15 The control of blood glucose and drug treatment of diabetes mellitus Flashcards
15.01 INSULIN
Human recombinant insulin (or analogues) - actions
promotes tissue uptake and storage of glucose, amino acids and fats
acutely lowers blood glucose
inhibits hepatic glycogenolysis and gluconeogenesis
inhibits lipolysis
increases glycogen synthesis in muscle/liver
stimulates protein synthesis
longer-term effects on growth and gene expression
15.01 INSULIN
Human recombinant insulin (or analogues) - MOA
binding to its receptor (tyrosine kinase type) causes autophosphorylation of the receptor
subsequent tyrosine phosphorylation of ‘insulin receptor substrates’ leads to activation of SH2 domain proteins, which regulate the action of various intracellular enzymes and cell membrane glucose transporters
15.01 INSULIN
Human recombinant insulin (or analogues) - abs/distrib/elim
free insulin in the blood has a half-life of only 10 min so slow-release preparations are needed for regular use
given SC or IV
short-acting (3-5h): soluble (regular) insulin, insulin lispro, insulin aspart
intermediate-acting (10-12h): isophane insulin
long-acting (24h): insulin zinc suspension (crystalline), insulin glargine or detemir
15.01 INSULIN
Human recombinant insulin (or analogues) - clinical use
life-long treatment of type 1 diabetes
also for type 2 diabetes not controlled by oral hypoglycaemic agents
soluble insulin also for emergency IV treatment of diabetic ketoacidosis
15.01 INSULIN
Human recombinant insulin (or analogues) - adverse effects
hypoglycaemia - treated by glucose administration (by mouth, if conscious, otherwise IV or glucagon (IM))
weight gain (mainly in type 2 diabetes)
15.02 SULFONYLUREAS
Gliclazide, tolbutamide, glipizide, glimepiride, glibenclamide - actions
increase insulin release from functioning β-cells, thus producing the effects of insulin
15.02 SULFONYLUREAS
Gliclazide, tolbutamide, glipizide, glimepiride, glibenclamide - MOA
interaction with the sulfonylurea receptor (a subunit of the KATP channel in the cell membrane of β-cells) causes the K+ channel to close
this causes the cell to depolarise and activates voltage-dependent Ca2+ channels
Ca2+ entry stimulates exocytosis of insulin
15.02 SULFONYLUREAS
Gliclazide, tolbutamide, glipizide, glimepiride, glibenclamide - abs/distrib/elim
given orally, they bind extensively to plasma proteins
half-lives: tolbutamide 4h, glipizide 4h, glimepiride 5h, glibenclamide 10h
actions prolonged in patients with renal disease
15.02 SULFONYLUREAS
Gliclazide, tolbutamide, glipizide, glimepiride, glibenclamide - clinical use
type 2 diabetes mellitus, effective in 30% of patients
15.02 SULFONYLUREAS
Gliclazide, tolbutamide, glipizide, glimepiride, glibenclamide - adverse effects
association with cardiovascular disease and hypoglycaemia
weight gain
15.03 BIGUANIDES
Metformin - actions
lowers blood glucose concentration
15.03 BIGUANIDES
Metformin - MOA
inhibits gluconeogenesis in the liver by activating AMP-activated protein kinase
may also enhance tissue sensitivity to insulin
increases glucose uptake into tissues
15.03 BIGUANIDES
Metformin - abs/distrib/elim
given orally
half-life 3h
mostly excreted unchanged in urine (avoid in patients with renal insufficiency)
15.03 BIGUANIDES
Metformin - clinical use
type 2 diabetes (alone or with other oral hypoglycaemic agents)
particularly useful in obese patients
15.03 BIGUANIDES
Metformin - adverse effects
anorexia and GI upset including diarrhoea (leading to weight loss)
may rarely cause potentially fatal lactic acidosis
