Sultatos Lectures 7, 10, 15, 17, 20

Front 1

Activates iodide

Back 1

TPO

Front 2

An intermediate on the way to a highly reactive species of iodide

Back 2

Iodine

Front 3

Adds I to thyroglobulin via organification

Back 3

TPO

Front 4

Will couple diiodotyrsoine residues to monotyrosines to make T3 and T4

Back 4

TPO

Front 5

This enzyme works in peripheral tissues to make T3 from T4

Back 5

5'-Diodinase

Front 6

Used for replacement therapy to give back the hormones that are no longer being produced, must be careful as to not produce symptoms of hyper or hypo thyroidism

Back 6

Thyroid drugs

Front 7

- Most popular drug for replacement therapy in hypothyroidism because they can produce T3 from this so the patient ends up with a lot of T3 and T4.
- Give it once 1x/day
- The levels of T3 will not be as much as a person with normal thyroid levels, but this does not seem to make a difference

Back 7

Levothyroxine (pure T4)

Front 8

Levothyroxine (thyroxine, tetraiodthyronine) half life

Back 8

~7 days

Front 9

- Has to be given several times a day, effective orally
- Not sufficient on its own to given to a hypothyroid patient because still T4 deficient

Back 9

Liothyronine (T3)

Front 10

Usually used in emergency situations and you need to get thyroid hormone in quickly because T3 is 4-5x quicker in its ability to bind thyroid receptor and T3 is also more potent

Back 10

Liothyronine (T3)

Front 11

Liothyronine (T3, Triiodothyronine half life)

Back 11

~24 hours

Front 12

Tries to mimic normal natural mixture of a euthyroid person, not seen to have an advantage over giving T4 on it's own

Back 12

Liotrix (T4 +T3 in a 4:1 ratio)

Front 13

Discouraged because
- Not pure, there are other proteins in these hormones and patients can develop allergies
- Levels of T3 and T4 can vary from one batch to another

Back 13

Thyroid hormones from pigs

Front 14

Will inhibit the enzyme thyroid peroxidase, thus will inhibit iodination and coupling in the thyroid.

Back 14

Propylthiouracil and Methimazole

Front 15

Inhibit peripheral conversion from T4 to T3

Back 15

PTU

Front 16

Clinical response to these drugs is usually observed after 3-4 weeks of therapy

Back 16

Thioamides: PTU and Meth

Front 17

PTU half life and how many times given a day?

Back 17

- 1 hr
- Once every 6-8 hrs

Front 18

Methimazole half life and how many times given a day?

Back 18

- 7 hr
- Once a day

Front 19

Potential adverse side effects
- Maculopapular rash (4-6%)
- Liver failure
- Agranulocytosis (0.1-0.5%)

Back 19

Thioamides, mainly PTU

Front 20

- Corticosteroid
- A very large dose will stop peripheral conversion of T4 to T3
- Only use in an emergency like thyroid storm because of the high dose

Back 20

Dexamethasone

Front 21

- Quickly inhibits T3 and T4 secretion (unknown mechanism) also transiently inhibits TPO
- Effect only lasts for about 10-14 days and for some reason the thyroid hormones begin secreting again (thyroid escape)

Back 21

Iodide (at high doses), lugol's (5% iodine, 10% potassium iodide) solution and potassium iodide

Front 22

- Blocks increased sympathetic activity in hyperthyroidism mediated by beta blockers
- May also inhibit 5'deiodinase

Back 22

Propranolol

Front 23

- Used because T3 and T4 help regulate the # of adrenergic receptors in various locations throughout the body.
- We have beta 1 receptors in the heart (control heart rate, play a big role in controlling systolic bp.)
- So in a hyperthyroidic patient, they have a lot of B1 in the heart causing arrthymias
- Tremors also because of B1 recepors in the CPS

Back 23

Propranolol

Front 24

- Can be taken orally as sodium iodide for thyroid ablation

- Beta emitter

- kills cells in the thyroid, patients can become hypothyroid, but it is easer to treat hypo than hyper so it is worth the risk

Back 24

Radioactive iodine (131I)

Front 25

Radioactive iodine (131I) half life

Back 25

~ 8 days

Front 26

Very fast acting drugs because they via protein phosphorylation in the cell

Back 26

Peptide drugs

Front 27

Not available after oral administration, so they need to be administered in other ways because they become degraded in the stomach

