A Textbook of Clinical Pharmacology and Therapeutics

DIGOXIN

Myxoedematous patients are extremely sensitive to digoxin,
whereas unusually high doses are required in thyrotoxicosis.
In general, hyperthyroid patients have lower plasma digoxin
concentrations and hypothyroid patients have higher plasma
concentrations than euthyroid patients on the same dose.
There is no significant difference in half-life between these
groups, and a difference in Vdhas been postulated to explain
the alteration of plasma concentration with thyroid activity.
Changes in renal function, which occur with changes in thy-
roid status, complicate this interpretation. GFR is increased in
thyrotoxicosis and decreased in myxoedema. These changes
in renal function influence elimination, and the reduced plasma
levels of digoxincorrelate closely with the increased creatinine
clearance in thyrotoxicosis. Other factors including enhanced
biliary clearance, digoxinmalabsorption due to intestinal
hurry and increased hepatic metabolism, have all been postu-
lated as factors contributing to the insensitivity of thyrotoxic
patients to cardiac glycosides.

ANTICOAGULANTS

Oral anticoagulants produce an exaggerated prolongation of
prothrombin time in hyperthyroid patients. This is due to
increased metabolic breakdown of vitamin K-dependent clot-
ting factors (Chapter 30), rather than to changes in drug phar-
macokinetics.

GLUCOCORTICOIDS

Glucocorticoids are metabolized by hepatic mixed-function
oxidases (CYP3A4) which are influenced by thyroid status.
In hyperthyroidism, there is increased cortisol production
and a reduced cortisol half-life, the converse being true in
myxoedema.

THYROXINE

The normal half-life of thyroxine(six to seven days) is reduced
to three to four days by hyperthyroidism and prolonged to
nine to ten days by hypothyroidism. This is of considerable
clinical importance when deciding on an appropriate interval
at which to increase the dose of thyroxinein patients treated
for myxoedema, especially if they have coincident ischaemic
heart disease which would be exacerbated if an excessive
steady-statethyroxinelevel were achieved.

ANTITHYROID DRUGS

The half-life of propylthiouracilandmethimazoleis pro-
longed in hypothyroidism and shortened in hyperthyroidism.

THYROIDDISEASE 39

Key points

Disease profoundly influences the response to many drugs

by altering pharmacokinetics and/or pharmacodynamics.

• Gastro-intestinal disease:
  (a) diseases that alter gastric emptying influence
  the response to oral drugs (e.g. migraine reduces
  gastric emptying, limiting the effectiveness of
  analgesics);
  (b)ileum/pancreas – relatively minor effects.


• Heart failure:
  (a) absorption of drugs (e.g. furosemide) is reduced as a
  result of splanchnic hypoperfusion;
  (b) elimination of drugs that are removed very
  efficiently by the liver (e.g. lidocaine) is reduced as a
  result of reduced hepatic blood flow, predisposing
  to toxicity;
  (c) tissue hypoperfusion increases the risk of lactic
  acidosis with metformin (cor pulmonale especially
  predisposes to this because of hypoxia).


• Renal disease:
  (a) chronic renal failure – as well as reduced excretion,
  drug absorption, distribution and metabolism may
  also be altered. Estimates of creatinine clearance or
  GFR based on serum creatinine concentration/
  weight/age/sex/ ethnicity provide a useful index of
  the need for maintenance dose adjustment in
  chronic renal failure;
  (b)nephrotic syndrome leads to altered drug
  distribution because of altered binding to albumin
  and altered therapeutic range of concentrations for
  drugs that are extensively bound to albumin (e.g.
  some anticonvulsants). Albumin in tubular fluid
  binds diuretics and causes diuretic resistance.
  Glomerular filtration rate is preserved in nephrotic
  syndrome by compensatory increased prostaglandin
  synthesis, so NSAIDs (see Chapter 26) can precipitate
  renal failure.


• Liver disease – as well as effects on drug metabolism,
  absorption and distribution may also be altered because
  of portal systemic shunting, hypoalbuminaemia and
  ascites. There is no widely measured biochemical marker
  (analogous to serum creatinine in chronic renal failure)
  to guide dose adjustment in liver disease, and a cautious
  dose titration approach should be used.


• Thyroid disease:
  (a) hypothyroidism increases sensitivity to digoxin and
  opioids;
  (b)hyperthyroidism increases sensitivity to warfarin and
  reduces sensitivity to digoxin.

These values return to normal on attainment of the euthyroid

state, probably because of altered hepatic metabolism.

OPIATES

Patients with hypothyroidism are exceptionally sensitive to

opioid analgesics, which cause profound respiratory depres-

sion in this setting. This is probably due to reduced metab-

olism and increased sensitivity.