2. Drugs used in the management of diabetes mellitus Flashcards
How is insulin synthesized?
- Proinsulin is the immediate precursor of insulin.
- Enzymes cleave off the connecting peptide (C-peptide) to release active insulin, composed of two peptide chains
- These 2 chains are connected by disulphide (S-S) bonds.
- Since C-peptide arises only from endogenous insulin, its presence in blood indicates endogenous synthesis of insulin.
How does glucose stimulate insulin secretion?
Increased levels of glucose in the circulation lead to increased glucose uptake into pancreatic beta cells through the low affinity glucose transporter, GLUT2.
Increased intracellular glucose then leads to increased production of ATP, and an increase in the ATP/ADP ratio; the increased ATP/ADP ratio leads to closing of the potassium channel and depolarization of the cell; and cell depolarization opens a calcium channel which leads to insulin secretion.
Which glucose transporter is constitutively expressed in β-cells?
GLUT 2 → has low substrate affinity (high Km) → low affinity for glucose → requires greater conc. of glucose to achieve maximal enzymatic activity
Function of insulin
It maintains blood glucose by
- Facilitating cellular glucose uptake
- Regulating carbohydrate, lipid and protein metabolism
- Promoting cell division and growth
How is insulin cleared from the body?
- About 50% of endogenous insulin is removed during first-pass
- The kidney is the major site of insulin clearance from the systemic circulation, removing about 50% of peripheral insulin via glomerular filtration and proximal tubular reabsorption and degradation.
Exogenous insulin is mainly cleared by the kidneys
When is insulin indicated for patients?
- Type 1 diabetes
- Type 2 diabetes
- Severe hyperglycaemia
- Glycemic targets were not reached with 2 or more oral hypoglycaemic agents (OHAS)
- Insulin can be given alone or in combination with OHAs
Types of insulins
- Rapid-acting insulins
- Short-acting insulins
- Intermediate-acting insulins
- Long-acting insulins
- Ultra-long-acting insulins
Examples of rapid-acting insulins
Insuline Lispro
Insulin Aspart
Insulin Glulisine
Short duration of action → lower incidence of hypoglycaemia
Example of short-acting insulin
Regular human insulin
Hypoglycaemic risk with short-acting insulin
Greater hypoglycaemic risk than rapid acting insulin
Pharmacokinetics of short-acting insulin when injected IV
Acts almost instantly → in situations of hyperglycemic crisis or DKA
Example of intermediate-acting insulin
Neutral Protamine Hagedorn (NPH)
Hypoglycaemic risk with NPH
High risk due to
- High intra and inter patient variability of NPH action
- Long peak effect. NPH insulin acts as a basal and a prandial insulin, necessitating that patients eat a meal at the time the insulin is peaking.
Examples of long-acting insulin analogues
- Insulin Glargine
2. Insulin Detemir
Which insulins cannot be mixed with any other insulin in a single syringe
Insulin Glargine and Insulin Detemir
Example of an ultra-long-acting insulin
Insulin Degludec
How is insulin administered
- SC injection
- IV → emergency
- IM → not recommended
- Nasal
Factor influencing PK of insulin
- Site of injection
- Depth of injection
- Larger volumes can delay absorption
- Exercise
- Massage of injection site (Heat)
How does stressful situations (acute infection) and corticosteroids affect insulin demand?
Stressful situations and corticosteroids → increase in blood glucose levels → hyperglycaemia → insulin levels may need to be increased
Adverse effects of insulin
- Hypoglycaemia → dizziness, tremor, shaky hands, feeling hungry, weak or confused, sweating
- Lipodystrophy
Classifications of oral & injectable hypoglycaemic agents
- Insulin sensitizers
- Biguanide
- Thiazoldinediones - Insulin secretagogues
- Sulfonylureas
- Meglitinides - Alpha glucosidase inhibitors
- Incretin based therapy
- Dipeptidyl peptidase-4 inhibitors
- GLP-1 receptor agonist - Sodium-glucose co-transporter 2 inhibitors
Examples of Biguanide
Metformin
MOA of Metformin
Metformin decreases hepatic glucose production, increases the density of insulin receptors at the tissues, decreases intestinal glucose absorption and improving muscular glucose absorption. It does not affect insulin secretion.
Which drug is the first line of therapy for T2DM unless contraindicated
Metformin
Side effect of Metformin
- Gastrointestinal issues including diarrhea, vomiting, indigestion and flatulence, Take with meals or after meals to reduce side effects.
- Increase risk of Vit B12 malabsorption and hence Vit B12 deficiency.
- Use with caution in patients with renal problems or lactic acidosis (hepatic disease and cardiovascular problems).
Does not result in hyperinsulinemia or hypoglycaemia. Can help with weight loss and in improving lipid levels
Examples of Thiazolidinediones
- Pioglitazone
2. Rosiglitazone
MOA of Thiazolidinediones
Primary mechanism of action is via the activation of the nuclear transcription factor peroxisome proliferator-activated receptor-γ (PPAR-γ). PPAR-γ ligands are known to regulate glucose metabolism, adipogenesis, and improve insulin sensitivity at adipose tissues, liver and skeletal muscles. Stimulation of these receptors may result in increased production of GLUT1 and GLUT 4, and enhances tissue sensitivity to insulin.
