Pharmacology Flashcards
Types of estrogen
Estradiol is the most potent , produced by ovary , the principal estrogen in premenopausal women.
Estrone is a metabolite of estradiol has one-third the estrogenic potency of estradiol, the primary circulating estrogen after menopause, generated from conversion of androstenedione in peripheral tissues.
Estriol metabolite of estradiol, significantly less potent than estradiol, present in significant amounts during pregnancy, produced by placenta.
Naturally occurring estrogens
Conjugated equine estrogens (Premarin)-natural
equilin (obtained from urine of pregnant mares)undergo some firstpass metabolism, but it is not sufficient to lessen the effectiveness when taken orally,
Synthetic estrogen analogs such as
ethinylestradiol, mestranol and estradiol valerate, analogs have a prolonged action and a higher potency compared to those of natural estrogens.
Estrogen actions
Actions
Side effects
Development of female genital tract Mild anabolic Normal function of skin & bl.vess. Sodium and water retention Raise HDL, lower LDL Decrease Bone Resorption Increase blood coagulability may Improve mood, concentration, reduce Alzheimer’s Disease
Estrogens side effect
Irregular withdrawal vaginal bleeding Breast tenderness Nausea, vomiting Water retention Increase coagulability, thromboembolism Impaired glucose tolerance Endometrial hyperplasia & cancer Cholestasis & gallbladder disease
Progesterone/ progestogens actions
Secretory endometrium Anabolic Increase Bone Mineral Density Fluid retention Mood changes( depressant)
Side effects of progesterone
Weight gain Fluid retention Acne Hirsutism Nausea vomiting Depression, PMS lack of concentration
Progesterone derivatives
Oral
Medroxyprogesterone, Dyhdrogesterone
Testosterone derivatives
Oral
Norethisterone, Norethindrone , norgestrel, Norgestimate
Testosterone
Actions/Side effects
Male secondary sex characteristics Anabolic Acne Voice changes Aggression Metabolic adverse effects on lipids
Dec HDL
WHILE ESTROGEN INC HDL
Implants form of E
Vaginal
Etonorgestrel
estradiol cream for vaginal atrophy
Testosterone Implants
IM
Oral
Testosterone
Enenthate, Proprionate
Undecanoate, Mesterolone
منو اكثر شي يتأثر بال first pass metabolism ايستروجين لو بروجستيرون
Transport bound to SHBG and albumin ➢ Liver metabolism, progesterone almost metabolised in one passage through liver ➢ Metabolites excreted in Urine (as glucuronides and sulphates)
In estrogen no effect of fast effect metabolism
But in progesterone effect is higher
Combined Oral Contraceptive Pill
Oestrogens: high/low dose: 50, 35, 30, 20mg/day
ethinylestradiol mestranol
Progestogens: which generation?
1 st : norethynodrel 2 nd : levonorgestrel, norethisterone 3 rd : desogestrel, gestodene, norgestimate 4 th : drospirenone (Yasmin:antimineralocorticoid, antiandrogen), norelgestromin (Evra: patch)
Progestogens: which generation?
1 st : norethynodrel 2 nd : levonorgestrel, norethisterone 3 rd : desogestrel, gestodene, norgestimate 4 th : drospirenone (Yasmin:antimineralocorticoid, antiandrogen), norelgestromin (Evra: patch)
Adverse Effects of COC
▪Venous thromboembolism ▪Myocardial infarction ▪Hypertension ▪Decrease glucose tolerance ▪Increase risk of stroke in women with focal migraine ▪Headaches ▪Mood swings ▪Cholestatic jaundice ▪Increase incidence of gallstones ▪Precipitate porphyria
The Mini-pill
COC طريقة أخذ الدواء
28 days progestogen
COC
Monophasic = 21
Triphasic = 21
Every Day: ED = 21+7 placebo
Other progestogens
Implant
Medroxy Progesterone Acetate
▪Depot provera: MPA
Etonogestrel
▪ Female implants: Implanon ▪ Male implants ▪Vaginal ring
POP side effect
Side-effects of all POPs include possible irregular bleeding, persistent ovarian follicles (simple cysts) and acne. If a POP is missed then the woman should continue taking the POP and use extra precautions (e.g. condoms) for the next 48 hours until the progestogen effect on the mucus is built up. If unprotected sex occurs during this time, then emergency contraception is required.
Steroids in HRT
Oestradiol e.g. valerate, enanthates, Micronised oestradiol, 1-2mg/day Premarin 0.625-1.25mg/day
Medroxyprogesterone acetate (Provera) Norethisterone Duphaston
دوفاستون والمسمى بالدوديجسترول
Risks of HRT
▪Unopposed oestrogen: increase endometrial cancer, and ovarian cancer ▪Increased Breast cancer ▪Increased Ischaemic Heart Disease, and stroke ▪Increase risk of venous thromboembolism ▪Uterine bleeding
▪Adverse effect on lipid profile
SERM
Selective Estrogen Receptor Modulators
estrogen related compounds, which interact at estrogen receptors but have different effects on different tissues, so they display selective agonism or antagonism according to the tissue type
Raloxifene
Protects against osteoporosis ▪ No proliferative effects on endometrium ▪ No proliferative affect breast ▪ Increases hot flushes ▪increased risk of DVT, pulmonary embolism, & retinal vein thrombosis
Weak oestrogens that block receptors
Clomiphene: ovulation induction: inhibit oestrogen binding to anterior pituitary, inhibit negative feedback, results in increased GnRH and FSH, LH .Side effects : hot flushes, ovarian enlargement & risk of multiple pregnancy .
