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Pharmacology B > Lecture 6 - Drugs for Diabetes > Flashcards

Lecture 6 - Drugs for Diabetes Flashcards

1
Q

Define Diabetes

A

Insufficiency of insulin singling relative to the requirements of the tissues for this hormone

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2
Q

Symptoms of diabetes

A

Polyuria - production of abnormally large volumes of dilute urine

Polydipsia - excessive thirst

Polyphagia - excessive hunger

Elevated fasting blood sugar, ketosis, weight loss, etc.

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3
Q

Impaired fasting glucose (IFG) levels for Diabetes

A
  1. 1 - 6.9 mmol/L

* impaired = pre diabetes

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4
Q

Impaired glucose tolerance levels (IGT) for fasting plasma glucose?

A

< 7 mmol/L

*impaired = pre diabetes

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5
Q

Diabetes Mellitus (DM) for fasting plasma glucose?

A

> or equal to 7 mmol/L

*we know this for the OSCE man

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6
Q

Impaired glucose tolerance levels (IGT) for plasma glucose 2 hours after 75g glucose load?

A
  1. 8 - 11 mmol/L

* impaired = pre diabetes

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7
Q

Diabetes Mellitus (DM) for plasma glucose 2 hours after 75g glucose load?

A

> or equal to 11.1 mmol/L

  • this is the OGTT
  • we know this for the OSCE as well
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8
Q

What are the normal glucose levels?

A

4.4 - 6.1 mmol/L

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9
Q

What is the difference between Type 1 and Type 2 Diabetes?

A

Type 1:

  • 10-20% of cases
  • Insulin dependent
  • Juvenile onset
  • Autoimmune destruction of beta cells of pancreas

Type 2:

  • 80%
  • Positive family history
  • Insulin resistance
  • Non-Insulin dependent
  • Mature onset
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10
Q

Briefly describe natural history of “Pre” type 1 Diabetes

A
  • B cell mass 100%
  • Genetic predisposition
  • Putative trigger
  • Insulitis B cell injury
  • B cell insufficiency
  • Clinical onset
  • Diabetes

*slide 7

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11
Q

Describe the resting state of the B cell

A
  • ATP gets turned into ADP
  • Opens K channels and K leaves the cell
  • The cell gets hyper polarized and causes voltage gated Ca channels to close
  • Cell remain hyperpolarized
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12
Q

Describe the glucose-stimulated state of the B cell

A
  • Glucose enters the cell
  • Causes ADP to be converted into ATP
  • K channel closes
  • Cell becomes depolarized
  • Causes voltage-gated Ca channels to open (Ca comes into the cell)
  • Insulin is released from the cell
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13
Q

What body parts have an increased uptake of glucose based on insulin?

A
  • Skeletal muscle
  • Cardiac muscle
  • Smooth muscle mucosa
  • Adipose tissue
  • Leukocytes
  • Pituitary

*affected directly by insulin, brings in glucose no matter what the concentration outside is

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14
Q

What body parts does insulin’s effect have no effect on glucose uptake?

A
  • Brain
  • Kidney
  • Instestinal Liver
  • RBC
  • Endothelium
  • Pancreas

*tissues allow glucose in based on concentration. If there’s a high extracellular concentration, cells that express these receptors will allow glucose in - can lead to problems

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15
Q

List some effects of insulin on the liver

A

Reversal of catabolic features of insulin deficiency:

  • inhibits glycogenolysis (prevents glycogen breakdown)
  • inhibits conversion of fatty acids and amino acids to kept acids
  • Inhibits conversion of amino acids to glucose

Anabolic action:

  • Promotes glucose storage as glycogen (induces glucokinase and glycogen synthase, inhibits phosphorylase)
  • Increases triglyceride synthesis and very low density lipoprotein formation
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16
Q

List some effects of insulin on muscle

A

Increased protein synthesis:

  • Increases amino acid transport
  • Increases ribosomal protein synthesis

Increased glycogen synthesis:

  • Increases glucose transport
  • Induces glycogen synthase and inhibits phosphorylase
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17
Q

List some effects of insulin on adipose tissue

A

Increased triglyceride storage:

  • Lipoprotein lipase is induced and activated by insulin to hydrolyze triglycerides from lipoproteins
  • Glucose transport into cell provides glycerol phosphate to permit esterification of fatty acids supplied by lipoprotein transport
  • Intracellular lipase is inhibited by insulin
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18
Q