Side effects of Thiazolidinediones
Weight gain, peripheral edema, increased risk of heart failure (fluid retention) and bone fractures
Pioglitazone induce CYP450 enzyme activity and can reduce the serum concentrations of drugs metabolized by these enzymes, which include oral contraceptives.
Examples of sulfonylureas
Tolbutamide, Gibenclamide, Glipizide, Gliclazide, Glimepiride
MOA of sulfonylureas
- Principal target of sulfonylureas is the pancreatic β-cell ATP-sensitive potassium (KATP) channel, which plays a major role in controlling the β-cell membrane potential.
- Sulfonyureas (SU) bind to the SU receptor proteins, subunits of the KATP channels. Drug binding inhibits KATP channel mediated K+ efflux, triggering a calcium-dependent exocytosis of insulin granules from the pancreatic β-cells.
Side effects of sulfonylureas
- Weight gain
- Risk for hypoglycemia (highest with Glibenclamide), especially in the elderly and those with renal or hepatic impairment.
Sulfonylureas are contraindicated in….
sulpha allergy
Examples of Meglitinides
- Nateglinide
2. Repaglinide
MOA of Meglitinides
Meglitinides bind and close the ATP-dependent potassium (KATP) channels on the pancreatic beta cells in a glucose-dependent manner stimulating insulin release. This action is mediated through a unique binding site on the SUR1 of the beta cell that differs from sulfonylureas’ site of action.
Rapid onset and short duration of action → useful of administration just before a meal to control post prandial glucose levels
Side effects of Meglitinides
Used with caution in patients with hepatic impairment.
Insulin release is glucose-dependent and diminishes at low glucose concentrations, hence reducing the risk of hypoglycaemia.
Example of alpha glucosidase inhibitors
- Acarbose
2. Miglitol
MOA of alpha glucosidase inhibitors
- The α-glucosidase inhibitors reversibly inhibit membrane- bound α-glucosidase in the intestinal brush borders slowing down the rise in glucose levels after a meal (inhibits postprandial hyperglycemia).
- Stronger affinity to α-glucosidase than dietary carbohydrates.
- They neither stimulate insulin increase, nor increase insulin action at target tissues, and must be administered with food.
Side effects of acarbose
The higher glucose load in the colon leads to gaseous distention and flatulence that some patients may tolerate poorly.
Acarbose is contraindicated in…
patients with gastrointestinal diseases such as inflammatory bowel disease, and in severe renal or hepatic disease
Example of dipeptidyl peptidase-4 inhibitors
Sitagliptin, Vildagliptin, Linagliptin
MOA of DDP4 inhibitors
DPP-4 inhibitors binds and inhibits DDP-4 thus prolonging the action of endogenous incretins, which then stimulate pancreatic beta-cells to increase glucose-stimulated insulin release, and suppress alpha-cell mediated glucagon release and hepatic glucose production
Side effects of DDP-4 inhibitors
- Gastrointestinal problems such as nausea, diarrhoea, and stomach pain.
- Flu-like symptoms such as headache, runny nose and sore throat.
- Skin reactions
- Use with caution in patients with a history of pancreatitis.
Examples of Glucagon-like peptide-1 receptor agonist
- Exenatide
2. Liraglutide
MOA of glucagon-like peptide-1 receptor agonist
- Exenatide and liraglutide activates the GLP-1 receptor, a membrane-bound cell-surface receptor in pancreatic beta cells.
- This increases insulin release in the presence of elevated glucose concentrations.
- This insulin secretion subsides as blood glucose concentrations decrease and approach euglycemia.
Side effects of GLP-1 receptor agonist
- Gastrointestinal problems such as nausea, vomiting, diarrhea
- The use of exenatide is not recommended in patients with a history of pancreatitis.
- Low risk of hypoglycaemia.
Additional benefits of GLP-1 receptor agonists
- Since it reduces appetite it can result in weight loss. It has been utilised in the management of obese patients.
- Reduce major adverse cardiovascular events
Examples of sodium-glucose co-transporter 2 (SGLT2) inhibitors
Empagliflozin, Canagliflozin, Dapagliflozin
MOA of SGLT2 inhibitors
- SGLT2, expressed in the proximal renal tubules, is responsible for 90% of the reabsorption of filtered glucose from the tubular lumen.
- By inhibiting SGLT2, reabsorption of filtered glucose is reduced and lowers the renal threshold for glucose, and thereby increases urinary glucose excretion.
Additional benefits of SGLT2 inhibitors
- Reduce the risk of a major cardiac event
- Reduction for hospitalisation due to heart failure
- Reduce the risk for worsening renal function
Adverse effects of SGLT2 inhibitors
- Urinary tract infection
- Increased urination
- Female genital mycotic infections
- Increased risk of lower limb amputation (Canagliflozin)
- Diabetic ketoacidosis
