Thursday, August 26, 2010

Pharmacotherapy in Male Reproductive system disorders



Pharmacotherapy of ED could intervene in the CNS: ALPHA 2 ADRENERGIC BLO0CKERS (YOHIMBINE,PHENTOLAMINE)and dopaminergic antagonist (APOMORPHINE ) or peripherally agents that enhance , elevate or directly stimulates the synthesis of secondary messenger molecules such as c AMP or c GMP and direct activators of adenylate cyclase for ex: Phosphodiesterase inhibitors :non selective –papaverine, Type 5 –sildenafil citrate,vardenafil,Tadalafil,Type 3 Milirinine and Type 4 roliparm
Drugs for treating ED can be taken orally, injected directly into the penis, or inserted into the urethra at the tip of the penis. In March 1998, the Food and Drug Administration (FDA) approved Viagra, the first pill to treat ED. Since that time, vardenafil hydrochloride (Levitra) and tadalafil (Cialis) have also been approved. Additional oral medicines are being tested for safety and effectiveness. Viagra, Levitra, and Cialis all belong to a class of drugs called phosphodiesterase (PDE) inhibitors. Taken an hour before sexual activity, these drugs work by enhancing the effects of nitric oxide, a chemical that relaxes smooth muscles in the penis during sexual stimulation and allows increased blood flow.While oral medicines improve the response to sexual stimulation, they do not trigger an automatic erection. The recommended dose for Viagra is 50 mg, and the physician may adjust this dose to 100 mg or 25 mg, depending on the patient. The recommended dose for tadalafil(Megalis,Forzest) is 10 mg, and the physician may adjust this dose to 20 mg if 10 mg is insufficient. A lower dose of 5 mg is available for patients who take other medicines or have conditions that may decrease the body's ability to use the drug.
None of these PDE inhibitors should be used more than once a day. Men who take nitrate-based drugs such as nitroglycerin for heart problems should not use either drug because the combination can cause a sudden drop in blood pressure. Also patients have severe cardiac diseases like recent Myocardial Infarction, reduced stress tolerance should avoid PDE-5 inhibitors.

Maximum plasma concentration
30-120 (median 60)
30-360 (median 120)
30-120 (median 60)
Half life hours
Duration of action
up to 4-12
up to 36
Up to 4-12
Food restriction
may take longer to work with meals
can be taken with or with out food
can be taken with or without fatty foods
Many men achieve stronger erections by injecting drugs into the penis, causing it to become engorged with blood. Drugs such as papaverine hydrochloride(15- 60 mg), phentolamine, and alprostadil (marketed as Caverject) widen blood vessels. These drugs may create unwanted side effects, however, including pain (36%) persistent erection (4%) and scarring. It gives a success rate of 70-90 % but these injections have a drop-out rate of 25-60% because of mainly pain or sometimes development of corporal fibrosis.
Methodology of giving papavarine/bimix:
Start with 29-30 G Insulin syringe for the injection therapy.

Papavarine:It can be started with 15 and given till 60 mg. Inject in any corpus.
Bimix: Add chlorpromazine ( 4 ml papavarine to 0.1 ml chlorpromazine combination) start with 0.1 to 0.2 ml and then gradually increased .Again the injection can be given in any one of the corpus
Drug therapy for Peyronie’s disease:
Medical Treatments
Various medications like Vit E 400 mgs three times a day for 3 months, Cochicine 0.5 mg 2 bd for 3 months or Tamoxifen 20 mg BD for 3 months.The placebo controlled trioals have not shown efficacy of the medications but colchicines there are no placebo studies. It seems to be effective.

Researchers have also tried injecting chemical agents such as verapamil, collagenase, steroids, and interferon alpha-2b directly into the plaques. Verapamil and interferon alpha-2b seem to diminish curvature of the penis. The other injectable agent, collagenase, is undergoing clinical trial and results are not yet available. Steroids like triamcilone have caused loss and atrophy of the local tissues and weakening of the tunica. The surgical planes also become difficult after steroid injection.
The intralesional injections are given with 24 G needle making multiple passes through the plaque.There is a possibility that the multiple passes make the plaque weak by mechanical disruption.
Intralesional Therapy:
1) Intralesional Verapamil
Dose 10 mg verapamil/4ml+6mlsaline total 10 ml ;2 weekly for 12 injections
Promising but un proven
2)Intralesional interferon -alpha-2b
Dose: 1millon units 2 weekly for 12 injections
Placebo trial-ongoing
Possibly useful
3)Intralesional Steroids
Dose 40 mg triamcinolone /ml, dilute as per size 6 weeks total 6 injections
Steroids may weaken tunica loss of surgical planes due to trauma


