Term
mineralocorticoids: aldosterone - Na, K, and water homeostasis
glucocorticoids: cortisol - glucose homeostasis and many others
androgens: DHEA, testosterone, estrogen - sex hormones |
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Definition
| major representation and physiological effects of mineralocorticoids, glucocorticoids, and androgens |
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Term
| the distal tubule of the kidney |
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Definition
| the major target of aldosterone is ( ) |
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Term
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Definition
increases reabsorption of sodium
increases reabsorption of water, with consequent expansion of extracellular fluid volume
increased renal excretion of K and H ions |
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Term
concentration of K ions in extracellular fluid
angiotensin II: activation of the renin-angiotensin system as a result of decreased renal blood flow (usually due to decreased vascular volume) results in release of angiotensin II, which stimulates aldosterone secretion |
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Definition
| the 2 most significant regulators of aldosterone secretion |
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Term
metabolism: stimulation of gluconeogenesis (particularly in the liver), mobilization of amino acids from extrahepatic tissues, inhibition of glucose uptake in muscle and adipose tissue (a mechanism to conserve glucose), stimulation of fat breakdown in adipose tissue
inflammation and immune function: potent anti-inflammatory and immunosuppressive properties |
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Definition
| glucocorticoid effects on metabolism, inflammation and immune function |
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Term
like the other steroid receptors, the structure of GR consists of a variable domain, the DNA-binding domain with zinc fingers, a hinge region, and the hormone binding domain with a final carboxy terminal
cortisol diffuses through the cell wall and binds to the glucocorticoid receptor forming a GR-hormone complex
dissocitation of the GR complex releases the heat shock chaperones leaving the free cortisol-receptor subunits that link up as homodimers
translocated into the nucleus, binds to a specific DNA region and activates gene transcription
mineralocorticoid signaling works in a similar fashion |
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Definition
| glucocorticoid receptor signaling |
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Term
kidneys and sweat glands
its activation leads to transport of ions and water resulting in an increase in extracellular volume, increased blood pressure, and decrease in K |
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Definition
| where are there high concentrations of mineralocorticoid receptors? |
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Term
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Definition
a hormone (endocrine) disorder caused by high levels of cortisol in the blood
a non-cancerous tumor in the pituitary gland that produces large amounts of ACTH, which in turn elevates cortisol
it can usually be cured by surgery |
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Term
moon face
buffalo humps
obesity
hypertension
diabetes
weakness
excessive body hair
menstrual abnormalities/sexual dysfunction |
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Definition
| clinical features of Cushing's syndrome |
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Term
steroidogenic inhibitor; can be used for Cushing's syndrome
inhibits cortisol production by inhibiting 11beta-hydroxylase
[image]
may also suppress biosynthesis of aldosterone
removal of the strong inhibitory feedback mechanism exerted by cortisol results in increased ACTH
there is an increase in the immediate precursors of cortisol, which can be measured in a diagnostic test to measure pituitary ACTH responsiveness |
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Definition
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Term
steroidogenic inhibitor; can be used for Cushing's syndrome
inhibits conversion of cholesterol to pregnenolone, inhibiting cortisol synthesis
does not effect the underlying disease state
primarily used as an interim measure until more definitive therapy such as surgery can be undertaken or in cases where such therapy is not appropriate
only a small number of patients can be treated for longer than 3 months
results in the decreased production of glucocorticoids, mineralocorticoids, estrogens, and androgens |
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Definition
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Term
steroidogenic inhibitor; can be used for Cushing's syndrome
inhibits 11beta and 17alpha-hydroxylase
[image]
imidazole derivative, normally used to treat fungal infections
inhibits the first step in cortisol synthesis |
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Definition
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Term
