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endocrine and reproductive systems > Ph- Endocrine Drugs > Flashcards

Ph- Endocrine Drugs Flashcards

1
Q

What is endocrinology?

A

The branch of medicine that studies the action of hormones and the organs in which hormones form and act.

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2
Q

What is a hormone?

A

A product of living cells that circulates in body fluid to act on cells remote from the point of origin.

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3
Q

What is the difference between endocrine, paracrine and autocrine? Give an ex. of each.

A

Endocrine- acts on cells remote from the point of origin [GH, estrogen, insulin]

Paracrine- acts on cells of a DIFFERENT cell type, but that are in close proximity [testosterone from Leydig acts on adjacent Sertoli cells, insulin and glucagon on endocrine pancreas]

Autocrine - acts on cells of the same cell type [tumors producing VEGF to support growth]

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4
Q

What determines specificity for endocrine signaling?

A
  1. Target tissue specificity is determined by the type and number of receptors
  2. hormone receptor specificity is the ability of a hormone to interact with its cognate receptor but NOT with other receptors
    [specific vs. promiscous]
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5
Q

What is meant by a promiscuous hormone?

A

It can cause a phenomenon called “spillover”. It is a hormone that if at high enough concentrations it can act on receptors it is not specific for.

Ex. LH and hCG both act on LH receptor

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6
Q

What are the 2 classes of endocrine hormones?

A
  1. peptide - derived from protein [hypothalamic releasing factors, pituitary hormones, catecholamines]
  2. Steroid -derived from cholesterol [steriods, thyroxine, retinoids, vit D]
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7
Q

How do peptide hormones and steroid hormones differ in terms of synthesis and secretion?
What is the sole exception to the rule?

A

Peptide hormones are made of prohormones and stored in intracellular vesicles. Secretion is regulated by specific stimuli.

Steroid hormones are synthesized on the spot and released immediately. [exception is thyroid hormone which is stored in the lumen of gland]

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8
Q

How do peptide hormones and steroid hormones differ in terms of circulation?

A

Peptide- circulate free [except somatomedins like IGF-1].

Steroid- circulate bound to serum proteins

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9
Q

How do peptide hormones and steroid hormones differ in terms of :

  1. onset of action
  2. duration of action
  3. degradation
  4. activity
A

Peptides have:

  1. short onset of action
  2. short duration
  3. rapid degradation
  4. activity directly proportional to circulating conc.

Steroids have:

  1. slower onset of action
  2. longer acting
  3. more slowly degraded
  4. activity correlates with FREE concentration
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10
Q

How do peptide hormones signal in cells? How does this differ from steroids?

A

Peptides- plasma membrane receptors [tyr kin, 7TMGPCR, adenyl cylcase, kinase cascades]

Steroids - intracellular receptors [ cytoplasmic and nuclear]

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11
Q

How are peptide hormones and steroid hormones degraded and excreted?

A

Peptides= degraded in the KIDNEY [liver/lungs]

Steroids = degraded in the LIVER [p450 cytochromes]

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12
Q

What are the 3 main sites of action for drugs for peptides and catecholamines?

A
  1. stim or inhibit synthesis/secretion of peptide hormone
  2. bind directly to receptor and activate/repress function
  3. inhibit downstream second messenger signaling
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13
Q

What are the 2 main targets for drugs for steroid hormones?

A
  1. stimulate or inhibit synthesis/release of steroid

2. bind directly to nuclear receptor and activate or repress function

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14
Q

Feedback mechanisms regulate biosynthesis and/or secretion of endocrine hormones. What is an example of a “simple” feedback loop?

A
  1. Glucose stimulates the release of insulin.
  2. Insulin stimulates glucose uptake into skeletal muscle
  3. Serum glucose is reduced and no longer stimulates insulin
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15
Q

What stimulates the synthesis and secretion of anterior pituitary hormones?

A

Hypothalamic releasing hormones are synthesized by hypothalamic neurons, transported to median eminence and are secreted into HP portal circulation to reach the anterior pituitary

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16
Q

Hypothalamic release of hormones to act on the pituitary are ________. The frequency can be from __________ to ______________.

A

pulsatile and can be from minutes to hours

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17
Q

What is the direct effect of the pituitary hormone?

