Exam 1 Flashcards
chemical messenger system comprising of feedback loops of hormones released by internal glands of the body directly into the blood, regulating distant target organs, functions to maintain homeostasis through the release of hormones by endocrine glands, works together with autonomic nervous system and is integrated by the hypothalamus
endocrine system
chemical synthesized by certain cells and released directly into the blood, produces its effect on cells distant from the site of release
hormones
short or long chains of linked amino acids, water soluble, all pituitary hormones and hypothalamic releasing factors EXCEPT dopamine
peptide and protein hormones
derived from cholesterol, fat soluble, cortisol, testosterone, estradiol
steroid hormones
amino acids with modified groups, water or fat soluble, thyroid hormones, epinephrine, dopamine
amine hormones
cell surface receptors for peptide and water soluble amines that interact with cell surface receptors, signal transduction via second messengers, alteration in cell activity, quick onset and short duration of action
receptors for water soluble hormones
nuclear receptors for steroid and thyroid (fat soluble amine) hormones that diffuse through the plasma membrane, hormone binds with receptor in cytoplasm forming a receptor hormone complex, receptor hormone complex enters the nucleus and triggers gene transcription, transcribed mRNA is translated into proteins that alter cell activity, late onset (because has to make protein) and long duration of action
receptors for lipid soluble hormones
master regulators of the endocrine system
hypothalamus and pituitary
______ produces releasing factors that regulate the following _______ hormones:
1. Growth hormone (GH)
2. Prolactin (PRL)
3. thyroid stimulating hormone (TSH)
4. adrenocorticotropic hormone (ACTH)
5. follicle stimulating hormone (FSH)
6. luteinizing hormone (LH)
hypothalamus, anterior pituitary
________ releases two hormones that are synthesized by the _________:
1. vasopressin
2. oxytocin
posterior pituitary, hypothalamus
- replacement therapy for hormone deficiency states
- antagonists for diseases that result in hypersecretion
- diagnostic tools for identifying endocrine abnormalities
drugs to treat hypothalamic and pituitary disorders
- hypothalamus releases growth hormone releasing hormone (GHRH) which ____________ GH release and somatostatin which __________ GH release
- anterior pituitary –> GH release by GHRH
- liver –> GH ________ IGF-1 production
stimulates, inhibits, stimulates
GH has negative feedback on which endocrine gland?
pituitary
IGF-1 has negative feedback on which endocrine glands?
pituitary and hypothalamus
releasing factor secreted by the hypothalamus to stimulate GH secretion from anterior pituitary
growth hormone releasing hormone (GHRH)
- synthetic N-terminally modified form of human GHRH, resistant to degradation for prolonged duration of action (whereas giving human GHRH easily broken down by enzymes) to increase GH and IGF-1
- clinical use is for reduction of excess abdominal fat in HIV-associated lipodystrophy but not for GH deficiency
- administered SC
- adverse effects: hypersensitivity, joint pain/arthralgia, muscle pain/myalgia, peripheral edema, hyperglycemia, injection site reactions
tesamorelin acetate (EGRIFTA SV)
how must all peptide hormones be administered?
SC
- peptide hormone secreted by somatotroph cells of anterior pituitary, most abundant pituitary hormone that is released in a pulsatile fashion, maximal at night at deep sleep, other stimuli include high protein meals, exercise, stress, hypoglycemia
- in childhood/adolescence this is required for attainment of normal size (deficiency in childhood means dwarfism)
- in adult life has important effects on carbohydrate/lipid metabolism and on lean body mass and bone density
- effects of this are mediated by IGF-1 released from the liver
growth hormone (GH)
increased glucose synthesis and release which increased blood glucose (can lead to hyperglycemia), increased lipolysis (fat breakdown), stimulates protein synthesis for increased muscle growth, increased longitudinal growth until puberty, increased bone mineral density after puberty
pharmacological effects of GH
short stature and low growth rate caused by decreased GHRH for hypothalamic version of this or decreased GH for pituitary version of this, proportional decrease in size of all body parts, treatment includes somatropin (GH analog)
dwarfism
inherited, relatively rare, defective GH receptors in liver (inadequate IGF-1 production), like the other form but plasma GH levels are normal or increased whereas IGF-1 levels are decreased, liver can’t produce IGF-1 b the because GH receptors on the liver are defective, treatment includes mecasermin (IGF-1 analog)
Laron dwarfism
- recombinant human GH preparations that are modified in some way to decrease breakdown by enzymes, restores normal growth and metabolism in GH-deficient individuals
- clinical uses: replacement therapy as daily SC injection for GH deficiency in children (varies in adults) or to treat AIDS-induced wasting syndrome which is a severe loss of muscle mass due to AIDS (because GH increases muscle mass)
- adverse effects: well tolerated, rare intracranial hypertension, arthralgia, myalgia, peripheral edema, HYPERGLYCEMIA main adverse effect –> SHOULD NOT be given to patients with active malignant tumors or a history of recurrent tumor growth
somatropin (HUMATROPE, NUTROPIN, GENOTROPIN)
- MOA: recombinant IGF-1 analog that stimulates IGF-1 receptors and improves growth (bone) and metabolic effects (increased muscle mass, decreased body fat) mediated by IGF-1
- clinical use: replacement therapy as SC injection in iGF-1 deficiency/Laron dwarfism that is not responsive to exogenous GH
- adverse effects: hypoglycemia (because IGF-1 analog and IGF-1 is insulin like and insulin causes hypoglycemia), rare intracranial hypertension –> to AVOID HYPOGLYCEMIA, patients should take with a carbohydrate containing meal/snack 20 minutes before or after taking drug –> SHOULD NOT be given to patients with active malignant tumor or history of recurrent tumor growth
mecasermin (INCRELEX)
- excessive secretion of GH (usually from pituitary adenoma –> tumor)
- before puberty causes gigantism in children (person is very large but proportional)
- after puberty acromegaly in adults, disproportionate growth of the body due to bone thickening not getting any longer, slow onset
- treatment options: transsphenoidal surgical resection, radiation therapy, pharmacological includes drugs that inhibit GH secretion (somatostatin analogs, dopamine agonists) or block GH action (GH receptor antagonist) –> pharmacological therapy is considered when surgery or radiation is contraindicated
syndromes of GH excess
- the human form of this inhibits GH release but not useful clinically because has 1-3 min half life, analogs substitute D amino acids (unnatural ones) so enzymes can’t recognize as quickly
- MOA: inhibit GH release with higher potency than what it is an analog for, normalize GH and IGF-1 levels in 60-80% of patients
- mainstay drugs given SC or IM to treat acromegaly
- adverse effects: GI disturbances, GALLSTONES (decreases bile secretions) main adverse effect, sinus bradycardia, conduction abnormalities
somatostatin (SST) analogs: octreotide (SANDOSTATIN), lanreotide (SOMATULINE), pasireotide (SIGNIFOR)
- MOA: decrease GH release in acromegaly patients, advantage is that they are administered orally, disadvantage is that they are less effective than other drugs that decrease GH release (normalize GH and IGF-1 levels in only 10-30% of patients)
- used orally as second-line agents
- adverse effects: nausea, headache, orthostatic hypotension
dopamine (DA) agonists: bromocriptine (PARLODEL), cabergoline (DOSTINEX)
which is more advantageous (because it has less GI side effects and has more convenient once to twice weekly dosing), cabergoline or bromocriptine?