Back 27

Peptide drugs

Front 28

Hormones of the pituitary as drugs
- TSH, TRH

Back 28

Not used

Front 29

Hormones of the pituitary as drugs
- ACTH, CRH

Back 29

Not used as drugs, but used diagnostically

Front 30

Uses

- Growth hormone deficiency
- Growth failure in children with kidney disease
- Administered subcutaneous 6-7

Back 30

Clinical uses of GH

Front 31

- Idiopathic short stature

- Anti-aging hormone (unsubstantiated)
- Improvement of athletic performance (unsubstantiated)

Back 31

Controversial uses of GH, GRH, Somatostatin (GHIH)

Front 32

Drugs used to suppress GH levels, or inhibit GH activity in acromegaly

Back 32

- Somatostain analogs
- Octreotide

Front 33

Somatostatin analogs half life

Back 33

3 minutes

Front 34

Octreotide half life and how often you give

Back 34

Give subcutaneous every 8 hour, 1.5 half life

Front 35

- Effective in 50-75% of patients
- Causes pituitary adenoma to shrink in some patients
- Can also inhibit release of insulin and glucagon, affecting glucose regulation (some patients could become hyper or hypo glycemic)

Back 35

- Somatostatin analogs
- Octreotide

Front 36

- Inhibits release of CCK
- Abdominal pain
- Nausea
- Diarrhea
- Flatulence

Back 36

- Somatostatin analogs
- Octreotide

Front 37

- Overall effective in 1/3 patients
- effective in 1/2 patients not responding to octreotide
- Unsure why these drugs cause drop in GH in patients with acromegaly

Back 37

Dopaminergic agonists - Cabergoline

Front 38

- Can be used in combo with somatostatin analogs or alone
- Normalizes Insulin Like growth factor (IGF) - which is very high in patients with acromegaly
- Does not normalize glucose because it is not acting at the pituitary
- does not cause shrinkage of pituitary tumors because it is just a receptor blocker

Back 38

Competitive antagonists of GH - Pegvisomant (Give SC 1x/day because it is a peptide)

Front 39

Side effects include abnormal LFTs and hypoglycemia

Back 39

Competitive antagonists of GH - pegvisomant

Front 40

Will see elevated FSH and LH in first few days of treatment and will see elevated estrogen in the blood because LH stimulates elevated production of estrogen

Back 40

GnRH effects

Front 41

- Stays bound to the receptor much longer than GnRH
- Because of prolonged binding, it causes the GnRH receptors to down regulate and start to disappear so drop in FSH, LH and estrogen
- High enough dose will completely turn of GnRH action

Back 41

Leuprolide

Front 42

- Used for its FSH activity
- Isolated from the urine of postmenopausal women who are not taking estrogen replacement therapy

Back 42

Human menopausal gonadotropin (HMG)

Front 43

- Agonist of LH
- Similar in structure to LH and can activate LH receptors, produced by the placenta in high levels

Back 43

Human Chorionic Gonadotropin (HCG)

Front 44

- Synthetic GnRH
- Treats infertility but the problem is with its administration
- Needs to follow the pulsatile release of regular GnRH
- Hooked up to a venous line and that has to sense and release, patients do not like this

Back 44

Gonadorelin

Front 45

- Long acting GnRH agonist
- Often used for estrogen dependent disorders like endometriosis

Back 45

Leuprolide

Front 46

Condition in pre-menopausal women where a piece of the endometrium ends up in the peritoneal cavity.

Back 46

Endometriosis

Front 47

Vasopressin half life

Back 47

20 min

Front 48

Desmopressin half life

Back 48

2 hr

Front 49

Acts on V1 and V2 (ADH)

Back 49

Vasopressin

Front 50

Only at V2

Back 50

Desmopressin

Front 51

Will cause constriction to help decrease hemorrhaging. (The SST analogs are used for bleeding esophageal varices-especially octreotide.)

Back 51

Vasopressin causing bleeding esophageal varices

Front 52

Which receptor is responsible for vasoconstriction?

Back 52

V1

Front 53

Which receptor is responsible for reabsorption of water by the kidney?

Back 53

V2

Front 54

Will cause release of VW factor and factor VIII so can only give it to mild forms of these diseases because they need some of the factor to release

Back 54

Treat with IV desmopressin

Front 55

Why can desmopressin by given orally despite it being a peptide?

