13. Pancreatic hormones and parenterally applied antidiabetic drugs. Pharmacotherapy of IDDM. 14. Oral antidiabetics. Pharmacotherapy of non-insulin dependent diabetes mellitus. Flashcards
rapid acting insulin analogues
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.)
Short acting Insulin analogue
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.)
intermediate acting insulin analogue
(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
long acting insulin analogue
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
liraglutide
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
agents controlling hypoglycemia
Glucose Glucagon (Diazoxide) thiazide with no diuretic effect but opens potassium-channel Ocreotide (Streptozocin)
side effects of insulin therapy
- hypoglycemia
- hypokalemia
- neurologic damage
- immune complication
- injection site reaction
- edema
Oral antidiabetics. Pharmacotherapy of non-insulin dependent diabetes mellitus
- insulin secretagogues: 1st and 2nd gen.: suphonylureas and meglitinideanalogue
- Biguanides
- Thiazolidinediones
- Agents affecting endogenous incretin system
- SGLT-2 inhibitor
- Alpha-glucosidase-inhibitor
- Amylin mimetics
- bile-acid sequesterants - Colesevelam, unknown mechanism
- dopamine agonist - Bromocriptine, unknown mechanism
- insulin secretagogues
1st gen. suphonylureas:
(1. Tolbutamide)
(2. Chlorpropamide)
2nd gen. suphonylureas:
- Glimepiride
- Glipizide
also enhances tissue response to insulin (muscle + liver) via changes in receptor function
meglitinide analogues:
- Repaglinide
(2. Nateglinide)
- Biguanides
Metformin
- 1st line
- AMP kinase++, gluconeogenesis–, intestinal glucose absorption –, Insulin sensitivity++
- Thiazolidinediones
not on the list
PPAR-gamma activator:
(Rosiglitazone)
(Pioglitazone)
GLUT4++, hepatic gluconeogenesis–, adiponectin++, lipid metabolism++)
- Agents affecting endogenous incretin system
insulin++, glucagon–, delayed gastric emptying, satiaty
DPP-4 is endogenous inhibitor of incretins
- GLP-1 analogue: Liraglutide (Exenatide)
- DPP-4-inhibitor: Vildagliptin (Sitagliptin)
- SGLT-2 inhibitor
Dapagliflozin
Canagliflozin
- Alpha-glucosidase-inhibitor
Acarbose
miglitol
- Amylin mimetics
not on the list
Glucagon–, delayed gastric emptying, satiety,
peptide hormone from ß-cells
(Pramlintide) synthetic
Insulin, general
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)
Side effects of insulin
- Hypoglycemia
- Risk of neurological damage in case of severe hypoglycemia (high-risk groups → advanced renal disease, elderly, children < 7 years old)
- Hypokalemia
- Insulin-induced immunologic complications (very rare with modern preparations)
- Injection site reaction
- Edema
Multiple components insulin regimens (combination of basal insulin and bolus insulin)
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.
▪ Therapeutic goals of glycemic control in diabetic patient:
- HbA1c < 7%
- Pre-prandial plasma glucose < 7.2 mmol/L
- 2 h’ post-prandial plasma glucose < 10.0 mmol/L
GLP-1 analogue
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
Tolbutamide
Chlorpropamide
(not on the list)
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
Glimepiride
Glipizide
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
Repaglinide
Nateglinide
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
Metformin
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)
Rosiglitazone
Pioglitazone
(not on the list)
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
Vildagliptin
Sitagliptin
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
Dapagliflozin
Canagliflozin
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
Acarbose
Miglitol
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)
Pramlintide
not on the list
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
Colesevelam
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
Bromocriptine
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
Glucose
- IV
- Dextrose solution (dextrose + water)
- Hypoglycemia not associated with water loss or electrolyte imbalances
Glucagon
- 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
Diazoxide
not on the list
- 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
Octreotide
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
Streptozocin
not on the list
- Nitrosourea derivative
- Inhibits DNA synthesis
- Malignant pancreatic insulinoma
- Side effects: hepatotoxicity, nephrotoxicity,
hematological abnormalities