Despite advances in diagnostic modalities up to 25% patients exhibits unexplained infertility. A variety of medical therapies have been suggested to treat this group. However none of these have sown effective to be repeated controlled trials. A meta-analysis of all controlled studies for idiopathic male infertility has failed to reveal significant efficacy of currently available treatment .In the hope that they may be effective in a selective group of people a minimum of 3-6 months trial should be given to include at least one cycle of spermatogenesis
The empirical therapy includes the following drugs:
1) Hormonal agents (direct or rebound effect):The testosterone undecanoate 80-160mg/d, Testosterone enanthate or propionate inj 2-3 weekly Side effects: Azoospermia ,gynecomastia, cholestasis and hepatic dysfunction

2) Antiestrogens : Clomiphene citrate 25-50 mg daily, Tamoxifen 10-30 mg daily, Side –effects: nausea, weight gain loss of libido, headache ,gynecomastia, dermatitis.

3)Antioxidants: The oligospermia is many a times attributed to Reactive Oxygen Species.Various agents are prescribed to nullify the effects of Reactive Oxygen Species like glutathione,Lycopene-4mg/d, Vitamin E 400-800mg/d,N-Acetyl Cysteine 1000 mg/day.
4)Sperm vitalizers : Cellular Energisers like L-Arginine,Zinc, Selenium, proanthrocyanidin , Carnitine 1-2 mg/d CoQ10 10-400mg/d,Pentoxiphylene

If this is unsuccessful ,Assisted Reproductive Technique (ART) is employed or a combined approach may be started simultaneously in older couples.

Specific medical therapy in oligospermia:
Chronic fungal dermatitis
Anti fungal topical cream For ex.Candid B ointment locally

Chronic filarial epididymo-orchitis
Anti filarial &anti-inflammatory drugs-Hetrazan 100 mg three times a day for 3 weeks
Seminal Infections:-
Whether infection causes infertility is still controversial. There are several conflicting reports of benefit of treatment. The semen analysis showing plenty of pus cells should be discussed with the seminologist so as to remove any confusion of round cells with immature spermatogonia. Semen culture should be done in such cases.The common seminal organisms are:Streptococcus fecalis,E coli,Coagulase +ve staph (albus) or Occasionally Klebsilla , proteus,pseudomonas. Ciprofloxacin/doxycyclins can be administered as per the semen culture sensitivity report for a period of 4-6 weeks. As a rule, both sexual partners should be treated at the same time.In the mean time condom intercourse can be performed. At the end of the treatment it should be confirmed that infection is eradicated as there is tendency for chronicity

Antisperm antibodies: The direct test should be done for ASA and if present should be treated on priority with Intra-Uterine Insemination.The other modality of treatment is giving prednisolone 5 mg three times a day for 3-12 months.

Management of hypogonadotrophic hypogonadism:
Management delayed puberty: No initiation of puberty by age 13 in girls and 14 in boys
Delayed puberty Management
Injection testosterone esters are given in the strength of 50-100mg per month for 3-6 months.This This dose will advance puberty without impairing height potential.The spontaneous onset of puberty should be awaited for 3-6 months if there is no initiation formal testosterone replacement therapy should be given.
Management of pre pubertal Hypogonadotropic Hypogonadism

The treatment should be based on androgenising the patient. So it is usually done by giving testosterone or HCG.

Testosterone Replacement Therapy for Androgenisation:
Inj Sustanon deep IM in the following protocol:to start with 100 mg deep intramuscular every month for 3 months.This dosage is progressively increased to 250 mg once a month followed by 250 three weekly for long term treatment. When fertility is desired LH and FSH support is usually given with proper counseling as the cost of the therapy may be 2-3 lakhs with 50 % chance of conception.
The underlying principle is to achieve initial testicular growth with LH (LH is given as HCG. 5000 u one injection per week , 2000 u two to three injections per week.HCG dose monitoring is done by assaying testosterone on Day 3(for response) and Day 7(for sustenance).Testicular volume is monitored along with the signs of androgenisation. When testicular volume become 18 ml and ejaculation starts then FSH are added to complete spermatogenesis.FSH is started in the form of HMG
Dose options:37.5 units thrice-a-week/75 u thrice-a-week/150 u thrice-a-week
This is continued till pregnancies occur. The count may increase from azoospermia to 5-10 millions/ml so Assisted Reproductive Technology may be needed.Testosterone is restarted after pregnancy is over.

