Diabetes pharm - Martin

Question 1

rapid-acting insulin drugs

Answer 1

insulin lispro, aspart, glulisine

Question 2

short-acting insulin drugs

Answer 2

regular insulin

Question 3

intermediate acting insulin drugs

Answer 3

NPH and NPL

Question 4

ultra-long acting insulin drugs

Answer 4

Glargine insulin

insulin deetmir

Question 5

Fixed – Mix Insulins

Answer 5

NPH / Regular (50%/50%)
NPH / Regular (70%/30%)
NPL / Lispro (75%/25%)
NPL/ Lispro (50%/50%)
Aspart protamine/aspart (70%/30%)

Question 6

Hypoglycemic Agents

Answer 6

biguanides
sulfonylureas
meglitinides
alpha-glucosidase inhibitors
TZDs
glucagon-like Peptide-1 (GLP-1) agonists
dipeptidyl-peptidase-4 inhibitors (DPP-4)
Amylin analog 
Sodium-Glucose Co-transporter 2 (SGLT2) Inhibitors

Question 7

Biguanides

Answer 7

Metformin

Question 8

Sulfonylureas

Answer 8

Glipizide, Glyburide, Glimepiride

Question 9

Meglitinides

Answer 9

(“Glinides” or Non-sulfonylurea Insulin Releasers)

Repaglinide, Nateglinide

Question 10

a-Glucosidase Inhibitors

Answer 10

Acarbose, Miglitol

Question 11

TZDs

Answer 11

Rosiglitazone, Pioglitazone

Question 12

Glucagon-like Peptide-1 (GLP-1) Agonists

Answer 12

Exenatide

Question 13

Dipeptidyl-Peptidase-4 (DPP-4) Inhibitors

Answer 13

“Gliptins”

Question 14

Amylin analog

Answer 14

Pramlintide

Question 15

Sodium-Glucose Co-transporter 2 (SGLT2) Inhibitors

Answer 15

flozins”

Question 16

Insulin: Biosynthesis and Chemistry

Answer 16

Biosynthesis of Insulin
 cells of pancreatic islet
Preproinsulin - proinsulin - insulin
A and B chains, C peptide

Chemistry:
monomers, dimers, hexamers
Zn2+
Soluble versus semi-crystalline states of the molecule - onset and duration of action

Question 17

Regulation of Insulin Secretion

Answer 17

Insulin secretion is tightly regulated by the interplay of:
nutrients, especially glucose
GI hormones
pancreatic hormones
autonomic neurotransmission

**Glucose is the principal stimulus of insulin secretion

Question 18

Biphasic Insulin Secretion

Answer 18

Normal individuals have two phases of insulin secretion in response to a meal

Phase I - rapid rise and fall
Phase II - slower, more gradual increase

Question 19

things that can stimulate insulin secretion

Answer 19

glucose, of course
amino acids, ketoacids
ach, CCK
Glucagon, GLP-1

Epi, Norepi, Somatostatin inhibit

Question 20

insulin and diabetes

Answer 20

Type 1 diabetes mellitus
no insulin secretion

Type 2
initially, Type 2 DM patient may have elevated plasma insulin levels and tissue insulin resistance, but often 1st phase of insulin release is dysregulated
years later, beta cells fail and insulin levels are low

Question 21

Distribution and Degradation of Insulin

Answer 21

Insulin circulates as the free monomer
Degradation in the liver operates at near maximal capacity
Degradation in the kidney after tubular reabsorption
Uptake by the muscle
t1/2 of insulin is about 5 - 15 minutes
Plasma levels measured by RIA (if necessary)

Question 22

Insulin- Molecular Mechanism of Action

Answer 22

All cells have insulin receptors

Insulin receptor stimulates phosphorylation or dephosphorylation of cell-specific intracellular signal transduction proteins