cabergoline
- MOA: pegylated mutant GH analog, acts as competitive GH receptor antagonist that prevents GH receptor activation and inhibits IGF-1 production, blocks site but doesn’t activate so no IGF-1 secretion, pegylation prolongs drug’s half life and allows for once daily SC dosing
- CAUTION: may increase growth of GH-secreting adenomas so annual pituitary MRI is recommended for patients taking this (blocks whole feedback in hypothalamus so it doesn’t stop releasing GH)
- adverse effects: increased liver enzymes (hepatotoxicity, requires monitoring of liver function)
GH receptor antagonist: pegvisomant (SOMAVERT)
- peptide hormone secreted by lactotrophs of the anterior pituitary gland
- principal hormone responsible for lactation and proliferation/differentiation of breasts during pregnancy, function not known in males
- secretion is under tonic inhibitory control (always under check) by the hypothalamus via dopamine acting at D2 receptors
- major stimulus for secretion is suckling, possible stimulants also include TRH and oxytocin
- dopamine inhibits this
- not used clinically because high levels of this leads to infertility as it suppresses FSH/LH secretion in males and females
prolactin (PRL)
- high prolactin levels causes by prolactin secreting adenomas, hypothyroidism, dopaminergic antagonists (second generation antipsychotics that can cause infertility)
- characterized by amenorrhea (no menstrual cycle), galactorrhea (milk production from the breast unrelated to pregnancy or lactation), infertility in females
- characterized by loss of libido, gynecomastia (breast development) and infertility in males
- treatment options include transsphenoidal surgical resection/radiation therapy for adenomas or pharmacological (dopamine agonists bromocriptine and cabergoline as first line agents)
hyperprolactinemia
- MOA: inhibit prolactin release by stimulating dopamine D2 receptors in hypothalamus
- normalize serum prolactin levels, restore FSH/LH production, shrink tumor size
- clinical uses: hyperprolactinemia and acromegaly (acromegaly requires higher dose)
- adverse effects: nausea, headache, orthostatic hypertension
dopamine receptor agonists: bromocriptine (PARLODEL) and cabergoline (DOSTINEX)
two posterior pituitary hormones that are cyclic nonapeptides:
1. _____________: antidiuretic hormone for urinary water retention
2. _____________: controls uterine contraction and lactation
- because these two are similar in structure, if using one drug to treat problem with one you get effects on the other
vasopressin, oxytocin
- released by posterior pituitary in response to increased plasma osmolarity (thirst) or decreased blood volume (hypovolemia)
- possesses vasopressor and antidiuretic properties
- activates two types of G-protein coupled receptors (V1 receptors in blood vessels leading to vasopressor effect like constriction of blood vessels and V2 receptors in kidneys leading to antidiuretic effect like insertion of water channels)
vasopressin (ADH, PITRESSIN, AVP)
refers to inadequate ADH secretion, large volumes of dilute urine, thirst, dry mouth, excessive urination
diabetes insipidus
- a long acting vasopressin analog with minimal vasopressor activity and an antidiuretic to vasopressor activity 4,000 times that of vasopressin
- clinical uses: primary agent to treat diabetes insipidus (used IV, SC, intranasally, orally), decreases nocturnal urine production (used for nocturnal enuresis/bedwetting), releases von Willebrand factor and clotting factor VIII from vascular endothelium (used for treating various bleeding disorders)
- adverse effects: GI disturbances, HYPONATREMIA (low sodium in blood because sodium is diluted since kidney is retaining water), allergic reactions
desmopressin (DDAVP)
- ____________ is excessive ADH secretion (persistent stimulation of V1 and V2 receptors leading to hypertension and excessive water retention, this leads to dilution of extracellular Na+ leading to hyponatremia, coma, convulsions, death)
- causes: malignancy, CNS injury/disease, general surgery, medications (SSRIs, TCAs, haloperidol, sulfonylureas, Vinca alkaloids)
- treatment includes _____________ which is IV and blocks both V1 and V2 receptors and ______________ which is oral and is a selective V2 receptor antagonist, adverse effects of these are dry mouth, increased thirst, excessive urination, HYPERNATREMIA
syndrome of inappropriate ADH (SIADH), conivaptan (VAPRISOL), tolvaptan (SAMSCA)
- peptide hormone released from posterior pituitary gland
- stimuli for release: sensory stimuli from dilation of cervix during labor, stimulation of breast
- pharmacological/physiological effects: activates G-protein coupled receptors to contract uterine smooth muscle and myoepithelial cells in breast, input from cervix means uterine contractions (increased frequency and force), input from breast means milk letdown via contraction of myoepithelial cells (“milk letdown factor”, normal lactation can’t occur without oxytocin induced contraction)
- clinical uses:
1. for initiation and augmentation of labor (IV) - frequency and force of contractions is gestation dependent
2. to reduce or prevent post-partum hemorrhage (IM) - firm, contracted uterus less likely to bleed, given after delivery
3. to promote milk letdown (nasal spray) - relief of engorgement during inadequate breastfeeding, simple, safe, but usually only 50% effective
oxytocin
comprised of functional units called follicles which are single layers of epithelial cells arranged in a cavity with follicular lumen (where this stores hormones)
thyroid gland
cells that secrete thyroxine (T4) and triiodothyronine (T3)
follicular cells
cells that secrete calcitonin (which decreases plasma calcium levels)
parafollicular cells
- _______: released from the hypothalamus that stimulates the release of TSH from anterior pituitary
