Cardiac Output, Venous Return, and Their Regulation
Drugs for Malaria
1. Malaria and Drugs For Malaria
Malaria is a protozoal disease, caused by:
1. Plasmodium vivax
2. Plasmodium malariae
3. Plasmodium ovale
4. Plasmodium falciparum
Most of the serious complications and death occur
due to Plasmodium falciparum.
Antimalarial drugs are used for the prophylaxis,
treatment and prevention of relapses of malaria.
10. CHLOROQUINE (CQ)
Chloroquine is a rapidly acting erythrocytic schizontocide
against all species of plasmodium; controls most clinical
attacks in 1–2 days with disappearance of parasites from
peripheral blood in 1–3 days.
Mechanism of Action
Chloroquine accumulates in food vacuoles, specifically binds
to heme, preventing its polymerization to hemozoin.
The increased pH and the accumulation of heme result in
oxidative damage to the membranes, leading to lysis of both
the parasite and the red blood cell.
Heme
CQ
Hemozoin
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12. Indication
• Malaria
• Rheumatoid arthritis
• Extraintestinal amoebiasis
Contraindication and Precaution
• Contraindicated in patients with hypersensitivity, retinal damage.
• Precaution should be taken by patients with hepatic or renal
impairment, G6PD deficiency, epilepsy etc.
Adverse Effects
• GI disturbance, aplastic anaemia, dizziness, psychosis, alopecia,
ratinopathy, hypokalaemia, headache etc.
Dose
• Adult: 600 mg stat, then 300 mg 6-8 hr on day 1 & 300mg on day 2
& 3.
• Child: initially 10mg base/kg, followed by 5mg base/kg after 6 hrs.
single doses of 5 mg base/kg on day 2 and 3.
• Prphylaxic dose: 300 mg once a week.
13. PRIMAQUINE
Primaquine eradicates primary exoerythrocytic forms of P.
falciparum and P. vivax and the secondary exoerythrocytic
forms of recurring malarias (P. vivax & P. ovale).
It has marked effect on primary as well as tissue phase of
malarial parasite and highly active against gametocytes and
hypnozoites.
Mechanism of Action
• It acts by interfering with a part of the parasite electron
transport chain (mitochondria) that is responsible for
supplying it with energy.
• It acts as an antagonist of Ferriprotoporphyrin IX.
• It prevent relapse of vivex & ovale malarias following
treatment with a blood schizontocide.
14. Indication
• Used in the treatmentof vivax or ovale malaria.
Contraindication and Precautions
• Contraindicated in patients with agranulocytopenia.
• Precaution should be taken by patients with G6PD
deficiency.
Adverse Effects
• Nausea, Epigastric distress, vomiting, abdominal
cramps, methaemoglobinemia etc.
Dose
• Adult: 15 mg daily for 14 days, increased to higher
doses or longer coarse if resistance in P. vivax occurs.
• Child: 0.5 mg/kg once daily for 14 days.
15. MEFLOQUINE (MQ)
Mefloquine is a fast acting erythrocytic schizontocide but has
prolonged absorption time. It is effective against CQ-sensitive as well
as resistant plasmodia. It controls fever and eliminates circulating
parasites in infections caused by P. falciparum or P. vivax
Mechanism of Action:
• Mefloquine accumulates in infected RBCs binds to haeme and
damages the parasite membranes.
• It produces swelling of P. falciparum food vacules and may form
toxic complexes with free heme that damage membranes and
interact with other plasmodial components.
Indication:
• Reserved for prevention and treatment of drug resistant
P.falciparum and P. vivax
• Used in combination with artemisinin
• Chemoprophylaxis- travellers spending long duration in endemic
regions
16. Adverse Effects:
• Bitter taste, dizziness, nausea, vomiting, diarrhoea, abdominal pain
• Sinus bradycardia and QT prolongation
• Neuropsychiatric reactions
• Rarely haematological, hepatic and cutaneous toxicity can occur
Contraindication and Precautions:
• Contraindicated in patients treated with quinine before 12 hr and
patients with history of psychiatric illness, seizure and hepatic
disorder.
• Precaution should be taken by patients with epilepsy and children
bellow 3 months or 5 kg.
Dose
• Adult: 20-25 mg/kg as a single dose or in two to three divided dose
(Max. 1.5 gm/dose)
• Child: 25 mg/kg BID.
17. QUININE & QUINIDINE
• Quinine and its stereoisomer, Quinidine, are erythrocytic
schizontocide for all species of plasmodia. But is less effective and
more toxic than chloroquine.
Mechanism of Action
• They interfere with heme polymerization, resulting in death of the
erythrocytic form of the plasmodial parasite.
