Diabetes pharmacology Flashcards
describe metformin mechanism of action
inhibits complex 1 of mitochondria respiratory chain
fall in cell ATP and rise in AMP:ATP so stimulates AMPK so reduction in gluconeogenesis
what cells is metformin taken up into
liver, kidneys and intestine
what effects does metformin have on GI tract
alters microbioma and increases gut glucose metabolism
increases GLP-1 secretion to increase insulin production, delay gastric emptying and food intake
what effects does metformin have on the liver
decreases lipogenesis
decreases gluconeogenesis
how much does metformin reduce HbA1c and is it weight gaining or reductive
~18mmol/mol
weight neutral/loss
side effects metformin and how to reduce
diarrhoea, bloating, abdo pain, dyspepsia, metallic taste in mouth
use modified release capsule or start low dose and go slowly
true/false - metformin has no CV benefit
false - it is beneficial
what is MALA
metformin associated lactic acidosis
metformin increases lactate production due to blocked gluconeogenesis
in AKI, often sepsis, there is raised risk
in eGFR <45ml/min what is the max dose of metformin
1g daily
in eGFR <30ml/min what is the max dose of metformin
none, it is contraindicated
name 4 suplhonylureas
glicazide, glipizide, glimepride, glibenclamide
describe mechanism of action of SUs
bind to SUR1 and cause closure of ATP sensitive K channel
rise in membrane potential causing depolarisation and opening of voltage gated potassium channel
leads to insulin exocytosis
most common dosage and drug used for SU therapy
glicazide 40-80mg OD
how much does SU lower HbA1c and is it weight gaining or losing
around 18mmol/mol
weight gaining due to anabolic insulin action
true/false - SUs havea. positive impact on CV risk
false - they are thought to be neutral
side effects of SUs
weight gain
hypoglycaemia - esp in elderly and where hypoglycaemia at risk eg work
describe the molecular mechanism of thiazolidinediones
PPARy ligands that bind to co-activator and cause transactivation/transrepression of PPARy target genes
increased differentiation of pre-adiposite to adiposite to increase s/c fat mass and remove FFA from liver
increases adiponectin to increase insulin sensitivity
clinical use of TZDs and their effect on HbA1c and blood pressure
reduces by 15-20mmol/mol
reduces blood pressure
what is the only TZD available
pioglitazone
who are TZDs most effective in
obese women
side effects of TZD
weight gain
fracture risk due to fat accumulation in bone marrow, esp elderly
fluid retention, peripheral oedema and heart failure so check pt first
describe how the incretin effect is seen on OGTT compared to IVGTT
in OGTT vs IVGTT isolgycaemic standardised glucose is used to demonstrate the same peak in blood glucose but in the OGTT there is a higher peak of insulin to that of IVGTT so there must be something else secreted from gut
what are 2 incretins and the cells they are released from
GLP-1 from L cells
GIP from K cells
describe the half life of incretins and how they are broken down
they have a very short half life and are broken down by DPPIV
describe how GLP-1 augments insulin release
binds to GPCR. via camp to trigger further insulin release from beta cell, but only when the glucose trigger pathway is stimulated already
what are some of the actions of GLP-1?
delays gastric emptying
increases muscle glucose uptake and storage
increases insulin secretion/reduces glucagon
reduce appetite
decrease gluconeogenesis
increase beta cell proliferation
mechanism of action of gliptins and their drug class?
DPPIV inhibitors
inhibit DPP4 in different ways to prevent the breakdown of GLP-1 and GIP
true/false - DPPIV inhibitors and GLP-1 receptor agonists can cause hypoglycaemia
false - as they only operate when the glucose triggering pathway is already stimulated
how much does DPPIV inhibitor lower HbA1c and is it weight losing/gaining?
lowers around 5-8mmol/mol
weight neutral
side effects of DPPIV inhibitors
not really any as they are quite well tolerated
may lead to pancreatitis
are DPPIV inhibitors good for CV risk?
some studies show there is increased HF admission
describe mechanism of action of GLP-1 agonist
GLP-1 like molecule activates GLP-1 receptors but avoids breakdown by DPPIV
administration of GLP-1 agonist?
s/c but new oral preparation been developed
risk of hypoglycaemia in pt on GLP-1 agonist
very low as only promotes insulin secretion in glucose dependent manner
benefits of GLP-1 agonist?
potent reduction in HbA1c with 11-15mmol/mol
2-3kg weight loss
reduced SBP and increased HR by 3-10BPM
side effects of GLP-1 agonist
nausea and vomiting
increased amylase and lipase but unlikely to cause pancreatitis
gallstones but slim risk
effects of GLP-1 agonist on CV and renal outcomes?
renal outcomes are improved
reduction in CV mortality
describe reuptake of glucose in the kidneys
glucose filtered by glomerus and into renal tubule
reuptake by SGLT1 and SGLT2
describe how glucosuria occurs in the kidney
more glucose in blood enters kidney than SGLT1/2 can handle and so enters the urine instead of being filtered
why does phlorizin cause osmotic diarrhoea
non-specific blocker of SGLT1/2
SGLT1 is present in the colon and so blockage also draws water into the colon
how much blood glucose is lost due to SGLT2i and how much weight is lost
1/4 blood glucose
half a kilo weight loss weekly
true/false - SGLT2i induced weight loss continues indefinitely
false - it has a physiological plateau
direct side effects of SGLT2i
renal protective
diuretic as also blocjks Na reabsorption
increased urate excretion
how is an SGLT2i renal protective
increased Na delivery to distal convoluted tubule so increased Na uptake by Na/K/Cl transporter at macula densa
causes increased adenosine secretion so renal afferent vasodilation and so reduces renal filtration pressure
indirect side effects of SGLT2i
reduced glucose so reduced insulin and increased glucagon
increased FFA and ketone body production
why is increased FFA and ketone body production in SGLT2i a good thing but also a bad thing
good for cardiac myocytes as FFA and ketone bodies act as a fuel
bad as increases risk of ketosis and ketoacidosis
how much does SGLT2i lower HbA1c, what is its effect on LDL/HDL and blood pressure
lowers ~11mmol/mol
raises LDL/HDL modestly
lowers blood pressure due to diuresis
name 3 SGLT2i
dapagiflozin, cacagiflozin, empagiflozin
undesired side effects caused by SGLT2i
thrush secondary to glycosuria
fornier gangrene
hypovolaemia/hypotension, esp if low BP or diuretics
DKA, even with normal blood glucose
true/false - avoid SGLT2i in prolonged fasting or acute illness
true, as they may lead to hypovolaemia or DKA
how are SGLT2i in terms of CV risk and renal status
massive CV benefit
renal protective
true/false - efficacy of SGLT2i is lost eGFR <45ml/min and glucose benefit gone <30ml/min
false - efficacy begins to be lost around 90ml/min and there is no glucose benefit <45ml/min, but below this it is still renal protective
