A Textbook of Clinical Pharmacology and Therapeutics

358 HIVANDAIDS

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

Pentamidineis administered parenterally. The t1/2is 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

Pentamidineinhibits cholinesterase. This suggests potential
interactions in enhancing/prolonging the effect of suxametho-
niumand 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.

TOXOPLASMA GONDII

PYRIMETHAMINE AND SULFADIAZINE

Use

This combination is the first-line therapy for cerebral and tis-

sue toxoplasmosis. Pyrimethamineis given as an oral loading

dose followed by a maintenance dose, together with sulfadi-

azine. 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

Sulfadiazineacts as a competitive inhibitor of dihydropteroate

(folate) synthase (competing with p-aminobenzoic acid) in folate

synthesis.Pyrimethamineis a competitive inhibitor of dihydro-

folate reductase, which converts dihydrofolate to tetrahydrofo-

late. 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 pyrimethamineis good (90%). It under-

goes extensive hepatic metabolism, but approximately 20% is

recovered unchanged in the urine. It has a long plasma t1/2

(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.

Sulfadiazineis rapidly and completely absorbed after oral

administration. However, there is substantial first-pass hepatic

metabolism. The mean plasma t1/2is 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

pyrimethaminein combination with clindamycinwith folinic

acid as above. Newer therapies for cerebral toxoplasmosis as

Table 46.4:Alternative regimens for treating PCP

Alternative PCP treatment Additional comments

Trimethoprim, in two Oral therapy for 21 days, used in

divided doses plus mild to moderate PCP. Check

dapsone, daily glucose-6-phosphate

dehydrogenase

Primaquine, p.o. and Used in mild to moderate PCP.

clindamycin, i.v. for 11 days Check glucose-6-phosphate

and then p.o. for 10 days dehydrogenase

Atovaquone (a Oral therapy used in mild to

hydroxynaphthoquinone), moderate PCP. Blocks protozoan

for 21 days mitochondrial electron transport

chain and de novo pyrimidine

synthesis. Side effects include

nausea, vomiting, rash and

hepatitis