Pharmacology of Drugs Used for the Treatment of Diabetes Mellitus Flashcards
(132 cards)
1
Q
What are the drug treatment strategies for reducing hyperglycemia? (5)
A
- Increasing insulin levels
- Improving sensitivity to insulin
- Delaying the delivery and absorption of carbohydrates (glucose) from the GIT
- Increasing urinary glucose excretion
- Combination of the above
2
Q
What are the classifications of anti-diabetic drugs? (7)
A
- Insulin Secretagogues: agents that stimulate the secretion of insulin
- Insulin sensitizers: agents that sensitive tissues to insulin
- α-Glucosidase Inhibitors
- Amylin Analog
- Incretin-based therapies
- SGLT2 Inhibitors (Sodium Glucose Co-Transporters 2)
- Miscellaneous Agents
3
Q
What are the different types of Insulin Secretagogues?
A
Sulfonylureas: first and second generations
Non-sulfonylureas: meglitinides and D-phenylalanine derivative
4
Q
What are the different types of Insulin sensitisers?
A
Biguanides
Thiazolidinediones
5
Q
What are the different types of incretin-based therapies?
A
- GLP-1 agonists
- Dipeptidyl - Peptidase 4 Inhibitors
- Dual GIP and GLP1 receptor agonists
6
Q
What are the different types of miscellaneous agents?
A
Bile acid Sequestrants
Dopamine agonists
7
Q
Which agents for type 2 diabetes are not taken orally? How are they taken?
A
Most GLP-1 agonists and Amylin analog (Pramlintide) –> Taken via injection
8
Q
Which anti-diabetes drugs can be used for both diabetes types?
A
Insulin and Amylin analog
9
Q
What are examples of Sulfonylureas?
A
First generation: Tolbutamide, Chlorpropamide, Tolazamide
Second Generation: Glyburide, Glipizide, Gliclazide, Glimepiride
10
Q
What is the MOA of Sulfonylureas?
A
- Insulin release from beta cells (a major mechanism) –> Binds to sulfonylurea receptor 1 (SUR1) present on K(ATP) channels in the bet cell membrane and blocks ATP-dependent K+ channels –> Inhibition of K+ efflux, which causes depolarization, the opening of voltage Ca2+ channels which means Ca2+ influx and thus the release of insulin
- Inhibit Glucagon secretion –> due to enhanced release of somatostatin, which inhibits glucagon secretion from alpha cells
- Decrease hepatic glucose production
4Increased peripheral insulin sensitivity
11
Q
What is the difference between first and second generations of Sulfonylureas?
A
Second generation is less protein binding, higher potency and longer half-life
12
Q
What are the PK of Sulfonylureas?
A
They are well absorbed orally, but their duration of action and half-lives vary
Metabolized by the liver, excreted in the urine
Crosses placenta and secreted in breast milk –> contraindicated in pregnancy and breast feeding
13
Q
What are the relative potency and half-life of Tolbutamide?
A
Relative potency: 1
Half-life: 6 to 12 hours
14
Q
What are the relative potency and half-life of Glibenclamide?
A
Relative potency: 150
Half-life: 18 to 24 hours
15
Q
What are the relative potency and half-life of Glipizide?
A
Relative potency: 100
Half-life: 16 to 24 hours
16
Q
What is the PK of 1st generation of Sulfonyluraes?
A
1st generation: high protein binding –> drug interactions
17
Q
What is the PK of the 2nd generation of Sulfonyluraes?
A
Minimal protein binding -=> less interactions
18
Q
What are the adverse effects of Sulfonyluares?
A
Hypoglycemia
Weight gain
Cholestatic jaundice, bone marrow damage & allergic reactions,
Should be administered with caution in patients with renal or hepatic insufficiency
19
Q
What is the incidence of hypoglycemia highest/lowest?
A
Highest incidence –> Chlorpropamide & Glyburide
Lowest incidence –> Tolbutamide
20
Q
Which drug is the safest for elderly diabetes?