Back 55

Only 0.1% is absorbed, but that is all you need

Front 56

In control of ATII, a little bit in control of ACTH

Back 56

Aldosterone

Front 57

Mostly controls ACTH and a little bit of ATII

Back 57

Cortisol

Front 58

Can have CV effects because adrenergic receptors (B1, B2, A1)

Back 58

Glucocorticoids

Front 59

- It was discovered because of its effect on the immune system and inflammation
- Discovered by doctor that realized symptoms of rheumatoid arthritis (RA) disappeared in populations

Back 59

Cortisol

Front 60

Inhibitor of phospholipase A2, which will block production of PGE and leukotrienes

Back 60

Lipocortin (annexin A-1) stimulated by Cortisol

Front 61

Stimulate synthesis of lipocortin (Annexin A-1)

Back 61

cortisol

Front 62

Inhibit synthesis of NF-Kb (nuclear factor kappa-light-chain-enhancer of activated B cells)

Back 62

Cortisol

Front 63

Induce tdag8 (T-cell death associated gene 8) in lymph tissue

Back 63

Cortisol

Front 64

This receptor can be activated by a number of things (including a slight change of pH) but when it is activated it leads to apoptosis of lymph tissue

Back 64

tdag8

Front 65

What does inhibit synthesis of NF-kB and activator protein-1 do?

Back 65

Pro-inflammatory cytokines

Front 66

Result of altered Gene expression, which step?
- Decrease influx of neutrophils, monocytes, macrophages and lymphocytes to site of inflammation due to inhibition of chemotaxis

Back 66

Step 1

Front 67

Result of altered Gene expression, which step?
- Inhibit phagocytosis and pinocytosis

Back 67

Step 2

Front 68

Result of altered Gene expression, which step?
- Reduce size and content of lymph tissue

Back 68

Step 3

Front 69

Result of altered Gene expression, which step?
- Decrease proliferation of T and B cells, reducing antibody production, comes from drops in cytokine levels

Back 69

Step 4

Front 70

Result of altered Gene expression, which step?
- Drop in cytokine levels

Back 70

Step 5

Front 71

IgE ABs bind to receptors on mast cells causes release of what?

Back 71

Histamine

Front 72

Stabilize mast cell membranes (also happens in basophils) so will stop the release of histamine.

Back 72

Cortisol and cortisol-like agonists

Front 73

Giving back cortisol that is not there, replacement therapy for that?

Back 73

Addison's disease

Front 74

This is for a long treatment by chronic condition, wouldn't use glucocorticoids in acute settings

Back 74

Severe allergic reactions

Front 75

Glucocorticoids used to suppress immune system for this

Back 75

Autoimmune diseases

Front 76

OTC topical application. Oral glucocorticoids only by Rx. Some are so lipid soluble they can get across skin

Back 76

Skin diseases

Front 77

To trigger apoptosis of cancer cells and some to suppress nausea and vomiting only in chemotherapy (not motion sickness)

Back 77

Oncology - lymphoma and acute lymphocytic leukemia, nausea and vomiting

Front 78

Chronic inflammatory disease, suppresses the chronic inflammation, can be taken via inhalation or orally or injected

Back 78

Bronchial asthma

Front 79

About 10% of babies born less than 34 weeks gestation (premature). Biggest problem is lack of surfactant in lungs, give glucocorticoids to the mom 48 hrs and 24 hrs before delivery

Back 79

Fetal lung maturation

Front 80

Side effects and toxicities of glucocorticoids:
Because suppression of immune system

Back 80

Increase susceptibility to infections

Front 81

Side effects and toxicities of glucocorticoids:
Because inhibit absorption of calcium in GI tract, increase calcium excretion in the kidneys, and inhibit activity of osteoblasts

Back 81

Osteoprosis

Front 82

Side effects and toxicities of glucocorticoids:
Because need prostaglandins to make mucous that protects stomach from acid

Back 82

Peptic ulcers

Front 83

Side effects and toxicities of glucocorticoids:
Cataracts are not reversible, we are not sure why it causes this

Back 83

Cataracts, glaucoma

Front 84

Side effects and toxicities of glucocorticoids:
Because inflammation is part of wound healing process

Back 84

Slow wound healing

Front 85

Side effects and toxicities of glucocorticoids:

because cortisol is telling muscle to break down protein, to release amino acid's to be converted to glucose

