Hypoglycaemic Agents Flashcards
What are the functions of insulin?
Facilitate diffusion of glucose into cells
Stimulate hepatic glycogen production
Stimulate hepatic fatty acid synthesis for transport of lipoproteins and increase the amount of free FAs in the circulation
Inhibit breakdown of far in adipocytes by inhibiting lipase
Can cause weight gain, is anabolic
Which cells produce insulin and glucagon?
Alpha cells produce glucagon
Beta cells produce insulin
Function of glucagon?
To increase glucose levels by stimulating glycogenolysis and gluconeogenesis in the liver
What needs to be changed about diet in type II diabetics?
Reduce energy intake if overweight Encourage carbohydrate complexes Limit salt and alcohol intake Stop smoking Start exercising
What are the classes of oral hypoglycaemics?
Insulin sensitisers
- biguanides
- thiazolidinedione
Beta cell stimulators
- sulphonylureas
- meglitidines
Appetite suppressants
-GLP-1 analogues
Weight loss agents
Give an example of a biguanide
Metformin
How do biguanides work?
Metformin
Mechanism not fully understood
-increase insulin receptor sensitivity, reducing resistance
-stimulate uptake if glucose in muscle and adipose tissue
-decrease absorption of glucose in gut
What effects can biguanides have on blood results?
Reduce HbA1c by up to 2%
Reduce VLDLs and LDLs
Extra benefits of biguanides (Metformin)?
Weight neutral
Lowers CVS risk
May have possible anti-cancer benefits
No risk of hypoglycaemia
What is the half-life of biguanides/Metformin? What affect does this have on dosage?
2-3 hours
Requires dosing 2-3 times a day
How is Metformin eliminated?
Entirely by the kidneys
-not metabolised
ADRs of Metformin?
GI symptoms in a third
- increased wind
- abdominal discomfort
- loose stools/diarrhoea
Potential for lactic acidosis
Contraindications for Metformin?
Renal failure
Cardiac, liver and respiratory failure
Stop in intercurrent illness with risk of tissue hypoxia and contrast imaging
Give some examples of sulphonylureas
Gliclazide
Glimepiride
Glipizide
General action of sulphonylureas?
(Gliclazide)
Stimulates beta cells therefore requires some residual function
Mechanism of action of sulphonylureas?
Antagonise β-cell K/ATP channels
Potassium accumulates in the cell causing depolarisation
Allows Ca entry
Increases fusion rate of insulin vesicles with the beta-cell membrane and their release into the circulation
Half-life of sulphonylureas? Effect on dosing?
Gliclazide has a short half-life of 10-12 hours
Glimepiride has a longer half-life of 18-24 hours
Given once daily
Adverse effects of sulphonylureas?
Hypoglycaemia - concern in elderly, missed meals or excess alcohol
GI disturbance
Weight gain - can limit use in obese patients
Name some meglitinides
Repaglinide
Nateglinide
Mechanism of action of meglitinides?
Same as sulphonylureas
-act on K+/ATP
Half-life of meglitinides? Effect on dosing?
1-3 hours
Taken before meals for shorter-term control of post-meal glucose elevation
Benefits of meglitinides?
Reduce HbA1c by 1%
Relatively lower risk of hypoglycaemia
Not associated with weight gain - extends utility in treating obese patients
General mechanism of action of thiazolidinedione? (TZDs)
Insulin sensitisers
Increase glucose uptake in muscle
Increase glucose utilisation
Reduce gluconeogenesis in muscle, adipose tissue and the liver
Mechanism of action of TZDs?
Agnostically bind to a nuclear hormone receptor site - peroxisome proliferator-activated receptor gamma (PRAR-γ)
This binds with another nuclear receptor - the retinoid X receptor (RXR)
The PRAR-γ/RXR complex upregulates genes important for insulin signalling - govern glucose and lipid metabolism
Name some thiazolidinediones
Rosiglitazone
Pioglitazone
Dosing of TZDs?
Once a day for prolonged control of glucose levels
-reach peak effects after 1-2 months
ADRs of thiazolidinediones?
Weight gain
Possible bladder cancer
Fractures in post-menopausal women
Fluid retention and oedema
Contraindications of TZDs?
Heart failure
Do TZDs induce hypoglycaemia?
No
Name a GLP-1 analogue
Exenatide
Where is GLP-1 secreted from and when?
L-cells of the intestine
Upon ingestion of food
Action of GLP-1?
Stimulates beta cells to release insulin and decreases glucagon levels Stops the liver from producing glucose Decreases gastric emptying Increases glucose uptake in muscle Decreases appetite
How are GLP-1 analogues administered?
Injected
Extra benefits of exenatide/GLP-1 analogues?
Promotes weight loss
Lowers HbA1c
Adverse effects of exenatide?
GI symptoms
Painful to inject
Nausea
What drug class does acarbose belong to?
Alpha-glucosidase inhibitor
How does acarbose work?
Inhibits breakdown of carbohydrates to glucose by blocking the enzyme glucosidase
ADRs of acarbose?
Flatulence
Loose stools and diarrhoea
Therefore no longer used much
Effect of NSAIDs on glucose levels?
Can cause hypoglycaemia with sulphonylureas
What can diabetes be due to?
Genetic defects of beta cells
Genetic defects of insulin action
Drug-induced diabetes
Associated with other hormone disorders
List the main treatment steps in type II combination therapy
Begin with lifestyle changes
Drug therapy - Metformin
If HbA1c levels go above 7% - sulphonylurea introduced
If HbA1c goes above 7.5% - add TZD or start insulin
If HbA1c goes above 7.5% again, tirade dose upwards
