A Textbook of Clinical Pharmacology and Therapeutics

Hyperosmolar non-ketotic coma

Lessinsulinis required in this situation, as the blood pH is
normal and insulinsensitivity is retained. Fluid loss is restored
using physiological saline (there is sometimes a place for half-
strength, 0.45% saline) and large amounts of intravenous
potassium are often required. Magnesium deficiency is com-
mon, contributes to the difficulty of correcting the potassium
deficit, and should be treated provided renal function is nor-
mal. In this hyperosmolar state, the viscosity of the blood is
increased and a heparinpreparation (Chapter 30) should be
considered as prophylaxis against venous thrombosis.

Mechanism of action

Insulinacts by binding to transmembrane glycoprotein recep-
tors. Receptor occupancy results in:

1. activation of insulin-dependent glucose transport
   processes (in adipose tissue and muscle) via a transporter
   known as ‘Glut-4’;
   2.inhibition of adenylyl cyclase-dependent metabolism
   (lipolysis, proteolysis, glycogenolysis);
   3.intracellular accumulation of potassium and phosphate,
   which is linked to glucose transport in some tissues.
   Secondary effects include increased cellular amino acid
   uptake, increased DNA and RNA synthesis and increased
   oxidative phosphorylation.

Adverse reactions

1. Hypoglycaemia is the most important and severe
   complication of insulintreatment. It is treated with
   an intravenous injection of glucose in unconscious
   patients, but sugar is given as a sweet drink in those
   with milder symptoms. Glucagon(1 mg intramuscularly,
   repeated after a few minutes if necessary) is useful if
   the patient is unconscious and intravenous access is
   not achievable (e.g. to ambulance personnel or a family
   member).
   2.Insulin-induced post-hypoglycaemic hyperglycaemia
   (Somogyi effect) occurs when hypoglycaemia (e.g. in the
   early hours of the morning) induces an overshoot of
   hormones(adrenaline, growth hormone, glucocorticosteroids,
   glucagon) that elevate blood glucose (raised blood glucose
   on awakening). The situation can be misinterpreted as
   requiring increased insulin, thus producing further
   hypoglycaemia.
   3.Local or systemic allergic reactions to insulin, with
   itching, redness and swelling at the injection site.
   4.Lipodystrophy: the disappearance of subcutaneous fat at
   or near injection sites. Atrophy is minimized by rotation of
   injection sites. Fatty tumours occur if repeated injections
   are made at the same site.
   5.Insulinresistance, defined arbitrarily as a daily
   requirement of more than 200 units, due to antibodies, is
   unusual. Changing to a highly purified insulin
   preparation is often successful, a small starting dose being
   used to avoid hypoglycaemia.

Pharmacokinetics

Insulinis broken down in the gut and by the liver and kidney,

and is given by injection. The t1/2is three to five minutes. It is

metabolized to inactive αandβ peptide chains largely by

hepatic/renal insulinases (insulin glutathione transhydroge-

nase).Insulinfrom the pancreas is mainly released into the por-

tal circulation and passes to the liver, where up to 60% is

degraded before reaching the systemic circulation (presystemic

metabolism). The kidney is also important in the metabolism of

insulinand patients with progressive renal impairment often

have a reduced requirement for insulin. There is no evidence

that diabetes ever results from increased hepatic destruction of

insulin, but in cirrhosis the liver fails to inactivate insulin, thus

predisposing to hypoglycaemia.

ORAL HYPOGLYCAEMIC DRUGS AND

TYPE 2 DIABETES

Oral hypoglycaemic drugs are useful in type 2 diabetes as

adjuncts to continued dietary restraint. They fall into four

groups:

1. biguanides (metformin);
   2.sulphonylureas and related drugs;
   3.thiazolidinediones (glitazones);
   4.α-glucosidase inhibitors (acarbose).
   Most type 2 diabetic patients initially achieve satisfactory con-
   trol with diet either alone or combined with one of these agents.
   The small proportion who cannot be controlled with drugs at
   this stage (primary failure) require insulin. Subsequent failure
   after initially adequate control (secondary failure) occurs in
   about one-third of patients, and is treated with insulin. Inhaled
   insulinis effective but expensive. Its bioavailability is affected
   by smoking and by respiratory infections, and currently should
   only be used with great caution in patients with asthma/
   COPD.

BIGUANIDES: METFORMIN

Uses

Metforminis the only biguanide available in the UK. It is used

in type 2 diabetic patients inadequately controlled by diet. Its

anorectic effect aids weight reduction, so it is a first choice drug

for obese type 2 patients, provided there are no contraindica-

tions. It must not be used in patients at risk of lactic acidosis and

is contraindicated in:

• renal failure (it is eliminated in the urine, see below);


• alcoholics;


• cirrhosis;


• chronic lung disease (because of hypoxia);


• cardiac failure (because of poor tissue perfusion);


• congenital mitochondrial myopathy (which is often
  accompanied by diabetes);


• acute myocardial infarction and other serious intercurrent
  illness (insulinshould be substituted).

288 DIABETES MELLITUS