U2iii / 20B06: Understand the pharmacology of oral hypoglycaemic drugs

20B06: Exam Report

Classify the oral hypoglycaemic drugs (20% marks); include their mechanism of action (40% marks) and their most significant side effects (40% marks)

37% of candidates passed this question.

High scoring answers most often started with a strong and logical structure and focused on the requested categories of information. Many candidates gave good answers across the wide range of drugs. Several candidates could have scored more highly by giving more correct information on biguanides and sulphonylureas.

U2iii / 20B06: Understand the pharmacology of oral hypoglycaemic drugs

Diabetes mellitus (DM) results from lack of or reduced effectiveness of endogenous insulin

 

Oral hypoglycaemic drugs can be divided into 4 broad categories, drugs which:

 

1) ↑ endogenous release of insulin and cause a genuine ↓ in BSL

  1. Sulphonylureas e.g. gliclazide
    1. MOA: Bind to sulphonylurea receptor in pancreatic β cells, closing ATP-sensitive K+ channels > leads to depolarisation + influx of Ca2+ > exocytosis of insulin containing vesicles
    2. SEs: hypoglycaemia, GI disturbances, cholestatic jaundice
  2. Meglitinides e.g. repalinidine
    1. MOA: short acting insulin secretagogues, similar to sulfonylureas
    2. SEs: hypoglycaemia, caution with clarithromycin &antifungals (↓↓BSL)

2) ↓ GI absorption or ↓ renal absorption of glucose

  1. Intestinal a-glucosidase inhibitors e.g. acarbose
    1. MOA: inhibit α-glucosidase, which cleaves disaccharides into monosaccharides > therefore ↓ glucose absorption
    2. SEs: GI disturbance
  2. Sodium-glucose linked transport inhibitors (SGLT2) e.g. empagliflozin
    1. MOAs: prevents glucose reabsorption in PCT of kidneys
    2. SEs: euglycaemic ketoacidosis, UTI, candidiasis

3) ↑ sensitivity to endogenous insulin and ↓ gluconeogenesis / glycogenolysis

  1. Biguinides e.g. metformin
    1. MOA: ↑ sensitivity to endogenous insulin (↑ insulin receptor expression, ↑ tyrosine kinase activity), suppresses gluconeogenesis + glycogenolysis, delays glucose uptake in GIT (inhibits intestinal dissacharidase)
    2. SEs: lactic acidosis, AKI, GI upset
  2. Thiazolidineodines e.g. pioglitazone
    1. MOA: acts on PPARγ (a transcription factor) which alters many genes involved in glucose + other substrate metabolism, ↑ sensitivity to endogenous insulin
    2. SEs: fluid retention, ↑ risk bladder cancer, deranged LFTs

4) Act on incretin pathway

  1. Glucagon-like peptides-1 analogues e.g. exenatide
    1. MOA: GLP-1 enhances glucose-dependent insulin secretion, inhibits glucagon secretion (α-cells), ↓ gastric emptying (↓ postprandial rise in glucose), ↓ appetite
    2. SEs: prolongs gastric emptying
  2. DPP-4 inhibitors e.g. linagliptin
    1. MOA: prevent breakdown of endogenous GLP-1 by DDP4
    2. SEs: pancreatitis, pancreatic cancer

Author: Madeline Coxwell Matthewman

Drug Class & Example

Biguanides - Metformin

MoA

  1. Stimulates movement of GLUT-4 to PM of     sk m & AT
  2. Inhibits hepatic & renal gluconeogenesis
  3. ↓glucose absorption from gut

A/E

Lactic acidosis with renal impairment – binds to mitoch membrane inhibiting aerobic glycolysis →↑ ­anaerobic glycolysis →↑ ­lactate production

Diarrhoea, n/v, abdm discomfort

Must be withheld prior to admin of iodinated IV contrast

Drug Class & Example

Sulfonylureas - Glicazide

MoA

Combines w KATP receptors on panc b cells → closes ATP-K-channels →cell depolarizes → Ca influx → insulin secretion

A/E

Hypoglycaemia

GI disturbance

Wt gain

Drug Class & Example

Thiazolidinediones – Rosiglitazone

MoA

Selective potent agonist at nucleus receptors (PPARy) in AT, m, liver → ¯ins resistance

A/E

Hepatitis

Peripheral oedema

CCF

Wt gain

­risk # in post-menopausal women

C/I w IHD

Drug Class & Example

A-glucosidase inhibitors - Acarbose

MoA

Inhibits enz that breaks down dietary carbs to glucose → ↓ glucose available for absorption

A/E

Abdm discomfort & distention

Flatulence

Elevates serum transaminases

Not suitable as sole agent – only ↓post prandial spikes in glucose

Drug Class & Example

Meglitinides - Repaglinide

MoA

Blocks K in panc b cells → Ca influx → insulin release

A/E

Similar to Sulphonylureas but ↓risk due to shorter DoA

Repaglinide is a major substrate of CYP3A4, caution when administering w clarithromycin or antifungals as high levels of Repaglinide & consequent hypoglycaemia

Drug Class & Example

DDP-IV inhibitors - Sitagliptin

MoA

Inhibit enzyme DDP-IV wh breaks down gut hormones GLP-1 and protein GIP

GLP-1 & GIP stimulate insulin release from pancreas

A/E

Euglycaemic diabetic ketoacidosis.  Must be ceased at least 3d pre-op

Drug Class & Example

SGLT-2 Inhibitor Dapagliflozin

MoA

SGLT-2 proteins expressed on PCT of kidneys reabsorb glucose back into plasma, inhibition stimulates glucosuria

A/E

UTI risk

Predisposition to DKA through lowering plasma glucose