Pharmacology Flashcards
first line treatment for diabetes
metformin
MOA of metformin
Inhibits complex 1 of mitochondrial respiratory chain
Binds to complex one, reduces efficiency of mitochondrial respiratory, resulting in a fall in cellular energy/ cellular ATP
consequences of metformin MOA
- Rise in amp; atp, activates amp kinase;
- Reduction in gluconeogenesis
is metformin hydrophobic or philic
hydrophilic so it is not readily taken up into cells
what does metformin require
active transport by organic cation transporters
where are organic cation transporters
intestines, liver and kidneys
where is metformin excreted
kidneys
main site of action of metformin
liver
how is metforminexcreted in the urine
unchanged, it is not metabolised in any way
main effect of metformin
to increase glucose utilisation and lower hepatic glucose production
metformin and gi tract
alters microbiome
side effects of metformin
GI side effects, diarrhoea, bloating, abdominal pain, dyspepsia, metallic taste in mouth , highly concentrated in intestine
how to reduce side effects of metformin
initiate slowly , start low and go slow
main concern of metformin
lactic acidosis as it increases lactate production
acute kidney failure and metformin
metformin may accumulate and so lactate isnt cleared
which drug has a sustained benefit of CDV disease
metformin
clinical benefits of metformin
potent
lowers HbA1c
cheap
well tolerated
weight losing
side effects of SGLT2 inhibitors
thrush
risk of ketoacidosis
second line drugs to metformin if have previous CVD,CKD or heart failure
SGLT2 inhibitors
role of SGLT2I
makes you pee out sugar which is good to remove sugar and lower caolires- plateaus after a while
clinical benefits of SGLT2I
- Diuresis
- Improved myocardial energetics
- Renal protection
- Increased renal glucose losses
- Lowers blood pressure
- Moderate efficacy
Good for kidneys and heart
second line drug in africans
sulphonylureas
which class of drugs have an increased CDV risk
sulphonylureas
which class of drug has an increased weight risk
sulphonylureas
clinical disadvantages
increase weight
hypoglycaemic risk
increased CDV risk
examples of sulphonylureas
gliclazide- pancreatic specific so doesn’t bind to cardiac , glipizide, glimepiride, glibenclamide
which type of sulphonylureas is pancreatic specific
gliclazide
where do sulphonylureas act
kATP channels
MOA of sulphonylureas
Bind to extracellular s1 sulfonylureas receptor
Cause closure of ATP sensitive potassium channels
Rise in membrane potential calcium influx- insulin secretion
do sulphonyljureas act to close or open kATP channels
close
clinical benefits of sulphonylureas
potent glucose lowering
lowers Hb1Ac
clinical benefits of TZDs
dont cause hypoglycaemia
reduce harmful adipose cytokines
- Reduction in liver fat
- Increase in glucose uptake in muscle
- Reduction in atherosclerotic disease
- Potent in obese women
Beneficial effect on blood pressure ; pioglitazone reduced cdv risk
side effects of TZDs
weight gain
fluid retention
fracture risk
what drugs are not used in over 65s and why
TZDs due to fracture risk - osteoporosis
MOA of TZDs
PPARgamma is a transcription factor
TZD’s are ligands which bind to PP gamma receptors
Present in lots of diff tissues and TZDs will bind
Binding results in formation of a complex with a co factor
site of main effect of TZDs
Main on adipose tissue ; cause pre adipocytes to mature into adipocytes- immature to mature; increase fat mass storage ; healthy place to store fat
Increases triglyceride storage
Increase uptake in free fatty acids; remove fat from viscera and muscle; remove lipotoxicity; fat in liver, pancreas, taking fat out is beneficial
example of TZD
pioglitazone
example of SGLT2I
empagliflozin (Jardiance®) dapagliflozin (Forxiga®) canagliflozin (lnvokana®)
what is metformin contraindicated in
renal impairment, cardiac failure and hepatic failure because of the risk of lactic acidosis
when are sulphonylureas indicated
when cost is a mjaor issue - developing countries
when should SGLT2I be given with metformin
Diabetic patients with heart failure or chronic kidney disease
main indications of DPP4s
- Most effective in the early stages of type 2 diabetes, when insulin secretion is relatively preserved
- Can be used as a monotherapy when metformin not tolerated/contraindiated, or as an addon
which drug is most effective in early stages of type 2 when insulin is preserved
DPP4s
what are incretins
group of metabolic hormones that are released after eating and play a crucial role in regulating blood glucose levels
what are incretins produced by and what is their role
the gut and stimulate the release of insulin from the pancreas in response to food intake, even before blood glucose levels rise.
what are the two main incretins
GIP (Glucose-dependent insulinotropic polypeptide) and GLP-1 - glucose like peptide
where are the two mian incretins produced
small intestine
function of DPP4
breaks down incretins so reduces their ability to stimulate the release of insulin
MOA of DPP4 inhibitors
- Inhibit DPP4 , which usually inactivate GLP-1 (incretin effect)
- This in turn increases insulin secretion and reduces glucagon secretion
what drug class has a possible increased risk of pancreatitis
DPP4Is
Examples of DPP4is
sitagliptin, alogliptin, saxagliptin
examples of GLP-1 receptor antagonists
liraglutide, semaglutide
main indications of GLP-1 receptor antagonists
- Diabetic patients with atherosclerotic CVD (e.g. previous MI) should be given metformin + GLP-1 receptor antagonist
- Diabetic patients with heart failure or chronic kidney disease where SGLT2i are contraindicated/not tolerated should be given metformin + GLP-1 receptor antagonist
- Valuable in diabetic patients who need to loose weight
administration of GLP-1 recpetor antagonists
injection once a week
avderse effects of GLP-1 receptor antagonist
- GI - nausea, vomiting, bloating, diarrhoea
- Often improves after ~6 weeks but can be intractable
- May be related to early satiety with reduced gastric emptying
- Small increase in incidence of gallstones
contraindications of GLP-1 receptor antagonists
Contraindicated in patients with a history of pancreatitis due to a risk of acute pancreatitis
