Q1

Outline the groups of drugs that are used to treat hyperglycaemia in diabetes mellitus?

  • Insulin
  • Sulfonylureas
  • Biguanides
  • Meglitinides
  • D- phenylalanine derivatives
  • Thiazolidinediones
  • Alpha-glucosidase inhibitors


Pass Criteria:

  • Must get 3 bolded groups to pass

Contrast the mechanism of action of sulfonylureas and biguanides?

Sulfonylurea:

  • Increase insulin release from pancreas
  • Reduction of serum glucagon levels
  • Closure of potassium channels in extrapancreatic tissues

Biguanide:

  • Action does not depend on functioning pancreatic B cells
  • May directly stimulate glycolysis in tissues with increased glucose removal from blood;
  • May reduce hepatic gluconeogenesis;
  • May slow of absorption of glucose from the GI tract;
  • May reduce glucagon levels


Pass Criteria:

  • Bold to pass

Q2

What are the mechanisms of action of the Sulfonylureas?

Prompt: How do sulphonylureas lower glucose? Describe another mechanism?

 

  • Increased secretion of insulin
  • Bind to pancreatic B cell receptor causing increased release of Insulin
  • Reduced serum glucagon levels – with chronic use thought to be due to indirect inhib effects of insulin and somatostatin on a cells
  • Potentiation of insulin action on target tissues – increased binding of insulin to tissue receptors ?due to indirect effect of reduced glycemia or FFA levels

Pass Criteria:

  • Bind to B cell; 1 of other 2

What are the adverse effects of sulfonylurea therapy?

  • Prolonged hypoglycemia;
  • Alcohol intolerance – flushing;
  • Dilutional hyponatremia (genetic predisposition)
  • Jaundice,  Leucopenia, thrombocytopenia (Chlorpropamide)


Pass Criteria:

  • Hypoglycemia

Q3

What are the mechanisms of action of the Sulfonylureas?
Prompt: How do sulphonylureas lower glucose? Describe another mechanism?

  • Increased secretion of insulin
  • Bind to pancreatic B cell receptor causing increased release of Insulin
  • Reduced serum glucagon levels – with chronic use thought to be due to indirect inhib effects of insulin and somatostatin on a cells
  • Potentiation of insulin action on target tissues – increased binding of insulin to tissue receptors ?due to indirect effect of reduced glycemia or FFA levels

Pass Criteria:

  • Bind to B cell; 1 of other 2

What are the adverse effects of sulfonylurea therapy?

  • Prolonged hypoglycemia;
  • Alcohol intolerance – flushing;
  • Dilutional hyponatremia (genetic predisposition)
  • Jaundice,  Leucopenia, thrombocytopenia (Chlorpropamide)

Pass Criteria:

  • Hypoglycemia

Q4

How does carbimazole act in thyroid disease?

  • Metabolised to methimazole:
  • Major action block hormone synthesis T3 and T4
  • Inhibits thyroid peroxidase – limits organification of iodine.   Also blocks coupling of iodotyrosines
  • Small action in blocking peripheral deiodination of T3 and T4.  Slow onset as T4 may takes weeks to become depleted

 

Pass Criteria:

  • Bold to pass

What are the major side effects of carbimazole?

  • Rash maculopapular, pruritus – common;
  • Bone marrow suppression: neutropenia, agranulocytosis (reversible).
  • Others – urticaria, arthralgia, lupus reaction, vasculitis, jaundice/hepatitis; nausea and GI, occur early


Pass Criteria:

  • 1 side effect

How does carbimazole differ from propylthiouracil?

  • Carbimazole is a prodrug – converted to methimazole in vivo.  Methimazole is 10 times more potent
  • PLUS
    • PTU has greater action in inhibiting peripheral deiodination of T4 and T3
    • Propylthiouracil is strongly protein bound: preferred in pregnancy; not secreted in breast milk
    • PTU has shorter half life 1.5 vs 6 hours.  PTU given qid, Carbimazole is daily
    • PTU bioavail 50-80%, vs Carb 100%  Vd = TBW)
    • PTU excreted in urine as glucuronide metabolite <24 hours, carb in 48+ hours)


Pass Criteria:

  • Bold PLUS one of the other statements for BONUS point

Q5

What is erythropoietin?

  • Glycoprotein produced by kidney

What are its clinical applications?

  • Stimulates red cell precursors to proliferate and differentiate. Also releases reticulocytes from marrow
  • Main use is for the anaemia of chronic renal failure, where erythropoietin production in impaired
  • Helps some marrow failure states (aplastic anaemia, myeloproliferative/myelodysplastic disorders, multiple myeloma, AIDS and cancer)


Pass Criteria:

  • 1 of 3

What toxic effects may occur?

  • Toxicity mainly related to rapid Hb rise
    • Hypertension
    • Thrombosis
  • NOTE: Allergic reactions are infrequent and mild


Pass:
1 of 2


Q6

Regarding glucagon outline its pharmacodynamic effects and relate these to its clinical use?

  • Glycogenolysis and gluconeogenesis thus increasing serum glucose –treatment of hypoglycaemia
  • Positive ionotropic and chronotropic effect on the heart via glucagon receptors and cAMP – treatment of B Blocker OD.
  • Relaxation of intestinal smooth muscle –treatment of food bolus obstruction or to aid radiology of the bowel

Pass criteria:

  • Must get hypoglycaemia AND one other

Regarding sulphonylureas and bigaunides, compare their mechanisms of action.

