Endo Flashcards
Describe amine hormone synthesis
Hormones get stored for release; cells typically contain many granules filled with stored hormone
What are some amine hormones?
Catecholamines, thyroid hormone, releasing or stimulating hormones
Describe peptide-protein hormone synthesis
Stored for release; cells typically contain granules filled with stored hormone
Examples of peptide-protein hormones
Insulin, GH, gonadotropins, releasing or stimulating hormones
Describe steroid hormone synthesis
Produced when needed and released immediately because they are lipophilic; have delayed biological effects
Examples of steroid hormones
Sex steroids, corticosteroids, vitamin D, cholesterol precursor
Release patterns of endocrine hormones
Constitutive, stimulated, pulsation, circadian rhythm
Describe constitutive release pattern
Constant release of hormone
Describe stimulated release pattern
Released when stimulated by environment or CNS activity
Describe pulsatile release pattern
Released in pulses
Hormones that follow constitutive pattern
Insulin, cortisol, thyroxine
Hormones that are stimulated
Insulin, cortisol, thyroxine (?)
Hormones that are released in pulses
Hypothalamic releasing hormones
Hormones that follow circadian rhythms
Cortisol, thyroxine
How are hormone receptors relevant to pharmacology?
Key points of intervention; agonists and antagonists
Describe cell surface receptors
GPCRs; used by proteins, polypeptides, and amines because they are less lipophilic; cause intracellular signal transduction and rapid response
Describe nuclear/cytosolic receptors
Used by steroids and vitamin D and retinoic acid because these ligands are lipophilic; ligand binding causes transcription; response is delayed (hours later)
Traditional endocrine system
Hypothalamus-AP-target gland axes; gonads, thyroid, adrenal cortex; regulated by CBS feedback
Name the independent endocrine glands
Pancreas, posterior pituitary, parathyroids
Name the dispersed endo cells
IGFs from the liver, GI hormones, renin from kidney
Etiologies of pathway dysfunction
Hypersecretion, hyposecretion, inappropriate target tissue response
Hypersecretion etiology
Primary or secondary tutors
Hyposecretion etiology
Autoimmune dysfunction, genetics, surgery, atrophy, toxicity
Inappropriate response etiology
Abnormal receptor expression, mutated receptors, iatrogenic
Non-endo uses for glucocorticoids
Inflammation, allergy, septic shock, immunosuppression, hematologic malignancy
Alpha cells secrete ________, beta cells secrete ________
Glucagon; insulin
What controls insulin release?
increase: [Glucose], vagus, B2-adrenergic stimulation, leucine, arginine, gi hormones
Decrease: somatostatin, A-adrenergic stimulation
Process of insulin release
Glucose enters cell, ATP increases, ATP-K+ channel depolarizer cell, Ca2+ increases, insulin is released
Insulin receptor
Extracellular alpha and beta subunits with intracellular tyrosine kinase domain
Effects of insulin
*Anabolism
Increase glycogen storage in liver and muscle, increase fatty acid synthesis in liver, increase triglyceride synthesis in adipose, increase protein synthesis in muscle
Type 1 diabetes characteristics
Insulin deficiency, childhood or puberty onset, immune-mediated or idiopathic, coxsackievirus B1
Type 1 diabetes treatment
Insulin therapy
Type 2 diabetes characteristics
Insulin resistance and eventual insulin deficiency
Type 2 diabetes treatment
Lifestyle changes or oral hypoglycemic agents
What is lispro insulin?
Lysine and proline residues inverted so monomers are released quickly (fast acting)
What is aspart insulin?
One proline changed to aspartate so monomers are released quickly (fast acting)
What is NPH?
Protamine that modulates monomer release (intermediate acting)
What is Lente?
Zinc aggregate in acetate buffer so monomer is slowly released (intermediate acting)
What is glargine?
Replacement with glycine in A chain and arginines in B chain, plus high zinc concentration, causing very slow release and metabolism (long acting)
What is ultralente?
