have good effects on the infection give local irritation and pruritus. It is of course difficult to diagnose what are symptoms from the original infection or the result of fungal growth or ADRs from the drugs in question. The fact that the frequency of such reported observation varies very much among different drugs may indicate that the symptoms results from the dugs in themselves in a certain situation. Thus, miconazole represents 90 % of all local irritations in the genitalia of treated women and all the other drugs together only for the other 10%. This may depend on a local effect on the sensory endorgans in the external genitalia.
There are rather few reports were cytostatic agenst are suspected to give sADRs- Probably this is an example of under reporting since we know that such treatment often suppresses gonad hormone production. If this in itself is not the reason for the treatment, the sADRs can be counteracted with hormone substitution. Thus cytostatic drugs may give impotence and gynecomastia in men and amenorrhoea in women. Gynekomastia sometimes is interpreted in such a way that the man believes himself to be changed into women. Hence it is important to inform the male patients in forehand. Cytostatic drugs may also in rare cases give rise to a polyneuropathy which can result in impotence.
The most important nerves giving erections, nn. erigentes, belong to the parasympathetic nervous system. Thus, it would be expected that anticholinergic drugs could case impotence. However, this is not the fact. In acute human experiments it has been shown that parenteral atropine does not block erection. There is a very weak effect. However, one particular cholinergic compound, bethanecol, has been tried against impotence that has started during treatment with tricyclic antidepressant drugs. These drugs have anticholinergic properties.
The histamine 2-receptor antagonists (cimetidine, ranitidine, famotidine and nizatidine) are a group of drugs where impotence often has been reported as well as decrease in sexual desire. These drugs can also give gynecomastia in men and amenorrhoea and galactorrhoea in women. Cimetidine, the original drug, gives gynecomastia 10 times more often than decrease in libido and four times more often impotence than decrease in libido. Decrease in sexual desire has thus a relatively low incidence and orgasm problems are seldom reported. One probable mechanism is that these drugs bind to androgen receptors.
Other antihistamines (cetirizine. terfenadine. loratadine) taken against allergic problems have only been reported to give impotence in a few patients. However, one should observe that these types of drugs are usually not taken contiguously...
Proton pump inhibitors have about the same profile as the histamin-2-receptor antagonists as regards sADR. However, it is not possible to compare the two groups because the latter group has been on the market for many more years. Acid binding drugs are rarely reported to have given sADRS.
Impotence is one of the most common complications of diabetes mellitus, irrespective of type. About every second man with diabetes type II has problems with the erection and every fifth woman has problems with lubrication and /or orgasm. However, there are few reports of sADR in patients taking insulin or antidiabetic drugs.
The nerve cells contains enzymes which can metabolize hormones e g. testosterone testradiol or 5a-reduced metabolites. The synthesis of sex steroid does not only take part in the gonads and suprarenal glands but also in the brain, irrespective of the production from other parts of the body. These steroids are called neurosteroider in analogy with the neuropeptides. These hormones affects neurotransmission in two different ways.
1. They can function within nucleus of the cell through induction of the genome. This lead to the production of substances such as enzymes, receptors, structure proteins and neuropeptides. This is a slow process.
2. They may act on receptors in the cellmembrane which has a more direct and rapid effect.
Male hypogonadism is most often caused by a decrease of testosterone. If the blood levels of free testosterone are significantly lowered this will result in loss of sexual desire. This is easily corrected by administration of testosterone. Even men with normal serum testosterone values may get an increase of sexual desire when they for other reasons are taking testosterone or anabolic steroids. Thus, illegal use of such steroids may contribute to sexual behaviour problems such as aggressively. Through the hypothalamo-pituitary negative feed back mechanisms administration of high doses of androgens suppresses the normal production of testosterone in the body. Thus, the end result in men abusing androgens may be decrease in sexual desire, impotence and gynecomastia.
Women, especially postmenopausal, may get an increase in sexual desire when taking testosterone or DHEA. However, this can not be used as a treatment in fertile women because of the risk of masculinization of a foetus. When its has been given on the indication of decrease in sexual desire, the positive effects often subsides, probably because of the negative hypothalamo-pituitary feed-back mechanism mentioned above. Anticonceptive pills based on an estrogen/gestagen combination or gestagenes are rather often reported to gives decrease in sexual desire as a sADR. Gestagens in high doses may give amenorrhoéa, galactorrhoéa and hypertricosis.
Antiandrogen drugs such as cyproteronacetate or flutamide as well as estrogener given to men result in decrease of sexual desire and impotence. This may be a disturbing sADR in the treatment of for example prostatic carcinoma but can be used in the treatment of sexual offenders.
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