Androgens and Drugs for Erectile Dysfunction

Chapter 21

Androgens and Drugs for Erectile Dysfunction

ANDROGENS

• These are substances which cause development of secondary sex characters in the castrated male. That testes are responsible for the male characters is known since prehistoric times. Its endocrine function was established by Berthold in 1849. Testosterone was isolated, its structure worked out and synthesized by the year 1935.

Natural androgens

• Testes of adult male produce 5–12 mg of testosterone daily, a part of which is converted in extraglandular tissues to the more active dihydrotestosterone; by the enzyme steroid 5 α-reductase; cholesterol is the starting material and the same pathway depicted in Fig. 20.1 is utilized. Adrenal cortex produces small quantities of dehydroepiandrosterone and androstenedione which are called ‘weak androgens’ (potency 1/20 to 1/30), but are infact inactive as such and derive their weak activity from partial conversion to testosterone by peripheral tissues. Adrenals themselves do not produce significant quantity of testosterone. In women ovary produces small quantity of testosterone; this together with that derived indirectly from adrenals amounts to 0.25–0.5 mg/day.

• Androsterone It is a metabolite of testosterone which is excreted in urine. It has 1/10 the activity of testosterone.

Synthetic androgens

Methyltestosterone and fluoxymesterone are 17-alkyl substituted derivatives of testosterone which are orally active because of resistance to first pass metabolism but have submaximal androgenic efficacy and potential to cause cholestatic jaundice. Other orally active compounds are testosterone undecanoate which administered as oily solution is absorbed through lymphatics bypassing the liver, and

• mesterolone. A number of lipid-soluble esters of testosterone have been produced, suitable for injection in oily vehicle, from which they are absorbed slowly and exert prolonged action after deesterification in the body.

Regulation of secretion

• Testosterone is secreted by the interstitial (Leydig) cells of the testes under the influence of pulsatile secretion of LH from pituitary. FSH is mainly responsible for promotion of spermatogenesis in tubular (Sertoli) cells. The mediator of feedback relationship with pituitary is uncertain. While relatively high concentration of testosterone inhibits LH secretion and in time causes atrophy of interstitial cells, it has only weak inhibitory action on FSH secretion. Estrogens are more potent inhibitors of Gn secretion even in males and it is believed that the small amount of estradiol produced by testes and that resulting from conversion of testosterone to estradiol plays a role in feedback inhibition. Inhibin, (a protein) produced by Sertoli cells, has strong FSH inhibitory action and may be mediating the feedback inhibition. Testosterone and estradiol act on hypothalamus to reduce GnRH as well as act directly on pituitary. The plasma level of testosterone in adult males ranges from 0.3 to 1 μg/dl and in females from 20 to 60 ng/dl.

ACTIONS

• Testosterone is responsible for all the changes that occur in a boy at puberty: Growth of genitals—penis, scrotum, seminal vesicles, prostate. Growth of hair—pubic, axillary, beard, moustache, body hair and male pattern of its distribution. Thickening of skin which becomes greasy due to proliferation and increased activity of sebaceous glands—especially on the face—frequently the duct gets blocked, infection occurs resulting in acne. Subcutaneous fat is lost, and veins look prominent.

• Larynx grows and voice deepens. Behavioral effects are—increased physical vigour, aggressiveness, penile erections. Male libido appears to be activated by testosterone directly as well as by estradiol produced from testosterone. Testosterone is also important for the intrauterine development of the male phenotype; relatively large amounts are produced by the foetal testes during the first half of intrauterine life.

Testes 

• Moderately large doses cause testicular atrophy by inhibiting Gn secretion from pituitary. Still larger doses have a direct sustaining effect and atrophy is less marked. Testosterone is needed for normal spermatogenesis and maturation of spermatozoa. High concentration of testosterone attained locally in the spermatogenic tubules by diffusion from the neighbouring Leydig cells stimulates spermatogenesis.

