A Textbook of Clinical Pharmacology and Therapeutics

364 MALARIA AND OTHER PARASITIC INFECTIONS

8-AMINOQUINOLINES (PRIMAQUINE)

Primaquineis used to eradicate the hepatic forms of P. vivaxor
P. malariaeafter standard chloroquine therapy, provided that the
risk of re-exposure is low. It may also be used prophylactically
withchloroquine. It interferes with the organism’s mitochon-
drial electron transport chain. Gastro-intestinal absorption is
good and it is rapidly metabolized, with a mean t1/2of six
hours. Its major adverse effects are gastro-intestinal upsets,
methaemoglobinaemia and haemolytic anaemia in G6PD-
deficient 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. Artenusateandartemetherare
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 deriva-
tives are not yet licensed and can only be used on a named-
patient basis. Currently, there is no clinical evidence of resistance
to artemesinin derivatives. Treatment can be started i.v. and
switched to oral with adjunctive doxycyclineorclindamycinas
withquinine.

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 (F0.3).Artenusateandartemether
reach peak plasma concentration in minutes and two to six
hours, respectively. Both are extensively metabolized to di-
hydroartemesinin (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 biosynthe-
sis 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

(proguanilorpyrimethamine). 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 falciparumdoes 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 stand-

ard 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 pre-

vented (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 nat-

urally, 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. falciparumis 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. ovaleorP. vivaxrequires
  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

andT. rhodesiense. The insect vector is the Glossina(tsetse) fly.

Drugs used in antitrypanosomal therapy include:

• those active in blood and peripheral tissues: melarsoprol,
  pentamidine,suraminandtrimelarsan;


• those active in the central nervous system: tryparsamide
  andmelarsoprol.
  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 com-

mon helminthic infections.