Pharm 1st half block 4

Aromatase

17 hydroxysteroid dehydrogenase

an enzyme that, in the liver, converts estradiol into estriol.

Ovaries in pre menopausal

• Other sources
• Liver- makes estriol and esterone from estradiol
• Adipose tissue, testes, bones, placenta
• Breast and cns tissue produce it locally

Estrogen deficiency leads to macroorchidism, increasedtestosterone, and abnormalities in metabolism and fertility

• Bone: Positive effect on bone mass– Stimulate osteoblasts– Increase collagen synthesis
• Lipid homeostasis– Increase HDL– Decrease LDL
• Serum proteins– Increase binding globulins: cortisol, thyroxin, sex hormones
• Other– Slightly decrease serum glucose and insulin– Slightly increase coagulation factors

• Can be given any way
• highly absorbed b/c lipophillic
• low oral bioavailability becasue of first pass metabolism can use modified versions to bypass

• possible increase in cancer risk
• Reduce the risk for cardiovascular disease in postmenopausal women but increases the risk of thrombosis in premenopausal (especially in smokers)
• Increase the risk of dementia

Hormonal replacement to prevent osteoporosis, vaginal dryness, UG atrophy, cardiovascular disease, and reduce vasomotor symptoms (reduce hot flashes)

Oral contraception

• Tamoxifel, Raloxifen, and Toremifen
• These have tissue specific action- antagonistic in breast and endometrium
• Agonistic activity in bone, brain, and liver

• Clomiphene and Fulvestrant
• pure antagonists
• Clomiphene used to treat infertility in anovulatory women
• Fluvestrant used in breast cancer treatment.

• Usually used in breast cancer,
• Inhibits proliferation of breast cancer cells
• Reduces the size and number of tumors
• Decreases total cholesterol and LDL
• Increases risk of deep vain thrombosis
• Increases risk of pulmonary embolism
• Increases risk of endometrial carcinoma
• Induces hot flashes– Does not increase incidence of bone fractures

Pharmacokinetic– Orally administered– 4-OH-tamoxifen (more potent ER antagonist)– Hepatic metabolism, enterohepatic cycle, excreted in feces

• Breast cancer and osteoporosis treatment
• ER agonist
• In bone: Dose-dependently reduces the number of bonefractures
• Serum: Reduces total cholesterol and LDL
• ER antagonist
• Antiproliferative in ER-positive breast cancers Hot flashes
• Pharmacokinetics– Rapid oral absorption– Hepatic metabolism, enterohepatic cycle, excreted in feces

• Used in infertile women with INTACT hypothalamic- hypophyseal- ovarian system and adequate estrogen production.
• Increases FSH, Enlarges the ovaries, Induces ovulation
• Absorbed well orally, large plasma protein binding, eliminated in feces
• Increased risk of multiple births, hot flashes, and possible increase in risk of ovarian cancer

In tamoxifen resistant breast cancers

Given in monthly injections, has several active metabolites, and is eliminated in feces

conversion of androstenedione to estrone and conversion of testosterone to estradiol

• Aromatse inhibitors
• they are highly effacacious in breast cancers
• do not increase cervical cancer or thrombosis
• Block estrogen synthesis in ALL tissues
• Could be used as prophylaxis against breast cancer

• Decrease the frequency of GnRH pulses
• Decrease endometrial proliferation
• Increase endometrial secretion and viscosity
• Prepares the uterus for implantation and pregnancy by decreasing motility and suppressing menstruation
• quick drop in progesterone causes menstruation
• Increases vascularization of mammary glands in late pregnancy and increases prolif of glands

• Increase body temp by 1 degree C
• Increases ventilatory response to CO2 reducing PCO2
• potential depressand and hypnotic effects

Increases insuli, enhances fat deposition and potentially increases LDL

• Contraception- alone in medroxy progesterone acetate( MPA) or in combination with estrogens in oral contraceptives
• Hormonal replacement in menopause
• Control of amenorrhea and abnormal bleeding
• Support of luteal phase in infertility

Progesterone antagonists- competitive antagonists that delay or prevent ovulation

• Used in early termination of pregnancy (morning after pill) effective up to 49 days
• Can cause severe vaginal bleeding.

For estrogens to reduce amplitude of GnRH and gonadotropin (FSH/LH) release and for progestins to reduce the frequency

Estrogen contraceptives

Progestin based oral contraceptives.