Contraindication and Precausions
• Contraindicated in patients with atrial fibrillation (irregular heart
beat that can lead to cloting, stroke &heart fail), atrial flutter (abnormal
heart rhythm).
• Precaution should be taken by patients with myathenia gravis
(neuromuscular disease that leads to fluctuating muscle weakness and fatigue).
18. Indication
• Uncomplicated resistant falciparum malaria
• Complicated and severe malaria including cerebral malaria
• Nocturnal muscle cramps
Adverse Effects
• The major adverse effect of quinine is cinchonism, a
syndrome causing nausea, vomiting, tinnitus, and vertigo.
• Other side effects including, hypoglycaemia, hypotension,
hypersensitivity, respiratory depression, sinus tracycardia,
visual disturbance, black water fever, etc.
Dose
• Adult and child: 10 mg/kg, IV or PO
19. Antifolates/Antimetabolites
• Sulfadoxine
• Dapsone
• Pyrimethamine
• Proguanil
MOA: These drugs inhibit enzyme dihydrofolate
reductase (DHFR) & other enzymes for folate
synthesis and affect protozoal DNA synthesis.
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21. Antibiotics
• Doxycycline
• Tetracycline
• Clindamycin
• Slow acting erythrocytic schizontocides
• Active against all plasmodial species, including CQ, MQ and
S/P resistant P. falciparum
Mechansim of Action:
• Delayed death mechanism resulting from their inhibition of
protein translation in the parasite
• Used in combination with quinine or artesunate for
uncomplicated and severe falciparum malaria
Adverse Drug Reactions
• Discolouration of bones and teeth
• Not to be given to pregnant women or to children < 8 yrs
(Clindamycin used)
• Photosensitivity reactions
22. Amino Alcohols
• Halofantrine
• Lumefantrine
• Halofantrine is blood schizontocide effective against P.
falciparum resistant to CQ and S/P, as well as against P.
vivax.
• It possess Cardiac toxicity so limited use!
• Not to be used for chemoprophylaxis
• ADR- abdominal pain, diarrhea, vomiting, cough, rash,
headache, pruritis, elevated liver enzyme
• Contraindicated in pregnancy, patients with cardiac
conduction defects and who have recently taken mefloquine
• Lumefantrine is used in combination with artemisinin
derivative as first line therapy for uncomplicated falciparum
malaria
23. Artemisinin & its derivatives
Artemisinin is the active compound of the plant Artemisia
annua (तििेपािी) used in Chinese traditional medicine as
‘Quinghaosu’ discovered by Tu Youyou.
It is a sesquiterpine lactone endoperoxide active against P.
falciparum resistant to all other antimalarial drugs as well as
other malarial species. Potent and rapid blood schizontocide
action is exerted eliciting quicker parasitic clearance.
Artesunate oral, i.m. or i.v. route
Artemether oral or i.m. route
α/β Arteether i.m. 150mg daily for 3 days
Arterolane oral; combined with Piperaquine
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25. Mechanism of Action:
• Artemisinin is metabolised into dihydroartemisinin which
interacts with ferriprotoporphyrin IX and generates toxic
substances that acts against erythrocytic stage of
plasmodium.
• The endoperoxide bridge in artemisinin interact with haeme
in the parasite. Ferrous iron-mediated cleavage of the
bridge releases a highly reactive free radical species that
binds to membrane proteins, causes lipid peroxidation,
damages endoplasmic reticulum, and ultimately results in
lysis of the parasite.
• It has potent schizontocidal action and are lethal to early
stage malarial gametes.
Indication:
• ACT-Standard of Care for uncomplicated malaria
• Complicated falciparum malaria
• Severe malaria
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27. Adverse Drug Reactions
• Nausea, vomiting, diarrhea, dizziness
• Rare serious toxicities:- decreased reticulocyte
and neutrophil counts, increased transaminase
levels, allergic reactions
• Recommended not to be used for children </=
5kgs or during the first trimester of pregnancy
Contraindication and Precautions
• Contraindicated in hypersensitivity.
• Precaution should be taken by patients with
hepatic impairment, pregnant and lactating
mothers.
28. Artemisinin Based Combination Therapy (ACT)
WHO has recommended that all cases of acute
uncomplicated falciparum malaria should be treated
only by combining one of the artemisinin compounds
with another effective erythrocytic schizontocide.
Because artemisinins are short acting drugs, artemisinin
is usually combined with a long acting drug.
Advantages of ACT over other antimalarials are:
1. Rapid clinical and parasitological cure.
2. High cure rates (>95%) and low recrudescence rate.
3. Absence of parasite resistance (the components
prevent development of resistance to each other).
4. Good tolerability profile.
