13. Pancreatic hormones and parenterally applied antidiabetic drugs. Pharmacotherapy of IDDM. 14. Oral antidiabetics. Pharmacotherapy of non-insulin dependent diabetes mellitus.

Question 1

rapid acting insulin analogues

Answer 1

Insulin Lispro
(Insulin Aspart)
(Insulin Glulisine)

Analogue insulin
(amino acid sequence modified to accelerate entry into the circulation, without affecting its interaction with insulin receptor)

onset of action: 5-15 min’

Peak: 1 h’

duration of action: 3-4 h’

• Pre-prandial injections in ordinary maintenance regimens
• Preferred insulin for continuous subcutaneous insulin
  infusion devices
• Emergency treatment of diabetic ketoacidosis (IV adm.)

Question 2

Short acting Insulin analogue

Answer 2

regular insulin

Human insulin

Onset of action: 30 min’ - 1 h’

Peak: 1-3 h’

Duration of action: 4-8 h’

• Pre-prandial injections in ordinary maintenance regimens
• Emergency treatment of diabetic ketoacidosis (IV adm.)

Question 3

intermediate acting insulin analogue

Answer 3

(isophan-) NPH insulin (+protamine)

Human insulin
(regular insulin and protamine)

onset of action: 1-2 h’

Peak: 4-6 h’

Duration of action: 8-12 h’

• Combined with short-/rapid-acting insulin preparations

Question 4

long acting insulin analogue

Answer 4

Insulin Glargine
(Insulin Detemir)
(Insulin Degludec)

Analogue insulin

Onset of action: 2 h’

Peak: Flat

Duration of action: 12-24 h’

• Provide basal insulin levels in ordinary maintenance regimens

Question 5

liraglutide

Answer 5

GLP-1 analogue

Agents affecting the endogenous incretin system
Incretin is a family of peptide hormones, released from endocrine cells of the small intestine in response to food; DPP-4 is the endogenous inhibitor of these hormones.
- Insulin release ↑
- Glucagon release ↓
- Delayed gastric emptying
- Satiety

• Parenteral
• Expansive
• Type 2 D.M (monotherapy or in combination with metformin or sulfonylurea)
• Weight-loss (liraglutide)
• Side effects: GI symptoms, nausea, hypoglycemia,
  acute pancreatitis

Question 6

agents controlling hypoglycemia

Answer 6

Glucose
Glucagon
(Diazoxide) thiazide with no diuretic effect but opens potassium-channel
Ocreotide
(Streptozocin)

Question 7

side effects of insulin therapy

Answer 7

1. hypoglycemia
2. hypokalemia
3. neurologic damage
4. immune complication
5. injection site reaction
6. edema

Question 8

Oral antidiabetics. Pharmacotherapy of non-insulin dependent diabetes mellitus

Answer 8

1. insulin secretagogues: 1st and 2nd gen.: suphonylureas and meglitinideanalogue
2. Biguanides
3. Thiazolidinediones
4. Agents affecting endogenous incretin system
5. SGLT-2 inhibitor
6. Alpha-glucosidase-inhibitor
7. Amylin mimetics
8. bile-acid sequesterants - Colesevelam, unknown mechanism
9. dopamine agonist - Bromocriptine, unknown mechanism

Question 9

1. insulin secretagogues

Answer 9

1st gen. suphonylureas:

(1. Tolbutamide)
(2. Chlorpropamide)

2nd gen. suphonylureas:

1. Glimepiride
2. Glipizide

also enhances tissue response to insulin (muscle + liver) via changes in receptor function

meglitinide analogues:

1. Repaglinide
   (2. Nateglinide)

Question 10

2. Biguanides

Answer 10

Metformin

• 1st line
• AMP kinase++, gluconeogenesis–, intestinal glucose absorption –, Insulin sensitivity++

Question 11

3. Thiazolidinediones

not on the list

Answer 11

PPAR-gamma activator:
(Rosiglitazone)
(Pioglitazone)

GLUT4++, hepatic gluconeogenesis–, adiponectin++, lipid metabolism++)

Question 12

4. Agents affecting endogenous incretin system

Answer 12

insulin++, glucagon–, delayed gastric emptying, satiaty

DPP-4 is endogenous inhibitor of incretins

1. GLP-1 analogue: Liraglutide (Exenatide)
2. DPP-4-inhibitor: Vildagliptin (Sitagliptin)

Question 13

5. SGLT-2 inhibitor

Answer 13

Dapagliflozin

Canagliflozin

Question 14

6. Alpha-glucosidase-inhibitor

Answer 14

Acarbose

miglitol

Question 15

7. Amylin mimetics

not on the list

Answer 15

Glucagon–, delayed gastric emptying, satiety,

peptide hormone from ß-cells

(Pramlintide) synthetic

Question 16

Insulin, general

Answer 16

Insulin preparations are generated by bacterial recombinant DNA techniques; consist on the amino acid sequence of insulin or variation of it.

