A-Textbook-of-Clinical-Pharmacology-and-Therapeutics-5th-edition
A-Textbook-of-Clinical-Pharmacology-and-Therapeutics-5th-edition
A-Textbook-of-Clinical-Pharmacology-and-Therapeutics-5th-edition
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408 CLINICAL IMMUNOPHARMACOLOGY<br />
hypogammaglobulinaemia <strong>and</strong> IgG subclass deficiency<br />
(e.g. Bruton’s agammaglobulinaemia, Wiskott–Aldrich syndrome),<br />
idiopathic thrombocytopenic purpura <strong>and</strong> for<br />
prophylaxis <strong>of</strong> infection in bone marrow transplant patients.<br />
Adverse effects<br />
The most common adverse effects occur during the first infusion<br />
<strong>and</strong> are dependent on the antigenic load (dose) given.<br />
They include the following:<br />
• fever, chills <strong>and</strong> rarely anaphylaxis – most commonly seen<br />
with the first dose, <strong>and</strong> reduced by slow administration<br />
<strong>and</strong> premedication with antihistamines <strong>and</strong><br />
glucocorticosteroids;<br />
• increased plasma viscosity – caution is needed in patients<br />
with ischaemic heart disease;<br />
• aseptic meningitis (high dose).<br />
Contraindications<br />
Normal immunoglobulin is contraindicated in patients with<br />
known class-specific antibody to IgA.<br />
Interactions<br />
Live virus vaccinations may be rendered less effective.<br />
SPECIFIC IMMUNOGLOBULINS<br />
These antibodies are prepared by pooling the plasma <strong>of</strong><br />
selected donors with high levels <strong>of</strong> the specific antibody<br />
required. The following are currently available <strong>and</strong> effective:<br />
rabies immunoglobulin, tetanus immunoglobulin (human<br />
origin-HTIG), varicella zoster immunoglobulin (VZIG) (limited<br />
supply); anti-CMV immunoglobulin (on a named patient<br />
basis).<br />
ANTI-D (RHO) IMMUNOGLOBULIN<br />
This immunoglobulin is used to prevent a rhesus-negative<br />
mother from forming antibodies to fetal rhesus-positive cells<br />
that enter the maternal circulation during childbirth or abortion.<br />
An intramuscular injection is given to rhesus-negative mothers<br />
up to 72 hours after the birth/abortion. This prevents a subsequent<br />
child from developing haemolytic disease <strong>of</strong> the newborn.<br />
Case history<br />
A 35-year-old woman had a cadaveric renal transplant for<br />
polycystic kidneys two years previously <strong>and</strong> was stable on her<br />
immunosuppressive regimen <strong>of</strong> ciclosporin, 300 mg twice a<br />
day, <strong>and</strong> mycophenolate m<strong>of</strong>etil, 1 g twice a day. Her usual<br />
trough ciclosporin concentrations were 200–250 μg/L <strong>and</strong> her<br />
hepatic <strong>and</strong> liver function was normal. She went on holiday<br />
to southern California for ten days, where she was well, but<br />
drank plenty <strong>of</strong> fluids (but no alcohol) as she was warned<br />
about the dangers <strong>of</strong> dehydration. By the end <strong>of</strong> her visit,<br />
she noted some nausea <strong>and</strong> a mild tremor. Following a long<br />
return flight, she went to her local hospital <strong>and</strong> sustained a<br />
brief spontaneously remitting epileptic fit in the outpatient<br />
department where she was having her blood ciclosporin<br />
concentration checked. The fit lasted about one minute <strong>and</strong><br />
she was taken to the Accident <strong>and</strong> Emergency Department.<br />
Examination revealed no abnormalities apart from slight<br />
tremor which she said she had noted for the last 48 hours.<br />
Her ciclosporin concentration was 650 μg/L. All other medical<br />
biochemistry tests were normal. She was not taking any<br />
other prescribed medications or over-the-counter drugs.<br />
Questions<br />
What caused this patient’s seizures<br />
How can you explain the markedly elevated trough<br />
ciclosporin concentration<br />
Answer<br />
In this patient, the development <strong>of</strong> an acute epileptic seizure<br />
in the context <strong>of</strong> a very high ciclosporin trough concentration<br />
indicates ciclosporin toxicity; epilepsy is a well-recognized<br />
toxic effect <strong>of</strong> high ciclosporin concentrations. The difficult<br />
issue in the case is why she developed high ciclosporin blood<br />
concentrations (in the face <strong>of</strong> normal renal <strong>and</strong> hepatic function)<br />
when she was adamant that there had been no alteration<br />
in the daily dose <strong>of</strong> ciclosporin she was taking, nor had<br />
she started any other drugs (prescribed or over-the-counter<br />
agents). Further questioning defined that she was drinking<br />
about 1 L/day <strong>of</strong> grapefruit juice – a taste she had acquired<br />
while on holiday in California. Grapefruit juice contains psoralens<br />
<strong>and</strong> flavonoids which inhibit CYP3A (gastrointestinal<br />
<strong>and</strong> hepatic) <strong>and</strong> flavonoids which inhibit P-gp in the gut wall,<br />
increasing the bioavailability <strong>of</strong> ciclosporin by 19–60%, the<br />
combined effect leading to higher concentrations without a<br />
change in dose. The patient had her ciclosporin dosing<br />
stopped until the concentration was 300 μg/L. She had no<br />
further fits, her nausea <strong>and</strong> tremor subsided, <strong>and</strong> she was<br />
then restarted on her normal dose with clear instructions not<br />
to drink grapefruit juice.<br />
Examples <strong>of</strong> other drugs whose oral bioavailability is<br />
increased in humans with co-ingestion <strong>of</strong> grapefruit juice<br />
include midazolam, oestrogens, atorvastatin (<strong>and</strong> most<br />
statins except pravastatin), testosterone, felodipine, nifedipine<br />
(but not diltiazem), some anti-HIV protease inhibitors,<br />
other calcinerin inhibitors. Patients who are taking these<br />
agents or other drugs metabolized by CYP3A/P-gp should be<br />
warned not to ingest even single cupfuls <strong>of</strong> grapefruit juice,<br />
as this may precipitate toxic drug concentrations.<br />
FURTHER READING<br />
Golightly LK, Greos LS. Second-generation antihistamines: actions<br />
<strong>and</strong> efficacy in the management <strong>of</strong> allergic disorders. Drugs 2005;<br />
65: 341–84.<br />
Lindenfeld J, Miller GG, Shakar SF et al. Drug therapy in the heart<br />
transplant recipient: part II: immunosuppressive drugs. Circulation<br />
2004; 110: 3858–65.<br />
Lipsky JJ. Drug pr<strong>of</strong>ile. Mycophenolate m<strong>of</strong>etil. Lancet 1996; 348:<br />
1357–9.<br />
Plaut M, Valentine MD. <strong>Clinical</strong> practice. Allergic rhinitis. New<br />
Engl<strong>and</strong> Journal <strong>of</strong> Medicine 2005; 353: 1934–44.<br />
Simons ERF, Simons KJ. Drug therapy:the pharmacology <strong>and</strong> use <strong>of</strong><br />
H 1 -receptor antagonist drugs. New Engl<strong>and</strong> Journal <strong>of</strong> Medicine<br />
1994; 330: 1663–70.<br />
Waldman TA. Immunotherapy: past, present <strong>and</strong> future. Nature Medicine<br />
2003; 9: 269–77.