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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5406_Библиотеки_им_академика_М_И_Перельмана.pdf
222 Pharmaceutical Chemistry
MeMe
OO
Me
O
Al(TMS)
DMAP, EtCOCl
-78°C
Al-Hg
Me
THF
S
PhO
MeMe
3
OO
Me
Me3Si
Me
MeMe
TsNHNH
OO
Me
2
O
Me
MeMe
OO
TsNHN
Me
TMEDA
MeMe
Me
LDEA
Me
Me
OO
CH3I
LDA
Me3Si
O
COOH
O
Me
O
O
O
O
O3, DCM, -78°C
3M H
2SO4
Me
Me3Si
MeMe
Me
OO
O
O
MeHOOC
Me
O
Artemisinin
9.3.4.5 Alternative Way of Synthesis of Artemisinin from Cyclohexenone
BuLi
Me
Me
Me3Si
MeMe
OO
HOOC
MeMe
Me
OO
H
O
Me
Me
O
1. Me2Zn, Cu(OTf)
Toluene, -30°C
2. RBr, -30°C to RT
OMeTlPSO
Me
25-50% Et2AlCl
DCM, -78°C to RT
1. (NH4)2MoO4(0.2-1 eq)
(excess)
H
2O2
-BuOH, RT, 3dt
2. -TSA (10%)p
DCM, RT, 3d
Me
(1%)
2
Me
Me
Me
O
MeO OTlPS
O
O
O
O
MeO OTlPS
Me
Me
Me
Me
O
1. TsNHNH
MeOH, RT
2. -BuLi, DMFn
2
Me
Me
O
Me
O
Me
PdCl
H
2O2
(5%)
2
(excess)
O
Me
MeO OTlPS
Me
O
Me
O
O
O
Me
O
Artemisinin
Antimalarial Agents 223
9.3.4.6 Absorption, Metabolism and Excretion
Artemisinin derivatives are well absorbed and can be given orally or intra-muscularly.
After metabolism of artemisinin, a number of metabolites are produced and they can be
distinguished by their structural features such as active hydroxylated compounds with an
intact endoperoxide bridge along with the inactive deoxy-metabolites where the peroxide
bridge is usually reduced to an epoxide (viz., deoxydihydroartemisinin, 9,10-dihydrodeoxy
artemisinin, deoxyartemisinin and crystal-7) (Fig. 9.7).
Me
Me
O
O
O
O
Me
OH
Dihydroartemisinin
Me
O
Deoxyartemisinin
Me
O
Deoxydihydro
artemisinin
Me
O
O
Me
O
Fig. 9.7: Metabolites of artemisinin
Me
O
O
Crystal-7
Me
9,10-Dihydrodeoxy-
Me
Me
O
O
Me
OH
O
Me
HO Me
O
O
O
O
artemisinin
OH
Me
All four metabolites except dihydroartemisinin are inactive because they lack an
endoperoxide bridge. The glucuronidated conjugate of these metabolites is eliminated
through urine and faeces. No reports are available that artemisinin exists as such in
biological system, however its metabolite dihydroartemisinin is considered to be the
main active metabolite. Dihydroartemisinin is further converted to its inactive
glucuronidated metabolite by interfering with UDP-glucuronosyl transferases
(particularly UGT1A9, UGT2B7 and sometimes UGT1A1 & UGT1A8). It is also reported
that dihydroartemisinin is eliminated in the bile as minor glucuronides (in the form of
tetrahydrofurano acetate). The artemisinins t
is between 2-5 hours whereas 2-4 hours
1/2
for artemether and <1 hour for artesunate. Thus, it can be considered that artemisinins
are safe due to their fast elimination.
9.3.4.7 Side Effects
Low level of toxicity has been reported with the artemisinins in a combination therapy but
still there are some common toxic effects, viz., nausea, vomiting, anorexia and dizziness.
More serious toxic effects include neutropenia, neurotoxicity, anemia, hemolysis, etc. Some
fat-soluble artemisinins are more toxic than artesunate. Oral administration of artesunate
can lead to ataxia while artemether–lumefantrine combination can lead to hearing loss in
patients. Artemisinins also have embryotoxic side effects when used in animals.
224 Pharmaceutical Chemistry
9.3.5 Primaquine
It was first developed in 1945 and introduced in the early 1950s
MeO
as an antimalarial drug. Primaquine contains an asymmetric
HN
N
NH
2
chiral centre, thus it is a racemic mixture of D- and L-enantiomer
of primaquine. It has a powerful and unique role in the
prevention and cure of malaria and also in the treatment of
Pneumocystis pneumonia.