List some defects of glucose levels in diabetes

A
  • Increase in extracellular glucose
  • Decrease in intracellular glucose (in tissues with insulin-sensitive glucose transporters)
  • Increase in intracellular glucose in tissues with non-insulin selective transporters
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19
Q

In type __ diabetes, the insulin receptor have insensitivity

A

2

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20
Q

List some macrovascular complications of diabetes

A

Blood vessels (angiopathy):

  • Heart disease (x4 higher death rates)
  • Stroke (up to x4 risk)
  • Hypertension (67% of diabetics)
  • Impact of microangiopahty on other organs
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21
Q

List some microvascular complications of diabetes

A
  • Eyes (retinopathy)
  • Kidneys (nephropathy)
  • Nerves (neuropathy)
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22
Q

Describe the insulin synthesis pathway (treatment for type 1 diabetes)

A

Preproinsulin is given and signal sequence allows it to enter the rough ER.
Disulfide bonds break and it gets turned into proinsulin, then enters the golgi, where it gets turned into insulin and is packaged into insulin granules in golgi

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23
Q

List the rapid acting insulins

A
  • Lispro (Humalog)
  • Aspart (NovoLog)
  • Glulisine (Apidra)
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24
Q

List the short acting insulins

A

Regular:

  • Humulin R
  • Novolin R
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25
Q

List the intermediate acting insulins

A

NPH:

  • Humulin N
  • Novolin N
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26
Q

List the long-acting insulins

A
  • Glargine (Lantus)

- Detemir (Levemir)

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27
Q

Describe the characteristics of the rapid-acting insulin: Insulin Lispro

A
  • Reduces anti-parallel dimer formation
  • Monomer > dimer
  • Rapid absorption and shorter duration of action
  • More closely resembles insulin response to a meal
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28
Q

When should Insulin Lispro (Humalog) be taken?

A

15 mins prior to a meal

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29
Q

Who is Insulin Lispro (Humalog) for?

A

Type 1 and Type 2

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30
Q

Benefits of Insulin Lispro (Humalog)?

A
  • Tighter control of glucose, no adverse effect on HbA1c

- Decreased incidents and risk of hypoglycemia

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31
Q

Describe the short-acting insulin (Regular Novolin R)

A
  • Recombinant insulin
  • Dimers form hexameters in the vial - stable
  • Delays absorption into blood stream - acts as a depot
  • Over time hexamers break down to release bioactive insulin monomers
  • Taken 30-45 min before a meal
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32
Q

Describe the long acting insulin (Insulin Glargine)

A
  • Human long acting insulin
  • Differs in 3 amino acids in beta chain
  • Aspargine replaced by glycine, 2 arginine added at C-terminus
  • Soluble and clear in pH 4 solution
  • Precipitates at neutral pH in subcutaneous tissue
  • One injection per day usually
  • Slowly absorbed, duration of action = 24 hours
  • No peak
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33
Q

Benefits of long acting basal insulins

A

less nocturnal hypoglycemia

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34
Q

Adverse effects of insulin glargine (long acting basal insulin)

A

pain at site of injection

**it cannot be diluted or mixed with any other insulins

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35
Q

What medications can increase hypoglycaemic actions of insulin?

A
  • ACEi
  • Alcohol
  • Salicylates
  • B blockers
  • MAOi
36
Q

What medications can decrease hypoglycaemic actions of insulin?

A
  • Glucocorticoids
  • Glucagon
  • Epinephrine
  • Growth Hormone
  • Thyroid Hormone
37
Q

List 3 adverse effects of insulin

A

1) hypoglycemia
2) lipoatrophy (loss of fat tissue around sites of injection)
3) allergy

38
Q

List some signs of hypoglcemia

A
  • hunger
  • sweating
  • blurred vision
  • headache
  • fatigue
  • coma and death
  • unawareness in elderly
39
Q

What can contribute to causing hypoglycaemia?

A
  • insulin overdose
  • overexertion from exercise
  • failure to eat
  • labile disease
40
Q

How do you treat hypoglycaemia?

