DIABETIC DRUG THERAPY Flashcards
MoA of gliclazide
Promotes insulin secretion from pancreatic beta cells by binding to sulfonylurea receptor SUR1 which then blocks KATP channels - so reduced efflux of potassium which results in depolarisation of beta cells - stimulates calmodulin to release insulin containing secretory granules
What are sulfonylureas?
Insulin secretagogues that stimulate insulin release from pancreas to restore early phase insulin release - can get short acting e.g. gliclazide / tolbutamide or long acting e.g. glibenlamide
Side effects of sulfonylureas
weight gain - not in overweight pts
risk of hypoglycaemia
How much do sulfonylureas reduce HbA1c by?
1.5-2%
when are meglitanides used i.e licensing?
Only licensed for use with metformin
MoA of meglitanides e.g. repaglinide and netaglinide?
Increase insulin release (early phase response) by binding to a different . but closely related receptor recognised by sulfonylurea - mechanism same - closes k ATP channels
Are the side effects less marked in meglitanides?
Yes - less weight gain compared to other short acting ones, reduced risk of hypoglycaemia due to action being dependent . on the presence of glucose
What are short acting sulfonylureas?
Gliclazide
What drug classes come under the umbrella term insulin secretagogues?
Sulfonylureas e.g gliclazide
meglitanides e.g repaglinide and nateglinide
what drugs work on the . liver?
Biguanides and thiazolidinediones - reduce glucose production
What drugs work on the pancreas?
- insulin secretagogues . - sulfonylureas and meglitinides
- GLP-1 incretins improve response to glucose level
What drugs work on skeletal muscle / adipose tissue?
thiazolidinediones and biguanides also work on here to reduce insulin resistance
What drugs work on small intestine?
Alpha- glucosidase inhibitors e.g. ascarbose to slow absorption of sucrose and starch
what are insulin sensitisers?
Require some residual beta cell capacity - enhance the effect of endogenous circulating insulin to reduce insulin resistance and decrease hepatic glucose production
e.g biguanides and thiazo
1st line drug in type 2 diabetes?
Metformin - a biguanide
Why is metformin particularly good? / used in overweight too?
- suppresses appetite . so weight loss i.e doesnt get as much weight gain as others
- reduced risk of hypo
- cardioprotective
What are the s/e of metformin and how can they be overcome?
GI side effect - but can be overcome by gradually . increasing the dose to therapeutic levels or using modified release forms
- also risk of lactic acidosis
when is metformin contra-indicated?
renal, cardiac, liver . impairment due to inhibition of pyruvate metabolism leading to increased lactic acid build up - if renally impaired for example - cannot excrete the LA
MoA of metformin?
Reduce glucose production in liver, increases glucose utilisation and uptake in periphery, decreases glucose absorption - via activation of AMPK in liver and skeletal muscle
Example of a thiazolidinedione?
Pioglitazone
MoA of pioglitazone?
Reduces peripheral insulin resistance and hepatic . glucose production by stimulating PPAR-gamma (peroxisome proliferator activated receptor gamma) - this modulates the expression of insulin-sensitive genes which control glucose production /transport/utilisation in adipose/muscle/liver
What are . the risks of pioglitazone?
Can increase risk of heart failure (fluid retention) thus C/I in at risk pts
also small increased risk of bladder cancer so caution in elderly and at risk pts .
How long does pioglitazone take to work and why?
up to 3 months . due to indirect effect on blood glucose
Side effects of pioglitazone
- fluid retention
- weight gain but note . that it is a less . risk of distiribution (hips and thighs)
- anaemia . and . GI effects
Positive point about pioglitazone?
can improve . diabetic dyslipidaemia
What is an example of a class and . drug that has inhibiting effects on GI glucose . absorption?
Alpha glucosidase inhibitors such as ascarbose
MoA of ascarbose
Binds to alpha glucosidase with . higher affinity than dietary starch/sucrose - so breakdown of carbs inhibited/ Slows digestion and absorption of carbs post meals - reduces post prandial peak in blood glucose . so stabilises levels.
Not as good at reducing hba1c than metformin and still has GI disturbances e.g. flatulence/diarrhoea
what therapies are based on glucagon like peptide?
- dipeptidyl peptidase 4 inhibitors (DPP4)
- GLP-1 analogues
What are DPP-4 inhibitors?
Gliptins –> They inhibit the enzyme DPP4 which usually breaks down GLP-1 - this means that GLP is free to act (not degraded)and stimulate insulin secretion, and decrease glucagon secretion. Also decreases appetite so good for weight loss
Licensing for DPP4 inhibitors and guidance?
In combination with either metformin / sulfonylurea / pioglitazone (or sitagliptin also monotherapy with insulin)
Also NICE –> only continue after 6 months if hbA1c reduced by at least 0.5%
what drugs are GLP-1 analogues?
Exenatide and liraglutide - subcutaenous admin
What are GLP-1 analogues?
DPP-4 resistant analgoues of GLp1 that bind to and activate GLP-1 receptor so then get the actions of GLP-1, stimulating insulin secretion, reducing glucagon secretion, reducing gastric emptying so weight loss (suppress appetite). Used in combo again
What is the guidance on GLP-analogues e.g exenatide or liraglutide?
Only continue after 6 months if hba1c reduction of 1% and weight loss of 3%
When are sodium-glucose co transporter inhibitors (gliflozins) used?
canagliflozin etc
used as monotherapy if diet fails and metformin is inappropriate/contraindicated
Also as an add on therapy with other medicines
MoA of sodium-glucose co transpoter inhibitors?
Independent of insulin mediated glucose control pathways - actually act on nephron in tubules to block reabsorption of glucose in kidney and promote urinary excretion of it
treatment of hypoglycaemia episodes?
oral glucose 10-20 g if conscious / swallow
IM/SC glucagon or IV glucose if unconscious or cannot swallow
Once episode is over - give longer acting carbs because glucagon mobilises the glycogen stores and must replenish these using the carbs
Common complication in type 1 diabetics?
Diabetic ketoacidosis - chronic uncontrolled hyperglycaemia and ketones are due to a build up of free fatty acids due to mobilisation of the other stores. treat with IV rehydration 0.9% saline, insulin infusion and . careful correction of electrolyte . balance
What is a common issue with diabetics when they are ill?
They . stop taking . insulin . if they feel . unwell and lose their . appetite as . they think it will cause hyperglycaemia. But . in fact - infections increase insulin . requirements
Common complication in type 2 diabetics?
Hyperglycaemic hyperosmolar state
Medical emergency, very high blood glucose >30mmol/L and hyperosmolality >320 mOsm/L. Due to illness and severe dehydration .
Treatment for HHS
IV fluids
Normalise blood glucose with low dose IV insulin
LMWH prophylaxis
Prevention of foot ulcers
