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23) Diabetes Flashcards

1
Q

The endocrine pancreas in the adult human consists of

A
  • Approximately 1 million islets of Langerhans
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2
Q

Within the islets, at least five hormone-producing cells are ­present. The hormone products related to diabetes include:

A
  • Insulin
  • Islet amyloid polypeptide (IAPP, or amylin)
  • Glucagon
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3
Q

Insulin

A
  • Storage and anabolic hormone of the body
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4
Q

Islet amyloid polypeptide (IAPP, or amylin)

A
  • Also secreted by β-cells

- Modulates appetite, gastric emptying, and glucagon/insulin secretion

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5
Q

Glucagon

A
  • Hyperglycemic factor that mobilizes glycogen stores
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6
Q

Diabetes mellitus

A
  • Elevated blood glucose associated with absent or inadequate pancreatic insulin secretion
  • With or without concurrent impairment of insulin action
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7
Q

The disease states underlying the diagnosis of diabetes mellitus are now classified into four categories

A
  • Type 1
  • Type 2
  • Other
  • Gestational
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8
Q

Pre-diabetes glucose test values

A
  • A1C = 5.7-6.4%
  • Fasting = 100-125 mg/dL
  • 2 hour OGTT 140-199 mg/dL
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9
Q

Confirmation diagnostic glucose test values

A
  • A1C = >6.5%
  • Fasting = >126 mg/dL
  • 2 hour OGTT = >200 mg/dL (or random > 200 with classic symptoms)
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10
Q

GDM (1-step strategy) glucose values

A
  • A1C = N/A
  • Fasting = ≥92 mg/dL
  • 1 hr: ≥180 mg/dL
  • 2 hr: ≥153 mg/dL
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11
Q

OGTT

A
  • Oral glucose tolerance test (75g glucose)
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12
Q

Types of drugs used in diabetes mellitus

A
  • Insulins

- Non-insulin drugs

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13
Q

Types of insulin used in diabetes

A
  • Rapid, short acting
  • Intermediate acting
  • Slow, long-acting
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14
Q

Rapid, short acting insulin drugs

A
  • Lispro, regular
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15
Q

Intermediate acting insulin drugs

A
  • NPH

- Lente

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16
Q

Slow, long acting insulin drugs

A
  • Glargine
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17
Q

Types of non-insulin drugs used in diabetes

A
  • Insulin secretagogues
  • Biguanides
  • Alpha-glucosidase inhibitors
  • Thiazodinediones
  • Amylin analogs
  • Incretin modulators
  • SGLT2 inhibitors
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18
Q

Insulin secretagogues

A
  • Glipizide
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19
Q

Biguanides

A
  • Merformin
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20
Q

Alpha-glucosidase inhibitors

A
  • Acarbose
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21
Q

Thiazolidinediones

A
  • Pioglitazone
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22
Q

Amylin analogs

A
  • Pramlintide
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23
Q

Incretin modulators

A
  • GLP-1 analog (exenatide)

- DPP-4 inhibitor (sitagliptin)

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24
Q

SGLT2 inhibitors

A
  • Canalgiflozin
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25
Q

Insulin is a small protein or peptide i.e. it cannot be taken orally because

A
  • Digestive enzymes will break the peptide or protein into basic unit amino acids
  • Therefore insulin is given as an injection (except for the new Afrezza®)
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26
Q

Insulin is secreted in response to

A
  • All insulin secretagogues
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27
Q

Insulin is classified based on

A
  • How quickly they take effect (onset of action)

- How long they work for (duration of action)

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28
Q

Basal-bolus strategy

A
  • Taking a longer acting form of insulin to keep blood glucose levels stable through periods of fasting
  • Take separate injections of shorter acting insulin to prevent rises in blood glucose levels resulting from meals
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29
Q

The goal of subcutaneous insulin therapy

A
  • Replicate normal physiologic insulin secretion

- Replace the background or basal (overnight, fasting, and between-meal) as well as bolus or prandial (mealtime) insulin

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30
Q

_____ % of the exogenous insulin is cleared by the _____ and ____ % is removed by the _____

A
  • 60% by kidneys

- 30-40% by liver

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31
Q

Four principle types of injected insulin

A
  • Rapid
  • Short
  • Intermediate
  • Long
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32
Q

