A-Textbook-of-Clinical-Pharmacology-and-Therapeutics-5th-edition

364 MALARIA AND OTHER PARASITIC INFECTIONS
8-AMINOQUINOLINES (PRIMAQUINE)
Primaquine is used to eradicate the hepatic forms of P. vivax or
P. malariae after standard chloroquine therapy, provided that the
risk of re-exposure is low. It may also be used prophylactically
with chloroquine. It interferes with the organism’s mitochondrial
electron transport chain. Gastro-intestinal absorption is
good and it is rapidly metabolized, with a mean t 1/2 of six
hours. Its major adverse effects are gastro-intestinal upsets,
methaemoglobinaemia and haemolytic anaemia in G6PDdeficient
individuals.
ARTENUSATE AND ARTEMETHER
Uses
Artemisinin (derived from the weed Quin Hao, Artemesia annua)
is a sesquiterpene lactone endoperoxide. It has been used in
China for at least 2000 years. Artenusate and artemether are
semi-synthetic derivatives of artemisinin and are effective and
well-tolerated antimalarials. They should not be used as
monotherapy or for prophylaxis because of the risk of resistance
developing. In many developed countries, artemisinin derivatives
are not yet licensed and can only be used on a namedpatient
basis. Currently, there is no clinical evidence of resistance
to artemesinin derivatives. Treatment can be started i.v. and
switched to oral with adjunctive doxycycline or clindamycin as
with quinine.
Mechanism of action
Artemesinins undergo haem-mediated decomposition of the
endoperoxide bridge to yield carbon-centred free radicals. The
involvement of haem explains why they are selectively toxic to
malaria parasites. The resulting carbon-centred free radicals
alkylate haem and proteins, particularly in the membranes of the
parasite’s food vacuole and mitochondria, causing rapid death.
Adverse effects
Side effects are mild and include the following:
• nausea, vomiting and anorexia;
• dizziness.
Preclinical toxicology suggested neuro-, hepato- and bone
marrow toxicity.
Pharmacokinetics
Oral absorption is fair (F 0.3). Artenusate and artemether
reach peak plasma concentration in minutes and two to six
hours, respectively. Both are extensively metabolized to dihydroartemesinin
(active metabolite) which has a half-life of
one to two hours. They autoinduce their CYP450 catalysed
metabolism. Drug–drug interactions are still being elucidated.
ANTI-FOLATES (DAPSONE PROGUANIL,
PYRIMETHAMINE)
Combinations of these drugs are taken orally in malaria
prophylaxis, but their efficacy in acute malaria treatment is
limited due to resistance. These agents inhibit folate biosynthesis
at all stages of the malaria parasite’s life cycle, acting
as competitive inhibitors of the malarial dihydropteroate
synthase (dapsone) or the malarial dihydrofolate reductase
(proguanil or pyrimethamine). They exhibit typical anti-folate
adverse effect profiles (gastro-intestinal upsets, skin rashes,
myelosuppression; see Chapters 43 and 46).
TREATMENT OF A MALARIA RELAPSE
Plasmodium falciparum does not cause a relapsing illness after
treating the acute attack with schizonticides, because there is no
persistent liver stage of the parasite. Infections with P. malariae
can cause recurrent attacks of fever for up to 30 years, but standard
treatment with chloroquine eradicates the parasite.
Following treatment of an acute attack of vivax malaria with
schizonticides, or a period of protection with prophylactic
drugs, febrile illness can recur. Such relapsing illness can be prevented
(or treated) by eradicating the parasites in the liver with
primaquine, as described above. Proguanil hydrochloride
administered continuously for three years, in order to suppress
the parasites and allow time for the hepatic stages to die out naturally,
is a useful alternative for patients with G6PD deficiency.
Key points
Treatment of acute malaria
• If the infective species is not known or is mixed, initial
therapy is with intravenous quinine or mefloquine.
• P. falciparum is mainly resistant to chloroquine; treat
with quinine, mefloquine or halofantrine.
• Benign malaria (caused by P. malariae) is treated with
chloroquine alone.
• Benign malaria due to P. ovale or P. vivax requires
chloroquine therapy plus primaquine to achieve a
radical cure and prevent relapse.
• Careful attention to hydration and blood glucose is
necessary.
• Anticipate complications and monitor the patient
frequently.
TRYPANOSOMAL INFECTION
African sleeping sickness is caused by Trypanosoma gambiense
and T. rhodesiense. The insect vector is the Glossina (tsetse) fly.
Drugs used in antitrypanosomal therapy include:
• those active in blood and peripheral tissues: melarsoprol,
pentamidine, suramin and trimelarsan;
• those active in the central nervous system: tryparsamide
and melarsoprol.
Table 47.2 summarizes the drugs used to treat trypanosomal
and other non-malarial protozoan infections.
HELMINTHIC INFECTION
Table 47.3 summarizes the primary drugs used to treat common
helminthic infections.