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203: Theme 1: The Endocrine System > Drug treatment of type 2 diabetes > Flashcards

Drug treatment of type 2 diabetes Flashcards

1
Q

Insulin effects on hepatic cells

A

Decreases gluconeogenesis, glycogenolysis, ketogenesis

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2
Q

Insulin effects in muscle cells

A

Increases GLUT-4 translocation to the membrane

Increases glucose uptake, glucose oxidation, glycogen synthesis, amino acid uptake, protein synthesis

Decreases glycogenolysis and amino acid release

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3
Q

Insulin effects in adipocytes

A

Increase glucose uptake, increase triglyceride synthesis

Decrease FFA and glycerol release

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4
Q

Net effect of insulin

A

To cause hypoglycaemia and increase fuel storage in muscle, fat tissue and liver

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5
Q

Sulfonylureas

A

e.g. gliclazide, glipizide, glimepriride

All orally active

All bound to plasma protein

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6
Q

Primary mechanism of action of sulfonylureas

A

Stimulates endogenous insulin release

Binding site on ATP sensitive K-channel to inhibit the opening of the channel similar to ATP

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7
Q

Secondary mechanism of action of sulfonylureas

A

Evidence these drugs:

  • sensitise B-cells to glucose
  • decrease lipolysis
  • decrease clearance of insulin by the liver
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8
Q

Therapeutic uses of sulfonylureas

A

Useful in type-2 DM only

  • over 40 years old
  • DM duration less than 10 years
  • daily insulin less than 40 units

Can be used in combination with other anti-diabetic drugs

Major side effect: hypoglycaemia

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9
Q

Biguanide drugs

A

Oral antihyperglycaemic agents

Differ from sulfonylureas and meglitinides both chemically and in mechanism of action

Do not stimulate insulin release or cause hypoglycaemia

Appear to increase glucose uptake in muscle and decrease glucose production by liver

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10
Q

Biguanide drugs mechanism of action

A

Suppression of hepatic glucose production through gluconeogenesis through AMP - AMPK dependent and independent pathways

AMPK increases expression of nuclear transcription factor SHP

SHP inhibits expression of hepatic gluconeogenesis genes (PEPCK) and G-6-Pase

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11
Q

Biguanides action

A

Increase insulin sensitivity
- possibly through improved 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 decreased insulin induced suppression of fatty acid oxidation

Decreases glucose absorption from GI tract

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12
Q

Properties of metformin

A

Orally active

Does not bind plasma proteins

Excreted unchanged in urine
- half life 1.3-4.5 hours

Often combined in single pill with other anti-diabetic medications

Also used for polycystic ovary syndrome

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13
Q

Adverse effects and toxicity of biguanides

A

Metormin produces lactic acidaemia only rarely
- more frequent in patients with renal impairment

Nausea, abdominal discomfort, diarrhoea, metallic taste, anorexia

Vitamin B12 and folate absorption decreased with chronic metformin

MI or septicaemia mandate immediate stoppage

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14
Q

Metformin contraindications

A

Hepatic disease

Past history of lactic acidosis

Cardiac failure

Chronic hypoxic lung disease

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15
Q

Glitazones e.g.

A

Thiazolidinediones

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16
Q

Glitazones

A

Troglitazone was first approved for use in NIDDM; off the market now due to hepatic failures

Rosiglitazone now off the market due to CVS damage

Pioglitazone now only one remaining approved

Activate peroxisome proliferator activated receptor gamma (PPARy)

17
Q

Glitazone pharmacodynamics

A

In presence of endogenous or exogenous insulin, gliatozones will:

  • decrease gluconeogenesis, glucose output and triglyceride production in liver
  • increase glucose uptake and utilisation in skeletal muscle
  • increase glucose uptake and decrease fatty acid output in adipose tissue
  • cause differentiation of adipocytes
18
Q

Glitazone pharmacokinetics

A

Pioglitazone: taken once or twice daily orally

  • plasma levels peak about 3 hours
  • plasma half life is 3-7 hours; active metabolites
  • liver metabolism and excreted in faeces (2/3) and urine (1/3)
19
Q

Adverse effects and drug interactions of gliatazones

A

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

20
Q

Pioglitazone adverse effects and drug interactions

A

Subject to interactions due to liver metabolism

May lower oral contraceptive levels containing ethinyl estradiol and norethindrone

21
Q

Glucagon like peptide 1 analogs

A

Facilitate 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
22
Q

Side effects of glucagon like peptide 1 analogs

A

Mainly GI in nature

Acid or sour stomach

Belching

Diarrhoea

Heartburn

23
Q

Exenatide

A

High plasma concentration

Strong effects on receptors

Injectables only

New oral formulation in clinical trials

24
Q

Dipeptidyl peptidase 4 inhibitors

A

Class of oral hypoglycaemic agents

Mechanism of action is via increased levels of incretins GLP1 and GIP

Increased incretins

  • inhibit glucagon release
  • increase glucose induced insulin secretion
  • decrease gastric emptying
  • reduce hepatic glucose production
  • improved peripheral glucose utilisation
25
Q

Types of DPP-4 inhibitors

A

Vildagliptin (reversible)

Sitagliptin (reversible)

Saxagliptin (covalently bound)

26
Q

DPP-4 inhibitor features

A

Orally active

Few side effects

Modest elevations of incretins

Weight neutral, no GI side effects

27
Q

DPP-4 inhibitors and cancer

A

Enzyme known to be involved in suppression of certain malignancies as it functions as a tumour suppressor

Not yet seen with drugs in long term preclinical studies

28
Q

SGLTs

A

SGLT1 found in small intestine 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

Blocking this transporter causes blood glucose to be eliminated through the kidney

29
Q

SGLT2 inhibitors

A

Dapagliflozin- approved for use in Europe April 2012
- IC50 for SGLT2 is less than 1/1000 of the IC50 for SGLT1

Canagliflozin- approved by FDA 10th Jan 2013 to treat type 2 diabetes in adults

30
Q

Effects of SGLT2 inhibitors

A

Inhibition of renal tubular Na+ glucose cotransporter –> reversal of hyperglycaemia –> reversal of glucotoxicity

Increase insulin sensitivity in muscle

  • increase GLUT4 translocation
  • increase insulin signalling

Increase insulin sensitivity in liver
- decrease G-6-Pase

Decrease gluconeogenesis

  • decrease Cori cycle
  • decrease PEP carboxykinase

Increase beta cell function

31
Q

Side effects of SGLT inhibitors

A

Rapid weight loss (due to glycosuria)

Tiredness

Osmotic diuretic so dehydration

Can worsen UTI and thrush

203: Theme 1: The Endocrine System (22 decks)

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