ANTIMALARIAL DRUGS

 DL       = Drug interaction Cl      = Contraindications

ADR   = Adverse Drug reactions

Chloroquine

 10 mg base/kg PO (max 600 mg), then 5 mg base/kg PO (max 300 mg) at 6h, 24h, and 48h (total 25mg/kg)

Same dose in children, as in adults.

ADR- Hypotension which given IV, impairs intradermal rabies vaccine, exacerbates psoriasis, causesretinopathy with 100 mg cumulative dose.

Dl- Penicillamine and chloroquine should not be used concurrently

Quinine sulfate

10 mg salt/kg PO q8h for 3-7d Same dose in children, as in adults.

ADR- Allergy, hypoglycemia, myasthenia gravis, thrombocytopenic purpura, Blackwater fever, G6PDdeficiency, or history of cardiac dysrhythmias (Stop if QTC is > 0.6/QRS is increased by >25% of the baseline).ECG monitoring is therefore required.

Dl- Delays absorption of digoxin which can lead to increased serum concentration, antagonizeseffects of antimyasthenics and mefloquine increases risk of seizures.

Quinine dihydrochloride (for severe or complicated malaria)

20 mg salt/kg IV load 5% dextrose over 4h; then 10 mg salt/kg IV q8h until PO therapy possible (max,1800 mg/d); (EKG monitor in intensive care unit)

Same dose in children, as in adults.

ADR- Allergy, hypoglycemia, myasthenia gravis, thrombocytopenic purpura, Blackwater fever, G6PDdeficiency or history of cardiac dysarrhythmias (above are given the ECG indications to stop therapy).

Dl- Delays absorption of digoxin which can lead to increased serum concentration, antagonizeseffects of antimyasthenics and mefloquine increases risk of seizures.

Clindamycin

10 mg/kg PO (max 900 mg) q6h for 3-5d Same dose in children, as in adults.

Cl- Risk-benefit should be considered with hypersensitivity of patient to lincomycins or doxorubicin, patients with history of severe gastrointestinal disease or severe liver dysfunction.

ADR- May cause pseudomembranous colitis and vomiting.

Primaquine(for prevention of relapse with P.Vivax and P.ovale)

Adults- 0.25 mg base/kg PO qd for 14d (usual dose 15 mg base [26.3 mg salt] PO qd for 14d) or 0.8mg base/kg PO once/wk for 6-8 wk (usual dose 45 mg base[79 mg salt] PO once/wk for 6-8 wk)

Chilldren – 0.25 mg base/kg PO qd for 14d or 0.8 mg base/kg PO once/wk 6-8 wk.

ADR- Hemolysis in G6PD deficiency, methemoglobinemia, rare agranulocytosis, and vomiting.

Dl- Quinacrine(may increase toxic effects of primaquine).

Pyrimethamine-sulpadoxine (Fansidar)

 Pyrimethamine 1 mg/kg- sulfadoxine 20 mg/kg PO once (1 tablet=25 mg pyrimethamine -500 mgsulfadoxine; usual dose 3 tablets once on last day of quinine).

Cl- Allergy to sulfonamides, pyrimethamine, furosemide, thiazide diuretics, sulfonylureas, or carbonic anhydrase inhibitors preclude use of drug combination. Should not be used in patients withanemia, bone marrow depression, hepatic or renal dysfunction, porphyria or history of seizure disorders. May cause exfoliative dermatitis, Stevens-Johnson syndrome, hepatitis or pancytopenia.

Dl- In combination with bone marrow depressants, may cause increased leukopenia and/or thrombocytopenic effects. With folateantagonists combination can cause development of megaloblastic anemia.

Tetracycline

4 mg/kg PO (max 250 mg) q6h for 7d

Greater than 8y:kg PO (max 250 mg) q6h for 7d Contraindicated for children 8y or under.

Unsafe in pregnancy.

Women who are breast-feeding should not use tetracycline.

Dl- Antacids, calcium supplements, salicylates, iron supplements,

Magnesium-containing laxatives, cholestyramine, colestipol or oral estrogen-containing contraceptives.

