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Year 2 Medicine > Drug Treatment of Type 2 Diabetes > Flashcards

Drug Treatment of Type 2 Diabetes Flashcards

1
Q

Glucagon-like peptide-1 analogs

  • Exenatide for example
    • Administered s.c. injection …-… mins before last meal of day
    • Facilitates glucose control by:
      • Augmenting … response
      • Suppresses pancreatic release of … helping stop the liver overproducing glucose
      • Slows down gastric …
      • Reduces … and promote … via hypothalamic receptors
      • Reduces liver … content
A
  • Exenatide for example
    • Administered s.c. injection 30-60 mins before last meal of day
    • Facilitates glucose control by:
      • Augmenting pancreas response
      • Suppresses pancreatic release of glucagon helping stop the liver overproducing glucose
      • Slows down gastric emptying
      • Reduces appetite and promote satiety via hypothalamic receptors
      • Reduces liver fat content
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2
Q

Insulin - Net Effect is what? (in what 3 types of cell/tissue?)

A

Net effect is to cause hypoglycemia and increase fuel storage in muscle, fat tissue and liver

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3
Q

Thiazolidinediones - Glitazones

  • … now only remaining approved
  • It activates … proliferator-activated receptor-y (PPAR-y)
    • PPARs involved in … of insulin-responsive genes and in regulation of adipocyte … metabolism
A
  • Pioglitazone now only remaining approved
  • It activates peroxisome proliferator-activated receptor-y (PPAR-y)
  • PPARs involved in transcription of insulin-responsive genes and in regulation of adipocyte lipid metabolism
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4
Q
  • Pioglitazone subject to interactions - why?
  • May lower … … level containing ethinyl estradiol and norethindrone
A
  • Due to liver metabolism
  • May lower oral contraceptive levels containing ethinyl estradiol and norethindrone
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5
Q

Insulin Action

  • Insulin affects all major … pathways
    • carbohydrate, fat, protein
  • Major target tissues are: (3)
A
  • Insulin affects all major metabolic pathways
    • carbohydrate, fat, protein
  • Major target tissues are:
    • Liver, adipose, and skeletal muscle
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6
Q

Effects of SGLT2 inhibitors

  • Inhibition of renal tubular Na+-glucose cotransporter -> reversal of hyperglycaemia -> reversal of “gluco…”
    • Increased Insulin … in muscle, increase GLUT… translocation, increased insulin signalling
    • Increased sensitivity in liver - decreased glucose-…-…
    • Decreased gluco… - decreased Cori cycle - decreased PEP carboykinase
    • Improved …cell function
A
  • Inhibition of renal tubular Na+-glucose cotransporter -> reversal of hyperglycaemia -> reversal of “glucotoxicity”
    • Increased Insulin sensitivity in muscle, increase GLUT4 translocation, increased insulin signalling
    • Increased sensitivity in liver - decreased glucose-6-phosphatase
    • Decreased gluconeogenesis - decreased Cori cycle - decreased PEP carboykinase
    • Improved beta cell function
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7
Q

How does glucose cause insulin release?

  • Glucose in bloodstream - picked up by beta cell using GLUT-… transporter - glucose into beta cell - metabolised by … - increase ATP levels inside cell - inhibits ATP sensitive … channels - close them - potassium ions cannot leave cell - stuck inside - change voltage of cell - open voltage dependent calcium channels - calcium ions outside cell enter - contribute … charge to depolarise cell - also involved in … process - calcium ions cause insulin granules to move to plasma membrane - release insulin into bloodstream
A

Glucose in bloodstream - picked up by beta cell using GLUT-2 transporter - glucose into beta cell - metabolised by glycolysis - increase ATP levels inside cell - inhibits ATP sensitive potassium channels - close them - potassium ions cannot leave cell - stuck inside - change voltage of cell - open voltage dependent calcium channels - calcium ions outside cell enter - contribute positive charge to depolarise cell - also involved in exocytosis process - calcium ions cause insulin granules to move to plasma membrane - release insulin into bloodstream

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8
Q

Sulphonylureas - T2 diabetes

  • Examples include:
    • Gliclazide, glipizide, glimepride
  • All are … active
  • Are they bound to anything?
A
  • Examples include:
    • Gliclazide, glipizide, glimepride
  • All are orally active
  • All bound to plasma protein (90-99%)
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9
Q