• Decrease risk of ovarian cancer and endometriosis
• Decrease osteoporosis
• Increase risk of venous thromboembolism
• Possible increase risk of cancers

• Thromboembolic disease
• Cerebrovascular disease
• MI
• Coronary artery disease
• Congenital hyperlipidemia
• Carcinoma of the breast or female reproductive tract
• Any hormone-dependent/responsive neoplasias
• Abnormal undiagnosed vaginal bleeding
• Known or suspected pregnancy
• Past or present liver tumors or impaired liver function
• use extreme caution in women with long smoking history

• Norethindrone
• Orally
• Daily
• Levonorgesterol
• Subcutaneous implant
• Up to several years
• Medroxyprogesterone Acetate (MPA; Depo-Provera)
• IM injection
• Several months
• Advantageus for women with high risk factors Smokers
• High failure rates

• Side effects/fear of side effects
• Bleeding, weight gain, reduced libido, increased libido
• Safety- makes you sick, infertile, or causes cancer
• Family, friends, and societal factors influencing use

• Free and slbumin bound.
• bound to steroid hormone bingind globulin is not.

• Made from testosterone by 5 alpha reductase
• External genetalia
• prostate growth
• Acne
• Facial and body hair
• Scalp hair loss
• sexual maturation at puberty

• Wolffian duct- efferent ducts of testis
• Bone formation
• Muscle mass
• Spermatogenesis
• sexual differentiation

• Made from testosterone by aromatase
• Hypothalamic feedback
• Bone resorption
• Epiphyseal closure
• Gynecomastia
• Vascular and behavioral defects

• During fetal development
• Partial deficiency: Incomplete sexual differentiation
• Complete deficiency: Entirely female external genitalia
• Before completion of puberty
• Failure to complete puberty
• External genitalia, sexual hair, muscle mass, voice, behavior
• Gynecomastia

• For a few weeks- decreased energy and libido
• For months- decreased hematocrit and Hemoglobin
• For years- decrease in bone density
• For many years- decrease muscle mass, pubic hair, and increase bone fracture

• Esters like Testosterone Enanthate which is more lipophillic.
• given IM every 2 weeks, absorbed well orally and bypasses hepatic metabolism
• Alkylating agents like Methyl Testosterone, Oxandrolone, and Fluoxymesterone retard hepatic metabolism
• cause hepatotoxicity when given orally

• Male hypogonadism
• Male senescence to increase bone density- risk of prostatic hyperplasia
• Female hypogonadism
• Enhancement of athletic performance

• GnRH analogs and antagonists
• Abarelix, an antagonist, is approved for use in prostate cancer

• Flutamide, Biclutamide, and Nilutamide
• Limited efficiency b/c increase LH=> testosterone secretion
• should be used with GnRH analog
• Used to treat prostate cancer and Hirsutism

• An aldosterone antagonist that has some androgen antagonist activity
• causes gynecomastia in men

• Finastride and Dutasteride
• block conversion of Testosterone to Dehydrotestosterone
• used to treat BPH

Heat intolerance, tachycardia (a fib), Tremors, menstrual irregularities, increased basal metabolic rate decreased cholesterol and triglycerides .

• Cold intolerance, dry brittle skin/hair/nails, bradycardia, fatigue, depression, hyporeflexia
• Menstrual irregularities, decreased libido, increased cholesterol and triglycerides

create reverse T3- inactive

outer ring deiodination= activation

beta blockers, high dose propythiouraci and steroids

block conversion of T4 to T3 leaving low t3 and high rT3

• Thioamides- Propothiouracil and Methimazole
• Inhibit peroxidase activity
• Methimazole is more potent and longer acting than propothiouracil
• Takes about a month for actions to show up because pool of hormone must be depleted

Iodides and Iodinated contrast media

• anion inhibitors
• Perchlorates and Thiocyanates

• Treatment of thyrotoxicosis and in prep for surgery
• Propothiouracil is preferred in pregnancy

• Side effects- maculopapular rash, arthralgia, vasculitis
• rarely- reversible agranulocytosis and hepatits

• Block organification and clevage of hormone from TBG which inhibits release- woll chaikoff effect
• Decreases sizee and vascularity used pre op
• rapid improvement within 2-5 days
• thyroid can escape so only used pre op and for thyroid storm and to protect thyroid from radiation
• Do not use in preggo

• Fetal goiter
• Thyrotoxicosis at low doses ( jod basedow's rxn)
• Salivary gland inflamm and acne

• used in treatment of thyrotoxicosis and cancer
• Takes 1-3 months to destroy thyroid depending on beta ray emission
• painless alternative to surgery
• Patient will become hypothyroid but that is easily managed with replacement

inhibit Iodine uptake effective for iodine induced hyperthyroidism.

