Park lecture 4 Flashcards by Matti Daniel

Drug interactions with progestins

Other steroids
Anticonvulsants

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Why are other steroids contraindicated when taking birth control?

Oral contraception will increase blood levels of other steroids

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why do anticonvulsants such as phenytoin decrease effectiveness of Oral BC

phenytoin induces drug metabolizing enzymes in liver

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Use of gut flora with regard to estrogen

estrogen needs to go through enterohepatic circulation and gut flora is necessary for that.

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relationship between gut flora, enterohepatic circulation and estrogen activity

less gut flora= less enterohepatic circulation= estrogenic activity drops

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how does tetracycline affect birth control. Why?

Tetracycline reduces efficacy of birth control. Tetracycline reduces gut flora.

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Plan B is a combination between these two drugs

Ethinyl estradiol+norgestrel

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progestin only plan B name

Levonorgestrel

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What are the two parts of adrenal gland?

Cortex and medulla

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What does medulla produce in adrenal gland

Epinephrine and norepinephrine

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What does cortex produce in adrenal gland

Glucocorticoid, mineralocorticoids and androgens

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What are glucocorticoids

stress hormones

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What is the structural difference between aldosterone and cortisol

cortisol has 17-OH

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Other name for glucocorticoid

cortisol (stress hormones)

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Physiological effects of glucocorticoids

increase circulating glucose concentrations
potent anti inflammatory effects

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Physiological effects of mineralcorticoids (aldosterone)

increases Na+ retention. This will lead to an increase in water volume. Leading to an uptick in BP

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Difference in where epinephrine and cortisol bind

Epinephrine binds glucocorticoid receptor, epinephrine binds B adrenergic receptor

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Difference in response time between epinephrine and cortisol (hydrocortisone)

Epinephrine has an immediate response whereas cortisol has a long term persistent biologic response

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what stimulates the release of ACTH from the pituitary?

CRH

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what stimulates cortisol release from adrenal gland?

ACTH

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How is CRH inhibited

cortisol has a negative feedback loop that inhibits CRH

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Why are the levels of aldosterone not affected with pituitary gland removal?

Because liver releases aldosterone precursor (angiotenstinogen)

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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

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What enzyme converts angiotensin 1 to ang 2

ACE

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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