Type 2 diabetes: treatment options

  • Tackle …dysfunction:
    • ​Sulphonylureas, GLP-1 analogues, DDP-4 inhibitors (these … insulin release)
  • … resistance reduction:
    • … and TZD’s
  • … glucose absorption:
    • SGLT-2 inhibitors
  • Loss of … mass:
    • Insulin replacement
  • Lifestyle changes such as … and …, also treat underlying conditions such as … and … associated with T2 diabetes
A
  • Tackle B-cell dysfunction:
    • ​Sulphonylureas, GLP-1 analogues, DDP-4 inhibitors (increase insulin release)
  • Insulin resistance reduction:
    • Metformin and TZD’s
  • Renal glucose absorption:
    • SGLT-2 inhibitors
  • Loss of B-cell mass:
    • Insulin replacement
  • Lifestyle changes such as exercise and diet, also treat underlying conditions such as obesity and dyslipidaemia associated with T2 diabetes
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10
Q

Drugs that lower blood glucose levels in T2 diabetes are usually trying to mimic or enhance …

A

insulin

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11
Q

Side effects of SGLT2 inhibitors

  • Rapid weight … (Due to glycosuria (up to 70g/day))
  • Tiredness
  • Osmotic diuretic so …
  • Can worsen … infections and …
A
  • Rapid weight loss (Due to glycosuria (up to 70g/day))
  • Tiredness
  • Osmotic diuretic so dehydration
  • Can worsen UTI and thrush
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12
Q

Glitazones (Thiazolidinediones) can be used in …, but more commonly used with other anti diabetic medications

A

Glitazones (Thiazolidinediones) can be used in monotherapy, but more commonly used with other anti diabetic medications

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13
Q

Give 2 examples of SGLT2 inhibitors

A

Dapagliflozin and Canagliflozin

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14
Q

Dipeptidyl peptidase-4 (DPP-4) Inhibitors

  • Oral … agents
  • Mechanism of action is via increased levels of Incretins …-1 and G…
  • Increased Incretins
    • Inhibit … release
    • Increase glucose-induced … secretion
    • Decrease gastric …
    • Reduce … glucose production
    • Improved … glucose utilisation
A
  • Oral hypoglycemic agents
  • Mechanism of action is via increased levels of Incretics GLP-1 and GIP
  • Increased Incretins
    • Inhibit glucagon release
    • Increase glucose-induced insulin secretion
    • Decrease gastric emptying
    • Reduce hepatic glucose production
    • Improved peripheral glucose utilisation
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15
Q

Glucagon-like peptide-1 analogs are an adjuvant therapy for type II diabetic on …, a …, …. or a combination of these drugs

A

Glucagon-like peptide-1 analogs are an adjuvant therapy for type II diabetic on metformin, a sulfonylurea, thiazolidinediones or a combination of these drugs

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16
Q

SGLT2 Inhibitors

  • Dapagliflozin
    • IC50 for SGLT2 is 1/… of the IC50 for SGLT1
  • Canagliflozin
    • IC50 for SGLT2 is less than 1/… of the 1C50 for SGLT1
  • Why is this important?
A
  • Dapagliflozin
    • IC50 for SGLT2 is 1/1200 of the IC50 for SGLT1
  • Canagliflozin
    • IC50 for SGLT2 is less than 1/160 of the 1C50 for SGLT1
  • Important because it is specific for SGLT2 and will have very little effect on SGLT1
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17
Q

Exenatide

  • … plasma concentration
  • Strong effects on …
  • … only (So far)
  • New … formulation in clinical trials - neutralizes the acid in local area protecting against breakdown while also enhancing absorption
A
  • High plasma concentration
  • Strong effects on receptors
  • Injectables only (So far)
  • New oral formulation in clinical trials - neutralizes the acid in local area protecting against breakdown while also enhancing absorption
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18
Q

Gliclazide, glipizide, glimepride are examples of what class of drug?