Suspension of high concentration of zinc aggregate in acetate buffer (long acting)
Types of insulin therapy
Basal-bolus or split-mixed (NPH + lispro or aspart mixed)
Complications of insulin therapy
Hypoglycemia or immunopathology
Types of oral hypoglycemics
Insulin secretagogues, insulin sensitizers, alpha glucosidase inhibitors, and incretins
Insulin secretagogues mechanism
Bind and inhibit ATP-K+ channel, leading to cell depolarization and insulin release ; caution with hypoglycemia
Types of insulin secretagogues
Sulfonylureas- longer acting so can use once daily but has risk of hypo
Meglitinides- rapid action, can use in combo with long- acting agents, causes less hypo
Insulin sensitizer mechanism
Increase sensitivity of peripheral cells to insulin but do not promote its release
Thiazolidinediones
Type of insulin sensitizer; ligand at ppar-gamma; regulate genes for lipid and glucose metabolism (glucose transporters);work downstream of insulin
Alpha glucosidase inhibitors
Inhibit alpha-glucosidases so digestion and absorption of starches decreases; can cause abdominal pain, diarrhea, flatulence
Incretins
Stimulated by glucose in intestine; tell the pancreas to increase insulin release
Types of incretins
Gastric inhibitory peptide (GIP) and glucagon like peptide 1 (GLP-1); very similar in structure and both N terminals are severed by DPP-4; get recognized by the pancreas to increase sensitivity
DPP-4 inhibitors
Inhibit the enzyme that inactivates incretins; could be used as an oral hypoglycemic to treat type 2 diabetes; sitagliptin
Biguanides
Type of insulin sensitizer; reduce hepatic gluconeogenesis and increase insulin utilization by peripheral cells; can use with secretagogues or insulin
Synthetic GLP-1
Liraglutide and exenatide
Liraglutide
Long-acting synthetic GLP-1 with fatty acid residue so it is bound to albumin and slowly released; decreases appetite and serum triglycerides but must be injected because it’s a peptide
Exenatide
GLP-1 agonist produced by gila monsters in saliva to rapidly activate beta cells and release insulin; may cause nausea, diarrhea, etc.
Glucagon
Hormone produced by alpha cells that opposes insulin; used in hypoglycemic emergency
Cortisol regulation
Hypothalamus is stimulated by stress, cold, etc. To release CRH, which causes ACTH release from the AP and results in cortisol synthesis from the adrenal cortex; negatively feeds back
Aldosterone regulation
Adrenal cortex is stimulated by ATII, potassium, and somewhat by ACTH
The zona glomerulosa releases
Aldosterone
The zona fasciculata releases
Primarily cortisol
The zona reticularis releases
Androgens and estrogen
Function of the renal juxtaglomerular apparatus
Monitors osmolarity and BP using macula densa and renin-secreting cells; when BP drops, renin increases
Action of renin
Produces angiotensin I
Effects of angiotensin II
Vasoconstriction and increased aldosterone secretion from adrenals
Rate limiting step of steroidogenesis
Conversion of cholesterol to pregnenolone by p450scc by knocking off the side chain
Key enzyme for glucocorticoid synthesis
P450c11, which hydroxylates carbon 11 so it can now bind the glucocorticoid receptor
Production of androgens
Pregnenolone follows a different conversion pathway to produce androstenedione
Production of aldosterone from pregnenolone
P450aldo adds additional groups to the molecule so it can now bind the mineralocorticoid receptor
Function of transcortin (CBG)
Carries cortisol in the blood stream and protects it from degradation until it reaches the target cell
How is aldosterone unique among the steroids?