-_______: acts on receptors in thyroid follicle cells and stimulates the synthesis and release of T3 and T4 from thyroid - _______ and _______ inhibit both TSH and TRH synthesis and release by negative feedback regulation
TRH, TSH, T3, T4
inhibitors of TSH secretion other than T3 and T4 are ______ and _______
somatostatin and glucocorticoids/dopamine
small amounts of this are necessary for T3 and T4 synthesis but large amounts actually inhibit T3 and T4
iodide
________ belong to nuclear receptor family, exist as dimers with retinoid X receptors (RXR), within the cells T4 is converted to T3, T3 binds to these and activates transcription and protein synthesis of target genes, effects of these takes hours or days to manifest (latency)
thyroid hormone receptors/thyroid hormones
- all tissues: increase oxygen consumption, basal metabolic rate (BMR) and heat production
- heart: increase contractility, HR, cardiac output which leads to cardiac adverse effects
- nervous system: critical for optimal growth, development, and function
- liver: stimulate gluconeogenesis leading to hyperglycemia
- skeletal muscle: increase protein degradation and bone turnover leading to muscle and bone loss
- adipose tissue: stimulate lipolysis (increase fat metabolism) leading to weight loss
- OVERALL EFFECT IS CATABOLIC (breaks everything down)
pharmacological effects of thyroid hormones
_______ is more potent but less stable compared to _______ (thyroid hormones)
T3, T4
- myxedema (adults) due to autoimmune destruction of the thyroid
- Cretinism (congenital)
- secondary due to pituitary or hypothalamic disease (decrease TRH or TSH secretion)
hypothyroidism
- toxic goiter (Grave’s disease, antibodies stimulate thyroid)
- thyroid cancer
- inflammatory thyroid disease (thyroiditis)
- iodine-induced thyrotoxicosis (amiodarone)
hyperthyroidism
preferred and most widely used agent for thyroid replacement (pure form of T4) because of its stability, low cost, lack of antigenicity, and long half life (7 days which permits once daily dosing), T4 gets converted to T3 intracellularly so administration of T4 produces BOTH HORMONES
levothyroxine (T4) (SYNTHROID, LEVOXYL, LEVOTHROID)
3 to 4 times more potent than levothyroxine, faster onset but shorter duration of action, short half life means multiple daily doses so not recommended for routine replacement, disadvantages include higher incidence of cardiac adverse effects, higher cost, difficulty in monitoring, used in myxedema coma
liothyronine (T3) (CYTOMEL)
a mixture of T4 and T3 in 4:1 ratio to mimic the body composition of thyroid hormones, more potent than levothyroxine
liotrix (T4/T3) (THYROLAR)
porcine or bovine origin thyroid hormone replacement, disadvantages include protein antigenicity, product instability, variable hormone concentrations greatly limit their use in hypothyroidism
Armour Thyroid, Nature Thyroid
________ inducers like rifampin, phenytoin, phenobarbital, carbamazepine ________ clearance of T3 and T4 so patients on these require _______ doses of thyroid preparations due to increased clearance
CYP, increase, higher
- MOA: block iodide uptake by the gland through competitive inhibition of the iodide transport
- adverse effect: aplastic anemia so rarely used clinically (suppress bone marrow growth)
anion inhibitors: perchlorate (CIO4), pertechnetate (TcO4), thiocyanate (SCN0
- MOA: prevent hormone synthesis by inhibiting the thyroid peroxidase-catalyzed organification of tyrosine residues in thyroglobulin and coupling of iodotyrosine
- hormone synthesis but not the release is inhibited so clinical response takes 3-4 weeks since thyroid has large stores of T4)
- adverse effects: SKIN RASH, nausea, GI distress, agranulocytosis (rare but fatal), hypothyroidism
thioamides: methimazole (TAPAZOLE), PTU
which of the following (along with is MOA) inhibits peripheral conversion of T4 to T3 making it useful to treat thyroid storm, is preferable in pregnancy because it crosses the placenta less readily, and has risk of severe hepatitis that can be fatal so it’s reserved for first trimester of pregnancy and in thyroid storm?
- methimazole
- PTU
PTU
- MOA: high doses of this inhibit thyroid hormone synthesis, coupling, proteolysis, release
- clinical uses: effects occur rapidly within 2-7 days so useful in treating thyroid storm, decrease the size and vascularity of thyroid gland so used in preoperative preparation for thyroidectomy, CAUTION: effects are transient and reversible so these products should not be used as monotherapy
- adverse effects: iodism (acneiform rash, metallic taste, increased salivation, mucous membrane ulcerations)
iodides: Lugol’s solution (iodine and potassium iodide), Saturated potassium iodide solution (SSKI)
- MOA: beta and gamma emitter leads to follicular disruption and destruction of thyroid gland within few weeks after oral administration WITHOUT pain, destroys cancerous and normal thyroid cells (doesn’t discriminate)
- adverse effects: hypothyroidism, worsening of ophthalmopathy, contraindications are pregnancy and lactation because it’s a radioactive isotope
radioactive iodine
- MOA: block beta-1 adrenergic receptors in the heart –> decrease HR and contractility (which is increased in hyperthyroidism), not an anti-thyroid medication necessarily
- clinical use: adjunct therapy to treat symptoms of hyperthyroidism like tachycardia, arrhythmia, hypertension especially in thyroid storm
- adverse effects: bradycardia, AV block, hypotension, bronchospasm in asthmatics
beta-blocker: propranolol
which part of the adrenal gland secretes adrenal steroids like aldosterone, cortisol, DHEA?
cortex
which part of the adrenal gland secretes catecholamines like epinephrine and norepinephrine?
medulla
what is a precursor to several hormones?
