Section 25 Pharmacology

Insulin and Hypoglycaemics

Function of insulin
 Binding of insulin to insulin receptor → Network of phosphorylations within the cell → Translocation of GLUT-4 receptors
to cell membrane → Uptake of glucose
 Endocrine effects of insulin:
o Effects on liver:
 Reversal of catabolic features of insulin deficiency (Anti-catabolic) → Inhibition of glycogenolysis,
inhibition of lipolysis, inhibition of gluconeogenesis
 Anabolic action → Induces glucokinase and glycogen synthase (inhibits phosphorylase) → Glycogen
synthesis
o Effects on muscle
 Increased protein synthesis → Increased amino acid transport, increased ribosomal protein synthesis
 Increased glycogen synthesis → Increased glucose transport, induces glycogen synthase, inhibits
phosphorylase
o Effects on adipose tissue:
 Increased triglyceride storage → Induces and activates lipoprotein lipase, inhibits intracellular lipase

Insulin
An important drug
 A polypeptide hormone
 Mechanism of action:
o Binds to specific membrane-bound receptor
 Muscle & adipose tissue: GLUT-4 transporters that are sequestered in cell move to surface → Uptake of
glucose → Receptors internalised after cessation of insulin activity
 Liver: Uptake of glucose by induction of glucokinase
o Effects of insulin are divided into:
1. Rapid (seconds)
 Increased transport of glucose, amino acids, and K+ into insulin sensitive cells
2. Intermediate (minutes)
 Stimulation of protein synthesis / inhibition of protein degradation
 Activation of glycolytic enzymes and glycogen synthase / inhibition of phosphorylase and
gluconeogenic enzymes
3. Delayed (hours)
 Increase in mRNAs for lipogenic and other enzymes
 Pharmacokinetics
o Absorption: Inactive when administered orally
o Distribution: Little protein-binding
o Metabolism: Rapidly metabolised in liver, muscle, kidney (by glutathione insulin transhydrogenase)
o Excretion: Metabolites in urine
 Pharmacodynamics
o Metabolic → see above
 Toxicity/side effects → hypoglycaemia.
 Interactions → steroids, thyroxine, thiazide diuretics, sympathomimetics → counteract effects of insulin on carbohydrate
metabolism.
 Preparations
o Four principal types of insulin available:
1. Rapid-acting with very fast onset and short duration (Examples: Humalog, Novolog)
2. Short-acting, with rapid-onset of action (Examples: Regular Humulin, Regular)
3. Intermediate-acting (Examples: Lente Humulin, Lente)
 Lente = 30% semilente + 70% ultralente;
 NPH (neutral protamine Hagendorn = isophane) → absorption and onset of action is delayed by
combining with protamine
4. Long-acting, with slow onset of action (Examples: Ultralente Humulin U, Insulin glargine)
o Mixtures (Examples: 70%/30% or 50%/50% NPH and regular)
 Delivery system
 o Portable pen injectors
o Continuous SC insulin infusion devices (CSII, ‘insulin pumps’)
 Complications of therapy.
1. Hypoglycaemia
 From delay in taking a meal, inadequate carbohydrate consumed, unusual physical exertion → Treatment
with oral or IV glucose, glucagon
2. Immunopathology
 Insulin allergy: Rare, immediate-type hypersensitivity, anti-insulin IgE → Anaphylaxis may result
 Immune insulin resistance → Low titre of circulating IgG anti-insulin antibodies → Neutralise action of
insulin (develops in most insulin-treated patients, effect normally negligible; rarely leads to insulin
resistance)
3. Lipodystrophy at injection sites
 Occurred with older insulin preparations, almost never seen in newer, neutral pH insulin preparations.

Oral hypoglycaemics
 Four groups of oral antidiabetic agents are now available:
1. Insulin secretagogues
a. Sulfonylureas (Examples: Tolbutamide, glipizide)
b. Meglitinides (Example: Repaglinide)
c. D-phenylalanine derivatives (Example: Nateglinide)
2. Biguanides (Example: Metformin)
3. Thiazolidinediones (Examples: Pioglitazone, rosiglitazone)
 Act to decrease insulin resistance
2. α-glucosidase inhibitors (Examples: Acarbose, miglitol)
 Delay digestion and absorption of starch and disaccharides
Sulphonylureas
 Mechanism of action:
o Increase insulin release from the pancreas (also reduce serum glucagon concentrations and close K+ channels in
extrapancreatic tissues).
o Bind to a sulfonylurea-receptor that is associated with a β-islet cell inward rectifier ATP-sensitive K+ channel →
Inhibition of K+ efflux → Depolarisation → Opening of voltage-gated Ca2+ channels → Ca2+ influx → Release of
preformed insulin.
 First-generation sulfonylureas
o Tolbutamide, chlorpropamide, tolazamide
o Tolbutamide is well-absorbed, but rapidly metabolised in the liver (half-life 4-5h); duration of effect relatively short,
best administered in divided doses.
 Second-generation sulfonylureas
o Glipizide, glimepiride
o Glipizide has the shortest half-life (2-4h) → Least risk of serious hypoglycaemia.
o Hepatic metabolism, can use in renal impairment
 Adverse effects:
o Hypoglycaemia
o Flushing (with alcohol)
o Dilutional hyponatraemia

Metformin
 A biguanide euglycaemic agent
 Mechanism of action (there is no full explanation)
o Activation of AMP-activated protein kinase (AMPK) → ↓ Hepatic glucose production
o Its blood-glucose lowering effect does not depend on the presence of functioning pancreatic B cells.
 Metformin has a half-life of 1.5-3 h, is not bound to plasma proteins, is not metabolised, and is excreted by the kidneys as the
active compound.
o Metformin blocks gluconeogenesis → May impair hepatic metabolism of lactic acid → ↑ Risk of lactic acidosis.
 Toxicities
o Rarely causes hypoglycaemia
o Gastrointestinal: Anorexia, nausea, vomiting, abdominal discomfort; sometimes has to be discontinued because of
persistent diarrhoea
o Absorption of vit. B12 appears to be reduced → Annual screening is recommended
 o Contraindicated in conditions that carry an increased risk of lactic acid formation
 Renal disease, alcoholism, hepatic disease, conditions predisposing to tissue anoxia (Example: Chronic
cardiopulmonary dysfunction)
 Clinical applications
o Useful in insulin resistance (e.g. refractory obesity) where sulphonamides are less effective

Glucagon
 An endogenous hormone produced by α-cells of pancreatic islets
 Mechanism of action
1. Metabolic effects
 Binds to receptors on liver → Gs protein-linked increase in adenylyl cyclase activity → Production of cAMP
 Facilitates catabolism of stored glycogen
 Increases gluconeogenesis and ketogenesis
 Immediate effect is to raise blood glucose at the expense of stored hepatic glycogen.
 Stimulates release of insulin from normal pancreatic β-cells.
2. Cardiac effects (do not forget these!)
 Potent inotropic and chronotropic effect on the heart (mediated by the cAMP mechanism above, does not
require functioning β-adrenoreceptors)
3. Effects on smooth muscle
 In high doses: produces profound relaxation of the intestine.
 Clinical applications:
o Severe hypoglycaemia → Emergency treatment when unconsciousness precludes oral feeding and IV glucose use is
not possible
o Endocrine diagnosis → Glucagon is administered, which may elicit a pancreatic β-cell response → C-peptide is
measured
o Beta-blocker poisoning → Sometimes useful for reversing the cardiac features, a physiologic antagonist
o Radiology of the bowel → Aids visualisation on X-rays because it relaxes the intestine
o Food bolus obstruction → Intestinal relaxation