Rapid acting has a very fast onset and short duration of action, and also contains

A
  • Small amount of zinc to improve the stability
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33
Q

Short acting has a fast onset of action, and also contains

A
  • Small amount of zinc to improve the stability
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34
Q

Intermediate acting insulin

A
  • Neutral protamine Hagedorn [NPH] insulin
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35
Q

Rapid acting insulin injection schedule

A
  • Should be taken immediately before the meal

- Insulin lispro, aspart and glulisine DOA: 4-5 h i.e. decrease the risk of post-meal hypoglycemia

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36
Q

Rapid acting insulin brand/generic names (LAAG)

A
  • Humalog (insulin lispro)
  • Novolog (insulin aspart)
  • Apidra (insulin glulisine)
  • Afrezza (oral inhalation)
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37
Q

Humalog, novolog, apidra OAA/peak/DOA

A
  • OAA = 5-15 min
  • Peaks = 1 h
  • DOA = 4-5 h
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38
Q

Afrezza OAA/peak/DOA

A
  • OAA = 15 min
  • Peaks = 1 h
  • DOA = 3 h
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39
Q

Short acting insulin injection schedule

A
  • Administered 30-45 min before mealtime

- Only type that should be administered IV

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40
Q

Short acting insulin is useful for

A
  • Management of diabetic ketoacidosis

- Insulin requirement after a surgery

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41
Q

Short acting insulin brand/generic names

A
  • Humulin R U500 (regular)

- Novolin R (regular)

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42
Q

Short acting insulin (Humulin R U500 and Novolin R) OAA/peak/DOA

A
  • OAA = 30 min
  • Peak = 2 h
  • DOA = 5-8 h
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43
Q

Long acting insulins characteristics

A
  • Soluble, peakless, long acting insulin analogue

- Usually given once a day

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44
Q

Intermediate acting insulins brand/generic names

A
  • Humulin N (NPH)

- Novolin N (NPH)

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45
Q

Intermediate acting insulins OAA/DOA

A
  • OAA = 1-3 h

- DOA = 4-12 h

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46
Q

Long acting insulins brand/generic names

A
  • Levemir (Insulin detemir)
  • Lantus, Toujeo, Basalgar (Insulin glargine)
  • Tresiba U200 (Insulin degludec)
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47
Q

Levemir (long acting insulin) OAA/DOA

A
  • OAA = 3 h

- DOA = 24 h

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48
Q

Lantus, Toujeo, Basalgar (long acting insulin) OAA/DOA

A
  • OAA = 3 h

- DOA = 24 h

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49
Q

Tresiba U200 (long acting insulin) OAA/DOA

A
  • OAA = 1 h

- DOA = 24 h

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50
Q

Hypoglycemia signs/symptoms

A
  • Sympathetic: tachycardia, palpitations, sweating
  • Parasympathetic: nausea and hunger
  • Severe hypoglycemia may lead to coma
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51
Q

Treatment for hypoglycemia

A
  • Glucose administration
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52
Q

Side effects of insulin

A
  • Hypoglycemia
  • Insulin allergy
  • Atrophy of subcutaneous tissue at injection site, redness, itching, edema
  • Hunger and nausea
  • Potassium shift
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53
Q

Insulin allergy is usually reduced with

A
  • Human analogue insulin
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54
Q

Potassium shift from insulin administration

A
  • Extra to intracellular space

- Decreasing serum potassium concentration

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55
Q

Afrezza side effects

A
  • Cough, pulmonary function should be monitored

- Caution in smokers and patients with COPD

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56
Q

Drugs that primarily stimulate insulin release by binding to the sulfonylurea (SU) receptor

A
  • First generation SU
  • Second generation SU
  • Meglitinide analogues
  • Drugs that mimic incretin and amylin
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57
Q

Drugs that primarily lower glucose levels by their actions on the liver, muscle and adipose tissue

A
  • Biguanides

- Thiazolidinediones

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58
Q

Drugs that affect absorption of glucose

A
  • α-glucosidase inhibitors
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59
Q

Drugs that mimic incretin effect or prolong incretin action

A
  • Glucagon-like peptide 1 (GLP-1)

- Dipeptidyl peptidase-4 (DPP-4) inhibitors

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60
Q

Other hypoglycemic drugs

A
  • Amylin mimetic
  • Bile acid sequestrant
  • Dopamine-2 agonist
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61
Q

