Endocrinology: Pharmacology - Drugs used in the treatment of diabetes Flashcards
Mechanism of action of insulin, including five downstream effects of receptor binding
Binds extracellular a subunits of insulin receptor, resulting in conformational changes which induces tyrosine kinase activity of intracellular portion of B-subunits (autophosphorylation)
Subsequent phosphorylation cascade of cytoplasmic proteins, starting with insulin receptor substrates (IRS)
Downstream effects include:
1. Translocation of glucose transporters (especially GLUT4) to membrane to increase glucose uptake
2. Increased glycogen synthase activity to increase glycogen formation
3. Increased protein synthesis
4. Decreased lipolysis and increased lipogenesis
5. Activation of transcription factors that increase DNA synthesis and cell growth and division
Describe the three anticatabolic and four anabolic effects of insulin on the liver
Anticatabolic:
- Inhibits glycogenolysis
- Inhibits lipolysis
- Inhibits gluconeogenesis
Anabolic:
- Induces glucokinase
- Induces glycogen synthase
- Inhibits phosphorylase
- Increases triglyceride and VLDL synthesis
Describe the effects of insulin on protein and glycogen synthesis in muscle
Increases protein synthesis by increasing AA transport and ribosomal protein synthesis
Increases glycogen synthesis by increasing glucose transport, inducing glycogen synthase and inhibiting phosphorylase
Describe the effects of insulin on triglyceride storage in adipose tissue
Increases TG storage by:
- Inducing lipoprotein lipase
- Increasing glucose entry, which is then converted to glycerol phosphate
- Inhibiting intracellular lipase
Describe the rapid, intermediate, and delayed effects of insulin
Rapid (within secs):
- Increased glucose, AA and K+ entry into cells
Intermediate (within mins):
- Increased protein synthesis and decreased catabolism
- Activation of glycolytic enzymes and glycogen synthase
- Inhibition of phosphorylase and gluconeogenic enzymes
Delayed (within hours):
- Increased mRNA expression for lipogenic and other enzymes
Describe the pharmacokinetics of insulin
Absorption: inactive when administered orally
Distribution: little protein-binding
Metabolism: rapidly metabolised in liver, muscle and kidney by glutathione insulin transhydrogenase
Excretion: metabolites in urine
What drugs interact with insulin and what are their effects?
Counteract effects on carbohydrate metabolism:
- Steroids
- Thyroid hormones
- Thiazide diuretics
- Sympathomimetics
Inhibit secretion:
- Diazoxide
- Phenytoin
- Colchicine
- VInblastine
Stimulate secretion:
- Sulfonylureas
- Isoprenaline
- ACh
- Meglitinide
- Nateglinide
Three rapidly-acting human insulin analogs
- Lispro (Humalog)
- Aspart (Novolog)
- Glulisine (Apidra)
NPH
Neutral protamine hagedorn
Three long-acting human insulin analogs
- Glargine
- Detemir (levemir)
- Degludec
What pH are the rapidly-acting insulins?
Neutral
Are rapidly acting insulins clear or cloudy?
Clear
Time to peak serum values of rapidly acting insulins
1hr
When should rapidly acting insulins be administered?
15mins before meal
How does receptor binding, half-life and immunogenicity of rapidly-acting insulin analogs compare with human regular insulin?
Identical
Which of the subtypes of insulin preparations has the lowest variability of absorption?
Rapidly acting
Are short-acting insulins clear or cloudy?
Clear
What pH are the short acting insulins?
Neutral
Three examples of short-acting insulins
Novolin
Humulin R
Regular
What is the time to effect of short-acting insulins? Time to peak serum values? Duration of action?
Time to effect: 30mins post subcut injection
Peak serum levels: 2hrs
Duration of action: 5-7hrs (at usual doses)
What is the effect of increased dose of short acting insulin on its duration of action?
Duration of action significantly prolonged with larger doses
What clinical situations are short-acting insulins most useful for?
Management of DKA
Perioperative management of diabetes
What is NPH?
Human insulin formulated in combination with protamine which delays its absorption and onset of action (proteolytic tissue enzymes must first degrade protamine to permit insulin absorption)
Onset and duration of action of NPH. What is the effect of dose on these parameters?
Onset of action: 2-5hrs
Duration of action: 4-12hrs
Smaller doses have earlier, lower peaks and a shorter duration of action (vice versa for larger doses)
How is NPH usually administered?
