(pharm) pharmacology of diabetes Flashcards
what are four commonly prescribed drugs for diabetes?
metformin
DPP-4 inhibitors (dipeptidyl-peptidase 4)
sulphonylurea
SGLT2 inhibitors (sodium-glucose cotransporter inhibitors)
explain the primary mechanism of action of metformin
1 - metformin activates AMPK in hepatocyte mitochondria
= inhibits ATP production + blocks hepatic gluconeogenesis and subsequent hepatic glucose output
2 - blocks adenylate cyclase which in turn promotes fatty acid oxidation (reduces accumulation of FAs and lipids)
both mechanism help to restore insulin sensitivity
what is the drug target for metformin?
5′-AMP-activated protein kinase (AMPK)
what are the main side effects of metformin?
(mainly GI side effects in 20-30% of patients)
abdominal pain
diarrhoea
vomiting
decreased appetite
what is the primary site of action of metformin?
hepatic mitochondria
what is AMPK?
adenosine monophosphate-activated protein kinase
an enzyme that switches on an off to regulate energy intake and expenditure and control energy metabolism
what is the function of AMPK?
switches on and off to regulate control energy metabolism
what is AMPK an effective drug target in diabetes?
once activated by metformin, AMPK inhibits hepatic gluconeogenesis, reducing hepatic glucose output AND increases insulin sensitivity
= reduces the further exacerbation of the hyperglycaemia in T2DM patients
how is insulin sensitivity restored using metformin?
1 - activation of AMPK will inhibit hepatic gluconeogenesis and reduce subsequent hepatic glucose output
2 - blocking of adenylyl cyclase increases fatty acid oxidation (reduced accumulation of FAs and lipids)
= both restore insulin sensitivity
how many people who take metformin experience GI side effects?
approx 20-30% of people
how can dosage monitoring improve outcomes for metformin patients and why?
high doses of metformin tend to lead to GI side effects and so a slow increase in dose may improve tolerability
how does metformin access tissues?
via the OCT-1 transporter (organic cation transporter)
why is OCT-1 important for metformin?
to enable uptake into hepatocytes
as metformin is an organic cation (i.e. polar) and cannot cross the non-polar lipid bilayer of hepatocytes unless the carrier protein OCT-1 is present
where is metformin most likely to accumulate?
liver and GI tract
why does metformin accumulate in the liver?
the metformin-specific transporter OCT-1 is found predominantly in the liver and GI tract
why does metformin accumulate in the GI tract?
the metformin-specific transporter OCT-1 is found predominantly in the liver and GI tract
when is metformin most effective?
in the presence of endogenous insulin so when there are some residual functioning pancreatic beta islet cells
why must be present for maximal metformin efficiency?
endogenous insulin (so there must be some residual functioning pancreatic beta islet cells)
how can the tolerability of metformin be improved?
a slow increase in the dose (especially if high doses are prescribed) = prevent GI side effects
what are DPP-4 inhibitors?
dipeptidyl peptidase - 4 inhibitors
give an example of a DPP-4 inhibitor
sitagliptin
explain the primary mechanism of action of DPP-4 inhibitors
bind to and inhibit the enzyme DPP-4 in the vascular endothelium so incretin levels are increased
increased incretin levels will work to increase insulin production, reduce glucagon secretion, decrease appetite and slow down digestion = decrease blood glucose levels
what is the drug target for DPP-4 inhibitors?
the DPP-4 enzyme found in the vascular endothelium
what is the primary site of action of DPP-4 inhibitor action?
vascular endothelium
what are the most common side effects of DPP-4 inhibitors?
upper respiratory tract infections
flu-like symptoms = headache, runny nose, sore throat
what are the less common side effects of DPP-4 inhibitors?
serious allergic reactions
in whom is the administration of DPP-4 inhibitors contraindicated?
patients w pancreatitis
give one reason why are DPP-4 inhibitors preferred to other anti-diabetic drugs
do not appear to cause weight gain (like metformin)
what are incretins?
gut hormones that are secreted by enteroendocrine cells that stimulate a decrease in blood glucose by augmenting the secretion of insulin from pancreatic beta cells from the islets of Langerhans
give an example of an incretin
GLP-1
where is incretin secreted from?
enteroendocrine cells
why must be present for maximal DPP-4 inhibitor efficiency and why?
some functional residual pancreatic beta cells must be present as DPP-4 inhibitors work by augmenting incretin function to stimulate insulin secretion
what are sulphonylureas?
a class of drugs that lower blood sugar levels by stimulating insulin production but run the risk of causing hypoglycaemia
give an example of a sulphonylurea
gliclazide
explain the primary mechanism of action of sulphonylureas
bind to the ATP-sensitive potassium channels on pancreatic beta cells inhibiting them and inducing depolarisation and the subsequent calcium influx causes vesicular exocytosis of insulin into the bloodstream
what is the drug target for sulphonylureas?
the ATP-sensitive potassium channels on the pancreatic beta cell membrane
what is the primary site of action for sulphonylureas?