Question 23

The Insulin Receptor

Answer 23

The insulin receptor is an integral plasma membrane protein complex
Receptor is a heterodimer of alpha and b subunits
Intracellular beta subunits have *** tyrosine kinase enzyme activity
Insulin binding to the receptor stimulates autophosphorylation of the receptor beta subunits and activation of tyrosine kinase activity
Docking proteins bind to the receptor and recruit other mediator proteins to the plasma membrane

Question 24

Regulation of Glucose Transport

Answer 24

Glucose transport is a crucial component of the physiological effects of insulin
Glucose is transported into cells by facilitated diffusion by means of Glucose Transporters (GLUT)
Insulin stimulates reversible translocation of glucose transporters to the plasma membrane
GLUT-4 - muscle and fat cells
GLUT-2 pancreas, liver
Insulin increases synthesis of GLUT1 and GLUT4

Question 25

Regulation of Glucose Metabolism

Answer 25

Insulin stimulates glucose uptake Insulin stimulates glucose storage and utilization Insulin inhibits glycogen breakdown (glycogenolysis) Insulin inhibits glucose synthesis (gluconeogenesis)

Question 26

Central Features of Diabetes Mellitus

Answer 26

Insulin deficiency Insulin resistance Hyperglycemia

Question 27

Type I vs Type II DM

Answer 27

Type 1- young, frequently undernourished, 10-20% prevalence, moderate genetic predisposition, beta cells are destroyed- eliminating the production of insulin Type 2- often over age 35, obesity usually present, 80-90 percent of diagnosed diabetics, very strong genetic predisposition, inability of beta cells to produce appropriate quantities of insulin; insulin resistance; other defects

Question 28

ACCORD Trial

Answer 28

The ACCORD Trial was a large clinical trial in >10,000 patients with patients with Type 2 D, with or at high-risk for CV disease. This trial found that treating patients intensively to a HbA1C target of under 6.0% did not significantly reduce the incidence of major CV events and was associated with increased all-cause mortality compared to patients treated to a target HbA1C of 7.0-7.9%

Question 29

Diabetes Control and Complications Trial (DCCT)

Answer 29

Conclusion: Intensive therapy to attain euglycemia dramatically reduces the incidence of and severity of long-term complications Major problem: * Hypoglycemia The more intense the attempt to maintain “normal” glucose levels, the greater the risk of hypoglycemia Maintenance of Intensive Insulin Therapy requires educated, motivated patient

Question 30

Hemoglobin A1c

Answer 30

``` A convenient index of long-term exposure to elevated glucose. Hemoglobin becomes glycosylated t1/2 120 days Used to monitor therapeutic goals ** Recommendation: Hemoglobin A1c < 7.0% ```

Question 31

Diagnosis of Diabetes

Answer 31

``` Classic signs and symptoms Unequivocally high FPG >126 mg/dL Random glucose of >200 mg/dL FPG of >126 mg/dL on two or more occasions Failure on Oral Glucose Tolerance Test ```

Question 32

Typical Insulin Regimen

Answer 32

Example: 30 Units (U) per day 2/3 total dose before breakfast - 2/3 NPH (14U) - 1/3 Regular (6U) 1/3 total dose in the evening - 1/3 Regular before dinner (3U) - 2/3 NPH at bedtime (7U)

Question 33

Adverse Reaction to Insulin Therapy: Hypoglycemia

Answer 33

``` Hypoglycemia due to: inappropriate dose mismatch of time of injection versus food intake exercise-induced glucose demand increase need for insulin ```

Question 34

hypoglycemia- signs and symptoms, treatment

Answer 34

Signs and Symptoms Sweating, hunger, paresthesias, palpitations, tremor, anxiety confusion, weakness, drowsiness, blurred vision, loss of consciousness ** Treatment Glucose Glucagon

Question 35

Type 2 Diabetes Mellitus

Answer 35

``` Diminished insulin secretion Tissue resistance to insulin Enhanced glucagon Enhanced gluconeogenesis Obesity ```