Primaquine
FDA has approved this drug due to its ability to kill all liver
stages (hypnozoites and schizonts) of the parasite. Primaquine also shows potent activity
against both asexual and sexual blood stages of the parasite. Primaquine is also a drug of
choice since 1950s due to its radical curability to P. vivax, very effective in eliminating the
hypnozoites of P. ovale and P. vivax from the bloodstream and acts as gametocytocidal
agent for P. falciparum malaria.
Primaquine can result in haemolysis (most common human genetic enzymatic
disorder) particularly in those patients who have deficiency of glucose-6-phosphate
(G6P) dehydrogenase enzyme. Particular patients with less than 10% of normal enzyme
activity may have greater chance of severity of haemolysis even after a single dose of
primaquine.
9.3.5.1 Specification
Name : N4-(6-Methoxy-8-quinolinyl)-1,4-pentanediamine and 6-Methoxy-
8-(4-amino-1-methylbutylamino) quinoline
Molecular formula : C
15H21N3
O
Molecular weight : 259.38 g/mol
Melting point : < 25°C
Physical state : Viscous liquid to solid
Solubility : Soluble in methanol, ethanol, acetone and water.
9.3.5.2 Synthesis of Primaquine
Chemoprophylaxis
The traditional uses of primaquine in malaria caused by P. vivax are threefold: primary
(causal) prophylaxis, terminal prophylaxis and radical cure.
Primary (causal) prophylaxis: Primaquine is an ideal drug against P. ovale and P. vivax
species as a primary prophylaxis, at the time when parasite successfully completes its
hepatic stage just before entering the erythrocytic stage. Thus, ~30 mg/day is prescribed
one day before the exposure and continued for another seven days till the end of exposure.
Terminal prophylaxis: Primaquine is also prescribed at the end of the exposure period of
the parasite or so-called terminal prophylaxis. It is suggested that primaquine should be
administered to avoid remaining relapses in hepatic reservoir which are actually caused
by the liver hypnozoites. Thus, ~30 mg/day is prescribed for another 14 days to clear
Antimalarial Agents 225
relapses. The combination of primaquine and chloroquine may be administered for this
purpose because chloroquine enhances the hypnozoite clearance of primaquine.
MeO HNO3/NaNO
CHCl3, rt
HCl
EtOH, reflux
O
AcOH/NaBH4, 20°C
MeO
NO
O
N
O
2
2
MeO
MeO
NH2.HCl
HN
NO
Glycerine
Sulfomix
130°C
N
O
Pd/NH2NH
H
O
2
EtOH, reflux
2
MeO
O
N
,
2
MeO
N
NO
2
1. NH2NH2, H2O
EtOH, reflux
PO
2. H
3
4
1. Ac2O
AcOH, rt
2. HNO
NO
2
10°C
Pd/NH2NH2, H
EtOH, reflux
MeO
MeO
,
3
MeO
O
2
N
HN
Primaquine
N
H
NO
2
NH
.2 H3PO
NH
2
O
N
2
4
Radical cure: Primaquine is also used as a radical cure. Primaquine (~15 mg) with blood
schizontocidal agents may be administered twice a day for 14 days. This combination
results in better clearance of the liver hypnozoites.
9.3.5.3 Mechanism of Action
Antimalarial drug, primaquine is the essential co-drug of another antimalarial drug
chloroquine which is used in treating all types of malaria. It is lethal to P. ovale and P. vivax
in the liver stage, and also to P. vivax in the blood stage through its ability to oxidatively
damage the cell. However, the exact mechanism of action is not fully understood.
Haemoglobin is divided into heme and globin when malaria parasites enter the
bloodstream. Haem is toxic and able to damage malaria parasite. Thus, to prevent this
damage, malaria parasite generates a chemical which helps in the conversion of toxic
heme into a non-toxic heamozoine. Primaquine is believed to act by interfering with a
part of the parasite or so-called mitochondria which is actually responsible for supplying
energy. It is considered that without energy the parasite dies and eventually stops the
infection and allows patients to recover. Thus, exact mechanism is still a topic of
discussion whereas it is believed that primaquine exerts its activity by accumulation
within the mitochondria and destroys the mitochondrial function by performing
conformational manipulation and swelling within the inner membranes. It also prevents
the development of gametocytes and erythrocytic forms by killing the intrahepatic form
of P. ovale, P. vivax and P. falciparum.
