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Pharmacology Test 4 > Chapter 41: Pancreatic Hormones and Anti-diabetic Drugs > Flashcards

Chapter 41: Pancreatic Hormones and Anti-diabetic Drugs Flashcards

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1
Q

What are the two main functions of the pancreas?

A

Endocrine Function- Islet of Langerhans

Exocrine Function - majority of the pancreas, produce digestive enzymes for proteins, lipids, and carbohydrates

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2
Q

What are the type of cells within the Islet of Langerhans?

A

Alpha cell- Glucagon, proglucagon
Beta cell- Insulin, C-peptide, proinsulin, amylin
Delta cell- Somatostatin (inhibitory peptide- insulin, glucagon)
G cell- Gastrin
F cell- Pancreatic polypeptide (PP)- GI motility

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3
Q

What are the Four Types of Diabetes Mellitus?

A

Type I - Insulin Dependent (IDDM), destruction of beta cells, no insulin, greater than 80% loss of beta cells
Type II - Non-insulin Dependent (NIDDM)
Type III - Other causes elevate blood glucose (pancreatitis, drug therapy)
Type IV- Gestational

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4
Q

What are the 3 main symptoms of diabetes?

A

Polyuria
Polydipsia (thirsty)
Polyphagia (hungry)

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5
Q

What is glycosylation?

What happens when glucose levels are too high?

A

Attaching a glucose molecule to another protein.

You will have nonenzymatic attachment of glucose molecules to proteins hence nonenzymatic glycosylation. This is mostly seen in HgB A1c. Normal level is 4-5%, Diabetics is 7-8%

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6
Q

What is the Polyol Pathway?

A

Glucose enter into certain cells in the body like the eye, nerve, and RBC will convert glucose into sorbitol and fructose.

Sorbitol and fructose can’t leave the cell and will attract water increasing intracellular osmotic pressure leading to cell injury.

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7
Q

What enzyme can be turned on by glycosylation?

A

Protein Kinase C, random activation of proteins

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8
Q

What are microvascular disease associated with chronic complication of DM?

A

Retinopathy (blindness)
Diabetic Nephropathy - kidney damage

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9
Q

What cells produce insulin?

What is measured to see how much endogenous insulin a patient is producing?

A

Beta cells produce pro forms of insulin, activated in the granules.

C-peptide

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10
Q

Describe the insulin receptor?

What are the effects of the receptor?

A

Tyrosine Kinase Receptor

Multiple effects:
Membrane Translocation of GLUT
Increase glycogen formation
Activation of multiple transcription factors

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11
Q

What is the term that describes something that causes the release of insulin?

A

Insulin Secretagogue

Glucose is the number 1 insulin secretagogue

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12
Q

Describe how insulin is released from the beta cells.

Essay Question

A
  1. The pancreas has GLUT-2 (low affinity for glucose)
  2. After a meal, there will be a high amount of glucose circulation that will enter GLUT-2.
  3. Glucose goes through metabolism in the pancreas and generates a lot more ATP
  4. ATP in the pancreatic beta cell closes K+ channel (Rectifier current), causing depolarization.
  5. Depolarization causes VG Ca2+ to open
  6. Ca2+ floods into the cell and causes exocytosis of insulin
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13
Q

What is the affinity for glucose for these GLUTs?
GLUT-1
GLUT-2
GLUT-4

A

GLUT-1- High affinity (brain, RBC)
GLUT-2- Low affinity (pancreas)
GLUT-4- Intermediate affinity (skeletal muscles)

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14
Q

What are the endocrine effects of insulin?

A

Inhibits glycogenlysis (decrease release of glucose)
Inhibits fatty acid release
Promotes glucose storage as glycogen

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15
Q

What are the 4 different types of insulin preparations?

A
  1. Rapid Acting - Lispro, aspart, glulisine
  2. Short Acting (Regular)- Novolin, Humulin
  3. Intermediate Acting- Neutral protamine Hagedorn (NPH)
  4. Long Acting- Glargine, detemir, degludec* (Basal)
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16
Q

What are the different types of Insulin Regimens?

