IC10 Pharmacology of Endocrine Disorders (DM & Thyroid) Flashcards
What classes of oral antidiabetic medications lower the HbA1c levels by > 1.5%, > 1.0% and > 0.5% respectively?
> 1.5% - Metformin, Sulfonylureas
1.0% - GLP-1, TZDs
0.5% - SGLT2i, DPP-4i, Acarbose
What classes of oral antidiabetic medications are administered regardless of meals, before meals or with meals respectively?
- Regardless - Metformin, GLP-1, TZDs, SGLT2i, DPP-4i
- Before meals - Sulfonylureas
- With meals - Acarbose
What classes of oral antidiabetic medications have weight loss / gain / neutral effect?
Weight loss - Metformin, GLP-1, SGLT2i (Mild)
Weight gain - Sulfonylureas, TZDs
Weight neutral - DPP-4i, acarbose
What are the main classes of oral antidiabetic medications used?
- Biguanide (Metformin)
- Sulfonylurea (Glipizide)
- Dipeptidyl Peptidase-4 Inhibitor (Sitagliptin)
- Glucagon-Like Peptide-1 (Liraglutide)
- Sodium Glucose Cotransporter 2 (Empagliflozin)
What are the effects of different classes of oral antidiabetic medications on FBG and PBG?
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
What is the MOA of Metformin?
Inhibit liver gluconeogenesis by increasing AMP-activated protein kinase
Enhance tissue sensitivity to insulin (Increase tissue glucose uptake)
What is the ADME PK profile of Metformin?
Absorption – Oral
Distribution – Minimal plasma protein binding
Metabolism – NA
Excretion – Renal clearance unchanged
What are some ADRs of Metformin?
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)
What is the MOA of Glipizide?
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
What is the ADME PK for Glipizide?
Absorption – Oral (Delayed with food intake)
Distribution – Extensive plasma protein (albumin) binding
Metabolism – Liver (Hydroxylation)
Excretion – Urine and feces (Action prolonged in renal disease)
What are 2 ADRs of Glipizide?
Hypoglycemia (Elderly), Weight gain
What is the MOA of Sitaglipitin?
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
What is the ADME PK profile of sitagliptin?
Absorption – Oral
Distribution – 10-12h half-life
Metabolism – Liver (Low)
Excretion – Urine
What are 4 ADRs of sitagliptin?
- GI
- Flu-like symptoms (Headache, runny nose, sore throat)
- Skin reaction
- Caution in history of pancreatitis
What is the MOA of liraglutide?
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)
What is the PK Profile of Liraglutide?
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)
What is the MOA of empagliflozin?
SGLT2 inhibition – Reduced glucose tubular reabsorption (Reduced renal threshold for glucose)
What is the PK profile of empagliflozin?
Absorption – Oral
Distribution – High plasma protein binding
Metabolism – Liver
Elimination – Half in feces, half in urine
What is 4 ADRs of empagliflozin?
UTI
Urination increases
Female genital mycotic infection
Diabetic ketoacidosis
What is the medication used for hyper and hypothyroidism?
Carbimazole - Hyperthyroidism
Levothyroxine (T4 analog) - Hypothyroidism
What is the MOA and PK profile of carbimazole?
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
What are 6 ADRs of carbimazole?
- Rashes
- Joint pains
- Nausea
- Jaundice
- Agranulocytosis (rare)
- 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.
What is a counselling point when taking carbimazole?
Counseling point – Takes several weeks (3-6 wks) to develop clinical response due to T4 long half-life
What is the MOA and PK of levothyroxine?
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
What are 7 ADRs of levothyroxine?
- Reduced appetite
- Anxiety
- Diarrhea
- Difficulty sleeping
- Hair loss
- Rare and Serious: Heart issues (eg. arrhythmias, high BP, pain, failure), Seizures (Contraindications)