Oral anti-diabetic drug options/actions

A
  • Drugs that primarily stimulate insulin release by binding to the sulfonylurea (SU) receptor
  • Drugs that primarily lower glucose levels by their actions on the liver, muscle and adipose tissue
  • Drugs that affect absorption of glucose
  • Drugs that mimic incretin effect or prolong incretin action
  • Sodium-glucose cotransporter 2 (SGLT2) inhibitors
  • Other hypoglycemic drugs
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62
Q

Sulfonylureas (SU) MOA

A
  • SU binds to SU receptor that is associated with a beta-cell inward rectifier ATP-sensitive potassium channel
  • Binding of a SU inhibits the efflux of potassium ions through the channel
  • Results in depolarization which opens a voltage-gated calcium channel
  • Results in calcium influx and the release of preformed insulin
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63
Q

SU metabolism

A
  • Metabolized in the liver to inactive metabolites
  • Metabolites are excreted in the kidney
  • 2nd generation has metabolites partly excreted in the bile
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64
Q

Advantages of 2nd generation SU

A
  • Greater affinity to receptor which lower effective doses and plasma levels
  • 100 times more potent
  • Have shown less hypoglycemic side effects
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65
Q

2nd generation SU generic names

A
  • Glyburide
  • Glipizide
  • Glimepiried
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66
Q

Glyburide (2nd generation SU) brand names/DOA

A
  • Diabeta
  • Miconase
  • Glynase
  • DOA = 10-24 h
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67
Q

Glipizide (2nd generation SU) brand names/DOA

A
  • Glucotrol
  • Glucotrol XL
  • DOA = 10-24 h
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68
Q

Glimepiride (2nd generation SU) brand names/DOA

A
  • Amaryl

- DOA = 12-24 h

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69
Q

2nd generation SU side effects

A
  • Hypoglycemia (unknown MOA)
  • At higher doses, block K+ channels (might increase cardiovascular events)
  • Sulfate allergy (contains sulfonamide moiety)
  • Nausea, headaches, weight gain
  • Hepatitis
70
Q

Hematologic side effects associated with 2nd generation SU

A
  • Thrombocytopenia
  • Leukopenia
  • Aplastic anemia
  • Hemolytic anemia
71
Q

Glipizide and glimepiride are substrates of

72
Q

MOA of meglitinide analogues

A
  • Modulate β-cell insulin release by inhibiting the efflux of K+
  • Overlap with the SU in their molecular sites of action (two binding sites in common with the SU and one unique)
73
Q

Meglitinide analogues generic/brand names

A
  • Repaglinide (Prandin)

- Nateglinide (Starlix)

74
Q

Repaglinide (Prandin) T1/2, DOA, metabolism

A
  • T1/2 = 1 h
  • DOA = 4-7 h
  • Metabolism = hepatic CYP3A4
75
Q

Nateglinide (Starlix) T1/2, DOA, metabolism

A
  • T1/2 = 1 h
  • DOA = 4 h
  • Metabolism = hepatic CYP3A4 and CYP2C9
76
Q

Because of its rapid onset, meglitinide analogues are used in controlling

A
  • Postprandial glucose excursions
77
Q

Meglitinide analogues can be used in patients with

A
  • Renal impairment

- Elderly

78
Q

Meglitinite analogues do NOT contain

A
  • Sulfure moiety

- Can be used in sulfur allergy patients that cannot take SU

79
Q

Meglitinide analogue side effects

A
  • Hypersensitivity to the molecule
  • Diabetic ketoacidosis
  • Patients with hepatic impairment
  • Causes hypoglycemia
  • Headaches
  • Upper respiratory tract infections
  • Urinary tract infections
  • Heartburn
  • Weight gain
80
Q

Biguanides

A

Generic
- Metformin

Brands

  • Glucophage
  • Glumetza
  • Glucophage XR
  • Fortamet
  • Riomet
81
Q

Metformin MOA

A
  • Full explanation remains elusive

- Primary effect is reduction of hepatic glucose production

82
Q

Biguanides (metformin) are called

A
  • Euglycemic agents

- Rarely cause hypoglycemia

83
Q

Metformin T1/2

84
Q

Metformin is not bound to

A
  • Plasma protein
85
Q

Metformin metabolism/excretion

A
  • Not metabolized

- Excreted by kidneys as the active compound

86
Q

Biguanide GI toxicities

A
  • Dose related
  • Occur in up to 20%
  • Anorexia, nausea, vomiting, abdominal pain, and diarrhea (discontinue if persistent diarrhea)
87
Q