adrenolytic agent
used for adrenal carcinoma but also useful for Cushing's syndrome
cytotoxic drug - impairs steroid synthesis, which in turn causes adrenal atrophy and tumor death
structurally related to the insecticide DDT
the drugs causes atrophy in the zona fasciculata and zona reticularis, the site of aldosterone synthesis (zona glomerulosa)is only minimally damaged |
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Definition
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Term
neuromodulatory agent
lack of consistent clinical efficacy in Cushing's syndrome
decreases ACTH hormone
long term use is not possible due to negative feedback loop |
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Definition
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Term
neuromodulatory agent
lack of consisten clinical efficacy in Cushing's syndrome
a progesterone and glucocorticoid receptor antagonist
it has no estrogenic, antiestrogenic, mineralocorticoid, or antimineralocorticoid activity
will result in higher cortisol and ACTH levels (FEEDBACK LOOP STILL ACTIVE!) |
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Definition
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Term
| secondary adrenal insufficiency |
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Definition
occurs when the anterior pituitary does not produce enough ACTH to adequately stimulate the adrenal glands
usually occurs via exogenous glucocorticoid use |
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Term
Addison's disease
lack of aldosterone is lethal due to electrolyte imbalances and the resulting hypotension and cardiac failure |
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Definition
primary adrenal insufficiency
the adrenal glands themselves malfunction
causes: destruction of the adrenal glands by infection, their destruction by autoimmune attack, an inherited mutation in the ACTH receptor on adrenal cells
90% failure before symptoms occur
a deficiency in aldosterone can occur by itself or more commonly in conjunction with a glucocorticoid deficiency |
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Term
hydrocortisone, prednisone, cortisone - mineralocorticoid and glucocorticoid activity
fludrocortisone - aldosterone-like synthetic steroid |
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Definition
| treatment options for Addison's disease |
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Term
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Definition
| antidiuretic hormone is produced in the ( ) and is transported by axons to the posterior pituitary where it is dumped into the blood |
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Term
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Definition
| effects of antidiuretic hormone |
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Term
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Definition
located in the anterolateral hypothalamus
measure Posm
play a key role in water and sodium balance
signals the release (or prevents the release) of ADH |
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Term
baroreceptors
unlike osmoreceptors, baroreceptors must be suppressed in order to stimulate the release of ADH
larger changes in the dependent value are needed to release ADH (10-15% blood volume loss) |
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Definition
located in the carotid sinus and aortic arch
measure blood pressure |
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Term
| distal convoluted tubule and collecting duct |
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Definition
| vasopressor receptor (V2) action is primarily in the ( ) |
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Term
controls free water resorption in the distal convoluted tubules and collecting ducts of the kidneys
activation of AC causes increased cAMP which leads to insertion of aquaporin channels (water channels) into the apical membrane of the cells lining the collecting duct
this allows water to be reabsorbed from the urine (making urine more concentrated)
the basolateral membranes are freely permeable to water, so any water that enters via the apical membrane exits the cell via the basolateral membrane |
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Definition
| actions of vasopressor receptor |
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Term
stimulates the contraction of vascular smooth muscle in coronary, splanchnic, GI, pancreatic, skin, and muscular vascular beds
glycogenolysis
platelet aggregation
ACTH release |
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Definition
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Term
diabetes insipidus (DI)
similar to DM, but urine is not sweet and there is no hyperglycemia, blurred vision is a rarity |
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Definition
a disease characterized by excretion of large amounts of severely diluted urine, which cannot be reduced when fluid intake is reduced
can be caused by: ADH deficiency, kidneys insensitive to ADH |
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Term