Skeleton and skeletal muscles (Anabolic)

• Testosterone is responsible for the pubertal spurt of growth in boys and to a smaller extent in girls. There is rapid bone growth, both in thickness as well as in length. After puberty, the epiphyses fuse and linear growth comes to a halt. There is evidence now that estradiol produced from testosterone, and not testosterone itself, is responsible for fusion of epiphyses in boys as well as girls. Moreover, estradiol appears to supplement the effect of testosterone on bone mineralization. Testosterone also promotes muscle building, especially if aided by exercise. There is accretion of nitrogen, minerals (Na, K, Ca, P, S) and water—body weight increases rapidly, more protoplasm is built. Appetite is improved and a sense of well-being prevails. Testosterone given to patients prone to salt and water retention may develop edema.

Erythropoiesis

• Testosterone also accelerates erythropoiesis by increasing erythropoietin production and probably direct action on haeme synthesis.

Mechanism of action

• Testosterone can largely be regarded as the circulating prohormone. In most target cells, the 4 double bond is reduced → dihydrotestosterone— which binds more avidly with the cytoplasmic receptor, and this complex is more active than testosterone-receptor complex in combining with DNA. After combining with androgen response elements of the target genes, DNA transcription is enhanced, and effects are expressed through modification of protein synthesis.

• The 5α-reductase enzyme exists in two isoforms: 5αreductase-1 and 5α-reductase-2. The genital skin of both sexes and urogenital tract of male contains 5α- reductase2 which is more sensitive to inhibition by finasteride. Genetic deficiency of this isoenzyme causes male pseudohermaphroditism because of inability of male genitalia to produce the active hormone dihydrotestosterone from circulating testosterone. 5α-reductase-1 has a wider distribution in the body including nongenital skin and liver; it is less inhibited by finasteride.

• Testosterone itself appears to be the active hormone at certain sites—foetal genital rudiments, hypothalamus/pituitary site involved in feedback regulation, erythropoietic cells and spermatogenic cells in testes.

PHARMACOKINETICS

• Testosterone is inactive orally due to high first pass metabolism in liver. The duration of action after i.m. injection is also very short, therefore, slowly absorbed esters of testosterone are used by this route—are hydrolysed to the active free form. Testosterone in circulation is 98% bound to sex hormone binding globulin (SHBG) and to albumin.

• The major metabolic products of testosterone are androsterone and etiocholanolone which are excreted in urine, mostly as conjugates with glucuronic acid and sulfate. Small quantities of estradiol are also produced from testosterone by aromatization of A ring in extraglandular tissues (liver, fat, hypothalamus). Plasma t½ of testosterone is 10–20 min

• Methyltestosterone and fluoxymesterone are metabolized slowly and have a longer duration of action. Estrogens are not produced from fluoxymesterone and dihydrotestosterone.

Preparations and Dose

1. Testosterone (free): 25 mg i.m. daily to twice weekly; AQUAVIRON 25 mg in 1 ml inj.
2. Testosterone propionate: 25–50 mg i.m. daily to twice weekly: TESTOVIRON, PARENDREN, TESTANON 25, 50 mg/ml inj
3. TESTOVIRON DEPOT 100: testo. propionate 25 mg + testo. enanthate 100 mg in 1 ml amp; 1 ml i.m. weekly.
4. TESTOVIRON DEPOT 250: testo. propionate 250 mg + testo. enanthate 250 mg in 1 ml amp; i.m. every 2–4 weeks
5. SUSTANON ‘100’: testo. propionate 20 mg + testo. phenyl propionate 40 mg + testo. isocaproate 40 mg in 1 ml amp; 1 ml i.m. every 2–3 weeks.
6. SUSTANON ‘250’: testo. propionate 30 mg + testo. phenylpropionate 60 mg + testo. isocaproate 60 mg + testo. decanoate 100 mg in 1 ml amp; 1 ml i.m. every 3–4 weeks.
7. NUVIR: Testosterone undecanoate 40 mg cap, 1–3 cap daily for male hypogonadism, osteoporosis.
8. Mesterolone: Causes less feedback inhibition of Gn secretion and spermatogenesis; PROVIRONUM, MESTILON 25 mg tab; 1–3 tab daily for androgen deficiency.

