IC11 PK of drugs for DM

Question 1

Metformin MOA

Answer 1

Increase glucose uptake into tissues
* Reduces gluconeogenesis in liver → increase AMP-activated protein kinase
* May enhance tissue sensitivity to insulin

Question 2

Metformin PK
absorption

BA, duration of action

Answer 2

Oral; F ~40-60%
Duration of action: 8-12 hours

Question 3

Metformin PK
distribution

Vd, t1/2

Answer 3

Rapidly distributed to all parts of the body

Minimal plasma protein binding
Large Vd (>5-8L)

t1/2: 3h

Question 4

Metformin PK
excretion + precaution

Answer 4

Unchanged in urine

To avoid in patients with renal insufficiency → retains metformin in body; higher t1/2
Important to monitor kidney function

Question 5

Metformin
clinical uses & benefits

Answer 5

1. T2DM → alone or with other oral hypoglycemic agents (combination therapy)
   Does not result in hyperinsulinemia/ hypoglycemia
2. Useful in obese patients
   Reduces appetite; helps regulate body weight
   Improves lipids levels

Question 6

Metformin Adverse effects

A, GI, V, R, LA

Answer 6

1. Anorexia
2. GI disturbances: to take with or after meal
   Diarrhoea & vomiting → weight loss
   Indigestion
3. Increase risk of Vit B12 malabsorption → Vit B12 deficiency
4. Use with caution in patients with renal problems/ lactic acidosis
   Gluconeogenesis: glucose generated from lactate
   Metformin reduces amount of lactate to be broken down ⇒ lactic acidosis

Question 7

glipizide MOA

Answer 7

Lowers blood glucose by increasing release of insulin from pancreas

Main target: pancreatic β-cell ATP-sensitive (KATP) channel
controls β-cell membrane potential

Question 8

glipizide requirements

Answer 8

functioning β-cells in pancreas islets

Question 9

glipizide effects in b-cells

Answer 9

1. glipizide bind to SU receptor proteins
2. Inhibition of KATP channel mediated K+ efflux (membrane depolarisation)
3. Ca2+ channel opens → Ca2+ enters cell
4. Formation of vesicles containing insulin granules
5. Triggers Ca-dependent exocytosis of vesicles with insulin granules

Question 10

glipizide PK
absorption

F, onset, duration of action

Answer 10

Oral; F>95% (delayed with food intake)
Onset of action: 30 mins
Duration of action: 12-24 hours

Question 11

glipizide PK
distribution

Binding & t1/2

Answer 11

Binds extensively (~99%) to plasma proteins [primary albumin]
t1/2 = 4h

Question 12

glipizide PK
metabolism

Answer 12

By liver (90%); hydroxylation
10% remain as parent drug (unchanged)

Question 13

glipizide PK
excretion

problem?

Answer 13

<10% unchanged & metabolites excreted in urine & faeces

Actions prolonged with patients with renal disease
Reduction in excretion of parent compound ⇒ overdose; over lowering of blood glucose

Question 14

glipizide (compared to other SU)

Answer 14

Lower risks of hypoglycemia

Question 15

glipizide AE

Answer 15

Hypoglycemia (more common in elderly)
Possibly due to DDI/ lower kidney function (lesser clearance of drug)

Weight gain ⇒ not ideal for obese patients

Question 16

Sitagliptin (DPP-4i)
role of incretins

Answer 16

Group of metabolic hormones released after eating
Augment secretion of insulinin glucose-dependent manner
* presence of hyperglycemia = triggers secretion of insulin

Question 16

Sitagliptin (DPP-4i)
requirements for incretins to work

Answer 16

Requires pancreas to be working → inflamed pancreas will have decreased effects on insulin production

Question 17

Sitagliptin (DPP-4i)
how incretin works

Answer 17

1. Hormones passes through circulation & enters pancreas ⇒ stimulates insulin production
   Results in lower glucose levels due to increased uptake by cells & decreasing gluconeogenesis
2. Inhibition of glycogenesis by GLP-1 ⇒ reduction in hepatic glucose production
3. Gastric emptying delayed ==> feel more full