Question 36

Metformin [Glucophage]

Answer 36

Antihyperglycemic action, ** not hypoglycemic increases insulin action, glycolysis, uptake and utilization by muscle DECREASES gluconeogenesis, hepatic glucose output, intestinal absorption of glucose

Question 37

Metformin [Glucophage] therapy and advantages

Answer 37

Drug of first choice for type II diabetes Monotherapy or added to GLP-1 agonist, DPP-4 inhibitor, glinide, sulfonylurea, or TZD step-up to daily divided doses Advantages: * no weight gain * no hypoglycemia * favorable lipid profile

Question 38

Metformin [Glucophage] side effects

Answer 38

Metformin has advantages over SUs & insulin in some obese, insulin-resistant patients Concern is lactic acidosis (but rare) especially in patients with: - renal or hepatic insufficiency - CV disease Common side effects GI: anorexia, nausea, abdominal discomfort, diarrhea

Question 39

Combinations with metformin

Answer 39

``` Since most patient end up needing more than one drug a number of combination products have been introduced including: Metformin plus: Glipizide Glyburide Linagliptin Pioglitazone Repaglinide Sitagliptin Saxagliptin ``` Combination products simplify dosing but reduce the flexibility in adjusting doses

Question 40

Oral Hypoglycemic Agents Sulfonylureas - the generations

Answer 40

[First Generation: No longer used- Acetohexamide, Chlorpropamide, Tolbutamide, Tolazamide] Second Generation * Glipizide * Glyburide “Third” Generation * Glimeperide

Question 41

Sulfonylureas (SUs): Mechanism of Action

Answer 41

Block ATP-sensitive K+ channel Leads to depolarization and influx of Ca++ * Results in insulin secretion * Adverse Effects: Weight gain and Hypoglycemia

Question 42

Sulfonylureas- key points

Answer 42

* stimulate insulin release SUs indirectly increase tissue sensitivity to insulin, i.e., help overcome insulin resistance Help suppress hepatic glucose output Success depends on functionality of b-cells20-25% of patients fail to respond adequately Subsequent failures result from eventual b-cell failure

Question 43

2nd or 3rd generation Sulfonylureas

Answer 43

Glimeperide Glipizide Glyburide ``` same mechanism, release insulin equally efficacious more potent than 1st generation most costly than 1st generation less severe/persistent hypoglycemia ```

Question 44

Glimepiride

Answer 44

appears to cause * less weight gain than all the other SUs contraindications include sulfa allergy, pregnancy, type 1 DM, ketoacidosis, renal failure, hepatic failure, and major surgery. Once daily doses possible

Question 45

Glipizide and Glyburide

Answer 45

Glipizide Intermediate-acting QD dosing, if >15 mg per day give BID inactive metabolites, no special precautions Glyburide greater incidence of severe prolonged hypoglycemia than glipizide use cautiously in elderly or anyone predisposed to hypoglycemia

Question 46

Non-Sulfonylurea Secretogogues

Answer 46

Repaglinide & Nateglinide Non-sulfonylurea insulin releasing agents Blocks ATP-sensitive K+ channel Binds at different site than sulfonylureas * Short half-life; rapid action * Taken right before meals

Question 47

a-Glucosidase Inhibitors

Answer 47

Acarbose Miglitol Inhibit digestion of complex sugars Decrease sugar uptake after a meal * Cause flatulence and GI upset - leads to poor acceptance & compliance Watch out for hypoglycemia when used with insulin or sulfonylurea

Question 48

Glucagon-like Peptide 1 (GLP-1 agonists)

Answer 48

Exenatide, Liraglutide, Albiglutide, Dulaglutide GLP-1 is a peptide hormone produced from cleavage of the proglucagon precursor - Secreted by intestinal L cells - First discovered from saliva of the Gila monster - Exenatide is an analog of GLP-1 that is highly resistant to inactivation by dipeptidyl peptidase-4 (DPP-4) - Binds to GLP-1 receptor as an agonist

Question 49

GLP-1 Agonists

Answer 49

GLP-1 agonists stimulate: - Glucose-dependent enhancement of insulin secretion - Inhibition of glucagon secretion - Appetite suppression and satiety induction - Reduction of gastric emptying - Possible stimulation of islet cell growth, differentiation, and regeneration *decreases HbA1c, decreases postprandial glucose, causes weight loss * Little hypoglycemia GI upset most common adverse effects but there appears to be some risk for pancreatitis.

Question 50

GLP-1 Agonists therapy regimens

Answer 50

Use as monotherapy or in combination with: - Metformin (in dual therapy) - Metformin + TZD (triple therapy) - Metformin + Sulfonylurea (triple therapy) Not approved for use with insulin Exenatide requires twice-daily SQ injections or there is an extended-release formulations that is injected once per week Liraglutide requires only once-daily injections

Question 51

Dipeptidyl Peptidase-4 Inhibitors(DPP-4 Inhibitors)- administration

Answer 51