A

Pituitary hormone (signaling hormone) goes to the periphery to bind to membrane-bound receptors specific for it at either:

  1. primary endocrine organ (thyroid, adrenals, gonad) and stimulates the synthesis and release of a secondary (effector) hormone
  2. direct biological effect that does not require effector hormone (GH-certain functions)
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18
Q

What is the indirect effect of pituitary hormone?

A

Indirect effect is mediated by secondary hormone on target tissue.

  1. peptide –> membrane bound receptors
  2. steroids –> cytoplasmic or nuclear receptors
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19
Q

What are the 2 ways a secondary (effector) hormone can cause feedback regulation?

A
  1. at the hypothalamus affecting the releasing hormone

2. at the pituitiary affecting the anterior pituitiary hormone

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20
Q

In most cases, feedback on the HP axis is _____________. What is the notable exception?

A

In most cases, feedback is inhibitory.

The exception is Estogen’s effect on GnRH and LH/FSH. It can be inhibitory AND secretory

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21
Q

How do the anterior and posterior pituitary differ in terms of hormone secretion and release?

A

Posterior pituitary stores and secretes hormones that were synthesized in the hypothalamus.

Anterior pituitary synthesizes and secretes its own hormones.

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22
Q

What are the 2 somatotropic hormones?
What cell type is associated with each?
What are the receptors for these hormones?

A
  1. growth hormone (GH) from somatotrophs
  2. prolactin (PRL) from lactotrophs

Both synthesized in cells with common precursors in the ant. pituitary and have spillover effect.
Receptor for these is Tyr Kin.

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23
Q

What are the 3 glycoprotein hormones made in the anterior pituitary?
What is the structure of this family?
What are the receptors?
What other hormone is in this family, but synthesized elsewhere?

A
  1. Leutenizing hormone (LH) - gonadotrope
  2. Follicle-stimulating hormone (FSH)-gonadotrope
  3. Thryoid stimulating hormone (TSH) - thyrotrope

Structure: a-b heterodimers [specificity in b]

Receptor: GCPR

hCG is in this family but is synthesized in the placenta

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24
Q

What is the major proopiomelanocortin (POMC) derive hormone in the ant. pituitiary?
What cell type does it come from?

A

ACTH from the corticotrope cells

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25
Q

Why does surgical removal of the pituitiary (hypophysectomy) usually result in death?

A

Usually due to deficiency of cortisol

  • the lack of ant. pituitary hormones leads to atrophy of the primary target gland [adrenal, gonad]
  • many functions can be rescued by giving back secondary hormones (glucocorticoids, thyroid hormone, sex steroids etc)
26
Q

What are the 3 main categories of disease of the HP axis?

Which 2 are usually lumped together and why?

A
  1. Primary disease- failure of the target endocrine gland [ex. failure of thyroid to make T3/T4]
  2. Secondary disease - failure of the pituitary gland [ex. lack of TSH from pituitary]
  3. Tertiary disease - failure of the hypothalamus [ex. failure to secrete TRH]

Secondary and tertiary are looped together because they have the same lab evaluation and treatments.

27
Q

What lab value is used to differentiate between primary and central disease? Use hypothyroidism as an example.

A

In primary, TSH will be high because there is no problem with the hypothalamus or pituitary.

1 = high TSH, low T3/T4
2/3 = low TSH, low T3/T4
28
Q

What are the 6 steps where defects can occur in endocrine system proper functioning?

A
  1. hormone biosynthesis [synth, secretion, storage]
  2. transport to site of action
  3. Receptor at target cell
  4. Initiation of biological response
  5. termination/antagonism of response
  6. degradation/elimination of hormone
29
Q

What are the 5 scenarios that can cause lack of hormone secretion/synthesis?

A
  1. Incomplete biosynthesis
  2. reduced signal for biosynthesis
  3. Hyperplasia/neoplasia of synthetic gland
  4. Loss of gland that secretes hormone
  5. iatrogenic suppression/loss of gland
30
Q

What is an example of incomplete biosynthesis that leads to lack of hormone?

A

Salt-losing CAH caused by homozygous mutation in 21 hydroxylase [CYP21].

Adrenal is intact, but cannot make cortisol, aldosterone. Secretes excess 17OH progesterone.

31
Q

What is an example of reduced signaling for biosynthesis of hormones that leads to lack of that hormone?

