Pharm 1st half block 4
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What is the enzyme that converts testosterone into estradiol?
What is the enzyme that turns sndrostenedione into testosterone and esterone into estradiol?
17 hydroxysteroid dehydrogenase
What is 16 alpha hydroxylase?
an enzyme that, in the liver, converts estradiol into estriol.
What is the predominant source of circulating estrogen in women?
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
What are the effects of estrogen deficiency in males?
Estrogen deficiency leads to macroorchidism, increasedtestosterone, and abnormalities in metabolism and fertility
What are some metabolic effects of estrogens?
- 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
What are the pharmacokinetics of estrogens?
- Can be given any way
- highly absorbed b/c lipophillic
- low oral bioavailability becasue of first pass metabolism can use modified versions to bypass
What are some side effects of estrogen use?
- 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
What are the clinical uses of estrogens?
Hormonal replacement to prevent osteoporosis, vaginal dryness, UG atrophy, cardiovascular disease, and reduce vasomotor symptoms (reduce hot flashes)
What are selective estrogen receptor modulators?
- Tamoxifel, Raloxifen, and Toremifen
- These have tissue specific action- antagonistic in breast and endometrium
- Agonistic activity in bone, brain, and liver
What are some estrogen antagonists?
- Clomiphene and Fulvestrant
- pure antagonists
- Clomiphene used to treat infertility in anovulatory women
- Fluvestrant used in breast cancer treatment.
What are the actions of Tamoxifen?
- 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
What is Raloxifen used for?
- 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
How does Clomiphene work?
- 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
When is Fluvestrant used?
In tamoxifen resistant breast cancers
Given in monthly injections, has several active metabolites, and is eliminated in feces
What do aromatase inhibitors block?
conversion of androstenedione to estrone and conversion of testosterone to estradiol
What are Exemestin, Letrozole, and Anastrozol?
- 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
What efffects to progestins have on the body?
- 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
What effects do progestins have on the CNS?
- 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
What are some theraputic uses for progestins?
- 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
What are Mifepristone and Onapristone?
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.
What is the goal of estrogens and progestins ing contraception?
For estrogens to reduce amplitude of GnRH and gonadotropin (FSH/LH) release and for progestins to reduce the frequency
What are Ethinyl Estradiol and Mestranol?
What are Norethindrone, Norgestrel, Levongestrel, Desogestrel, Etonogestrel, and Drospirenone?
Progestin based oral contraceptives.
What are the benefits and side effects of combinational oral contraceptives?
- Decrease risk of ovarian cancer and endometriosis
- Decrease osteoporosis
- Increase risk of venous thromboembolism
- Possible increase risk of cancers
What are the contraindications for contraception use?
- Thromboembolic disease
- Cerebrovascular disease
- 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
How are progestin only ora lcontraceptives used?
- 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
What are some concerns with oral contraceptive use?
- 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
What portion of the testosterone in the body is bioavailable?
- Free and slbumin bound.
- bound to steroid hormone bingind globulin is not.
What are the effects of Dihydrotestosterone?
- Made from testosterone by 5 alpha reductase
- External genetalia
- prostate growth
- Facial and body hair
- Scalp hair loss
- sexual maturation at puberty
What are the effects of testosterone?
- Wolffian duct- efferent ducts of testis
- Bone formation
- Muscle mass
- sexual differentiation
What are the effects of estradiol in males?
- Made from testosterone by aromatase
- Hypothalamic feedback
- Bone resorption
- Epiphyseal closure
- Vascular and behavioral defects
What are the effects of androgen deficiency during fetal development and before puberty completion?
- 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
What are the effects of androgen deficiency after puberty?
- 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
What are some theraputic testosterone preparations?
- 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
What are the clinical indications for testosterone use?
- Male hypogonadism
- Male senescence to increase bone density- risk of prostatic hyperplasia
- Female hypogonadism
- Enhancement of athletic performance
What are inhibitors of androgen synthesis?
- GnRH analogs and antagonists
- Abarelix, an antagonist, is approved for use in prostate cancer
What are antagonists of androgens?
- 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
What is Spironolactone?
- An aldosterone antagonist that has some androgen antagonist activity
- causes gynecomastia in men
What are 5 alpha reductase inhibitors?
- Finastride and Dutasteride
- block conversion of Testosterone to Dehydrotestosterone
- used to treat BPH
What are the symptoms of hyperthyroidism?
Heat intolerance, tachycardia (a fib), Tremors, menstrual irregularities, increased basal metabolic rate decreased cholesterol and triglycerides .
What are the symptoms of hypothyroidism?
- Cold intolerance, dry brittle skin/hair/nails, bradycardia, fatigue, depression, hyporeflexia
- Menstrual irregularities, decreased libido, increased cholesterol and triglycerides
What happens when you deiodinate the inner ring of Thyroxine?
create reverse T3- inactive
outer ring deiodination= activation
What kinds of drugs inhibit 5 deiodinase?
beta blockers, high dose propythiouraci and steroids
block conversion of T4 to T3 leaving low t3 and high rT3
What are the drugs that inhibit thyroid hormone synthesis?
- 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
What are the drugs that block thyroid hormone release?
Iodides and Iodinated contrast media
What drugs block the uptake of iodine anions?
- anion inhibitors
- Perchlorates and Thiocyanates
What are the clinical uses of thioamides?
- Treatment of thyrotoxicosis and in prep for surgery
- Propothiouracil is preferred in pregnancy
- Side effects- maculopapular rash, arthralgia, vasculitis
- rarely- reversible agranulocytosis and hepatits
How do Potassium Iodide drugs work?
