Exam 1 Med Chem Flashcards
1
Q
Steroids are a broad group of lipids known as
A
isoprenoids or terpenes
2
Q
Cholesterol is derived from
A
Acetate as well as dietary sources
3
Q
Where are steroids produced?
A
Adrenal cortex, testes, ovaries, and some peripheral tissues (adipose tissue, the brain)
4
Q
Steroid hormones only differ in
A
the ring structure and side changes attached. They are all derived from cholesterol.
5
Q
Common sites where modifications occur to change the specificity of hormones in vivo
A
19, 11, 18, 16, 17. 5
6
Q
What switch is important for producing estrogens?
A
The switch from hydroxyl to ketone at the C3 position
7
Q
Stereochemistry of steroids
A
Beta- upward
Downward- alpha
8
Q
C-17 R group on sterol
A
Aliphatic side chain. Usually contain one or more hydroxyl group
9
Q
C-17 R group of sex hormones
A
Ketone or hydroxyl group. Usually have 2 carbon side chain.
10
Q
C-17 R group of cardiac glycoside
A
Lactone ring, usually with O-liked sugars
11
Q
C-17 R groups for bile acids
A
5-carbon side chain ending in carboxylic acid moiety
12
Q
C-17 R group for sapogenins
A
Oxacylic (ethereal) ring system.
one or more oxygens in the ring
13
Q
Glucocorticoids trivial name and site of modification
A
Cortisol (hydrocortisone), corticosterone
C-21 steroids, pregnane-derivative
14
Q
Mineralocorticoids trivial name and site of modification
A
Trivial name- aldosterone
C-21 steroids, pregnane- derivatives
15
Q
Androgenic steroids trivial name and site of modification
A
Trivial name- 11-Deoxycorticosterone, dehydroepiandrosterone, testosterone
C-19 steroids, androstane-derivatives
16
Q
Estrogenic steroids trivial name and site of modification
A
Estradiol
C-18 steroids, estrane derivative
17
Q
Pregestens trivial name and site of modification
A
Pregnenolone, progesterone
C-21 steroids, pregnane-derivative
18
Q
C-21 steroids, pregnane derivatives
A
Glucocorticoids, mineralocorticoids, progestens
19
Q
C-19 steroids, androstane derivatives
A
Androgenic steroids
20
Q
C-18 steroids, estrange derivatives
A
Estrogenic steroids
21
Q
What group is required for mineralocorticoid activity and potent glucocorticoid activity?
A
Hydroxyl group
22
Q
Sex steroid function is conferred by deletion of
A
C20, C21, and introduction of oxygen functional group at C17
23
Q
Adrenal blood flow
A
Due to the blood flow in the adrenal gland, the cortisol produced in the adrenal cortex will be at its highest concentration in the medullary region.
24
Q
Cortisol impacts
A
catecholamine release
25
Zona glomerulosa in the adrenal gland produces predominantly
Aldosterone
26
Zona fasciculata in the adrenal gland produces
Predominantly cortisol
27
Zona reticularis in the adrenal gland produces
androgens
28
In the medulla, cells are of neuronal origin and make primarily
catecholamines
29
What inactivates glucocorticoids and mineralocorticoids?
11-keto group (conversion by type II 11bHSD) inactivates glucocorticoids and mineralocorticoids
30
Why is aldosterone not inactivated by the 11-keto group conversion by type II 11bHSD?
Aldosterone is protected against 11bHSD action by the 18 aldehyde group
31
Sex steroid function is conferred by
Deletion of C20, C21
| Introduction of oxygen function group at C17
32
What is produces very early in steroidogenesis?
Progesterone
33
A deficit in an enzyme in steroidogenesis means
that you cant get to the end product and precursors build and diffuse into the neighboring cells. The neighboring cells can then turn them into other hormones which leads to the pathologies and phenotypes related to defects and inhibition of steroidogenic enzymes.
34
Regulators of aldosterone
Extracellular K and Angiotensin II
35
21-Hydroxylase (CYP21A2) relevance
Accounts for 95% of genetic abnormalities in adrenal steroid synthesis.
Converts progesterone to 11-deoxycorticosterone
and
17a-hydroxyprogesterone to 11-deoxycortisol
36
21-Hydroxylase consequences of deficiency
Decreased cortisol and aldosterone. Loss of sodium because of mineralocorticoid deficiency. Virilization because of excess androgen production.