Back 85

Muscle wasting

Front 86

Side effects and toxicities of glucocorticoids:
Range from insomnia to suicide ideation and attempted suicide (small number of patients though)

Back 86

Behavioral disturbances

Front 87

Hydrocortisone duration of action

Back 87

8-12 hrs

Front 88

Prednisone duration of action

Back 88

18-36 hrs

Front 89

Betamethasone, dexamethasone duration of action

Back 89

1-3 days

Front 90

Drug for fetal lung maturation

Back 90

Betamethasone

Front 91

Can be used in emergency hyperthyroidism to stop peripheral conversion of thyroid hormone

Back 91

Dexamethasone

Front 92

Stimulates the release of ACTH and ACTH stimulates the release of what?

Back 92

Vasopressin and cortisol

Front 93

Competitive inhibitor of aldosterone at the MR receptor

Back 93

Spironolactone

Front 94

- Inhibits CYP17
- Anti-fungal drug, but at high doses (larger doses than used as anti-fungal agent) it inhibits the synthesis of cortisol
- Can be used to treat Cushing's disease

Back 94

Ketoconazole

Front 95

Like cortisol, this hormone will increase or decrease transcription of certain genes in certain tissues

Back 95

Estrogens

Front 96

Causes negative feedback on the hypothalamus to stop producing estradiol, exert feedback inhibition on the hypothalamus thus causing decreasing GnRH = lower FSH, LH

Back 96

Estradiol or a drug that is an agonist of estradiol

Front 97

Increase in GnRH, FSH, LH and increase synthesis of estradiol

Back 97

Estradiol antagonist

Front 98

Prototype, responsible for most of actions of estrogen in the body because it is more potent at the estrogen receptor

Back 98

Estradiol

Front 99

- Required for normal maturation
- Affect synthesis of certain proteins by the liver
- Alter bone resorption
- Integral role of menstrual cycle

Back 99

Estrogen

Front 100

When is it okay to give unopposed estrogen?

Back 100

Women w/o uterus

Front 101

Stabilizes endometrium

Back 101

Progesterone

Front 102

Estradiol levels go up as you approach this

Back 102

Ovulation stage

Front 103

When is estrogen replacement therapy indicated?

Back 103

Women who are in a high risk category for osteoporosis

Front 104

Premenopausal replacement therapy such as premature ovarian failure

Back 104

- Estrogen
- Progesterone

Front 105

Can treat endometriosis because it exerts negative feedback inhibition to dial down levels of estradiol

Back 105

oral contraceptives

Front 106

Used to to treat PCS
- Ovaries are enlarged and get fluid filled cysts, ovaries start to turn out large numbers of steroids hormones especially androgens which cause acne, body hair and painful menses.

Back 106

Oral contraceptives

Front 107

The estrogen and progesterone in oral contraceptives work to inhibit feedback at the hypothalamus, why do you still have to give estradiol and progesterone?

Back 107

Because the hormones in OCs do not do the normal job on estradiol and progesterone

Front 108

- Metabolites of the natural estrogens
- Still have estrogenic activities, but not as potent
- Difficult to make in lab, thus collected in horse urine
- Bad taste

Back 108

Conjugated estrogens - estradiol sulfate

Front 109

- Made an ester at the 17c position of estradiol
- Estrogenic activity

Back 109

Esterified estrogens - estradiol valerate

Front 110

- Converted to ethanol estradiol by removing the methyl group and leaving an OH
- The active ingredient in any oral contraceptive

Back 110

Mestranol

Front 111

- Nausea
- Post menopausal bleeding
- changes in serum proteins
- Headaches

Back 111

OC ADR

Front 112

Mothers who are taking estrogens as a drug who are pregnant with a female fetus, that female fetus has an increased risk for what?

Back 112

Vaginal adenocarcinoma

Front 113

Two major pathways for ethinyl estradiol to be broken down?

Back 113

- P450
- Glucuronyl transferases

Front 114

If ethinyl estradiol is broken down by P450, what does it become?

Back 114

2-hydroxy ethinyl estradiol

Front 115

If ethinyl estradiol is broken down by glucuronyl transferases, what does it become?

