drugs and diabetes

• Classical pathways including the endocrine control of the thyroid and adrenal cortex involve the hypothalamic/pituitary axis. However, at least 2 other major endocrine pathways  in the body are less dependent of pituitary control, including the renin-angiotensin system and the pancreas in the treatment of diabetes

  
• Drugs and Diabetes - Insulins

  •Originally beef and pork sources –

  •Prescribed in UNITS based on hypoglycaemic activity in rabbits (25 units /mg)
• Drugs and Diabetes - Insulins

  •First protein sequenced - 2 peptide chains (21/30aa) joined by disulphide bridges both derived from a single sequence - proinsulin.

  
• Drugs and Diabetes - Insulins

  •Recombinant human protein (rh Insulin) - administered parenterally (commonly subcutaneously) – 100units/ml in insulin syringes.

  •Allergy (rare) - reduced immunogenicity of recombinant human protein  not proven.

  •Resistance (rare) to rh insulin due to antibody formation
• Proinsulin is synthesised as a single amino acid chain which is then cleaved at two major sites to produce insulin, which has two amino acid chains (the alpha and beta chains) joined by cysteine bridges and an inactive central C-peptide.

  
• The use of a recombinant human protein (insulin) was hoped to improve two problems posed by the use of animal sourced products, the incidence of allergic responses to foreign protein and the development of resistance due to antibody formation
• Insulin : Mechanism of Action

  1. Insulin binds to specific high affinity membrane receptors with tyrosine kinase activity
  2. Phosphorylation cascade results in translocation of GLUT-4 (and some Glut-1) transport proteins into the plasma membrane.
  3. It induces the transcription of several genes resulting in increased glucose catabolism & inhibits the transcription of genes involved in gluconeogenesis
  4. Insulin promotes the uptake of K+ into

  
• Insulin : Mechanism of Action

  Insulin binds to a homodimeric cell membrane receptor. Acutely insulin increases the cellular uptake of glucose by increasing the number of glucose transporters (including Glut-2 & Glut-4) trafficked to the cell membrane. Its transcriptional effects include enhancing glucose breakdown (glycolysis), inhibiting glucose synthesis (gluconeogenesis) but enhancing glucose storage as glycogen
• Soluble Insulin

  s/c inject 15-30 minutes before meals

  •Onset action : 30-60min

  •Peak action : 2-4 hours

  •Duration : upto 8 hours

  Insulin Issues

  •Lipodystrophy  - vary s/c site

  •Reduce dose - hepatic/renal impairment

  •Increase dose - pregnancy

  •Hypoglycaemia – avoid.

  Tight control of blood sugar may reduce the warning signs of hypoglycaemic episodes (driving etc)

  
• Soluble insulin doesn’t have an immediate effect and is no longer the shortest acting insulin available. The reason is that in its injected form, the insulin molecule is bound in the form of a hexamer (6 molecules of insulin bound together) and it takes time for dissociation of the hexamer into single insulin molecules, before it can exert its therapeutic effect.

  
• Rapidly Acting Insulins - Insulin aspart

  Avoids insulin dimer/hexamer formation

  Faster onset, shorter duration of action  - Inject directly before a meal

  Multiple daily injection with meals  - Longer acting insulin used at night
• Rapidly Acting Insulins

  Insulin lispro was produced simply by swopping  the lysine and proline residues  in the beta chain around at B28/29.
• Rapidly Acting Insulins

  Insulin aspart, which is currently the rapidly acting insulin in widest use, was produced by replacing the proline residue at B28 with aspartate
• Rapidly Acting Insulins

  insulin glulisine was produced by introducing glutamic acid for lysine at B29 and lysine for asparagine at B3
• Rapidly Acting Insulins

  Each of these changes prevents insulin hexamer formation allowing s/c injection directly before a meal with reduced chance of hypoglycaemia. However, the use of rapidly acting insulins at meal times, requires the use of longer acting insulin to provide basal insulin cover for example at night.
• Intermediate Insulins

  Precipitation with protamine or zinc to give finely divided amorphous solid or relatively insoluble crystals. Insulin slowly absorbed from a subcutaneous  suspension
• Intermediate Insulins

  Isophane Insulin 

  suspension with protamine

  (twice daily)

  Insulin Zinc Suspension 

  30% amorphous, 70% crystalline

  (once daily)

  Biphasic Insulin

  short acting/soluble plus isophane

  (mixed well in the syringe)
• the intermediate insulins were developed by 2 different methods, either in crystalline form, called insulin zinc suspension, or bound to protamine, termed isophane insulin, a form tended to be used in pregnancy. Biphasic forms of soluble and isophane insulin are also available.
• Long Acting Insulins

  Protein Binding  -  Insulin Detemir

  Substitution  lysine (B29) with myristic acid (fatty acid) binds to albumin.

