Question 6

Classify the oral hypoglycaemic drugs; include their mechanism of action, and their 
most significant side effects.

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College Answer

A good answer would have best been served by a tabular structure and some understanding of the information required. One system of classification of oral hypoglycaemic drugs is by their mechanism of action, or drug group e.g. Biguanides, Sulfonylureas, Thiazolidinediones, Alpha-glucosidase inhibitors, Meglitinides and Dipeptidyl peptidase (DPP) -IV inhibitors.

Discussion

Class mechanism of action Adverse effects

Biguanides:

By disabling the mitochondrial respiratory chain, decrease the ATP supply to hepatocytes, activating AMPK (a fuel-sensing enzyme which regulates the balance of anabolic and catabolic activity). The result is an activation of fatty acid oxidation and a deactivation of glycogenolysis and gluconeogenesis. Systemic glucose delivery from the liver is therefore decreased.


- lactic acidosis
- diarrhoea
- abdominal discomfort
- anorexia
- taste disturbance

Sulfonylureas:

By binding to the ATP-sensitive K channel, these drugs act like ATP (i.e. same as a rise in blood glucose), closing the channel and stopping the efflux of potassium from the cell, which promotes depolarisation. The depolarisation then leads to insulin release

- undesirable severe hypoglycaemia
- hypokalemia
- secondary failure of therapy (as beta-cells burn out)
- erythema multiforme
- exfoliative dermatitis
- photosensitivity

α-glucosidase inhibitors:

By acting as a pseudocarbohydrate, they substitute themselves as a substrate for α-glucosidase enzymes such as sucrase, maltase, dextranase and glucoamylase, which results in decreased intestinal absorption of complex carbohydrates

- malabsorption of carbohydrates
- diarrhoea
- flatulence
- abdominal bloating

Meglitinides:

By binding to the ATP-sensitive K channel, meglitinides act like ATP (i.e. same as a rise in blood glucose), closing the channel and stopping the efflux of potassium from the cell, which promotes depolarisation. The depolarisation then leads to insulin release

- undesirable severe hypoglycaemia
(but less likely than with sulfonylureas)
- respiratory tract infections
- headache

Thiazolidinediones:

PPARγ receptor activation leads to the increased synthesis and activity of cellular proteins involved in glucose uptake and processing, which results in an increased effect from any insulin binding in insulin-sensitive tissues (espeically adipocytes). The result is an increase in insulin sensitivity

- weight gain
- increased risk of bone fractures
- fluid retention and oedema
- cardiac ischaemia (rosiglitazone only)

DPP-4 inhibitors:

By decreasing the degradation of GLP-1, DPP-4 inhibitors produce an increase in insulin secretion. GLP-1 binds to its G-protein-coupled receptors on pancreatic β-cells, where it increases intracellular cAMP, and therefore the availability of intracellular calcium that drives insulin exocytosis

- headache
- nasopharyngitis

GLP-1 receptor agonists:

By directly activating GLP-1, receptors, these drugs produce an increase in insulin secretion. This occurs because of an increase in intracellular cAMP, and therefore the availability of intracellular calcium that drives insulin exocytosis

- pancreatitis
- weight loss

SGLT-2 inhibitors:

Inhibit the reabsorprtion of glucose in the proximal tubule, increasing glucose loss via the urine. In this fashion 30-50% (50-90g) of the total daily filtered glucose is lost, resulting in reduced hyperglycaemia and total body calorie loss

- euglycaemic ketoacidosis
- polyuria
- volume depletion
- UTIs

References

Lorenzati, Bartolomeo, et al. "Oral hypoglycemic drugs: pathophysiological basis of their mechanism of action." Pharmaceuticals 3.9 (2010): 3005-3020.

Kimmel, Bonnie, and Silvio E. Inzucchi. "Oral agents for type 2 diabetes: an update." Clinical Diabetes 23.2 (2005): 64-76.

Fowler, Michael J. "Diabetes treatment, part 2: oral agents for glycemic management." Clinical diabetes 25.4 (2007): 131-134.

Blanchard, Tiphaine, et al. "Two cases of suspected poisoning with goat's rue (Galega officinalis L.) in horses." Journal of Equine Veterinary Science 117 (2022): 104084.

Selizer, H. S. "Efficacy and safety of oral hypoglycemic agents." Annual review of medicine 31.1 (1980): 261-272.