Transdermal androgen

• Recently delivery of androgen across skin has been achieved by developing suitable solvents and absorption facilitators. By cutaneous delivery, testosterone/dihydrotestosterone circumvent hepatic first pass metabolism; uniform blood levels are produced round the clock. A gel formulation has been marketed for once daily application in hypogonadism and impotence.

• ANDRACTIM: Dihydrotestosterone 25 mg/g gel (100 g tube); 5–10 g gel to be applied over nonscrotal skin once daily.

SIDE EFFECTS

1. Virilization, excess body hair and menstrual irregularities in women; many effects, e.g., voice change may be permanent after prolonged therapy
2. Acne: in males and females. 
3. Frequent, sustained and often painful erections in males in the beginning of therapy, subside spontaneously after some time.
4. Oligozoospermia with moderate doses given for a few weeks. 
5. Precocious puberty and shortening of stature due to early closure of epiphysis—if given to children for more than a few weeks.
6. Edema: especially when large doses are used in patients with heart or kidney disease. It is rare with the doses used for hypogonadism. 
7. Cholestatic jaundice occurs with methyltestosterone, and other 17-alkyl substituted derivatives (fluoxymesterone and some anabolic steroids like oxymetholone, stanozolol) in a dose dependent manner, but not with parenterally used esters of testosterone. For this reason, the latter are preferred, especially for prolonged therapy. However, jaundice is reversible on discontinuation. 
8. Hepatic carcinoma: incidence is higher in patients who have received long-term methyltestosterone or other oral androgens.
9. Gynecomastia: may occur, especially in children and in patients with liver disease. This is due to peripheral conversion of testosterone to estrogens. Dihydrotestosterone does not cause gynecomastia because it is not converted to estradiol.
10. Lowering of HDL and rise in LDL levels, especially with 17α-alkylated analogues.

Contraindications

• Androgens are contraindicated in carcinoma of prostate and male breast, liver and kidney disease and during pregnancy (masculinization of female foetus). They should be used cautiously in patients who may be adversely affected by fluid retention—such as CHF, epilepsy, migraine.

USES

Testicular failure

• It may be primary—in children, resulting in delayed puberty. Treatment with parenteral testosterone esters or transdermal testosterone/dihydrotestosterone in courses of 4–6 months at a time is highly satisfactory. Secondary testicular failure occurring later in life manifests mainly as loss of libido and impotence. These are corrected by androgen treatment. However, impotence due to psychological and other factors, and not testosterone deficiency, does not respond.

Hypopituitarism

• Hypogonadism is one of the features of hypopituitarism. Androgens are added at the time of puberty to other hormonal replacement.

AIDS related muscle wasting

• Testosterone therapy has been shown to improve weakness and muscle wasting in AIDS patients with low testosterone levels

Hereditary angioneurotic edema

• This is a genetic disorder; attacks can be prevented by 17α-alkylated androgens (methyltestosterone, stanozolol, danazol) but not by testosterone. They act by increasing synthesis of complement (C1) esterase inhibitor.

Ageing

• Because testosterone levels decline in old age, it has been administered to elderly males and found to improve bone mineralization and muscle mass. However, safety of such therapy in terms of metabolic, cardiovascular and prostatic complications is not known.

• The use of androgens in cancer breast is rare as is their addition to postmenopausal hormone replacement.

ANABOLIC STEROIDS

These are synthetic androgens with supposedly higher anabolic and lower androgenic activity. Drugs are Nandrolone, Oxymetholone, Stanozolol and Methandienone

The anabolic: androgenic activity ratio is determined by injecting the drug in castrated rats and measuring the increase in weight of levator ani muscles to that of ventral prostate. The anabolic: androgenic ratio of testosterone is considered as 1; The anabolic selectivity of these steroids is modest with ratios between 1 to 3 in the rat model, and probably still lower in man. The anabolic effects are similar to that of testosterone and are mediated through the same receptor as the androgenic effects; for all practical purposes, they are androgens.

