Post on 23-Dec-2015
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SEX HORMONES
.
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REGULATORS
gonadotropin-releasing hormone (GnRH)
follicle-stimulating hormone (FSH)
luteinizing hormone (LH)
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INTENSITY OF HORMONAL SECRETION IN THE CYCLE
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FEED BACK-REGULATION
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Biosynthesis of steroids
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ESTROGEN-FUNCTIONS
IN WOMENDevelopmental effects,
neuroendocrine actions- in the control of ovulation-Cyclical preparation for fertilization
ACTIONS Mineral,carbohydrate,protein and lipid
metabolism
Estrogens and males on bone, spermatogenisis,& behaviour
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STRUCTURAL FEATURES OF ESTROGENS
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BIOSYNTHESIS
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DIFFERENT ESTROGENS
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BENEFITS ASSOCIATED WITH POSTMENOPAUSAL ESTROGEN REPLACEMENT
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SIDE EFFECTS ---ESTROGENSNausea vomiting
Breast tenderness
Migraine headache
Uterine bleeding
Hyper pigmentation
Cholestiasis
Gall bladder disease
Edema
Hypertension
Breast cancer
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HORMONAL CONTRACEPTIVES
ORAL, PARENTERAL & IMPLANTED CONTRACEPTIVES
O.C – 1.Combinations of estrogens and progestins 2.Sole progestin therapy
Monophasic Biphasic Triphasic
FORMS
No change of both componentsduring the cycle
Dosage of one or both components changed Once during the cycle
Dosage of one or both components changed twice during the cycle
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PROGESTERONE
14Properties of commonly used progestin
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ESTROGENS AND PROGESTINS -CLINICAL USE
Contraception
Hormone replacement therapy-post menopasal, hypogonadism, (along with
Gonadotropins/growth hormones in delay)
Antiprogestins abortifacients, contraception
Estrogen antagonists estrogen dependent
neoplasm
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TRANSPORT - KINETICS Estradiol binds to α2 globulin (SHGB)And to albumin in lower affinity.
Estradiol Liver estrone, estriol 2hydroxylated derivatives Conjugated metabolites Water soluble excreted in bile Small amounts in breast milk
Can be activated in the intestines
Hepatic first pass effect is minimized by other routes-Transdermal,Vaginal or by injection.
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Steroid hormones diffuse across the cell membrane and bind with high affinity to specific nuclear receptor proteins
Mechanism of action
Ligand – receptor complexForms a dimer before binding DNA
PRE -ORE
Activate gene transcriptionhormone-specific RNA synthesis
synthesis of specific proteins that mediate a number of physiologic functions
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MECHANISM, EFFECTS OF CONTRACEPTIVES
Combinational Contraceptives block pituitary functionLeads to inhibition of ovulation
Continuous use of progestin alone does not always inhibit ovulation
Combinational agents also produce change in the cervical mucus in the uterine tubes all of which decreaseThe likelihood of conception and implantation
Effects on ovary- depress ovarian functionEffects on uterus- Hypertrophy and polyp formationEffects on breasts- Enlargement, suppress lactation, less amt. transverse in to milkCNS--------------- estrogen excites, progestin depress the brainEndocrine –inhibition of gonadotropins, adrenal structure d function, high conc. Increase in α2 globulinBlood- increased coagulability, increased dosage of coumarin analogs required, increased sr. iron and total iorn binding capacity.
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ANTAGONISTS AND INHIBITORS
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Danazol, clomiphene action
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Androgen regulation
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Finastride, Anastrazole action
ERECTILE DYSFUNCTION
THE FIGURE BELOW SHOWS THE MECHANISM OF ACTION OF VIAGRA, AND THE OTHER PDE5 INHIBITORS, ON THE NITRIC OXIDE CYCLE.
