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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
Long-Acting Insulins
``` Insulin glargine (Lantus) Insulin detemir (Levemir) Insulin degludec (Tresiba) ```
26
Dipeptidyl-peptidase-4 (DPP-4) Inhibitors
Sitagliptin (Januvia®) | Linagliptin (Tradjenta®)
27
Dipeptidyl-peptidase-4 (DPP-4) Inhibitors - MoA
• DPP-4 inhibitors • Potentiates the effects of endogenous incretin hormones,by inhibiting their break down by DPP-4
28
Dipeptidyl-peptidase-4 (DPP-4) Inhibitors - Pharmacokinetics
* Oral, once/day | * Eliminated by the kidney, except linagliptin -> liver/GI
29
Dipeptidyl-peptidase-4 (DPP-4) Inhibitors - Therapeutics
Cardiovascular effects: • Neutral CVD effects Other effects: • Weight neutral
30
Dipeptidyl-peptidase-4 (DPP-4) Inhibitors - Adverse Effects
* Hypoglycemia: low * Hypersensitivity reactions * Associated with acute pancreatitis * Joint pain (severe)
31
Dipeptidyl-peptidase-4 (DPP-4) Inhibitors - Contraindications/Precautions
* Slow GI problems * Renal impairment -> except linagliptin * History of, or acute, pancreatitis
32
SGLT-2 Inhibitors
Canagliflozin (Invokana®) Dapagliflozin (Farxiga®) Empagliflozin (Jardiance®)
33
SGLT-2 Inhibitors - MoA
• Inhibits the sodium-glucose co-transporter 2 (SGLT-2) | in the kidney
34
SGLT-2 Inhibitors - Pharmacokinetics
Oral
35
SGLT-2 Inhibitors - Therapeutics
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
SGLT-2 Inhibitors - Adverse Effects
• 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
SGLT-2 Inhibitors - Contraindications/Precautions
* C/I: Severe renal impairment or dialysis | * Prone to UTIs or other genitourinary infections
38
Thiazolidinediones
Pioglitazone (Actos®) | Rosiglitazone (Avandia®)
39
Thiazolidinediones - MoA
• “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
Thiazolidinediones - Pharmacokinetics
* Oral * Plasma half-life = 103-158 hours * Metabolized by the liver * Onset and offset of action can take weeks to months
41
Thiazolidinediones - Therapeutics
•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
Thiazolidinediones - Adverse Effects
* Hypoglycemia: low * Weight gain (might be edema) * Edema – ↑ risk of heart failure in patients with HF * ↑ bone fracture risk * Back pain, fatigue, headache
43
Thiazolidinediones - Contraindications/Precuations
* Hepatic disease (troglitazone -> hepatotoxicity!) | * C/I: HF
44
Alpha-glucosidase Inhibitors
Acarbose (Precose®) | Miglitol (Glyset®)
45
Alpha-glucosidase Inhibitors - MoA
• Used in both type 1 (off-label) and type 2 DM • Inhibit alpha-glucosidases in small intestine -> delayed carbohydrate digestion and absorption
46
Alpha-glucosidase Inhibitors - Pharmacokinetics
* Oral, pre-prandially | * Half-life ~2 hours
47
Alpha-glucosidase Inhibitors - Therapeutics
Glycemic effects: • ↓ postprandial glucose only Other effects: • Weight neutral
48
Alpha-glucosidase Inhibitors - Adverse Effects
• Hypoglycemia: never • Frequent (56-76%) GI effects (abdominal pain, diarrhea, flatulence) • Elevated hepatic enzymes, jaundice
49
Alpha-glucosidase Inhibitors - Contraindications/Precautions
• C/I: GI disease, GI obstruction, ileus, inflammatory bowel disease, hiatal hernia • Hepatic disease • Renal impairment
50
Sulfonylureas - MoA
• Binding to and blocking ATP-sensitive K+ channel to cause membrane depolarization and increase Ca2+ influx on βcells.
51
Sulfonylureas - Indications/Therapeutic Effects
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
Sulfonylureas - Pharmacokinetics
Oral
53
Sulfonylureas - Adverse Effects
• 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
Sulfonylureas - Contraindications/Precautions
• Caution with severe renal disease or hepatic dysfunction • C/I: in patients with allergies to sulfa drugs
55
Sulfonylureas
•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
Meglitinides: Repaglinide (Prandin®) - MoA
• 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
Meglitinides: Repaglinide (Prandin®) - Pharmacokinetics
• Rapid action & short half-life: peak effect at 1 hour – mimics insulin • Oral, preprandially (1-10 min) • Liver metabolism – CYP3A4
58
Meglitinides: Repaglinide (Prandin®) - Therapeutic Effects
Glycemic effects: • ↓ postprandial glucose only Other effects: • Weight neutral
59
Meglitinides: Repaglinide (Prandin®) - Adverse Effects
• Repaglinide: Hypoglycemia: moderate (less than 2nd | generation sulfonylureas)
60
Meglitinides: Repaglinide (Prandin®) - Contraindications/Precautions
* Not to be used in combination with sulfonylureas | * Caution in liver impairment
61
Colesevelam (WelChol®) - MoA
* Bile acid binding resin | * Unknown for glycemic effect
62
Colesevelam (WelChol®) - Therapeutic Effects
``` • Glycemic effects: – Combination with other antidiabetic agents, ↓basal plasma glucose • Cardiovascular effects: – Beneficial effects for hyperlipidemia: reduces LDL levels • Other effects: – Weight neutral ```
63
Colesevelam (WelChol®) - Adverse Effects
* Relatively safe | * Most common toxic effects are constipation and bloating
64
Bromocriptine (Cycloset®) - MoA
• 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
Bromocriptine (Cycloset®) - Pharmacokinetics
* Oral, within 2 h of awakening | * Metabolized by CYP3A4
66
Bromocriptine (Cycloset®) - Therapeutic Effects
Glycemic effects: • ↓ postprandial glucose levels Cardiovascular effects: • ↓ free fatty acid and triglyceride levels • ↓ cardiovascular end point problems (40%) Other effects: • Weight neutral
67
Bromocriptine (Cycloset®) - Contraindications/Precautions
• Caution with CYP3A4 inhibitors, inducers, or | substrates
68
Amylin-like Peptide: Pramlintide (Symlin®) - MoA
• Synthetic analog of amylin, a hormone co-secreted with insulin • Only an adjunct to insulin therapy in type 1 and 2 DM
69
Amylin-like Peptide: Pramlintide (Symlin®) - Pharmacokinetics
* S.C. injection, 3X per day (with meal bolus of insulin) * Eliminated by the kidney * Half-life ~48 minutes, therapeutic effects ~3 hours
70
Amylin-like Peptide: Pramlintide (Symlin®) - Therapeutic Effects
``` Glycemic effects: • In combination with insulin -> ↓ postprandial glucose levels Other effects: • Weight loss ```
71
Amylin-like Peptide: Pramlintide (Symlin®) - Adverse Effects
* Hypoglycemia: None by itself (but yes w/ insulin) * GI disturbance, nausea, etc. * Injection site lipodystrophy
72
Amylin-like Peptide: Pramlintide (Symlin®) - Contraindications/Precautions
• C/I: slow GI problems (gastroparesis)

Pharmacology II (4 decks)

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