  • Sulphonylureas increase insulin release.
    • Act via a specific receptor which causes an increase in intracellular Ca, which triggers insulin release.
    • There are also receptors in cells on binding proteins in secretory granules, which may cause a direct action on exocytosis of insulin.
    • Other peripheral effects may be to reduce serum glucagon and potentiate insulin effects on cells.
  • Biguanides are ‘euglycaemic agents”.
    • They do not require functional islet cells to reduce blood sugar.
    • Their possible actions are
      • to directly stimulate glycolysis in tissues and blood;
      • reduce hepatic gluconeogenesis;
      • reduce GIT absorption;
      • reduce plasma glucagon

How do the major side effects of the two groups of drugs differ?

  • Biguanides can cause lactic acidosis. They reduce gluconeogenesis and reduce lactic acid uptake in the liver. More likely in patients with renal disease, alcoholism, liver disease and chronic tissue hypoxia.
  • Sulphonylureas more commonly cause hypoglycaemia.
  • More likely in the elderly and with drugs with long t ½ e.g. chlorpropamide

Q7

Regarding hydrocortisone, what are its pharmacodynamics?

  • Anti-inflammatory
  • Immunosuppressive
  • Catabolic effects
  • Permissive effects
  • Metabolic effects
  • Other: endo, psych

Describe the anti-inflammatory and immunosuppressant effects of hydrocortisone.

  • Altered leucocyte concentration, distribution and function
  • Inhibit macrophages and antigen presenting cells
  • Reduce interleukins and other mediators
  • Phospholipase A2 and COX 2
  • Decrease histamine release by mast cells, etc
  • Reduce Ab production

What are the effects of chronic steroid use?

  • Cushings

Q8

What are the different types of oral hypoglycemic agents?

  1. Insulin secretagogues (sulfonylureas, meglitinides)
  2. Biguanides
  3. Thiazolidinediones – enhance target tissue insulin sensitivity
  4. Alpha-glucosidase inhibitors – competitive inhibitors of intestinal alpha glucosidases – defers digestion to distal small intestine

What is the mechanism of action of the sulfonylureas?

  • Increase insulin release from pancreas
  • Reduce serum glucagons levels
  • Extrapancreatic effect to potentiate action of insulin on target cells

How do the biguanides differ from the sulfonylurease in their action?

  • Not need functioning pancreatic B cells
    • Direct simulation of glycolysis in tissue
    • Reduce hepatic gluconeogensis
    • Slowing glc.absorption from GI tract
    • Reduction of plasma glucagons levels

What are the clinical advantages of the different oral antidiabetic agents?

  1. Biguanides = Refractory obesity where insulin resistance
  2. Combination with sulfonylureas in Type II Diabetes
  3. Newer sulfonylureas are liver metabolized so can be used in renal failure

Q9

Describe the action of insulin on the liver.

Anabolic, anti catabolic

What are the complications of insulin therapy?

2 of immune,hypoglycaemia, lipodystrophy, immune resistance


Q10

Describe the different types of insulin used in the routine management of Type I Diabetes.
Prompt: Please describe in terms of duration of action.

Rapid and short acting

Clear soln, neutral pH, contain Zn rapid onset, short duration

e.g. insulin neutral, insulin lispro, insulin glulusine


Intermediate acting

Turbid soln, neutral pH, protamine in phosphate buffer

(NPH) to prolong action

e.g. insulin isophane, insulin aspart protamine

 

Long acting

Clear solution, soluble

Slow onset, prolonged action

Daily admin mimics basal insulin secretion e.g. insulin glargine, insuline detemir

Pass criteria: Identify existence of rapid, intermediate and long-acting insulin

Aware that combination of therapies required to cover both basal requirements and post-prandial periods

How are these properties used to achieve optimum glycaemic control?

Tight glycaemic control is achieved by a combination of insulins with different durations of action with an aim of replacing the basal insulin requirements (50%) and meal requirements (50%). This is done with combinations of insulins with different duration of actions.

What type of insulin is used for intravenous infusion and why?

Short-acting regular soluble insulin as it immediately dissociates on dilution and so is able to more precisely delivered.

Optional: Describe the principles of operation of a subcutaneous insulin infusion device.
Prompt: Insulin pump.

External open-loop pump for insulin delivery. Delivers individualised basal and bolus insulin replacement doses based on blood glucose monitoring. Programmed by user.

Consists of insulin reservoir, program chip, keypad and display screen attached to subcutaneously inserted infusion set.

 


Q11

What class of drug is glicazide?

  • Sulphonylurea

Pass Criteria:

  • Bold to pass

Describe the mechanism of action of sulphonylureas.

  • Stimulates insulin secretion from functional pancreatic beta cells
    • Binding of sulphonylurea to receptor inhibits potassium efflux causing extracellular depolarisation
    • Results in opening of voltage gated calcium channels
    • Calcium influx causes release of preformed insulin

Pass Criteria:

  • Bold to pass

What are the pharmacokinetic properties of gliclazide?

  • Administered orally – good oral bioavailability (80%)
  • Protein bound – volume of distribution ~20L
  • Hepatic metabolism to inactive metabolites
  • Half life approx 12 hours
  • Predominantly renally excreted (80%)

Pass Criteria:

  • Bold to pass

What are the potential adverse effects of gliclazide?

  • Hypoglycaemia
  • GI upset – nausea, vomiting, abdominal pain, diarrhoea
  • Rash/pruritus

Pass Criteria:

  • Hypoglycaemia + one

 

 


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