Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

CHAPTER 10 ANTIPARASITIC DRUGS
Table 10.2 Selective toxicity (continued)
Mechanism Parasite receptor Susceptible
parasite group
Antiparasitic
agents
Mixed-function oxidases Arthropods Piperonyl butoxide,
MGK 264
Ornithine decarboxylase
(ODC)
Phosphofructokinase
Pyruvate:ferrodoxin
oxidoreductase
(PFOR)
Sterol 14α-demethylase
Protozoa (especially
trypanosomatids)
Protozoa (especially
trypanosomatids)
Protozoa (especially
anaerobic
flagellates)
Protozoa (especially
trypanosomatids)
Eflornithine (DFMO,
DL-α-difluoro
methyl ornithine)
Antimonials
Metronidazole (MNZ)
Azoles (albaconazole,
itraconazole)
Antiparasitic action
Antagonist
Synergize pyrethrin
and SP antiparasitic
agents by inhibition
of metabolic
inactivating
enzymes
Antagonist
Trypanosomes are
fully dependent on
intrinsic polyamine
biosynthesis. DFMO
irreversibly inhibits
ODC resulting in
inhibition of
biosynthesis of
trypanothione and
the polyamines
putrescine,
spermidine and
spermine
Antagonist
Inhibition of PFK
prevents
phosphorylation of
fructose-6-
phosphate,
resulting in
decreased
fructose-1,6-
diphosphate, lower
aldolase activity,
and energy
depletion
Agonist (subversive)
Under anaerobic
conditions in
trichomonads and
Giardia, MNZ can
accept electrons to
form cytotoxic
anions
Antagonist
Inhibition of sterol 14-
demethylase (that
removes the 14-
methyl group from
lanosterol) prevents
the subsequent
synthesis of
ergosterol
Comments on
selective toxicity*
PK: dermal barrier
PD: no selectivity
PK: low oral
bioavailability and
rapid excretion
PD: ODC turnover in
mammals is 100-fold
faster than in
trypanosomes
PK: low selectivity, high
bioavailability
PD: differences in
enzyme affinity
PK: rapid and extensive
metabolism
PD: PFOR is not present
in mammals.
Cytotoxic anions
produced only under
anaerobic conditions
PK: low selectivity,
preferred agents are
well absorbed with
long residence time
PD: mammals do not
synthesize ergosterol,
and azoles have
lower affinity for the
mammalian enzyme
202