A
Tolbutamide
21
Q
What do Sulfonylureas act synergistically with?
A
Metformin
22
Q
What do Sulfonylureas have clinically shown to decrease?
A
Decrease macro and microvascular complications of diabetes
23
Q
What are examples of Non-sulfonylureas?
A
Meglitinides –> Repaglinide (PRANDIN)
D-Phenylalanine Derivatives –> Nateglinide (STARLIX)
24
Q
What are non-sulfonylureas?
A
A newer class of agents that lack sulfonylurea moiety but stimulate insulin secretion
Exhibit fast onset and short-duration action (2-hour duration of action)
25
What is the MOA of Non-sulfonylureas?
Bind and inhibit ATP-sensitive K+ channels to increase Ca2+ influx and insulin secretion. Similar to sulfonylureas except that they require the presence of glucose to stimulate insulin secretion (e.g. glucose-dependent)
26
What are the clinical uses of Non-sulfonylureas?
For administration just before meals to reduce the post-prandial rise in glucose levels in type 2 diabetic patients
27
What are the advantages/disadvantages of Non-sulfonylureas?
Advantages: less hypoglycemia & weight gain (least with Nateglinide) than conventional sulfonylureas
Disadvantages: hypoglycemia; not been shown to reduce macro and micro-vascular complications
28
What is an example of Insulin Sensitizers?
Biguanides: Metformin
29
What is the MOA of Metformin? (5)
Primary mechanism: 1. Decreased hepatic glucose production (gluconeogenesis) through activation of the enzyme AMP-activated protein kinase
2. Increased glucose uptake & utilization in skeletal muscle
3. Increased insulin action in muscle & fat (reduction in insulin resistance)
Minor mechanisms:
1. Showing of glucose absorption from GIT
2. Increased conversion of glucose to lactate in enterocytes
30
What are the advantages of Metformin?
1. Euglycemic agent --> does not cause hypoglycemia, as it does not cause release of insulin from beta cells, even in large doses
2. Reduces LDL and VLDL
3. Does NOT cause weight gain
31
What are the PK of Metformin?
1. Not bound to plasma proteins & half-life is about 3 hours
2. Excreted unchanged in urine
32
What are the clinical uses of Metformin?
First-line therapy as a single agent for patients with type 2 diabetes
It can also be given in combination with other anti-diabetic drugs
33
What drug does Metformin act synergistically with?
Acts synergistically with Suphonylureas
34
What are the adverse effects of Metformin?
GI: anorexia, nausea, vomiting, abdominal discomfort and diarrhea
Lactic acidosis: rare but potentially fatal toxic effect
Vitamin B12 deficiency: may occur with long-term use
35
What causes Vitamin B12 deficiency with Metformin?
Due to its interference with the intestinal absorption of vitamin B12
36
Which drug was withdrawn from the market due to incidence of severe lactic acidosis?
Phenformin
37
How to prevent Vitamin B12 deficiency with Metformin?
Periodic screening should be considered, especially in patients with peripheral neuropathy or macrocytic anemia
38
What are the contraindications of Metformin?
Patients with renal or hepatic disease, alcoholism --> increased risk of lactic acidosis
39
What are TZDs?
Agonists of peroxisome proliferator-activated receptor gamma family of nuclear receptirs
40
Where are proliferator-activated receptor - gamma found?
Fat, muscle, and liver
41
What is the function of proliferator-activated receptor - gamma?
Modulate the expression of genes involved in lipid & glucose metabolism, insulin signaling, and adipocyte differentiation
Agonsim increases insulin sensitivity by increasing glucose utilization and decreasing glucose production
42
What is the MOA of TZDs?
Stimulate PPAR-gamma receptors to bind to DNA & promote transcription of insulin-responsive genes
43
What are the principal effects of TZDs?
1. Increase insulin sensitivity in peripheral tissues (reduce insulin resistance)
2. Increase glucose uptake by increasing GLUT-4 expression in muscle and fat
44
What are the clinical advantages of TZDs?