It is almost completely unbound in the bloodstream
Actions of cortisol
Increase carb, lipid, and protein metabolism, as well as gluconeogenesis and glycogen synthesis in liver; inhibits production of proinflammatory mediators; short-term mood enhancement; vasoconstriction and CV support; stimulates fetal lung surfactant
Aldosterone actions
Fluid and electrolyte balance; promotes sodium reabsorption and proton/potassium excretion; maintains BP
Where aldosterone exerts effects
Distal tubule and collecting duct
3 categories of steroid preparations
Short-medium acting, intermediate acting, long-acting
Short-medium acting steroids
Cortisone, prednisolone, methylprednisolone
Intermediate-acting steroids
Triamcinolone
Long-acting steroids
Betamethasone, dexamethasone
Mineralocorticoid preparations
Fludricortisone, desoxycorticosterone; strong salt-retaining ability
What is fluticasone propionate (Flonase)
Topically active glucocorticoid that binds the corticosteroid receptor, but is hydrolyzed as soon as it hits the bloodstream and is inactivated; useful for asthma inhalers
What is mifepristone
Glucocorticoid and progesterone antagonist; binds receptor but prevents receptor folding
Cushing’s syndrome
Hyperadrenocorticism; buffalo hump, thin skin, muscle wasting at periphery, osteopenia, prone to infection, high BP
Causes of cushing’s syndrome
Pituitary adenoma (cushing’s disease), iatrogenic, ectopic ACTH syndrome, adrenal gland tumors
Diagnosis of cushing’s syndrome
Adrenal: elevated cortisol, low ACTH, glucocorticoid injection will do nothing
Pituitary: elevated ACTH, glucocorticoid injection will suppress ACTH
Adrenocorticosteroid inhibitors
Mitotane; inhibits production of cortisol
Corticosteroid synthesis inhibitors
Ketoconazole, aminoglutethimide, trilostane
Addison’s disease
Adrenal insufficiency; usually from autoimmune destruction of adrenals, can also be from abrupt steroid withdrawal or removal of adrenal or pituitary tumors
Acute adrenal insufficiency
Emergency; need IV fluid and corticosteroids
Chronic adrenal insufficiency
Less severe; can use long-term glucocorticoid and mineralocorticoid replacement therapy
Minimizing adverse effects of steroids
Use low dose and low potency steroids (prednisone), use alternate day therapy, taper reduction
Mineralocorticoid antagonists
For primary aldosteronism (see hypertension and hypokalemia); spironolactone, eplerenone block the mineralocorticoid receptor
3 forms of thyroid hormones
T4, T3, rT3
3 deiodinases
D1, D2, D3
D1 deiodinase action
Deiodinates both the inner and outer ring (produce T3, inactivate everything)
D2 iodinase action
Deiodinates the outer ring (T4 —> T3 intracellularly)
D3 iodinase action
Deiodinates the inner ring (inactivates T4 and T3)
T4 production in thyroid
Tyrosine is iodinated by TPO and then these are combined to form T4. Thyroglobulin is then proteolyzed and release into the blood as either T4 or T3
Ratio of t4 to t3
4:1
Action of TBG
Bind thyroid hormone and greatly increase their half-life
T3 is __________ as potent as T4
4 times
Actions of thyroid hormones
Control transcription and translation of genes for metabolism; increase cellular oxygen use; allow for growth and development of tissues; increase myocardial contractile proteins
Hypothyroidism etiology
Most commonly primary; can also be TSH insufficiency or iodine deficiency; gland absence; autoimmune thyroiditis (Hashimoto’s; AB’s against TPO); surgery, radioactive iodine; thioamides; chemo
Hypothyroidism clinical signs
Lethargy, weakness, fatigue, cold intolerance, weightgain, Bradycardia, myxedema
Goitrous hypothyroidism
From iodine deficiency, neoplasms, autoimmune destruction; causes gland growth
Hypothyroidism diagnosis
Low T4, elevated TSH
Levothyroxine
Synthetic T4; long half-life so you can take once daily, easily monitored, reaches steady-state in 6-8 weeks
Liothyronine
T3; has shorter half-life so it is used much less
Liotrix
Mixture of T4/T3 in 4:1 ratio; used for long-standing disease, in elderly, for CV disease, given in myxedema medical emergency
Other treatments for hypothyroidism
Removal of drugs, iodine supplementation
Hyperthyroidism ethology
Graves’ disease (antibodies activate TSH receptor), too much t4 supplementation, neoplasms, infection o inflammation of thyroid (transient)
Clinical signs of hyperthyroidism
Hyperactive, nervous, insomnia, heat intolerance, tachycardia, weight loss, muscle wasting, exophthalmos
Hyperthyroidism diagnosis
High T3/T4, low TSH, can use radioiodine uptake scan, MRI, or ultrasound
Thioamides
Inhibit TPO so hormone synthesis is blocked; given orally
Iodinated contrast medic
Inhibit conversion of t4 to t3 so there is less biological effect, but have short-term effects
Adjunct drugs for hyperthyroidism
Beta blockers or calcium channel blockers
Radioiodine therapy
Use i131- give orally and gets taken up by thyroid to destroy cells; some need second treatment, but most become hypo
Thyroidectomy
Used for large glands or multinodular goiters;use antithyroid drugs pre-surgery; will need replacement t4 therapy after surgery
Type of release of GNRH
Pulsatile (same with FSH and LH but less so)
What is GNRH?
