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Pharmacology II > Antidiabetic Agents > Flashcards

Antidiabetic Agents Flashcards

1
Q

Physiological Changes in Insulin Deficiency

A
  • Hyperglycemia
  • Hyperlipidemia
  • Hyperketonemia
  • Myoglobinuria
  • Glucosuria
  • Microangiopathy
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2
Q

Actions of Insulin

A

• Insulin promotes entry of glucose into skeletal muscle,
heart muscle, fat tissue and leukocytes.
• However, insulin is not required for glucose transport
into the brain and liver tissue and red blood cells.
•When insulin is injected in normal or diabetic individuals:
– Blood glucose level decreases
– Blood pyruvate and lactate increase
– Inorganic phosphate decreases
– Plasma potassium decreases

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3
Q

Anabolic Actions of Insulin

A 
• Insulin inhibits catabolic processes such as breakdown of glycogen, fat and protein and promotes an anabolic state
   – Liver
       • Decreases gluconeogenesis
       • Increases glycogen synthesis
   – Muscle
       • Stimulates glucose uptake
       • Promotes protein and glycogen synthesis
   – Adipose
       • Stimulates glucose uptake
       • Increases lipogenesis
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4
Q

Toxicity and Adverse Reactions of Insulin

A 
• Hypoglycemia (hyperinsulinism)
 – Tachycardia
 – Confusion
 – Vertigo
 – Sweating
 – S&S disappear after repeated events
• Weight gain
• Cough (inhaled only)
• Local reactions (allergy)
• Lipodystrophy and lipohypertrophy
• Insulin resistance
• Interactions with other drugs
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5
Q

Glucagon - MoA

A

• Hormone produced by a-cells of the pancreas
• Regulates glucose, amino acids, and possibly free fatty
acid homeostasis
• ↑ Blood glucose levels by mobilizing hepatic glycogen when available.

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6
Q

Glucagon - Therapeutic Effects

A

• Juveniles respond less favorably than adults with
stable diabetes.
• Not very effective in patients with reduced glycogen
stores
• Potent inotropic and chronotropic effects on the heart
(used in beta blocker overdose)
• Produces profound relaxation of the intestine (used in
radiology)

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7
Q

Glucagon - Pharmacokinetics

A
  • Administered parenterally (S.C., I.M., I.V.)

* Onset of action is gradual

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8
Q

Diazoxide (Proglycem®) - MoA

A

• Non-diuretic thiazide, vasodilator and hyperglycemic
• Hyperglycemia by:
– Directly inhibiting insulin secretion
– Or decreasing peripheral glucose utilization
– Or stimulating hepatic glucose production

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9
Q

Diazoxide (Proglycem®) - Therapeutic Effects

A

• Used in patients with insulinoma

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10
Q

Diazoxide (Proglycem®) - Pharmacokinetics

A
  • Oral administration

* Fairly long duration of action (t½= 24-36 hours)

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11
Q

Metformin (Glucophage) - MoA

A

• Overall: ↓ glucose levels in a predominantly insulin-independent manner
– ↑glucose removal from blood (AMPK)
– ↑ secretion of glucagon-like peptide-1 (GLP-1)
– ↓glucose absorption from the GI
– ↓ glucagon levels
– ↓gluconeogenesis (mitochondrial enzyme inhibition)

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12
Q

Metformin (Glucophage) – Therapeutics

A

• Initial drug of choice for Type 2 diabetics if A1C is <10%
• Glycemic effects:
– Promotes a euglycemic state
• Glucose is not lowered in normal subjects
• Cardiovascular effects:
– 15-20% reduction of plasma triglyceride levels
– ↓macrovascular events
• Other effects:
– Weight neutral
– ↓all-cause mortality events
– Best pharmacologic therapy for diabetes prevention

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13
Q

Metformin (Glucophage) - Pharmacokinetics

A
  • Oral administration
  • Renal excretion
  • Extended release available for once/day dosing
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14
Q

Metformin (Glucophage) - Adverse Effects

A

• Hypoglycemia: rare
• Most Common -> Diarrhea (53%), anorexia, nausea,
vomiting (30%—gets better)
• Most Dangerous -> Lactic acidosis (rare but may be
lethal), dose dependent
• Reversible vitamin B12 deficiency ->
anemia/neuropathy -> check levels annually

