2 Insulin & Oral Hypoglycemic Drugs Flashcards
Insulin
Preproinsulin
- synthesized in ER
Proinsulin
- proteolytic cleavage product of preproinsulin in the Golgi body
- single chain 86 a.a. polypeptide
Insulin
- conversion of proinsulin by 2 distinct endopeptidases
- 2 chains (A chain 21 a.a. and B chain 30 a.a.)
- stored in granules
Pharmacokinetics of Insulin:
Endogenous insulin
- secreted into portal circulation, as monomer
- t-1/2 of 5-6 min
- hydrolysis of disulphide bonds btwn A & B chains by glutathione insulin transhydrogenase (insulinase)
Exogenous insulin
- dimers in solution due to hydrogen-bonding btwn C-end of B chain & like monomers readily diffuse into blood
- in presence of zinc ions, insulin dimers associate into hexamers & diffuse slowly into blood
Mechanism & Effects:
- short acting
- clear neutral solution, crystalline zinc insulin
Clinical Use:
- s.c.
- metabolised by kidneys (exogenous; c.f. endogenous insulin degraded in liver)
Treatment of Diabetes
- relieve immediate signs & symptoms
- prevent development of long term complications
- proper glycaemic control
Type 1
- insulin therapy
Type 2
- appropriate diet: low sugar, low fat, high fibre
- regular exercise
- maintenance of a reasonable body weight
- oral anti-diabetic agents / insulin therapy
Insulin Therapy: - aim to reproduce normal pancreatic secretion - basal output nearly constant day long insulin level suppress hepatic glucose production btwn meals and overnight fasting - meal time surge immediate rise and sharp peak at 1 hour limit postprandial hyperglycaemia
Insulin Preparations:
- human insulin by recombinant technique
- 100 U/ml solution or suspension for s.c. injection
- various formulations varying in peak effect & duration
avoid wide variations in plasma concentration
Isophane (neutral protamine Hagedorn -NPH) Lentes Insulin (insulin Zinc suspensions)
Ultralente
Intermediate & Long Acting human insulin
Mechanism & Effects:
- intermediate acting
- suspension of insulin w/ protamine (Isophane)
- mixture of amorphous & crystalline insulin (Lentes)
Mechanism & Effects:
- long acting
- suspension of crystalline insulin (Ultralente)
- extended insulin zinc suspension
Lispro
Aspart
Glulisine*
Ultrashort Acting insulin analogues
Mechanism & Effects:
- ultrashort acting
- switching of B28 proline & B29 lysine in B chain (Lispro)
- replace B28 proline w/ aspartic acid (Aspart)
- asparagine for lysine at B3 & glutamic acid for lysine at B29 (Glulisine)
Clinical Use:
* no dimerization following s.c. injection
- ideal for s.c. before meal (Prandial Regulation)
- therapeutic advantage over regular insulin
reduce prevalence of hypoglycaemia
improved glucose control
Glargine
Detemir*
Long Acting insulin analogues
Glargine Mechanism & Effects:
- 2 arginine to C-terminus of B chain + replace A21 asparagine w/ glycine
- acidic insulin analogue soluble only at pH 4 (clear solution)
- insoluble in body pH, hence precipitate after s.c. injection
- stable hexamer dissociate slowly
Detemir Mechanism & Effects:
- fatty acid (myristic acid) bound to lysine at B29
- quickly absorbed after s.c. injection
- bind w/ plasma albumin through fatty acid
- slowly dissociate from this complex
Clinical Use:
- sustained peakless absorption profile spanning 24h
- better basal insulin replacement during night or btwn meals
- less variability & lower hypoglycemic incidence
Insulin Side Effects
insulin edema
- initial transient blurring of vision & edema of feet
lipohypertrophy
- benign proliferation of s.c. adipose tissue at recurrent injection site
- local lipogenic effect of insulin
allergy
- rare, associated w/ protamine added
hypoglycemia
- overdose, missed meal or excess exercise
- autonomic symptoms; hunger, palpitation, sweating, trembling, tingling around mouth
- neuroglycopenia; difficult concentrating, confusion, weakness, drowsy, blurred vision
- coma, convulsion, death
- may need replenish glucose or glucagon injection (severe)
extract from bovine or porcine pancreas
Treatment of Type 2 Diabetes
- weight loss: reduce fasting and postprandial glucose level
- increasing physical activities: improves insulin sensitivity
- glycaemic control provided by oral anti-diabetes agents
Sulphonylureas (insulin secretion)
Meglitinides (insulin secretion)
Biguanides (insulin sensitivity)
Thiazolidinedione derivatives (insulin sensitivity)
a-glucosidase inhibitors (dec glucose absorption) - Glucagon-likepeptide-1 (GLP-1) mimetics
- Dipeptidylpeptidase-4 (DPP-4) inhibitor
- Exogenous Insulin
Oral anti-diabetes agents:
Oral hypoglycaemic agents
Tolbutamide (1st gen)
Glipizide* (2nd gen)
Glibenclamide (2nd gen)
Glimepiride* (2nd gen)
Insulin secretion stimulant (Sulphonylureas)
Mechanism & Effects:
- 2nd gen 10 - 100x more potent
- bind to high affinity receptors on K-ATP channel
- closes K-ATP channel
- membrane depolarization
- open Ca2+ channel
- insulin release
- Tolbutamide; safe, least hypoglycaemic, freq admin
- Glibenclamide; non-ionic protein bound, active metabolite
Clinical Use:
- inc basal insulin release
- dec glucagon concentration
- improve tissue sensitivity to insulin (dec hepatic glucose output, inc glucose uptake in mm)
- oral w/ meal (30 min before)
- 90-99% bound to plasma protein, esp albumin
- metabolized by liver, excreted in urine
Side Effect:
- severe hypoglycemia
- least w/ tolbutamide bc potency & duration
- potentiated in patients w/ renal & hepatic deficiency
- stim appetite -> weight gain
- <3% mild GI disturbance
- bone marrow damage (rare)
- ? adverse cardiovascular effect ?
