Diabetes Pharmacology

Question 1

Insulin Release Physiological Steps (5)

Answer 1

Glucose binds GLUT2 receptor and enters cell
Glucose metabolized and increased ATP closes K+ channel
Depolarization causes Ca2+ influx through VDCC
Gs-Linked GPCR also increases Ca2+ influx
Ca2+ influx causes vesicular insulin release

Question 2

Insulin Types with Modifications and Pharmacokinetics

Rapid (3), Short (1), Intermediate (1), Long (2)

Answer 2

Rapid:
Aspart, Lispro, Glulisine
Decreased oligomer formation
Onset in 5-10 minutes, lasts for 1 hour

Short:
Natural Insulin-Zinc crystals
Normal oligomer formation,
Onset in 30-60 minutes, lasts 10 hours

Intermediate:
NPH (protamine complex)
Normal oligomer formation,
Onset in 1-2 hours, Lasts 10-12 hours

Long:
Detemir, Glargine
Enhanced oligomer formation
Onset 3-4 hours, Lasts 24 hours

Question 3

Insulin

Signal Transduction Pathway (4) and Resultant Actions (2)

Answer 3

Binds receptor tyrosine kinase insulin receptor
PI3K Signaling increases GLUT4 translocation and metabolic enzyme activity
MAPK Signaling increases cell growth and gene expression

GLUT4 increases muscle and adipocyte uptake and utilization of glucose
Increased synthesis of lipids, proteins, glycogen

Question 4

Insulin

Indications (2) Adverse Effects (5)

Answer 4

Diabetes (T1DM, T2DM, Gestational)
Severe Hyperkalemia (with glucose and furosemide)

Hypoglycemia
Lipodystrophy
Insulin resistance
Allergic reactions
Hypokalemia

Question 5

Hypoglycemia

Signs (4) and Treatment (2)

Answer 5

Confusion/Seizure/Coma
Tachycardia/Palpitations/Tremor
Hunger/Nausea
Hypoglycemic unawareness (if on tight control)

Glucose
Glucagon

Question 6

Amylin

Example, Uses (2) Mechanisms of Action (3) Adverse Effects (3) Drug Interaction

Answer 6

Pramlintide

Type 1 and Type 2 Diabetes

Inhibit glucagon secretion
Enhance insulin sensitivity
Decrease gastric emptying (induce satiety)

N/V/D
Anorexia
Severe hypoglycemia

Enhances anticholinergics in GI tract (constipation)

Question 7

Incretins

Example, Mechanism of Action, Effects (5)

Answer 7

GLP-1

Binds Gs GPCR to increase Ca2+ influx and insulin release

Beta cell proliferation
Increased insulin gene expression
Increased insulin secretion
Decreased glucagon secretion
Decreased gastric emptying and satiety

Question 8

Long Acting GLP-1 Agonists

Examples (2) Use, Adverse Effects (4)

Answer 8

Exenatide
Liraglutide

Supplement insufficient GLP-1 action in T2DM

Pancreatitis/Pancreatic cancer
N/V/D
Anorexia
Hypoglycemia

Question 9

DPP-4 Inhibitors

Examples (4) Mechanism of Action, Use and Adverse Effects (4)

Answer 9

Sitagliptin
Linagliptin
Saxagliptin
Alogliptin

Blocks DPP-4 mediated degradation of GLP-1

Adjunct therapy or monotherapy for T2DM

URI’s
Nasopharyngitis
Acute Pancreatitis
Hypoglycemia

Question 10

Sulfonylurea Drugs

First (3) and Second (3) Generation Examples and Differences (2)

Answer 10

Chlorpropamide
Tolbutamide
Tolazamide

Glipizide
Glyburide
Glimepiride

Second generation is more potent and less toxic

Question 11

Sulfonylurea Drugs

Mechanism of Action, Use, Adverse Effects (4)

Answer 11

Bind SUR to block K+ ATP channel

Adjunct therapy or monotherapy for T2DM

Hypoglycemia
Weight Gain
Secondary failure to respond to sulfonylureas
Sulfa allergies

Question 12

Sulfonylurea Drug Interactions

Enhancing (3) and Diminishing (3)

Answer 12

Enhancing:
Sulfonamides, NSAIDs, Clofibrate and Salicylates displace from plasma proteins
Alcohol enhances K+ channel effects
Azoles, Gemfibrozil and Cimetidine inhibit CYPs

Diminishing:
Beta blockers and CCB’s inhibit insulin secretion
Diazoxide antagonizes K+ channel effects
Phenytoin, Griseofulvin and Rifampin induce CYPs

Question 13

Meglitinide Drugs

Examples (2), Mechanism of Action, Use and Adverse Effects (3)

Answer 13

Repaglinide
Nateglinide

Inhibit K+ ATP channel

Control of postprandial hyperglycemia

Hypoglycemia
Secondary failure
Weight gain

Question 14

Metformin

Mechanisms of Action (2) Effects (3) Use, Adverse Effects (3) and Contraindications (3)

Answer 14

Activates AMP-dependent protein kinase
Blocks mitochondrial oxidative phosphorylation

Inhibits lipogenesis and gluconeogenesis
Increases glucose uptake, glycolysis and FA oxidation
Increases insulin sensitivity

First line T2DM treatment

N/V/D
Anorexia
Lactic Acidosis: especially in hypoxia, renal failure and hepatic insufficiency

Hypoxic conditions: Heart failure, COPD
Renal failure
Cirrhosis, Alcoholism

Question 15

Thiazolidinedione Drugs

Examples (2) Mechanism of Action, Effects (5), Pharmacokinetics (3) Uses (2) and Adverse Effects (5)

Answer 15

Pioglitazone
Rosiglitazone

Ligand of nuclear receptor PPAR-gamma

Increased GLUT4 and Insulin receptor transcription
Decreased PEPCK, NFKB, AP-1

Taken oral daily
1-3 months to take effect and persists after stopped
Metabolized by CYPs in liver

Slows progression of prediabetes to T2DM
Type 2 Diabetes maintenance

Weight gain
Edema (increased vascular permeability)
Exacerbation of heart failure
Increased cholesterol
Osteoporosis

Question 16

SGLT2 Inhibitors

Examples (3) Mechanism of Action (2) Effects (5) Uses, Adverse Effects (5)

Answer 16

Canagliflozin
Dapagliflozin
Empagliflozin

Blocks Sodium-Glucose Cotransporter 2 in proximal tubule
Increase glucose excretion by the kidneys

Reduce hyperglycemia
Osmotic diuresis
Weight loss
Decreased blood pressure
Decreased uric acid

Adjunct T2DM therapy

Hypotension
Hypovolemia
Mycotic infections and UTI's
Decreased renal GFR
Hyperkalemia

Question 17

alpha-Glycosidase Inhibitors

Examples (2) Mechanism of Action (2) Use, Adverse Effects (3) Drug Interactions (3)

Answer 17

Acarbose
Miglitol

Impairs alpha-glycosidase to block starch and disaccharide metabolism to monosaccharides
Decreases absorption of sugars (insulin sparing)

Monotherapy or adjunct therapy in T2DM

Malabsorptive diarrhea
Flatulence and bloating
Hypoglycemia (if used with other drugs)

Decreases absorption of Digoxin, Propranolol and Ranitidine