HUF 2-28 Pharmacology of insulin and oral hypoglycaemic drugs Flashcards
Pharmacokinetics of endogenous insulin
- Secreted into portal circulation
- Circulate in blood as monomer
- Plasma t1/2 = 5-6 min
- Hydrolysis of S-S bonds by glutathione insulin transhydrogenase (insulinase)
- Degradation mainly in liver
Pharmacokinetics of exogenous insulin
- Dimers in solution
∵ H-bonding between C-termini of B chains - Readily diffuse into blood
- Presence of Zn2+ ions => Hexamers; diffuse slowly into blood
- Variable duration of action
- Metabolised mainly by kidneys
Treatment of DM
- Relieve immediate signs and symptoms
- Prevent long term complications (micro-/macrovascular)
- Proper glycaemic control
1. Insulin therapy
2. Appropriate diet: low sugar and fat, high fibre
Regular exercise
Reasonable body weight
Oral anti-DM agents / Insulin therapy
Insulin therapy in treatment of DM
- Aim to reproduce normal pancreatic secretion
Basal output
- Nearly constant day long insulin level
- Suppress hepatic glucose production between meals and overnight fasting
Meal time surge
- Immediate rise and sharp peak at 1 h
- Limit postprandial hyperglycaemia
Insulin preparations
- Human insulin by recombinant technique
- 100 Y/ml solution or suspension for sc injection
- Various formulations in peak effect and duration (avoid wide variations in plasma conc.)
Short acting
- Clear neutral solutions of regular, crystalline zinc insulin
Intermediate acting
- Isophane insulin: suspension of insulin with protamine
- Lentes insulin: mixture of amorphous and crystalline insulin
Long acting
- Ultralente insulin: suspension of crystalline insulin
Insulin Analogs
Ultrashort acting
- Insulin Lispro, Aspart, Glulisine
- No dimerisation following sc injection
- sc injection before meal (prandial regulation)
- Therapeutic advantages:
(1) ↓ prevalence of hypoglycaemia
(2) ↑ glucose control
Long acting
(a) Insuline Glargine
- Soluble only at pH 4 (clear solution); insoluble at body pH (precipitate after sc injection)
- Stable hexamers dissociate slowly
(b) Insulin Detemir
- Quickly absorbed after sc injection
- Binds to plasma albumin => slowly dissociates from complex
- Sustained peakless absorption profile that spans 24h
- Better basal insulin replacement during night and between meals
- Less variability and lower hypoglycaemic incidence
Side effects of insulin treatment
- Insulin edema
- Blurring of vision; edema of feet - Lipohypergrophy
- Benign proliferation of sc adipose tissues at recurrent injection site
- Local lipogenic effect of insulin - Allergy
- Rare; associated with protamine added - Hypoglycaemia
- Overdose, missed meal, excess exercise
- Autonomic symptoms: hunger, palpitation, sweating, Trembling
- Neuroglycopenia: difficult in concentrating, confusion, weakness, drowsiness, blurred vision
- Coma, convulsions, death
- Treated by replenishing glucose (injection of glucagon)
Treatment of DM2
Weight loss: ↓ fasting and postprandial glucose level
↑ physical activities: ↑ insulin sensitivity
Glycaemic control by oral anti-diabetes agents
- Sulphonylurea
- Meglitinide
- Biguanide
- Thiazolidinedione derivatives
- α-glucosidase inhibitor
GLP-1 mimetics
DPP-4 inhibitors
Exogenous insulin
Sulphonylurea
1st gen.: Tolbutamide
2nd gen.: Glibenclamide, Glipizide, Glimepiride
Bind to high affinity SUR1 receptors on K+-ATP channels
=> K+-ATP channels close
=> Depolarisation
=> VGCC opens
=> ↑ basal insulin release (exocytosis by Ca2+ influx)
=> ↓ glucagon conc.
↑ tissue sensitivity to insulin (↓ hepatic glucose output and glucose uptake in ms.)
- Well absorbed orally (30 min prior meal)
- 90% binding to plasma albumin
- Metabolised in liver; excreted in urine
Side effects and DDI of sulphonylureas
Side effects:
- Severe hypoglycaemia: potency and duration of action; least with Tolbutamide (potentiated with renal and hepatic deficiency)
- Stimulate appetite => Weight gain
- GI disturbances; mild rashes
- Bone marrow damage
- Adverse CVS damage (?)
DDI
- Hypoglycaemic effect enhanced by drugs which compete for metabolising enzyme, interfere with plasma albumin or excretion
e. g. NSAID, MAOI, alcohol, antibacterials, antifungals
Meglitinide
Repaglinide and Nateglinide
- Acts like extremely short acting SUR
- Block K-ATP channels in β cells
- Repaglinide binds to distinct site from SUR
- Rapidly and completely absorbed from GI
- Rapid onset with short t1/2 = 1h
- Taken prior meal => replicates physiological insulin profile
- Prandial glucose regulation
- Extensive hepatic metabolism => contraindicated in patients with liver disease
Biguanide
Metformin
- Complex action
- Does not cause insulin release from β cells
- Does not cause hypoglycaemia in normal or diabetic patients
- ↓ Gluconeogenesis: ↓ hepatic glucose production (AMPK)
- ↑ Insulin sensitivity: ↑ GLUT4 (glucose uptake)
- ↓ plasma glucagon level
- Anorexic => ↓ weight in obese
- Delay intestinal glucose absorption
- ↓ Low and very low density lipoproteins => ↓ atheroma
PK profile and side effects of Metformin
- Orally active, plasma t1/2 = 3h
- Taken with or after food
- Excreted unmetabolised in urine
Side effects:
- Transient GI disturbance
- Potentially fatal lactic acidosis
- Accumulation of lactate in patients with renal diseases (↓ drug elimination) or cardiac diseases (↑ anaerobic metabolism)
- Contraindication: liver diseases, alcoholism, iodinated contrast materials (X-ray)
Thiazolidinedione (Glitazone)
Pioglitazone and Rosiglitazone
- Peroxisome proliferator-activated receptor-gamma (PPARγ) in nucleus
=> Transcription of insulin responsive genes (glucose and liver metabolism)
- Max effects after 1-2 months
- ↑ Insulin actions
- ↑ Glucose utilisation in peripheral tissues and suppress gluconeogenesis in liver
PK profile and side effects of Thiazolidinedione
PK profile
- Rapid and almost complete oral absorption
- Peak plasma level w/i 2h
- Highly protein bound (99%)
- Short plasma t1/2 = 7h
- Metabolised to active metabolites in liver with long plasma t1/2
- Rosiglitazone metabolites: urine; Pioglitazone: bile
- Once or twice daily => ↑ fasting and postprandial hyperglycaemia
Side effects
- Triglycerides may ↓
- Slight ↑ in cholesteral (LDL/HDL unaltered)
- Fluid retention
- Weight gain
- ↑ ECF fluid and plasma volume
- ↓ [Hb] - Contraindication: liver disease
- Pioglitazone and bladder cancer