ERECTILE DYSFUNCTION = CONSISTENT INABILITY TO OBTAIN AND/OR MAINTAIN AN ERECTION SUFFICIENT FOR SATISFACTORY SEXUAL RELATIONS
NIH 1992
DIAGRAM OF PENILE ERECTION
RISK FACTORS FOR ED Vasculogenic factors Age Certain medications Psychosocial/psychological factors Neurogenic factors Hormonal factors
ENDOTHELIAL DYSFUNCTION IS A RISK FACTOR FOR CVD AND ED
Heart failureHeart failure AtherosclerosisAtherosclerosis SmokingSmoking
HypertensionHypertension Oxidative stress DiabetesDiabetes
Endothelial dysfunctionEndothelial dysfunction
EDED
Adapted from Rubanyi GM. J Cardiovasc Pharmacol 1993; 22 (Suppl 4): S1–S4
CAUSES OF ED
1. Organic (80 %)diabetes mellitus, hypertension,
hyperlipidemie, benign prostate disease, peripheral vascular disease, cardiac problems, hormonal problems (pituitary, testis, thyroid, adrenal), neurogenic (cerebral, spinal, dorsal nerve, cavernous nerve)
postsurgical: radical prostatectomy, abdominoperineal resection
2. Psychogenic, drugs (20 %)
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DRUGS ASSOCIATED WITH ED Alcohol
· Estrogens
· Antiandrogens
· H2 receptor blockers
· Anticholinergics
· Ketoconazole
· Antidepressants
· Marijuana
· Antihypertensives
· Narcotics
· ß-blockers
· Psychotropics
· Cigarettes
· Cocaine
· Spironolactone
· Lipid-lowering agents
· NSAIDs
· Cytotoxic drugs
· Diuretics
CAUSES OF ED Neurogenic
Parkinson´s disease – 60%Multiple sclerosis – 70%Spinal cord trauma, tumor etc.Peipheral neuropathy: diabetes,
alcoholism, chronic renal failure
DIAGNOSIS OF ED MAY UNCOVER OTHER SERIOUS TREATABLE DISORDERS Hypertension
68% of men with hypertension had ED to some degree
Dyslipidemia60% of men with ED had dyslipidaemia
Heart disease56% of men with ED were found to have a
positive stress test40% of men with ED had significant
coronary occlusions
ORAL THERAPY
PDE 5 inhibitors (95%) 2-blockers (Yohimbin) hormonal therapy (testosterone)
PHOSPHODIESTERASES
Main role: termination of cyclic nucleotide second messenger signal, often cGMP
11 PDE groups (PDE 1-11) PDE-5 breaks down cGMP (the second
messenger of Nitric Oxide—NO), reversing the muscle-relaxant effect of NO
PDE-5 is found in corpus cavernosum, vascular and visceral muscles, and in platelets
N.O. Release Increases Penile Bloodflow
Lue,T. NEJM 2000. 342:1802
PDE5 INHIBITORS
cGMP
Sildenafil
Tadalafil
Vardenafil
NN
O
N
O
O
O
ONH
2N
NH
N
NH
O
OP
OO
0H
0H
N
NHN
NO
S
O
O O
N
N
N
NH NO
S
O
O O
N
N
N
Caffeine
OCH3
CH3
H3C
O
PDE5: LOCALIZATION PDE5 is localized in vascular smooth
muscle cells PDE5 is not localized in the following:
cardiac myocytesendothelial cells lymphatic cellscardiac conduction tissue
PDE5 INHIBITION WITH SILDENAFIL
PDE5
cGMP
GMP
GTP
Sexualstimulation
Smoothmusclerelaxationof the cavernosal arteries &the corpora
Erection
Corpus cavernosum
NO
NANC
NO=nitric oxide; NANC=nonadrenergic-noncholinergic neurons;PDE5=phosphodiesterase type 5
PDE5 INHIBITORS: PHARMACOKINETICS
1Klotz et al. ACCP. 2002;2 As reported in Kim et al. Formulary. 2002;37. *Median (range).
Tadalafil(Cialis)20mg
Vardenafil(Levitra)
20mg
Sildenafil(Viagra) 100mg
T1/2, h 17.5 4.6 3.7
Tmax, h* 2.0 (0.5-12) 0.8 (0.3-2.0) 1 (0.5-2)
Metabolism CYP3A4 CYP3A4CYP3A5CYP2C9
CYP3A4 CYP2C9
PDE5 INHIBITORS – SIDE EFFECTS
sildenafil tadalafil vardenafil
(N = 724/379) (N = 1812/793)
headache 15% 14,5 / 5,5% - placebo 16 / 6%
dyspepsia 6% 12,3 / 1,8% 4 / 1%
backache 0% 6,5 / 4,2% 0%
rhinitis 2% 4,3 / 3,2% 10 / 4%
myalgia 0% 5,7 / 1,8% 0%
flushing 14% 4,1 / 1,6% 12 / 1%
abnormal vision 5% 0% <2 / 0%
PDE5 INHIBITORS
sildenafil vardenafil tadalafil apomorfinEffect PDE5, PDE6
inhibitionPDE5, PDE6
inhibitionPDE5, PDE11 -
inhibitioncentral effect
efficacy 82 % 80 - 86 - 92 % 81 % 45 %
Start time to efficacy
12 - 37 min 15 - 30 min 30 min 18 min
Time of efficay 3,5 - 5 h. 4 - 5 h. 24 - 36 h. 2 h.
Side effect nausea
contraindication nitrates taking nitrates taking nitrates taking
timing 1x / 24 h. 1x /24 h. No-every 24 h. 1x/ 8 h.
cost 4 x 100 mg 1832,61 Kč
4 x 10 mg1528,01 Kč
4 x 20 mg1538,80 Kč
4 x 3 mg1414,32 Kč
CONTRAINDICATIONS Since PDE5 inhibitors such as
sildenafil, tadalafil, and Vardenafil may cause transiently low blood pressure (hypotension), organic nitrates should not be taken for at least 48 hours after taking the last dose of tadalafil. Using organic nitrates within this timeframe may increase the risk of life-threatening hypotension.