Decapeptide from hypothalamic neurofibers
What releases FSH and LH
Anterior pituitary
Effect of continuous release of GnRH
Down-regulation of the receptor
What is inhibin?
Protein produced by sertoli cells and granulosa cells; inhibits FSH release selectively
Action of FSH
Stimulates follicular development; converts androgen to estrogen j acts on sertoli cells to increase spermatogenesis
Action of LH
Stimulates ovulation; produces androgens; regulates testosterone production
Gonadorelin
Synthetic GnRH used in both sexes for hypogonadotrophic hypogonadism
Leuprolide
Long-acting GnRH agonist used to induce hypogonadism; used for prostate cancer and hyperplasia, uterine fibroids, early puberty, assisted reproduction
FSH analogues
human menopausal gonadotropins extracted from urine of postmenopausal women (have to use in conjunction with LH) ; recombinant FSH
LH analogues
Human chorionic gonadotropins produced by placenta and excreted in urine; recombinant LH and hCG
Where testosterone is produced
Leydig cells
Testosterone synthesis
Comes from cholesterol and pregnenelone; converted to estradiol by aromatase and DHT by 5alpha-reductase in peripheral tissues
What is TeBG
Testosterone binding globulin; carries 98% of testosterone in the blood
DHT versus testosterone
DHT has higher affinity for the receptor
Effects of androgens
Secondary sex characteristics; spermatogenesis, deepening of voice, facial hair, libido, behaviorer, body mass, erythropoiesis, decreased HDL, growth plate closure
Testosterone preparations
1:1 androgen: anabolic effect
Long-acting testosterone analogues
Have a longer half-life due to ester addition
Side effects of androgen preparations
Prostate enlargement, aggression, hepatic dysfunction, sterility, heart disease, masculinization of women
Androgen replacement therapy
Replaces or augments androgens in hypogonadal men; use testosterone
Uses for androgens and anabolic steroids
- Androgen replacement therapy
2.Gynecologic disorders - Use as protein anabolic agent
- Growth stimulators and aging
- Steroid abuse
Danazol
Weak synthetic androgen used in endometriosis that inhibits estrogen-induced growth of endometrial tissue
Uses for Anti androgens
For prostatic cancer, benign prostatic hyperplasia, endometriosis, male pattern baldness, excessive sex drive, early puberty in men
Ways to suppress androgen action
- GnRH agonists (leuoprolide)
- Testosterone synthesis inhibitors (ketoconazole, spironolactone)
- Inhibition of 5alpha-reductase (finasteride)
- Androgen receptor antagonists (flutamide, cyproterone)
Estrogen synthesis in premenopausal women
Estradiol mostly, produced by ovary
Steroidal estrogens
From testosterone or androstenedione in ovaries, converted to estrogen via aromatase
Estriol
Synthesized from estradiol in liver, as well as in placenta during pregnancy
Estrogen synthesis in post menopausal women
From adipose tissue, adrenals also produce estrone
Estrogen synthesis in men
Extra-gonadal conversion of testosterone, DHEA, and androstenedione
Synthetic estrogens
Ethinyl estradiol, diethylstilbesterol
Progestin meaning
Any steroid with progesterone activity
Progesterone
Most important natural progestin in women,produced in ovaries, adrenals, and placenta; can be precursor for estrogens, androgens, and adrenocorticoids
Synthetic progestins
L-norgestrel, norethidrone, medroxyprogesterone
Progestins in men are produced where?