A

Intensive
IDDM:Tight control
Basal + bolus (calculated)

Conventional
70:30 mix of regular/nph, okay control
Sliding scale regimen

Illness: Metabolic rate increases, need more glucose into the cell.
DKA/ HHS

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17
Q

Calculating Insulin Dose

A

Basal- 1 injection of long acting insulin in the AM
Bolus - Carb Coverage (1 unit of rapid acting insulin covers 12-15g of carbs)

Example: lunch you eat 60g of carbs
Inject 4 units of RA insulin (60/15 = 4 units)

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18
Q

What is the calculation for a correction of high glucose?

A

1 unit of RA insulin needed to drop 50 mg/dL

Example: Glucose spikes to 200 mg/dL
Inject 2 units of RA insulin (50 mg/Dl x 2 = 100 mg/dL drop)

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19
Q

What are the 8 oral antidiabetic agents (type II)?

A
  1. Biguanides- metformin
  2. Insulin Secretagogues- sulfonylureas
  3. Thiazolidinediones (TZDs)- decrease insulin resistance
  4. Alpha-glucosidase Inhibitors- Acarbose - used in pre-diabetics
  5. Bile Acid Sequestrant- BABR
  6. Amylin Analogs - Suppress Glucagon Release
  7. Incretin-base Therapies- GLP-1 agonist, DPP-4 antagonist
  8. SGLT2 Inhibitors - Gliflozins
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20
Q

What is first line treatment for NIDDM?

How does it work?

A

Biguanides (metformin, glucophage)

Reduce hepatic glucose production, less glucose removed from glycogen, less glucose going out into the blood stream

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21
Q

How do Insulin Secretagogues work?

What are the classes of Insulin Secretagogues?

What is the biggest difference between 1st and 2nd generation of Insulin Secretagogues?

A

Insulin Secretagogues bind to the K+ Channel and closes the channel causing depolarization which will release insulin.

Sulfonylureas- 1st gen, sulfa allergies
Meglitnide/Glipizide/Glyburide - 2nd gen, short half life

grams to milligram doses.
2nd gen is safer do to smaller dose.

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22
Q

What adverse effects was reported for Tolbutamide (Sulfonylureas)?

A

Adverse Cardiac Effects.
first generation sulfonylureas

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23
Q

How do Thiazolidinediones (TZDs) work?

What are the risk associated with TZDs?

A

Decrease insulin resistance- Peroxisome proliferator-activated receptors (PPAR mediated), increase gene products associated with insulin receptors. This will increase GLUT-4 and Increase insulin signal transduction, without needed insulin binding to the receptor.

Risk of MI
Avandia - Rosiglitiazone Medicine Access Program

24
Q

What are Incretins?

A

GI hormones.
Body produces Incretin and GLP-1 and are release when you have a meal.

These hormones stimulate insulin release while inhibiting glucagon release. Prepares the cell for uptake of glucose.

25
Q

How do Incretin-Base Therapies work?

Risk factor?

A

Taking artificial Glucagon-Like Polypeptide-1 (GLP-1) Agonist and Dipeptidyl Peptidase-4 (DDP-4) Antagonist to stimulate insulin release and decrease blood glucose.

Long term effects: Pancreatic cancer risk

26
Q

What does DDP-4 do?

A

Enzyme that breaks down Incretin and GLP-1.

27
Q

What does SGLT-2 do?

What do Gliflozins do?

What are examples of SGLT-2 Inhibitors?

A

SGLT-2 transport glucose back into the blood stream from the kidneys.

Gliflozins are SGLT-2 inhibitors that block the reuptake glucose in the PCT and promoting glucose excretion out into the urine.

Dapagliflozin (Farxiga)
Canagliflozin (Invokana)
Empagliflozin (Jardiance)

28
Q

What are the toxicity of SGLT-2 inhibitors?