• Human insulin: original amino acid sequence (not altered)
• Analogue insulin: amino acid sequence has been modified to generate either a more rapid-acting, or more uniformly-acting insulin

Basal insulin requirements are provided by long-acting insulin, prescribed with short-acting insulin in an attempt to mimic physiologic insulin release with meals.

• Rapid-acting
• Short-acting
• Intermediate acting
• Long-acting

▪ Modes of insulin administration:

• Subcutaneous injections with conventional disposable needles and syringes
• Portable pen-sized injectors to facilitate subcutaneous injections
• Continuous subcutaneous insulin infusion devices (avoid the need for multiple daily injections and provide flexibility in the scheduling of patients’ daily activities)

▪ Total daily insulin needs:

• Type 1 D.M ∼ 0.55 Unit/Body-weight (kg)
• Type 2 D.M ≥ 1.0 Unit/Body-weight (kg)

Question 17

Side effects of insulin

Answer 17

1. Hypoglycemia
2. Risk of neurological damage in case of severe hypoglycemia (high-risk groups → advanced renal disease, elderly, children < 7 years old)
3. Hypokalemia
4. Insulin-induced immunologic complications (very rare with modern preparations)
5. Injection site reaction
6. Edema

Question 18

Multiple components insulin regimens (combination of basal insulin and bolus insulin)

Answer 18

1.
- The timing and dose of short-acting (pre-prandial insulin) are altered to accommodate the SMBG results, anticipated food intake, and physical activity.
- Such regimens offer the patient with type 1 diabetes more flexibility in terms of lifestyle and the best chance for achieving normoglycemia.
- Frequent SMBG (at least 3 times/day) is absolutely essential for this
type of insulin regimen.
*SMBG – self-monitoring of blood glucose

2. • Twice-daily injections of NPH mixed with a short-acting insulin before the morning and evening meals.
   • Such regimens usually prescribe 2⁄3 of the total daily insulin dose in the morning (with about 2⁄3 given as long-acting insulin and 1⁄3 as short-acting), and 1⁄3 before the evening meal (with approximately one half given as long- acting insulin and one-half as short-acting).
   • The drawback to such regimen is that it forces a rigid schedule on the patient, in terms of daily activity and the content and timing of meals.

Question 19

▪ Therapeutic goals of glycemic control in diabetic patient:

Answer 19

• HbA1c < 7%
• Pre-prandial plasma glucose < 7.2 mmol/L
• 2 h’ post-prandial plasma glucose < 10.0 mmol/L

Question 20

GLP-1 analogue

Answer 20

Liraglutide

Agents affecting the endogenous incretin system

Incretin is a family of peptide hormones, released from endocrine cells of the small intestine in response to food; DPP-4 is the endogenous inhibitor of these hormones.

• Insulin release ↑
• Glucagon release ↓
• Delayed gastric emptying
• Satiety

Question 21

Tolbutamide
Chlorpropamide

(not on the list)

Answer 21

Insulin secretagogues

• Closure of K+-channels in pancreatic β-cells → membrane depolarization → Ca2+ influx triggers insulin release, glucagon release from α-cells ↓
• Continuous use of sulfonylureas enhances tissue response to insulin (especially muscle and liver) via changes in receptor function
  Sulfonylurea 1st gen’
• Oral
• Short onset of action
• More toxic
• Type 2 D.M

- Side effects: 
weight gain, 
hypoglycemia, 
rash,
sulfonamide hypersensitivity reaction, 
increased
cardiovascular risk, 
hematological abnormalities (rare)

• Drug interactions (mainly 1st gen’ agents) → CYP3A4??
  hypoglycemia with cimetidine, insulin, salicylates, sulfonamides

Question 22

Glimepiride

Glipizide

Answer 22

Insulin secretagogues

• Closure of K+-channels in pancreatic β-cells → membrane depolarization → Ca2+ influx triggers insulin release, glucagon release from α-cells ↓
• Continuous use of sulfonylureas enhances tissue response to insulin (especially muscle and liver) via changes in receptor function

