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Flashcards in Pancreatic Hormones & Diabetic Drugs Deck (57):
1

Which diabetes has more of a genetic predisposition

Type II

2

Which diabetes has insulin deficiency

Type 1

3

Which diabetes has a loss of beta cells

Type 1

4

Which diabetes is more prone to ketoacidosis

Type 1

5

Which diabetes is prone to a non-ketototic hyperosmolar coma

Type II

6

K+/ATP and Insulin:

Open state of K+/ATP channel

hyperpolarize the cell by causing outflow of K+ and inhibit insulin release

7

K+/ATP and Insulin:

Closed state of K+/ATP channel

depolarize the cell and insulin released.

8

Insulin Receptor signaling:

insulin binding to alpha subunit regulates beta subunit activity -->

autophosphorylation of beta subunit -->

increase tyrosine kinase activity -->

phosphorylation of other substrates -->

activation of phosphoinositide 3-kinase

9

Effects of insulin on the liver

Stimulates:
- glycogen synthesis
- triglyceride synthesis

Inhibits:
- glycogenolysis
- ketogenesis
- gluconeogenesis

10

Effects of insulin on skeletal muscle

Stimulates:
- glucose uptake
- protein synthesis
- glycogen synthesis

Inhibits:
- Protein degradation
- Glycogenolysis

11

Effects of insulin on adipose tissue

Stimulates:
- Glucose uptake
- Triglyceride storage

Inhibits:
- lipolysis

12

Overall, insulin stimulates ____and inhibits ____

Promotes anabolic processes and

Inhibits catabolic processes

13

advantages to recombinant DNA insulin

• Less insulin resistance
• Less allergy
• Less lipodystrophy

14

Rapid/ short-acting insulin:
onset and duration

Onset: 5-15 min
Duration: 3-5 h

15

Rapid insulin

• Insulin lispro, aspart, glulisine given s.c
• Inhaled human insulin - Indicated only in adults,
• Contraindicated- children, asthma, bronchitis, smokers

16

short-acting insulin
• duration
• what? method given?
• use?

• Duration: 5-8h
• Regular insulin given s.c and i.v.
• Use in diabetic ketoacidosis and other emergency situations

17

intermediate-acting insulin:
• onset
• duration
• what?

• onset: 2-5h
• duration: 4-12h
• Lente insulin, NPH insulin (Neutral protamine Hagedorn or isophane) mixture of insulin with protamine (basic substance obtained from fish sperm)

18

Ultra-long acting insulin
• onset
• duration
• what?

• onset: slow
• duration: 20-24h
• Ultra lente, Insulin glargine, Insulin detemir
• Peakless, given once daily

19

Hypoglycemia
• S/Sx
• Tx

• Sympathetic signs (tachycardia, sweating, palpitations, tremors) parasympathetic signs (nausea, hunger)
• Treatment : Glucose or glucagon treatment

20

Allergy and resistance to insulin

• Local cutaneous reactions or systemic
• Human insulin are less antigenic than insulin from animal sources

21

lipodystrophy

• Atrophy of fatty tissue at the site of injection
• Never seen since the development of highly purified insulin

22

Treatment of Type II DM includes

• Diet
• Exercise
• Wt reduction
• Step wise approach to drug treatment
• Patient education
➢ Oral drugs for reduction of blood glucose
• Used only in the Rx of Type II DM
• Oral medication is initiated when 2-3 months of diet and exercise alone are unable to achieve or maintain their optimal plasma glucose levels

23

Insulin secretogogues

• Sulfonyureas
• Meglitinides

24

Oral Hypoglycemics

1. Insulin secretogogues
• Sulfonyureas
• Meglitinides
2. Biguanides
3. Thiazolidinediones
4. Alpha glucosidase inhibitors

25

First Generation Sulfonylurea

• Chlorpropramide
• Tolbutamide
• Tolazamide

26

2nd Generation Sulfonuylurea

• Glipizide
• Glyburide
• Glimepiride

27

Mechanism of action of Sulfonylurea

• Block ATP sensitive K+ channels in pancreatic beta cells --> Inhibits the efflux of K+ resulting in depolarization
• Opening of voltage gated Ca influx --> release of preformed insulin -->
• Increase the sensitivity to insulin by increasing number of insulin Receptors

28

Chloropropamide (Diabinese)

• Long acting for 32 hours
• Can cause prolonged hypoglycemia in elderly patients (contraindicated age)
• Slowly metabolised in liver, so Contraindicated in patients with hepatic disease

29

Tolbutamide (Orinase)

• Rapidly metabolised in liver
• Short half life - safest SU in elderly

30

2nd generation SU drugs:

• glipizide (glucotrol)
• glyburide (micronase, glynase prestab)
• glimepiride

➢ Second generation drugs commonly prescribed agents because of fewer side effects and drug interactions

31

glipizide (glucotrol)

• 2nd generation SU drug.
• commonly prescribed agents because of fewer side effects and drug interactions
• Half-life - 2 to 4 hours
• Potency – High (2.5 to 40 mg/d)
• 90% is oxidized to inactive metabolites in liver
• Contraindicated in patients with hepatic disease - can cause hypoglycemia

32

Glyburide (Micronase, Glynase PresTab)

• 2nd generation SU drug.
• commonly prescribed agents because of fewer side effects and drug interactions
• Half-life - 6 hours

33

Glimepiride

• Approved for once-daily use
• Potency – Highest (1 to 8 mg/d)