Combination of TZDs with metformin does not case hypoglycemia
45
What are Pioglitazone?
Tzd with both PPAR-alpha and gamma agonist activity, not reported to cause hepatotoxicity
46
What is the purpose of Pioglitazone?
Lowers plasma triglyceride levels and increases HDL
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What kind of tests need to be performed prior to administratin of Pioglitazone?
Liver fuction tests
48
What are the adverse effect of Pioglitazone?
Weight gain and fluid retention --> edema
Hear failure
Increased risk of bone fracture in women
49
What are the contraindications for Pioglitazone?
Heart failure, pregnancy& breast fedding, children
Not recommended in patients with active liver disease or pretretment elevation of ALT
50
What ae examples of α-Glucosidase inhibitors?
Acarbose
Miglitol
Voglibose (available only in Japan, Korea and India)
51
What is the MOA of α-Glucosidase inhibitors?
Competitive inhibitors of intestinal α-Glucosidases
52
Where are α-Glucosidases found?
In brush border cells of the small intestine convert to starch, oligosaccharides & disaccharides into monosaccharides
53
What is the function of α-Glucosidase inhibitors?
Inhibitors slow hydrolysis of carbohydrates into glucose and thus inhibit GI absorption of glucose
Relatively minor glucose lowering effect
54
What are the adverse effects of α-Glucosidase inhibitors?
GI: Flatulence, diarrhea, and abdominal pain
55
What are the contraindications for α-Glucosidase inhibitors?
Patients with inflammatory bowel disease (IBD)
56
What is amylin?
37 amino acid peptide co-secreted with insulin by pancreatic beta cells
57
What are the physiological effects of Amylin?
Reduces glucagon secretion --> modulates postprandial glucose levels
Slows gastric emptying
Decreases apetite
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What are type 1 diabetics like?
Lack of amylin (similar to insulin)
59
What are type 2 diabetics like?
Relatively deficient in amylin
60
What are the limitations of Amylin?
Forms aggregates and insoluble fibrils upon infusion
Not feasible for therapeutic use
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What is an example of amylin analogs?
Pramlintide
62
What is Pramlintide?
A synthetic analog of amylin (with three proline substitutions, which reduce their tendency to aggregate into insoluble fibrils)
63
What are the pharmacologic effects of Pramlintide?
Suppress glucagon release; delay gastric emptying and reduce food intake
64
What is the clinical use of Pramlintide?
For pre-prandial use in type 1 and 2 DM patients
Administered SC in addition to insulin in those who are unable to achieve their target postprandial blood sugar levels
65
What are the adverse effects of Pramlintide?
Nausea, vomiting and anorexia
Hypoglycemia (when combined with insulin; therefore, mealtime insulin doses should be reduced by 50% or more to avoid the risk of hypoglycemia))
66
What are incretin and incretin-based therapies?
Peptide hormones released in response to food intake from enterocytes in small intestine that augment glucose-dependent insulin secretion
67
What is the difference between sulfonylureas and incretins & incretin-based therapies?
Do not increase insulin secretion by themselves; they require glucose to augment insulin secretion (like non-sulfonylureas)
68
What are the two major types of incretin?
Glucagon-like peptide 1 (GLP-1)
Glucose-dependent insulinotropic polypeptide or Gastric Inhibitory Peptide (GIP)
69
When are both types of incretin decreased?
In type 2 DM
70
What are the clinically available incretin based therapies?
Synthetic GLP-1 agonists
Inhibitors of GLP-1 degradation (DPP4 inhibitors)
Dual acting GLP-1 and GIP agonists
71
Where is GLP-1 secreted from?
L cells of jejunum and ileum
72
What are the physiological actions of GLP-1?
Increase glucose-dependent insulin secretions
Decrease glucagon secretion
Decrease gastric emptying
Decrease appetite
--> They are all unique properties to reduce postprandial hyperglycemia & also to induce weight loss
73
What are the PK of GLP-1?