Biguanide interferes with

A
  • Calcium dependent absorption of vitamin B12

- Can lead to deficiency (especially for patients with peripheral neuropathy and macrocytic anemia)

88
Q

Biguanides in patients with renal insufficiency

A
  • Accumulate

- Cause lactic acidosis

89
Q

Cautions when taking biguanides

A
  • Hypersensitivity
  • Renal dysfunction
  • Acute or chronic metabolic acidosis
  • Congestive heart failure patients
  • GI: nausea, vomiting, and diarrhea
  • Chest discomfort, abdominal discomfort
  • Upper respiratory tract infection
90
Q

Thiazolidinediones act to

A
  • Decrease insulin resistance
91
Q

Thiazolidinediones are ligands of

A
  • Peroxisome proliferator-activated receptor gamma (PPAR-Ɣ), part of the steroid and thyroid superfamily of nuclear receptors
92
Q

PPAR-Ɣ receptors are found in

A
  • Muscle
  • Fat
  • Liver
93
Q

Thiazolidinedinones modulate the expression of genes involved in

A
  • Lipid and glucose metabolism
  • Insulin signal transduction
  • Adipocyte and other tissue differentiation
94
Q

Effects of thiazolidinediones

A
  • Increase glucose transporter expression (GLUT 1 and 4)
  • Decrease free fatty acid levels
  • Decrease hepatic glucose output
  • Increase differentiation of preadipocytes to adipocytes
95
Q

Thiazolidinediones generic/brand names

A
  • Pioglitazone (Actos)

- Rosiglitazone (Avandia)

96
Q

Pioglitazone (Actos) metabolism

A
  • Hepatic

- Substrate and inhibitor of CYP2C8 and CYP3A4

97
Q

Rosiglitazone (Avandia) metabolsim

A
  • Hepatic

- Substrate and inhibitor of CYP2C8

98
Q

Other effects of Pioglitazone (Actos)

A
  • Decrease TG

- Increase HDL

99
Q

Other effects of Rosiglitazone (Avandia)

A
  • Increase HDL
  • Increase LDL
  • Increase total cholesterol
100
Q

Pioglitazone (Actos) peak, T1/2, binding

A
  • Peak = 2 h
  • T1/2 = 7 h
  • 99% protein bound
101
Q

Rosiglitazone (Avandia) peak, T1/2, binding

A
  • Peak = 1 h
  • T1/2 = 4 h
  • 99% protein bound
102
Q

Thiazolidinediones side effects

A
  • Fluid retention, edema (may increase plasma volume/cardiac hypertrophy)
  • Heart failure
  • Anemia (mostly because of dilutional effect of increase plasma volume)
  • Weight gain
  • Headaches
103
Q

Thiazolidinediones contraindications

A
  • Contraindicated if hypersensitivity

- Contraindicated if acute liver disease (transaminases more than 2.5 times the upper limits)

104
Q

MOA of α-glucosidase inhibitors

A
  • Competitively inhibit the intestinal α-glucosidase enzymes

- Reduce post-meal glucose excursions by delaying the digestion and absorption of starch and disaccharides

105
Q

Acarbose (Precose) and miglitol (Glyset) are potent inhibitors of

A
  • Glucoamylase
  • α-amylase inhibited by Acarbose
  • Sucrase
  • Less effect on isomaltase, hardly any on trehalase and lactase
106
Q

α-glucosidase inhibitors binding site/type

A
  • Reversibly, competitively, and in a dose-dependent manner

- Oligosaccharide binding site of α-glucosidase enzymes in the brush border of the small intestinal mucosa

107
Q

As a consequence of α-glucosidase inhibitors binding, hydrolysis is prevented

A
  • Effect lasts for 4 to 6 hours if acarbose is present at the site of enzymatic action at the same time as the oligosaccharides
  • Thus acarbose must be administered with the first bite of a main meal
108
Q

α-glucosidase inhibitors metabolism

A
  • Exclusively via GI tract principally by intestinal bacteria and digestive enzymes
  • 35% is urine excreted (dose adjustment needed in case of renal impairment)
109
Q