Drugs Therapy in Premature Ejaculation
Local anaesthesia: Topical anesthetics/gel are sometimes given with the idea of desensitizing the glans and delaying the orgasm. Lignocaine cream can be given for application for 20 minutes before the sexual act.
Normally Selective Serotonin Uptake Inhibitors are used for such patients along with psychotherapy. The mechanism of action of SSRIs is linked to their inhibition of neuronal uptake of serotonin in the CNS. They prolong the sexual climax causing relief from early unwanted ejaculation.
These SSRI (Sertraline,Paroxetene.Fluoxitine)may take until at least 3 weeks following initiation of treatment to cause improvement in sexual latency.
Dose of the medications:
Clomipramine (clonil) 10-25 mg
Paroxetine(parotin) 10-20 mg
Sertaline (sertima) 25-100 mg
Fluoxetine(prodep) 20-40 mg
These drugs may cause side effects like yawning,anejaculation,decreased libido,perspiration and increased fatigue.

It has been seen that many patients with PE have undelying erectile dysfunction also so adding PDE-5 inhibitors like Viagra(sildenafil),Tadalafil works well.
Dapoxetine is an SSRI developed specifically for the treatment of premature ejaculation. Dapoxetine may be effective at first dose (ie, on-demand) for premature ejaculation when given 1-3 hours prior to sexual intercourse.
The optimal medical treatment for premature ejaculation has not been established but single dosing prior to sexual relations can work for many males.While raised blood levels through daily use of the medication may be unnecessary resulting in many CNS side effects. Obviously, if single dosing is successful, therapy is simpler and is associated with fewer adverse effects. Therefore, this may be the preferred initial therapy.
Dapoxitine right now although is manufactured in India ;is not available in market.But it soon expected after Food Drug Administration approves it.

Dosage of the testosterone and diagnostic evaluation:
The level of total testosterone below < 200-250 ng/dl of total testosterone /,8 nmol/L total testosterone or <3.8nmol/L bioavailable testosterone/<0.255 nmol/L free testosterone is indicative of low testosterone level. The actual threshold will vary as per previous levels life styles and habits.
Various types of testosterone replacement:

Testosterone therapy injectable
· Testosterone enanthate (testoviron depot)200-400 mg/4 weekly deep IM
· Mixed testosterone esters (sustanon) 250 mg/3 weekly deep IM
Highly effective inexpensive but causes Wide variations in level so the effect can be erratic like mood variations in the patient.

Testosterone undecoate (andriol)160mg/day. It should be taken
after full meals.

Available in 5g to 10g sachets. It is applied to shoulders and chest. After application 15-20 minutes are allowed to dry. The patient should avoid bath or swimming for 6 hours there after. The gel causes physiological levels to be attained without variations. The side effects are skin rash in some.

4-6 sprays every day. It is applied to shoulders and chest. After application 5 minutes should be given for application. The patient should avoid bath or swimming for 6 hours thereafter as in gel. The gel causes physiological levels to be attained without variations.

Adjusting dose schedule:
Check testosterone level before using the 30 week dose
Testosterone level recommended dosing interval
10-15 nmll/L continue at 12 weekly intervals
<10nmol/L continue at 10 weekly intervals
<15 nmol/L continue at 14 weekly intervals

a)Monitoring during testosterone therapy

b) Monitor for response: Primarily symptomatic, there will be increase in libido, energy and feeling generalized well being. The erectile dysfunction will start resolving. Generalised muscle strength as witnessed by handgrip and cognition will also improve.Bone density will also increase.

c) Monitor for complications: Hyperviscosity syndrome, increase in RBC mass,so complete blood count and hematocrit should be monitored. If hematocrits increase more than 55% then therapy should be stopped. There is a risk of exaggeration of pre-existing carcinoma prostate. The therapy as such doesnot increases the risk of prostatic malignancy. The risk of sleep apnea syndrome is increased as the central response to CO2.Liver Function tests also may deteriorate so need to monitor LFT,PSA,Hematocit.

No comments:

Post a Comment