37
11b-Hydroxylase (CYP11B1) relevance
Second most frequent abnormalities in adrenal steroid hormone synthesis
Converts 11-deoxycorticosterone to corticosterone
and
11-deoxycortisol to cortisol
38
11B-Hydroxylase consequences of deficiency
Excess 11-deoxycortisol and 11-deoxycorticosterone. Excess mineralocorticoid activity. Salt and water retention.
Because these are the 2 precursors will activate mineralocorticoid receptor and increase activity, not aldosterone itself
39
11B-Hydroxysteroid dehydrogenase type II relevance
```
Inhibited by glycyrrhetinic acid, a compound in authentic licorice
Converts cortisol (active) into cortisone (inactive) that has less affinity for the mineralocorticoid receptor.
```
40
11B-Hydroxysteroid dehydrogenase type II consequences of deficiency
Decrease in glucocorticoid inactivation in mineralocorticoid-sensitive cells, leading to excess mineralocorticoid activity.
41
Progesterone is a precursor for
androgens and estrogens
42
Androstenediol and testosterone are percursors for
estrogens, you have to make testosterone to make estrogen
43
5a reductase activates what?
Testosterone into its more active form dihydrotestosterone. It is often expressed in target tissues.
44
How many steps is progesterone from cholesterol?
2
45
What is the principle corticosteroid in rats?
corticosterone
46
11-B-OHSD inhibitors
```
Glycerrhetinic acid (licorice)
Bioflavonoids: quercetin, morin, naringenin, gossypol= Cotton seen oil
```
47
What do 11-B-OHSD inhibitors lead to?
pseudo hyperaldosteronism OR syndrome of apparent mineralocorticoid excess (AME)- the patient will present as if they have high levels of aldosterone, but upon measurement they will have very low levels. This is diagnostic of 11BHSD type II deficiency
48
How does the 18-aldehyde of aldosterone protect it from 11BHSD type II?
It prevents it from acting on the 11-OH by forming a hemiacetal to protect it.
49
11-B-OHSD inhibitors lead to
decreased amounts of inactivation of glucocorticoids in the principal cells. This leads to upregulated ENAC. increased salt and water retention, and HTN
50
What does the F on fludrocortisone do?
Increases its water solubility
51
Properties of fludrocortisone
Has a much higher GR activity so cannot be used orally to correct glucocorticoid activity if they have a normal MR aldosterone level as this would lead to HTN. Topical only when aldosterone levels are normal.
Fludrocortisone is better as an aldosterone rerplacement
52
Prednisolone properties
Increased GR activity
No change in MR activity
More effective as a glucocorticoid replacement when aldosterone levels are normal
53
Dexamethasone properties
Active and stable GR activity
Reduced mineralocorticoid effects
Even better as a glucocorticoid replacement therapeutically than prednisone
54
Why do we need to have 11-BHSD type II in cells that are responsive to changes in aldosterone?
Glucocorticoids can bind to the MR receptor
Glucocorticoids also circulate more than mineralocorticoids, so if we did not activate glucocorticoids, the cells wouldn't be able to detect small changes in mineralocorticoid concentration. 11-BHSD type II is critical to having appropriate response to aldosterone.
55
Forms of estrogen
Estrone, Estradiol, Estriol
56
Estrone (E1)
Storage form of E2. The difference between E1 and E2 is an oxidation-reduction reaction.
57
Estradiol (E2)
Most active form of estrogen
58
Estriol (E3)
Weak activity, acts as an antagonist.
Only really need to consider estriol during pregnancy because the 16-hydroxylase enzyme is in the fetal liver only. Estriol levels go up around 12 weeks of gestation and continue to increase throughout pregnancy and diffuse back into the maternal circulation to protect the mother against the high levels of estradiol during pregnancy.
59
Difference between testosterone and estradiol
Aromatase aromatizes the ring of estradiol creating a hydroxyl group and getting rid of 19 carbon
60
Equine estrogens
Horses (pregnant mares) excrete a variety of equine estrogens, including equilenin and equilin. These equine estrogens are not synthesized in humans but readily bind to human estrogen receptors. Equine estrogens have an aromatic A ring and therefore lack a 19 methyl group. These substances are excreted in large quantities in equine urine.
61
Antiestrogens
SERMS (selective estrogen receptor modulator)
Aminoether derivatives of stillbene (NOT based on cholesterol)
Block TAF1 transcription factor preventing transcription activation.
