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203: The endocrine system > T2 DM drugs > Flashcards

Flashcards in T2 DM drugs Deck (32)
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1

Insulin hepatic effects

Increases glycogenesis

Inhibits:
- Gluconeogenesis
- Glycogenolysis
- Ketogenesis

2

Insulin skeletal muscle effects

Increases:
- GLUT-4 translocation= more glucose uptake
- Glucose oxidation
- Glycogenesis
- Amino acid uptake
- Protein synthesis

Decreases:
- Glycogenolysis
- Amino acid release

3

Insulin adipocytes effects

Increase:
- Glucose uptake
- TG synthesis

Decreases:
- FFA release
- Glycerol release

4

Sulfonylurea examples

Glyburide

Glipizide- short half life

Glimepiride- long acting

5

Sulfonylurea drug properties
- Oral activity
- Protein bound
- Side effects

Orally active

Bound to plasma protein

Side effect: Hypoglycaemia

6

Sulfonylurea indication

In T2 DM when:
- Patient <40, but can now be younger.
- DM for <10 yrs
- Daily insulin <40 units.

7

Sulfonylurea primary mechanism of action

Stimulates endogenous insulin release from beta-cells
- Binds to ATP-sensitive K+ channel to inhibit it
- Triggers depolarisation of the cell
- Entry of Ca2+ triggers release of insulin

8

Sulfonylurea secondary mechanism of action

Sensitise beta-cells to glucose

Decreased lipolysis

Decreased clearance of insulin by the liver

9

Biguanide/ Metformin
- Metabolic mechanism

Increase glucose uptake in muscle and decrease glucose production in the liver.

In hepatocytes
- Stimulates AMP-activated protein kinase [AMPK] dependant and independant pathways.
- AMPK inhibits expression of PEPCK and Glucose-6-phosphates by increasing SHP
- PECK and Glucose-6-phosphatase drive gluconeogenesis

10

SHP

A nuclear transcription factor

It's expression is increased by AMPK
- An effect of metformin

Inhibits expression of genes for PEPCK and Glucose-6-phosphatase

11

PEPCK

Phosphoenolypyruvate carboxykinase

Protein that drives gluconeogenesis

It's synthesis is inhibited by SHP via AMPK pathway

12

Biguanides on insulin sensitivity

Increases insulin sensitivity
- Improves binding ability of insulin receptors.

13

Biguanides on peripheral glucose uptake.

Increases uptake

AMPK pathway
- Increases GLUT-4 translocation

AMPK-independant
- Changes heart muscle to metabolise glucose more using p38 MAPCK
- PKC-depedant

14

Biguanides effects on
- Adipose tissue
- GIT

Adipose [opposes insulin]
- Increases fatty acid oxidation by decreasing insulin-induced suppression of FA oxidation

GIT:
- Decreases glucose absorption

15

Metformin properties
- Oral activity
- Plasma proteins
- Metabolism and excretion
- Other indications

Orally active

Does not bind to plasma proteins

Not metabolised + excreted in urine

Other indications
- Polycystic ovarian syndrome

16

Adverse effects of biguanides

Lactic acidemia [increased glucose metabolism in muscle]
- Especially in those with renal impairment

GI symptoms [decreased glucose absorption]
- Nausea
- Abdominal discomfort
- Diarrhoea
- Metallic taste
- Decreased Vit B12/ Folate absorption [chronic]

Anorexia

Metallic taste

MI/ Septicaemia

17

Metformin contraindications

Hepatic disease

Lactic acidosis history

Cardiac failure

Chronic hypoxic lung disease

18

Thiazolindinediones [glitazones]
- Mechanism
- Action on: liver, skeletal muscle, adipose

Mechanism
- Activates peroxisome proliferator-activated receptor-gamma [PPAR-gamma]

Liver
- Decreases: gluconeogenesis, glucose output, TG production

Muscle
- Increase glucose uptake and utilisation

Adipose
- Increase glucose uptake
- Decrease FA output
- Causes differentiation of adipocytes

19

Peroxisome proliferator-activated receptor-gamma [PPAR-gamma]

Receptor that is activated by Glitazones

Receptor involved in the transcription of insulin-responsive genes

Regulates adipose lipid mechanism.

20

Use of glitazones

Can be used as monotherapy

Can be used with metformin or sulfonylureas.

Dose: one/twice daily

21

Glitazones
- Example
- Plasma life
- Metabolism
- Excretion

Example
- Pioglitazone

Half life
- 3-7hrs
- Active metabolites= 16-24 hrs

Metabolism
- Liver

Excretion
- Faeces [mainly]
- Urine

22

Glitazones
- Adverse effects

Fluid retention
- Oedema
- Mild anaemia

Weight gain

Not safe for breastfeeding and pregnancy

Requires regular blood tests if liver damaged
[due to liver metabolism]

23

Glitazone drug interactions

Due to metabolism in the liver
- Interacts with enzymes

Lowers oral contraceptive level

24

Glucagon-like peptide-1 [GLP-1] analogs

GLP-1 is an incretin released from intestinal cells
- Stimulates the release from insulin from beta cells.
- Its analogs perform a similar action

Example
- Exenatide

25

Exenatide
- Drug type
- Mechanism [liver, stomach, satiety]

GLP-1 analog
- Resistant to DPP-4 degradation
- Long half life

Mechanism
- Inhibits liver glucose output---> Suppresses release of glucagon in pancreas
- Slows gastric emptying= allows more time for glucose control.
- Reduces liver fat content
- Reduces appetite + increases satiety

26

Exenatide
- Use

Subcutaneous
- 30-60mins before last meal of the day.

27

DPP-4 inhibitors
- Overall function

- Examples

DPP-4 degrades incretins and inhibits insulin secretion.
- Inhibitors act to increase GLP-1 and GIP levels = increased incretins
- Increases the effects of incretins

Examples
- Vildagliptin
- Sitagliptin
- Saxagliptin [irreversible]

28

DPP-4 inhibitors
- Oral activity?

Orally active

29

SGLT-2 inhibitors
- Examples

Increases excretion of glucose via the urine
- Inhibits low affinity, high capacity SGLT-2 protein carrier

Examples
- Dapagliflozin
- Canagliflozin

30

SGLT-2 inhibitors
- Effects

Reverses hyperglycaemia by inhibiting glucose absorption

Increases insulin sensitivity in muscle and liver

Decreases gluconeogenesis

Improves beta cell function