Diabetics therapeutics Flashcards
Types of drugs used to treat diabtetes ?
Oral anti-hyperglyceamics - lower blood sugar - management of non -insulin diabetes mellitus or type 2 diabetes.
Insulin - protein - so not given orally but injection as it would break down in stomach.
What is the action of Insilun ?
Stops Glycogenolysis Gluconeogenesis lipolysis proteilysis ketogenesis
Start :
Glycolysis - convertion of glucose into pyruvate
Glucose uptake in muscle and adipose tissue
also (liver)
conc grafient eas maintained.
(
Glycogen synthesis
Protein ssynethesis
uptake of is -k & po34-
Insulin release .
Insulin released from pancreas cells.
Can receive either sympathetic or parasympathetic nerve stimulation
0 parasympathetic -increase release of insulin
Sympathetic - decease in stimuls to release
Sympatheic - increase the stimulus to
0 incretins
What are incretins ?
hormones that stimulates pancreatic insulin release from B cell in response to nutrient ingestion (e.g glucose and fat ) by targeting G protein coupled receptors
0 secreted by endocrine cells in epithelium of small intestines in response to glucose in SI.
- increase in conc of glucose ex in lumen of digestive tract triggers its release - hormone secretion.
Examples :
0 GIP - glucose dependent insulinotrophic peptide
0 GLP -1 - Glucagon like peptide 1
List the oral agents used to treat Type 2 Diabetes ?
Sulfonylureas
Meglitinides
0 Increase pancreatic secretions
Biguanides
0 Decrease hepatic gluconeogenesis
Thiazolidinediones - TZDs
0 improve insulin sensitivity in peripheral tissues .
Alpha- Glucosidase inhibitor (AGI’s)
0 prevent breakdown of complex carbohydrates into simple sugars
Dipeptidyl Peptidase 4 Inhibitors (DPP4) -
0 secretion of insulin through incretin pathway ( prevent breakdown of incretins. )
Sodium Glucose Transporter protein 2 (SGLT2) inhibitor. - increase renal excretion of glucose.
( work on preventing re - uptake of glucose , increasing urination )
What are Sulfonyureas & megalitinides ?
Insulin secretogogues
- Increase Insulin secretion. It inhibits adenosine Triphosphate- sensitive to K + (ATP- sensitive k +) in B cells , ———->
membrane can depolarize ———> calcium influxes
success depends on a least some partial pancreatic B cell activity
CONTRA -INDICATIONS (for both)
0 presence of Ketoacidosis
SIDE EFFECTS
- Hypoglycemia
- Abdominal
pain - nausea
Diarrheoa - can develop secodary pancretic B- cell failure (cell burn out )
ex -
SULFONYLUREAS - (commonly begins with Gli , Gyl
Glipizide
Gylburide
glimepiride
Megalitinides - common to have glinide)
- Repaglinide
- nateglinide
- Hypoglycemia
- Abdominal
pain - Diarrheoa
can develop secodary pancretic B- cell failure (cell burn out ) - medicines can make you gain weight - insulin storage hormone encourage storage of fat . the medicines increase insulin level so promote weight gain.
- ATP sensitive K channels - K channels that close when ATP binds .
Greater the ATP the more the K channels will close.
This prevents K from effluxing . This means K cannot pass through.
Difference between sulfonylureas and meglitdes ?
meglitinides - fast onset of action and shorted duration of a
activity - ideal for pateints with postprandial hyperglycemia - taken just before meal to produce this.
Both sulfonylureas (s) and meglitinides (M)
have to be taken before meal to prevent hypoglycemia - higher risk with S.
( skip meal - skip drug)
- Postprandial - after dinner / lunch/ food.
What are Biguanides ?
EXAMPLE
Metformin
0 Monotherapy or
0 used in conjunction with meglitinides , sulfonylureas. and anti-diabietic drugs.
First line for obese patients with type diabetes.
0 promote may weight loss as they do not stimulate more insulin.
Inhibit hepatic production of glucose
(inhibit :
- gluconeogenesis - glycogenolysis )
and increase peripheral utilisation of glucose ,
and decreases absrption of glucose —— > ( however , this can lead to a lot of anaerobic glucose metabolism leading to the bild up of lactate - risk of lactic acid acidosis - discontinue
Contraindicated - kidney failure - linked to lactic acidosis risk - lf gfr is above 30 ml / min
SIDE EFFECTS
0 Abdominal 0 pain;
0 appetite 0 decreased; diarrhoea (usually transient); gastrointestinal disorder; nausea; taste altered; vomiting
NO DANGER OF HYPOGYLCEMIA - DOES NOT EFFECT INSULIN LEVELS. -
caution in chronic stable heart failure (monitor cardiac function), and use of drugs that can acutely impair renal function;
- over 80 years - more likely to have age related kidney problems- monitor
- given iodine containing radio graphic contrast media (used in some MRI , CT) - AVOIOD.
*only acts in presence of insulin so need to be residual B cell function.
What is Thiazolidinedione ?
Reduce peripheral insulin resistance - increase sensitivity.
causing blood glucose reduction.
how :
activate PPARy - peroxisome ploliferator receptor y - nuclear receptor ) activated receptor y to transcribe more GLUT 4 receptors - (increase expression of GLUT 4 )
——–> blood glucose enters muscle and adipose tissue —–> lowered levels in the blood..