unlike sulfonylureas, does not cause hypoglycaemia
15.04 MEGLITINIDES
Repaglinide, nateglinide - actions
lowers blood glucose concentration
stimulates insulin release from β-cells in pancreatic islets
15.04 MEGLITINIDES
Repaglinide, nateglinide - MOA
similar to sulfonylureas
interaction with the sulfonylurea receptor, which is a subunit of the KATP channel in the cell membrane of B cells, causes the K+ channel to close
this causes the cell to depolarise and activates voltage-dependent Ca2+ channels
Ca2+ entry stimulates exocytosis of insulin
15.04 MEGLITINIDES
Repaglinide, nateglinide - abs/distrib/elim
quick onset and short duration of action
half-lives: repaglinide 1h, nateglinide 1.5h
(its actions can be reduced by drugs that induce hepatic P450 enzymes, e.g. carbamazepine)
15.04 MEGLITINIDES
Repaglinide, nateglinide - clinical use
type 2 diabetes mellitus
rapid action allows good control of postprandial hyperglycaemia
may be combined with metformin or a glitazone
mainly metabolised in liver, so useful in patients with renal insufficiency
15.04 MEGLITINIDES
Repaglinide, nateglinide - adverse effects
hypoglycaemia (uncommon unless its metabolism is inhibited by other drugs, e.g. gemfibrozil)
15.05 GLUCAGON-LIKE PEPTIDE-1 AGONISTS
Exenatide, liraglutide, lixisenatide, dulaglutide, albliglutide - actions
lowers blood glucose after a meal by increasing insulin secretion, suppressing glucagon secretion and slowing gastric emptying
15.05 GLUCAGON-LIKE PEPTIDE-1 AGONISTS
Exenatide, liraglutide, lixisenatide, dulaglutide,
albliglutide - MOA
glucagon-like peptide-1 (GLP-1) is secreted by L cells which are widely distributed in the gut, including in the ileum and colon as well as more proximally
release of gastric inhibitory polypeptide (GIP) and GLP-1 in response to ingested food provides an early stimulus to insulin secretion before absorbed glucose or other products of digestion reach the islet cells in the portal blood
GLP-1 also inhibits pancreatic glucagon secretion and slows the rate of absorption of digested food by reducing gastric emptying
it is also implicated in control of food intake via appetite and satiety
15.05 GLUCAGON-LIKE PEPTIDE-1 AGONISTS
Exenatide, liraglutide, lixisenatide, dulaglutide, albliglutide - abs/distrib/elim
given via SC injection either daily or weekly (dulaglutide, albliglutide)
half lives: exenatide 2.4h, liraglutide 13h, lixisenatide 3h, dulaglutide 4.5 days, albiglutide 5 days
15.05 GLUCAGON-LIKE PEPTIDE-1 AGONISTS
Exenatide, liraglutide, lixisenatide, dulaglutide, albliglutide - clinical use
type 2 diabetes mellitus, alone or in combination with other drugs
liraglutide is approved for treatment of obesity
15.05 GLUCAGON-LIKE PEPTIDE-1 AGONISTS
Exenatide, liraglutide, lixisenatide, dulaglutide, albliglutide - adverse effects
nausea and diarrhoea
acute pancreatitis, rapid weight loss, hypoglycaemia (especially when used in combination with sulfonylureas)
15.06 DIPEPTIDYL PEPTIDASE INHIBITORS
Sitagliptin, saxagliptin, vildagliptin, linagliptin, alogliptin - actions
lowers blood glucose by inhibiting dipeptidylpeptidase-4 (DPP-4)
15.06 DIPEPTIDYL PEPTIDASE INHIBITORS
Sitagliptin, saxagliptin, vildagliptin, linagliptin, alogliptin - MOA
competitively inhibit DPP-4, thereby lowering blood glucose by potentiating endogenous incretins (GLP-1 and GIP) which stimulate insulin secretion
15.06 DIPEPTIDYL PEPTIDASE INHIBITORS
Sitagliptin, saxagliptin, vildagliptin, linagliptin, alogliptin - abs/distrib/elim
absorbed from the gut and administered once daily orally
