IC10 Pharmacology of Endocrine Disorders (DM & Thyroid)

Question 1

What classes of oral antidiabetic medications lower the HbA1c levels by > 1.5%, > 1.0% and > 0.5% respectively?

Answer 1

> 1.5% - Metformin, Sulfonylureas
1.0% - GLP-1, TZDs
0.5% - SGLT2i, DPP-4i, Acarbose

Question 2

What classes of oral antidiabetic medications are administered regardless of meals, before meals or with meals respectively?

Answer 2

1. Regardless - Metformin, GLP-1, TZDs, SGLT2i, DPP-4i
2. Before meals - Sulfonylureas
3. With meals - Acarbose

Question 3

What classes of oral antidiabetic medications have weight loss / gain / neutral effect?

Answer 3

Weight loss - Metformin, GLP-1, SGLT2i (Mild)

Weight gain - Sulfonylureas, TZDs

Weight neutral - DPP-4i, acarbose

Question 4

What are the main classes of oral antidiabetic medications used?

Answer 4

1. Biguanide (Metformin)
2. Sulfonylurea (Glipizide)
3. Dipeptidyl Peptidase-4 Inhibitor (Sitagliptin)
4. Glucagon-Like Peptide-1 (Liraglutide)
5. Sodium Glucose Cotransporter 2 (Empagliflozin)

Question 5

What are the effects of different classes of oral antidiabetic medications on FBG and PBG?

Answer 5

FBG
1. Marked: Metformin
2. Moderate: GLP-1, TZDs, SGLT2i
3. Mild: SUs, DPP-4i

PBG
1. Marked: SUs, GLP-1
2. Moderate: TZDs, DPP-4i, Acarbose
3. Mild: Metformin, SGLT2i

Question 6

What is the MOA of Metformin?

Answer 6

Inhibit liver gluconeogenesis by increasing AMP-activated protein kinase

Enhance tissue sensitivity to insulin (Increase tissue glucose uptake)

Question 7

What is the ADME PK profile of Metformin?

Answer 7

Absorption – Oral
Distribution – Minimal plasma protein binding
Metabolism – NA
Excretion – Renal clearance unchanged

Question 8

What are some ADRs of Metformin?

Answer 8

Anorexia

GI (diarrhea weight loss; vomiting, indigestion)(take with or after meal)

↑ risk of Vit B12 malabsorption → Vit B12 deficiency

Use with caution in patients with renal problems or lactic acidosis (hepatic disease and cardiovascular problem)

Question 9

What is the MOA of Glipizide?

Answer 9

2nd generation insulin secretagogues (Lower risk of hypoglycemia within drug class)

(1) Increase insulin release from pancreas (Functional Beta cells)

(2) Principal target: Bind to SU receptor protein subunit of ATP-sensitive potassium channels on

(3) Beta cells (Control membrane potential)
Triggers calcium dependent exocytosis of insulin granules

Question 10

What is the ADME PK for Glipizide?

Answer 10

Absorption – Oral (Delayed with food intake)
Distribution – Extensive plasma protein (albumin) binding
Metabolism – Liver (Hydroxylation)
Excretion – Urine and feces (Action prolonged in renal disease)

Question 11

What are 2 ADRs of Glipizide?

Answer 11

Hypoglycemia (Elderly), Weight gain

Question 12

What is the MOA of Sitaglipitin?

Answer 12

Incretin Based Therapy

1) Incretin hormone secretion during food consumption causing gut movement – Released by K and L cells ⇒ Release GIP & GLP-1 hormones ⇒ Stimulate pancreatic release of insulin (Glucose-dependent manner)

2) Inhibition of DPP-4 affects:
- GLP-1 – Reduced enzyme degradation
- Incretin – Prolonged action
- Beta cells – Increase
- Glucose-stimulated insulin release – Increase
- Alpha cell mediated glucagon release –Suppressed

Question 13

What is the ADME PK profile of sitagliptin?

Answer 13

Absorption – Oral
Distribution – 10-12h half-life
Metabolism – Liver (Low)
Excretion – Urine

Question 14

What are 4 ADRs of sitagliptin?

Answer 14

1. GI
2. Flu-like symptoms (Headache, runny nose, sore throat)
3. Skin reaction
4. Caution in history of pancreatitis

Question 15

What is the MOA of liraglutide?

Answer 15

Glucagon-Like-Peptide-1 (GLP-1) receptor activation on Beta cells
1) Adenylyl cyclase → cAMP → PKA → Insulin secretion with less glucagon release
2) Insulin secretion subsides as glucose conc in blood approach euglycemia

C16 Fatty acid chain – Cleavage protection by DPP-4 (Long acting peptide)

Question 16

What is the PK Profile of Liraglutide?

Answer 16

Absorption – SC, once-daily dose, 3mg maintenance dose
Distribution – Plasma protein binding by C16
Metabolism – Protein degradation pathway (No major route)
Elimination – Urine and feces (Low amounts)

Question 17

What is the MOA of empagliflozin?

Answer 17

SGLT2 inhibition – Reduced glucose tubular reabsorption (Reduced renal threshold for glucose)

Question 18

What is the PK profile of empagliflozin?

Answer 18

Absorption – Oral
Distribution – High plasma protein binding
Metabolism – Liver
Elimination – Half in feces, half in urine

Question 19

What is 4 ADRs of empagliflozin?

Answer 19

UTI
Urination increases
Female genital mycotic infection
Diabetic ketoacidosis

Question 20

What is the medication used for hyper and hypothyroidism?

Answer 20

Carbimazole - Hyperthyroidism
Levothyroxine (T4 analog) - Hypothyroidism

Question 21

What is the MOA and PK profile of carbimazole?

Answer 21

Mechanism of Action: Thyroid peroxidase inhibition = Reduced iodination

Pharmacokinetics:
Absorption – Oral (Converted to active methimazole)
Distribution – No plasma protein binding, concentrates in thyroid, clinical effect lasts a day (12h)
Metabolism – CYP450 and Flavin-containing monooxygenase (FMO)
Excretion – Mainly urine, some feces

Question 22

What are 6 ADRs of carbimazole?

Answer 22

1. Rashes
2. Joint pains
3. Nausea
4. Jaundice
5. Agranulocytosis (rare)
6. Hypothyroidism (due to over treatment) – monitor thyroid size and serum TSH level; once reduced thyroid size and achieved normal TSH level, carbimazole dose should be titrated (reduced) to avoid hypothyroidism.

Question 23

What is a counselling point when taking carbimazole?

Answer 23

Counseling point – Takes several weeks (3-6 wks) to develop clinical response due to T4 long half-life

Question 24

What is the MOA and PK of levothyroxine?

Answer 24

Mechanism of Action: Restore body to normal T4 levels

Pharmacokinetics:
Absorption – Oral (take on empty stomach with water; 30min before meal), mainly absorbed in duodenum / jejunum but affects gastric pH (antacid, PPI)
Distribution – High plasma protein binding (Once a day dosing, t1/2 7 days)
Metabolism – T4 deiodination in liver, kidney, peripherally; Liver – glucuronidation, sulfation)
Excretion – Feces, urine

Question 25

What are 7 ADRs of levothyroxine?

Answer 25

1. Reduced appetite
2. Anxiety
3. Diarrhea
4. Difficulty sleeping
5. Hair loss
6. Rare and Serious: Heart issues (eg. arrhythmias, high BP, pain, failure), Seizures (Contraindications)