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 V d has been postulated to explain
the alteration of plasma concentration with thyroid activity.
Changes in renal function, which occur with changes in thyroid
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 digoxin correlate closely with the increased creatinine
clearance in thyrotoxicosis. Other factors including enhanced
biliary clearance, digoxin malabsorption due to intestinal
hurry and increased hepatic metabolism, have all been postulated
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 clotting
factors (Chapter 30), rather than to changes in drug pharmacokinetics.
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 thyroxine in patients treated
for myxoedema, especially if they have coincident ischaemic
heart disease which would be exacerbated if an excessive
steady-state thyroxine level were achieved.
ANTITHYROID DRUGS
The half-life of propylthiouracil and methimazole is prolonged
in hypothyroidism and shortened in hyperthyroidism.
Key points
THYROID DISEASE 39
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 depression
in this setting. This is probably due to reduced metabolism
and increased sensitivity.
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.