eliminated partly by renal excretion and also metabolised by cytochrome P450 enzymes
half-lives: sitagliptin 12h (mainly renal clearance), saxagliptin 2-3h, vildagliptin 3h
15.06 DIPEPTIDYL PEPTIDASE INHIBITORS
Sitagliptin, saxagliptin, vildagliptin, linagliptin, alogliptin - clinical use
type 2 diabetes mellitus in addition to other oral hypoglycaemic drugs
15.06 DIPEPTIDYL PEPTIDASE INHIBITORS
Sitagliptin, saxagliptin, vildagliptin, linagliptin, alogliptin - adverse effects
heart failure (particularly saxagliptin or alogliptin), liver disease, GI adverse effects, pancreatitis
concern they may act as tumour promoters
15.07 SGLT-2 INHIBITORS
Canagliflozin, dapagliflozin, empagliflozin - actions
reduce concentration of circulating glucose by promoting glucose excretion into the urine
15.07 SGLT-2 INHIBITORS
Canagliflozin, dapagliflozin, empagliflozin - MOA
act by promoting glucose excretion into the urine, thereby reducing the concentration of circulating glucose
the resulting glycosuria is associated with an osmotic diuresis and salt excretion
15.07 SGLT-2 INHIBITORS
Canagliflozin, dapagliflozin, empagliflozin - abs/distrib/elim
rapidly absorbed, with time to peak plasma concentrations of less than 2h
they are highly bound to plasma proteins (>80%)
15.07 SGLT-2 INHIBITORS
Canagliflozin, dapagliflozin, empagliflozin - clinical use
type 2 diabetes mellitus - either alone (when metformin is inappropriate) or in combination with insulin or other oral hypoglycaemic agents
15.07 SGLT-2 INHIBITORS
Canagliflozin, dapagliflozin, empagliflozin - adverse effects
significant increase in the risk of urinary tract and fungal infections such as candidal vaginitis or balanitis
susceptibility to diabetic ketoacidosis, volume depletion, fractures, acute renal impairment and lower limb amputations
15.08 α-GLUCOSIDASE INHIBITORS
Acarbose, miglitol - actions
delay carbohydrate absorption from intestine
15.08 α-GLUCOSIDASE INHIBITORS
Acarbose, miglitol - MOA
inhibits intestinal α-glucosidase and pancreatic α-amylase so reduces the rise in blood glucose which follows a meal
α-glucosidase is the enzyme responsible for breaking down starches and oligosaccharides to yield the absorbable monosaccharides
15.08 α-GLUCOSIDASE INHIBITORS
Acarbose, miglitol - abs/distrib/elim
metabolised in GIT by bacteria and digestive enzymes
half-life 2h
15.08 α-GLUCOSIDASE INHIBITORS
Acarbose, miglitol - clinical use
type 2 diabetes mellitus not controlled by other drugs
15.08 α-GLUCOSIDASE INHIBITORS
Acarbose, miglitol - adverse effects
GI discomfort - flatulence, diarrhoea
15.09 GLUCAGON
Human recombinant glucagon - actions
elevates blood glucose concentration
increases rate and force of heart contraction
15.09 GLUCAGON
Human recombinant glucagon - MOA
glucagon activates adenylate cyclase by acting on G protein-coupled receptors linked to Gs
its actions thus mimic those of adrenaline-activating β adrenoceptors
it elevates blood glucose by stimulating hepatic gluconeogenesis and glycogenolysis and by inhibiting glycogen synthesis
15.09 GLUCAGON
Human recombinant glucagon - abs/distrib/elim
glucagon is a peptide hormone - must be given by injection
plasma half-life 5 min
15.09 GLUCAGON
Human recombinant glucagon - clinical use
emergency treatment of hypoglycaemia (caused by insulin overdose), when oral or IV glucose administration is not possible
(also used to treat heart failure precipitated by α-adrenoceptor antagonists)
15.09 GLUCAGON
Human recombinant glucagon - adverse effects
uncommon
cardiac stimulation in patients taking β blockers or with pheochromocytoma
