2.19.2010 - Medchem Iii Test 1

Front 1

What is the action of insulin on the liver?

Key words: triglyceridogenesis, Glycogenolysis, glycogenesis, lipolysis, LDL formations, ketogenesis

Back 1

INHIBIT: glycogenolysis, lipolysis, ketogenesis
PROMOTES: glycogenesis, triglyceridogenesis & LDL formation

Front 2

What is the action of insulin on skeletal muscle?

Back 2

PROMOTES protein synthesis:
-Increases amino acid transport
-Increases ribosomal protein synthesis
INCREASES glycogenesis:
-Increases myocyte glucose uptake
-Inhibits glycogenolysis

Front 3

What is the action of insulin on Adipose Tissue?

Back 3

INCREASE TG storage
-Lipoprotein lipase is induced and activated by insulin to mobilize TGs from lipoproteins(which reside in blood)
-Intracellular (adipocyte) lipase is inhibited
-The net effect is to increase fat storage

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Front 5

What are the differences b/w human, pork, and beef insulins in terms of the number of aa differences and relative immunogenic potency?

Back 5

Beef insulin differs from human insulin @ 3 aa positions, whereas pork differs only by one.
BEEF > PORK > HUMAN

Front 6

Note the connection b/w solubility and onset-duration following SubQ administration for Isophane NPH insulin. How does the presenceof protamine in the NPH(neutral prtamine Hagedorn) formulation dealy onset and prolong the action of insulin?

Back 6

Form a depot that slowly releases into the blood. Protamine is arginine rich peptide. Enzymes digest protamine to get to insulin.

Front 7

What is the mechanism of action of Crystalline Zinc Insulin Formulation?

Back 7

Human insulin crystal dissolve rapidly after S.C. injection - gives rapid onset and shorter duration

Front 8

What physical features characterize an Ultralente formulation?

Back 8

Large crystals of insulin with high zinc content. Relatively insoluble

Front 9

Amorphous(non-crystalline) insulin precipitated at high pH with zinc. Readily soluble and rapidly absorbed; onset and peak effect are rapid.

Back 9

Semilente

Front 10

Intermediate acting. Give combo percentages. Provide rapid absorption with sustained action. Therapeutic

Back 10

Lente
70% Ultralente ++ 30% Semilente

Front 11

What is the reason for the switch of two amino acids in Lispro(Humalog)? Which two aa are switched and on which chain?

Back 11

Blocks aggregation-improves solubility. 28 and 29 of the B chain. Pro-Lys switched to Lys-Pro.

Front 12

Explain Glargine. Soluble at which pH?

Back 12

Soluble in solution at pH4, but precipitates after S.C.(pH 7), forming a microprecipitate depot. Insulin slowly dissolves from the depot providing peakless basal insulin replacement

Front 13

Is Detemir long or short acting?

what structural feature causes this?
What does it bind to?

Back 13

Long action. Addition of 14-carbon fatty acid binds plasma albumin, increasing DOA.

Front 14

What is a feature of all sulfonylureas?

Back 14

Feature a urea function with a sulfonyl group directly attached to one of the urea nitrogens.

Front 15

A first generation sulfonylurea with a chloro group that blocks oxidation to the carboxylic acid, which prolongs DOA.

Back 15

Chlorpropamide

Front 16

Second generation sulfonylureas have this feature. Purpose?

Back 16

Large non-polar substituent on the benzene ring. Improves potency

Front 17

Sulfonylurea MOA?

Back 17

interact w/ various pancreatic beta-cell receptors to block ATP-gated K+ channels. This depolarizes the cell, opening Ca++ channels. Ca influx induces beta-cell insulin secretion

Front 18

What first generation provided the core for the second generation sulfonylurea?

Back 18

Acetohexamide

Front 19

This generation of Sulfonylureas have no metabolites that exhibit useful theraeutic activity

Back 19

2nd gen

Front 20

Name 2nd gen Sulfonyls.

Back 20

Glipizide. Glyburide

Front 21

Meglitinides(Repaglinide):
a) MOA
b) duration and potency compared to Glyburide
c) how metabolized

Back 21

a) Binds to a unique site as well as sites in common with sulfonyls. Closes ATP-dependant K+ channels in Beta-cell membranes. Depolarizes to open Ca channels. Insulin secreted.
b) more rapid and shorter acting and 10X more potent(free of prolonged hyperinsulinemia seen with various sulfonlyureas).
c) Glucoronidation

Front 22

Second Meglitinides that was approved in 2000. Free of prolonged hyperinsulinemia.

