Androgens and Drugs for Erectile Dysfunction Dr. Vishaal Bhat Associate Professor MMMC, Manipal
Androgens and Drugs for Erectile Dysfunction
Dr. Vishaal BhatAssociate ProfessorMMMC, Manipal
FeMale
WoMan
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Androgens:
2o sex characteristics
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• Transport & MOA of androgens: SHBG
5α-reductaseTestosterone 5α-dihydrotestosterone (sex organs)
(skeletal muscles)
cytosloic; nuclear receptors increase transcription of a specific protein androgen effects
DHT is 10 times more potent than testosterone and mediates effects of testosterone on skin and sexual apparatus (prostate; seminal vesicle, epididymis…)
MOA:
Testosterone to DHT in target organ
DHT + cytoplasmic receptor (AR) complex formation
This complex moves towards DNA and binds with
androgen response elements of target gene
Specific mRNA transcription is enhanced
Protein synthesis
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1.Androgenic action
2. Anabolic action – skeleton and muscle building, wt.↑
3.Erythropoiesis - ↑erythropoietin & haeme production
4.Feed back - large dose inhibits Gn secretion from pituitary,
causes testicular atrophy
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Testosterone
Aromatase Estradiol
5-α-reductase Dehydrotestosterone
Testosterone Dihydrotestosterone Estrogen
Internal genitalia growth in fetus(epididymis, vasdeference, seminal vesicle)
External genitalia growthin fetus (scrotum, penis, urethra). Maturation in adult
Libido
Testis -spermatogenesis
Prostate growth, male behavior, hair growth in puberty, hair loss in adult
Erythropoiesis
Feed back - LH inhibition in pituitary
↑ bone & muscle mass and strength ↑ bone growth, epiphyseal closure 8
Synthetic androgens:
1. Methyltestosterone
2. Testosterone undecanoate
3. Fluoxymesterone
4. Mesterolone
Natural androgens:
1. Testosterone
2. Dihydrotestosterone
3. Dehydroepiandrosterone
4. Androstenedione
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1. Testicular failure:
Primary – delayed puberty in children.
Secondary - loss of libido, impotence in adult.
Parenteral and transdermal preperations
2. Hypopituitarism:
Lead to hypogonadism. Androgens added during puberty.
3. Ageing – testosterone is declined in old age, osteoporosis.
↑ muscle mass & bone mineral density
Therapeutic uses of androgens:
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4. AIDS related muscle wasting:
Improve weakness, muscle wasting
5.Carcinoma of breast:
Tumor contains estrogen receptor (ER).
Testosterone is the physiological antagonist to estrogen
6. Osteoporosis in elder male due to prolonged
immobilization. BPNs preferred
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6. Hereditary angioneurotic edema:
Deficiency of C1Inh (complement esterase inhibitor)
Swelling - skin, mucous membrane, intestinal organs
Chronic use - ↑ synthesis of complement esterase inhibitor. 12
Adverse effects of androgens:
Acne – in male and female
Precocious puberty and closure of epiphysis
Reversible cholestatic jaundice with synthetic drugs
oral route, not in parenteral
Hepatic carcinoma
Gynaecomastia – children with liver disease.
Peripheral conversion of testosterone to estrogen13
Lowering of HDL level with synthetic androgens
Painful erection in males
Oligozoospermia – due to feedback inhibition
Edema – due to salt and water retention.
Seen in heart and kidney diseases
Female – Virilization (masculinization).
Excess body hair, menstrual irregularity, voice change,
breast atrophy 14
C/I of androgens:
Carcinoma of prostrate
Kidney, liver diseases – edema develops
Pregnancy - masculinization of female fetus
Androgenic + Anabolic = Androgen
Androgen – Androgenic activity = ???
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Danazol
1. Gonadotropin inhibitor with antiestrogen,
progestational and androgenic properties
2. Synthetic version of the male hormone testosterone
3. Inhibits the release of FSH and LH by the pituitary
gland
4. Decreases estrogen levels similar to menopause, stops
ovulation
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Danazol
Indications:
1. Endometriosis
2. Mammary dysplasia (fibrocystic breast
nodularity)
3. Menorrhagia
4. Infertility in women
5. Gynaecomastia.
Danazol
Side effects
• androgenic effects (deepening of the voice, abnormal hair growth, reduced breast size, water retention, acne, weight gain ;nearly all gain weight between 8-10 lbs.)