Preparations and dose

• Methandienone: 2–5 mg OD–BD oral; children 0.04 mg/kg/day, 25 mg i.m. weekly; ANABOLEX 2, 5 mg tab, 2 mg/ml drops, 25 mg/ml inj.
• Nandrolone phenyl propionate: 10–50 mg; children 10 mg; i.m. once or twice weekly; DURABOLIN 10, 25 mg/ ml inj.
• inj. 3. Nandrolone decanoate: 25–100 mg i.m. every 3 weeks, DECADURABOLIN, 25, 100 mg/ml inj.
• inj. 3. Nandrolone decanoate: 25–100 mg i.m. every 3 weeks, DECADURABOLIN, 25, 100 mg/ml inj.
• Stanozolol: 2–6 mg/day, MENABOL, NEURABOL, TANZOL 2 mg tab. Combination of a

Side effects

• Anabolic steroids were developed with the idea of avoiding the virilizing side effects of androgens while retaining the anabolic effects. But the same side effect profile applies to these compounds.

• The 17-alkyl substituted compounds oxymetholone, stanozolol, can produce jaundice and worsen lipid profile. Contraindications are same as for testosterone.

Uses

1. Catabolic states Acute illness, severe trauma, major surgery, etc. are associated with negative N balance. Anabolic steroids can reduce N2 loss over short periods, but long-term benefits are questionable. They may cause a transient response in the elderly, under-nourished or debilitated individuals, but controlled studies have failed to demonstrate a difference in the total weight gained. However, short-term use may be made during convalescence for the sense of wellbeing and improvement in appetite caused by such treatment.
2. Renal insufficiency Anabolic steroids reduce urea production—frequency of dialysis needed in renal failure can decrease. However, because this effect is short lasting, only transient improvement is seen in chronic renal failure.
3. Osteoporosis In elderly males and that occurring due to prolonged immobilization may respond to anabolic steroids, but bisphosphonates are preferred now.
4. Suboptimal growth in boys Use is controversial; somatropin is a better option. Brief spurts in linear growth can be induced by anabolic steroids, but this probably does not make a difference in the final stature, except in hypogonadism. Use for more than 6 months is not recommended—premature closure of epiphyses and shortening of ultimate stature may result.
5. Hypoplastic, haemolytic and malignancy associated anaemia Majority of properly selected patients respond with an increase in RBC count and Hb%. However, erythropoietin therapy is more effective.
6. To enhance physical ability in athletes When administered during the period of training, anabolic steroids can increase the strength of exercised muscles. However, effects are transient and contrary to popular belief, there is no scientific evidence that performance is enhanced except in women. This is considered an abuse and anabolic steroids are included in the list of ‘dope test’ performed on athletes before competitive games.

IMPEDED ANDROGENS / ANTIANDROGENS

• Superactive GnRH agonists are the most potent inhibitors of gonadal function. Administered over a few days, they markedly inhibit LH and FSH release, resulting in loss of androgen secretion.

• Ketoconazole at high doses inhibits steroidogenic CYP 450 enzymes: testosterone as well as adrenal steroid production is interfered. Plasma protein binding of testosterone is also reduced. However, toxicity of high doses precludes its use to suppress androgens.

• Cimetidine and spironolactone have weak antiandrogenic action which manifests as side effects. Progesterone has weak androgen receptor blocking action.

• Drugs that have been clinically used to modify androgen action are:

Danazol

• It is an orally active ethisterone derivative having weak androgenic, anabolic and pregestational activities. Though labelled as an impeded/attenuated androgen, because it binds to the androgen receptor and induces some androgen-specific mRNA production, the most prominent action is suppression of Gn secretion from pituitary in both men and women → inhibition of testicular/ovarian function. Itsuppresses gonadal function directly as well by inhibiting steroidogenic enzymes. Endometrial atrophy occurs over few a weeks and amenorrhoea may supervene. Danazol is metabolized with a t½ of 12–18 hours.

