Pharmacology

Question 1

What are the steps of insulin synthesis? (3)

Answer 1

1. Pancreatic B-cells make pre-pro-insulin
2. SP domain is removed to result in pro-insulin
3. 3 disulfide bridges are formed and the C peptide is removed = insulin

Question 2

Main MOA of action of the counterregulatory hormones
Epinephrine
Cortisol
Growth hormone

Answer 2

Epinephrine
- glycogenolysis
- gluconeogenesis

Cortisol
- promotes gluconeogenesis
- impairs insulin secretion

Growth hormone
- decreases glucose utilization/transport

Question 3

What is the structure of insulin?

Answer 3

51 amino acids with A and B chains linked by 3 disulfide bonds

Question 4

What is the primary regulator of insulin secretion?

Answer 4

Glucose

Question 5

What are the steps for insulin secretion? (6)

Answer 5

1. B-cells are hyperpolarized in resting state (insulin stored in vesivles)
2. Glucose enters the cell through GLUT4 (glucose transporters)
   - hexokinase converts glucose to G6P
3. Glucose is metabolized to inc ATP production
4. inc ATP and depolarization closes the K+ channel
5. Depolarization leads to opening voltage Ca2+ channels
6. Calcium enters the cell leading to exocytosis of insulin vesicles into bloodstream

Question 6

What are the physiological effects when insulin is released? (3)

Answer 6

1. Inc glucose in muscle, liver, and adipose tissue
2. Suppresses gluconeogenesis and FFA release
3. Anabolic actions: glycogenesis, lipogenesis, protein synthesis

Question 7

How does the insulin receptor work?

Answer 7

Insulin receptor 2 subunits A and B
1. Insulin binds A subunits –> brings B subunits close together
2. B subunits (contain tyrosine kinase) phosphorylate each other –> activate other proteins

Question 8

What is the structure of amino acids for the following insulin
Lispro
glulisine
aspart
detemir
degludec
glargine

Answer 8

Lispro Lys Pro
glulisine Lys Glu
aspart Asp
detemir Lys
degludec Asp Pro Lys A-chain
glargine Gly Arg Arg

Question 9

Which insulins bind to albumin

Answer 9

Detemir and degludec

Question 10

Rank the insulin from quickest to longest acting.

Answer 10

Aspart (Fiasp)

Pre-mixed rapid acting

Fast-acting
- Aspart Novorapid
- Glusline/lispro

Short-acting
- Regular human insulin (humulin)

pre-mixed NPH

intermediate-acting NPH

Long acting
Detemir
glargine U-100
glargine U-300
glargine biosimilar
Degludec

Question 11

Which insulin can you not mix with other insulins

Answer 11

insulin glargine because it will precipitate with the other insulins

Question 12

Where does glucagon come from?

Answer 12

Secreted by A cells of the pancreas in response to hypoglycemia
- derived from a larger precursor protein, proglucagon

Question 13

What is the glucagon receptor structure?

Answer 13

GPCR and coupled G-alpha subunits

Question 14

What is the MOA of glucagon (2)

Answer 14

1. Promotes breakdown of glycogen to glucose
2. Increases gluconeogenesis and ketogenesis

Question 15

What are other uses for glucagon

Answer 15

• reverse B-blocker overdose
• bowel radiology (antiperistaltic - promotes bowel distension)

Question 16

What is the primary MOA of sulfonylureas? How does it work

Answer 16

Primary MOA: stimulate the release of insulin from B cells
- act directly on the ATP driven potassium channel to close it
- depolarization of the cell (without glucose intake) to open Ca2+ channel
- Ca2+ influx to release insulin via exocytosis

Question 17

What are ADRs of sulfonylureas? is it safe in renal-failure

Answer 17

Hypoglycemia
Weight gain

safe in renal-failure

Question 18

Which drug class is the most similar to sulfonylureas? whats the difference

Answer 18

Meglitinides (repaglinide)

Difference
- less risk of hypoglycemia
- better postprandial control
and usually dosed around meals (no meal = no drug)

Question 19

What is the MOA of biguanides? metformin

Answer 19

Increased insulin sensitivity in target tissues
- antihyperglycemic drug
- NO HYPO

Question 20

What are ADRs of metformin/biguanides? is it safe in renal-failure?

Answer 20

GI N/V/D
Anorexia

Completely cleared by kidneys
- not safe in eGFR under 30

Question 21

What are long-term effects of taking metformin?

Answer 21

Reduced vitamin B12 levels

Question 22

What is the primary MOA of thiazolidinediones TZDs

Answer 22

Changes in the transcription of genes
- indirectly inc insulin sensitivity

Question 23

What are the ADRs for TZDs

Answer 23

CV disease mimic Heart failure such as fluid retention and edema

Weight gain

Question 24

What is the MOA of alpha-glucosidase inhibitors

Answer 24

oligosaccharide competitively binds to alpha-glucosidase to prevent breakdown of disaccharides to monosaccharides

Acarbose

Question 25

What are the ADRs of alpha-glucosidase inhibitor

Answer 25

Limited systemic absorption, act locally in the GI tract Lots of diarrhea

Question 26

What is the MOA of GLP-1 receptors agonists? Which lab value does it effect more?

Answer 26

Bind to G alpha/s coupled receptor --> promote insulin secretion - reduced glucagon secretion - slower gastric emptying as soon as you have food in the stomach insulin is released BEFORE glucose levels start to rise Problem: GLP-1 is broken down in 1-2 mins by DPP-IV Solution: GLP-1 agonists and DPP-IV inhibitors - therefore, best for PPG (less effect on fasting glucose)

Question 27

What are some ADRs of GLP-1 receptor agonists?

Answer 27

N/V (up to 50%) due to delayed gastric emptying Weight loss Acute pancreatitis Risk of cancer thyroid

Question 28

What is the newest GLP-1 receptor agonist that has more efficacy for glycemic control and weight loss

Answer 28

Tirzepatide dual GIP and GLP-1 receptor agonist

Question 29

Which GLP-1 receptor agonist are clearned by the kidney? (2)

Answer 29

Exenatide Lixisenatide

Question 30

What is the MOA of DPP-IV inhibitor

Answer 30

Increases half-life of GLP-1 and GIP problem: DPP-IV usually removes 2 AA off incretins (GLP-1,GIP) which results in their inactivation improves insulin secretion in response to food - reduces glucagon release - reduces hyperglycemia - little effect on gastric emptying or satiety no weight loss

Question 31

Which DPP-IV inhibitors are renally cleared? Which are not

Answer 31

Renaly cleared - sitagliptin (januvia) - saxagliptin Not renally cleared - Linagliptin (trajenta)

Question 32

What is the MOA of SGLT-2 inhibitors

Answer 32

prevents/decrease glucose reabsorption in the kidneys - glucose remains in urine - results in glycosuria (sugar in pee) + osmotic diuresis (pee more)

Question 33

What are the benefits of SGLT-2 inhibitors

Answer 33

Loss of calories in excreted glucose --> weight loss Lower BP through water loss low hypo risk

Question 34

What are the ADRs of SGLT-2 inhibitors

Answer 34

- Glucose in urine --> yeast infection -> UTI - Thirst, inc urination, nausea - hypovolemic - risk of DKA - postural hypotension, lightheadedness

Question 35

T/F SGLT-2 inhibitors have reduced efficacy in renal patient but still have renal protective effects?

Answer 35

True