Produced in testes
Estrogen binds to ______ in the blood stream, while progesterone binds to ______
TeBG; CBG
Estrogen receptor types
Alpha and beta
Effects of estrogens
Sexual maturation, sense of well-being, ovulation, parturition, endometrial growth, reduced resorption of sone, increased clotting factors, growth, epiphysis closure
Effects of progesterone
Modulates carb metabolism, suppresses ovulation, deposits adipocytes, sexual maturation, behaviour, mood
Uses for estrogens, progestins, and gonadal inhibitors
- Fertility control (Post-coital contraception, Contragestation)
- Hormone replacement therapy
- Ovulation induction
- Cancer chemo
Post-coital contraception
Large dose of estrogen alone or with progestin; prevents implantation; must be taken within 72 hours
Contragestation
Mifepristone; antiprogestin that blocks progesterone receptor so implantation cannot occur and endometrium is shed; usually given with prostaglandin for contraction
Two types of oral contraceptives
Combination of Estrogen and progestins or continuous therapy of only progestins
Combined oral contraceptives
Ethinylestradiol plus l-norgestrel or norethindrone; can vary levels of progestin throughout 28 day cycle; inhibits ovulation because estrogen and progestin inhibit gonadotropin release; thickens cervical mucus; progestins protect endometrium
Progestin-only mini pill
Slightly higher failure, higher incidence of menstrual irregularity; contains either norgestrel or norethindrone; still inhibits cycle and thickens mucus
Alternative contraceptives
Norplant-2 placed subcutaneously in arm, medroxyprogesterone intramuscular injections, progesterone IUDs
2 uses for estrogen or progesterone replacement therapy
Congenital primary hypogonadism, menopause/surgical removal of ovaries
Treatment for congenital primary hypogonadism
Low dose estrogen for most of month and then progestin to initiate uterine bleeding
Treatment for menopause/surgical removal of ovaries
Estrogens and progestins to antagonize estrogen effects on endometrium
Symptoms of menopause or ovarectomy
Atrophy of genitalia, depression, loss of libido, lack o energy, hot flashes (vasomotor spasm), osteoporosis, cardiovascular disease
Drugs for ovulation induction
GnRH analogues it pituitary is functioning, gonadotropins if ovary is functioning; clomiphene citrate
Clomiphene citrate
Partial agonist/antagonist at estrogen receptor that decreases estrogen to stop negative feedback on hypothalamus/pituitary → increases FSH → increased follicles; repeat every cycle (SERM)
Drugs for cancer chemo
Diethylstilbesterol for prostate cancer, selective estrogen receptor modulators, estrogen synthesis inhibitors
Selective estrogen receptor modulators
Selectively antagonize certain estrogen receptors; used for treatment of breast cancer but have low risk of osteoporosis
Estrogen synthesis inhibitors
Aromatase inhibitors that function everywhere in the body so they’re more effective for breast cancer but have higher risk of osteoporosis; can use with tamoxifen
Mild effects of estrogens and progestins
Nausea, headaches, endocrine changes
Moderate effects of estrogens and progestins
Weight gain, vaginal and uterine tract infections, bleeding, depression
Severe effects of estrogens and progestins
Hepatic dysfunction, cancers (breast, endometrial) thromboembolic disease, MI, hypertension, stroke, concern with other risk factors
Oxytocin structure
Nonapeptide
Oxytocin synthesis
In paraventricular nuclei and supraoptic nuclei, secreted from nerve endings, also synthesized in luteal cells of ovary, uterus, and fetus
Oxytocin stimulation
Sensation from cervix and vagina, suckling
Effects of oxytocin
Increases frequency and force of uterine contractions, stimulates milk ejection