α-glucosidase inhibitors side effects

A
  • GI: Flatulence, diarrhea and abdominal pain
  • Increase in liver enzymes (AST and ALT)
  • May increase the risk of hypoglycemia when administered with SU
110
Q

Cause of GI side effects associated with α-glucosidase inhibitors

A
  • Unabsorbed starches and sugars entering the large bowels are fermented by the bacteria there
  • Causes flatulence and diarrhea as a commonly seen side effect in higher doses
111
Q

α-glucosidase inhibitors contraindications

A
  • Hypersensitivity
  • Diabetic ketoacidosis or cirrhosis
  • Inflammatory bowel disease
  • Colonic ulceration
  • Partial or predisposed intestinal obstruction
  • Chronic intestinal diseases
112
Q

An oral glucose load (glucagon-like-peptide-1) provokes

A
  • Higher insulin response compared with an equivalent dose IV
  • This is because the oral glucose causes a release of gut hormones
113
Q

Release of gut hormones with oral glucose

A
  • Incretins or glucagon-like peptide-1 (GLP-1)

- Glucose-­dependent insulinotropic peptide (GIP), that amplify the glucose-induced insulin secretion

114
Q

Other biologic effects of GLP-1

A
  • Suppresses glucagon secretion
  • Delays gastric emptying
  • Reduces apoptosis of human islets in culture
115
Q

GLP-1 is rapidly degraded by

A
  • Dipeptidyl peptidase-4 (DPP-4)
  • Other enzymes such as endopeptidase
  • Cleared by the kidney
116
Q

Generic GLP-1 names

A
  • Exenatide
  • Liraglitude
  • Lixisenatide
  • Albiglutide
  • Dulaglutide
117
Q

Exenatide (GLP-1) brand names

A
  • Byetta (IR): Twice a day

- Bydureon (ER): Once a week

118
Q

Liraglutide brand names

119
Q

Lixisenatide brand names

A
  • Adlyxin

- If combined with insulin the brand is Soliqua

120
Q

Albiglutide brand names

121
Q

Dulaglutide brand names

122
Q

Exenatide, liraglutide, and lixisenatide dose, T/12, peak, DOA

A
  • Once a day
  • T1/2 = 12 h
  • Peak = 2 h
  • DOA = 10 h
123
Q

Albiglutide and dulaglutide dose, T1/2, peak, DOA

A
  • Once a week
  • T1/2 = 5 d
  • Peak = 1 d
  • DOA = one week
124
Q

GLP-1 side effects

A
  • Nausea
  • Erythema @ injection site
  • Increase risk of pancreatitis (persistent abdominal pain)
  • History of stomach or bowel problems (trouble digesting food, gallbladder problems as gallstones, pancreatitis, dialysis)
125
Q

MOA of Dipeptidyl peptidase-4 (DPP-4) inhibitors

A
  • Inhibit the degradation of the incretins/GLP-1 and GIP
126
Q

Dipeptidyl peptidase-4 (DPP-4) inhibitors generic/brand names

A
  • Sitagliptin (Januvia)
  • Saxagliptin (Onglyza)
  • Linagliptin (Tradienta)
  • Alogliptin (Nesina)
127
Q

Dipeptidyl peptidase-4 (DPP-4) inhibitors dose, T1/2, peak (ALL)

A
  • Once a day
  • T1/2 = 12 h
  • Peak = 2 h
128
Q

Sitagliptin (Januvia) elimination

129
Q

Saxagliptin (Onglyza) elimination

A
  • Hepatic by CYP3A4/5

- Kidney

130
Q

Linagliptin (Tradienta) elimination

A
  • Unchanged in feces
131
Q

Alogliptin (Nesina) elimination

132
Q

Dipeptidyl peptidase-4 (DPP-4) inhibitors side effects

A
  • Nasopharynghitis
  • Upper respiratory infections
  • Headaches
  • Hypoglycemia if in combo with insulin secretagogues
  • Pancreatitis
133
Q

Glucose is freely filtered by the renal glomeruli and is reabsorbed in the proximal tubules by the action of

A
  • Sodium-glucose transporters (SGLTs)
134
Q

SGLT2 in the proximal tubule

A
  • Accounts for 90% of glucose reabsorption

- Its inhibition causes glycosuria and lowers glucose levels in patients with type 2 diabetes