cholesterol
rate limiting step regulated by ACTH in conversion of cholesterol to aldosterone and cortisol
cholesterol to pregnenolone
adrenal corticosteroids that regulate glucose metabolism (protein and lipid metabolism) and suppress immune function for anti-inflammatory and immunosuppressive effects (more important clinically)
glucocorticoids (cortisol)
adrenal corticosteroids that regulate water and electrolyte balance (promotes Na+ and water retention causing an increase in BP, promotes K+ excretion causing hypokalemia
mineralocorticoids (aldosterone)
- the __________ secretes CRH (corticotropin) releasing hormone) which regulates ACTH release
- the _________ secretes ACTH which stimulates the synthesis and release of glucocorticoids and androgens
- the _________ secretes cortisol and exerts a negative feedback effect on previous two, decreasing CRH and ACTH secretion
hypothalamus, pituitary, adrenal gland
what are other regulators of cortisol mediated by the hypothalamus other than CRH and ACTH release?
circadian rhythm (levels are highest in the morning), hypoglycemia, stress
_________ is the principal glucocorticoid in humans, synthesized from cholesterol and released in response to ACTH, always present in blood and levels are related to circadian rhythm, highest concentrations occur early in the morning and decrease throughout the day, 90% is bound to corticosteroid binding globulin (CBG) and the rest is free or loosely bound to albumin (available to act on target cells)
cortisol
- these enter cells via passive diffusion and bind to intracellular receptors in cytoplasm, these receptors are nuclear receptors
- in the absence of these the receptors exist as a complex with heat shock protein 90 (Hsp90) in cytoplasm
- hormone binding to receptor induces conformational changes meaning dissociation of R from Hsp90
- hormone bound receptor complex dimerizes and translocates to the nucleus
- the homodimer binds to receptor elements in the promoters of responsive genes and regulates their transcription
glucocorticoids (MOA)
long term effect of corticosteroids use is ________
osteoporosis (drug induced)
- decrease glucose uptake and utilization, increase gluconeogenesis, both leading to hyperglycemia which stimulates insulin release
- decrease protein synthesis and increase protein breakdown leading to muscle wasting (catabolism)
- stimulates lipase leading to lipolysis (catabolism) and fat redistribution due to lipogenic effects of insulin secreted in response to hyperglycemia
- decrease GI absorption of calcium, increase renal calcium excretion leading to osteoporosis
metabolic effects of glucocorticoids
- inhibit phospholipase A2 (PLA2) activation which reduces the synthesis of prostaglandins, leukotrienes, and platelet activating factor, reduces swelling and pain associated with inflammation
- decrease the migration of neutrophils to the site of inflammation
- decrease the circulating T and B cells, monocytes, eosinophils, basophils
- inhibit the function of macrophages and antigen presenting cells (APCs)
- decrease the production of cytokines like TNF-alpha, interleukins, IgG and interferon-Y –> useful in treating cytokine release syndrome/cytokine storm
- inhibit T cell activation and proliferation by decreasing IL-2 synthesis –> useful in prevention and treatment of organ transplant rejection
anti-inflammatory and immunosuppressive effects of glucocorticoids
ADVERSE EFFECTS OF ___________:
1. immunosuppression (increased susceptibility to infections)
2. hypertension and edema (due to sodium and water retention) hypokalemia
3. hyperglycemia (increased gluconeogenesis and insulin resistance)
4. muscle wasting and weakness
5. fat redistribution, weight gain
6. osteoporosis (reduced bone formation and increased bone resorption)
7. peptic ulcers (decreased immune response against H. Pylori)
8. insomnia, euphoria, depression
9. cataracts, glaucoma
10. suppression of growth in children
11. HPA axis suppression
glucocorticoids
why do we gradually taper the dose of glucocorticoids when stopping them?
gives the adrenal gland time to start producing its own cortisol again, gave a lifeline then need to gradually decrease dose to avoid adrenal gland problems
- syndrome caused by excessive exposure to glucocorticoids
- causes: tumors, chronic therapy with glucocorticoids (iatrogenic)
- S/S: depression, psychosis, cataracts, hypertension, increased abdominal fat, muscle wasting, poor wound healing
Cushing’s syndrome (hypercortisolism)
11beta-HSD__ deactivates cortisol into cortisone whereas 11beta-HSD__ activates cortisone into cortisol
2, 1
11beta-HSD2 is a protective enzyme that makes it so _______ can’t activate mineralocorticoid receptors in kidneys
cortisol
synthetic corticosteroids have _______ (high or low) aldosterone like activity
low
addition of a _________ and a ________ at carbon 6 increases glucocorticoid activity of the compound relative to that of cortisol, methylprednisolone and prednisolone are examples
1-2 double bond, methyl group
addition of a _____ to carbon 9 increases glucocorticoid activity and markedly increases mineralocorticoid activity, example is fludrocortisone
fluorine
mineralocorticoid effect is blunted if 9-fluorination is combined with ____________ (antagonistic or nullifying effect)
16-methylation
simultaneous addition of 1-2 double bond, methyl at carbon 16, fluorine at carbon 9 creates a very potent glucocorticoid with no mineralocorticoid activity, what drugs are these?