  Half-life 5-8h

  
• Long Acting Insulins

  Microcrystals - Insulin Glargine

  Asparagine (A21) substitution with glycine plus 2 arginines (B30). Aggregates form at neutral pH in extracellular space following s/c injection. Soluble at acidic pH. Duration 18-24h

  Advantage : lower risk of nocturnal hypoglycaemia

  
• Insulin detemir is produced by the incorporation of myristic acid into the beta chain at B29 which allows insulin to bind to albumin, prolonging its circulating half-life
• Insulin glargine (Lantus, Sanofi-Aventis) incorporates 2 arginines at B30, altering the isoelectric point of the peptide, producing a soluble injection at acidic pH. The introduction of glycine at A21 protects the insulin from degradation in acidic solution. However, when injected subcutaneously into the neutral pH of the interstitial space, complex insulin hexamers are formed with only slowly dissociation into monomeric forms which then diffuse into the circulation
• • Long-acting insulins provide night-time cover, reducing the risk of nocturnal hypoglycaemia.
• Insulins Duration of Action

  
• Insulin Degludec(ultra-long acting)

  The newest long-acting insulin is insulin degludec. It contains a fatty acid substituent on the end of the B-chain which form di-hexamers. When injected, it firstly generates multi-hexamers in the interstitial space which degrade into dimers and finally into monomers which diffuse into the circulation. It is described as an ultra long-acting insulin.

  
• Diabetic Ketoacidosis - (insulin underdosing)

  1. The liver produces more glucose to feed the body, but without insulin, the glucose accumulates in the bloodstream.
  2. The body needs to find an alternative source of energy and starts breaking down fat. The breakdown of fat produces ketones, which then build up in the bloodstream.
  3. Ketones and glucose are transferred into the urine. The kidneys use water to clear the blood from excess glucose and ketones.

  
• Diabetic Ketoacidosis - (insulin underdosing)

  While the body attempts to get rid of the ketones and glucose, a lot of water is lost. This can lead to dehydration and may worsen the ketoacidosis.
• Diabetic Ketoacidosis - (insulin underdosing)

  Without insulin, glucose is unable to be processed by the body.
• Diabetic Ketoacidosis - (insulin underdosing)

  A) Feeling tired and sleepy

  B) Confusion, passing out

  C) Stomach pain, feeling or being sick

  D) Needing to pee more often, high ketones

  E) High blood sugar levels

  F) Being very thirsty,

  G) sweet smelling breath (like nail varnish or pear drop

  H) blurred vision

  
• Insulin underdosing - Without enough insulin, glucose is not metabolised to provide enough energy.
• insulin underdosing -

  The liver then produces more glucose which, without enough insulin, stays in the blood potentiating hyperglycaemia. This has two consequences firstly, the liver breaks down fat to provide energy producing ketones such as acetone which gives the breath a fruity smell. Secondly, the kidney excretes ketones and glucose causing an osmotic diuresis and dehydration.
• insulin underdosing -

  In severe cases in children, this can lead to cerebral oedema which can be fatal. Treatment is a short acting insulin IV, together with IV saline. Potassium supplements maybe required since insulin stimulates potassium uptake into muscle. Bicarbonate administration is not recommended since the rapid reversal of acidosis may promote hypokalemia, impair cardiac function and reduce tissue oxygenation. 
• Hypoglycaemia (insulin overdosing)

  A) shaking

  B) sweating

  C) confusion

  D) faster heart rate

  E) extreme hunger

  F) dizziness

  
• Hypoglycemia unaware

  • older patients
  • patients with frequent hypoglycemic episodes
  • patients with diabetic autonomic neuropathy

  
• Insulin Overdosing Hypoglycaemia (below 3.5 mmol/L) stimulates the release of glucagon, while a reduction in glucose delivery to the brain enhances sympathetic outflow resulting in elevated heart rate, muscle trembling and sweating.  A further decrease in  blood sugar causes confusion, irritability, leading to dizziness and loss of consciousness.
• Hypoglycaemia can be fatal producing cardiac arrhythmias, seizures and coma.  Self-awareness of the autonomic symptoms allows a diabetic patient to take on sugar through a fruit drink, biscuit or chocolate.  However, in older patients including those with diabetic autonomic neuropathy, autonomic symptoms may not develop until after the onset of CNS problems. These patients are said to be  hypoglycaemic unaware.
• Hypoglycaemia - (insulin overdosing)

  B-Blockers may induce a pharmacological form of ‘unawareness’ by blocking the sympathetic response although, the sweating element will remain unaffected since sympathetic nerves to sweat glands use acetylcholine not noradrenaline as the post-ganglionic transmitter.
• Glucagon & Hypoglycaemia

  Hypoglycaemia, a low blood sugar, in the conscious patient maybe treated using glucose administered orally in the form of a biscuit or chocolate.

  
• Glucagon & Hypoglycaemia

  In the unconscious patient, an intravenous glucose infusion maybe required.

  
• Glucagon & Hypoglycaemia

  Hypoglycaemia may also be treated using recombinant human glucagon to mimic its normal release from the alpha cells in the Islets to stimulate glycogen breakdown by the liver and is also useful for the unconscious patient.