A
  1. Reduced or absent releasing hormone for example:
    hypogonadotrophic hypogonadism = no sex steroids because of lack of GnRH
  2. reduced signal due to lack of receptor
32
Q

How can hyperplasia or neoplasia lead to lack of a hormone?

A

Mass effect from an adenoma can compress normal pituitary and suppress the synthesis/release of other pituitary hormones.

33
Q

There are 3 common examples about how loss of glands can lead to lack of hormone. What are they?

A
  1. T1D = autoimmune destruction of B-islet cells
  2. Hashimotos = autoimmune destruction of thyroid gland
  3. Classic Addison’s disease = TB destruction of adrenal gland
34
Q

What are the 2 major causes of iatrogenic suppression leading to lack of hormone?

A
  1. PTH deficiency following thyroid surgery due to loss of parathyroid gland with the thyroid
  2. adrenal insufficiency due to large doses of corticosteroids
35
Q

What are the 4 scenarios where the hormone is present, but it is not working?

A
  1. altered form of the hormone
  2. altered receptors
  3. post-receptor activity is altered
  4. inappropriate secretion/release
36
Q

What are 2 examples of altered hormones leading to improper function?

A
  1. rare form of diabetes where insulin is made but is inactive
  2. dwarfism- GH is made in abnormally large form and is not as active as normally process GH
37
Q

What are 2 examples of altered receptors leading to improper hormone function?

A
  1. Adrogen insensitivity - male pseudohermaphrodites result from androgen insensitivity
  2. Laron’s dwarfism = deletions in GH receptor leads to high GH and low IGF-1
38
Q

What are 3 scenarios where the hormone receptors are fine, but the downstream signaling is messed up?

A
  1. PTH Resistance = pseudohypoparathyroidism due to Gs mutation [no increase in cAMP when PTH binds]
  2. Insulin resistance = type 2 have post-receptor insulin resistance
  3. GH resistance = appear like Laron’s but with normal GH receptors. STAT5b is the mutation in the tyr kinase. High GH, low IGF-1
39
Q

Inappropriate secretion/release of hormone can be excess hormone or insufficient hormone. Give an example of each.

A

Excess - Cushing disease = excess release of ACTH stimulates production of excess glucocorticoids in adrenal gland

Insufficiency = monogenic diabetes [MODY]

40
Q

The function of hormones can be altered secondary to disease, treatment, drugs. What 3 situations are examples of this?

A
  1. Trauma/stress- release catecholamines, glucocorticoids and cytokines that lead to insulin resistance
  2. Altered kidney or liver functions can alter pharmacokinetics of hormones
  3. Drug interactions can change hormone systems
    - increase or decrease synthesis [lithium decreases thyroid synthesis]
    - bind to serum protein and displace hormone making more “free” and increasing hormone activity [ex. aspirin displaces thyroid hormone]
    - increased serum binding protein decreases hormone action [pregnancy increases thyroid binding globulin]
41
Q

What is the most common way to generate hormone excess?

A

Loss of feedback control

42
Q

Describe what occurs in Grave’s disease.

A

Antibodies hyperstimulate TSH receptor in the thyroid leading to excess production of T3 and T4.

T3 and T4 cannot do feedback control because even if they stop making TSH, the antibodies of Graves will still stimulate the receptors.

43
Q

Why are FSH and LH increased post-menopausally?

A

Estrogen usually is feedback inhibition for these, but after menopause estrogen depletes.
This leads to lack of feedback inhibition

44
Q

What are the 2 ways to treat decreased hormone action [deficiency/resistance] and hormone function altered by disease?

A
  1. HRT - DM1 and 2 [insulin], adrenal insufficiency [glucocorticoids], hypothryroidism [thyroxine], diabetes insipitus [DDAVP]
  2. Direct stimulation of natural secretion - ex. DM2 you can use drugs to stimulate B cells to stimulate insulin secretion
  3. Indirect stimulation of natural secretion - ex. clomiphene is an estrogen receptor antagonist so it removes neg feedback and increases FSH, LH [ used in fertility]
45
Q

What are 3 possible treatments for too much hormone activity?

A
  1. inhibit biosynthesis/secretion [ex. dopamine agonist to stop prolactin release, PTU inhibits thyroid hormone synthesis in hyperthyroidism]
  2. interfere will/oppose actions of hormones [competitive inhibitors]
  3. take out gland [surgical or radiation]
46
Q

Tissue containing the ___________ receptors are the most sensitive at low hormone concentrations.

