Park lecture 4 Flashcards
Drug interactions with progestins
Other steroids
Anticonvulsants
Why are other steroids contraindicated when taking birth control?
Oral contraception will increase blood levels of other steroids
why do anticonvulsants such as phenytoin decrease effectiveness of Oral BC
phenytoin induces drug metabolizing enzymes in liver
Use of gut flora with regard to estrogen
estrogen needs to go through enterohepatic circulation and gut flora is necessary for that.
relationship between gut flora, enterohepatic circulation and estrogen activity
less gut flora= less enterohepatic circulation= estrogenic activity drops
how does tetracycline affect birth control. Why?
Tetracycline reduces efficacy of birth control. Tetracycline reduces gut flora.
Plan B is a combination between these two drugs
Ethinyl estradiol+norgestrel
progestin only plan B name
Levonorgestrel
What are the two parts of adrenal gland?
Cortex and medulla
What does medulla produce in adrenal gland
Epinephrine and norepinephrine
What does cortex produce in adrenal gland
Glucocorticoid, mineralocorticoids and androgens
What are glucocorticoids
stress hormones
What is the structural difference between aldosterone and cortisol
cortisol has 17-OH
Other name for glucocorticoid
cortisol (stress hormones)
Physiological effects of glucocorticoids
increase circulating glucose concentrations
potent anti inflammatory effects
Physiological effects of mineralcorticoids (aldosterone)
increases Na+ retention. This will lead to an increase in water volume. Leading to an uptick in BP
Difference in where epinephrine and cortisol bind
Epinephrine binds glucocorticoid receptor, epinephrine binds B adrenergic receptor
Difference in response time between epinephrine and cortisol (hydrocortisone)
Epinephrine has an immediate response whereas cortisol has a long term persistent biologic response
what stimulates the release of ACTH from the pituitary?
CRH
what stimulates cortisol release from adrenal gland?
ACTH
How is CRH inhibited
cortisol has a negative feedback loop that inhibits CRH
Why are the levels of aldosterone not affected with pituitary gland removal?
Because liver releases aldosterone precursor (angiotenstinogen)
What are the steps of aldosterone synthesis
-Angiotensinogen released from liver
-angiotensinogen is digested by renin and converted to angiotensin 1
-ACE (angiotensin converting enzyme) converts to angiotensin 2
-angiotensin 2 binds to adrenal glands
- adrenal glands release aldosterone
What enzyme converts angiotensin 1 to ang 2
ACE
how does losartan lower BP
Blocks angiotensin 2 in adrenal gland
glucocorticoids up-regulate enzymes for ___________&____________
gluconeogenesis
anti-inflammatory proteins
DNA binding domains of activated dimers bind to specific sequences called
GRE( glucocorticoid response element_
rate limiting step for gluconeogenesis in glucocorticoids in catalyzed by
PEP carboxylase
What are the cytokines the promote inflammation called
Eicosanoids
How does lipocortin II suppress eicosanoid production
It suppresses phospholipase A2, which has a critical role in eicosanoid synthesis
What is NFkB
NFkB is a promoter that induces a lot of pro-inflammatory genes in immune cells
Effects of glucocorticoids on NFkB.
Glucocorticoids bind NFkB receptors and prevent the binding of NFkB
Glucocorticoid physiological effect on liver
increase gluconeogenesis
increase glycogen storage
Physiological effect of glucocorticoid on muscle
promotes protein degradation
Why does glucocorticoid promote degradation of protein?
degrade protein to use for amino acid as an energy source
Physiological effect of glucocorticoid on protein synthesis and sensitivity to insulin
Decreases protein synthesis and decreases sensitivity to insulin
Physiological effect of glucocorticoid on adipose tissue
Promotes lipolysis and decreases sensitivity to insulin
Physiological effect of glucocorticoids on immune system
Blocks synthesis on cytokines (immunosuppresor) and inhibitor of eicosanoids (anti-inflammatory)
what is adrenal insufficiency (hypo-adrenalism)
Decrease in secretion of steroid hormone by adrenal cortex
What is (primary) addisons disease caused by
destruction of cortex by tuberculosis or atrophy.
symptoms of hypoadrenalism
low bp, hyper pigmentation, anorexia, anemia, vomiting
cessation of long term systemic glucocorticoid therapy can lead to
addisonian symotoms
Name the 3 types of adnreal insufficiency and what organ they affect.
Primary- adrenal defect
secondary- pituitary defect
tertiary- hypothalamic defect
What hormone levels are affected by primary adrenal insufficiency? why?
Both cortisol and aldosterone levels go down.
How are the CRH and ACTH levels in primary adrenal insufficiency?
Both are high
What happens to the size of the adrenal gland in primary insufficiency? why? What do we call this?
cortisol levels low so ACTH continuously stimulates the adrenal gland, causing it to get bigger, this is called congenital hyperplasia
What hormone levels are affected by secondary adrenal insufficiency? why?
pituitary can not make ACTH, Leads to low cortisol. Aldosterone is not affected.
CRH levels in secondary adrenal insufficiency?
High because of the lack of negative feedback from cortisol
Which hormones will be low in tertiary adrenal insufficiency?
