T2DM Pharmacology Flashcards
what are the insulin dependent mechanisms of treating T2DM
increasing insulin secretion (sulfonylureas, incretin mimetics, glinides, DPP-4 inhibitors)
decreasing insulin resistance abd reducing hepatic glucose output (glitazones)
what are the insulin independent mechanisms for treating T2DM
slowing glucose absorption from the GI tract (alpha-glucosidase inhibitors)
enhancing glucose excretion by the kidney (SGLT-1 inhibitors)
describe the relationship between cellular energy and insulin secretion in beta cells starting with blood glucose
increased blood glucose
glucose diffuses down conc gradient into B cell via GLUT2
phosphorylation of glucose by glucokinase
glycolysis of glucose - 6 - phosphate in mitochondrian making ATP
increased ATP/ADP ration
closure of ATP sensitive K+ channels
membrane depolarisation
opening of voltage activate Ca+ channels
release of intracellar Ca+
insulin secretion by exocytosis of storage granules
what are the components of KATP and their function
4 Kir6.2- form potassium channel
1 SUR1- regulates potassium channel activity
how does the ATP/ADP ratio determine the opening/ closing of KATP
ATP binds to Kir6.2- closes channel
ADP binds to SUR1 opening the channel
how do sulfonylureas (SU) act of KATP
displace ADP from SURI to close channel- cause depolarisation and the release of insulin
what do SU require
a functional mass of beta cells (to stimulate them to release insulin)
give exmaples of SU
gliclazine, glipizide
how do SU work
displace ADP from SUR1 subunit, closing KATP channel
what is the short ans long term effect of SU’s
decrease fasting and post prandial (after a meal) blood glucose
long term reduce the microvascular complications
undesirable weight gain
how long to peak release of insulin after SU
1-2 hours- some longer and shorter acting
what is the risk of the longer acting SU (glicazide, glipizide)
may cause hypos by excessive insulin secretion
who is most at risk of getting a hypo when using an SU
elderyl, reduced hepatic/ renal function, chronic kidney disease
when can SU be given
first line in those who cant tolerate metformin/ or with weight loss
second line in conjunction with metformin
third line in conjunction with metformin + thiazolidinediones/ other drugs
why do SUs cause weight gain
anabolic effect of insulin increased
appetite increased
urinary loss of glucose decreased
who should SUs not be given to
pregnant, breast feeding or elderly
are SUs dependent of glucose concentration
no work independently to it
how do glinides work
like SUs but action increased by glycaemia
bind to SUR1 to close the KATP channel and trigger insulin release
give examples of glinides
repaglininde
nateglinide
what is the onset of glinides
30-60 mins
promote insulin secretion in response to meals
why are glinides sometimes better than SUs
less likely to cause hypos (than long acting SUs)
metabolised mainly by liver- safer than SUs in CKD
when can and cant glinides be used
can be used in conjunction with metformin and thiazolidinediones
cant be given in severe hepatic impairment, pregnancy and breast feeding
is the insulin response greater to oral or IV glucose- why
oral
the incretin effect (GLP-1 and GIP)
describe the incretin effect
ingestion of food stimulates release of GLP-1 and GIP from enteroendocrine cells in the small intestine
these enter the portal blood stream which goes to the pancreas
GLP-1 and GIP enhance (increment) insulin release from beta cells and delay gastric emptying (enhanced glucose uptake and utilisation)
GLP-1 decreases glucagon release from alpha cells
decreased glucose production
all together decrease the blood glucose
what are the gliptins, give examples
DPP-4 inhibitors: sitagliptin and others all ending in gliptins
what happens to the incretin effect in T2DM
is reduced
what terminates the actions of GLP-1 and GIP
the enzyme DPP-4
how do gliptins work
competitively inhibit DPP-4, prolonging the actions of endogenous GLP-1 and GIP, increasing plasma insulin
how can gliptins be administered
is orally active
usually used in combo with SU, or metformin
can be given as monotherapy
what are the effect and adverse affects of sitagliptin
no hypoglycaemia, weight neutral
nausea main adverse affect
what are incretin analogues
give examples
peptides that mimic the action of GLP-1 but are longer lasting as can resist breakdown by DPP-4
extenatide, liraglutide
how do incretin analogues work
bind as agonists to GPCR GLP-1 receptors that increase intracellular cAMP concentration in B cells to stimulate insulin secretion
also;
suppress glucagon secretion
slow gastric emptying
decrease appetite
are incretin analogue weight neutral
no cause modest weight loss, reduce hepatic fat accumulation
what are the adverse affects of incretin analogues
may cause nausea and pancreatitis (rare)
how are incretin analogues given
subcutaneously
what must happen to carbs before it is absorbed into the small intestine and how is this done
must be digested into monosaccharides
alpha-glucosidase (a brush border enzyme) breaks starch and disaccharides into absorbable glucose
how do alpha-glucosidase inhibitors work
when taken with a meal, delay absorption of glucose thus reduce post prandial increase in blood glucose
when are alpha-glucosidase inhibitors used
in T2DM inadequately controlled by life style measures or other drugs
(not commonly used)
what are the adverse affects of alpha-glucosidase inhibitors
flatulence, loose stools, diarrhoea, abdominal pain, bloating
(all due to undigested carb)
what are the pros and cons of alpha-glucosidase inhibitors
pose no risk to hypos
only moderately control glycaemia
what is the only theraputic biguanides
metformin
when is metformin used
is first line for T2DM irrespective of obesity, with normal hepatic and renal function
when is metformin contraindicated
in severe hepatic or renal impairment
what are the actions of metformin
reduce hepatic gluconeogenesis- stimulate AMP activates protein kinase
increases glucose uptake and utilisation by skeletal muscle (increases insulin signalling)
reduces carbohydrate absorption
increases fatty acid oxidation
what are the desirable clinical effects of metformin
reduces microvascular complications of diabetes
doesnt cause hypos
given orally
causes weight loss
can be combines (insulin, thiazolidine, SUs)
what are the adverse clinical effects of metformin
lactic acidosis (rare)- avoid in patients with severe hepatic or renal disease/ excessive alcohol consumption
how do thiazolidineones (TZDs) work
enhance the action of insulin at target sites
- do not affect insulin secretion
- reduce insulin resistance
activates PPARgamma - RXR complex which is a transcription factor that promotes the expression of genes encoding proteins involved in insulin signalling and lipid metabolism
why do TZDs have delayed onset
as work on transcription factors
what are the desirable affects of TZDs
promote fatty acid uptake and storage of adipocytes- rather than in skeletal muscle and liver
reduce hepatic glucose output
enhance peripheral glucose uptake
dont cause hypos
what are the adverse affects of TZDs
weight gain
fluid retention (Na+ absorption in the kidney)
increased incidence of bone fractures
when should TZDs not be used
in heart failure- as increase circulating volume
give an example of TZD (a.k.a glitazones) used and what it can be used in combo with
pioglitazone
metformin, SUs
are SGLT2 inhibitors dependent on insulin
no
how do SGLT 2 inhibitors work
selsctively block the re absorption of glucose by SGLT 2 in the proximal tubule of the kidney nephron
deliberately causes glucosuria
cause a decrease in blood glucose with little risk of hypos
what are the secondary affects of SGLT 2
osmotic diuresus (water loss) and weight loss
give 3 examples of SGLT 2 inhibitors
dapagliflozin
canaglifozin
empagliflozin