dexamethasone, betamethasone
short acting corticosteroids with equal Na+ retention activity compared to cortisol
hydrocortisone, cortisone
intermediate acting corticosteroids with less Na+ retention so less increase in BP
prednisone, prednisolone, methylprednisolone, triamcinolone
long acting corticosteroids with no Na+ retention so no increase in BP
betamethasone, dexamethasone
- replacement therapy for adrenal insufficiency (Addison’s, hydrocortisone and fludrocortisone)
- anti-inflammatory and immunosuppressive therapy (asthma, inflammatory states, autoimmune diseases, hypersensitivity states, organ transplant rejection)
- cancer associated pain and other complications
clinical uses of glucocorticoids
patients with peptic ulcers, hypertension, heart disease, infectious diseases, psychoses, diabetes, osteoporosis, glaucoma should not take _______
glucocorticoids
- DRUG INTERACTIONS OF _______:
1. combination with NSAIDs, increased risk of ulcers and GI bleeding
2. these increase blood glucose levels and work against glucose-lowering effect of insulin and other antidiabetic drugs, may need to increase dose because insulin blunting
glucocorticoids
- steroidogenesis inhibitors (inhibit cortisol synthesis): ketoconazole, metyrapone, osilodrostat
- adrenolytic agents (cytotoxic to adrenal gland): mitotane
- glucocorticoid receptor antagonists (block cortisol receptors): mifepristone at high doses
- clinical use (oral): to reduce cortisol hypersecretion due to pituitary adenoma, adrenocortical carcinoma, ectopic ACTH
drugs to treat Cushing’s syndrome (glucocorticoid excess)
- MOA: at high doses this drug NON-SELECTIVELY inhibits the conversion of cholesterol to pregnenolone (first/rate limiting step) and multiple steroidogenic enzymes
- blocks synthesis of all adrenal steroids (cortisol, aldosterone, androgens)
- used to treat Cushing’s syndrome cause by several pathophysiologies
- adverse effects: hepatotoxicity
ketoconazole
- MOA: SELECTIVE 11-hydroxylase inhibitors, inhibit the last step of cortisol synthesis, reduces cortisol and aldosterone synthesis
- ________ is the only one used in pregnancy, because others are contraindicated
- side effects: increased salt and water retention leading to hypertension, increased androgen synthesis leading to hirsutism and acne
metyrapone and osilodrostat, metyrapone used in pregnancy
- MOA: cytotoxic agent causing atrophy of the adrenal cortex
- used mainly for inoperable adrenocortical carcinoma
- side effects: GI disturbances, ataxia (loss of muscle control), sleepiness, lethargy
mitotane (LYSODREN)
- MOA: anti-progestin, inhibits glucocorticoid receptors at high doses
- reserved for patients with inoperable causes of Cushing’s syndrome and not responded to other agents
- side effects: hypokalemia, hypertension
mifepristone (MIFEPREX)
- male sex hormone made from cholesterol (pregnenolone), 95% of this is produced by testes, other 5% by adrenals
- MOA: most of this is bound to sex hormone binding globulin (SHBG) or albumin, only the free form of this enters the cells easily due to lipophilicity, free form gets converted to DHT if 5-alpha reductase is present in the tissue, this or DHT binds to androgen receptors in cytosol, receptor complex enters nucleus and binds to androgen response elements which stimulates the transcription of genes that are dependent on this –> protein synthesis –> response
- gets metabolized to two other active steroids: DHT by 5-alpha reductase and estradiol (E2) by aromatase
- has very low bioavailability due to high first pass metabolism in liver
- responsible for maintenance of muscle mass, bone density, erythropoiesis (red blood cells)
testosterone
responsible for male pattern baldness, prostate diseases (BPH, prostate cancer)
dihydrotestosterone (DHT)
responsible for maintenance of bone density and libido in males
estradiol (E2)
- erectile dysfunction, decreased libido and energy, decreased muscle mass, decreased bone density, decreased hematocrit (RBC volume), decreased facial hair growth
- patients with this due to testicular, hypothalamic or pituitary abnormalities require hormone replacement therapy
effects of testosterone deficiency
- parenteral short acting IM injections to treat hypogonadism in males, 25-50 mg 2-3 times per week
- metabolism: oxidation of 17-OH group leads to short duration of action, large doses need to be administered more frequently for replacement
testosterone (TESTOJECT), testosterone propionate (TESTOVIRON)
- parenteral long acting IM injections to treat hypogonadism in males, 50-200 mg every 2-4 weeks
- esterification of 17beta-hydroxyl group with fatty acids slows the release of steroid for prolonged duration of action
testosterone enanthate (Delatestryl), testosterone cypionate (Depo-Testosterone)
- orally active treatment for hypogonadism in males
- alkylation at C-17alpha position is slowly metabolized by liver meaning high oral bioavailability that requires smaller daily doses
- NOT PREFERRED for management of hypogonadism because not metabolized to DHT or estradiol, severe hepatotoxicity, hyperlipidemia (increased LDL and decreased HDL)
methyltestosterone (Virilon), fluoxymesterone (Halotestin)
- buccal tablets applied to the gum above the upper incisor (front) teeth twice per day, over time it forms a gel from which testosterone is absorbed
- bypasses first pass metabolism which increases bioavailability
- serum testosterone levels are maintained in normal range for about 80% of the day
Striant
- applied to clean dry intact skin to an area of the back, stomach, upper arms, thighs (rotate sites daily)
- bypasses first pass metabolism which increases bioavailability
- proved more stable serum testosterone levels than the injections of testosterone esters
transdermal patches, Testoderm, Androderm
- adequate lipophilicity for topical delivery of testosterone
- applied at the same time each morning to clean dry intact skin to an area of the shoulder, upper arms, abdomen that will be covered by short sleeved shirt
- NOT to be applied to other body parts like genitals, chest, back, underarms, knees
1% testosterone gel, AndroGel
why can mood swings/aggression be seen in parenteral forms of testosterone?
supra-pharmacologic (above toxic levels) serum testosterone levels
- acne due to overstimulation of oil glands and clogging of pores from DHT
- prostate enlargement from increased DHT levels
- gynecomastia due to increased estradiol levels
- weight gain due to increased muscle mass and bone density
- polycythemia due to increased RBC synthesis
- suppression of hypothalamic pituitary testes axis leading ot decreased testicular function, sperm production, impaired fertility, testicular atrophy (all because less GnRH and LH release)
adverse effects of testosterone replacement therapies
- failure to achieve penile erection to allow for satisfactory sexual intercourse
- causes include psychologic, drug induced, hormonal (hypogonadism), neurologic (spinal injury, stroke, diabetes), vascular insufficiency (peripheral vascular disease, atherosclerosis, hypertension)
erectile dysfunction (ED)
- normal erection requires _________ in parasympathetic activity and ___________ in sympathetic activity leading to increased blood flow to penile tissue
increase, decrease
- MOA: SELECTIVELY INHIBIT PDE-5 enzyme which degrades cGMP into 5’ cGMP, increases cGMP levels thus increasing smooth muscle relaxation, increase in blood flow and penile erection
- clinical use: most common drugs to treat ED
- drug interactions: nitrates because increase cGMP too much (fatal hypotension), all of these drugs are metabolized by CYP3A4 so their dose should be reduced if coadministered with drugs that inhibit CYP3A4
- excreted in feces and some in urine
- side effects: headache, flushing, nasal congestion, dyspepsia due to PDE-5 inhibition in other tissues
selective PDE-5 (phosphodiesterase 5) inhibitors: sildenafil, vardenafil, avanafil, tadalafil
which has longer onset but also longer half life, sildenafil/vardenafil/avanafil or tadalafil?