Very short half-life
GLP-1rapidly inactivated within 1 to 5 minutes
74
What is GLP-1 deactivated by?
Dipeptidyl peptidase IV enzyme
75
What is GLP-1 inactivated into?
GLP-1 and Dipeptide
76
What are the uses of GLP-1 action therapeutically?
1. Use long-acting DPP4-resistant analogs
2. Block DPP-4, the enzyme that degrades GLP-1
3. Dual-acting GLP-1 and GIP agonists
77
What are the different types of GLP-1 targeted therapy?
Injectables
Oral agents
78
What are the examples of GLP-1 targeted therapy that are injectable ?
GLP-1 analogs (Incretin mimetics)
1. Exenatide
2. Albiglutide
3. Liraglutide
4. Dulaglutide
79
What are examples of GLP-1 targeted therapy that are oral agents?
DDP-4 Inhibitors (Incretin enhancers)
1. Sitagliptin
2. Linagliptin
3. Saxagliptin
4. Alogliptin
80
What is the examples of dual acting GLP-1 and GIP agonist?
Tirzepatide
81
What is the FIRST orally active GLP-1 agonist?
Semaglutide
82
What is the MOA of Incretin (GLP-1) based therapies?
1. DDP-4 inhibitors block Dpp-4 and decrease glucose
2. DDP-4 enzyme inactivates GLP-1
3. Increatin, GLP-1
4. Either stimulates insulin release or inhibits glucagon release
5. Lowering of blood glucose levels
Acts as a GLP-1 agonist and case potentiation of glucose-mediated insulin secretion, suppression
83
What are examples of GLP-1 analogs?
Exenatide
Liraglutide
Albiglutide
Dulaglutide
84
What is exenatide?
A synthetic form of the peptide exendin-4 (similar to GLP-1) found in Gila monster venom
85
What is the difference between GLP-1 and Exenatide?
Unlike GLP-1, it is not degraded by the enzyme DPP-4
86
What is the half-life of Exenatide like?
About three hours
87
How is Exenatide excreted?
Glomerular filtration
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What are the clinical uses of Exenatide?
Injected SC (twice daily) for type 2 DM patients not achieving target glycemic levels with other agents
A once a week release is now available
89
What is Liraglutide?
Long-acting synthetic GLP-1 analog --> more stable than Exenatide
90
What is Albiglutide?
Recombinant modified human GLP-1 dimer fused to albumin
91
What is Dulaglutide?
Consists of two GLP-1 analog molecules covalently linked to an Fc fragment of human Ig
92
What is a characteristic of all GLP-1 analogs administered?
All offer the advantage of once-weekly dosing (SC)
93
What are the adverse effects of GLP-1 analogs?
Nausea, vomiting and diarrhea (the most common)
Hypoglycemia (when combined with sulfonylureas and insulin)
Weight loss
Necrotizing and hemorrhagic pancreatitis
94
What is Semaglutide co-formulated with?
An absorption enhancer, salcaprozate sodium (SNAC)
95
How is Orally active semaglutide administered?
Orally; given once daily (3mg, 7mh or 14mg)
Taken at least 30 minutes before the first food, beverage or other oral medications of the day.
Food should be eaten 30 to 60 minutes after taking oral semaglutide
96
Why should food be eaten about an hour after oral semaglutide administration?
Oral semaglutide has low bioavailability and requires optimal conditions for absorption
97
What is the safety profile of Semaglutide like?
Similar to other injectable GLP-1 agonists
98
What is Tirzepatide?
Markets, as Mounjaro, it is a first-in-class dual GIP and GLP-1 agonist
99
What is the purpose of Tirzepatide?
HAs remarkable glycemic and weight-reducing efficacy compared to GLP-1 agonists alone in diabetic or obese patients
100
How is Tirzeparide administered?
Half-life --> 5 days, once weekly administration by SC injection
101
What are the safety profile and adverse effects of Tirzepatide like?
SImilar to other GLP-1 agonists
102
What are examples of DPP-4 inhibitors?