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15
Q

Metformin (Glucophage) - Contraindications/Precautions

A

• Lactic acidosis conditions
– Kidney disease -> C/I in renal failure or severe renal
impairment (eGFR<30)
– Hepatic disease
– Alcoholism
– Diseases predisposing to tissue hypoxia (HF, COPD,
etc)

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16
Q

GLP-1 Receptor Agonists

A

Exenatide (Byetta®, Bydureon®)
Liraglutide (Victoza®)
Semaglutide (Rybelsus®)

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17
Q

GLP-1 Receptor Agonists - MoA

A

• GLP-1 agonists that are resistant to DPP-4 degradation

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18
Q

GLP-1 Receptor Agonists - Therapeutics

A

Cardiovascular effects:
• Liraglutide (Victoza®) decreases macrovascular events
– FDA approved liraglutide use to reduce the risk of
major CV events in type 2 diabetics
– Semaglutide similar, but not FDA approved
• ↓BP (potentially)

Other effects:
• Slows gastric emptying
— patient eats less
• Weight loss, at worst, weight neutral
– Liraglutide (Saxenda®) is only approved for weight loss
• Potential increased βcell number and function

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19
Q

GLP-1 Receptor Agonists - Pharmacokinetics

A 
• S.C. injections
 – 2X/day
 – 1X/week
• Semaglutide (Rybelsus®) is oral
• Eliminated by the kidney
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20
Q

GLP-1 Receptor Agonists - Adverse Effects

A
  • Hypoglycemia: low risk
  • GI disturbance, nausea, vomiting, diarrhea, etc.
  • Hypersensitivity reactions
  • Associated with acute pancreatitis
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21
Q

GLP-1 Receptor Agonists - Contraindications/Precautions

A

• Slow GI problems, GI disease
• Other oral medications that cannot be exposed to
stomach acid too long
• Renal impairment
• History of, or acute, pancreatitis
• C/I: Thyroid Cancer -> Black Box Warning

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22
Q

Rapid-Acting Insulins

A 
Insulin lispro (Humalog)
Insulin aspart (NovoLog)
Insulin glulisine (Apidra)
Insulin, Inhaled (Afrezza)
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23
Q

Short-Acting Insulins

A

Regular Insulin (Novolin R, Humalin R)

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24
Q

Intermediate-Acting Insulins

A

NPH Insulin (Humalin N, Novolin N)

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25
Q

Long-Acting Insulins

A 
Insulin glargine (Lantus)
Insulin detemir (Levemir)
Insulin degludec (Tresiba)
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26
Q

Dipeptidyl-peptidase-4 (DPP-4) Inhibitors

A

Sitagliptin (Januvia®)

Linagliptin (Tradjenta®)

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27
Q

Dipeptidyl-peptidase-4 (DPP-4) Inhibitors - MoA

A

• DPP-4 inhibitors

• Potentiates the effects of endogenous incretin
hormones,by inhibiting their break down by DPP-4

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28
Q

Dipeptidyl-peptidase-4 (DPP-4) Inhibitors - Pharmacokinetics

A
  • Oral, once/day

* Eliminated by the kidney, except linagliptin -> liver/GI

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29
Q

Dipeptidyl-peptidase-4 (DPP-4) Inhibitors - Therapeutics

A

Cardiovascular effects:
• Neutral CVD effects

Other effects:
• Weight neutral

30
Q

Dipeptidyl-peptidase-4 (DPP-4) Inhibitors - Adverse Effects

A
  • Hypoglycemia: low
  • Hypersensitivity reactions
  • Associated with acute pancreatitis
  • Joint pain (severe)
31
Q

Dipeptidyl-peptidase-4 (DPP-4) Inhibitors - Contraindications/Precautions

A
  • Slow GI problems
  • Renal impairment -> except linagliptin
  • History of, or acute, pancreatitis
32
Q

SGLT-2 Inhibitors

A

Canagliflozin (Invokana®)
Dapagliflozin (Farxiga®)
Empagliflozin (Jardiance®)

33
Q

SGLT-2 Inhibitors - MoA

A

• Inhibits the sodium-glucose co-transporter 2 (SGLT-2)

in the kidney

34
Q

SGLT-2 Inhibitors - Pharmacokinetics

A

Oral

35
Q

SGLT-2 Inhibitors - Therapeutics

A

Cardiovascular effects:
• Empagliflozin & Canagliflozin -> ↓ CV events
– FDA approved Empagliflozin & Canagliflozin: ↓risk of
major CV events in T2D
• Canagliflozin -> ↓ chronic kidney disease (CKD)
progression
• Canagliflozin and Dapagliflozin -> ↓ HF hospitalizations
• ↓ BP (3-6 mm Hg)