• Dose: 200–600 mg/day; DANAZOL, LADOGAL, DANOGEN, GONABLOK 50, 100, 200 mg cap.

Uses are:

Endometriosis

• Danazol causes marked improvement in ~75% cases. Relief of dysmenorrhea is prompt. Pain, dyspareunia and excessive bleeding regress slowly. After a 3–6-month course, prolonged relief occurs in over half of the patients. Severe cases derive incomplete relief. Androgenic side effects are the limiting feature, because of which use has declined.

Menorrhagia

• It reduces menstrual blood loss. Usually, complete amenorrhoea does not occur with 200 mg/day. When withdrawn after 3 months therapy—blood loss continues to be smaller than previously in many cases.

Fibrocystic breast disease

• chronic cystic mastitis): 3–6 months treatment causes improvement with decrease in pain, nodularity and engorgement in 75% cases.

Infertility

• Withdrawal of danazol after 3-month treatment results in resumption of ovulation and rebound fertility in some women; pregnancy rate is increased in the subsequent 6 months Side effects are frequent and dose related. Complete amenorrhoea occurs with higher doses as long as drug is given. Occasional spotting may be seen in some. Androgenic side effects are acne, hirsutism, decreased breast size, deepening of voice, edema and weight gain. Loss of libido in men, hot flashes in women and night sweats, muscle cramps, g.i. upset, elivation of hepatic enzymes are the other side effects.

Cyproterone acetate

• It is chemically related to progesterone—has pregestational activity which inhibits LH release augmenting the direct antiandrogenic action. More importantly, it competes with dihydrotestosterone for the intracellular androgen receptor and inhibits its binding. Larger doses prevent pubertal changes while in the adult libido and androgenic anabolism are lost, gynaecomastia can occur.

• Cyproterone has been clinically tested in precocious puberty in boys, inappropriate sexual behaviour in men, acne and virilization in women, but is not marketed.

Flutamide

• A nonsteroidal drug having specific antiandrogenic, but no other hormonal activity. Its active metabolite 2-hydroxyflutamide competitively blocks androgen action on accessory sex organs as well as on pituitary—increases LH secretion by blocking feedback inhibition. Plasma testosterone levels increase in males which partially overcome the direct antiandrogenic action. Palliative effect may occur in metastatic prostatic carcinoma, but it is better used in conjunction with a GnRH agonist (to suppress LH and testosterone secretion) or after castration to block residual action of adrenal androgens. Along with oral contraceptives it has been tried in female hirsutism. Though gynaecomastia and breast tenderness occur frequently, libido and potency are largely preserved. Reports of liver damage have restricted its use.

• Dose: 250 mg TDS; PROSTAMID, FLUTIDE, CYTOMID 250 mg tab.

Bicalutamide

This more potent and longer acting congener of flutamide is suitable for once daily administration in metastatic carcinoma of prostate. When used along with a GnRH agonist or castration, 50 mg OD affords marked relief in bone pain and other symptoms due to the metastasis. Side effects are hot flashes, chills, edema and loose stools, but it is better tolerated and less hepatotoxic than flutamide. Elevation of hepatic transaminase above twice normal is a signal for stopping the drug.

BIPROSTA, CALUTIDE, TABI 50 mg tab.

5 α-REDUCTASE INHIBITO

Finasteride

• A competitive inhibitor of the enzyme 5 α-reductase which converts testosterone into more active dihydrotestosterone responsible for androgen action in many tissues including prostate gland and hair follicles. It is relatively selective for 5 α-reductase type 2 isoenzyme which predominates in male urogenital tract. Circulating and prostatic dihydrotestosterone concentration are lowered but plasma LH and testosterone levels are unchanged because testosterone itself mediates feedback pituitary LH inhibition.

• Treatment with finasteride has resulted in decreased prostate size and increased peak urinary flow rate in ~50% patients with symptomatic benign hypertrophy of prostate (BHP). The beneficial effects are typically delayed needing ~6 months for maximum symptomatic relief. Patients with large prostate (volume > 40 ml) obtain greater relief than those with smaller gland; but it is the only drug which can retard disease progression.

