drugs to treat male endocrine disorders

GnRH

-released by hypothalamus

-stimulates release of LH and FSH

-intermittent and pulsatile release

LH

-stimulates leydig cells to produce testosterone

FSH

-stimulates sertoli cells to produce ABP

ABP

-binds to T in seminiferous tubules resulting in spermatogenesis

biosynthesis of T

-made from cholesterol

-95% produced by testis

-5% produced by adrenals

T moa

-free T converted to DHT by 5-alpha reductase

-T or DHT binds to androgen receptors in cytosol

-receptor complex enters nucleus and binds to androgen response elements (ARE)

-transcription > protein synthesis > response

metabolism of T forms two active steroids

-DHT via 5-alpha reductase

-estradiol (E2) via aromatase

T PK

-very low oral bioavailability

-highly metabolized in the liver

pharmacological effects of T

maintenance of

-muscle mass

bone density

-erythropoiesis

-spermatogenesis and libido

pharmacological effects of DHT

-male pattern baldness

-prostate diseases (BPH or cancer)

-acne

pharmacological effects of E2

maintenance of

-bone density

-libido

effects of T deficiency

-ED (impotence)

-decresed libido and energy

-decreased muscle mass

-decreased bone density

-decreased hematocrit

-decreased facial hair growth

hypogonadism

-low T levels

types of parenteral T replacement preparations

-short acting

-long acting

short acting parenteral T replacement preparations (drug)

-testosterone

-testosterone propionate

long acting T replacement preparations (drug)

-testosterone enanthate

-T. cypionate

oral T replacement preparations (drug)

-methyltestosterone

-fluoxymesterone

other routes of admin for T replacement

-buccal tablets

-TD patches

-gel

T replacement buccal tabs (drug)

-Striant

T replacement TD patches (drug)

-Testoderm

-Androderm

T replacement gel (drug)

-AndroGel

short acting parenteral T administration

-IM injections

-25-50mg 2-3 times per week

short acting parenteral T metabolism

-oxidation of 17-OH group

long acting parenteral T administration

-IM injections

-50-200 mg every 2-4 weeks

long acting parenteral T metabolism

-esterification of 17B-hydroxyl group with fatty acids (slows the relase of steroid)

orally active T preparations PK

-alkylation at C-17a

-slowly metabolized by the liver = high bioavailability

-requires smaller daily doses

clinical use of orally active T perparations

not preferred for hypogonadism bc

-not metabolized to DHT or E2

-severe hepatotoxicity

-hyperlipidemia

T replacement buccal tablets

-applied to gum BID

-bypasses first-pass metabolism

-serum T levels maintained in normal range for 80% of the day

T replacement TD patches

-applied to back/stomach/upper arms/thighs

-rotate sites daily

-bypasses first-pass metabolism

-more stable serum T levels than injections

T replacment gels

-lipophilic enough for topical delivery

-applied to shoulder/upper arms/abdomen (will be covered)

-not to be applied to privates/chest/ack/underarms/knees

T replacement ADEs

-acne

-prostate enlargement

-gynecomastia

-weight gain

-polycythemia

-suppression of HPA axis

result of decreased HPA axis

-impaired fertility

-testicular atrophy

decreased

-testicular function

-sperm production

ED treatment strategy

-increase parasympathetic activity

-decrease sympathetic activity

-increase blood flow to penile tissue

drug classes to treat ED

-selective PDE-5 inhibitors (inc cGMP)

-prostaglandin E1 analogs (inc cAMP)

short acting PDE-5 inhib drugs

-sildenafil

-vardenafil

-avanafil

E1 analog drug

-alprostadil

PDE-5 moa

-selectively inhibit PDE-5 enzyme to increase cGMP levels

-smooth muscle relaxation and increased blood flow

PDE-5 clinical uses

-most commonly used for ED

-can be used for pulmonary HTN (sildenafil and tadalafil)

PDE-5 PK

-all metabolized by CYP3A4

PDE-5 ADEs

-headache

-flushing

-nasal congestion and dyspepsia

sildenafil, vardenafil, avanafil specific ADEs

-hypotension

-loss of blue-green color discrimination

tadalafil specific ADEs

-myalgia

PDE-5 drug interactions

-nitrates (profound hypotension)

-CYP3A4 inhibitors

E1 analog moa

-stimulates adenylyl cyclase to increase cAMP levels and decrease Ca levels

-smooth muscle relaxation and increased blood flow

alprostadil clinical use

-alternative agent for ED

alprostadil administration

-intracevernous injection (CAVERJECT)

-urethral suppository (MUSE)