Diabetes Drugs - Endocrine - Medbullets Step 1

Overview

Goals of diabetes treatment
- lower serum glucose to physiologic range
- keep insulin levels in physiologic range
- eliminate insulin resistance
- best initial step in management: weight loss, contractile-based exercise
  - weight loss is more important for insulin sensitivity than is a low-carb diet
Modalities of diabetes treatment
- type I DM
  - insulin
  - low-sugar diet
- type II DM
  - exercise
  - diet
  - insulin
  - 6 classes of drugs shown below

Class	Example	↑ Insulin secretion	↑ Insulin sensitivity	↓ Glucose production	↓ Glucose absorption	Weight	Hypoglycemia
Insulin	Insulin					↑	++
Sulfonylureas	Glyburide	++	+	+		↑	++
Meglitinides	Nateglinide	++	+	+		↑	++
Biguanides	Metformin		+	++			None
Glitazones (thiazolidinediones)	Pioglitazone		++	+/-		↑↓	+
α-glucosidase inhibitors	Acarbose				++		None
GLP-1 mimetics (incretin mimetics)	Exenatide	++		+		↓	+
Amylin analog	Pramlintide	+		+			+

Insulin

Insulin is only given parenterally (subcutaneous or IV)
Various preparations have different durations of action

Other preparations include aspart (rapid), detemir (long)

Preparation	Onset (hrs)	Peak (hrs)	Duration (hrs)
Lispro (rapid-acting)	15 min	0.5-1.5	3-4
Regular (short-acting)	0.5-1	2-4	5-7
NPH (intermediate)	1-2	6-12	18-24
Glargine (long-acting)	1	None	>24

Mechanism
- bind transmembrane insulin receptor
  - activate tyrosine kinase
  - phosphorylate specific substrates in each tissue type
- liver
  - ↑ glycogenesis
    - store glucose as glycogen
- muscle
  - ↑ glycogen and protein synthesis
  - ↑ K⁺ uptake
- fat
  - increase triglyceride storage
Clinical use
- type I DM
- type II DM
- life-threatening hyperkalemia
  - increases intracellular K⁺
- stress-induced hyperglycemia
Toxicity
- hypoglycemia
- hypersensitivity reaction (very rare)
Insulin Synthesis
- first generated as preproinsulin with an A chain and B chain connected by a C peptide.
- c-peptide is cleaved from proinsulin after packaging into vesicles leaving behind the A and B chains

Sulfonylureas

Drugs
- first generation
  - tolbutamide
  - chlorpropamide
- second generation
  - glyburide
  - glimepiride
  - glipizide
Mechanism
- glucose normally triggers insulin release from pancreatic β cells by increasing intracellular ATP
  - → closes K⁺ channels → depolarization → ↑ Ca²⁺ influx → insulin release
- sulfonylureas mimic action of glucose by closing K⁺ channels in pancreatic β cells
  - → depolarization → ↑ Ca²⁺ influx → insulin release
- continued use results in
  - ↓ glucagon release
  - ↑ insulin sensitivity in muscle and liver
Clinical use
- type II DM
  - stimulates release of endogenous insulin
- cannot be used in type I DM due to complete lack of islet function
Toxicity
- first generation
  - disulfiram-like effects
    - especially chlorpropamide
- second generation
  - hypoglycemia
- weight gain

Megltinides

Drugs
- nateglinide
- repaglinide
Mechanism
- binds to K⁺ channels on β-cells → postprandial insulin release
  - different site than sulfonylureas
Clinical use
- type 2 diabetes mellitus
  - may be used as monotherapy, or in combination with metformin
Toxicity
- ↑ risk of hypoglycemia
  - at even greater risk in those with renal failure
- weight gain

Biguanides

Drugs
- metformin
Mechanism
- ↓ hepatic gluconeogenesis
  - exact mechanism unknown
  - appears to inhibit complex 1 of respiratory chain
- may also
  - ↑ insulin sensitivity
  - ↑ glycolysis
  - ↓ serum glucose levels
- ↓ postprandial glucose levels
Clinical use
- first-line therapy in type II DM
Toxicity
- no hypoglycemia
- no weight gain
- lactic acidosis is most serious side effect
  - contraindicated in renal failure