• Withdrawal of the drug results in regrowth of prostate, but with continued therapy benefit is maintained for 3 years or more. The relief of obstructive symptoms, however, is less marked compared to surgery and α1 blockers. It primarily reduces the static component of obstruction, while α1 blockers overcome the dynamic component. Concurrent treatment with both produces greater symptomatic relief.

• Finasteride has also been found effective in male pattern baldness. In such subjects it promotes hair growth and prevents further hair loss. Observable response takes 3 or more months therapy and benefit is reversed within 1 year of treatment cessation. However, 20–30% cases do not improve.

• Finasteride is effective orally, extensively metabolized in liver—metabolites are excreted in urine and faeces; plasma t½ 4–8 hours (elderly 6–15 hours). It is well tolerated by most patients; side effects are decreased libido, impotence and decreased volume of ejaculate (each in 3–4% patients), skin rashes, swelling of lips. Dose for BHP 5 mg OD, review after 6 months; for male pattern baldness 1 mg/day.

• FINCAR, FINAST, FINARA 5 mg tab; FINPECIA, ASTIFINE 1 mg tab.

Dutasteride

• This newer congener of finasteride inhibits both type 1 and type 2 5α-reductase and reduces dihydrotestosterone levels. It is metabolized by CYP3A4 and is very long-acting (t½ is ~ 9 weeks). It is approved for use in BHP and is being tested in baldness and for prevention of prostate carcinoma. Interactions with CYP3A4 inducers and inhibitors are possible. 

DRUGS FOR ERECTILE DYSFUNCTION

• Erectile dysfunction (ED) refers to the inability of men to attain and maintain an erect penis with sufficient rigidity to allow sexual intercourse. It occurs mainly past middle-age and is common after the age of 65 years. A variety of vascular, neurogenic, hormonal, pharmacologic or psychogenic causes may under lie the disorder.

• Sexual arousal increases blood flow to the penis and relaxes the cavernosal sinusoids so that they fill up with blood, making the penis rigid, elongated and erect. Nitric oxide (NO) released from parasympathetic nonadrenergic noncholinergic (NANC) nerves and vascular endothelium is the major transmitter causing relaxation of smooth muscle in corpus cavernosum and blood vessels supplying it; ACh and PGs also play a role. A variety of mechanical/prosthetic devices and surgery have been used for ED, but drug therapy has made a big impact recently.

Androgens

• Parenteral testosterone esters or transdermal testosterone therapy is effective only when androgen deficiency is demonstrated to be responsible for the loss of libido and ED.

Phosphodiesterase-5 (PDE-5) inhibitors

• Nitric oxide causes smooth muscle relaxation by generating cGMP intracellularly which then promotes dephosphorylation of myosin light chain kinase (MLCK) so that myosin fails to interact with action. Inhibition of PDE-5, the cGMP degrading isoenzyme in cavernosal and vascular smooth muscle, results in accumulation of cGMP and marked potentiation of NO action. Sildenafil, Tadalafil and vardenafil are selective PDE-5 inhibitors developed in the past decade and found effective in a majority of patients with ED.

Sildenafil:

• It is an orally active drug, marketed in the USA in 1998 and 2 years later in India, for treatment of ED. It became an instant hit, but the enthusiasm has passed off now. Sildenafil acts by selectively inhibiting PDE-5 and enhancing NO action in corpus cavernosum. Penile tumescence during sexual arousal is improved, but it has no effect on penile tumescence in the absence of sexual activity. It does not cause priapism in most recipients.

• Oral bioavailability of sildenafil is ~40%, peak blood levels are attained in 1–2 hr; it is metabolized largely by CYP3A4 and an active metabolite is produced; t½ in men <65 years averages 4 hours. It is recommended in a dose of 50 mg (for men > 65 years 25 mg), if not effective then 100 mg 1 hour before intercourse. Duration and degree of penile erection is increased in 74–82% men with ED including diabetic neuropathy cases. Over 20 controlled trials involving >3000 men have demonstrated improved erection with sildenafil compared to placebo. However, sildenafil is ineffective in men who have lost libido or when ED is due to cord injury or damaged nervi eregantis.