| central diabetes insipidus |
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Definition
DI caused by damage to the hypothalmus or pituitary gland as a result of surgery, infection, tumor, or head injury
if the hypothalamus is damaged, the feeling of thirst may be completely absent |
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Term
nephrogenic DI
limited treatment options, NSAIDs can reduce urination
most important treatment is to ensure constant access to water |
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Definition
DI due to the inability of the kidneys to respond to ADH
involves a deficit in the parts of the kidney that resorbs water back into the bloodstream
vasopressin resistant
genetic, kidney disease, drugs (demeclocycline, lithium, amphotericin B)
occurs less often than central DI |
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Term
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Definition
DI due to a defect or damage to the thirst mechanism, which is located in the hypothalamus
this defect results in an abnormal increase in thirst and fluid intake that suppresses ADH secretion and increases urine output
desmopressin is ineffective, and can lead to fluid overload as the thirst remains |
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Term
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Definition
DI that occurs only during pregnancy
while all pregnant women produce vasopressinase in the placenta, which breaks down ADH, this can assume extreme forms
most cases can be treated with desmopressin
if there is an abnormality in the thirst mechanism (rare cases) desmopressin should not be used |
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Term
synthetic analogue of vasopressin with a longer duration of action than vasopressin
more favorable adverse effects profile
drug of choice for central DI
binds to V2 receptors in the renal collecting ducts, increasing water reabsorption
desmopressin is degraded more slowly than vasopressin, requiring less frequent administration
desmopressin has little effect on BP, where vasopressin can cause arterial hypertension |
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Definition
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Term
NSAIDs: since prostaglandins reduce antidiuretic responses to vasopressin and NSAIDs inhibit prostaglandin synthesis; increases antidiuretic response
carbamazepine
chlorpropamide |
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Definition
| drugs that enhance the antidiuretic response to vasopressin |
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Term
lithium: reduces V2 receptor mediated stimulation of adenylyl cyclase; increases plasma levels of PTH, a partial antagonist to ADH
chochicine and vinca alkaloids: act on microtubule organelles required for movement of the aquaporins |
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Definition
| drugs that inhibit the antidiuretic response to vasopressin |
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Term
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Definition
seen when drugs or tumors result in continued secretion of ADH or increased action of ADH on the collecting ducts
the electrolyte disturbance hyponatremia results from this condition |
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Term
head injury
lung cancer
infections
brain abscess
pneumonia
lung abscess
drugs: chlorpropamide, carbamazepine, cyclophosphamide, SSRIs |
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Definition
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Term
V1 and V2 antagonist
used to treat hyponatremia associated with SIADH
V2 coupled with aquaporin channels in the collecting duct
conivaptan causes aquaresis (excretion of free water)
results: increased urine output, decreased urine osmolality |
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Definition
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Term
| a selective competitive V2 antagonist used to treat hyponatremia associated with CHF, cirrhosis, and SIADH |
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Definition
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Term
a tetracycline antibiotic used to block the action of ADH in the kidney in hyponatremia due to SIADH when fluid restriction has failed
demeclocycline produces nephrogenic diabetes insipidus
nephrogenic, dose-dependent and reversible on discontinuance of therapy. |
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Definition
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Term
follicle
colloid
parafollicular or C cells |
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Definition
Thyroid epithelial cells, the cells responsible for the synthesis of thyroid hormones, are arranged in spheres called ( ), the functional unit of the thyroid
They are filled with ( ), a proteinaceous deposit of thyroid hormone precursor
in addition to thyroid epithelial cells, there are also ( ) which secrete the hormone calcitonin and parathyroid hormone |
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Term
[image]
thyroid hormones are derivatives of the amino acid tyrosine bound covalently to iodide
