Anti-Diabetic Drugs Flashcards
(27 cards)
What categories of drug are used in the treatment of type 2 diabetes mellitus?
Biguanides
Sulphonylureas
Thiazolidinediones (Glitazones)
Alpha Glucosidase Inhibitors
DPP-4 Inhibitors
GLP-1 Receptor Agonists
SGLT2 Inhibitors
Insulin
What drugs are considered Biguanides? Please state how they are administered and describe their mechanism of action
Metformin is the only biguanide anti-hyperglycaemic drug available for clinical use - considered the 1st choice pharmacological intervention in all patient with T2DM
Metformin is delivered orally (for T2DM mono therapy or in conjunction with other therapies - initially 500mg per day for a week, then 500mg twice daily for a week, then 500mg thrice daily, can be increased to up to 2g (4 x 500mg) per day if neccesary)
Metformin decreases blood glucose concentration by…
Decreasing hepatic gluconeogenesis
Decreasing intestinal absorption of glucose
Increasing glucose uptake and oxidation by skeletal muscle
The mechanism of action of metformin is not entirely understood, but it is believed the following mechanisms are involved…
Metformin is positivity charged, so once it is taken up by the liver it accumulates within hepatocytes and their mitochondria. Metformin inhibits mitochondrial complex I, which prevents the production of mitochondrial ATP (adenosine triphosphate) leading to increased cytoplasmic ADP: ATP and AMP: ATP ratios. These changes activate AMP activated protein kinase (AMPK), a key regulator of cellular lipid and glucose metabolism, resulting in inhibited gluconeogenesis. Activated AMPK also phosphorylates two isoforms of acetyl-CoA carboxylase enzyme, thereby inhibiting fat synthesis and leading to fat oxidation, reducing hepatic lipid stores and increasing the liver’s sensitivity to insulin.
At the intestines, Metformin increases anaerobic glucose metabolism in enterocytes (intestinal cells) leading to reduced net glucose uptake and increased delivery of lactate to the liver.
Are Biguanides associated with hypoglycaemia or changes in weight?
Biguanides are not associated with a risk of hypoglycaemia, but are associated with weight loss.
What adverse effects are associated with metformin use?
Commonly Experienced Adverse Effects:
Abdominal discomfort
Decreased appetite
Gastrointestinal upset (e.g nausea, vomiting, diarrhoea) - these symptoms are dose related and can be minimised by gradual dose titration and by taking prescribed dose alongside meals
Vitamin b12 deficiency
Rarely Experienced Adverse Effects:
Lactic acidosis - Should not be used in individuals with an eGFR of less than 30ml/min/1.73m2, caution is advised in individuals with chronic heart failure, acute dehydration or in individuals currently taking medications that can acutely impair renal function
Hepatitis
Skin reactions
What drugs are considered sulfonylureas? Please state how they are administered and describe their mechanism of action
Glibenclamide (5mg daily, dose adjusted according to response, max of 15mg)
Gliclazide (40-80mg daily for standard release, dose adjusted according to response, max of 320mg; 30mg daily for modified release, max dose 120mg daily)
Glipizide (2.5-5mg once daily, max 20mg daily)
Tolbutamide (0.5-1.5g daily in divided doses, max dose of 2g daily)
Glimepiride (1mg daily, dose adjusted according to response, max dose of 4mg daily)
All sulphonylureas are delivered orally
Sulphonylureas treat T2DM by stimulating the secretion of insulin from pancreatic b-cells. They do this by binding to the b-cell’s sulfonylurea receptor (SUR1), blocking the ATP sensitive potassium channels, the resulting decrease in potassium efflux leads to depolarisation of b-cells. This opens voltage dependant calcium channels in the b-cell resulting in calmodulin activation, which in turn leads to exocytosis of insulin containing secretory granules. Functioning pancreatic tissue is therefore necessary for their action to be effective.
Are Sulphonylureas associated with hypoglycaemia or changes in weight?
Yes Sulphonylureas are associated with a risk of hypoglycaemia, which can be severe and prolonged, they are also generally associated with weight gain due to increased insulin secretion.
What adverse effects are associated with sulphonylurea use?