• Since NO is an important regulator of pulmonary vascular resistance, PDE-5 inhibitiors lower pulmonary arterial pressure. Sildenafil is more selective for pulmonary circulation than vardenafil, and is the only PDE-5 inhibitor shown to improve arterial oxygenation in pulmonary hypertension. It has now become the drug of choice for this condition.

• Adverse effects Side effects are mainly due to PDE-5 inhibition related vasodilatation— headache, nasal congestion, dizziness, flushing and fall in BP, loose motions. Sildenafil, in addition, weakly inhibits the isoenzyme PDE-6 which is involved in photoreceptor transduction in the retina. As such, impairment of colour vision, especially blue-green discrimination, occurs in some recipients. Few cases of sudden loss of vision due to nonarteritic ischaemic opticneuropathy (NAION) among users of PDE-5 inhibitors have been reported, but no causal relationship has been established.

• Sildenafil markedly potentiates the vasodilator action of nitrates; precipitous fall in BP and MI can occur. After >6 million prescriptions dispensed in USA, the FDA received reports of 130 deaths related to sildenafil use by the year 2002. Most deaths occurred in patients with known risk factors, drug interactions or contraindications, and were timed either during or within 4–5 hours of sex. Sildenafil is contraindicated in patients of coronary heart disease and those taking nitrates. Though sildenafil remains effective for <8 hours, it is advised that nitrates be avoided for 24 hours. Caution is advised in presence of liver or kidney disease, peptic ulcer, bleeding disorders. Inhibitors of CYP3A4 like erythromycin, ketoconazole, verapamil, cimetidine potentiate its action. Caution is required also in patients of leukaemia, sickle cell anaemia, myeloma which predispose to priapism.

• Sildenafil is erroneously perceived as an aphrodisiac. Men even without ED are going for it to enhance sexual satisfaction.

Tadalafil

• It is a more potent and longer acting congener of sildenafil; t½ 18 hours and duration of action 24–36 hours. It is claimed to act faster, though peak plasma levels are attained between 30–120 min. Side effects, risks, contraindications and drug interactions are similar to sildenafil. Because of its longer lasting action, nitrates are contraindicated for 36–48 hours after tadalafil. Due to its lower affinity for PDE-6, visual disturbances occur less frequently.

• MEGALIS, TADARICH 10, 20 mg tabs, MANFORCE 10 mg tab.

Vardenafil

• Another congener of sildenafil with similar time-course of action; peak levels in 30–120 min and t½ 4–5 hours. Side effects, contraindications and interactions are also the same. A weaker inhibition of PDE-6 is claimed, but photosensitivity is reported. It prolongs Q-T interval; should be avoided in hyperkalaemia and in patients with long Q-T or those receiving class IA and class III antiarrhythmics. Dose: 10 mg (elderly 5 mg), max 20 mg.

Papaverine/Phentolamine induced penile erection (PIPE) therapy

• Injection of papaverine (3–20 mg) with or without phentolamine (0.5–1 mg) in the corpus cavernosum produces penile tumescence to permit intercourse. However, the procedure requires skill and training. Priapism occurs in 2–15% cases, which if not promptly treated leads to permanent damage. This is reversed by aspirating blood from the corpus cavernosum or by injecting phenylephrine locally. Repeated injections can cause penile fibrosis. Other complications are—local haematoma, infection, paresthesia and penile deviation. In view of the availability of PDE-5 inhibitors, it is rarely used now; only in cases not responding to sildenafil and alprostadil.

Prostaglandin E1

• Alprostadil (PGE1) injected directly into the corpus cavernosum using a fine needle, or introduced into the urethra as a small pellet, produces erection lasting 1–2 hours to permit intercourse. Alprostadil injections are less painful than papaverine, but local tenderness may occur. Penile fibrosis and priapism are rare. It is now the most commonly used drug in patients not responding to PDE-5 inhibitors.