The 2 principle thyroid hormones are: thyroxine (T4) and triiodotyronine (T3)
The number and positions of the iodides are important
reverse T3 has little or no biological activity |
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Definition
| description of the thyroid hormones T3, T4, and reverse T3 |
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Term
anterior pituitary secretes thyroid stimulating hormone (TSH)
TSH is secreted in a pulsatile manner and circadian pattern, highest levels at night
TSH secretion is controlled by the hypothalamus through thyrotropin releasing hormone (TRH) and by the concentration of free thyroid hormone in the circulation
extra thyroid hormone inhibits transcription of both TRH and TSH
any decrease in the normal rate of thyroid hormone secretion by the thyroid enhances secretion of TSH in an attempt to stimulate the thyroid to secrete more hormone
low levels of I- are required for thyroxine synthesis, but high levels inhibit thyroxine synthesis and release |
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Definition
| regulation of thyroid hormone secretion |
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Term
TSH receptor is found mainly on thyroid follicular cells
stimulation of the receptor increases T3 and T4 production and secretion
stimulating antibodies to this receptor mimic TSH action and are found in Grave's disease
the TSH receptor is a GPCR, binding of TSH stimulates Gs
TSH acts on receptors on the membrane of thyroid follicle cells and its main second messenger is cAMP. It controls all aspects of thyroid hormone synthesis:
the uptake of iodide by follicle cells, by stimulating transcription of the Na/I transporter gene
the synthesis and secretion of thyroglobulin
the generation of peroxide and the iodination of tyrosine
endocytosis and proteolysis of thyroglobulin
secretion of T3 and T4
blood flow through the gland |
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Definition
| actions of thyroid stimulating hormone |
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Term
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Definition
a large glycoprotein that contains about 115 tyrosine residues
it is synthesized and secreted into the lumen of the tyroid follicle
where the iodination of tyrosine occurs
able to store great quantities of potential hormones this way |
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Term
1) uptake of iodide
2) oxidation and iodination
3) formation of thyroxine and triiodothyronine
4) resorption
5) proteolysis of colloid
6) secretion of thyroid hormone
7) conversion of thyroxine to triiodothyronine in peripheral tissues
[image] |
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Definition
| the 7 major steps to the biosynthesis and release of thyroid hormone |
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Term
[image]
due to sodium-iodide transporter: autoreceptor or feedback mechanism
decreased stores of iodide enhance iodide uptake
increased stores of iodide decrease iodide uptake
autoantibodies to the symporter protein adversely effect iodide transport - seen in the autoimmune disorder Hasimoto's (may also result from autoimmune attack on thyroid peroxidase, TSH, or thyroglobulin) |
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Definition
| description of step 1: uptake of plasma iodide by the follicular cells |
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Term
several step process
1) iodide has to be oxidized for tyrosine to be iodinated. oxidation (also referred to as organification) is accomplished by THYROPEROXIDASE AKA THYROID PEROXIDASE. it uses hydrogen peroxide as an oxidant to produce I+
[image]
2) iodination of tyrosines on thyroglobulin (through the enzyme thyroid peroxidase)
[image] |
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Definition
| description of step 2: oxidation of iodide and iodination of tyrosine residues |
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Term
[image]
thyroid peroxidase catalyzes formation of T3 and T4 - the same enzyme will allow the cleavage of a tyrosine and the addition of tyrosines to each other |
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Definition
| description of step 3: formation of triiodothyronine |
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Term
megalin, a thyroglobulin receptor ingests thyroglobulin
thyroglobulin turns into colloid droplets (T4 and T3 are still in there) |
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Definition
| description of step 4: resorption |
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Term
colloid droplets fuse with lysosomes with proteolytic enzymes
endopeptidases cleave thyroglobulin leaving hormone containing intermediates
TSH can enhance endopeptidase activity
the hormone is free |
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Definition
| description of steps 5 and 6: proteolysis of colloid and secretion of thyroid hormone |
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Term
metabolism of thyroxine to triiodothyroxine by sequential monodeiodination accounts for 80% of circulating T3.
