Transcript A. Androgens and antiandrogens

Basic & Clinical Pharmacology
Drugs affecting reproductive system
Drugs affecting male reproductive system
Classification
A. Androgens and antiandrogens
1. testosterone(睾酮 )
2. methyltestosterone(甲睾酮) orally effective
3. testosterone propionate (丙酸睾丸素) most commonly used
4. mesterolone (甲二氢睾酮，美睾酮)
5.fluoxymesterone(氟甲睾酮)
6.testosterone phenyl-acetate(苯乙酸睾丸素)
7.tristeronum compositum
testosterone propionate 25mg
estradiol benzoate(苯甲酸雌二醇) 1.25mg
progesterone 12.5mg，i.m
B. Antiandrogens
• cyproterone(环丙孕酮，环甲氯地孕酮)
C. Drugs used to treat erectile dysfunction
• sidenafil(西地那非)
A. Androgens and antiandrogens
Androgens
Testosterone 睾酮
Testosterone undecanoate 十一酸睾酮
O
O
O
C CH2CH2
H
Nandrolone phenylpropionate
苯丙酸诺龙
A. Androgens and antiandrogens
Pharmacological effects
(1) Development of the male sexual apparatus and secondary
sex characteristics
(2) Necessary for normal spermatogenesis (精子发生)
(3) Increasing protein anabolism
(4) Promoting growth of blood cells in bone marrow, especially
for red blood cells (EPO )
(5)Other effects: immune regulation, antiinflammation
effects,CVS effects
A. Androgens and antiandrogens
Clinical uses
(1) Replacement therapy in men: hypogonadism
(2)Female disorders: dysfunctional uterine bleeding,
endometriosis (子宫内膜异位症), advanced breast and
ovarian cancers
(3) Anemia: aplastic or other anemia (largely replaced by
recombinant erythropoietin )
(4) Infirmity (体质虚弱): anabolic steroids (同化激素)
(5) Others: male contraception, osteoporosis(either alone
or in conjunction with estrogens. Replaced by
bisphosphonates) etc.
A. Androgens and antiandrogens
Adverse effects
- due largely to their masculinizing actions and are most
noticeable in women and prepubertal children.
(1) Sex dysfunction:
• virilisation in female(hirsutism, acne, amenorrhea, clitoral
enlargement, and deepening of the voice, testosterone> 200–300
mg of per month)
• increased libido in male
(2) Hepatic toxicity
• occurs early in the course of treatment, the degree is proportionate
to the dose. bilirubin levels ↑
A. Androgens and antiandrogens
Contraindications
1. pregnant women, infants and young children (somatotropin
is more appropriate to produce a growth spurt).
2. male patients with carcinoma of the prostate or breast.
3. renal or cardiac disease predisposed to edema
Caution: Several cases of hepatocellular carcinoma have been
reported in patients with aplastic anemia treated with
androgen anabolic therapy. Erythropoietin and colonystimulating factors should be used instead.
A. Androgens and antiandrogens
Classic anabolic hormones
1. Growth hormone
2. IGF1 and other insulin-like growth factors
3. Insulin
4. Testosterone and analogs
5. Estradiol
A. Androgens and antiandrogens
Anabolic-androgen steroids (AAS)
• Drugs which mimic the effects of the male sex hormones
testosterone and dihydrotestosterone.
• They increase protein synthesis within cells, which results
in the buildup of cellular tissue (anabolism), especially in
muscles.
• Anabolic steroids also have androgenic and virilizing
properties, including the development and maintenance of
masculine characteristics such as the growth of the vocal
cords, testicles, and body hair (secondary sexual
characteristics).
Androgens: Preparations Available and Relative
Androgenic:Anabolic Activity in Animals.