Back 22

Nateglinide(Starlix)

Front 23

GIve some importatn components of metformin's action

Back 23

1. inhibits gluconeogenesis
2. increases anaerobic glucose use in the small intestine
3. increases aerobic glucose use in other tissues.
OVERALL increases glucose utilization

Front 24

Does not induce hypoglycemia at any reasonable dose. Not protein bound or metabolized, but undergoes rapid renal elimination. Active in pts unresponsive to sulfonylureas. DOA 12-12 hours

Back 24

Metformin

Front 25

A pseudotetrasaccharide with the ABILITY TO COMPETITIVELY INHIBIT ALPHA-GLUCOSIDASE VIA THE BASIC SECONDARY AMINE OF THE CARVSINE UNIT.

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Front 26

A small molecule alpha-glucosidase inhibitor that is rapidly abosorbed into the blood following oral admin.

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Front 27

Lowers blood glucose levels by improving target tissue(adipose, skeletal muscle, and liver) sensitivity to insulin(also referred to as insulin enhancers. Name two drugs and class

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Front 28

What do Thiazolidinediones bind to? What does this do in the presence of insulin. What follows?

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What makes estrogen susceptible to sulfation or glucoronidation?What makes estrogen susceptible to sulfation or glucoronidation?

Back 31

3-Hydroxyl Group

Front 32

A water soluble estrogen conjugate administered orally for its estrogenic effects and that requires intestinal sulfatases for in vivo activation

Back 32

sulfate group present. From Mare's urine

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An Active estrogen(not a prodrug) modified at C17 such that oxidation of the 17B-OH by 17B-HSD) is blocked, prolonging duration of action

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A long acting lipophilic ester prodrug of a natural estrogen employed IM for prolonged estrogenic actions.

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A semi-synthetic estrogen prodrug that requires P450-mediated dealkylation(or demethylation) to give active species.

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A totally synthetic estrogen(as opposed to semi-synthetic estrogen) that is employed in estrogen-sensitive breast cancer. Five examples given in lecture

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A natural product( flavonoid) present in certain vegetables(such as soy) that has weak estrogenic activity( a phytoestrogen).

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What is the name(chemical and common) of a selective estrogen receptor modulator(SERM) that lacks uterine and mammary effects, but prevents bone loss and lowers cholesterol in post menopausal women?

Back 38

Exhibit mixed agonist/antagonist activity at estrogen receptors.

Front 39

The progestin with the lowest oral bioavailability due to rapid first pass metabolism in the liver

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A long acting highly lipophilic progestin prodrug used IM in oil.

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Orally very active progestins(employed in oral contraception) that are less susceptible to 3-keto-4-ene reduction than progesterone.

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A 19-norandrostane C13-etyl derivative that requires metabolism by the intestinal mucosa and/or liver to give the active species. Considered a pro-progestin

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Front 43

An oral contraceptive that resists 17beta-OH metabolic and bacterial oxidation to the 17-keto. Five examples given in class

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Front 44

A progestin derivative that resists 20-keto reduction to the less active(and readily conjugated) alcohol.

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Front 45

A progesterone receptor antagonist that possesses abortifacient properties with a N,N-dimethylamino-phenyl fucntion that mediates, in large part, the progesterone receptor antagonism.

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The natural androgen that undergoes significant first pass metabolism in the liver, and therefore exhibits low oral bioavailability

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An ester prodrug that exhibits primarily androgenic effects and is administered IM for prolonged action

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The orally active androgen that provides the greatest androgenic activity

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The orally active drug that provides the greatest anabolic over androgenic activity.

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A 5-alpha-reductase competitive inhibitor that is employed to treat BPH and male pattern baldness(androgenic alopecia) by decreasing the xversion of testosterone to dihydrotestosterone

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a non-steroidal androgen receptor antagonist employed in the Rx of prostate cancer.

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The natural adrenocorticoid with the highest potency for retaining sodium in humans

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A mineralocorticoid with 1/10th the potency of aldosterone d ue to the absence of the hemiacetal bridge(11B-Oh and 18-aldehyde absent)

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The primary natural glucocorticoid in humans

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A glucocorticoid ester prodrug useful for IV admin.

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An ester of the 21-hydroxyl group of cortisone, that gives a highly liphophilic produrg for IM depot admin.