- 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
What are the adverse effects of potassium iodide use?
- Fetal goiter
- Thyrotoxicosis at low doses ( jod basedow's rxn)
- Salivary gland inflamm and acne
What is the action of Radioactive Iodine?
- 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
How do Perchlorate, pertechnetate, and thiocyanate work?
inhibit Iodine uptake effective for iodine induced hyperthyroidism.
Not often used because of aplastic anemia
What are the effects of propranalol, lithium, and Amiodarone on the thyroid?
- 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
What is the preferred treatment for myxedema coma?
- Myxedema coma is deterioration of mental status not necessarily comatose
- Levothyroxine T4
- Monitor levels by TSH
What is levothyronine?
- 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
What is the recommended treatment in thyroid storm?
- Propranalol for heart symptoms, high dose propylthiouracil to inhibit peripheral conversion of T4-T3
- and Potassium iodide to block hormone release.
What are the effects of PTH?
- 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)
What is Teriparatide?
Recombinant PTH approved for the treatment of osteoporosis in those who cannot tolerate bisphosphates.
low dose PTH stimulates bone formation without stimulating osteoclasts
What is the effect of vitamin D?
- 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
What are the effects of Vit D on parathyroid and the immune system?
- inhibits PTH secretion
- Promotes phagocytosis, anti tumor activity, and immunomodulatory functions
What are the clinical uses of vitamin D?
- 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
What are bisphosphates?
- 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
What are bisphosphates used to treat?
osteoporosis, paget's, and hypercalcemia of malignancy.
Can result in esophagitis and GIT distress
How do estrogens work to prevent osteoporosis?
They inhibit IL-1 and TNF decreasing osteoclast differentiation and activation.
What is Miacalcin?
- 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
What is Fluoride used for?
- 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
What is Denosumab?
Blocks RANKL blocking osteoclast activation
What are the principal indications for the use of thrombotic drugs?
- Prevention of venous thromboembolism
- prevention of stroke in patients with a fib
- Prevention and treatment of acute coronary syndrome
What is heparin?
- 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
What are the pharmacokinetics of heparin?
- 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
What is Low molecular weight heparin
- 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
What is Protamine Sulfate
- heparin antagonist
- less effective on LMWH
What is Fondaparinux?
- Direct Factor Xa inhibitor
- Along with LMWH has more anti Xa than Anti IIa activity
- very low risk for heparin induced thrombocytopenia
What are Hirudin, Argatroban, and Lepirudin?
Direct thrombin inhibitors- directly inhibit thrombin without involging antithrombin or Vitamin K
Used for anti coag therapy in patients with heparin induced thrombocytopenia
What is Danaparoid?
- 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
What are Warfarin, Dicumoral, and Phenindione?
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
What are the adverse effects of Warfarin treatment?
- 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
What is the antidote to Warfarin Toxicity?
- Vit K
- If have serious hemorrhage can use fresh frozen plasma of plasma contrates of II, VII, IX, and X
What is the action of Fibrinolytic drugs?
- 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
Which fibrinolytic drug(s) are selective for local plasmin formation?
Streptokinase and Urokinase produce plasmin everywhere.
What are Aminocaproic acid and Tranexamic acid?
Inhibitors of fibrinolysis, work by binding plasminogen and inhibiting its conversion to plasmin
Used to treat excessive abnormal menstrual bleeding/ post delivery bleeding
What are the effects of aspirin on platelet aggregation?
- 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
What is Dyridamole?
- 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
What are Ticlopidine and Clopidogrel?
- 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
What are Abciximab, Eptifabatide, and Tirofiban?
- 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
What is the only lipoprotein with ApoB-48?
What drugs increase the fecal excretion of cholesterol and bile salts?
- 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
What are the side effects of Cholestyramine and Colestipol?
Constipation and deficiency of fat soluble vitamins
What are Lovastatin, Simvastatin, Atorvastatin, and Rosuvastatin?
HMG CoA reductase inhibitors- block the synthesis of cholesterol. Most efficacious and well tolerated of the anti hyperlipoproteinemia drugs
What are the actions of HMG CoA reductase inhibitors?
- Increase LDL receptors in the liver
- decrease in VLDL synthesis
- Increased HDL
- Atorvastatin(lipitor) is the only statin that lowers TGs significantly
What are the cardioprotective actions of statins?
- 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
What are the side effects of HMG CoA reductase inhibitors?
Headache, Sleep Disturbances, Hepatotoxicity, rhabdomyolysis/myopathy
What are the contra indications for simvastatin use?
- 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
What are fibric acid derivatives?
- Fenofibrate and Gemfibrozil
- PPAR alpha agonists- involved in the regulation of carbohydrate and lipid metabolism
What are the actions of Gemfibrozil?
- 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
What are the adverse effects of fibric acid derivative use?
- Gall stones
- Fenofibrates less associated with myopathy than any other fibric acid derivative
What is Nicotinic acid?
- Broad spectrum anti hyperlipoproteinemia drug
- Reduces VLDL and TG production
- Increases HDL
- and reduces LDL
What is special about nicotinic acid and what are the side effects associated with its use?
- 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
- Can cause myopathy when used with statins
What is Ezetimibe?
- 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
What is the action of orlistat?
- reduces intestinal fat absorption by blocking pancreatic lipase.
- Can cause oily stools and loss of fat soluble vitamins
What is Sibutramine?
A centrally acting serotonin nor epi reuptake inhibitor- increases MI and stroke so is no longer used.
What is Rimonabant?
- 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
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