Top 100 Drugs: Metformin, SGLT2 inhibitors, Sulfonylureas, Insulins

MOA of metformin?

-metformin (a biguanide) lowers blood glucose primarily by reducing hepatic glucose output and, to a lesser extent, increasing glucose uptake and utilisation by skeletal muscle

-it does not stimulate insulin secretion and therefore doesn’t cause hypoglycaemia

-involves cellular mechanisms such as activation of AMP kinase, which is a cellular metabolic sensor, activation of which has diverse effects on cell function

warnings with metformin?

-metformin is excreted unchanged by the kidney

-must be used cautiously in renal impairment with dosage reduction if eGFR is <45mL

-metformin should be withheld in acute kidney injury or states of severe tissue hypoxia eg sepsis

-caution required in hepatic impairment as clearance of excess lactate may be impaired

-metformin should be withheld during acute alcohol intoxication and be used with caution in chronic alcohol abuse where there is a risk of hypoglycaemia

important adverse effects with metformin?

-GI upset, including nausea, vomitting, taste disturbances, anorexia, and diarrhoea.

-lactic acidosis - very rarely associated with metformin use

important interactions with metformin use?

-renal function should be checked in people taking metformin before they undergo radiological studies involving IV contrast media

-may be temporarily withheld if renal function is abnormal due to risk of metformin accumulation and lactic acidosis

-other drugs with potential to impair renal function should be used with caution (ACEi, NSAIDs, diuretics) if used alongside metformin

-prednisolone, thiazide, and loop diuretics elevate blood glucose and therefore oppose the actions of metformin

MOA of SGLT2 inhibitors?

-these drugs selectively and reversibly inhibit the SGLT2 transporter in the proximal convoluted tubule of the nephron

-SGL2 mediates active transport of glucose and sodium from filtrate into blood, controlling sodium content of the filtrate and under physiological conditions, recovering most of the filtered glucose

-SGLT2 inhibitors impairs glucose reabsorption in the nephron, increasing renal excretion of glucose and treating hyperglycaemia

-additionally, by increasing renal sodium excretion and water excretion, SGLT2 inhibitors reduce extracellular water volume, blood pressure and cardiac preload

-increased sodium delivery to the macula densa triggers tubuloglomerular feedback mechanism that reduce intra-glomerular feedback mechanisms that reduce intra-glomerular pressure

-together these actions have favourable effects on renal and cardiovascular outcomes in type 2 diabetes, heart failure and OCD.

important adverse effects with SGLT2 inhibitors?

-as the effect of SGLT2i diminishes at lower serum glucose concentrations, they rarely cause hypoglycaemia, although they may exacerbate hypoglycaemia due to other glucose-lowering drugs

-osmotic diuresis can cause thirst and increase risk of hypokalaemia and electrolyte distubance

-glycosuria increases risk of genital and urinary tract infections, and rarely fourniers gangrene

-SGLT2 inhibitors are associated with ketacidosis with a near-normal glucose contentration -rare in type 2 diabetes but common if the drugs are used in type 1.

warnings with SGLT2 inhibitors?

-withhold during intercurrent illness that causes or presents a risk of volume depletion or hypotension

important interactions with SGLT2 inhibitors?

-SGLT2 augment the effects of other glucose lowering drugs (insulin, sulphonylureas) with both therapeutic benefit and increased risk of hypoglycaemia; blood pressure drugs with increased risk of hypotension and diuretics with increased risk of volume depletion

MOA of sulfonylureas?

-sulfonylureas lower blood glucose by stimulating pancreatic insulin secretion

-they block ATP-dependent K+ channels in pancreatic B-cell membranes, causing depolarisation of the cell membrane and opening of VGCC

-this increases intracellular Ca2+ concentrations, stimulating insulin secretion

-sulfonylureas are effective only in people with residual pancreatic function

-as insulin is an anabolic hormone, stimulation of insulin secretion by sulfonylureas causes weight gain

-weight gain increases insulin resistance and can worsen diabetes in the long term

important adverse effects with sulphonyureas?

-dose related side effects eg GI upset are usually mild and infrequent

-hypoglycaemia is a potentially serious adverse effect which is more likely with high doses, if drug metabolism is reduced or if other glucose-lowering medications are prescribed

-depending on the duration of action of the drug, sufonylurea-induced hypoglycaemia may last for many hours

-rare hypersensitivity reactions including hepatic toxicity, drug hypersensitivity syndrome and haematological abnormalities.

important interactions with sulfonylureas?

-gliclazide is increased by co-prescription of other glucose-lowering drugs including metformin, insulin, DPP-4 inhibitors, thiazolidinediones, SGLT2 inhibitors and alcohol

-b-blockers may mask symptoms of hypoglycaemia

-the efficacy of sulfonylureas is reduced by drugs that elevate blood glucose eg prednisolone, thiazide, and loop diuretics

important interactions with sulfonylureas?

warnings with sulfonylureas?

-gliclazide is metabolised in the liver and has a plasma half life of 10-12 hours

-unchanged drug and metabolites are excreted in the urine

-a dose reduction may therefore be required in hepatic impairment and blood glucose should be monitored carefully in renal impairment

-sulfonylureas should be prescribed with caution for people at increased risk of hypoglycaemia, including those with hepatic impairment, malnutrition, adrenal or pituitary insufficiency and in older people

MOA of insulins?

-exogenous insulin functions similarly to endogenous insulin - it stimulates glucose uptake and utilisation from the circulation and tissues, including skeletal muscle and fat

-insulin stimulates glycogen, lipid, and protein synthesis and inhibits gluconeogenesis and ketogenesis

-the overall effect is to lower blood glucose concentration - this is the primary measure of its therapeutic effect

-insulin also activates Na+/K+/ATPase driving K+ into cells and reducing serum K+ concentrations

what are the different types of insulin ?

-rapid acting: immediate onset, short acting. eg novorapid (insulin aspart)

-short acting: early onset, short duration (actrapid)

-intermediate acting: inermediate onset and duration eg. Humulin I

-long acting: flat profile with regular administration eg Lantus, Levemir, Tresiba

what is biphasic insulin?

-contains a mixture of rapid and intermediate acting insulin

eg Novomix 30 (30% insulin, 70% insulin aspart protamine)

how are insulin preparations dosed?

in UNITS, which corresponds to the glucose lowering activity of a defined mass of an internationally approved ‘standard insulin’

important adverse effects with insulin?

-main adverse effect is hypoglycaemia, which can be severe enough to cause coma and death

-when administered by repeat SC injection at the same site, insulin can cause fat overgrowth (lipohypertrophy) which may be unsightly or uncomfortable

warnings with insulin?

-in renal impairment, insulin clearance is reduced, so there is an increased risk of hypoglycaemia

important interactions with insulin ?

-although often necessary, combining insulin with other hypoglycaemic agents increases the risk of hypoglycaemia

-concurrent therapy with systemic corticosteroids increases insulin requirements