Back 115

Ethinyl estradiol glucuronide

Front 116

If taking these drugs, oral contraceptives need to be broken down differently as they compete for P450 activity

Back 116

Griseofulvin, Rifampin

Front 117

- Developed to protect against osteoporosis, but has similar effects as tamoxifen for estrogen-dependent breast cancer.
- not as good as tamoxifen and only used in post menopausal women

Back 117

Raloxifine

Front 118

- For osteoporsis (agonist for osteoblasts)
- also antagonist in estrogen receptors in the uterus-blocks estrogen from activating them
- used along conjugated estrogens as post menopausal estrogens replacement therapy

Back 118

Bazedoxifene

Front 119

- Used to lower rate of recurrent estrogen dependent breast cancer
- Binds to estrogen receptor -> dimer -> enters nucleus -> binds to ERE which blocks estradiol from binding
- Partial agonist in endometrium is a side effect

Back 119

Tamoxifen in estrogen dependent breast cancer

Front 120

- Cause some increased proliferation of the endometrium and after 5 years, the risk benefit analysis goes upside down for endometrial cancer
- Some women have hysterectomies and continue taking it

Back 120

Tamoxifen in endometrium

Front 121

Acts as antagonist on receptors of hypothalamus blocks feedback inhibition of estradiol, opposite of oral contraceptives, tricks hypothalamus that is not enough estradiol and endogenous estradiol increases
- Used to treat certain type of infertility
- CANNOT be used to treat hypothalamic amenorrhea because problem is with GnRH not estradiol

Back 121

Clomiphene

Front 122

- Binds to ER (in estrogen dependent BC cells) but keeps the receptor as a monomer (unlike tamoxifen, which forms a dimer) and the complex stays in the cytosol and does not go into the nucleus so it gets broken down
- Only used in Breast cancer not being treated by tamoxifen

Back 122

SERDS (Selective estrogen receptor downregulators) - fulvestrant

Front 123

Sources of estrogen
- Gonadal
- Extra gonadal

Back 123

Premenopausal

Front 124

Sources of estrogen
- Extra-gonadal
- Fat

- Breast
- Liver
- Kidneys
- Adrenals
- Brain

Back 124

Postmenopausal

Front 125

- Only used in post-menopausal women because their source of estrogen is mainly extra-gonadal production, if given in premenopausal women, hypothalamus will turn out very large amounts of GnRH which will make lots of FSH and LH

Back 125

Aromatase inhibitors (CYP19A1, estrogen synthetase)

Front 126

Inhibits these reactions

Testosterone -> estradiol
Androstenedione -> Estrone

Back 126

Letrozole, aromatase inhibitors

Front 127

- Render endometrium inappropriate to implantation and production of mucus at the cervix
- Not as effective as oral contraceptives because they are very time dependent
- Taken by women who cannot tolerate oral contraceptives

Back 127

Progestins

Front 128

The main ingredient in plan B

Back 128

Levonorgestrel

Front 129

Progestins

- Anti-estrogenic only

Back 129

Progesterone

Front 130

Progestins

- Androgenic
- Anti-estrogenic

Back 130

Medroxy-progesterone

Front 131

Progestins
- Anti-estrogenic
- Anti-androgenic

Back 131

Megestrol

Front 132

- Chemical abortion

- Antagonist to progesterone
- Uterus lining will slough off and be shed
- Only works in first 7 weeks of gestation, beyond that the lining of the uterus is not so dependent on progesterone

Back 132

Antiprogestins - mifepristone

Front 133

- Required for normal maturation
- Maintain normal sperm production
- Increase protein synthesis in muscle
- Increase hemoglobin levels
- Alter bone resorption

Back 133

Androgens

Front 134

- Replacement therapy
- Cachexia
- Osteoporosis
- Endometriosis
- Fibrocystic breast disease

Back 134

Indications for Androgens

Front 135

Wasting syndrome sometimes in terminal cancer or AIDs patients

Back 135

Cachexia

Front 136

- Masculinization in women
- Feminization in men
- Acne
- Decreased spermatogenesis and steroidogenesis
- Liver disorders
- HCC
- Heart disease

Back 136

Androgens - ADR

Front 137

If you are taking anabolic steroids, what can you take to counter the decreased spermatogenesis?

Back 137

Human menopausal gondadotropin

Front 138

Inhibits 5a-reductase enzyme. Testosterone is converted to DHT to bind to the Androgen Receptor and this drug will inhibit that

Back 138

Anti-androgens: finasteride

Front 139

Will block binding DHT to the androgen receptor. approved to treat prostate cancer

Back 139

Anti-androgens: flutamide