Other effects:
• Weight loss

36
Q

SGLT-2 Inhibitors - Adverse Effects

A

• Hypoglycemia: rare
• Female genital mycotic infections, urinary tract
infection, and increased urinary frequency are the
most common
• Increased urinary Na+excretion and osmotic diuresis
– Hypotension, dizziness, orthostatic hypotension,
syncope, dehydration
• Increases in serum creatinine, decreases in eGFR, and
rarely renal impairment and acute kidney injury
• Increased LDL-C
• Increased incidence of bone fractures

37
Q

SGLT-2 Inhibitors - Contraindications/Precautions

A
  • C/I: Severe renal impairment or dialysis

* Prone to UTIs or other genitourinary infections

38
Q

Thiazolidinediones

A

Pioglitazone (Actos®)

Rosiglitazone (Avandia®)

39
Q

Thiazolidinediones - MoA

A

• “Insulin sensitizers” -> Specifically target insulin
resistance
• Ligands of the nuclear PPARg receptor which can
cause post-receptor insulin-mimetic action
– ↑ Glucose transporter synthesis in adipose
– ↓ Hepatic glucose production

40
Q

Thiazolidinediones - Pharmacokinetics

A
  • Oral
  • Plasma half-life = 103-158 hours
  • Metabolized by the liver
  • Onset and offset of action can take weeks to months
41
Q

Thiazolidinediones - Therapeutics

A

•Cardiovascular effects:
– ↓Triglycerides in long-term use–Slight ↑HDL

•Other effects:
 – Lower insulin resistance
 – Potential benefit in reducing the development of type 
    2 DM
     • Not as effective as metformin
42
Q

Thiazolidinediones - Adverse Effects

A
  • Hypoglycemia: low
  • Weight gain (might be edema)
  • Edema – ↑ risk of heart failure in patients with HF
  • ↑ bone fracture risk
  • Back pain, fatigue, headache
43
Q

Thiazolidinediones - Contraindications/Precuations

A
  • Hepatic disease (troglitazone -> hepatotoxicity!)

* C/I: HF

44
Q

Alpha-glucosidase Inhibitors

A

Acarbose (Precose®)

Miglitol (Glyset®)

45
Q

Alpha-glucosidase Inhibitors - MoA

A

• Used in both type 1 (off-label) and type 2 DM
• Inhibit alpha-glucosidases in small intestine -> delayed
carbohydrate digestion and absorption

46
Q

Alpha-glucosidase Inhibitors - Pharmacokinetics

A
  • Oral, pre-prandially

* Half-life ~2 hours

47
Q

Alpha-glucosidase Inhibitors - Therapeutics

A

Glycemic effects:
• ↓ postprandial glucose only

Other effects:
• Weight neutral

48
Q

Alpha-glucosidase Inhibitors - Adverse Effects

A

• Hypoglycemia: never
• Frequent (56-76%) GI effects (abdominal pain, diarrhea,
flatulence)
• Elevated hepatic enzymes, jaundice

49
Q

Alpha-glucosidase Inhibitors - Contraindications/Precautions

A

• C/I: GI disease, GI obstruction, ileus, inflammatory
bowel disease, hiatal hernia
• Hepatic disease
• Renal impairment

50
Q

Sulfonylureas - MoA

A

• Binding to and blocking ATP-sensitive K+ channel to
cause membrane depolarization and increase
Ca2+ influx on βcells.

51
Q

Sulfonylureas - Indications/Therapeutic Effects

A

Cardiovascular effects:
• Short-term: neutral CVD effects
• Long-term: ↓risk of MI (15%) and microvascular disease (24%)
– Better than placebo, but not metformin

Other effects:
• ↓all-cause mortality (13%)
• ↓serum glucagon -> ↓ hepatic glucose production
(long-term)
• Indirectly potentiate action of insulin on target
tissues(long-term)

52
Q

Sulfonylureas - Pharmacokinetics

A

Oral

53
Q

Sulfonylureas - Adverse Effects

A

• Hypoglycemia: highest risk of any noninsulin therapy
– Highly dependent on their half-life
– Typically less of a problem in the 2nd generation
agents
– Why these drugs are not used as much anymore
• Weight gain
• GI side effects
– 2nd generation agents typically better