Clomiphene- fertility
Tamoxifen0 antitumor
62
Synthetic estrogens
Ethinyl estradiol and mestranol are both used as oral contraceptives and have increased oral efficacy
63
Progestogens
Synthetic progesterone derivatives
Oral contraceptives- desogestrel, norethindrone, norgestrel, ethynodiol
Levonorgestrel (Plan B)- has a 17 alkyl group that slows metabolism and increases T1/2.
Progestogens have modifications to increase T1/2 and abs over progesterone
64
Estrogen and progesterone as pharma target
Estradiol ACTIVATES the ER
| Tamoxifen BLOCKS inactivation of ER
65
Phytoestrogens
Estrogen from plants
Isoflavones with antifertility activity
Coumestrol (some legumes), genistein (soy), daidzen (soy)
Eating a lot of soy can produce diminished reproductive ability because these phytoestrogens have estrogenic activity and slow fertility.
66
Steroid hormone elimination
inactivation of steroids involves reductions and conjugation to glucuronides or sulfate to increase their water solubility.
Most are metabolized by the liver and kidneys. 70% of the conjugated steroids are excreted in the urine, 20% leave through the feces, and the rest through the skin
steroids, being cholesterol based, will also recycle through the liver-bile-intestinal pathway
67
Hormones of the pituitary organ
Anterior- GH, somatotropin, TSH, ACTH, FSH, LH, prolactin, adorphin
Posterior- oxytocin, ADH
68
Hormones from the thyroid
Thyroxin (T4)
Triiodothyronine (T3)
Calcitonin
69
Hormones of the pancreas
insulin, glucagon, somatostatin, pancreatic peptide
70
Hormones of the ovaries
estrogen, progesterone, inhibin, relaxin
71
Hormones of the testes
testosterone, inhibin, mullerian regression factor
72
Hormones of the parathyroid
PTH
73
Hormones of the adrenal gland`
Cortex: cortisol, aldosterone, androgens
| Medulla- epinephrine, norepinephrine`
74
Hypothalamic nuclei
2 types of hypothalamic neurons
- Green (neurohypophysis pathway)
- Purple- (adenohypophysis pathway)
75
Magnocellular neurons
Large cell bodies capable of producing a lot of hormones or neurotransmitters, which is why when its release that the amount is enough ti change the circulating amount of hormone.
76
An important aspect of the hypothalamic and pituitary axis is that the infundibulum or pituitary stalk can be damaged or severed. What occurs when this happens?
Severed- the patient would lose both the regulation of anterior and posterior pituitary hormones. However, over time, via angiogenesis and revascularization, the vascular network can regenerate, thus restoring the ANTERIOR pituitary hormone regulation to some degree but since the posterior pituitary system involves these neuronal axons, if those axons are severed, they don't repair so readily so the patient may never have restoration in terms of the POSTERIOR pituitary hormones
77
Posterior pituitary hormone nuclei
Axons go down through the pituitary stalk or infindibulum into the posterior pituitary. Posterior pituitary hormones are produced in the hypothalamic cell bodies and go by axonal trafficking down to the terminus. When these neurons are stimulated they stimulate the release of the hormone into circulation.
Neuropophysis
78
Anterior pituitary hormone nuclei
Parocellular neurons terminate at the bottom of the hypothalamic region or the median eminence. They're releasing hormone into the portal circulation (hypothalamo-hypophyseal portal vessels). These hormones travel directly to the anterior pituitary where they work on cells within the anterior pituitary to secrete a 2nd level of hormone which goes into circulation.
79
Posterior lobe of the hypothalamic-pituitary pathway produces which hormones?
ADH/vasopressin and oxytocin
| Different hypothalamic nuclei produce the 2 different hormones
80
Pars intermedia
Area between the anterior and posterior pituitary.
| Makes melanocyte-stimulating hormone and regulates melanin
81
Oxytocin goes into
Uterine muscles, mammary glands
82
ADH goes into
Kidney tubules
83
Whatdoes gonadotropin-releasing hormone at the hypothalamic nuceli trigger the release of?
FSH and LH at the anterior pituitary
84
What do FSH and LH do?
Germ cell development
Female- ovum
Male- sperm
Secrete hormones
Female- estradiol, progesterone
Male- testosterone
85
What stimulates the release of growth hormone?
GHRH (growth hormone releasing hormone)
86
What inhibits the release of growth hormone?
Somatostatin
87
What does growth hormone do?
Secretes insulin-like growth factor 1 (IGF-1) which is critical
Protein synthesis, carbohydrate and lipid metabolism
88
TSH is triggered by
Thyrotropin releasing hormone (TRH)
89
What does TSH do?