tadalafil
_______ causes hypotension and loss of blue green color discrimination due to inhibition of PDE-5 in cones of eye whereas _________ causes myalgia due to PDE-5 inhibition in skeletal muscles
sildenafil/vardenafil/avanafil, tadalafil
- MOA: stimulates adenylyl cyclase which increases cAMP and decreases calcium leading to smooth muscle relaxation of the arterial blood vessels, increases blood flow and blood filling into tissue leading to erection
- clinical use: alternative agent to treat ED
- given as an intracavernous injection or urethral suppository
- adverse effects: penile pain, priapism (prolonged painful erection lasting longer than 1 hour), cavernosal fibrosis at injection sites or urethral pain with urethral inserts
prostaglandin E1 analog: alprostadil (CAVERJECT - intracavernous injection, MUSE - urethral suppository)
- male pattern baldness, BPH, prostate cancers that are testosterone dependent
effects of testosterone excess
- non-malignant adenomatous overgrowth of prostate gland
- urethral obstruction leading to urinary hesitancy, decreased bladder volume, increased urinary frequency, urgency, nocturia
- causes: combination of mechanical pressure on urethra due to increased smooth muscle tone by alpha 1 adrenergic receptors in prostate and bladder neck, increased smooth muscle mass by DHT
- treatments: alpha reductase inhibitors that get to root of problem or alpha 1 adrenergic blockers that treat symptoms
benign prostate hyperplasia (BPH)
- MOA: NON-SELECTIVE prostatic alpha 1A and vascular alpha 1B adrenergic receptor blockers
- side effects: first dose effect (happens after first dose, due to peripheral vascular alpha 1B adrenergic receptor blockade leading to orthostatic hypotension, syncope, dizziness)
second generation alpha 1 antagonists: terazosin, doxazosin
- MOA: FUNCTIONALLY UROSELECTIVE and closer to third generation agents
- side effects: less first dose effect than second generation agents, dizziness and headache
alfuzosin
- MOA: SELECTIVE prostatic alpha 1A adrenergic receptor blockers
- side effects: ejaculatory dysfunction, flu like symptoms and nasal congestion, intraoperative floppy iris syndrome (IFIS), less cardiovascular adverse effects than other generation
third generation alpha 1 antagonists: tamsulosin, silodosin
- interactions: NOT to be used with PDE-5 inhibitors due to risk of severe hypotension (additive effect)
- pharmacokinetics: metabolized by CYP3A4 so use caution when coadministered with drugs that inhibit CYP3A4
alpha 1 antagonists
- MOA: relax smooth muscle in prostate and bladder neck (decrease dynamic factor), works similar to others that treat BPH but less effective
- side effects: mild hypotension, myalgia
PDE-5 inhibitor: tadalafil
- MOA: inhibit the conversion of testosterone to DHT leading to reduction in prostate size (decrease static factor)
- two types: 1. Type II SELECTIVE (_______, less potent) and 2. NON-SELECTIVE type I and type II (______, more potent) –> EQUAL EFFICACY
- adverse effects: erectile dysfunction, decreased libido, gynecomastia (increased E2)
- clinical uses: to treat moderate to severe BPH and male pattern baldness, slow disease progression and decrease the need for surgery
5-alpha reductase inhibitors (5-ARIs): 1 finasteride, 2 dutasteride
hypothalamus secretes _____ in pulses for pulsatile release of _______ and _____ from anterior pituitary both which regulate the ovarian production of estrogen and progesterone which exert negative feedback on pituitary hormones and hypothalamic hormone
GnRH, LH, FSH
only at ____ -cycle does estrogen trigger a surge of LH release by pituitary for release of egg from ovary (ovulation)
mid
- during the first part of the menstrual cycle _______ are produced in the ovarian follicle
- after ovulation (luteal phase), the _______ and ______ are synthesized by corpus luteum
- ovary ceases its gametogenic and endocrine function with time which is accompanied by cessation of uterine bleeding (menopause)
- significant levels of _______ may persist in many postmenopausal women because of the conversion of other steroids to estrogen in adrenals, ovaries, adipose, and other non-endocrine tissues
estrogens, estrogen and progesterone, estrogen
MAJOR ESTROGENS PRODUCED BY FEMALES:
1. ________ - major secretory product of ovary that is more pharmacologically active
2. _______
3. _______
estradiol (E2), estrone (E1), estriol (E3)
when 50% of estradiol is excreted in urine as glucuronide and sulfate conjugate but the other 50% is a metabolite that gets re-absorbed from intestine into blood, re-secreted by the liver, re-absorbed from intestine again which all prolongs half-life
enterohepatic cycling
- this binds to nuclear receptors ER-alpha and ER-beta in cytosol
- ER complex dimerize and translocate to nucleus
- dimer binds to response elements and alters gene expression in cells responsive to this
- altered transcription –> altered translation –> cell response
estrogens
- breast development, pubic and underarm hair growth, body fat distribution
- anabolic effects: promotes bone growth and epiphyseal closure
- endometrial proliferation: uterine lining thickening, prepares uterus for pregnancy
- plasma lipid effects: hypolipidemic, increases HDL and decreases LDL/total cholesterol, acts like natural statin
- increase synthesis of clotting factors leading to increased risk for clots and DVT
- increase cholesterol in bile and decrease gall bladder emptying, increase risk of gallstones
- retention of salt and water leading to fluid retention which promotes aldosterone secretion
estrogens pharmacological effects
Has an ethinyl group at C17 which protects the OH group of estradiol from oxidation, confers oral activity and increases potency, this is 500 times more potent than estradiol, oral contraceptive
Ethinyl estradiol (EE)
A prodrug that is activated in the liver to ethinyl estradiol by O-demethylation, oral contraceptive
Mestranol
- Hormone replacement: primary hypogonadism (failure of development of ovaries or premature menopause), peri and post menopausal replacement therapy (to correct deficiency of this due to lack of secretion from ovaries)
- Contraception: cannot be used alone, must be in combo with progestin, only synthetic forms of this are used
Estrogen clinical uses
- Vasomotor symptoms: hot flashes and night sweats
- GSM: vaginal atrophy and dryness, burning, dyspareunia (painful intercourse), recurrent UTIs