Not often used because of aplastic anemia

• Propranalol used to manage cardiac symptoms of thyrotoxicosis, and blocks periph conversion of t4-t3
• Lithium inhibits synthesis and release of thyroid hormone
• Amiodarone can cause hypothyroid or less likely hypERthyroid

• Myxedema coma is deterioration of mental status not necessarily comatose
• Levothyroxine T4
• Monitor levels by TSH

• T3 preparation not used for routine replacement therapy becauce it is moreexpensive and has a shorter half life than levothyroxine.
• It also carries a higher risk of cardiotoxicity
• Best used to suppress TSH in short term

• Propranalol for heart symptoms, high dose propylthiouracil to inhibit peripheral conversion of T4-T3
• and Potassium iodide to block hormone release.

• Increase plasma Ca and decrease plasma PO4 by increasing renal absorption of Ca and secretion of PO4
• Increases Bone resorption in high dose
• Increases GIT absorption of Ca and PO4 by activating synthesis of Calcitriol (1, 25 dihydroxyvitamin D3)

Recombinant PTH approved for the treatment of osteoporosis in those who cannot tolerate bisphosphates.

low dose PTH stimulates bone formation without stimulating osteoclasts

• Increases Ca and PO4
• Primarily by increasing small intestine absorption
• promotes bone mineralization and formation
• May decrease renal excretion
• D-3 hydroxylated at 25 position in liver and in kidney at position 1 (stimulated by PTH)
• *At high levels stimulates bone resorption

• inhibits PTH secretion
• Promotes phagocytosis, anti tumor activity, and immunomodulatory functions

• prevention/treatment of osteoporosis, rickets, and osteomalacia
• must give active form to renal failure patients as kidney cannot activate
• Give topical Calipotriol/Calciptriene for psoriasis

• Alendronate, Risedronate, Ibandronate, Pamidronate, and Zoledronate
• these have a non hydrolyzable group compared to normal phosphates in bone- Adsorb to hydroxyapatite becoming part of bone
• slowly released during remodeling then block osteoclast activity by blocking attachment and decreasing activity

osteoporosis, paget's, and hypercalcemia of malignancy.

Can result in esophagitis and GIT distress

They inhibit IL-1 and TNF decreasing osteoclast differentiation and activation.

• Salmon calcitonin that is 100x more potent than human calcitonin
• Principal effects are to lower serum Ca and PO4
• Used in paget's, post menopausal osteoporosis, and hypercalcemia

• Well established for the prophylaxis of dental caries.
• Stimulated bone formation and increases the crystal size of new bone to make it more resistant to resorption
• can cause osteosclerosis if used excessively

Blocks RANKL blocking osteoclast activation

• Prevention of venous thromboembolism
• prevention of stroke in patients with a fib
• Prevention and treatment of acute coronary syndrome

• A polysaccharide with a unique pentasaccharide responsible for its action.
• Acts by enhancing the activity of the endogenous anticoagulant antithrombin 3 by increasing its affinity for thrombin
• Heparin antithrombin 3 complex also inhibits factors Xa, IXa and XIa

• not well absorbed orally b/c highly ionized, does not cross placenta
• dose dependent kinetics- same amount removed per hour so 1/2 life depends on dose. (zero order)
• Side effects- Bleeding, Thrombocytopenia, Osteoporosis, and alopecia

• Selective inhibitor of Xa with much better bioavailability than unfractionated heparin
• Lasts longer, does not require monitoring, and has less risk of thrombocytopenia/osteoporosis.

Enoxaparin, Dalteparin, and Tinzaparin are LMWHs

• heparin antagonist
• less effective on LMWH

• Direct Factor Xa inhibitor
• Along with LMWH has more anti Xa than Anti IIa activity
• very low risk for heparin induced thrombocytopenia

Direct thrombin inhibitors- directly inhibit thrombin without involging antithrombin or Vitamin K

Used for anti coag therapy in patients with heparin induced thrombocytopenia

• A heparinoid consisting of heparan sulfate, dermatan sulfate, and chondroitin sulfate.
• Has greater specific anti Xa activity than LMWH
• Can be used as anti coag therapy in patients with heparin induced thrombocytopenia

Vitamin K antagonists- block the formation of vit K dependent clotting factors II, VII, IX and X

Also block Protein C synthesis giving a transient hypercoagulable state before anti coag effects show in 3-5 days

• Bleeding - monitor with PT or INR
• Skin necrosis, purple toes and rarely alopecia
• Fetal warfarin syndrome
• Broad spectrum antibiotics decrease vit K synthesis increaseing warfarin efficacy

• Vit K
• If have serious hemorrhage can use fresh frozen plasma of plasma contrates of II, VII, IX, and X

• convert plasminogen to plasmin which catalyzes the degredation of fibrin.
• Used to lyse already formed clots
• Streptokinase, Urokinase, and t-PA
• Used in the treatment of pulmonary embolism and MI

t-PA

Streptokinase and Urokinase produce plasmin everywhere.