Tamoxifen
used for treatment of metastatic breast cancer, or as adjuvant therapy following mastectomy or radiation for breast cancer , and as prophylactic therapy to reduce the risk of breast cancer in high-risk patients.
Ospemifene
is indicated for the treatment of dyspareunia (painful sexual intercourse)
related to menopause.
Mifepristone
progesterone antagonist inhibits progesterone action ▪ Sensitises the uterus to prostaglandins ▪ Used for medical termination of pregnancy with misoprostol, and induction of labour
Anti-androgen
Cyproterone: Progesterone derivative
▪Weak progestogenic effect. Partial agonist to progesterone receptor, competes with dihydrotestosterone ▪Used in combined contraceptive pill (Dianette)
Finasteride
Flutamide
inhibit 5α-reductase
Antiandrogen
Finasteride inhibit 5α-reductase resulting in decreased formation of dihydrotestosterone. used for the treatment of benign prostatic hyperplasia .
competitive inhibitor of androgens
Flutamide act as competitive inhibitor of androgens at the target cell and are effective orally for the treatment of prostate cancer .
Glucocorticoid (GC) action
Increased glucose production
- Breakdown of protein
- Redistribution of fat
- Anti-inflammatory
- Immunosuppression
Corticosteroids and immune system
Inhibition of B and T cell responses
- Reduced transcription of cytokines
- Reduced cell adhesion by leucocytes
- Reduced phagocytic function
- Immune suppression
Corticosteroid Replacement
Hydrocortisone
Inflammatory
Disease
Prednisolone
Tumour
Oedema
Dexamethasone
Topical
Treatment
Betamethasone
Mineralocorticoid
Replacement
Fludrocortisone
Routes of administration
Intravenous
methylprednisolone
Routes of administration
Oral
prednisolone
dexamethasone
hydrocortisone
fludrocortisone
Routes of administration
Inhaled
fluticasone (high 1 stpass metabolism)
beclomethasone
Routes of administration
Topical
flexor>forehead>scalp>face>forearm
betamethasone
Routes of administration
Intra-articular
triamcinolone
depomedrone
Summary of clinical use
Adrenal insufficiency
- Inflammatory disease
- Immuno-suppression
- Malignancy
- Diagnosis of Cushing’s syndrome
Primary adrenal failure
Adrenal insufficiency
Primary adrenal failure
- Hydrocortisone (10/5/5mg)
- Fludrocortisone (100ug)
- Mimic normal physiology
- Fludrocortisone not in pituitary disease
Inflammatory disease
Vasculitis
- Sarcoidosis
- Rheumatoid arthritis
- Asthma
Gastro-intestinal disease
- Inflammatory skin conditions
- Nephrotic syndrome
- Haematological conditions
- Cerebral edema
Immuno-suppression
Acute transplant rejection
- Acute leukaemia
- Pemphigus
- Exfoliative dermatitis
Malignancy
- Hypercalcaemia
- Improve appetite
- Malignant oedem
Diagnosis of Cushing’s syndrome
Dexamethasone suppression test
- 2 days dexamethasone
- Measure cortisol levels before and after
- Normal individuals suppress < 50 nmol/l
- Failure to suppress in Cushing’s syndrome
Glucocorticoid side effect
Osteoporosis
- Avascular necrosis
- Peptic ulcers
- Increased infections
- Hypertension
- Diabetes
Impaired growth
- Skin atrophy
- Cataracts
- Corneal damage
- Cushingoid features
Cushingoid features
Rounded face
- Plethoric features
- Acne
- Poor wound healing
- Central obesity
- Proximal myopathy
Buffalo hump
- Thin skin
- Easy bruising
- Abdominal striae
- Hypertension
- Diabetes mellitus
Adrenal suppression
Suppression of HPA axis occurs after 3 weeks
- Prednisolone > 20mg will suppress HPA axis
- May persist for years if long term treatment
- Abrupt withdrawal may lead to hypo-adrenal crisis
Hypoadrenal crisis
- Hypotension
- Hypoglycaemia
- Hyponatraemia
- Hyperkalaemia
- Severe dehydration
- Death if untreated
Subtle symptoms of steroid withdrawal
- Fever
- Myalgia
- Arthralgia
- Weight loss
- Conjunctivitis
- Rhinitis
Laparotomy or major procedure
- Hydrocortisone 100mg IM at induction
- Hydrocortisone 100mg IM 6 hourly until eating and drinking
- Double normal dose oral steroids until full recovery
Less invasive surgery
Hydrocortisone 100mg at time of procedure
• Double normal oral dose until full recovery
‘Steroid sparing agents’
- Reduced steroid requirement
- Azathioprine
- Cyclophosphamide
- Biological therapies
- Important for reducing steroid side effects