A

Sulphonylureas

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19
Q

Glitazone pharmacokinetics

  • Pioglitazone: what is the daily dosage?
    • Plasma levels peak about … hr
    • Plasma half-life is …-… hr; active metabolites (t1/2 = …-… hr)
    • Liver metabolism and excreted in faeces (…/3) and urine (…/3)
A
  • Pioglitazone: taken once or twice a day orally
  • Plasma levels peak about 3 hr
  • Plasma half-life is 3-7 hr; active metabolites (t1/2 = 16-24 hr)
  • Liver metabolism and excreted in faeces (2/3) and urine (1/3)
20
Q

Pioglitazone is the only remaining approved …

A

Glitazones (thiazolidinediones)

21
Q

Metformin - mechanism of action

  • The exact mechanism is unknown but does involve primarily suppression of hepatic glucose production through …
    • Inhibition of mitochondrial complex …
      • … ATP synthesis (… is an energy intensive process)
      • … AMP:ATP ratio inhibits fructose-1,6-bisphosphate
    • Activating …-activated protein kinase (AMPK)
      • AMPK increases expression of the nuclear transcription factor SHP which in turn … the expression of hepatic gluconeogenic genes phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase
A
  • The exact mechanism is unknown but does involve primarily suppression of hepatic glucose production through gluconeogenesis
    • Inhibition of mitochondrial complex I
      • Decrease ATP synthesis (gluconeogenesis is an energy intensive process)
      • Increase AMP:ATP ratio inhibits fructose-1,6-bisphosphate
    • Activating AMP-activated protein kinase (AMPK)
      • AMPK increases expression of the nuclear transcription factor SHP which in turn inhibits the expression of hepatic gluconeogenic genes phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase
22
Q

Type 2 diabetes - A moving target

  • As you get impaired glucose … which is increasing, for example in …, basal … glucose levels increase and also ones after your meal increase (known as …) - until a diagnosis of T2 diabetes
A

As you get impaired glucose tolerance which is increasing, for example in obesity, basal plasma glucose levels increase and also ones after your meal increase (known as postprandial) - until a diagnosis of T2 diabetes

23
Q

Insulin Effects - Muscle cells

  • increases GLUT-… translocation to the membrane and hence increase … uptake, … oxidation, … synthesis, amino acid uptake, protein synthesis
  • decreases …, amino acid …
A
  • increases GLUT-4 translocation to the membrane and hence increase glucose uptake, glucose oxidation, glycogen synthesis, amino acid uptake, protein synthesis
  • decreases glycogenolysis, amino acid release
24
Q

Insulin Effects - Hepatic cells

• decreases gluco… ,glyco…, keto…, (increases … synthesis)

A

Hepatic cells

• decreases gluconeogenesis, glycogenolysis, ketogenesis, (increases glycogen synthesis)

25
Q
A
26
Q

Insulin Effects - Adipocytes

• increase … uptake, increase … synthesis; decrease FFA (what is this?) and … release

A

• increase glucose uptake, increase triglyceride synthesis; decrease Free Fatty Acids and glycerol release

27
Q

How do Sulphonylureas work?

  • Inhibit …-sensitive potassium channels - bind to site on these channels - close it - same effect of ATP - build up of K+ in cell - … cell - opening of … … calcium channels - insulin release
  • Overall - they are … beta cells and cause release of insulin … of glucose - directly affect the channel to inhibit opening and increase intracellular levels of …
A
  • Inhibit ATP-sensitive potassium channels - bind to site on these channels - close it - same effect of ATP - build up of K+ in cell - depolarise cell - opening of voltage gated calcium channels - insulin release
  • Overall - they are depolarising beta cells and cause release of insulin independently of glucose - directly affect the channel to inhibit opening and increase intracellular levels of potassium
28
Q

Glucagon-like peptide-1 analogs

  • What are they? How do they work?
A
  • GLP-1’s (incretin mimetics)
  • This type of medication works by increasing the levels of hormones called ‘incretins’. These hormones help the body produce more insulin only when needed and reduce the amount of glucose being produced by the liver when it’s not needed.
29
Q

Metformin - oral antihyperglycemic

  • Differ from … and meglitinides both chemically and in mechanism of action
  • Biguanides do not stimulate …release or cause …
  • Biguanides appear to increase glucose uptake in … and decrease glucose production by …
A
  • Differ from sulfonylureas and meglitinides both chemically and in mechanism of action
  • Biguanides do not stimulate insulin release or cause hypoglycemia
  • Biguanides appear to increase glucose uptake in muscle and decrease glucose production by liver
30
Q