- Osteoporosis: loss of bone mass and increased risk of fractures due to increased osteoclast activity
- Cardiovascular disease due to worsening lipid profile
Symptoms of menopause
- simple estrogens can’t be given this way because oxidized quickly into estrone
- conjugated equine estrogens from the urine of pregnant horses (Premarin, enjuvia)
- synthetic conjugated estrogens that are chemically modified from plants (Cenestin)
- micronized 17 beta estradiol (Estrace) for better absorption
Oral estrogen preparations
- 17 beta estradiol (Estraderm, Vivelle, Alora, Climara)
- advantages of this form include higher bioavailability because avoids first pass metabolism and lower risk of cardiovascular events because less stimulation of liver synthesis of clotting factors
Transdermal estrogen preparations
- 17 beta estradiol topical emulsion (Estrasorb)
- 17 beta estradiol topical gel (EstroGel, Elestrin, Divigel)
- 17 beta estradiol topical spray (Evamist)
- 17 beta estradiol vaginal tablets (Estrace, Vagifem)
- 17 beta estradiol vaginal ring (Estring)
- 17 beta estradiol vaginal cream (Estrace)
- conjugated equine estrogens vaginal cream (Premarin)
topical and vaginal menopausal hormone therapy
- for individuals with moderate to severe vasomotor symptoms (hot flashes) and GSM symptoms
- estrogen alone/as monotherapy is appropriate in females who have had __________
- in others, systemic estrogen must always be given with ________ to decrease the risk of endometrial hyperplasia and cancer (examples are CEE plus medroxyprogesterone acetate/Prempro, Premphase)
hysterectomy, progestin
COMBINED HORMONAL THERAPY REGIMENS:
1. ____________: to mimic normal menstrual cycle, daily estrogen plus coadministration of progestin with estrogen for last 12-14 days of a 28-day cycle, adverse effect is withdrawal bleeding (hormonal period)
2. ___________: more acceptable than previous, daily estrogen and progestin without a break, adverse effect is endometrial atrophy with breakthrough bleeding that reduces after 1 year due to downregulation of progesterone receptors caused by continued presence of progestin
3. ___________: to decrease uterine/breakthrough bleeding, to prevent the downregulation of progesterone receptors, 3 days of estrogen therapy alone followed by 3 days of combined estrogen and progestin which is then often repeated without interruption, fewer side effects and better tolerated of all therapies
continuous cyclic, continuous combined, intermittent combined (pulsed)
estrogen alone has favorable effect on lipid profile, decreases risk of osteoporosis, decreases risk of colon cancer
estrogen replacement benefits
- nausea (most common)
- migraines (mainly in patients with history of migraines)
- gallstones
- high BP, increases angiotensinogen production and water retention
- blood clots and DVT, increases vitamin K dependent clotting factors
- endometrial cancer, proliferation without sloughing in absence of progestin
- breast cancer, slight risk
estrogen replacement side effects and risks
- _________ are mixed agonist and antagonist
- goal is to increase estrogen benefits and decrease risks
- ## non-steroidal agents that are chemically distinct from estradiol, exhibit tissue selective actions-
- - adverse effects of all three include hot flashes, leg cramps, VTE, stroke
SERMs
_________: first generation SERM, agonist at uterus (increased risk of endometrial cancer)/bone/liver, antagonist at breast/brain, used to treat breast cancer, not used in postmenopausal women
tamoxifen
_________: second generation SERM, agonist at bone/liver, antagonist at uterus (decrease uterine cancer risk)/brain/breast, used to treat breast cancer and osteoporosis
raloxifene
________: third generation SERM, agonist at bone/liver, antagonist at uterus (decrease uterine cancer risk)/breast/brain, used in combination with conjugated estrogens to treat hot flashes and to prevent postmenopausal osteoporosis
bazedoxifene
___________: SERM, structurally similar to tamoxifen, has no effect on breast/uterus, exerts agonist effect on vagina, systemic treatment of GSM, box warning says increased risk of endometrial cancer but no reported cases so far
ospemifene
____________: SERM, partial agonist at estrogen receptors, acts as competitive inhibitor of endogenous estrogen, blocks negative feedback effect of estrogen on pituitary increasing FSH and LH leading to ovulation, used to induce ovulation and treat infertility in females with ovulation disorders, adverse effects include ovarian enlargement (due to growth of multiple follicles) and hot flashes
clomiphene
- hormone secreted by ovary from corpus luteum during the second half of the menstrual cycle under the influence of LH
- secreted by the placenta throughout pregnancy
- very important for maintenance of pregnancy/gestation, suppresses menstruation and uterine contractility, prevents miscarriage
- MOA: binds to nuclear receptors, hormone receptor complex dimerizes and translocates to nucleus, bind to hormone response elements, alter gene transcription in hormone responsive cells, cell response
progesterone
-increase vascularization/maintenance of endometrium in pregnancy, reduces proliferation, thinning of endometrial lining (atrophy)
- dyslipidemic effect (increase LDL, decrease HDL)
- mild diuretic effect (anti-mineralocorticoid activity, blocks mineralocorticoid receptors)
- insulin resistance due to glucocorticoid activity (inhibits glucose uptake leading to hyperglycemia)
- hyperthermia (increases core body temperature by about 1 degree F)
- proliferation of acini in mammary gland during pregnancy which prepares breast for milk production after delivery
- suppresses menstruation and decreases uterine contractility, prevents miscarriage
pharmacological effects of progesterone
progesterone has a _______ half life due to its ______ liver metabolism and renal elimination
short, rapid
________: long acting synthetic progesterone derivatives, vary in their progestational activity and their estrogenic and androgenic effects, lack anti-mineralocorticoid activity except 4th generation, CLINICAL USES - for hormone replacement therapy in combination with estrogen, these are added to protect from uterine cancer and for contraception either alone or with estrogen, serves as the primary agent for contraception
progestins
first generation progestins, high estrogenic and androgenic activity, several side effects
norethindrone, medroxyprogesterone acetate