Glitazones (thiazolidinediones)

Thiazolidinediones, also known as the "-glitazones"
Drugs
- pioglitazone
- rosiglitazone
Mechanism
- bind to nuclear receptors involved in transcription of genes mediating insulin sensitivity
  - peroxisome proliferator-activating receptors (PPARs)
- ↑ insulin sensitivity in peripheral tissue
- ↓ gluconeogenesis
- ↑ insulin receptor numbers
- ↓ triglycerides
Clinical use
- type II DM
  - as monotherapy or in combination with other agents
  - contraindicated in CHF
    - associated with increased risk of MI (in particular rosiglitazone)
Toxicity
- weight gain
- edema
- hepatotoxicity
- CV toxicity
- less risk of hypoglycemia vs. sulfonylureas

α-glucosidase inhibitors

Drugs
- acarbose
- miglitol
Mechanism
- inhibit α-glucosidases in intestinal brush border
  - delayed sugar hydrolysis
  - delayed glucose absorption
  - ↓ postprandial hyperglycemia
  - ↓ insulin demand
Clinical use
- type II DM
  - as monotherapy or in combination with other agents
Toxicity
- no hypoglycemia
- GI upset

Amylin mimetics

Drugs
- pramlintide
Mechanism
- synthetic analogue of human amylin that acts in conjunction with insulin
- ↓ release of glucagon
- delays gastric emptying
Clinical use
- type I and II DM
Toxicity
- hypoglycemia
  - if given with insulin
- nausea
- diarrhea

GLP-1 analogs

Drugs
- exenatide
Mechanism
- GLP-1 is an incretin released from the small intestine that aids glucose-dependent insulin secretion
  - basis for drug mechanism is the observation that more insulin secreted with oral glucose load compared to IV
- exenatide is a GLP-1 agonist
  - ↑ insulin
  - ↓ glucagon release
- the class of dipeptidyl peptidase inhibitors ↓ degradation of endogenous GLP-1
  - e.g.) sitagliptin, -gliptins
Clinical use
- type II DM
Toxicity
- nausea, vomiting
- pancreatitis
- hypoglycemia
  - if given with sulfonylureas

SGLT-2 Inhibitors

Drugs
- canagliflozin
- empagliflozin
Mechanism
- glucose is reabsorbed in the proximal tubule of the nephron by the sodium-glucose cotransporter 2 (SGLT2)
- SGLT2-inhibitors lower serum glucose by increasing urinary glucose excretion
- the mechanism of action is independent of insulin secretion or action
Clinical use
- type II DM
Toxicity
- dehydration
- urinary and genital infections

