L14 TD2 drug treatment

Question 1

Insulin targets

Answer 1

liver, adipose and skeletal muscle

Question 2

Effects of insulin of hepatic cells

Answer 2

decrease gluconeo, glycogenolysis, increase glycogen synthesis

Question 3

Insulin effect on muscle cells

Answer 3

increase 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

Question 4

Insulin effects on adipocytes

Answer 4

increase glucose uptake
increase triglyceride synthesis
decrease ffa and glycerol release

Question 5

Treatment options to target hyperglycemia

Answer 5

metformin TZDS for insulin resistance
SGLT2 inhibitors to block renal glucose absorption
Sulphonylureas DDP4 Inhibitors and GLP1 analogues to stop B cell dysfunction
loss of b cell mass - insulin replacement

Question 6

sulfonylureas

Answer 6

eg - gliclazide
release of insulin by sulfonylureas

Stimulate endogenous insulin release
binding site on ATP-sensitive K-channel to inhibiting the opening of the channel similar to ATP.
THEIR PRIMARY ACTION IS TO CLOSE ATP SENSITIVE POTASSIUM CHANNELS IN THE B CELL MEMBRANE SO TO INITIATE A CHAIN OF EVENTS WHICH RESULTS IN INSULIN RELEASE.
Secondary mechanisms of actions
Evidence these drugs :
Sensitize ß-cells to glucose
Decrease lipolysis
Decrease clearance of insulin by the liver

USEFUL IN TYPE 2 DIABETES ONLY

Question 7

biguanides - metformin

Answer 7

Differ from sulfonylureas and meglitinides both chemically and in mechanism of action
biguanides do not stimulate insulin release or cause hypoglycemia
biguanides appear to increase glucose uptake in muscle and decrease glucose production by liver.
Suppression of hepatic glucose production through gluconeogenesis through AMP-activated protein kinase (AMPK) 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

So increases insulin sensitivity possibly through improved insulin binding to insulin receptors

Enhanced peripheral glucose uptake by inc glut 4 translocation through AMPK

Question 8

Adverse effects of toxicity of biguanides

Answer 8

Metformin produces lactic acidemia rarely
nausea, abdominal discomfort, metallic taste,
vitamin B12 and folate absorption decreased with chronic metformin

Question 9

metformin contraindications

Answer 9

hepatic disease
 past history of lactic acidosis (any cause)
 cardiac failure
 chronic hypoxic lung disease 
 causes metabolic acidosis

Question 10

Gltiazones - pioglitazone

Answer 10

Pioglitazone acts as a selective agonist at Peroxisome Proliferator Activated Receptor Gamma (PPARγ) in target tissues for insulin action

PPARs involved in transcription of insulin-responsive genes and in regulation of adipocyte lipid metabolism

Question 11

Glitazones adverse effects

Answer 11

fluid retention 
oedema 
mild anemia 
dose related weight gain 
safety in pregnancy not determined 
liver damage 

Pioglitazone is subject to interactions due to liver metabolism
it may lower oral contraceptive levels containing ethinyl estradiol and norethindrone

Question 12

Glucagon-like peptide-1 analogs

Answer 12

Exenatide
administered 30-60 mins before last meal of the day

Facilitates glucose control by Augmenting pancreas response
Suppresses pancreatic release of glucagon helping stop the liver overproducing glucose
Slows down gastric emptying
Reduces appetite and promote satiety via hypothalamic receptors
Reduces liver fat content
Adjuvant therapy for type II diabetic on metformin, a sulfonylurea, thiazolidinediones, or a combination of these drugs who have not been able to achieve adequate control of blood glucose

Question 13

What is the difference between GLP-1 and exenatide ?

Answer 13

GLP1 is not resistant to DPP-IV regradation but exenatide is.
GLP1 duration within the plasma following injection is short whereas exenatide duration is long

Question 14

Dipeptidyl peptidase-4 (DPP-4) inhibitors

Answer 14

oral hypoglycemics such as sitagliptin and vildagliptin

Mechanism of action is via increased levels of Incretins GLP-1 and GIP
Increased Incretins
Inhibit glucagon release
Increase glucose-induced insulin secretion
Decrease gastric emptying
Reduce hepatic glucose production
Improved peripheral glucose utilisation

Question 15

Sodium-glucose transporter (SGLT) protein inhibitors

- where are they ?

Answer 15

Dapagliflozin
Canagliflozin

SGLT1 found in the small intestine to absorb glucose and PT of nephron
SGLT2 found in PCT
100% of glucose has be to reabsorbed along the nephron, 90% by SGLT2
Therefore blocking this transporter causes blood glucose to be eliminated through the kidney

Question 16

Effects of SGLT2 inhibitors

Answer 16

Sodium-glucose co-transporter-2 inhibitors work by inhibiting SGLT2 in the PCT, to prevent reabsorption of glucose and facilitate its excretion in urine.
inhibit renal tubular sodium glucose co transporter - resulting in reversal of hyperglycemia and reversal of glucotoxicity

Improved B cell function
reduced gluconeogenesis - dcreased cori cycle and reduced pep caroxykinase
increase insulin sensitivity in liver reduce g6p and increase insulin sensitivity in muscle inc glut4 translocation and inc insulin signalling

Question 17

side effects of SGLT2 inhibitors

Answer 17

rapid weight loss due to glycosuria
tiredness
dehydration
can worsen UTI and thrush