enzymes responsible for T4 to T3 conversion: iodothyronine 5' deiodinases (liver)
differentially expressed and regulated in various tissues
several different types of iodothyronine 5' deiodinases
upregulation of this enzyme in hyperthyroidism and down regulation in hypothyroidism |
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Definition
| description of step 7: conversion of T4 to T3 in peripheral tissues |
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Term
in the blood: 90-95% is T4, 5% is T3; 5% of iodide is circulating in the blood
thyroxine binding globulin is a plasma protein that binds and transports T4 (has less affinity for T3)
TBG protects thyroxine from being metabolized and excreted |
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Definition
| how are thyroid hormones transported in the blood? |
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Term
deiodination is the MAJOR pathway
liver is site of non-deiodination degradation (sulfation and glucuronidation)
T4 is eliminated slowly from the body with a half life of 6-8 days (in hyperthyroidism t1/2 is 3-4 days and in hypothyroidism t1/2 is 9-10 days) |
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Definition
| T4 and T3 degradation and excretion |
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Term
actions of thyroid hormones are mediated through nuclear receptors
they function as hormone activated transcription factors and thereby act by modulating gene expression
in contrast to steroid hormone receptors, thyroid hormone receptors bind DNA in the ABSENCE of hormone, usually leading to transcriptional repression
hormone binding causes a conformational change that causes the receptor to function as a transcriptional activator
the alpha 2 isoform does not bind T3
the beta 2 isoform activates expression of genes known to be important in brain development (showing the critical effects of thyroid hormones of the development of the fetus and neonatal brain) |
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Definition
| thyroid hormone receptors |
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Term
[image]
the difference in acidity of the phenol can explain differences in binding
T4 has greater electron withdrawing properties, making it more acidic
T3 is more basic, not as highly ionized, and thus is not bound as tightly to plasma proteins
[image]
alpha ring: removal of I atoms from the ring leads to loss of activity; Br can replace I and maintain activity; the conformational effects of the 3,5,3',5' are more important the the chemical nature; the 2 rings are angled at 120 degrees at the ether oxygen
the bridging atom between the 2 phenyl rings (O) can be replaced by S or methyl and still maintain activity; the key is that this bridging keeps the 2 aromatic rings almost perpendicular to each other
beta ring: removal of 5' I leads to an increased activity; the phenolic OH on the beta ring is essential for activity |
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Definition
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Term
thyroid hormones are essential for normal growth and development and play an important role in energy metabolism
plasma concentrations of cholesterol and TGs are inversely proportional with thyroid hormone levels (sign of hypothyroidism is hyperlipidemia)
calorigenic (increased O2 consumption)
growth, development, sexual maturation, CNS maturation
increased HR and contraction
increased metabolism of carbs, fats, and proteins
increased sensitivity of beta-adrenergic receptors to catecholamines
brain, retina, lungs, spleen, testes appear to be unaffected by thyroid hormones |
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Definition
| actions of thyroid hormones |
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Term
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Definition
irreversible form of mental retardation
caused by absence of thyroid hormone during period of active neurogenesis
can be prevented if supplemented with thyroid hormone the first 2 weeks of life
2 types: endemic - due to extreme iodine deficiency; sporadic - thyroid fails to develop normally or defect in synthesis of thyroid hormone |
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Term
liver: increased LDL, TGs
intestines: constipation, decreased GI activity
reproductive system: decreased fertility, menstrual abnormalities, may harm development of infant
brain: depression, decreased concentration, general lack of interest
heart: decreased HR, increased/decreased BP, decreased CO
kidneys: decreased function, fluid retention and edema |
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Definition
hypothyroidism is caused by insufficient production of thyroid hormone by the thyroid gland
most commonly caused by Hashimoto's thyroiditis and hypothyroidism following radiation therapy
secondary hypothyroidism occurs if there is pituitary gland damage by a tumor, radiation, or surgery
hypothyroidism is the most common disorder of thyroid function
usually results from iodine deficiency in 3rd world countries
what effects does it have on the body? |
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Term
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Definition
rare syndrome that represents extreme expression of severe, long-standing hypothyroidism
presents as: hypothermia, respiratory depression, and unconsciousness