Contraindications:
Drug Interactions
- drugs competing for metabolizing enzyme / interfere protein binding / excretion
- enhance hypoglycemic effect
- e.g. NSAIDS, MAOI, alcohol or antibotics
Meglitinides:
Repaglinide
Nateglinide
Oral Hypoglycaemic agents
Insulin secretion stimulant
Mechanism & Effects:
- act like short acting sulphonylurea
- block K-ATP channels in B cells
- Repaglinide binds to istinct site from sulphonylureas
Clinical Use:
- rapidly & completely absorbed from GI tract
- rapid onset, short t-1/2
- replicate physiological insulin profile when taken prior meal
- Prandial Glucose Regulation
- extensive hepatic metabolism
Contraindications:
- liver disease
Biguanides:
Metformin* (1st line)
Oral Anti-Hyperglycaemic agents
Insulin sensitizer
Mechanism & Effects:
- complex action, ? mech
- does not cause insulin release from B cells
- does not cause hypoglycemia in normal or diabetic patients
Clinical Use:
- dec gluconeogenesis: dec hepatic glucose production; activate AMPK
- inc insulin sensitivity: muscular glucose uptake & utilization
- dec plasma glucagon level
- anorexic -> reduce weight in obese
- slightly delay intestinal glucose absorption
- dec LDL & VLDL -> dec atheroma
- oral w/ food
- excreted unmetabolized in urine
Side Effect:
- transient GI disturbance
- potentially fatal lactic acidosis (rare)
- accumulation of lactate in patient w/ renal (reduced drug elimination) & cardiac disease (inc anaerobic metabolism)
Contraindications:
- liver disease
- alcoholism
- iodinated contrast materials before x-ray
Thiazolidinedione (glitazones):
Pioglitazone
Rosiglitazone
Oral Anti-Hyperglycaemic agents
Mechanism & Effects:
- act on PPARγ in nucleus
- modulate transcription of insulin responsive genes for control of glucose & lipid
- max effects after 1-2 months
- enhance actions of insulin
- promote glucose utilization in peripheral tissues & suppress gluconeogenesis in liver
- triglyceride may dcline
- slight inc in cholesterol (LDL/HDL ratio same)
- fluid retention; weight gain, inc ECF & plasma; reduce [haemoglobin]
Clinical Use:
- rapid & near all absorbed after ingestion; short t-1/2
- > 99% protein bound
- metabolized to active metabolites in liver w/ long t-1/2
- metabolites of Rosiglitazone eliminated in urine
- metabolites of Pioglitazone eliminated in bile
- once or twice daily improves both fasting & Postprandial hyperglycaemia
Contraindication:
- liver disease
- CVS risk w/ Rosilglitazone
- bladder cancer risk w/ Pioglitazone
a-glucosidase inhibitors:
Acarbose
Miglitol
Oral Anti-Hyperglycaemic agents
- reversible, competitive inhibitor of intestinal a-glucosidase
- slows the digestion of polysaccharides to monosaccharides
- delays absorption of the component sugars
- postprandial glycaemic rise is reduced and its peak delayed
- allow sluggish insulin secretion to catch up w/ carbohydrate absorption
Clinical Use:
- not absorbed & act in the intestinal lumen
- no risk of weight gain or hypoglycaemia
Side Effects:
- abdominal bloating & diarrhoea
Glucagon-like peptide (GLP-1) mimetics:
Exenatide (Byetta)
Liraglutide
Incretin Mimetics
Mechanisms & Effects
- biosynthetic form of natural exendin-4, w/ GLP-1 actions (from lizard)
- 53% aa homology w/ human GLP-1, but resistant to DPP-4
- t-1/2 of 2.4h & high affinity to GLP-1 receptor
- s.c. injection before meals
Clinical Use:
- use in combination w/ Metformin, Sulfonylureas or both
- restore first-phase insulin secretion & promote B-cell proliferation & islet neogenesis
- reduce body weight
Side Effects:
- nausea (gradually subsides), vomit & diarrhea
- hypoglycaemia when w/ sulphonylurea
Dipeptidyly peptidase-4 (DDP-4) inhibitors:
Sitagliptin (Januvia)
Vildagliptin
Saxagliptin
Incretin Mimetics
- chemically synthesized orally active DDP4-inhibitor
- prolongs the half-life of GLP-1 and GIP with resultant beneficial effects on glucose regulation
Clinical Use:
- approved by the FDA to improve glycaemic control in patients with T2DM, either as a monotherapy, or in combination with Metformin or a Thiazolidinedione
- oral, maximal effect after 2 to 3 hrs, t1/2 of 12 hrs
- mainly excreted unchanged in urine (79%)
- well tolerated with no increased risk of hypoglycaemia
Side Effects:
- increased incidence of nasopharyngitis, arthralgia and back pain
Sodium-glucose Co-Transporter 2 (SGLT-2)
- by inhibiting SGLT2 -> inc renal glucose excretion & dec plasma glucose
- body weight loss
- does NOT rely on B-cell function or tissue insulin-sensitivity
- no hypoglycaemia & GI discomfort