Secretes thyroxine, triiodothyronine in the thyroid
90
Prolactin is inhibited by
Dopamine
91
What does prolactin do?
Breast development and milk production (in male may facilitate reproductive function)
92
ACTH is triggered by
CRH (corticotropin releasing hormone)
93
What does ACTH do?
In the adrenal cortex it secretes cortisol.
| Activates the 1st step in conversion in steroidogenesis which eventually leads to cortisol.
94
What is growth hormone stimulated by?
GH-releasing hormone, ADH, GABA, Ghrelin, NE, DA, serotonin, estrogen, sleep, stress, exercise
Decreased glucose concentration
Fasting/starvation
Hormones of puberty (estrogen, testosterone)
alpha-adrenergic agonists (clonidine)
Beta-adrenergic antagonists (propranolol)
DA agonists (bromocriptine)
GABA agonists (muscimol)
95
What is prolactin inhibited by?
DA
GABA
DA agonists (bromocriptine, pergolide, cabergoline)
96
What is growth hormone inhibited by?
Somatostatin, elevated IGF-1, growth hormone, progesterone, glucocorticoids, postprandial hyperglycemia, elevated free fatty acids
DA antagonists (phenothiazines)
alpha adrenergic antagonists (phentolamine)
beta-adrenergic agonists (isoproterenol)
Serontonin antagonists (methysergide)
Pregnancy
96
What is ACTH stimulated by?
CRH
97
What is the physiologic effect of growth hormone?
Stimulate IGF-1 prodcution and IGF-1 and GH promote growth in all body tissues
98
Prolactin is stimulated by
TRH, VIP, estrogen, serotonin, histamin, endogenous opioids, pregnancy and nursing
DA antagonists (phenothiazines, haloperidol, methyldopa)
Opiates
Estrogens
H2RAs
MAOi
100
What is ACTH inhibited by?
Elevated cortisol
101
What are the physiologic effects of ACTH?
Glucocorticoid effects
| Pigmentation
102
What is ADH stimulated by?
Hyperosmolality and volume depletion
103
What is ADH inhibited by
hypervolemia, hypoosmolality
104
What is the physiologic effect of ADH
Acts on renal collecting ducts to prevent diuresis
105
What are the 3 effects of the nursing reflex?
1. ) Nursing stimulates mechanoreceptors in the nipples leading to inhibition of DA release and increased prolactin levels. Prolactin release stimulates milk production.
2. ) Neuronal pathway terminates on hypothalamic nuclei that are producing oxytocin which stimulates those neurons to release oxytocin which helps in terms of milk expression by leading to contraction of the myomammary epithelial
3. ) Suckling causes a decrease in gonadotropin releasing hormone which causes a delay in going back to regular menstrual cycle while nursing which lengthens the time before a female returns to normal reproductive cycle.
106
What happens in the nursing reflex?
1. ) Stimulus from suckling travels from breast to the hypothalamus
2. ) DA release is inhibited.
3. ) Oxytocin release is stimualted.
4. ) GnRH production is decreased which inhibits the ovarian cycle.
107
What does oxytocin do?
Released via posterior pituitary and goes into circulation where it acts to increase intracellular Ca and increase smooth muscle contraction.
Oxytocin enhances the expression of milk to help in feeding the neonate.
108
What are the effects of prolactin?
| Lactation
Increases milk yield
Promotes gene expression of milk proteins
Stimulates biosynthesis of lactose
Induces lipoprotein lipase in the breast
Stimulates reabsorption of Na from milk
109
What is the effect of prolactin? Reproduction
Hyperprolactinemia inhibits gonadotropin secretion
In nonlactating individuals, hyperprolactinemia induces galactorrhea, amenorrhea, and impotence
During lactation, inhibits follicular growth and aromatase levels (keep estrogen levels low)
110
What is the effect of prolactin? Water and electrolyte homeostasis
Milk production is regulated by loss of fluid and electrolytes.
Stimulates intestinal absorption of sodium
Stimulates renal 25 (OH) vitamin D which is the rate limiting step in forming vit D3
Increases intestinal Ca and phosphate abs
111
Growth hormone secretion
GHRH is released from hypothalamic nuclei and will bind to somatotrophs in the anterior pituitary via GHRH receptor which is Gas-coupled causing increased CAMP, activation of protein kinase A which affects plasma membrane Ca channels, and increased Ca, and vesicular fusion and release of growth hormones.
112
Why is growth hormone secretion inhibited during pregnancy?