Sulfonylurea 2nd gen’

• Oral
• Short onset of action
• More potent
• Type 2 D.M

- Side effects: 
weight gain, 
hypoglycemia, 
rash,
sulfonamide hypersensitivity reaction, 
increased
cardiovascular risk, 
hematological abnormalities (rare)

• Drug interactions (mainly 1st gen’ agents) → CYP3A4??
  hypoglycemia with cimetidine, insulin, salicylates, sulfonamides

Question 23

Repaglinide

Nateglinide

Answer 23

Insulin secretagogues

• Closure of K+-channels in pancreatic β-cells → membrane depolarization → Ca2+ influx triggers insulin release, glucagon release from α-cells ↓

Meglitinide analogues

• Weaker binding affinity and faster dissociation from the SUR1 subunit of the ATP-sensitive K+-channel
• Oral
• Rapid onset of action, duration of action 5-8 h’
• Type 2 D.M

Side effects:

• hypoglycemia
• No sulfonamide hypersensitivity

Question 24

Metformin

Answer 24

Biguanides

• Activates AMP kinase → reduces hepatic and renal gluconeogenesis → post-prandial and fasting glucose levels ↓
• Intestinal glucose absorption ↓
• Insulin sensitivity ↑
• Oral
• Maximal plasma concentration in 2-3 h’
• Renal elimination with no prior metabolism
• Requires cautions when GFR < 45 mL/min/1.73 m2,
  contraindicated when GFR < 30 mL/min/1.73 m2
• Type 2 D.M (currently 1st line therapy)
• Restore fertility in women with PCOS and evidence of
  insulin resistance
• Weight reduction in non-diabetic individuals with
  obesity (‘off-label use’)
• Hyperinsulinemia (mostly in obese patients)

Side effects:
- GI symptoms (nausea, diarrhea)
- Metformin-associated lactic acidosis (in susceptible
patients → impaired renal/hepatic function, CHF,
hypoxic/acidotic states, alcoholism)
- AKI in patients on metformin receiving IV iodine- containing contrast agent (stop metformin 1 day prior to examination)

Question 25

Rosiglitazone Pioglitazone (not on the list)

Answer 25

Thiazolidinediones Activate PPAR-γ (nuclear receptor, signaling pathway in adipose tissue): - GLUT-4 expression, glucose uptake by muscle and adipose tissue ↑ (reduce both fasting and post-prandial hyperglycemia) - Hepatic gluconeogenesis ↓ - Positive effect on lipid metabolism and the distribution of body fat - Adiponectin ↑ (increases insulin sensitivity and fatty acid oxidation) - Oral - Long duration of action (> 24 h') - Induce CYP450 activity - Type 2 D.M (in combination) - Side effects: weight gain, edema, anemia, increased risk of bone fracture, potential hepatotoxicity - Contraindicated in CHF and liver disease

Question 26

Vildagliptin | Sitagliptin

Answer 26

Agents affecting the endogenous incretin system Incretin is a family of peptide hormones, released from endocrine cells of the small intestine in response to food; DPP-4 is the endogenous inhibitor of these hormones. - Insulin release ↑ - Glucagon release ↓ - Delayed gastric emptying - Satiety DPP-4 inhibitor - Oral - Duration of action 24 h' - Expensive - Type 2 D.M (monotherapy or in combination with metformin or thiazolidinediones) - Side effects: headache, nasopharyngitis, upper respiratory tract infections

Question 27

Dapagliflozin | Canagliflozin

Answer 27

SGLT-2 inhibitors Inhibit sodium-glucose transporter (proximal convoluted tubule) → glucosuria → blood glucose level ↓ (reduce both fasting and post-prandial hyperglycemia) - Oral - Expensive - Contraindicated in impaired renal function - Type 2 D.M - Potential use in CHF Side effects: - genitourinary infections (high glucose content of urine), - osmotic diuresis may result in volume contraction and hypotension

Question 28

Acarbose | Miglitol

Answer 28

α-glucosidase inhibitors Inhibit intestinal brush border α-glucosidases → disaccharides degradation ↓ → glucose absorption ↓ (reduce post-prandial glucose level, no effect on fasting level) - Oral - Rapid onset of action - Contraindicated in impaired renal/hepatic function, intestinal disorders - Type 2 D.M - Side effects: hypoglycemia, diarrhea and abdominal pain (GI symptoms due to increased fermentation of unabsorbed carbohydrates by gut bacteria)