Inhibitors of fibrinolysis, work by binding plasminogen and inhibiting its conversion to plasmin

Used to treat excessive abnormal menstrual bleeding/ post delivery bleeding

• Aspirin inhibits Cox enzymes and irreversibly inactivates TXA2 synthase in platelets
• Low dose(only inhibits cox1) spares endothelial cell synthesis of PGI-2 giving better anti platelet activity
• Side effect is gastric bleeding

• A vasodilating antiplatelet agent
• Blocks the reuptake of adenosine by RBCs and Endothelial cells which increases cAMP in platelets
• Also inhibits PDE also increasing cAMP and cGMP in platelets
• Used with aspirin to prevent thromboembolism in prosthetic heart valves and stroke

• blocks adp receptors on platelets- blocks Ca release in platelets so no activation of IIb/IIIa receptor so platelets can't bind fibrin and aggregate
• highly available orally
• Less GI bleeding than aspirin
• Ticlopidine is associated with neutropenia and thrombocytopenia

• Glycoprotein IIb/IIIa inhibitors
• bind the receptor blocking binding of fibrinogen inhibiting platelet aggregation
• Used in acute coronary syndrome and coronary angioplasty
• Can be used with heparin or aspirin

Chylomicrons

• Bile Acid sequestrants- Cholestyramine and Colestipol
• Neither digested or absorbed in the gut, also upregulate LDL receptors in the liver because it is making more bile to make up for that excreted.
• HMG CoA reductase activity increases synthesis of cholesterol increasing VLDL and blunting long term effectiveness of monotherapy
• Can see a mild triglyceride increase

Constipation and deficiency of fat soluble vitamins

HMG CoA reductase inhibitors- block the synthesis of cholesterol. Most efficacious and well tolerated of the anti hyperlipoproteinemia drugs

• Increase LDL receptors in the liver
• decrease in VLDL synthesis
• Increased HDL
• Atorvastatin(lipitor) is the only statin that lowers TGs significantly

• Increase in Endothelial NO synthesis
• Suppression of smooth muscle proliferation and inhibition of metalloproteinase-> increased plaque stability
• Anti inflammatory
• Increase in paraoxanase activity- Anti oxidative enzyme
• Anticoagulation by reduction of platelet agg

Headache, Sleep Disturbances, Hepatotoxicity, rhabdomyolysis/myopathy

• when using potent inhibitors of Cytochrome P450-3A4
• When using Fibrates or Niacin- dose should be 10mg/ day or less
• When using Amiodarone or Verapamil (other 3A4 inhibitors) do not exceed 20mg/day
• do not consume grapefruit

• Fenofibrate and Gemfibrozil
• PPAR alpha agonists- involved in the regulation of carbohydrate and lipid metabolism

• activates lipoprotein lipase- key in the degredation of VLDL- lowering TG
• Also reduces VLDL secretion, increases HDL synthesis, and moderately decreases LDL levels
• can cause myopathy when combined with statins

• Gall stones
• Fenofibrates less associated with myopathy than any other fibric acid derivative

• Broad spectrum anti hyperlipoproteinemia drug
• Reduces VLDL and TG production
• Increases HDL
• and reduces LDL

• It is the most effective at increasing HDL and it reduces the incidence of death do to MI.
• It is a cutaneous dilator- causes flushing and itching- can use aspirin to block prostaglandins and stop flushing/itching
• Liver dysfunction
• Hyperglycemia
• Gout
• Can cause myopathy when used with statins

• Decreases cholesterol absorbtion by localizing to the brush border in small intestine.
• Decreased absorption causes increased LDL uptake in cells further lowering serum cholesterol.
• When combined with simvastatin called Vytorin
• Can cause GIT disturbance, hepatitis, myalgia, and myopathy

• reduces intestinal fat absorption by blocking pancreatic lipase.
• Can cause oily stools and loss of fat soluble vitamins

A centrally acting serotonin nor epi reuptake inhibitor- increases MI and stroke so is no longer used.

• It is an inverse agonist for the cannabinoid receptor (CB1). Its main effect is reduction in appetite.
• No longer used due to concerns of suicidality and depression