Blood, Plasma, Serum	Reference Range
ALT	8-20 U/L
Amylase, serum	25-125 U/L
AST	8-20 U/L
Bilirubin, serum (adult) Total // Direct	0.1-1.0 mg/dL // 0.0-0.3 mg/dL
Calcium, serum (Ca²⁺)	8.4-10.2 mg/dL
Cholesterol, serum	Rec: < 200 mg/dL
Cortisol, serum	0800 h: 5-23 μg/dL //1600 h: 3-15 μg/dL 2000 h: ≤ 50% of 0800 h
Creatine kinase, serum	Male: 25-90 U/L Female: 10-70 U/L
Creatinine, serum	0.6-1.2 mg/dL
Electrolytes, serum
Sodium (Na⁺)	136-145 mEq/L
Chloride (Cl^-)	95-105 mEq/L
Potassium (K⁺)	3.5-5.0 mEq/L
Bicarbonate (HCO₃^-)	22-28 mEq/L
Magnesium (Mg²⁺)	1.5-2.0 mEq/L
Estriol, total, serum (in pregnancy)
24-28 wks // 32-36 wks	30-170 ng/mL // 60-280 ng/mL
28-32 wk // 36-40 wks	40-220 ng/mL // 80-350 ng/mL
Ferritin, serum	Male: 15-200 ng/mL Female: 12-150 ng/mL
Follicle-stimulating hormone, serum/plasma	Male: 4-25 mIU/mL Female: premenopause: 4-30 mIU/mL midcycle peak: 10-90 mIU/mL postmenopause: 40-250
pH	7.35-7.45
PCO₂	33-45 mmHg
PO₂	75-105 mmHg
Glucose, serum	Fasting: 70-110 mg/dL 2-h postprandial:<120 mg/dL
Growth hormone - arginine stimulation	Fasting: <5 ng/mL Provocative stimuli: > 7ng/mL
Immunoglobulins, serum
IgA	76-390 mg/dL
IgE	0-380 IU/mL
IgG	650-1500 mg/dL
IgM	40-345 mg/dL
Iron	50-170 μg/dL
Lactate dehydrogenase, serum	45-90 U/L
Luteinizing hormone, serum/plasma	Male: 6-23 mIU/mL Female: follicular phase: 5-30 mIU/mL midcycle: 75-150 mIU/mL postmenopause 30-200 mIU/mL
Osmolality, serum	275-295 mOsmol/kd H₂O
Parathyroid hormone, serume, N-terminal	230-630 pg/mL
Phosphatase (alkaline), serum (p-NPP at 30° C)	20-70 U/L
Phosphorus (inorganic), serum	3.0-4.5 mg/dL
Prolactin, serum (hPRL)	< 20 ng/mL
Proteins, serum

Hematologic	Reference Range
Bleeding time	2-7 minutes
Erythrocyte count	Male: 4.3-5.9 million/mm³ Female: 3.5-5.5 million mm³
Erythrocyte sedimentation rate (Westergren)	Male: 0-15 mm/h Female: 0-20 mm/h
Hematocrit	Male: 41%-53% Female: 36%-46%
Hemoglobin A1c	≤ 6 %
Hemoglobin, blood	Male: 13.5-17.5 g/dL Female: 12.0-16.0 g/dL
Hemoglobin, plasma	1-4 mg/dL
Leukocyte count and differential
Leukocyte count	4,500-11,000/mm³
Segmented neutrophils	54%-62%
Bands	3%-5%
Eosinophils	1%-3%
Basophils	0%-0.75%
Lymphocytes	25%-33%
Monocytes	3%-7%
Mean corpuscular hemoglobin	25.4-34.6 pg/cell
Mean corpuscular hemoglobin concentration	31%-36% Hb/cell
Mean corpuscular volume	80-100 μm³
Partial thromboplastin time (activated)	25-40 seconds
Platelet count	150,000-400,000/mm³
Prothrombin time	11-15 seconds
Reticulocyte count	0.5%-1.5% of red cells
Thrombin time	< 2 seconds deviation from control
Volume
Plasma	Male: 25-43 mL/kg Female: 28-45 mL/kg
Red cell	Male: 20-36 mL/kg Female: 19-31 mL/kg

Cerebrospinal Fluid	Reference Range
Cell count	0-5/mm³
Chloride	118-132 mEq/L
Gamma globulin	3%-12% total proteins
Glucose	40-70 mg/dL
Pressure	70-180 mm H₂O
Proteins, total	< 40 mg/dL

Sweat	Reference Range
Chloride	0-35 mmol/L
Urine
Calcium	100-300 mg/24 h
Chloride	Varies with intake
Creatinine clearance	Male: 97-137 mL/min Female: 88-128 mL/min
Estriol, total (in pregnancy)
30 wks	6-18 mg/24 h
35 wks	9-28 mg/24 h
40 wks	13-42 mg/24 h
17-Hydroxycorticosteroids	Male: 3.0-10.0 mg/24 h Female: 2.0-8.0 mg/24 h
17-Ketosteroids, total	Male: 8-20 mg/24 h Female: 6-15 mg/24 h
Osmolality	50-1400 mOsmol/kg H₂O
Oxalate	8-40 μg/mL
Potassium	Varies with diet
Proteins, total	< 150 mg/24 h
Sodium	Varies with diet
Uric acid	Varies with diet
Body Mass Index (BMI)	Adult: 19-25 kg/m²