• hypoestrogenic reactions (flushing, sweating, vaginal dryness, irritation)
• amenorrhea
• irregular vaginal bleeding, muscle cramps
Anabolic steroids
1. Nandrolone
2. Oxymetholone
3. Methandienone
4. Stanzolol
Drugs with higher anabolic and lesser androgenic activity
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Therapeutic uses of anabolic steroids:
1. Catabolic states:
Negative nitrogen balance – acute illness, major surgery.
Under-nurished, during convalescence
Improve appetite, sense of well being, protein anabolism
2. Renal insufficiency: (R. failure)
Reduce urea production, dialysis frequency ↓
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4. Suboptimal growth in boys:
Linear growth is accelerated.
Premature closure of epiphysis may seen in long use
5. Severe anemia associated wit hypoplastic,
hemolytic and malignancy.
↑RBC count, ↑Hb%. Erythropoietin is preferred.
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6. To enhance physical ability in athletes
↑ strength of exercised muscles.
Drugs of abuse, dope test before competitive games.
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Adverse effects of anabolic steroids:
Produce jaundice
Worsen lipid profile
Similar to androgen
(retained minimal androgenic activity)
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Antiandrogens
1.GnRH Analogues – leuprolide, goserelin, nafarelin
2.Androgen synthesis inhibitor – ketoconazole, spironolactone
3.5-alpha-reducatase inhibitors – Finasteride, Dutasteride
4.Androgen Receptor antagonists – Flutamide, Bicalutamide
5.Cyproterone acetate
Anti Androgens
Androgen Receptor Blockers
• Block the activity of androgen hormones at target tissue (prostate) receptors
• flutamide
• nilutamide
• bicalutamide
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Flutamide and bicalutamide are nonsteroidal antiandrogens (androgen receptor blockers) for use in conjunction with the GnRH analogues (e.g. goserelin, leuprolide) in the treatment of prostatic cancer.
5-Alpha-Reductase Inhibitors
• Finasteride and dutasteride
• Block the effects of endogenous androgens
• Used to treat benign prostatic hyperplasia (BPH)
• Results in alleviation of symptoms of BPH– Easier passage of urine
• May also be used for treatment of
male-pattern baldness (minoxidil)
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Adverse effects of 5-alpha-reductase inhibitors• Impotence• Reduced libido• Gynecomastia• Dizziness• Heart failure• Angioedema• Allergic skin reactions• Male breast cancer
Drugs for Erectile Dysfunction
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Penile erection :
Physiological phenomenon where the penis becomes
enlarged and firm - enables sexual intercourse
Complex interaction of psychological, neural, vascular
and endocrine factors
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Sexual stimulation → parasympathetic stimulation
Ach → releases NO from endothelial cells of penile arteries
Arteriodilation, fill blood (cavernosal sinusoids) in corpora
cavernosa muscle
Venonstriction limits blood drainage - enlarge penis
Erection subsides when parasympathetic stimulation is
discontinued
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Erectile dysfunction: (impotence)
Inability to attain and maintain an erect penis
to allow sexual intercourse.
Psychology, hormone, neurogenic, vascular, autonomic
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Drugs used for erectile dysfunction:
1. Androgens – if androgen deficiency is seen
2. Prostaglandin E1 (PDE1) - Alprostadil
3. Papaverine / Phentolamine induced penile erection therapy
4. Phosphodiesterase-5 (PDE-5) inhibitors
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Drugs used to treat erectile dysfunction
PDE-5 Inhibitors
PDE-5 inhibitors:SildenafilTadalafilVardenafil
Introduced for pulmonary H.T – reduce pul. Pressure
50mg orally taken 1 hr. before intercourse
No erection in the absence of sexual activity
Useful in diabetic neuropathy ED
Ineffective – lost libido, spinal injury
Do not causes priapism (Painful condition, in which the
erect penis/clitoris do not return to its flaccid state)
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A/E:
Vasodilation
Headache, nasal congestion, fall in BP
Impairment of color vision, sudden vision loss
Potentiate dilatory action of nitrates
- worsen coronary cardiac disease
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