Glucagon-like peptide-1 vs Glucagon-like peptide-1 analogs (Exenatide)

  • Identical in almost all of the effects except duration in plasma following sc injection (what is it for each?) and whether it is resistant to DPP-IV degradation (which one is?)
A
  • Identical in almost all of the effects except duration in plasma following sc injection (GLP-1 has a short duration, Exendatide has a long duration (analog)) and whether it is resistant to DPP-IV degradation (GLP-1 analog - Exenatide is resistant)
31
Q

Metformin contraindications

  • … disease
  • Past history of lactic … (any cause)
  • … failure
  • Chronic … lung disease
    • Causes metabolic …
A
  • Hepatic disease
  • Past history of lactic acidosis (any cause)
  • Cardiac failure
  • Chronic hypoxic lung disease
  • Causes metabolic acidosis
32
Q

Biguanides are a type of medication used to treat what?

A

Treat T2 Diabetes (Metformin)

33
Q

Adverse effects and drug interactions

  • Glitazones
    • …retention (promotes amiloride-sensitive sodium ion reabsorption in renal collecting ducts) causing …, mild …
    • Dose-related weight …
    • Safety in … and … not determined
    • Do not cause lactic …, even in patients with renal impairment
    • Liver … may require regular blood tests
A
  • Glitazones
  • Fluid retention (promotes amiloride-sensitive sodium ion reabsorption in renal collecting ducts) causing oedema, mild anaemia
  • Dose-related weight gain
  • Safety in pregnancy and lactation not determined
  • Do not cause lactic acidosis, even in patients with renal impairment
  • Liver damage may require regular blood tests
34
Q
  • Non diabetic patients - insulin sensitive or not?
  • Type 2 diabetes - insulin sensitive or not?
A
  • Non diabetic - very insulin sensitive - beta cells don’t produce much as they don’t need to be that high to lower BG levels
  • Impaired glucose tolerance - normally associated with obesity - insulin sensitivity decreases - body increases insulin concentration - T2 diabetes - tackle with exercise, weight and drugs - can eventually get beta cell failure - end up on insulin as beta cells do not function to produce enough insulin to lower BG levels
35
Q

Glucagon Like Peptide (GLP) -1

  • Do they increase glucose-dependent insulin secretion?
  • Decrease glucagon secretion and hepatic glucose output?
  • Regulates gastric emptying and decrease rate of nutrient absorption?
  • Decrease food intake?
  • Decrease plasma glucose acutely to near-normal levels?
  • Resistant to DPP-IV degradation?
  • Duration in plasma is …
A
  • Do they increase glucose-dependent insulin secretion? - yes
  • Decrease glucagon secretion and hepatic glucose output? - yes
  • Regulates gastric emptying and decrease rate of nutrient absorption? - yes
  • Decrease food intake? - yes
  • Decrease plasma glucose acutely to near-normal levels? - yes
  • Resistant to DPP-IV degradation? - no
  • Duration in plasma is short
36
Q

Treating T2 diabetes - overview

​

A
  • Initially - diagnosis
  • Increase physical activity, weight control, diabetic education, healthy eating
  • Pharmacological intervention - gold standard drug - metformin - target HbA1c levels - 3 months monotherapy - failure = dual therapy - consider what you go for - dependent on patient
  • Usually dual therapy with one of 5 options before using insulin
  • If dual therapy does not work - try triple therapy
  • Not working - start considering injectable therapy
37
Q

Pharmacodynamics of Sulphonylureas

  • Primary mechanism of action
    • Stimulates … … release
    • Binding site on ATP-sensitive …-channel to inhibiting the opening of the channel similar to ATP
  • Secondary mechanisms of action
    • Evidence these drugs:
      • Sensitize …-cells to glucose
      • Decrease lipo…
      • Decrease … of insulin by the liver
A
  • Primary mechanism of action
    • Stimulates endogenous insulin release
    • Binding site on ATP-sensitive K-channel
  • Secondary mechanisms of action
    • Evidence these drugs:
      • Sensitize B-cells to glucose
      • Decrease lipolysis
      • Decrease clearance of insulin by the liver
38
Q

In presence of endogenous or exogenous insulin glitazones will:

  • Decrease gluconeogenesis, glucose output, and triglyceride production in …
  • Increase glucose uptake and utilization in … muscle
  • Increase glucose uptake and decrease fatty acid output in … …
  • Cause differentiation of …
A
  • Decrease gluconeogenesis, glucose output, and triglyceride production in liver
  • Increase glucose uptake and utilization in skeletal muscle
  • Increase glucose uptake and decrease fatty acid output in adipose tissue
  • Cause differentiation of adipocytes
39
Q

Therapeutic uses of sulphonylureas

  • Useful in Type-2 Diabetes
  • Can be used in combination with other anti-diabetic drugs
  • Major side effect: Hypoglycemia
  • Drug interaction:
    • Potentiate
      • Allopurinol
      • Aspirin
      • Alcohol
    • Decrease glucose tolerance
      • Oral contraceptives
      • Corticosteroids
A
40
Q

Side effects of glucagon-like peptide-1 analogs are mainly … in nature including … (4)

A

Side effects of glucagon-like peptide-1 analogs are mainly gastrointestinal in nature including acid or sour stomach, belching, diarrhea, heartburn etc

41
Q

Metformin - secondary mechanisms of action

  • Increases insulin …
    • Possibly through improved insulin binding to insulin receptors
  • Enhances peripheral glucose uptake
    • Increased GLUT … translocation through AMPK
    • … muscle metabolic changes by p38 MAPCK and PKC-dependent mechanisms and independent of AMPK
  • Increases fatty acid … via decreasing insulin-induced suppression of fatty acid …
  • Decreases glucose absorption from …
A
  • Increases insulin sensitivity
    • Possibly through improved insulin binding to insulin receptors
  • Enhances peripheral glucose uptake
    • Increased GLUT 4 translocation through AMPK
    • Heart muscle metabolic changes by p38 MAPCK and PKC-dependent mechanisms and independent of AMPK
  • Increases fatty acid oxidation via decreasing insulin-induced suppression of fatty acid oxidation
  • Decreases glucose absorption from GI tract
42
Q

Sodium-glucose transporter (SGLT) protein inhibitors

  • SGLT1 found in … intestine (to absorb glucose) and proxmal … tubule of the nephron
  • SGLT2 found in proximal … tubule
  • 100% of glucose has to be reabsorbed along the nephron, 90% by SGLT…
  • Therefore blocking this transporter does what?
A
  • SGLT1 found in small intestine (to absorb glucose) and proximal straight tubule of the nephron
  • SGLT2 found in proximal convoluted tubule
  • 100% of glucose has to be reabsorbed along the nephron, 90% by SGLT2
  • Therefore blocking this transporter causes blood glucose to be eliminated through the kidney
43
Q

Adverse effects and toxicity of biguanides

  • Metformin produces … … only rarely
    • More frequent in patients with … impairment
  • More common side effects include … (5)
  • Vitamin … and fo… absorption decreased with chronic metformin
  • Myocardial infarction or septicemia mandate immediate stoppage - why?
A
  • Metformin produces lactic acidemia only rarely
  • More frequent in patients with renal impairment
  • Nausea, abdominal discomfort, diarrhea, metallic taste, anorexia more common
  • Vitamin B12 and folate absorption decreased with chronic metformin
  • Myocardial infarction or septicemia mandate immediate stoppage (associated renal dysfunction)
44
Q

DPP IV inhibitors

  • Drugs in this class include …gliptin (Reversible), …gliptin (Reversible) and …gliptin (covalently bound)
  • … active
  • Side effects?
  • Modest elevations of …
  • Weight …, no … side effects
A
  • Drugs in this class include vildagliptin (Reversible), sitagliptin (Reversible) and savagliptin (covalently bound)
  • Orally active
  • Few side effects
  • Modest elevations of incretins
  • Weight neutral, no GI side effects
45
Q

Properties of Metformin

  • … active
  • Does not bind plasma …
  • Excreted unchanged in …
    • Half-life …-… hr
  • Often combined in a single pill with what?
  • Also used for … … syndrome
A
  • Orally active
  • Does not bind plasma proteins
  • Excreted unchanged in urine
  • Half-life 1.3-4.5 hr
  • Often combined in a single pill with other anti-diabetic medications
  • Also used for polycystic ovary syndrome

Year 2 Medicine (162 decks)

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