226 Pharmaceutical Chemistry
9.3.5.4 Absorption, Metabolism and Excretion
It is rapidly absorbed orally with overall 96% of bioavailability. Primaquine is generally
distributed (volume of distribution ~200-300 L) into body tissues, with a systemic clearance
of about 30-40 L/hour whereas elimination half-life is about 6 hours. The quick metabolism
of primaquine is noticed and very less amount (1-4%) is found in the urine, however it
accumulates various unstable intermediates. The inactive carboxyprimaquine is a major
plasma metabolite of primaquine and not found in the urine, thus it is believed that this
may have formed further metabolite. Other metabolites of primaquine include
5-hydroxyprimaquine, 6-desmethylprimaquine, 5,6-dihydroxy-8-aminoquinoline,
5,6-dihydroxyprimaquine, and 6-methoxy-8 aminoquinoline (Fig. 9.8).
MeO
HN
OH
N
NH
2
OH
HO
N
HN
5-Hydroxyprimaquine 5-Hydroxydemethyl
-primaquine
OH
MeO
N
HN
2-Hydroxy-primaquine
O
MeO
OH
MeO
NH
HN
2
4-Hydroxy-primaquine
OH
N
MeO
OH
OH
N
N
5-Hydroxylation quinone
-imine formation
&Trihydroxylation
MeO
NH
2
5-Hydroxylation quinone
-imine formation &
Dihydroxylation
MeO
N
HN
OH
HN
MeO
NH
2
Carboxyprimaquine
O
NH
2
5,6-Orthoquinone
O
OH
N
N
OH
N
OH
OH
HN
HN
O
NH
NH
MeO
N
O
OH
3-Hydroxy-primaquine
HO
N
NH
2
O
MeO
2
N
5-Hydroxylation quinone-
imine formation &
Hydroxylation
O
MeO
2
N
N
HN
OH
N
NH
2
5,6-Dihydroxy-8-
aminoquinoline
OH
N
NH
N
OH
OH
2
NH
2
4-(6-Methoxy-quinolin8-ylamino)-pentan-1-ol
Dihydroxy-primaquine
Fig. 9.8: Metabolites of primaquine
8-(4-Hydroxy-1-methyl-
butylimino)-6-methoxy-
8 -quinolin-5-oneH
Antimalarial Agents 227
These metabolites are believed to generate oxygen-active species which are responsible
for toxicity of the parasite and host cells. Research has been engaged to increase the quality,
stability and bioavailability of primaquine which includes various drug administration
mechanisms, viz., transdermal delivery systems, primaquine-amino acid conjugates,
primaquine encapsulation into liposomes and nanoparticles and galactose-coated
polypropyleneimine nanoparticles as the primaquine vehicle.
9.3.5.5 Side Effects
Though unique, effective and irreplaceable character of primaquine it has serious side
effects, viz., its ability to precipitate haemolysis in patients suffering with glucose-6phosphate (G6P) dehydrogenase deficiency. Its use in pregnant women must be
avoided.
9.3.6 Common Side Effects of Antimalarials
Vomiting, dizziness, itching, confusion, pain abdomen (abdominal cramps and abdominal
discomfort), delirium, cinchonism, altered behaviour, hallucinations, rare acute
neuropsychiatric syndrome, etc. Patient on long-term prophylaxis must contact a doctor.
9.4 NATIONAL DRUG POLICY ON MALARIA
“National drug policy on Malaria” by Directorate of National Vector Borne Disease Control
Programme, Directorate General of Health Services, Ministry of Health and Family
Welfare, Delhi, India, has planned a schedule for the ‘diagnosis and treatment for malaria’
as follows in Annexure-1(227).
228 Pharmaceutical Chemistry
ANNEXURE 1
DRUG SCHEDULE FOR TREATMENT OF MALARIA UNDER NVBDCP
Diagnosis and Treatment for Malaria
Diagnosis and Treatment
All fever cases diagnosed as malaria by either RDT or microscopy should be promptly
given effective treatment. The medicine chosen will depend upon whether the patient has
vivax malaria or falciparum malaria as diagnosed by the blood test. The flowcharts in
different settings for diagnosis and drug selection for the treatment of malaria are as under:
ACT-AL: Artemisinin-based Combination Therapy– Artemether-Lumefantrine
ACT-SP: Artemisinin-based Combination Therapy (Artesunate +SulfadoxinePyrimethamine)
CQ: Chloroquine
PQ: Primaquine
Antimalarial Agents 229
Note: If a patient has severe symptoms at any stage, then immediately refer to the nearest
PHC or other health facility with indoor patient management or a registered medical
doctor.