A

The most receptors

ex. high concentrations, insulin will affect MANY tissue, but at low concentrations it will affect fat, liver, muscle because they have the highest number of insulin receptors

47
Q

What is the law of mass action?

A

The concentration of hormone and the concentration of receptor determine the concentration of HR complex.
The concentration of complex is proportional to the size of the biological response.

48
Q

What is hormone spillover?

What determines the specificity of the response?

A

The affinity of a hormone for one or more receptors determines the specificity of the response.

Promiscuous hormone families have similar structures to each other and can stimulate other receptors besides their own.

Ex. receptors that regulate GCPR are often related and overlap binding specificity.

If H1 is at high concentrations it can act on R2 and produce an H2 response.

49
Q

What are the 3 common families of hormones that can have spillover?

A
  1. steroids
  2. TSH, FSH, LH hCG all have the same a unit
  3. IGF-1 and insulin
50
Q

What is cross-coupling?

A

When hormones influence/regulate the appearance of receptors for other hormones.

ex. estrogen increase receptors for oxytocin on uterine muscles during 3rd trimester of pregnancy because oxytocin causes contractions

51
Q

What is stimulus-response coupling? What are 2 examples?

A

It means that the ability of a target cell to respond to a hormone depends on the presence of an intact response pathway.

  1. ACTH cannot increase steroid synthesis in tissue that doesnt have the enzymes even though they have receptors (adipocytes)
  2. Insulin governs uptake of glucose in muscles but not liver
52
Q

Why is degradation a huge factor to consider when designing a drug/hormone?

A
  1. Steroids/lipophilic drugs are converted to less active form via oxidation/conjugation. Some that are inactive in vitro, may be more active in vivo
  2. Proteolysis breaks down peptides so they cannot be taken orally
53
Q

What are the 5 components of good drug design?

A
  1. active when administered orally
  2. highly specific [minimize spillover]
  3. suitable duration of action
  4. few side effects
  5. minimal drug-drug interactions [ex. OCP with xenobiotic receptors that induce p450s and where the drug down faster]
54
Q

What are the 5 ways hormones and hormone activity are measured?

A
  1. chemical methods - gas chromo/mass spec
  2. immunological methods
  3. bioassays
  4. receptor binding assays
    5, provocative tests
55
Q

What does gas chromatrography/mass spec rely on to measure hormones?
What is it the method of choice for measuring?

A

They rely on recognition of the chemical structure.

  1. catecholamines
  2. urinary cortisol
56
Q

What do RIA and ELISA rely on for hormone recognition?
What is its most important use?
What is the drawback ?

A

It relies on the recognition of the hormone by an antibody.

It is used most frequently to measure hormone concentrations.

Drawback: it doesnt always correlate with biological activity because it looks for epitopes and can’t really tell you biological activity of the hormone, just that it is there

57
Q

What is the only lab test that gives a definitive measure of biologic function?
What is the drawback of this test?

A

Bioassay

Drawback: low availability

58
Q

How does radioreceptor assay work?
What is the drawback?
When is it mostly used?

A

It measures quantity and quality (affinity) of a hormone’s binding to the receptor.

Drawback: requires biopsy of tissue from patient

Used to measure estrogen receptors in breast cancer

59
Q

What is the purpose of provocative tests?

What are the 2 types of provocative tests ?

A

Provocative tests are used to assay the body’s ability to normally suppress or stimulate hormone synthesis/secretion

  1. Suppression test- used when you suspect over production of a hormone
  2. stimulation test- used when you suspect under production of a hormone
60
Q

How does a suppression test work?

When do you use it?

A

You use a suppression test when you suspect a hormone is being over-produced.

Administer an agent that normally suppresses the hormone that is being over-expressed. If the agent does NOT suppress secretion of the hormone, this suggests abnormal regulation

ex. dexamethasone given in suspected Cushing. If cortisol is not suppressed, it is consistent

61
Q

When is a stimulation test given? How does it work?

A

It is given if you are suspecting under-production of a hormone.

ex. ACTH stimulation test to assess adrenal insufficiency

endocrine and reproductive systems (27 decks)

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