54
Q

Sulfonylureas - Contraindications/Precautions

A

• Caution with severe renal disease or hepatic
dysfunction
• C/I: in patients with allergies to sulfa drugs

55
Q

Sulfonylureas

A

•Second Generation – more potent

– Glyburide
 • 24 hour effect
 • Hypoglycemia  - worst of 2nd’s
– Glipizide
 • Half-life: 2-4 hours
 • Least hypoglycemia of 2nd’s
– Glimepiride
 • Once a day dosing
 • Has little hypoglycemic effect
56
Q

Meglitinides: Repaglinide (Prandin®) - MoA

A

• Not sulfonamides - can be used in SA allergy
• Same as sulfonylureas: binding to and blocking ATP-
sensitive K+channel to cause membrane depolarization
and increase Ca2+influx on βcells.

57
Q

Meglitinides: Repaglinide (Prandin®) - Pharmacokinetics

A

• Rapid action & short half-life: peak effect at 1 hour –
mimics insulin
• Oral, preprandially (1-10 min)
• Liver metabolism – CYP3A4

58
Q

Meglitinides: Repaglinide (Prandin®) - Therapeutic Effects

A

Glycemic effects:
• ↓ postprandial glucose only

Other effects:
• Weight neutral

59
Q

Meglitinides: Repaglinide (Prandin®) - Adverse Effects

A

• Repaglinide: Hypoglycemia: moderate (less than 2nd

generation sulfonylureas)

60
Q

Meglitinides: Repaglinide (Prandin®) - Contraindications/Precautions

A
  • Not to be used in combination with sulfonylureas

* Caution in liver impairment

61
Q

Colesevelam (WelChol®) - MoA

A
  • Bile acid binding resin

* Unknown for glycemic effect

62
Q

Colesevelam (WelChol®) - Therapeutic Effects

A 
• Glycemic effects:
 – Combination with other antidiabetic agents, ↓basal 
     plasma glucose
• Cardiovascular effects:
 – Beneficial effects for hyperlipidemia: reduces LDL 
     levels
• Other effects:
 – Weight neutral
63
Q

Colesevelam (WelChol®) - Adverse Effects

A
  • Relatively safe

* Most common toxic effects are constipation and bloating

64
Q

Bromocriptine (Cycloset®) - MoA

A

• Dopamine agonist – quick release
• Augments low hypothalamic dopamine levels ->
inhibits excessive sympathetic tone within the CNS ->
↓ post meal plasma glucose levels due to enhanced
suppression of hepatic glucose production

65
Q

Bromocriptine (Cycloset®) - Pharmacokinetics

A
  • Oral, within 2 h of awakening

* Metabolized by CYP3A4

66
Q

Bromocriptine (Cycloset®) - Therapeutic Effects

A

Glycemic effects:
• ↓ postprandial glucose levels
Cardiovascular effects:
• ↓ free fatty acid and triglyceride levels
• ↓ cardiovascular end point problems (40%)
Other effects:
• Weight neutral

67
Q

Bromocriptine (Cycloset®) - Contraindications/Precautions

A

• Caution with CYP3A4 inhibitors, inducers, or

substrates

68
Q

Amylin-like Peptide: Pramlintide (Symlin®) - MoA

A

• Synthetic analog of amylin, a hormone co-secreted
with insulin
• Only an adjunct to insulin therapy in type 1 and 2 DM

69
Q

Amylin-like Peptide: Pramlintide (Symlin®) - Pharmacokinetics

A
  • S.C. injection, 3X per day (with meal bolus of insulin)
  • Eliminated by the kidney
  • Half-life ~48 minutes, therapeutic effects ~3 hours
70
Q

Amylin-like Peptide: Pramlintide (Symlin®) - Therapeutic Effects

A 
Glycemic effects:
 • In combination with insulin -> ↓ postprandial glucose 
    levels
Other effects:
 • Weight loss
71
Q

Amylin-like Peptide: Pramlintide (Symlin®) - Adverse Effects

A
  • Hypoglycemia: None by itself (but yes w/ insulin)
  • GI disturbance, nausea, etc.
  • Injection site lipodystrophy
72
Q

Amylin-like Peptide: Pramlintide (Symlin®) - Contraindications/Precautions

A

• C/I: slow GI problems (gastroparesis)

Pharmacology II (4 decks)

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