Pharmacology of drugs for T2DM Flashcards
how do SGLT2 inhibitors work?
cause a decrease in the absorption of glucose in the so that it is excreted in the urine
what do SUs bind to?
SUR1
what do SUs cause the SUR1 to do & what does this cause?
close the cannel causing depolarisation & insulin release
what aspect of SUs mechanism of action could be the cause of their negative die effects?
the fact that insulin is released independent of plasma glucose concentration meaning there is a loss in the link between glucose & insulin secretion
give some examples of SUs
tolbutamide
glibenclamide
glipizide
how do SUs appear to act?
by displacing the binding of ADP-Mg2+f from the SUR1 subunit, closing the channel
which of the SUs are more potent and longer acting?
glibenclamide
glipazide
what adverse effect are the more potent & longer acting SUs more likely to cause?
episodes of hypoglycaemia
when are SUs 1st line?
in patients who are intolerant to metformin or who are not overweight
which other drugs can SUs be used in conjunction with?
metformin
thiazolidinediones
what can SUs cause that would be undesirable in diabetics?
weight gain
how do glinides work?
bind to SUR1 to close the Katp channel & trigger insulin release
give some examples of glinides
repaglinide
nateglinide
what is the benefit of glinides?
have rapid onset/offset kinetics so are less likely to cause hypos than SUs
when are glands taken?
before meals to reduce postprandial rise in blood glucose
which drugs can glinides be used in conjunction with?
metformin
thiazolidinediones
GIP
gastric inhibitory peptide
what do both GLP-1 & GIP do?
enhance insulin release from pancreatic beta cells & delay gastric emptying meaning enhanced glucose uptake & utilisation
what does GLP-1 do that GIP doesn’t do?
decreases glucagon release from pancreatic alpha cells so decreased glucose production
what stimulates the release of GLP-1 & GIP?
ingestion of food
GLP-1
glucagon like 1
where are GLP-1 & GIP released from?
enteroendocrine cells in the small intestine (L cells & K cells)
where are L cells found?
ileum & colon
where are K cells found?
jejunum/duodenum
which cells release GLP-1?
L cells
which cells release GIP?
K cells
how do incretin analogues work?
mimic the action of GLP-1 but are longer lasting
give an example of an incretin analogue
extenatide
how does extenatide work?
binds to GPCR GLP-1 receptor that increase intracellular cAMP concentration
what physiological effects does extenatide have?
increases insulin secretion
suppresses glucagon secretion
sloes gastric emptying
decreases appetite
what does extenatide do to the body?
causes modest weight loss & reduces hepatic fat accumulation
how is extenatide administered & how often?
subcutaneously twice daily
what side effects could extenatide cause?
nausea
hypoglycaemia
rarely pancreatitis
name a longer acting incretin analogue suitable for once daily subcutaneous administration
liraglutide
which ensyme rapidly terminates the actions of GLP-1 & GIP?
enzyme dipeptidyl peptidase-4 (DPP-4)
what do DPP-4/gliptins do?
competitively inhibit DPP-4 prolonging the actions of GLP-1 & GIP
what other drug classes are gliptins usually used in combination with?
thiazolidinediones
metformin
name some gliptins
sitagliptin
saxigliptin
vildagliptin
how is sitagliptin administered & how often?
orally once daily
what is alpha-glucosidase & what does it do?
a brush border enzyme that breaks down start & disaccharides to absorbable glucose
what do alpha-glucosidase inhibitors do?
delay absorption of glucose thus reducing postprandial increase in blood glucose
when are alpha-glucosidase inhibitors used?
in T2DM patients inadequately controlled by life style measures or other drugs
where do adverse affects of alpha-glucosidase inhibitors occur?
in the GI tract:
flatulence, loose stools, diarrhoea, abdominal pain, bloating
what adverse effect do alpha-glucosidase inhibitors pose no risk of?
hypoglycaemia
what type of drug is metformin?
biguanide
how does metformin work?
reduces hepatic gluconeogenesis by stimulating AMP-activated protein kinase
which drug is first line in the treatment of T2DM in obese patients?
metformin
what does metformin do to the body?
increases glucose uptake & utilisation by skeletal muscle (increases insulin signalling)
reduces carbohydrate absorption
increases fatty access oxidation
how is metformin administered?
orally
what desirable affects does metformin have?
prevents hypoglycaemia but doesn’t cause hypos
causes weight loss
may be combined with other agents
what adverse affects an metformin cause?
GI upsets (diarrhoea, nausea, anorexia) rarely lactic acidosis due to the reduction in gluconeogenesis
what do thiazolidinediones/glitazones (TZDs) do?
enhance the action of insulin at target tissues which reduces the amount of insulin required to maintain a given blood level of glucose
how do TZDs work?
act as exogenous agonists of the nuclear receptor PPAR-gamma which associated with retinoid receptor X (RXR)
what does an activated PRARgamma-RXR complex act as?
a transcription factor that binds to DNA to promote the expression of genes encoding several proteins involved in insulin signalling
what other proteins are involved in insulin signalling?
lipoprotein lipase
fatty acid transport protein
GLUT4
what are the desirable effects of TZD?
promote fatty acid uptake & storage in adipocytes rather than muscles & liver
reduced hepatic glucose output
what are the adverse effects of TZDs?
weight gain
fluid retention
increased incidence of bone fractures
name the only TZD currently used & why?
pioglitazone doesn’t cause hepatotoxicity
what other drugs can pioglitazone be used in combination with?
metformin or SUs
SGLT2
sodium-glucose contratransporter-2
how do SGLT2 inhibitors work?
act to selectively block the reabsorption of glucose by SGLT2 in the proximal tubule of the kidney nephron to deliberately cause glucosuria
glucosuria
glucose in urine, usually there is none found
what are the desirable effects of SGLT2 inhibitors?
cause decrease in blood glucose with little risk of hypos calorific loss (weight loss)
name the currently licensed SGLT2 inhibitor
dapagliflozin
what is the adverse effects of SGLT2?
glucosuria provides enhanced breeding ground for bacteria & fungi, increasing the incidence of lower UTIs