Gastrointestinal upset - abdominal pain, nausea, vomiting, diarrhoea, constipation
Hepatic impairment
Skin reactions - rash, pruritus, urticaria, angioedema, erythema, allergic dermatitis, photosensitivity reaction
Haemotological disorders - leucopenia, thrombocytopenia, agranulocytosis, pancytopenia, haemolytic, anaemia, hyponatraemia,
Dizziness, drowsiness, tremor
What drugs are considered glitazones? Please state how they are administered and describe their mechanism of action
The only glitazone (Also known as thiazolidinediones) available for clinical use in the UK is…
Pioglitazone - Initially 15-30mg daily, dose adjusted according to response to 45mg once daily (delivered orally)
Pioglitazone can be used alone or in conjunction with other anti-diabetic drugs in the treatment of T2DM.
Pioglitazone enhances cellular responsiveness to insulin by activating nuclear receptors (peroxisome proliferator-activated receptor-y or PPAR-y), increasing the transcription of insulin-sensitive genes. PRAR-y is predominantly expressed in adipose tissue and also in skeletal muscle and liver. The effect of Pioglitazone on glucose lowering is slow, and maximal effect may achieved only after 2-3 months.
Are glitazones associated with hypoglycaemia or changes in weight?
There is a risk of hypoglycaemia and mild weight gain with Glitazone use
What adverse effects are associated with glitazone use?
Commonly experienced adverse effects of glitazone include…
Osteoporosis and bone fracture
Increased susceptibility to infection
Visual impairment
Weight gain
Uncommon adverse effects of glitazone include…
Bladder cancer
Insomnia
What drugs are considered alpha glucosidase inhibitors? Please state how they are administered and describe their mechanism of action
The only alpha glucosidase inhibitor available for clinical use in the UK is…
Acarbose (initially 50mg a day daily, increased to 50mg 3x a day for 6-8 weeks, then increased if neccesary to 100mg 3x a day - max dose 200mg 3x a day)
Acarbose works to reduce blood sugar levels by inhibiting the breakdown of carbohydrates into absorbable monosaccharides, reducing carbohydrate absorption and subsequent postprandial insulin levels. It does this by inhibiting the action of alpha-glucosidase enzymes located in the brush boarder of the intestinal mucosa.
Are alpha glucosidase inhibitors associated with hypoglycaemia or changes in weight?
Yes they are associated with a small risk of hypoglycaemia, which becomes greater is used in conjunction other antidiabetic therapies associated with hypoglycaemia (e.g insulin and sulfonylureas). They are also associated with weight loss.
What adverse effects are associated with alpha glucosidase inhibitors?
Common adverse effects of alpha glucosidase inhibitors include…
Gastrointestinal discomfort
Diarrhoea
Uncommon adverse effects include…
Nausea & vomiting
Rare adverse effects include…
Hepatic disorders
Oedema
What drugs are considered DPP-4 inhibitors? Please state how they are administered and describe their mechanism of action
Alogliptin (25mg once daily - reduced to 12.5mg in renal impairment)
Linagliptin (5mg once daily - no dose adjustment is required)
Sitagliptin (100mg once daily - 50mg in renal impairment)
Saxagliptin (5mg once daily - 2.5mg in renal impairment)
Vildagliptin (50mg twice daily, reduced to once in renal impairment)
All gliptins (DPP-4 inhibitors) are delivered orally
DPP-4 inhibitors inhibit the action of the enzyme DPP-4, which inactivates incretin hormones like GLP-1 and GIP. Incretins are gut-derived hormones, members of the glucagon family, released in response to nutrient ingestion, mainly glucose and fat. Incretins stimulate pancreatic insulin secretion, lowering blood glucose, thus; inhibiting DPP-4 reduces the inactivation of incretins, increasing insulin secretion and lowering blood glucose.
Are gliptins associated with hypoglycaemia or changes in weight?
DPP-4 inhibitors are generally not associated with hypoglycaemia when taken alone, and some individuals taking a DPP-4 inhibitor may experience mild weight loss but they are generally considered to have no effect on weight.
What adverse effects are associated with DPP-4 inhibitor use?