second generation progestin, no estrogenic activity, very high androgenic activity (leading to weight gain, acne, hirsutism)
levonorgestrel
third generation progestins, less androgenic activity, less weight gain, acne, hirsutism
norgestimate, desogestrel
fourth generation progestin, anti-androgenic activity (minimal weight gain, acne, hirsutism), anti-mineralocorticoid activity (less increased BP and weight gain), better tolerated
drospirenone
MOA:
- estrogens: suppress FSH release from pituitary which prevent development of a dominant follicle that causes LH surge and ovulation (minor role), primary role is to stabilize endometrial lining and provide cycle control (keeps uterus healthy)
- progestins: provide most of the effect through GnRH inhibition –> blockade of LH surge –> inhibit ovulation, thickening cervical mucus to prevent sperm penetration, slowing tubal motility and delaying sperm transport, inducing endometrial atrophy (thinning)
hormonal contraceptives
- with perfect use they provide 99% efficacy rate
- high estrogen and progestin, not hormone replacements
- monophasic: contain same amounts of estrogen and progestin for 21 days followed by 7 day placebo phase
- biphasic: contain two varying amounts of estrogen and progestin for 21 days, 7 day placebo (less breakthrough bleeding than monophasic)
- triphasic: contain three varying amounts of estrogen and progestin for 21 days, 7 day placebo (less breakthrough bleeding than monophasic)
- adverse effects: breakthrough bleeding, estrogen deficiency in utero means early cycle bleeding, progesterone deficiency in utero means late cycle bleeding, estrogen specific (N/V, headache, breast tenderness, edema, hypertension, gallstones), progestin specific (increase appetite, weight gain, acne, hirsutism)
- contraindications: history of DVT, hypertension, CV disease, stroke, migraine, older than 35 and smoking 15 cigarettes per day, liver disease, breast cancer, pregnancy, lactation, 6 weeks postpartum
- interactions: CYP inducers, decreased efficacy of these drugs
combined oral contraceptives (OCs)
- effective as oral contraceptives only in patients weighing less than 200lbs, not recommended for patients weighing more than that
- adverse effects similar to oral contraceptives, application site reactions, increased risk of VTE/heart attack/stroke when compared to oral contraceptives (exposed to more estrogen in blood)
Ortho Evra, transdermal combined hormonal contraceptive containing ethinyl estradiol and norelgestromin, once weekly dosing
- less breakthrough bleeding and spotting and better menstrual cycle control compared to oral contraceptives
- adverse effects similar to oral contraceptives, other device related issues like foreign body sensation, device expulsion, vaginal symptoms
NuvaRing, flexible vaginal ring that contains EE and etonogestrel, 3 weeks of use and then 1 week break
- contraceptive that can be used in women who cannot take estrogen due to contraindications like breastfeeding, history of DVT/hypertension/CV diseases, active smokers over age 35
- less effective than combined OCs, must be taken every day (all 28 days of cycle) at about the same time every day to maintain efficacy, high risk of ectopic pregnancy due to decreased tubal motility, more breakthrough bleeding
progestin only pills (POPs)
- contraceptive given as IM/SC injection once every 3 months
- MOA: sustained progestin exposure blocks LH surge for inhibition of ovulation for high efficacy
- limitation: not desirable in women planning a pregnancy soon after cessation of therapy because ovulation suppression can persist up to 18 months after last injection
- adverse effects: breakthrough bleeding, amenorrhea, weight gain, short term bone loss which is most serious in young women), should not be used for longer than 2 years
long acting injectable contraceptive Depo-Provera, contains medroxyprogesterone acetate
- SC contraceptive progestin implant, MOA similar to injectable contraceptive
- extremely effective contraception that lasts up to 3 years
- fertility returns shortly after cessation of therapy (about 4 months later)
- adverse effects: breakthrough bleeding, fibrosis around device, difficulty removing device, pain at site, progestin related side effects
long acting implantable contraceptive Nexplanon containing etonogestrel
- small T shaped contraceptive device for insertion into the uterus
- MOA: localized action - blocks implantation and thins out endometrial lining of uterus
- advantages: quick onset and offset of action, immediate contraception and rapid return of fertility (1-3 months after cessation), long duration of action (about 5 years), reduction in menstrual blood loss, beneficial in menorrhagia, very low systemic absorption for minimal systemic side effects
- adverse effects: breakthrough bleeding for first 6 months
IUD Mirena, Skyla, Liletta, Kyleena containing levonorgestrel
- high dose progestin only EC, available as OTC
- MOA: inhibiting or delaying ovulation, should be taken within 72 hours of unprotected intercourse
- adverse effects: nausea, headache, abdominal pain, breast pain, irregular bleeding
Plan B One-Step, Next Choice, contains levonorgestrel
- EC that is a selective progesterone receptor modulator (SPRM)
- MOA: reversibly blocks progesterone receptors in the uterus, cervix, ovaries, hypothalamus, delays ovulation
- acts as an EC if taken within 120 hours/5 days of unprotected intercourse
- adverse effects: headache, abdominal pain
Ulipristal (Ella)
- non-hormonal EC
- T shaped plastic device for insertion into uterine cavity
- MOA: the metal this is made of affects sperm motility to prevent fertilization and implantation
- advantages: most effective option of EC (99% effective when inserted within 5 days of unprotected intercourse), contraception lasts 10 years but requires placement by a healthcare professional
- adverse effects: excessive vaginal bleeding
copper IUD (Paragard)
- MOA: progesterone receptor antagonist - degradation of uterine lining and contraction of uterus - detachment of embryo from uterine walls - pregnancy termination
- used in combination with misoprostol (stimulates uterine contractions and expulsion of the embryo from uterus) to serve as effective abortifacient
- can act as an EC if taken within 5 days of unprotected intercourse but not approved by FDA for that use
- adverse effect: excessive vaginal bleeding
mifepristone (Mifeprex)