Drug Androgenic: Anabolic Activity
Testosterone 1:1
Testosterone cypionate 1:1
Testosterone enanthate 1:1
Methyltestosterone 1:1
Fluoxymesterone 1:2
Oxymetholone 1:3
Oxandrolone 1:3–1:13
Nandrolone decanoate 1:2.5–1:4
A. Androgens and antiandrogens
Agents
1. Nandrolone phenpropionate(durabolin ，苯丙酸诺龙)
2. Nandrolonedecanoate(癸酸诺龙)
3. Metandienone (去氢甲睾酮，美雄酮)
4. Danazol (达那唑)
5. Stanozolol(司坦唑醇)
A. Androgens and antiandrogens
Antiandrogens
Cyproterone
环丙孕酮
• Antigonizing androgen receptor; inhibiting hypothalamuspituitary axis: LH↓, FSH↓, testosterone↓
• Used for treatment of prostatic cancer, severe acne and
hersulism, and contraception
A. Androgens and antiandrogens
Adverse effects
1. Antiandrogenic action gynecomastia (breast growth),
galactorrhea (milk outflow), and erectile dysfunction.
2.Liver toxicity high dose (200–300 mg/day).
3. Increased risk of DVT ( in combination with
ethinylestradiol )
4. Other reactions
•Depressive mood changes
•Suppression of adrenal function and reduced response to
ACTH
•Osteoporosis- suppresses production of estrogen due to its
antigonadotrophic effect
A. Androgens and antiandrogens
Other antiandrogens
1.Other receptor Inhibitors
•Flutamide(氟他米特)
•Bicalutamide(比卡鲁胺) & nilutamide(尼鲁米特)
•Spironolactone
2. Steroid synthesis inhibitors•Ketoconazole(酮康唑)
3. Conversion of Steroid Precursors to Androgens
•Abiraterone(阿比特龙) inhibitor of 17-hydroxylase
•Finasteride(非那雄胺) inhibitor of 5 -reductase
•Dutasteride(度他雄胺) similar to but much longer t1/2 than finasteride
×
×
B. Drugs used to treat erectile dysfunction
Phosphodiesterase type 5 isoenzyme inhibitors
(PDE5I)
• Sidenafil (西地那非,万艾可）
• Vardenafil (伐地那非,爱力达）
• Tadalafil (他达那非,希爱力）
B. Drugs used to treat erectile dysfunction
B. Drugs used to treat erectile dysfunction
Sildenafil citrate(Viagra)
• Acts by inhibiting cGMP-specific PDE5, an enzyme that delay
degradation of cGMP, which regulates blood flow in the penis
• The prime treatment for erectile dysfunction in all settings,
including diabetes.
B. Drugs used to treat erectile dysfunction
B. Drugs used to treat erectile dysfunction
Clinical uses
(1) Sexual dysfunction
(2) Pulmonary arterial hypertension (PAH)
• relaxes the arterial wall, leading to decreased pulmonary
arterial resistance and pressure→workload of the right
ventricle ↓, symptoms of right-sided heart failure↑
• acts selectively in the lungs and penis without inducing
vasodilation in other areas of the body →PDE-5 is
primarily distributed within the arterial wall smooth
muscle of the lungs and penis
(3) Altitude sickness
• prevention and treatment of high-altitude pulmonary
edema associated with altitude sickness -such as that
suffered by mountain climbers.
B. Drugs used to treat erectile dysfunction
Adverse effects
1.Headache, flushing, dyspepsia, nasal congestion and
impaired vision, including photophobia and blurred (lead to
vision impairment in rare cases) - the most common adverse
effects
2. Priapism, severe hypotension, myocardial infarction (heart
attack), ventricular arrhythmias, stroke, increased intraocular
pressure, and sudden hearing loss -rare but serious
B. Drugs used to treat erectile dysfunction
Contraindications
1. Administration of nitric oxide donors
2. Recent stroke or heart attack, or in men for whom sexual
intercourse is inadvisable due to cardiovascular risk factors
3. Hypotension (low blood pressure)
4. Severe hepatic/ renal function impairment
5. Hereditary degenerative retinal disorders (including genetic
disorders of retinal phosphodiesterases)
Further reading
1.Bertram G. Katzung, Susan B. Masters, Anthony J. Trevor
Chapter 40. The Gonadal Hormones & Inhibitors
Basic and Clinical Pharmacology, 11e. 2010 The McGraw-Hill
Companies.
2. http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001046/