A

oral or IV glucose

41
Q

Type 2 diabets is ______

A

preventable

42
Q

List 2 branches of Insulin releasing agents

A
  • Sulfonylureas
  • Meglitinides

*OSCE

43
Q

List 1 branch of weight reducing agents

A

Biguanides (ex. metformin)

(AMPK activator)

*OSCE

44
Q

List 1 branch of insulin sensitivity enhances

A

-Glitazones

45
Q

List 2 branches of incretin-related molecules

A

GLP-1 analogues

DPP-4 inhibitors

46
Q

What are the other two types of anti-diabetic meds

A

1) glucosidase inhibitors

2) sodium glucose transport protein 2 (SGLT2) inhibitors

47
Q

Glimepiride, glyburide, glipizide are all _______

A

sulfonylureas

48
Q

MOA of sulfonylureas (Glimepiride, glyburide, glipizide)

A
  • release insulin from pancreatic B cells
  • reduce serum glucagon levels
  • potentiate the action of insulin on its target tissues
  • sulfonylureas have a high affinity for SUR
  • sulfonylureas have a low affinity for KIR (not relevant in patients)
  • partial antagonists

*binding of SUR causes pore opening (K+ channel)

49
Q

Dose of glyburide?

A

5-20 mg/day

50
Q

Dose of glimepiride?

A

1-4 mg/day

51
Q

Dose of glipizide?

A

5-20 mg/day

52
Q

Adverse effects of sulfonylureas?

A
  • Hypoglycemia (glyburide worse)
  • weight gain
  • aggravation of myocardial ischemia
53
Q

What types of patients are sulfonylureas contraindicated with?

A
  • CI in patients with CV disease and elderly (hypoglycaemia more serious)
  • CI in patients with hepatic impairment and or renal insufficiency
54
Q

List 2 meglitinide analogs

A
  • repaglinide

- nateglinide

55
Q

Describe Meglitinide analogs (Repaglinide, natelinide)

A
  • Structurally different from sulfonylureas
  • Bind to SUR1 and KIR6.2
  • Rapidly absorbed with a short half life (4-7 hr)
  • MUST be taken 15-30 mins prior to meals
  • Fast onset of action (1hr peak)
  • can be combined with metformin
  • Repaglinide can be used in patients with renal impairment and in the elderly !!!
56
Q

Describe metformin (Biguanide)

A

MOA:

  • not fully understood
  • no effect on insulin secretion
  • activates cyclic AMP-activated protein kinase (AMPK) - regulator of hepatic glucose production and improves insulin resistance
  • euglycemic agent

insulin sensitizer
from OSCE

57
Q

Describe what it means that metformin is “euglycemic rather than hypoglycemic”

A

lowers blood glucose after food, but not fasting levels in steady state

58
Q

Describe some other perks of metformin

A
  • increases glycolysis and insulin binding
  • inhibit gluconeogensis in liver and glucose absorption from the gut
  • reduce plasma glucagon levels
  • mild weight los
59
Q

Metformin is not _____

A

metabolized
**excreted by the kidneys in the active form

half life = 1.5-3 hours

60
Q

Adverse effects of metformin

A
  • lactic acidosis (impaired liver metabolism of lactate)
  • range of GI effects
  • B12 deficiency
61
Q

List some glitazones

A
  • rosiglitazone

- pioglitazone

62
Q

MOA of glitazones

A
  • Decreases insulin resistance by binding to nuclear receptors which regulate genes responsible for lipid metabolism
  • Peroxisome proliferator-activated receptor (PPAR)-y agonists
  • Decreases gluconeogensis, glucose output and triglyceride synthesis in the liver
  • Increases glucose uptalk ein skeletal muscle and adipose tissues
  • Has no effect on insulin secretion
63
Q

Describe the metabolism of glitazones

A
  • Absorption better when taken with food
  • Plasma level peaks in 3 hours, and half-life 16-34 hours
  • Metabolized in the liver by CYP3A4
64
Q

Use of glitazones?

A

used for type 2 patients who need more than 30 units of insulin daily and have a HbA1c > 8.5%

max effect may require 12 weeks of treatment

taken orally

65
Q

Benefits of glitazones?

