Clinical Pharmacology and Therapeutics

358 HIV AND AIDS
Adverse effects
The adverse effects of the nebulized route include cough and
bronchospasm, pre-administration of a nebulized β 2 -agonist
minimizes these effects.
Intravenous route adverse effects include:
• hypotension and acidosis (due to cardiotoxicity) if given
too rapidly;
• dizziness and syncope;
• hypoglycaemia due to toxicity to the pancreatic β-cells,
producing hyperinsulinaemia;
• nephrotoxicity (rarely irreversible);
• pancreatitis;
• reversible neutropenia;
• prolongation of the QTc interval.
Pharmacokinetics
Pentamidine is administered parenterally. The t 1/2 is six hours
and it is redistributed from plasma by tissue binding. Renal
excretion is low (5% of dose). Nebulized therapy yields lung
concentrations that are as high or higher than those achieved
after intravenous infusion.
Drug interactions
Pentamidine inhibits cholinesterase. This suggests potential
interactions in enhancing/prolonging the effect of suxamethonium
and reducing that of competitive muscle relaxants, but it
is not known whether this is of clinical importance.
Alternative regimens for treating PCP are summarized in
Table 46.4.
Table 46.4: Alternative regimens for treating PCP
Alternative PCP treatment
Trimethoprim, in two
divided doses plus
dapsone, daily
Primaquine, p.o. and
clindamycin, i.v. for 11 days
and then p.o. for 10 days
Atovaquone (a
hydroxynaphthoquinone),
for 21 days
Additional comments
Oral therapy for 21 days, used in
mild to moderate PCP. Check
glucose-6-phosphate
dehydrogenase
Used in mild to moderate PCP.
Check glucose-6-phosphate
dehydrogenase
Oral therapy used in mild to
moderate PCP. Blocks protozoan
mitochondrial electron transport
chain and de novo pyrimidine
synthesis. Side effects include
nausea, vomiting, rash and
hepatitis
TOXOPLASMA GONDII
PYRIMETHAMINE AND SULFADIAZINE
Use
This combination is the first-line therapy for cerebral and tissue
toxoplasmosis. Pyrimethamine is given as an oral loading
dose followed by a maintenance dose, together with sulfadiazine.
Treatment is continued for at least four to six weeks
after clinical and neurological resolution, and for up to six
months thereafter. Folinic acid is given prophylactically to
reduce drug-induced bone marrow suppression.
Mechanism of action
Sulfadiazine acts as a competitive inhibitor of dihydropteroate
(folate) synthase (competing with p-aminobenzoic acid) in folate
synthesis. Pyrimethamine is a competitive inhibitor of dihydrofolate
reductase, which converts dihydrofolate to tetrahydrofolate.
Together they sequentially block the first two major steps in
the synthesis of folate in the parasite. Their selective toxicity is
due to the fact that humans can utilize exogenous folinic acid
and dietary folate, whereas the parasite must synthesize these.
Adverse effects
The major toxic effects of the combination are:
• nausea and vomiting;
• fever and rashes which may be life-threatening
(Stevens–Johnson syndrome);
• bone marrow suppression, especially granulocytopenia;
• hepatitis;
• nephrotoxicity, including crystalluria and obstructive
nephropathy.
Pharmacokinetics
Oral absorption of pyrimethamine is good (90%). It undergoes
extensive hepatic metabolism, but approximately 20% is
recovered unchanged in the urine. It has a long plasma t 1/2
(35–175 hours). Because of its high lipid solubility it has a
large volume of distribution, and achieves CSF concentrations
that are 10–25% of those in plasma.
Sulfadiazine is rapidly and completely absorbed after oral
administration. However, there is substantial first-pass hepatic
metabolism. The mean plasma t 1/2 is ten hours. Cerebrospinal
fluid concentrations are 70% of those in plasma. Clearance is a
combination of hepatic metabolism and renal excretion, with
50% of a dose being excreted in the urine, so dose reduction is
needed in patients with renal failure.
Drug interactions
These are primarily due to sulfadiazine (Chapter 43) and the
combined bone marrow suppressive effect of pyrimethamine
with other antifolates.
An alternative anti-toxoplasmosis regimen consists of
pyrimethamine in combination with clindamycin with folinic
acid as above. Newer therapies for cerebral toxoplasmosis as