L14 - Drug Treatment of Type 2 Diabetes Flashcards
what are the effects of insulin on hepatic, muscle and adipocytes
HEPATIC CELLS
decreases gluconeogenesis, glycogenolysis, ketogenesis,
(increases glycogen synthesis)
MUSCLE CELLS
• increases GLUT-4 translocation to the membrane and hence
increase glucose uptake, glucose oxidation, glycogen
synthesis, amino acid uptake, protein synthesis
• decreases glycogenolysis, amino acid release
ADIPOCYTES
increase glucose uptake, increase triglyceride synthesis;
decrease FFA and glycerol release
Net effect is to cause hypoglycemia and increase fuel storage in muscle, fat tissue and liver
what are the treatment options for T2DM
FOR INSULIN RESISTANCE:
metformin TZDs
RENAL GLUCOSE ABSORPTION
SGLT-2 inhib’s
diet exercise treatmets for obesity and dyslipidaemia
B CELL DYSFUNCTION
sulphonylureas
GLP-1 analogues
DDP-4 inhibitors
LOSS OF B CELL MASS
insulin replacement
Sulfonylureas
examples
how are they taken
how much is plasma bound
Examples include: gliclazide, glipizide, glimepiride
All orally active
All bound to plasma protein (90-99%)
pharmacodynamics of sulfonylureas
what is the primary mechanism
what is the secondary mechanism
• Primary mechanism of action stimulates endogenous insulin release
‘ binding site on ATP-sensitive K-channel to inhibiting the opening of the channel similar to ATP
- Secondary mechanisms of actions
- Evidence these drugs :
- Sensitize ß-cells to glucose
- Decrease lipolysis
- Decrease clearance of insulin by the liver
Therapeutics uses of sulfonylureas
what is it useful for
what is the best patient for this
what can it be used in combo with
what is a major side effect
' Useful in Type-2 DM only • best patient is • over 40 yrs. old • DM duration less than 10 yrs. • daily insulin (if taking) less than 40 units
’ can be used in combination with other anti-
diabetic drugs
’ Major side effect: Hypoglycaemia
Biguanides: metformin
how do they have their antihypergycaemic effect
Biguanide drugs - oral
antihyperglycemic agents
• biguanides do not stimulate insulin release or cause hypoglycemia
’ biguanides appear to increase glucose uptake in muscle and decrease glucose production by liver.
Biguanide drugs
what is the mechanism of action
what is the pathway
what happens in this
’ Suppression of hepatic glucose production
through gluconeogenesis through AMP- activated protein kinase (AMP K) dependent and independent pathways
’ AMPK increases expression of the nuclear transcription factor SHP which in turn inhibits the expression of hepatic gluconeogenic genes
phosphoenolpyruvate carboxykinase (PEPCK)
and glucose-6-phosphatase
biguanides drugs
what is the mechanism
in terms of the effect of the pathways
how it effect the body and glucose / insulin
- Increases insulin sensitivity
- Possibly through improved insulin binding to insulin receptors
’ Enhances peripheral glucose uptake
• Increased GLUT 4 translocation through AMPK
• Heart muscle metabolic changes by p38 MAPCK and PKC-dependent mechanisms and independent of AMPK
’ Increases fatty acid oxidation via decreasing
insulin-induced suppression of fatty acid oxidation
• Decreases glucose absorption from GI tract
what are the properties of metformin
’ orally active
‘ does not bind plasma proteins
‘ excreted unchanged in urine
——half-life 1.3 - 4.5 h
‘ often combined in a single pill with other anti-
diabetic medications
‘ also used for polycystic ovary syndrome
adverse effects and toxicity of biguanides
’ metformin produces lactic acidemia only rarely
• more frequent in patients with renal impairment
’ nausea, abdominal discomfort, diarrhea, metallic taste, anorexia more common
’ vitamin B12 and folate absorption decreased with
chronic metformin
' myocardial infarction or septicemia mandate immediate stoppage (associated renal dysfunction)
what are some contraindications for metformin
’ hepatic disease
past history of lactic acidosis (any cause)
’ cardiac failure
’ chronic hypoxic lung disease
causes metabolic acidosis
THIAZOLIDINEDIONES
what is approved
pioglitazone
Activate peroxisome proliferator-activated
receptor-gamma (PPAR-gamma)
• PPARs involved in transcription of insulin-responsive genes
and in regulation of adipocyte lipid metabolism
GLITAZONE
pharmacodynamics
what do they do in terms of glucose related processes
In presence of endogenous or exogenous insulin glitazones will
’ decrease gluconeogenesis, glucose output, and triglyceride production in liver
’ increase glucose uptake and utilization in skeletal
muscle
’ increase glucose uptake and decrease fatty acid output in adipose tissue
Cause differentiation of adipocytes
’ monotherapy or with other anti-diabetic medications
pioglitazone
how often a day and dosage
when do plasma levels peak and
how long is half life and
how much is metabolised and excreted
Pioglitazone: taken once or twice a day orally
’ plasma levels peak about 3 hr
plasma half-life is 3-7 hr; active metabolites (tl/2
16-24 h)
’ liver metabolism and excreted in feces (2/3) and urine
(1/3)
Adverse effects and drug interactions of GLITAZONES
and
PIOGLITAZONES
GLITAZONES:
- fluid retention (promotes amiloride-sensitive sodium ion reabsorption in renal collecting ducts) causing, edema, mild anemia
- dose-related weight gain
- safety in pregnancy and lactation not determined
- do not cause lactic acidosis, even in patients with renal impairment
- Liver damage may require regular blood tests
Pioglitazone subject to interactions due to liver
metabolism.
• may lower oral contraceptives levels containing ethinyl estradiol and norethindrone
