Allopurinol

Mechanism of Action:
The biosynthesis of uric acid from the immediate purine precursor. The enzyme xanthine oxidase is
involved in two steps the conversion of hypoxanthine to xanthine and the conversion of xanthine to uric
acid. Allopurinol was originally originally designed as an antineoplastic, antimetabolite to antagonist the
activity of key purines. It is an isomer of hypoxanthine in that the nitrogen and carbon serves as the 7 & 8
position of the purine are inverted. It was adequantly found that allopurinol serve as a substrate for
xanthine oxidase 15-20 times greater the affinity of xanthine and reversibly inhibit that enzymes.
Normally uric acid is major metabolite end product in humans but when allopurinol is adminstred
xanthine and hypoxanthine are decrease in the urine and uric acid level decreases when the uric acid
synthesis is inhibitd. Plasma urate level decreases super saturated solution of urate are no longer present
and cause crystal deposit dissolve eliminating the primary cause of gout. The increased plasma level of
hypoxanthine and xanthine pose no real problem since they are more soluble than uric acid and are
readily excreted

Absorption & Metabolism:

Allopurinol is a white fluffy powder processing a slight odour but no taste. It is only very slightly soluble
in water but is soluble in polar organic solvent and alkaline aqueous solution. It was synthesized as a part
of purine antagonist. It is well absorbed on oral administration with peak plasma concentration appearing
within one hr. decreases of uric acid can be observed within 24-48hrs. excretion of allopurinol and its
metabolite occur primarily in the urine with about 20% of being converted in the feces. The major
metabolite of allopurinol is the oxidation product alloxanthine or osypurinol. Allopurinol has much
longer half life (18-30hr vs 2-3hr) then the parent drug is an effective although less potent inhibitor of
xanthine oxidase. The longer plasma half life of alloxanthine ress its in an accumulation in the body
during chronic administration thus contributing significantly to the overall therapeutic effect of
allopurinol. The major adverse effect are primarily dermatologic in nature ( skin rash and exfoliative
lesions) other effects such as Gi distress ( nausea, vomiting,diarrohea), hematopoietic effect(Aplastic
anemia,bone marrow depression and transient leucopenia), neutrologic effects (cataracts) are less
commonly encountred. Allopurinol also has an inhibitory effect on liver microsomal enzymes thus
prolonging the half lives of drug such as oral anticoagulant that are normally metabolized and inactivated
by these enzymes, although this effect is quite variable. The incidence of ampicilin related skin rashes
increases with the concurrent administration of allopurinol.

Indication:
It is indicated for the treatment of primary and secondary gout for malignancies such as leukemia and
lymphoma and the management of patient with recurrent calcium oxalate calculi

Future development:
The continued exploration of selective COX-2 inhibitor with minimal GI effects. Additionally, the
continued exploration of the use of these agents for nonairthritic condition such as various cancer and for
conginitive disorder such as Alzheimer disease should increase. A third isoform of cyclooxygenase COX3 has been proposed that would represent a new therapeutic approach to the development of the next
generation anti inflammatory agents
Interleukins play an important role in the immune response and are also receiving a great deal of
attention. Interleukin-1 (II-1) is one of a class of pro-inflammatory proteins (Cytokines) produced by
stimulated mononuclear phagocytes which play a major role in inflammatory response.

Amodiaquine
Amodiaquine 4-(7-chloro-4-quinolyloamino)-2-(diethylaminomethyl)phenol
It is very pale yellow to light tan-yellow, odourless powder. Practically insoluble in water, slightly soluble
in alcohol, sparingly soluble in 1.0N hydrochloric acid. Store in air tight container

Pharmacokinetics:
It is readily absorbed from the gastrointestinal tract. It is rapidly converted in the liver to the active
metabolite desethylamodiaquine only a negligible amount is being excreted unchanged in the urine. The
plasma elimination half life of desethylamodiaquine has varied from 1-10days or more. Amodiaquine and
desthylamodiaquine have been detected in the urine several month after administration

Uses and Adminstration:

It is a aminoquinoline antimalarial with an action similar to that of chloroquine. It is an effective as
chloroquine against chloroquine-sensitive strains of plasmodium falciparum and is also effective against
some chloroquine resistrant strains although resistance to amodiaquine has developed and there may be

partial cross resistance between amodiaquine and chloroquine. Amodiaquine is not recommended for
prophylaxsis of malaria because of resistance and the risk of major toxicity
Amodiaquine is given by mouth as the hydrochloride, but doses are expressed in term of amodiaquine
bases; amodiaquine hydrochloride 260mg is approximately equivalent to 200mg of amodiaquine base.
For the treatment of falciparum malaria a total dose of 35mg/kg has been given over 3 days.

Adverse effect:
The acute toxicity is differ from chloroquine. large doses of amodiaquine produce
syncope,spasticity,convulsion and involuntary movements. It is also associated with hepatitis and
agranulocytosis when it was used for the prophylaxsis of malaria.