Note: PQ is contraindicated in pregnancy and in children under 1 year (infant).
ACT-AL: Artemisinin-based Combination Therapy- Artemether – Lumefantrine
ACT-SP: Artemisinin-based Combination Therapy (Artesunate+SulfadoxinePyrimetha-
mine)
CQ: Chloroquine
PQ: Primaquine
230 Pharmaceutical Chemistry
Where microscopy result is not available within 24 hours and Bivalent RDT is used
Suspected Malaria case
Do blood test with RDT
Positive for
P. vivax
Discard slide
Treat with: CQ 3
days + PQ 14
days
Positive for
P. falciparum
Discard slide
In North Eastern
states: Treat with
age specific ACT-
AL for 3 days +
PQ single dose
on second day
In other states:
Treat with: ACT-
SP for 3 days +
PQ single dose
on second day
Positive for
P. falciparum
Discard slide
In North Eastern
states: Treat with
age specific ACT-
AL for 3 days +
Premaquine 0.25
mg/kg body weight
daily for 14 days
In other states:
Treat with: ACT-
SP for 3 days + PQ
single dose on
second day
Negative
No antimalarial
treatment
Note:
(1) However, if malaria is strongly suspected, prepare and send slide for microscopy.
(2) If a patient has severe symptoms at any stage, then immediately refer to the nearest
PHC or other health facility with indoor patient management or a registered medical
doctor.
(3) PQ is contraindicated in pregnancy and in children under 1 year (infant).
Note: PQ is contraindicated in pregnancy and in children under 1 year (infant).
ACT-AL: Artemisinin-based Combination Therapy- Artemether – Lumefantrine
ACT-SP: Artemisinin-based Combination Therapy (Artesunate+SulfadoxinePyrimetha-
mine)
CQ: Chloroquine
PQ: Primaquine
9.5 WHO GUIDELINES FOR THE TREATMENT OF MALARIA
The WHO guidelines for the treatment of malaria contain updated recommendations
based on new evidence particularly related to dosing in children, and also includes
recommendations on the use of drugs to prevent malaria in groups at high risk. The
following core principles were used by the WHO for the betterment of malaria.
Antimalarial Agents 231
(a) Early diagnosis and prompt, effective treatment of malaria: Uncomplicated
falciparum malaria can progress rapidly to severe forms of the disease, especially in
people with no or low immunity, and severe falciparum malaria is almost always
fatal without treatment. Therefore, programmes should ensure access to early
diagnosis and prompt, and effective treatment within 24-48 hours of the onset of
malaria symptoms.
(b) Rational use of antimalarial agents: To reduce the spread of drug resistance, limit
unnecessary use of antimalarial drugs and better identify other febrile illnesses in
the context of changing malaria epidemiology, antimalarial medicines should be
administered only to patients who truly have malaria. Adherence to a full treatment
course must be promoted. Universal access to parasitological diagnosis of malaria
is now possible with the use of quality-assured rapid diagnostic tests (RDTs), which
are also appropriate for use in primary health care and community settings.
(c) Combination therapy: Preventing or delaying resistance is essential for the success
of both national and global strategies for control and eventual elimination of
malaria. To help protect current and future antimalarial medicines, all episodes of
malaria should be treated with at least two effective antimalarial medicines with
different mechanisms of action (combination therapy).
(d) Appropriate weight-based dosing: To prolong their useful therapeutic life and
ensure that all patients have an equal chance of being cured, the quality of
antimalarial drugs must be ensured and antimalarial drugs must be given at optimal
doses. Treatment should maximize the likelihood of rapid clinical and parasitological
cure and minimize transmission from the treated infection. To achieve this, dosage
regimens should be based on the patient’s weight and should provide effective
concentrations of antimalarial drugs for sufficient time to eliminate the infection in
all target populations.
QUESTIONS
1. What are antimalarial agents? Explain with an example.
2. Explain the life cycle of malaria parasite.
3. How are antimalarial drugs classified?
4. What is chloroquine and how does it synthesize?
5. Explain the mode of action of chloroquine.
6. What are the metabolites of chloroquine and how do they get excreted from the
host?
7. Write a short note on quinine.
8. How is quinine synthesized?
9. What are the metabolites of quinine? Explain the metabolic pathway.
10. Write a note on artemisinin.