All of them except aldosterone.
only defect where aldosterone is affected?
primary (adrenal)
Which hormone goes down in all of the defects
cortisol
Which defect is the only one to not cause a decrease in ACTH
Primary
Which defect is the only one to cause a decrease in CRH
Tertiary
What is the similarity between pituitary cushings disease and ectopic cushings disease
Both cause an increase in ACTH
what is the difference between pituitary cushings disease and ectopic cushings disease
both lead to increased production of ACTH, but pituitary cushings is due to pituitary carcinoma while ectopic cushings is due to non-pituitary carcinoma
symptoms of cushings disease
increased protein catabolism (easy bruising, delayed wound healing)
osteoporosis
opportunistic infections (anti-inflammatory caused by cortisol levels)
long term therapeutic use of systemic glucocorticoids can lead to
Cushings syndrome
what happens to the hormone levels in adrenal cushings
Increase in cortisol levels. This leads to a negative feedback loop and decreases ACTH and CRH
What happens to hormone levels in pituitary cushings syndrome
ACTH levels go up, leading to increase in cortisol, leading to negative feed back of CRH, decreasing it.
what happens to hormone levels in ectopic cushings disease
Ectopic ACTH is high, leadning to an increase in cortisol. This will lead to negative feedback of CRH, leadning to PITUITARY ACTH to be low
In synthetic glucocorticoid activity, addition of 9a-F to hydrocortisone will have this effect
strong miceralcorticoid and glucocorticoid activity. This will lead to intense Na+ retention. leading to edema
use of 9a- F
mineralcorticoid replacement therapy
what is the structural modification in the synthetic glucocorticoids prednisone/prednisolone?
An extra double bond between C1 and C2
How will this extra double bond between C1 and C2 affect the activity of prednisone/prednisolone
Will lead to better and tighter binding of glucocorticoid and reduced mineralcorticoid activity
methylprednisolone structural mpdification?
Addition of 6a group
What effect does addition of 6a group have on glucocorticoid activity
reduced mineralcorticoid activity
Difference and similarity between triamcinolone and fludrocortisone
Both have F but triamcinolone has a double bond between C1 and C2 and also a 16 OH to it.
Effect of 16-OH on triamcinolone
reduces mineralcorticoid activity
increases hydrophilicity
lowers oral bioavailability
dexamethasone and betamethasone structural modification from prednisone
16-a- methyl group added. (They are enantiomers of each other)
difference in structure between dexamethasone and triamcinalone
Triamcinalone has a 16-oh, whereas dexamethasone has a 16 methyl group
16-a-methyl substituent on prednisolone effect
increases lipophilicity (leads to increased receptor binding, leading to a stronger effect)
reduced mineralcorticoid activity
increases oral bioavailability
effect of long ester groups in 21 C position
It will be a pro drug that can be activated by esterases
increased lipophilicity and prolonged action
most potent synthetic glucocorticoid is
dexamethasone
glucocorticoid effect on acute bronchioconstriction, why?
No effect. Will not stop an acute asthma attack as it is happening. Takes hours/days for full effect, more long term
how are glucocorticoids more long term in terms of action in asthma
inhibit eicosanoids
decrease vascular permeability
modify cytokine and chemokine production
Inhaled glucocorticoid desired properties
high potency
minimal systemic effects
prolonged action
low oral bioavailability
short half life
how to make inhaled glucocorticoids prolonged?
lipophilicity
explain triamcinalone acetonide chemical tweaks for inhalation
Acetonide group on 16 and 17 OH leads to better bioavailability
Why does acetonide on 16 and 17 Oh groups in triamcinalone acetonide do?
Makes it resistant to hydrolysis, leading to better bioavailability
flunisolide chemical and structural properties
has acetonide covering 16 and 17 OH and has a 6-a Fluorine
Has a short half life (rapidly metabolized by liver, minimal side effects)
budensonide having butyl acetal group on 16,17 leads to
faster topical uptake and low oral bioavailability
mometasone furoate structural and chemical features
Has 21 Cl instead of 21 OH.
low oral bioavailability
rapid onset of action and highly potent
negligible systemic effect (rapid metabolism)
fluticasone propionate inactivated by
hydrolysis of thioesters
fluticasone propionate structural and chemical features
has S-F bond on 21 C
highly potent but poor solubility (forms microcrystals)
Desired properties of topical glucocorticoids
High lipophilicity
minimal systemic effects
prolonged action
adverse effects of glucocorticoids in terms of crossover activity
crossover mineralcorticoid activity
adverse effects of glucocorticoids in metabolism
Increased glucose production (may unmask diabetes)
osteoporosis (glucocorticoids inhibit osteoblasts)
premature epiphyseal closure
adverse effets of glucocorticoids on face shape and GI
cushings like effects, round face, hump back and peptic ulcers
___________ are usually potent topical glucocorticoids
halogenated analogues
recognize structures of topical and inhaled glucocorticoids
Substitution of chlorine atom for 17-OH does what
Enhances anti-inflammatory effects
_________and _______ have better potency for topical applications due to high lipophilicity
Ester and acetonides