Allows dysfunctional insulin receptors to b bypassed
Examples :
0 Pioglitazone
0 Rosiglitazone - banned - no longer used in UK.
0 mono-therapy
0 or combined with metfromin or/and sulfonylureas or insulin or with diet and exercise
- caution with combination of insulin + TZDs - can cause congestive heart failure and fluid retention. -combination should be closely monitored and discontinued if cardiac status deteriorates.
CONTRAINDICATIONS -
0 heart failure
0 previous / active bladder cancer
0 univestigated macroscopic haematuria - visible red blood cells in urine
(microscopic - is non visible in urine)
Side effects
0 Bone fracture;
0 increased risk of infection;
0 numbness;
0 visual impairment; 0 weight increased
What are alpha- Glucosidase inhibitors ?
Examples :
0 Miglitol
0 Acarbose
Action :
Delay breakdown/digestion of complex carbohydrates (Starch ,Sucrose ) by inhibiting alpha glucosidse enzyme found within brush border of epithelium of small intestine.
- brush border - folded inner wall of small intestine covered in villi and microvilli.
0 useful in treatment of postprandial hyperglycemia as prevent the final breakdown of disaccharide into monosaccharide in SI.
FOLLOWING INFO ABOUT ACARBOSE - BUT ASSUME FOR NOW MIGLITOL IS SIMILAR.
CONTRAINDICATIONS
- people with disorders of digestion, absorption - IBD
- Predisposition to intestinal obstruction.
- Hernia
Side effects (common )
0 Diarrhoea (due to undigested carbs)
0 Gastrointestinal discomfort :
- Flatulence
- Abdominal pain
0 Gastrointestinal disorders.
0 Intestinal obstruction.
SPECIAL CAUTION for Acarbose ?
Acarbose can enhance hypoglyceamic effects of insulin and sulfonyureas.
Patients should carry around glucose .
Important - sucrose will not help as acarbose inteferes with its absorption.
What is the maximum amount of glucose the Kidneys can reabsorb ?
180 g/DL - blood glucose - at this level glucose appears in urine.
In diabetics the level is much higher.
What ate DPP - 4 Inhibitors / Gliptins ?
DPP - 4 - dipeptidyl peptidase 4
ACTION -
- inhibits DDP-4 which destroy incretins ( suppress glucagon release)
- Increase postprandial insulin secretion
- reduce hepatic gluconeogenesis. during fasting
0 Glucagon like peptide - 1 (GLP - 1) - this suppresses glucagon release , promoting insulin release..
0 Glucose - dependent insulinotrophic peptide (GIP)
CAUTION
- RISK OF HYPOGLYCEMIA
EXAMPLES & common side effect next to it
0 Sitagliptin
- headache
CONTRAINDICATION - Ketoacidosis
0 alogliptin -
- Abdominal pain
- GORD
- Headache
- Increased risk
of infection
CONTRAINDICATION - Ketoacidosis
-skin ractions.
0 linagliptin
- Cough , Nasophayrngitis
0 saxagliptin
-
- Abdominal pain
- vomiting
- Headache
- Increased risk
of infection
- fatigue
- diziness
TREATMENT
- Mono therapy (if metformin not appropriate ) or in combination with other oral anti diabetic drugs - if existing treatment fails.
NEW CLASS OF DRUGS - NEEDS TO MONITORED
These class is being investigated for increasing risk of pancreatic cancer. - discontinue if symptoms of pancreatitis present. e.g persistent severe abdominal pain.
What are SGLT2 inhibitors ?
SGLT2 -
SGLT2 co - transporter - found in proximal convuted tubule .
Responsible for 80 -90 of re-absorption of glucose inside the tubules. (kidney) - maximum capacity of transporter - 180 g / DL.
SGLT2 Inhibitors - inhibit these transporters.
0 reduce re
absorption of
glucose
0 increase
excretion of
glucose via
urine.
Examples of SGLT2 inhibitors ?
0 Canagliflozin
- Constipation
- Urosepsis
(sepsis caused
by urogenital
infection)
- nausea , thirst
0 Dapagliflozin
- Diabetic
ketoacidosis -
(stop
immeadiately )
- diziness
- back pain
0 empaglozin
- urosepsis
- thirst
COMMON SIDE EFFECTS
-Increased risk of infection - UTI - due to increased glucose - more food for pathogens , genital infections , skin infections
- Osmotic diuersis - cause dehydration (dehydration - uncommon sideffect)
- volume depletion - risk in elderly (hypovolaemia should be corrected before starting treatment.)
- Balanopsthitis - inflammation of the foreskin & glans of penis.
- Hypoglycemia (when used in combo with insulin or sulfonyureas)
- Dyslipidemia - changes to conc of lipid in blood due to disturbances in fat metabolism.
- Diabetic ketoacidosis - but degree of risk varies btw each drug - IMPORTANT.
Angioedema - rare
CONTRAINDICATIONS - DKA.
TREATMENT
- Mono therapy (if metformin not appropriate ) or in combination with other oral anti diabetic drugs - if existing treatment fails.
SGLT2 Inhibitors - being investigated for increased incidence of bone fractures