You want mobilized nutrients from the mother to be going to grow the fetus, not growing the mother
113
Somatomedins (IGF) effect on GH
Inhibits in the anterior pituitary
| Stimulates in the hypothalamus
114
Growth hormone release
Short-loop feedback
| Amplitude of release is significantly higher at night because mobilized energy can be used for growth during sleep.
115
Growth hormone/ IGF-1 actions
In the adipose tissue:
- Decreased glucose uptake
- Increase lipolysis
Chondrocytes
- Increased AA uptake
- Increased protein synthesis
- Increased DNA and RNA synthesis
- Increased chondroitin sulfate
- Increased collagen
- Increased cell size and number
Muscle
- Increased glucose and AA uptake
- Increased protein synthesis
116
GH at high levels can activate
PRL receptors
| But, PRL does not activate GH receptor
117
Bell-shaped response curve of GH
In case of saturation due to excess GH, the receptors cannot dimerize and can't have an active receptor.
Must maintain optimal GH level
118
Actions of glucocorticoids
```
Increase gluconeogenesis
Increase proteolysis
Increased lipolysis
Decrease glucose utilziation
decrease insulin sensitivity
Inhibit inflammatory response
Suppress immune response
```
119
Actions of mienralocorticoids
Increase Na reabsorption
increase K secretion
Increase H secretion
120
Inhibitory factors of cortisol release
Opioids
| Somatostatin
121
Stimulatory factors of cortisol release
```
Sleep-wake transition
Stress
Hypoglycemia
ADH
alpha adrenergic agonists
Beta adrenergic antagonists
Serotonin
```
122
Diurnal secretion of cortisol
Highest during the day
123
CRH and ACTH signaling
CRH acts on its receptor at the level of corticotrophes in the anterior pituitary. Gas-linked producing a release of ACTH which goes into circulation. ACTH also via Gas-coupled receptor then activates cholesterol demolase starting the process of steroidogenesis within the adrenal cortex.
124
Regulation of CRH-ACTH- adrenocortical axis
IL-1B has a positive effect on teh release of cortisol. Cortisol is going to have a neg feedback on the monocytes and neutrophils. So in this way, there is a negative feedback loop on cortisol via the immune system. It is this reason that after trauma surgery glucocorticoids are oten administered as a means to diminish the immune response to avoid multi-organ failure or transplant rejection. Unfortunately, the high levels overwhelm 11BHSD in the kidney and leads to salt and water retention (edema/puffiness)
125
Actions of glucocorticoids: metabolism
Degrade muscle protein and increase nitrogen excretion
Increase gluconeogenesis and plasma glucose
Increase hepatic glycogen synthesis
Decrease glucose utilization (anti-insulin)
Redistribute fat
126
Actions of glucocorticoids: hemodynamic
Maintain vascular integrity
Maintain fluid volume
Maintain responsiveness to catecholamine pressor effects
127
Actions of glucocorticoids: immune function
Increase anti-inflammatory cytokine production
Impairs cell-related immunity
Increases neutrophil, platelet, RBC counts
Inhibits bradykinin and serotonin inflammatory effects
128
Why do people gain obesity in cushings syndrome?
Cortisol inhibits glucose uptake in adipose tissues and muscle cells. Cortisol will increase gluconeogenesis in the liver which will increase hepatocyte release of glucose that will result in a hyperglycemic effect. This leads to hyperinsulinemia that stimualtes lipogenesis in adipose tissues and inhibits lipolysis in adipose tissue. In this case, the addition of body fat is due to the hyperinsulinemia that is a secondary consequence of hypercortisolemia
129
Cortisol inhibits
ACTH secretion
130
ACTH stimulates
Steroidogenesis and has trophic effects on the adrenal cortex
131
Prolonged ACTH exposures causes
adrenal cortex hyperplasia, if genetic congenital adrenal hyperplasia (CAH)
132
Congenital adrenal hyperplasia (CAH)
Overproduction of androgens
Lack of sex hormones
Intersex development
Mineralocorticoid excess (HTN/hypokalemic alkalosis) if you can make aldosterone.
Mineralocorticoid deficits (salt wasting) if you cant make aldosterone
Adrenal insufficiency
133
The total absence of aldosterone is
lethal
134
A deficit in __________means we cant get aldosterone or cortisol
21-beta-hydroxylase
135
What is the rate limiting step of the renin-angiotensin-aldosterone system?
Renin release at the level of the kidney
136
Angiotensin II is necessary to activate
Aldosterone synthase which gives us aldosterone
137
ACEi can be used to knock down aldosterone production by
Decreasing angiotensin II