``` Sitagliptin, Saxagliptin, Linagliptin DPP-4 hydrolyzes: Glucagon-like peptide-1 (GLP-1) Glucose-dependent insulinotropic peptide (GIP) These drugs are administered * orally* ``` * Monotherapy or combined with metformin, SUs, or TZD * Increases insulin secretion, decreases glucagon and hepatic glucose production, * increases peripheral glucose uptake and utilization

Question 52

DPP-4 Inhibitors side effects/ DDIs

Answer 52

Little hypoglycemia because DPP-4 effects are glucose-dependent Not approved for use with insulin

Question 53

Pramlintide

Answer 53

Pramlintide is a synthetic analog of amylin, a peptide co-secreted with insulin from pancreatic b-cells. The identified metabolic effects of pramlintide are: - centrally-mediated induction of satiety and DECREASE: - of endogenous glucagon production, especially in the postprandial state. - of postprandial hepatic glucose production. - of gastric emptying time. - of postprandial glucose levels Used in Type 1 or type 2 diabetics already using insulin, especially those with insulin resistance requiring large doses of insulin ***Require SQ injections prior to meals and cannot be mixed with insulin

Question 54

Thiazolidinediones (TZDs)

Answer 54

* Pioglitazone * Rosiglitazone * Insulin Sensitizers

Question 55

Thiazolidinediones (TZDs) MOA, uses, risks

Answer 55

Bind to nuclear transcription factors involved in insulin action decreased insulin resistance increased peripheral action of insulin increased glucose uptake, and GLUT-1 & GLUT-4 decreased hepatic glucose output Takes several weeks to develop clinical effect Useful effect since many Type 2 patients are “insulin-resistant” Liver enzyme tests required - idiosyncratic hepatocellular injury Long-term risks have been debated, * ↑ risk of MI with rosiglitazone was reported but was never substantiated; both drugs cause * weight gain; rosiglitazone was restricted in use in the USA but restriction now lifted; pioglitazone taken off the market in Germany and France because of increased risk of bladder cancer. * Cause fluid retention and CHF (2X risk) and increase risk of

Question 56

Sodium-Glucose Co-transporter 2 (SGLT2) Inhibitors

Answer 56

* Canagliflozin, Dapagliflozin, Empagliflozin New drugs just approved in the last several years Oral treatment (once per day) of Type 2 diabetes; in combination with insulin or metformin, ± sulfonylurea or pioglitazone SGLT2 is a membrane protein expressed mainly in the kidney. It transports filtered glucose from the proximal renal tubule into tubular epithelial cells. By inhibiting SGLT2, “flozins” decrease glucose reabsorption, increase urinary glucose excretion, and lower blood glucose levels. Flozins are modestly effective in reducing HbA1c, systolic blood pressure and weight, with a low risk of hypoglycemia. Genital mycotic infections can occur in both men and women; long-term safety still unknown.