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

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

1
Q

rapid acting insulin analogues

A

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.)
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2
Q

Short acting Insulin analogue

A

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.)
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3
Q

intermediate acting insulin analogue

A

(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
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4
Q

long acting insulin analogue

A

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
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5
Q

liraglutide

A

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
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6
Q

agents controlling hypoglycemia

A 
Glucose
Glucagon
(Diazoxide) thiazide with no diuretic effect but opens potassium-channel
Ocreotide
(Streptozocin)
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7
Q

side effects of insulin therapy

A
  1. hypoglycemia
  2. hypokalemia
  3. neurologic damage
  4. immune complication
  5. injection site reaction
  6. edema
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8
Q

Oral antidiabetics. Pharmacotherapy of non-insulin dependent diabetes mellitus

A
  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
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9
Q
  1. insulin secretagogues
A

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)
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10
Q
  1. Biguanides
A

Metformin

  • 1st line
  • AMP kinase++, gluconeogenesis–, intestinal glucose absorption –, Insulin sensitivity++
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11
Q
  1. Thiazolidinediones

not on the list

A

PPAR-gamma activator:
(Rosiglitazone)
(Pioglitazone)

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

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12
Q
  1. Agents affecting endogenous incretin system
A

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)
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13
Q
  1. SGLT-2 inhibitor
A

Dapagliflozin

Canagliflozin

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14
Q
  1. Alpha-glucosidase-inhibitor
A

Acarbose

miglitol

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15
Q
  1. Amylin mimetics

not on the list

A

Glucagon–, delayed gastric emptying, satiety,

peptide hormone from ß-cells

(Pramlintide) synthetic

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16
Q

Insulin, general

A

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)
17
Q

Side effects of insulin

A
  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
18
Q

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

A

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

    • 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.
19
Q

▪ Therapeutic goals of glycemic control in diabetic patient:

A
  • HbA1c < 7%
  • Pre-prandial plasma glucose < 7.2 mmol/L
  • 2 h’ post-prandial plasma glucose < 10.0 mmol/L
20
Q

GLP-1 analogue

A

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
21
Q

Tolbutamide
Chlorpropamide

(not on the list)

A

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
22
Q

Glimepiride

Glipizide

A

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
23
Q

Repaglinide

Nateglinide

A

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
24
Q

Metformin

A

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)

25
Q

Rosiglitazone
Pioglitazone

(not on the list)

A

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
26
Q

Vildagliptin

Sitagliptin

A

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
27
Q

Dapagliflozin

Canagliflozin

A

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
28
Q

Acarbose

Miglitol

A

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)
29
Q

Pramlintide

not on the list

A

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
30
Q

Colesevelam

A

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
31
Q

Bromocriptine

A

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
32
Q

Glucose

A
  • IV
  • Dextrose solution (dextrose + water)
  • Hypoglycemia not associated with water loss or electrolyte imbalances
33
Q

Glucagon

A
  • 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
34
Q

Diazoxide

not on the list

A
  • 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
35
Q

Octreotide

A

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
36
Q

Streptozocin

not on the list

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

Endocrinological Pharmacology (6 decks)

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