Common adverse effects of DPP-4 inhibitors include…
Abdominal pain
Gastro-oesophageal reflux
Headache
Increased susceptibility to infection
Skin reactions
Adverse effects of an unknown frequency include…
Angioedema
Abnormal hepatic function
Acute pancreatitis
What drugs are considered SGLT-2 inhibitors (gliflozins)? Please state how they are administered and describe their mechanism of action
The following drugs are known as sodium-glucose co-transporter 2 inhibitors:
Canagliflozin
Dapagliflozin
Empaglifozin
Ertugliflozin
(All SGLT-2 inhibitors are delivered orally)
SGLT-2 inhibitors work to lower blood glucose levels by inhibiting renal glucose absorption, essentially reducing the amount of glucose that is reabsorbed into the bloodstream from the filtrate, leading to increased excretion of glucose in the urine. They do this by blocking the SGLT-2 protein located in the proximal convoluted tubule of the nephron, the protein responsible for the reabsorption of approximately 90% of filtered glucose.
SGLT-2 inhibitors have also been shown to reduce the likelihood of cardiovascular events and improved outcomes in heart failure.
Are SGLT-2 inhibitors associated with hypoglycaemia or changes in weight?
Yes SGLT-2 inhibitors are associated with a risk of hypoglycaemia, and are generally associated with moderate amounts of weight loss
What adverse effects are associated with SGLT-2 inhibitor use?
Common adverse effects of SGLT-2 inhibitors include…
Hypoglycaemia, hypovolaemia, increased risk of infection (particularly urinary tract infections), polydipsia, increased thirst, vulvovaginal pruritus (itch/thrush)
Rare adverse effects include…
Diabetic ketoacidosis
What drugs are considered GLP-1 receptor agonists? Please state how they are administered and describe their mechanism of action
Exenatide
Liraglutide
Semaglutide
Lixisenatide
Dulaglutide
All GLP-1 receptor agonists are delivered via subcutaneous injection
Glucagon-like peptide 1 (GLP-1) is secreted by the L-cells of the small intestine in response to food ingestion. Along with glucose-dependent insulinotropic polypeptide (GIP) it is believed to be responsible for the physiological incretin effect: the increased secretion of insulin in response to oral administration of glucose. GLP-1 receptor agonists mimic the effects of GLP-1 by stimulating GLP-1 receptors within the pancreas, increasing the secretion of insulin and decreasing the secretion of glucagon, lowering blood sugar levels. GLP-1 receptor agonists also slow gastric emptying and decrease appetite. Naturally synthesised human GLP-1 is rapidly broken down by DPP-4, limiting its therapeutic use. Whereas GLP-1 receptor agonists are resistant to degradation by DPP-4.
Are GLP-1 receptor agonists associated with hypoglycaemia or changes in weight?
GLP-1 receptor agonists are generally considered to have a low risk of hypoglycaemia when used alone, and are associated with significant weight loss.
What adverse effects are associated with GLP-1 receptor agonist use?
Common adverse effects of GLP-1 receptor agonists include…
Decreased appetite
GI disturbances (e.g constipation, diarrhoea, abdominal discomfort)
Fatigue
Sinus tachycardia
Atrioventricular block
Nausea and vomiting
Hypoglycaemia
Uncommon adverse effects of GLP-1 receptor agonists include…
Dehydration
Gallbladder disorders
Rare adverse effects of GLP-1 receptor agonists include…
Angioedema
Acute pancreatitis
How does insulin replacement therapy manage hyperglycaemia in both T1DM and long-standing T2DM?
As T1DM is characterised by a lack of endogenous insulin production due to autoimmune-related destruction of pancreatic beta cells, without insulin, glucose accumulates in the bloodstream as insulin is required for the uptake of glucose by skeletal muscle and adipose tissue, and for the hepatic conversion of glucose into stored glycogen. Therefore, replacing the deficit of insulin lowers the concentration of glucose within the blood.
In longstanding T2DM, insulin production can decline to the point that exogenous insulin is required. As insulin secretion is increased when the concentration of glucose within the blood is high, individuals with T2DM often produce excessive levels of insulin in an attempt to manage the prolonged state of hyper-glycaemia. It is thought that this excessive production of insulin can lead to dysfunction of the pancreatic beta cells over time in cases of poorly controlled T2DM. Therefore insulin replacement therapy is often used in individuals with T2DM and impaired insulin production, in conjunction with therapies that increase insulin sensitivity (e.g biguanides and glitazones).
Why is insulin delivered parenterally?
Insulin is destroyed in the GI tract and therefore cannot be administered via an enteral route.