A

Glucosuria
Osmotic diuretic - BP reduction
Weight loss
Dehydration
Necrosis of the Perineum

29
Q

What is the leading cause of death in the US?

A

Atherosclerosis (Heart Disease)

Plaque formation
Occlusion
CAD

30
Q

How are cholesterol mainly transported?

A

By low density lipoproteins (LDL)

31
Q

Where do excess LDL go?

What happens over time with these LDL?

A

It will be deposited in the space between endothelial cells of the blood vessels and the smooth muscles.

They become oxidized and become more pro-inflammatory. This will cause WBC to migrate into the area and try swallowing the oxidized forms of cholesterol = foam cells.

32
Q

Can cholesterol be broken down in our body?

A

No, nothing can break it down.
It is excreted into the bile.

33
Q

What are foam cells?

A

Macrophages that engulfs a cholesterol molecule that ends up stuck in the macrophage.

Since cholesterol can not be broken down, over time they precipitate and become crystalized. This will rupture the foam cell which will increase inflammation even further.

34
Q

What is the necrotic core formation?

A

A cluster of dead WBC and cholesterol crystals. This becomes lipid rich and becomes thicker as the disease progresses.

35
Q

What are sterol molecules?

Sterol molecules are important precursors in what?

How do we obtain sterol?

A

They are the four rings that are part of the cholesterol molecule.

They are important precursors in:
Steroid hormons
Cell membranes - adds fluidity
Vitamin D
Bile Salts

Sterol are obtained:
Through Diet (animal products)
Through body production: De Novo Synthesis (Liver)

36
Q

How is cholesterol made in the liver (pathway)?

What do statins target?

A

In the liver, cholesterol is made in the HMG-CoA Reductase Pathway. HMG-CoA is a byproduct of Acetyl-CoA.

HMG-CoA is converted to Mevalonate through HMG-CoA reductase.

Mevalonate makes Cholesterol.

Statins target and inhibit HMG-CoA Reductase

37
Q

What are Chylomicrons (exogenous pathway)?

A

They are lipoproteins formed in the intestines (dietary) that carry triglycerides and cholesterol.

Chylomicron is like Santa disposing cholesterol to all the good cells in the body.

The chylomicron remnant is degraded in the liver.
High remnants are pro-atherogenic.

38
Q

What are VLDL?

A

Very Low Density Lipoprotein are made in the liver and first ones secreted. Travel to peripheral tissues.

Enzymes will convert VLDL to IDL and LDL (endogenous pathway)

39
Q

What are LDLs?

What are HDLs?

A

Low density lipoprotein - not made, converted from VLDL
Transport to cells
Cells have LDL receptors - LDL bind and drop off fat
Excess-deposit in arteries

High density lipoprotein- reverse cholesterol transport
Scavenger of cholesterol from cells, other lipoproteins
Decrease levels associated with atherosclerosis

40
Q

What is the LDL/HDL Cholesterol Ratio?

A

Ratio/Risk
1.00—-1/2 average
2.5——average
6———2x average
8———3x average

41
Q

What are desirable levels of:
Total Cholesterol
LDL
HDL Men
HDL Women
Triglycerides

A

Total cholesterol: < 200 ( greater than 200, statin candidate)
LDL < 130
HDL Men: > 45
HDL Women: > 45
Triglycerides: < 120

42
Q

What are the 6 Hyperlipidemia Drug Classes

A
  1. Statins - HMG-CoA Reductase Inhibitors
  2. Niacin- Block transport to VLDL
  3. Fibrates - PPAR mediated lipolysis
  4. Binding Resins - Cationic bile acid binding (adjunct for diabetes and dyslipidemia)
  5. Absorption Inhibitors - Inhibit cholesterol absorption
  6. Monoclonal Antibodies - PCSK9 Inhibitors
43
Q

What is the MOA of Statins?

Main toxicity of statins?

A

Blocks the HMG-CoA reductase. Decrease overall cellular cholesterol synthesis.