Hormones needed for oxytocin to work
Estrogen for contractions, prolactin for milk formation
Hormone that antagonizes oxytocin
Progesterone; necessary to prevent premature labour
Pitocin
Synthetic oxytocin given intravenously to induce labour or by nasal spray for postpartum lactation
Contraindications for oxytocin administration
Fetal distress, premature labor, abnormal fetal positioning, cephalopelvic disproportion
Atosiban
Oxytocin antagonist used for premature labour (not used in NA)
What is vasopressin
Nonapeptide from posterior pituitary that acts as ADH
Stimuli for vasopressin
Increasing toxicity by osmoreceptors, BP drop by baroreceptors
Actions of vasopressin
Promotes water retention via v2 receptors, constricts vessels via v1 receptors
Synthetic vasopressin types
Vasopressin, desmopressin (long-acting, no vasoconstriction)
Uses for synthetic vasopressin’s
Pituitary diabetes insipidus, nocturnal enuresis
What electrolytes regulate bone homeostasis
Calcium and phosphate
Effects of bone abnormalities
Neuromuscular excitability, weakness, tetany, joint malfunction, decreased hematopoiesis
Effects of PTH
Increases serum calcium, decreases serum phosphate
Effects of vitamin D
Increases both serum calcium and phosphate; directly suppresses PTH production
Effects of calcitonin
Lowers serum calcium and phosphate; inhibits osteoclasts
Effect of estrogen on bones
Inhibit osteoclasts; slow bone turnover; increases vitamin D
What is osteoporosis
Low bone mass in long bones
Primary osteoporosis
Loss of estrogen production in postmenopausal women (and older men)
Osteoporosis risk factors
Female, Caucasian, smoking, fracture, age, low weight, family history
Secondary osteoporosis
From diet, gi disease, hyperparathyroidism, liver disease, alcoholism, vitamin D deficiency, corticosteroid use
Primary regulators of bone mass
Physical activity, calcium intake, reproductive statues
Therapies for osteoporosis
SERMs, bisphosphonates, PTH analogues, calcitonin, vitamin D
SERMs for osteoporosis
Raloxifene; Estrogen agonist in bone, antagonist in breast and uterus, doesn’t prevent hot flashes
Bisphosphonates
Most successful therapy; inhibit osteoclast function
PTH analogues
Recombinant PTH, stimulates bone formation at low doses
Calcitonin therapy
Inhibits osteoclasts
Vitamin D therapy
Improves intestinal calcium absorption to improve mineral density
Negative and positive stimuli for gh
Negative: somatostatin, positive: growth hormone releasing hormone
Effects of GH
Stimulates synthesis and release of IGF-1 from liver and growth plate; promotes lipolysis, gluconeogenesis, and protein synthesis, as well as skeletal and soft tissue growth
Causes of GH deficiency
Genetics, hypothalamus problem or pituitary problem
Signs of GH deficiency
Cardio problems, psychosocial problems, decreased muscle and bone mass, increased fat, less energy, poor libido
Diagnosis of gh deficiency
Measurement of serum gh levels
Gh deficiency treatments
Recombinant GH, rhIGF1/rhIGFBP3 for receptor defects of GH antibodies, synthetic GHRH (not if issue is at pituitary)
Effect of excess gh
Gigantism when young, acromegaly in adulthood
Signs of acromegaly
Soft tissue overgrowth, elevated serum IGF1 or GH
Therapies for gh excess
Ocreotide (somatostatin analogue) , pegvisomant (GH antagonist)
What is prolactin
Peptide hormone from ap that causes breast development and milk production
Effects of excess prolactin
Inappropriate breast development and lactation, reproductive difficulties
Effect of dopamine on prolactin
Decreases prolactin secretion from pituitary
Bromocriptine and cabergolide
Stimulates d2 receptors in ap to decrease prolactin; used for prolactinomas, acromegaly; can give orally or intravaginally