135
Q

SGLT-2 inhibitors generic/brand names

A
  • Canagliflozin (Invokana)
  • Dapagliflozin (Farxiga)
  • Empagliflozin (Jardiance)
136
Q

SGLT-2 inhibitors dose, T1/2, metabolism (ALL)

A
  • Once a day
  • T1/2 = 12 h
  • Hepatic metabolism
137
Q

SGLT-2 inhibitors side effects

A
  • Increase urination frequency, thirst
  • Pelvic/rectal pain
  • Decrease in amount of urine
    Increase risk of genital infections and UTI
  • Osmotic diuresis can cause intravascular volume contraction and hypotension
138
Q

Pramlintide (Symlin)

A
  • Islet amyloid polypeptide (IAPP, amylin) analogue

- Analog/mimetic of human amylin

139
Q

Amylin is co-located in _____ and co-secreted with insulin by _____

A
  • Secretory granules

- Pancreatic beta cells in response to food intake

140
Q

Amylin and insulin show similar

A
  • Fasting and postprandial patterns in healthy individuals
141
Q

IAPP effects

A
  • Reduces glucagon secretion
  • Slows gastric emptying (vagally medicated mechanism)
  • Centrally decreases appetite
142
Q

Amylin absorption

A
  • Rapidly absorbed after subcutaneous administration immediately before eating
143
Q

Amylin DOA

A
  • Not more than 150 minutes
144
Q

Amylin metabolsim

A
  • Metabolized and excreted by kidney
145
Q

Amylin side effects

A
  • Hypoglycemia

- GI: Nausea, vomiting and anorexia

146
Q

Glucagon brand names

A
  • Glucagen

- Glucagon

147
Q

Glucagon synthesis/degradation

A
  • Synthesized in the alpha cells of the pancreatic islets of Langerhans
  • Degraded in the liver, kidney, plasma, and its tissue receptor sites
148
Q

Glucagon half life in plasma

A
  • 3-6 min

- Similar to that of insulin

149
Q

Glucagon binding

A
  • Binds to specific Gs protein-coupled receptors on liver cells
  • Leads to increased cAMP
  • Facilitates catabolism of stored glycogen
  • Increases gluconeogenesis and ketogenesis
150
Q

Immediate pharmacologic result of glucagon infusion

A
  • Raise blood glucose at the expense of stored hepatic glycogen
151
Q

Cardiac effects of glucagon

A
  • Potent inotropic and chronotropic effect on the heart, mediated by the cAMP
  • Produces an effect very similar to that of β-adrenoceptor agonists
152
Q

Glucagon indication

A
  • Management of hypoglycemia

- Must monitor blood pressure and blood glucose

153
Q

Glucagon side effects

A
  • Nausea

- Vomiting

154
Q

Glucagon onset and DOA

A
  • Onset = 5-20 min

- DOA = 60 min

155
Q

Glucagon metabolism

156
Q

Glucagon administration routes

157
Q

Kazano (oral combination)

A
  • Alogliptin + metformin
158
Q

Ivokamet (oral combination)

A
  • Canagliflozin + metformin
159
Q

Xigduo (oral combination)

A
  • Dapagliflozin + metformin
160
Q

Synjardy (oral combination)

A
  • Empagliflozin + metformin
161
Q

Glucovance (oral combination)

A
  • Glyburide + metformin
162
Q

Jentadueto (oral combination)

A
  • Lingaliptin + metformin
163
Q

Actoplus (oral combination)

A
  • Pioglitazone + metformin
164
Q

Prandimet (oral combination)

A

Repaglinide + metformin

165
Q

Avandamet (oral combination)

A
  • Rosiglitazone + metformin
166
Q

Komboglyze (oral combination)

A
  • Saxagliptin + metformin
167
Q

Janumet (oral combination)

A
  • Sitagliptin + metformin
168
Q

Oseni (oral combination)

A
  • Alogliptin + pioglitazone
169
Q

Glyxambi (oral combination)

A
  • Empagliflozin + linagliptin
170
Q

Duetact (oral combination)

A
  • Pioglitazone + glimepiride
171
Q

Avandaryl (oral combination)

A
  • Rosiglitazone + glimepiride

Pharmacology (27 decks)

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