34

Clinical uses of Sulfonylureas

• Hypoglycemic agents for treatment of Type 2 DM
• Act by increasing endogenous insulin secretion \ not indicated for Type 1
• Most effective when ß cell function has not been severely compromised
• Increased insulin secretion favors lipogenesis
• Suitable drug in non obese diabetics

35

A/E in Sulfonylureas

• Severe hypoglycemia
• Most common with glyburide and chlorpropramide in elderly patient
• Weight gain
• Erythema, skin reactions
• Disulfiram like reaction with alcohol (chlorpropramide)

36

Contraindications for Sulfonylureas

• Pregnancy
• Surgery, Severe infections
• Severe stress or trauma
• Severe hepatic or renal failure
• Insulin therapy should be used in all of these

37

Meglitinides:

Repaglinide and Nateglinide

38

Meglitinides
• MOA
• DOA
• use
• a/e

➢ Insulin secretogogues….same as sulfonyl ureas
➢ Rapid onset and short duration of action
• Suitable for controlling postprandial hyperglycemia
➢ Approved for used alone or with biguanides
➢ Common adverse effect is Hypoglycemia

39

Biguanides

Metformin

40

Biguanides (Metformin) MOA

Antihyperglycemic:
• Increases peripheral insulin sensitivity
• Inhibits hepatic gluconeogenesis & glucose absorption from GI tract
• Reduction of plasma glucagon levels
• "Euglycemic", no hypoglycemia. *
• Does not alter insulin secretion *

41

Clinical use of Biguanides (Metformin)

• They are Insulin sparing agents
• Do not produce hypoglycemia

Secondary beneficial effects on lipids:
• Reduced triglycerides
• Reduced total cholesterol
• Reduced LDL
• Increased HDL
• Does not increase Weight

Use:
• Appropriate for obese Type 2 diabetics
• Other use: Polycystic ovarian syndrome - lowers the serum androgens and restores normal mentrual cycles and ovulation

42

used to control postprandial hyperglycemia

Meglitinides: Repaglinide and Nateglinide

43

Metformin A/E and contraindications

Adverse effects:
• *Gastrointestinal – anorexia, nausea, vomiting, diarrhea
• Lactic acidosis (increased risk in alcoholics & in Pts with hepatic impairment)
• Vitamin B 12 defeciency

Contraindications:
• Alchoholism, renal and hepatic disease- risk of lactic acidosis

44

Thiazolidinediones

Pioglitazone, Rosiglitazone

45

Thiazolidinediones MOA

➢ Mechanism: Stimulate the nuclear peroxisome proliferator-activating receptors (PPAR's) involved in transcription of insulin-responsive genes --> Increase the glucose uptake in muscle and adipose tissue & decreases hepatic gluconeogenesis
• They reduce plasma glucose and Triglycerides

46

Thiazolidinediones A/E

Adverse effects:
• Do not cause hypoglycemic, earlier drugs were hepatotoxic (troglitazone)

➢ Adverse effects
• Troglitazone*:
• Hepatotoxicity- Withdrawn from market

• Rosiglitazone, Pioglitazone*:
• No evidence of drug-induced hepatotoxicity
• Peripheral Edema, anemia
• * Are hepatic enzyme inducers
• TZDs- euglycemics

47

troglitazone

(Thiazolidinedione)

hepatotoxic--withdrawn from office

48

• Rosiglitazone, Pioglitazone*:
• No evidence of drug-induced hepatotoxicity
• Peripheral Edema, anemia
• * Are hepatic enzyme inducers
• TZDs- euglycemics

• No evidence of drug-induced hepatotoxicity
• Peripheral Edema, anemia
• Are hepatic enzyme inducers
• TZDs- euglycemics

49

Alpha glucosidase inhibitors

Acarbose, Miglitol

50

Alpha glucosidase inhibitors MOA

• Competitive and reversible inhibitors of a glucosidase in the small intestine
• Delay carbohydrate digestion and absorption
• Reduction in postprandial hyperglycemia

51

Alpha glucosidase inhibitors clinical use

• Individuals with significant postprandial hyperglycemia
• Monotherapy or in combination with other oral hypoglycemics

52

Alpha glucosidase inhibitors A/E

• Flatulence, Nausea, Diarrhea
• Due to increased fermentation of unabsorbed carbohydrate by colonic bacteria
• Do not produce hypoglycemia, lactic acidosis, or significant weight gain

53

Pramlintide

• Administered s.c
• Synthetic analog of amylin, supress glucagon release
• Targets post prandial blood sugar levels

54

Exenatide

(1st incretin therapy to be approved for DM)

• Administered s.c
• Synthetic glucagon like polypeptide (GLP-1)
• Potentiates insulin secretion

55

Sitaglyptin

Inhibitor of dipeptidyl peptidase-4-enzyme that degrades GLP-1

56

Glucagon effects

➢ The primary counter-regulatory hormone
• Effects are generally opposite those of insulin:
• Stimulates glycogenolysis, ketogenesis, and gluconeogenesis
• Inhibits glycogen synthesis and lipogenesis
• Increased hepatic glucose output
• Increased blood glucose level

➢ Other effects
• Inotropic and chronotropic effects on heart
• Relaxation of intestinal muscle

57

Glucagon clinical uses

• Severe hypoglycemia
• Overshooting in insulin therapy
• Hypoglycemia from long-acting oral agents
• Relaxation of the GI tract for X-ray and magnetic resonance visualization
• Inotropic effect on heart- can be used to reverse effects of ß-blocker overdose