Clinical Pharmacology and Therapeutics

DRUGS USED TO TREAT DIABETES MELLITUS 287
in prefilled injection devices (‘pens’) which are convenient for
patients. The small dose of soluble insulin controls hyperglycaemia
just after the injection. The main danger is of hypoglycaemia
in the early hours of the morning. When starting a
diabetic on a two dose per day regime, it is therefore helpful to
divide the daily dose into two-thirds to be given before breakfast
and one-third to be given before the evening meal. If the
patient engages in strenuous physical work, the morning dose
of insulin is reduced somewhat to prevent exercise-induced
hypoglycaemia.
Insulin is also required for symptomatic type 2 diabetics
in whom diet and/or oral hypoglycaemic drugs fail.
Unfortunately, insulin makes weight loss considerably more
difficult because it stimulates appetite, but its anabolic effects are
valuable in wasted patients with diabetic amyotrophy. Insulin is
needed in acute diabetic emergencies such as ketoacidosis, during
pregnancy, peri-operatively and in severe intercurrent disease
(infections, myocardial infarction, burns, etc.).
Insulin requirements are increased by up to one-third by
intercurrent infection and patients must be instructed to intensify
home blood glucose monitoring when they have a cold or
other infection (even if they are eating less than usual) and
increase the insulin dose if necessary. The dose will subsequently
need to be reduced when the infection has cleared. Vomiting
often causes patients incorrectly to stop injecting insulin (for
fear of hypoglycaemia) and this may result in ketoacidosis.
Patients for elective surgery should be changed to soluble
insulin preoperatively. During surgery, soluble insulin can be
infused i.v. with glucose to produce a blood glucose concentration
of 6–8 mmol/L. This is continued post-operatively until
oral feeding and intermittent subcutaneous injections
Key points
Type 1 diabetes mellitus and insulin
• Type 1 (insulin-dependent) diabetes mellitus is caused
by degeneration of β-cells in the islets of Langerhans
leading to an absolute deficiency of insulin.
• Without insulin treatment, such patients are prone to
diabetic ketoacidosis (DKA).
• Even with insulin treatment, such patients are
susceptible to microvascular complications of
retinopathy, nephropathy and neuropathy, and also to
accelerated atherosclerotic (macrovascular) disease
leading to myocardial infarction, stroke and gangrene.
• Management includes a healthy diet low in saturated
fat (Chapter 27), high in complex carbohydrates and
with the energy spread throughout the day.
• Regular subcutaneous injections of recombinant human
insulin are required indefinitely. Mixtures of soluble
and longer-acting insulins are used and are given using
special insulin ‘pens’ at least twice daily. Regular selfmonitoring
of blood glucose levels throughout the day
with individual adjustment of the insulin dose is
essential to achieve good metabolic control, which
reduces the risk of complications.
• DKA is treated with large volumes of intravenous
physiological saline, intravenous soluble insulin and
replacement of potassium and, if necessary, magnesium.
of insulin can be resumed. A similar regime is suitable for
emergency operations, but more frequent measurements of
blood glucose are required. Patients with type 2 diabetes can
sometimes be managed without insulin, but the blood glucose
must be regularly checked during the post-operative period.
Ketoacidosis
The metabolic changes in diabetic ketoacidosis (DKA) resemble
those of starvation since, despite increased plasma glucose concentrations,
glucose is not available intracellularly (‘starving
amidst plenty’). Hyperglycaemia leads to osmotic diuresis and
electrolyte depletion. Conservation of K is even less efficient
than that of Na in the face of acidosis and an osmotic diuresis,
and large amounts of intravenous K are often needed to
replace the large deficit in total body K . However, plasma K
concentration in DKA can be increased due to a shift from the
intracellular to the extracellular compartment, so large amounts
of potassium chloride should not be administered until plasma
electrolyte concentrations are available and high urine output
established. Fat is mobilized from adipose tissue, releasing free
fatty acids that are metabolized by β-oxidation to acetyl coenzyme
A (CoA). In the absence of glucose breakdown, acetyl CoA
is converted to acetoacetate, acetone and β-hydroxybutyrate
(ketones). These are buffered by plasma bicarbonate, leading to
a fall in bicarbonate concentration (metabolic acidosis – with an
increased ‘anion gap’ since anionic ketone bodies are not
measured routinely) and compensatory hyperventilation
(‘Küssmaul’ breathing). There are therefore a number of metabolic
abnormalities:
• Sodium and potassium deficit A generous volume of
physiological saline (0.9% sodium chloride), given
intravenously, is crucial in order to restore extracellular
fluid volume. Monitoring urine output is necessary. When
blood glucose levels fall below 17 mmol/L, 5% glucose is
given in place of N-saline. Potassium must be replaced
and if the urinary output is satisfactory and the plasma
potassium concentration is 4.5 mEq/L, up to
20 mmol/hour KCl can be given, the rate of replacement
being judged by frequent measurements of plasma
potassium concentration and ECG monitoring.
• Hyperglycaemia Intravenous insulin is infused at a rate of
up to 0.1 unit/kg/hour with a syringe pump until ketosis
resolves (judged by blood pH, serum bicarbonate and
blood or urinary ketones).
• Metabolic acidosis This usually resolves with adequate
treatment with physiological sodium chloride and insulin.
Bicarbonate treatment to reverse the extracellular
metabolic acidosis is controversial, and may paradoxically
worsen intracellular and cerebrospinal fluid acidosis. If
arterial pH is 7.0, the patient is often given bicarbonate,
should be managed on an intensive care unit if possible
and may need inotropic support.
• Other measures include aspiration of the stomach, as
gastric stasis is common and aspiration can be severe and
may be fatal, and treatment of the precipitating cause of
coma (e.g. antibiotics for bacterial infection).