Question 18

Sitagliptin (DPP-4i) MOA

Answer 18

• Binds & inhibits DPP-4 → reduces enzymatic degradation of GLP-1
• Prolongs action of endogenous incretins, increasing β-cells stimulation
  [Increase glucose-stimulated insulin release]
• Suppression of 𝝰-cell mediated glucagon release & hepatic glucose production

Overall: Decreased blood glucose level

Question 19

Sitagliptin (DPP-4i) PK

A, D, M, E

Answer 19

Absorption
Oral; F ~87%
Distribution
t1/2 = 10-12 hours
Metabolism
Low liver metabolism
Excretion
80% excreted unchanged in urine
Remaining metabolites excreted in faeces

Question 20

Sitagliptin (DPP-4i) AE

GI, F, S

Answer 20

GI disturbances
Flu-like symptoms: headache, running nose, sore throat
Skin reactions: rash/ itch

Question 21

Sitagliptin (DPP-4i) caution in patients

Answer 21

patients with hx of pancreatitis (inflamed pancreas)

Question 22

Liraglutide (GLP-1 agonist) Effects

Answer 22

Initial rapid release of endogenous insulin
Suppression of glucagon release by pancreas
Delay gastric emptying
reduces appetite → weight loss; beneficial for obese patients

Question 23

Liraglutide (GLP-1 agonist) MOA

Answer 23

Activates GLP-1 receptor on pancreatic β-cells
↑adenylate cyclase → ↑cAMP → ↑PKA → ↑insulin secretion & ↓glucagon release

Question 24

Liraglutide (GLP-1 agonist) MOA change in insulin levels

Answer 24

Insulin secretion reduces as glucose concentration decreases & approaches euglycemia

Question 25

Liraglutide (GLP-1 agonist) effect of DDP4 enzyme

Answer 25

Long acting peptide: DPP-4-resistant form of GLP-1 Delay in breaking down of drug by peptidases

Question 26

Liraglutide (GLP-1 agonist) PK absorption | route of administration, dose progession, F

Answer 26

SC: upper arm, abdomen, thigh Once-daily dose Increase dose weekly: 0.6mg → 1.2mg → 1.8mg → 2.4mg → 3.0mg Regime helps reduce GI symptoms 3mg maintenance dose F = 55%

Question 27

Liraglutide (GLP-1 agonist) PK distribution | t1/2

Answer 27

C16 fatty acid binds to plasma proteins (albumin) t1/2 = 13 hours

Question 28

Liraglutide (GLP-1 agonist) PK metabolism

Answer 28

Endogenously metabolised, similar to polypeptides No specific organ as major route of elimination

Question 29

Liraglutide (GLP-1 agonist) PK excretion

Answer 29

Little/ none excreted unchanged → all polypeptides broken down to amino acids

Question 30

Liraglutide (GLP-1 agonist) AE | GI, CNS

Answer 30

Nausea/vomiting (improves when body adjusts to treatment) GI: Diarrhoea/constipation CNS: Headache/tiredness

Question 31

Empagliflozin (SGLT2i) MOA

Answer 31

Inhibition of SGLT2 * Reduces reabsorption of filtered glucose back into bloodstream * Reduces renal threshold for glucose ⇒ increases urinary glucose excretion

Question 32

Empagliflozin (SGLT2i) normal function of SGLT

Answer 32

Normal function of SGLT Reabsorbs glucose back into bloodstream 90% by SGLT2 ⇒ target of drug 10% by SGLT1

Question 33

Empagliflozin (SGLT2i) PK | A, D, M, E

Answer 33

**Absorption** Oral; F = 60-80% Cmax = 1-2 hours **Distribution** Highly plasma protein bound t1/2 = 12 hour → dose OD **Metabolism** Minimal metabolism in liver via glucuronidation **Excretion** ~40% unchanged in faeces; ~27% unchanged in urine Majority not broken down

Question 34

Empagliflozin (SGLT2i) AE

Answer 34

UTI → important to drink more water Increased urination Female genital mycotic fungal infection Diabetic ketoacidosis