medical emergency: mortality rate is 60%
common precipitating factors: pulmonary infections, cerebrovascular accidents, congestive heart failure
can be hastened with drugs: sedatives, anti-depressants, narcotics, tranquilizers |
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Term
thyroxine (T4)
hormone of choice for thyroid hormone replacement
consistent potency and prolonged duration of action
absorption is variable and incomplete
absorption is slightly increased when taken on an empty stomach
the dose must by increased for hypothyroid patients who become pregnant due to increased estrogen among other factors
there are many different forms and bioequivalence may vary between types |
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Definition
| MOA of levothyroxine sodium |
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Term
interfere with absorption: calcium, soy products, cholestyramine, aluminum hydroxide, iron
enhanced metabolism: drugs that induce CYP P450 such as phenytoin, carbamezapine, rifampin |
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Definition
| drug interactions of levothyroxine |
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Term
triiodothyronine (T3)
may be used occasionally when quicker onset is desired (myxedema coma, first radioactive I treatment)
not desirable for chronic treatment b/c more frequent dosing, higher cost, and transient elevations of serum T3 above normal concentrations |
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Definition
| MOA of liothyronine sodium |
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Term
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Definition
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Term
nervousness
irritability
difficulty sleeping
bulging eyeballs/unblinking stare
swelling (goiter)
menstrual irregularities (light period)
frequent bowel movements
warm, moist palms
excessive vomiting in pregnancy
hoarseness or deepening of voice
persistent sore or dry throat
difficulty swallowing
rapid or irregular heartbeat
infertility
weight loss
heat intolerance
increased sweating |
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Definition
hyperthyroidism is caused by excess of free circulating T3, T4, or both
2 common types:
diffuse toxic goiter (grave's disease or exophthalamic goiter) - organ specific autoimmune disease caused by TSH immunoglobulins directed at the TSH receptor, may have protrusion of the eyeballs
what are signs of hyperthyroidism?
toxic nodular goiter |
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Term
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Definition
uncommon but life threatening complication of thyrotoxicosis precipitated by other medical problems
precipitating factors: stress, infection, trauma, surgery, thyroidal surgery, labor, heart disease
clinical features: fever, tachycardia, nausea, vomiting, agitation, confusion
treatment: beta-blockers, IV fluids |
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Term
perchlorate was discontinued, but is 10x more active than thiocyanate
ionic inhibitors that interfere with the concentration of iodide in the thyroid gland by inhibiting the Na/I transporter |
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Definition
| MOA of thiocyanate and perchlorate |
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Term
thioureylenes
antithyroid drugs that act as a substrate for thyroid peroxidase which inhibits the incorporation of iodine into thyroglobulin
propylthiouracil also inhibits deiodination of T4 which inhibits formation of T3
only when preformed hormone is depleted do clinical effects become noticeable (takes 3-6 weeks)
carbimazole is metabolized to methimazole |
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Definition
| MOA of propylthiouracil, methimazole, and carbimazole |
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Term
oldest remedy for hyperthyroidism
influences almost all aspects of iodine metabolism by thyroid gland
high plasma levels of I inhibit the release of thyroid hormone
advantage of being rapid and efficacious in severe hyperthyroidism
does not control manifestations of hyperthyroidism (tachycardia)
after a period of time, iodine's beneficial actions decrease |
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Definition
| MOA of iodide used to treat hyperthyroidism |
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Term
effects depend upon size of thyroid, iodine uptake of the gland, rate of release of radioactive iodine from gland subsequent from deposition in the colloid
given orally
advantages: fairly specific, no death as a result of using the isotope, no tissue other than the thyroid is exposed to sufficient ionizing radiation to be detectably altered
disadvantages: delayed hypothyroidism may be overlooked for a period of time, takes a long time before hyperthyroidism is controlled (if multiple doses are needed, may take many months or years for patient to feel better)
contraindications: pregnancy - may affect fetus's thyroid if given after 1st trimester, may preclude fetus towards neoplasms
concerns: colon cancer - increased incidence of colon cancer, recommended to give laxatives |
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Definition
| MOA of radioactive iodine |
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