Question 29

Pramlintide | not on the list

Answer 29

Amylin mimetics Amylin is a peptide hormone (IAPP – islet amyloid polypeptide); released from pancreatic β-cells in ratio of approx. 100:1 (insulin: amylin) Functions as synergistic partner to insulin: - Glucagon release ↓ - Delayed gastric emptying - Suppress appetite - Synthetic amylin agonist - Parenteral - Short duration of action - Type 2 D.M - Type 1 D.M (control post-prandial hyperglycemia) - Side effects: GI disturbances, hypoglycemia

Question 30

Colesevelam

Answer 30

Bile acid sequestrants Bile acid binders; lowers glucose through unknown mechanisms (possibly affect FXR receptors in the liver) - Oral - Duration of action 24 h' - Type 2 D.M - Side effects: constipation, maldigestion, flatulence Large, non-absorbable polymers that bind bile acids and similar steroids in the intestine and prevent their absorption – decreased enterohepatic recirculation - Divert hepatic cholesterol to the synthesis of new bile salts - Liver cholesterol ↓ - LDL receptor expression ↑ - Plasma LDL ↓ (15-25% reduction may be achieved) - Oral - Taken with meals - Not absorbed - Interfere with absorption of drugs (ex. warfarin, thiazides, digoxin, aspirin, statin), administer 4 h' apart - Primary hypercholesterolemia type IIa (isolated LDL increase) - In combination with statins - Reduce pruritus in patients with cholestasis and bile acid accumulation - Cholestyramine is used in the treatment of digoxin toxicity (enhances elimination) - Side effects: elevated VLDL and triglycerides, GI disturbances (bloating, constipation, diarrhea), malabsorption of lipid-soluble vitamins (DEAK), hyperglycemia, gall-stones

Question 31

Bromocriptine

Answer 31

Dopamine agonists D2 receptor agonists; lowers glucose through unknown mechanism - Ergot alkaloid derivatives - Partial agonists at D2 receptors - Oral - Parkinson disease (monotherapy/adjunct to levodopa); limited use (replaced by the newer agents) - Suppresses pituitary secretion of prolactin and GH (to lesser extent) - Prolactin-secreting adenoma - Acromegaly (effective only in high doses) - Neuroleptic malignant syndrome (NMS): - Oral - Duration of action 24 h' - Type 2 D.M - Side effects: nausea, vomiting, dizziness, headache GI disturbances, orthostatic hypotension, headache, psychiatric disturbances, vasospasm and pulmonary infiltrates in high doses - Dyskinesia - Psychosis, hallucination - Anorexia, nausea - Orthostatic hypotension

Question 32

Glucose

Answer 32

- IV - Dextrose solution (dextrose + water) - Hypoglycemia not associated with water loss or electrolyte imbalances

Question 33

Glucagon

Answer 33

- Parenteral - Acute hypoglycemia - Management of severe β-blocker overdose (glucagon stimulates the depressed heart by increasing cAMP without requiring β-receptors) - Side effects: hypertension, GI disturbances

Question 34

Diazoxide | not on the list

Answer 34

- Thiazide derivative with no diuretic effect - Opens K+-channels → membrane hyperpolarization → insulin ↓ - Oral or parenteral (IV bolus) - Hypoglycemia caused by insulin-producing tumors - Hypertensive emergencies (hyperpolarization prevent vascular smooth muscle contraction) - Side effects: edema, hypotension

Question 35

Octreotide

Answer 35

Agents controlling hypoglycemia - Somatostatin analogue (inhibitory effect on insulin release) Inhibit the release of GH, insulin, glucagon, gastrin - Parenteral administration - Regular formulation – inject 2-4 times daily - Slow-release formulation – inject every 4 w' - Hypoglycemia caused by insulin-producing tumors - Acromegaly (pituitary adenoma), gigantism - Endocrine tumors (carcinoid, gastrinoma, glucagonoma, insulinoma, VIPoma) - Control of bleeding from esophageal varices - Endocrine tumors → carcinoid, gastrinoma, glucagonoma, insulinoma, VIPoma - Side effects: GI disturbances, steatorrhea,(due to impaired pancreatic secretion) gall stone, cardiac conduction abnormalities

Question 36

Streptozocin | not on the list

Answer 36

- Nitrosourea derivative - Inhibits DNA synthesis - Malignant pancreatic insulinoma - Side effects: hepatotoxicity, nephrotoxicity, hematological abnormalities