Sitagliptin
Saxagliptin
Linagliptin
Alogliptin
Vildagliptin
103
What is the MOA of DPP-4 inhibitors?
Specific inhibitors of DPP-4, which is the enzyme that degrades GLP-1 and other incretins --> Increase in circulating levels of GLP-1 and GIP --> Decrease postprandial hyperglycemia by increasing glucose-mediated insulin secretion & decreasing glucagon levels
104
Do DPP-4 inhibitors affect gastric emptying and appetite?
Unlike GLP-1 and amylin analogs, they do not affect gastric emptying and appetite
105
What is the clinical use of DPP-4 inhibitors?
As adjunctive therapy for type 2 diabetics who have failed to achieve glycemic goals
106
What are the advantages of DPP-4 inhibitors?
Taken orally, once a day, unlike most GLP-1 agonists that must be infected
107
What are the adverse effects of DPP-4 inhibitors?
Upper respiratory tract infections, nasopharyngitis, headache, hypoglycemia (when combined with sulfonylureas), pancreatitis, and allergic recations
108
What are examples of SGLT-2 Inhibitors?
Canagliflozin
Dapagliflozin
Empagliflozin
109
What is the SGLT2?
A co-transporter responsible for 90% of glucose reabsorption in the kidney
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What is the MOA of SGLT2 inhibitors?
Block the reabsorption of glucose via SGLT2 in the proximal tubules of the kidney --> INcresaed glucose excretion --> Decrease in blood glucose levels
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What are the clinical uses of SGLT2 inhibitors?
To be used with diet and exercise, to improve glycemic control in adults with type 2 diabetes
--> Cna help prevent the development of heart disease and reduce the progression of renal impairment or ESRD
112
When can SLGT2 inhibitors not be used?
In patients with type1 diabetes, diabetic ketoacidosis, severe renal impairment or ESRD
113
What are the adverse effects of SLGT2 inhibitors?
Dehydration
Genital yeast infections
UTI
Hypoglycemia (when combined with sulfonylureas or insulin)
114
Why is dehydration an adverse effect of SLGT2 inhibitors?
Due to osmotic diuresis and frequent urination
115
What are examples of bile acid sequestrants (miscellaneous agents)?
Colesevelam
116
What are examples of dopamine agonists (miscellaneous agents)?
Bromocriptine
117
What are miscellaneous agents approved as?
Adjunctive therapy for type 2 diabetic patients
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What is the efficacy of miscellaneous agents in lowering glucose levels?
Very modest efficacy
119
What is the MOA of miscellaneous agents?
Exact MOA is still unknown
120
What are the adverse effects of bile acid sequestrants?
Constipation,
Indigestion,
Flatulence
Interfere with the absorption of several drugs
121
What is the MOA of Dopamine D2 receptor agonists?
Improves insulin sensitivity by altering hypothalamic circadian activity
Enhanced suppression of hepatic glucose production
122
What are the adverse effects of Dopamine D2 receptor agonists?
Nausea, vomiting, headache, dizziness, orthostatic hypotension, and hypoglycemia
123
What is the contraindication for Dopamine D2 receptor agonists?
Not recommended in patients with physchotic disorders
124
What is the diabetic treatment for cardiorenal protection in high risk patients?
GLP-1 agonists or SLGT 2 inhibitors
125
What is the diabetic treatment for weight control in obese patients?
Dual GLP-1/GIP agonsist or GLP-1 agonists
126
What are the drugs given for severe HYPOglycemia?
Glucagon and Diazoxide
127
When is glucagon given?
For severe hypoglycemia, parenterally
128
What is the action of glucagon?
Opposite actions to insulin --> increases hepatic glucose production
129
What is the purpose of Diazoxide?
Binds to K+ channels in beta cells to prevent the closing of these channels and inhibit insulin secretion
130
What drug does Diazoxide have opposite effect from?
Sulfonylureas as it binds to a unique site
131
When is Diazoxide given?
Chronic or recurring hypoglycemia
Treatment of inoperable inulinomas
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