pancreatic beta cells
what are the main side effects of sulphonylureas?
weight gain
hypoglycaemia
why must be present for maximal sulphonylurea efficiency and why?
sulphonylureas work by augmenting insulin release and so a baseline residual level of pancreatic beta cell function is required
how is the side effect weight gain due to gliclazide administration mitigated?
administer metformin
what must be discussed when prescribing a patient gliclazide?
the side effect of hypotension (especially if concomitant glucose-lowering drugs are also being taken)
why must the side effect of hypoglycaemia be discussed especially in patients taking gliclazide?
in case they also take concomitant glucose-lowering drugs
what are SGLT2 inhibitors?
sodium-glucose transport protein 2 inhibitors that are used to treat reduce blood glucose levels
give an example of an SGLT2 inhibitor
dapagliflozin
explain the primary mechanism of action of dapagliflozin
reversibly inhibits the sodium-glucose cotransporter (SGLT2) in the renal proximal convoluted tubule to reduce glucose reabsorption and increase urinary glucose excretion
what is the drug target for dapagliflozin?
SGLT2 in the renal proximal convoluted tubule
what is the primary site of action of dapagliflozin?
proximal convoluted tubule in the kidney
what are the main side effects of dapagliflozin?
urogenital infections
slight decrease in bone formation
can worsen diabetic ketoacidosis
in how many patients do dapagliflozin cause urogenital infections?
around 5% of patients
why does dapagliflozin affect bone formation?
linked to suppression of serum calcitonin and excretion of calcium
how can dapagliflozin cause urogenital infection?
increases glucose load of urine which can attract pathogenic organisma
what happens if dapagliflozin worsens diabetic ketoacidosis?
daptafliflozin administration must be stopped
how can dapagliflozin lead to diabetic ketoacidosis?
decreases blood glucose levels by decreasing endogenous insulin secretion
= subsequent increase in glucagon secretion causes ketogenesis that can potentially lead to ketoacidosis
what must be present for maximal SGLT2 inhibitor function?
depends on normal renal function and so cannot be given to patients with renal impairment
in whom is the administration of SGLT2 inhibitors contraindicated?
patients with renal impairment (as SGLT2 inhibitors have to act on the renal proximal convoluted tubule)
what commonly is the therapeutic objective for patients with diabetes?
normalise HbA1c, hypertension, HDL and LDL cholesterol levels and reduce BMI
why is it important to reduce HbA1c levels in patients with diabetes?
reduce the microvascular and macrovascular complications of diabetes
why is it important to reduce hypertension levels in patients with diabetes?
reduces the risk of cardiovascular disease
why is it important to regulate HDL and LDL levels in patients with diabetes?
linked to the formation of atherosclerotic plaques which increase the risk of an infarction and CVD
why is it important to reduce obesity in patients with diabetes?
reduces cardiovascular complications and insulin resistance
what are the indications for metformin administration?
lifestyle should be reviewed before every treatment escalation
if HbA1c rises still = metformin
if HbA1c rises to 58mmol/mol = dual therapy in the form of metformin AND either SU, DPP-4 inhibitor, SGLT2 inhibitor, or pioglitazone
if HbA1c continues to rise = insulin-based treatment OR triple therapy
how does the molecular structure of metformin influence its absorption into the blood and distribution to body tissues?
metformin is an organic cation and so is polar = cannot cross the non-polar lipid membranes of cells and so must be transported using the OCT1 transporter
in which tissues is the expression of OCT1 highest?
liver hepatocytes (highest) small intestinal enterocytes renal proximal tubules
in which tissues is the expression of OCT1 highest?
liver hepatocytes (highest)
small intestinal enterocytes
renal proximal tubules
why is OCT1 expression high in hepatocytes?
determines distribution to the site of action
why is OCT1 expression high in small intestine enterocytes?
site of absorption of metformin
why is OCT1 expression high in the renal proximal tubule?
site of excretion of metformin
what must you do in patents on metformin that show signs of renal impairment?
clinically essential that you monitor kidney function in any patient on metformin that shows signs of renal impairment (eGFR)
why can renal impairment cause problems for diabetic patients on metformin?
metformin is primarily excreted unchanged by the kidneys SO if there is renal impairment = metformin accumulates in the blood and the elevated serum metformin can lead to lactic acidosis + more extreme side effects
how is metformin administration altered in patients with renal impairment like CKD?
the dose is not usually halved as NICE guidelines suggest and so monitor eGFR regularly to ensure it does not fall below 30
(if it does, stop metformin immediately)
why is it important to ensure hypoglycaemia does not occur in older patients on metformin?
can risk falls and hip fractures and other injuries
what is the biggest problem for metformin adherence?
the GI side effects
what measures can someone take to tolerate the GI side effects of metformin?
practical measures such as take it after NOT before food, switch to a better tolerated preparation or sustained release metformin can be taken
how is sustained release metformin different?
absorbed more slowly (so less GI side effects) but it is more expensive