Cells will increase LDL receptors and scavenge LDL from blood.
Major effect in the Liver

Modest decrease of triglycerides
Small increase in HDL

Toxicity: Muscle (may be severe), d/t CK elevation

44
Q

What does Niacin (Vitamin B3) do?

Main toxicity of niacin?

A

Decreases VLDL, LDL. Niacin works by blocking transport of cholesterol into VLDL. Excess cholesterol goes out into the bile instead.

Increase HDL
Incorporated into NAD, precursor for ATP

Flushing d/t cutaneous vasodilation

45
Q

How do Fibrates work?

Examples.

Main toxicity with fibrate

A

Decrease VLDL and modest decrease in LDL, they work by increasing breaking of cholesterol in the liver through the PPAR pathway.

Gemfibrozil (Lopid) and Feenofibrate (Tricor)

Toxicity is rare (GI upset)

46
Q

How does Ezetimibe work?

Toxicity?

A

Inhibitor of Intestinal Sterol Absorption.
Ezetimibe is a NPC1L1 Transporter (cholesterol transporter) Antagonist and blocks the uptake of cholesterol.

Possible hepatic issues (pending)
Arterial wall thickening promoted (?)

47
Q

How do LDL receptors work?

A
  1. LDLR are located on all cell surfaces that bind to LDL.
  2. LDL is internalized, break down LDL and release cholesterol and proteins. Used in the cell.
  3. Cell will recycle LDLR back to the surface.
48
Q

How does PCSK9 work?

What is the problem with statin therapy with PCSK9?

What is an option to treat this?

A
  1. PCSK9 is a protein that occurs in the blood.
  2. PCSK9 binds to the LDLR, LDLR is internalized and is unable to get out onto the surface.
  3. End Result, LDLR bound to PCSK9 is digested in the lysosome.
  4. When this happens there will be fewer and fewer LDLR, resulting in higher blood cholesterol.

When we take statins, the promotes an upregulation of plasma PCSK9 level.

PCSK9 Inhibitors with the combination of statin therapy to bring down cholesterol levels.

49
Q

What are PCSK9 inhibitors?

Example drug?

How much will this lower LDL?

Side Effects?

A

Monoclonal antibodies that bind to PCSK9 and inhibit the protein.

Evolocumab (Repatha, Injection 1/2x week. VERY expensive ($15K/year)

Lower LDL 65% with statins to as low has 25 mg/dL
Long term side effects unknown.

Mild (nasopharyngitis, allergy)

50
Q

Statins (HMG-CoA Reductase Inhibitors) Effect on:
LDL
HDL
Triglycerides
LDL/when combined with PCSK9 Mab

A

Statins (HMG-CoA Reductase Inhibitors) Effect on:
LDL: -40%
HDL: +10%
Triglycerides: decrease
LDL/when combined with PCSK9 Mab: -65%

51
Q

Niacin effect on
LDL
HDL
Triglycerides

A

Niacin effect on
LDL: decrease
HDL: increase
Triglycerides: DECREASE

52
Q

Fibrates effect on
LDL
HDL
Triglycerides

A

Fibrates effect on
LDL: decrease
HDL: increase
Triglycerides: DECREASE

53
Q

Binding Resins effect on LDL.
Absorption Inhibitors on LDL

A

Decreases LDL
Decrease LDL

54
Q

How does Glucagon treat severe bradycardia and hypotension?

A

Glucagon acts through cardiac glucagon receptors to simulate the rate and force of contraction of the heart.

**Useful in treating beta blocker induced cardiac depression.

55
Q

What class of anti-diabetic drug when given alone can cause hypoglycemia?

A

Insulin Secretagouges (Sulfonylurea Glyburide/Glipizide)

56
Q

What class of anti-diabetic is linked to increase levels of lactic acidosis?

A

Biguanides (especially older drugs like phenformin).

Metformin should be avoided or used with extreme caution with acute ingestion of alcohol.

Pharmacology Test 4 (5 decks)

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