M4: Insulin and Anti-Diabetic Agents Flashcards
Indications of Insulin Therapy
- Type I diabetes
- Type II diabetes:
- Inadequate control by oral hypoglycemics
- Stressful conditions: e.g., infection
- During pregnancy → no oral hypoglycemic agents - Gestational diabetes → no oral hypoglycemic agents
Source of Insulin
- Bovine
- Porcine
- Human recombinant:
- Least antigenic
- Standardized to 100 U/ml
Administration:
- Injection: SC, IV, IM
- Alternative methods: e.g., pump
Pharmacodynamics of Insulin
Insulin:
Fast (Rapid):
- Onset = 5-15min
- Peak = 3/4-1h
- Duration = 2-4h
Short:
- Onset = 1/2-1h
- Peak = 2-3h
- Duration = 5-8h
Intermediate:
- Onset = 1-2-1h
- Peak = 4-12h
- Duration = 10-20h
Long:
- Onset = 1-2h
- Peak = minimal
- Duration = 18-24h
Ultra-Long:
- Onset = 1-2h
- Peak = minimal
- Duration = >24h
(6) Insulin Preparations
- Fast-acting: Lispro – Aspart
- Short-acting: Regular (crystalline) insulin
- Intermediate-acting: NPH (Neutral Protamine Hagedorn)
- Long-acting: Detemir – Glargine
- Ultra-long: Degludec
- Mixed types: (combinations)
- Rapid onset + prolonged duration e.g., NPH/regular 70/30
(2) Insulin Regimens
- Conventional Therapy:
- One or two injections per day
- Daily self monitoring of glucose
- Lower risk of hypoglycemia - Intensive Therapy:
- Multiple daily injections
- Daily self monitoring of glucose and dose adjustment
- Reduction in retinopathy, nephropathy, and neuropathy
- Higher risk of hypoglycemia (3-fold more than conventional) - Daily Route of Injection: SC
Daily Insulin Schedule:
1. Injection 1 peaks 7am - 12pm
2. Injection 2 peaks 7pm - 12am
Absorption of Insulin
Highly Variable:
- Interindividual
- Intraindividual
Factors Affecting Absorption:
- Site of injection: abdomen > arm > buttock > thigh
- Blood flow to site of injection
- Depth of injection
- Exercise increases absorption
- Massage of the area increases absorption
Alternatives to Insulin Injection
- Insulin pumps – commonly used
- Insulin pens (insulin containing cartridges) – commonly used
- Transdermal: jet injection, patches
- Inhaled insulin – Afrezza (WHO approved in 2014)
- Oral formulas (designed to resist insulin digestion in the GIT) – under investigation
(5) Commonly Used Insulin Delivery Devices
- Insulin syringe
- Insulin pen
- Jet injector
- Insulin pump
- Inhaled insulin
Complications of Insulin Therapy
- Systemic:
- Hypoglycemia → most dangerous
- Insulin allergy → rare with human insulin
- Insulin resistance - Local:
- Lipoatrophy
- Hypertrophy: change site of injection
(5) Oral Hypoglycemics Agents
- Sulfonyl
- Insulin secretagogues - Meglitinides
- Insulin secretagogues - Biguanides
- Thiazolidinediones (TZDs, glitazones)
- Alpha-glucosidase inhibitors
SULFONYLUREAS
- Mechanism of Action
- Pharmacokinetics
- Drug Interaction
- Preparations
- Duration of Action
- Adverse Effects
MECHANISM OF ACTION:
1. Stimulate insulin secretion by β-cell:
Inhibit K channels on β-cell → causing depolarization → increase calcium entry → increase insulin release
- Insulin secretagogues
- Increase receptor sensitivity → potentiate insulin action at different tissues
- Require functional β-cells to work:
Only useful for type 2 NOT type 1 DM
PHARMACOKINETICS:
- Bind to plasma proteins
- Metabolized in the liver
- Excreted through kidneys
- Exaggerated effects in elderly and renal or liver disease
- Cross the placenta teratogenic effect
Contraindicated During Pregnancy
DRUG INTERACTION:
1. Increase hypoglycemic effects:
- NSAIDs, warfarin, MAO inhibitors, alcohol, some antibacterials (e.g., sulfonamides)
- Microsomal enzyme inhibitors (e.g., cimetidine)
- Decrease hypoglycemic effects:
- Microsomal enzyme inducers (e.g., rifampicin)
- Phenytoin (inhibits insulin release)
- Beta blockers mask symptoms of hypoglycemia
PREPARATIONS:
1. First generation:
Drugs:
- Tolbutamide (D: 6-10h, DF: BID-TID)
- Chlorpropamide (D: 24-72h, DF: OD)
- Second generation:
Drugs:
- Glipizide (D: 6-10h, DF: BID-TID)
- Glibenclamide (D: 12-16h, DF: OD-BID)
- Gliclazide (D: 12-16h, DF: OD-BID) - Third generation:
Drugs:
- Glimepiride (D: 12-24h, DF: OD)
ADVERSE EFFECTS:
- Hypoglycemia (specially chlorpropamide)
- GI disturbances
- Hepatic toxicity
- Allergic skin reactions
BIGUANIDES
- Mechanism of Action
- Indications
- Advantage
- Side Effecyts
- Metformin (Dimethylbiguanide)
MECHANISM OF ACTION:
- Decrease gluconeogenesis in liver
- Increase glucose uptake by skeletal muscles
INDICATIONS:
- First choice for obese patients with type 2
- Can be combined with sulfonylurea or insulin
ADVANTAGE:
- Do not cause hypoglycemia as they do not alter insulin levels
SIDE EFFECTS:
1. Anorexia: dose dependent, can be severe
2. Nausea, diarrhea, metallic taste
3. Lactic acidosis: contraindicated in renal failure
METFORMIN (DIMEHTYLBIGUANIDE):
- only drug APPROVED in this class
2 Tablet Forms:
- Glucophage™
- Glucophage XR™ (extended-release tablets)
MEGLITINIDES
- Mechanism of Action
- Indications
- Adverse Effects
DRUGS = REPAGLINIDINE & NATEGLINIDINE
MECHANISM OF ACTION:
- Short acting insulin secretagogues
- Action is similar to sulfonylureas
- Short acting (t1/2: 1 hour)
INDICATIONS:
- Type 2 DM:
- Can be combined with metformin
ADVERSE EFFECTS:
- Hypoglycemia (rare)
THIAZOLIDINEDIONES (TZDs)
- Mechanism of Actions
- Indications
- Adverse Effects
DRUGS = ROSIGLITAZONE & PIOGLITAZONE
MECHANISM OF ACTION:
- Activate a transcription regulator, PPARγ (peroxisome proliferator-activated receptor gamma) →
- Improve glucose uptake in skeletal muscles
- Decrease hepatic glucose production
- Modulate lipogenesis in adipocytes
- Reverse insulin resistance
INDICATIONS:
- Type 2 DM
- Alone or combined with metformin, sulfonylurea
ADVERSE EFFECTS:
- May cause hepatic injury (monitor liver function)
ALPHA-GLUCOSIDASE INHIBITORS
DRUG = ACARBOSE
- Inhibits α-glucosidases in intestine
- Reduces absorption of carbohydrates
- Not absorbed from intestine
- Control post-prandial glucose levels not adequately controlled by diet and sulfonylureas
- Side effects: GI upset and flatulence