A
  • tighter control of glucose
  • HbA1c decreased by 0.6 - 1.6%
  • No lactic acidosis observed
  • Pioglitazone - lowers triglycerides and raises HDL cholesterol
  • Rosiglitazone - raises HDL cholesterol
66
Q

List some adverse effects of glitazones

A
  • Rosiglitazone - MI (use has been stopped in Europe)
    • CI in patients with heart failure and liver impairment
  • edema
  • macular edema
  • loss of bone density
  • weight gain
  • pioglitazone - bladder cancer

**Consequently, these drugs are used less and less

67
Q

List some glucosidase inhibitors

A

Acarbose (Prandase)

miglitol (Glyset)

68
Q

MOA of glucosidase inhibitors

A
  • Acts only in the gut, slows carbohydrate breakdown
  • Competitive inhibitors of alpha-glucosidase enzymes
  • Lowers post-prandial rise in blood glucose
  • Lowers HbA1c levels
69
Q

Glucosidase inhibitors are for Type __ diabetes

A

2

70
Q

Side effects of glucosidase inhibitors?

A
  • dose dependent abdominal bloating

- flatulence which is reduced in 3 months

71
Q

List the 2 incretin-related molecules

A

DPP-4 inhibitors

GLP-1 analogues

72
Q

Describe the incretin-related molecules

A
  • Meal ingestion leads to secretion of GLP-1 (glucagon like peptide-1) and gastric inhibitory peptide (GIP) from the gut
  • These agents increase insulin synthesis and release, and also decrease glucagon (from alpha cells of pancreas)
73
Q

List some DPP-4 inhibitors

A

Sitagliptin-PO4

Saxagliptin

74
Q

Describe DPP-4 inhibitors

A
  • Dipeptidyl peptidase-4 inhibitors
  • Orally active
  • Peak at 1-4 hours
75
Q

Adverse effects of DPP-4 inhibitors

A
  • Respiratory infections
  • May produce pancreatitis (sitagliptin)
  • Hypersensitivity reactions - anaphylaxis
76
Q

List some GLP-1 analogues

A

Exenatide

Liraglutide

77
Q

MOA of GLP-1 analogues

A
  • Enhances glucose-dependent insulin secretion from pancreatic B cells
  • Restores first-phase insulin response
  • Suppresses glucagon secretion from pancreatic alpha cell sunder conditions of hyperglycemia, which leads to a reduction in glucose output from the liver
  • Reduces food intake - weight loss
  • Slows gastric emptying, allowing for timely absorption of nutrients
78
Q

Describe Exanatide (GLP-1 analogue)

A
  • used for type 2 diabetes with either metformin or sulfonylurea
  • it is a synthetic version of a intestinal hormone
  • euglycemic on its own
  • injected twice a day
  • peak at 2 hrs, lasts 10 hrs
  • consider potential risks of pancreatitis, renal dysfunction
  • nausea
79
Q

List a SGLT2 inhibitor

A

-Dapagliflozin (Forxiga)

80
Q

Describe Dapagliflozin (Forxiga)

A
  • Functions in the proximal tubule of kidney

- Prevents re-absorption of glucose

81
Q

Side effects of Dapagliflozin (Forxiga)

A
  • Excessive glycosuria - hypotension

- Urinary tract & bladder infection

82
Q

Describe Pramlintide

A
  • Pramlintide is a synthetic analog of amylin, which is more soluble and dose not readily aggregate like amylin
  • Amylin is a hormone co-secreted with insulin from B cells in response to glucose
83
Q

MOA of pramlintide

A
  • suppresses glucagon secretion
  • rate of glucose absorption from the gut is slowed down
  • fructosamine is a surrogate marker which reflects average glucose concentration over 2-3 weeks prior to testing
  • pramlintide decreased fructosamine by 60%
84
Q

Uses of pramlintide

A
  • Pramlintide can be mixed with regular or NPH insulin just prior to injecting
  • Found to be useful for both type 1 and type 2
85
Q

Describe the treatment of type 1 diabetes

A

-control blood glucose with insulin and diet as best as possible

86
Q

Describe the treatment of type 2 diabetes

A
  • exercise, weight reduction and diet control
  • if mild then add anti-diabetic agents (metformin)
  • oral combination therapy and diet
  • add insulin
  • reduce hypertension
87
Q

Describe the treatment of diabetes in the elderly

A
  • In elderly people, sulfonylureas should be used with caution because the risk of hypoglycaemia increases exponentially with age
  • In general, initial doses should be half those for younger people, and doses should be increased more slowly.

Pharmacology B (21 decks)

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