Typically mixed with regular or rapidly-acting (lispro, aspart, glulisine) insulin
Given 2-4x daily
Onset of action, time to maximum effect, and duration of action for insulin glargine
Onset of action: 1-1.5hrs
Maximum effect: 4-6hrs
Duration of action: 11-24hrs
Why can’t insulin glargine be mixed with other insulins?
Due to its acidic pH
Which insulin uniquely has an acidic pH?
Insulin glargine
How does the immunogenicity of insulin glargine compare with regular human insulin?
Less immunogenicity than regular human insulin
Duration of action of insulin detemir
17hrs
Half-life, and onset and duration of action of insulin degludec
Half-life: 25hrs
Onset of action: 30-90mins
Duration of action: >42hrs
Four insulin delivery systems
- Syringes and needles
- Portable pen injectors
- Continuous subcutaneous insulin infusion devices (CSII; insulin pumps)
- Inhaled insulin
Three complications of insulin therapy
- Hypoglycaemia
- Immunopathology (insulin allergy and immune insulin resistance)
- Lipodystrophy (lipoatrophy and lipohypertrophy)
What is the benefit of intermediate insulin premix preparations?
More rapid onset of activity than NPH/regular 70/30 mix (can be given within 15mins of meal)
Superior glycaemic control after carbohydrate-rich meal
Which insulins cannot be formulated as premix preparations?
Insulin glargine and detemir
Three factors which increase risk of hypoglycaemia with insulin use
- Delay in taking meal
- Inadequate carbohydrate consumption
- Increased physical exertion
What is the mechanism of insulin allergy? What reduces risk of this reaction?
Immediate-type hypersensitivity reaction involving anti-insulin IgE, causing anaphylaxis in severe cases
Sensitivity is often to non-insulin protein contaminants, so incidence is decreased with human and analog insulins
What is the mechanism of immune insulin resistance?
Low titres of circulating anti-insulin IgG occurs to a negligible extent in most patients
In some patients this may cause insulin resistance
May be associated with other autoimmune processes (e.g. SLE)
Describe the two types of lipodystrophy seen with insulin administration
- Atrophy of subcut fatty tissue, more commonly with animal preparations (and with restoration of atrophic areas with injection of newer preparations into the same sites)
- Hypertrophy with repeated injection into same site
Six classes of oral hypoglycaemics with examples
- Agents acting on sulfonylurea receptors (increase insulin secretion): sulfonylureas, meglitinides, D-phenylalanine derivatives (nateglinide)
- Agents acting on liver, muscle, and adipose tissue: biguanides (metformin), thiazolidinediones
- Agents inhibiting intestinal absorption of glucose: a-glucosidase inhibitors
- Agents mimicking or prolonging incretin effect: GLP-1 agonists, dipeptidyl peptidase 4 (DPP-4) inhibitors
- Agents inhibiting renal reabsorption of glucose: SGLT inhibitors
- Agents acting by other mechanisms: pramlintide, bromocriptine, colesevam
What is the mechanism of action of sulfonylureas?
Bind sulfonylurea receptor to inactivate ATP-sensitive K+ channels, decreasing K+ efflux and causing depolarisation of B cell
Results in increased intracellular Ca2+ which triggers release of preformed insulin via exocytosis of granules
Also decreases serum glucagon and closes K+ channels in extrapancreatic tissues
List three first-generation sulfonylureas
Tolbutamide
Chlorpropamide
Tolazamide
Describe the pharmacokinetics of tolbutamide
Absorption: well-absorbed
Metabolism: rapidly metabolised in liver, t1/2 = 4-5hrs, duration of action relatively short (so best administered in divided doses)
Is tolbutamide safe in renal impairment and the elderly?
Yes, due to short half-life and hepatic metabolism
List four second-generation sulfonylureas. Which of these has the shortest half-life and what is the clinical significance of this? Which can be used once-daily?
Glyburide
Glipizide*
Glimepiride**
Gliclazide
- shortest half-life (2-4hrs) and therefore least risk of hypoglycaemia
** can be used once-daily
Describe the metabolism of second-generation sulfonylureas
Hepatic metabolism (safe in renal impairment)
How does the potency of second-generation sulfonylureas compared with tolbutamide?
100-200x more potent (should be used with caution in those with CV disease and the elderly)
Three adverse effects of sulfonylureas
- Hypoglycaemia
- Flushing with alcohol
- Dilutional hyponatraemia