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A semisynthetic glucocorticoid with roughly 4X the anti-inflmmatory action of hydrocortisne(cortisol_), but only slightly less salt-retaining activity than hydrocortisone

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A semi-synthetic glucocorticoid with prolonged DOA resulting from inhibition of 3-keto-4-ene reduction due to a methyl substituent and increased anti-inflammatory activity over hydrocortisone due to a delta1,2-alkene.

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A semi-synthetic glucocorticoid w/ mineralocorticoid activity; used in treating Addison's disease

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A semi-synthetic ketal glucocorticoid w/ substantial topical anti-inflammatory activity largely due to its high lipophilicity; useful for treating poison ivy

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Front 61

A glucocorticoid that exists in two isomeric forms. Both demonstrate 30-35X the anti-inflammatory action of hydrocortisone with greatly reduced salt-retaining activity

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A semi-synthetic glucocorticoid ester prodrug widely used in inhalers for asthma and/or allergic rhinitis

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Front 63

what are three organs involved in Vit D production?

Back 63

Skin, liver, and kidneys

Front 64

If an excess for vitamin D3 is present in the body, what organ plays a key role in eliminating this excess? What
chemical modification of vitamin D3
facilitates this elimination?

Back 64

Kidneys. Hydroxylation at C24 blocks receptor binding (inactivates) and increases the polarity (aqueous solubility) for renal elimination.

Front 65

What organ forms active Vit. D

Back 65

Kidneys

Front 66

Note the structural differences b/w the storage, active and inactive forms of Vit. D3

Back 66

All have the basic D3 core structure, but the storage
form has a single hydroxyl at C25, while the active
form features a second hydroxyl at C1- a key feature
for good receptor binding. As noted above, the inactive
forms are hydroxylated at C24, a modification that
decreases receptor binding. Generally speaking, the
polarity (aqueous solubility) increases from storage to
inactivation/elimination via the renal route.

Front 67

A guy comes to you claiming...

A guy comes to you claiming he was diagnosed with hypocalcemia and
that his physician recommends supplementation with oral vitamin D and
calcium. Unfortunately, this chap is very frugal, and has decided to “self-
medicate” with 7-dehydrocholesterol purchased from Aldrich at $72.60
for 25 g through a chemist friend. (He figures that at 10mg/day this
supply is good for 6.8 years.) He reveals that he works strictly graveyard
shifts, sleeps during the day, and prefers the dark (no, his name is not
Count Dracula). Using the chart on page 4 of the Calcium Modulation
handout, do you think this gentleman’s approach will be successful? Why
or why not?

Back 67

UV irradiation is req. for B-ring fission of 7-dehydrocholesterol to give Cholecalciferol(D3)), which leads to storage then active form

Front 68

Which of the vitamin D preparations
presented in lecture are appropriate for
treating hypocalcemia in combination with
oral calcium supplements in a patient with
frank liver disease (impaired liver function)?

Back 68

The key point is that any vitamin D
preparation given to a patient with depressed
liver function should not depend on hepatic
bioactivation. Calciferol [25(OH)D3],
Calcitriol [1,25(OH)2D3] and Paricalcitol are
reasonable choices.

Front 69

Suppose a genetic defect leads to very low
expression of vitamin D 1α-hydroxylase.
Which of the vitamin D preparations given in
lecture are appropriate for treating
hypocalcemia in such an individual?

Back 69

This question now assumes that kidney
bioactivation is compromised; agents that
avoid vitamin D 1α-hydroxylase mediated
activation should work. Dihydrotachysterol
[DHT], Calcitriol [1,25(OH)2D3] and
Paricalcitol are reasonable.

Front 70

Why is calcitonin-salmon preferred over
human calcitonin?

Back 70

CT-Salmon has greater potency (about 50X)
and a longer half-life than human CT.

Front 71

Are there any considerations or concerns
regard ongoing use of calcitonin-salmon?

Back 71

Being a foreign peptide, systemic allergic
reactions are possible and/or neutralizing
antibodies can render the agent inactive.

Front 72

What benefit does CT-Salmon have
beyond controlling hypercalcemia
and disorders of bone remodeling?

Back 72

Potent analgesic effect

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Front 79

3.It is important to know and understand the
different options for natural and synthetic thyroid drug treatment, as well as the
identities of antithyroid drugs:

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Cholesterol:
Be familiar with drug therapy options to decrease plasma cholesterol and LDL levels, to
increase triglyceride clearance and to decrease VLDL formation. Understand mechanism
of action for each class.

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