Doxycycline

100 mg PO bid 7d

Greater than 8 y of age: 2 mg/kg PO bid 7d

Cl- Pregnancy, children 8 years of age or younger Dl- Barbiturates, carbamazepine, and phenytoin.

Mefloquine

 15 mg base/kg PO, then 10 mg base/kg PO 6-8h later (max total dose 1250 mg: usually 750 mg PO,then 500 mg PO at 6-8h)

Safety and effectiveness have not been established in children.

Cl- Patients with seizure disorders, heart block, or psychiatric disorders. Toxic encephalopathy (in0.5-1.0% of Europeans and Africans and in 1% of Asians), seizures, prolonged Qtc syndrome, dysrhythmias, vomiting, dizziness, dysphoria, dissociation, ataxia and impairs fine spatial coordination.

Dl- Avoid use with halofantrine, addictive cardiotoxicity with quinine,quinidine and antiarrhythmics.

D- Unsafe in pregnancy.

Halofantrine 

8 mg/kg PO (max 500 mg) q6h for 3 doses; repeat course in 1 week for the non-immune. Same dose in children, as in adults.

Cl- Known congenital or family history of QT prolongation (risk of arrhythmia). Risk- benefit considered with AV conduction disorders, syncope, thiamine deficiency, ventricular dysrhythmias,cerebral malaria or other malarial complications.

Dl- With Mefloquine( increased risk of cardiac effects), quinine,quinidine, anti- arrhythmics, tricyclicantidepressants, neuroleptics, terfenadine and astemizole.

Artesunate

 4 mg/kg PO qd for 3d (total dose 12 mg/kg) (1 tablet=50mg). For severe or complicated malaria usethe following dosages: 2.4 mg/kg IV load, then 1.2 mg/kg IV at 12h and 24h, then 1.2 mg/kg IV q24huntil PO therapy possible.

Same dose in children, as in adults.

ADR- Brainstem neurotoxicity and death in non-human primates, drug fever C- Safety for use during pregnancy, has not been established.

Artemether(for severe or complicated malaria only) 1st day-80 mg IM BD, 2nd, 3rd, 4th, 5th days 80 mg OD

TOTAL DOSE= 480 mg; CAPSULES 1st day 4 caps (160 mg) in 2 doses Q 12 hrly, thereafter 2 (80 mg) caps daily. TOTAL DOSE= 480Mg

3.2 mg/kg IM (anterior thigh), then 1.6 mg/kg IM q24h until PO therapy possible (never IV)

ADR- Brainstem neurotoxicity and death in non-human primates, drug fever.

Further Inpatient Care:

 ·       The patient should have thick and thin blood smears performedevery 12h until parasitemia falls below 1% to ensure that the therapy instituted is clearing the infection. If paristemia does not fall by 75%within 48h or if the blood is not cleared of parasites after 7d, a differenttherapeutic regimen should be initiated immediately.

Chemoprophylaxis is available in many different forms. The drug of choice is determined by the destination of the traveler and any medical conditions the traveler may have that contraindicatethe use of a specific drug.

Complications:

·       Most complications are caused by P.Falciparum.

·       Coma (cerebral malaria) – Defined as coma, altered mental status or multiple seizures withP.Falciparum in the blood. This complication is the most common cause of death in malariapatients. If untreated, cerebral malaria is lethal. Even with treatment, 15% of children and 20% of adults who develop cerebral malaria die. The symptoms of cerebral malaria die. Thesymptoms of cerebral malaria are similar to those of toxic encephalopathy.

MANAGEMENT:

 ·       Meticulous nursing care

·       Initiate IV chemotherapy

·       Catheterize

·       Input/output chart, rehydrate cautiously, correct electrolytes

·       Q6 hrly blood glucose levels 10% dextrose 4-8 hr infusions.

·       Monitor GCS, TPR, BP, maintain temp <38.5C

·       Mannitol/glycerol to decrease oedema

·       >15% parasitic index – exchange transfusion

·       Treat convulsions with diazepam or paraldehyde

AVOID :Steroids, NSAIDS, Low mol. Wt dextran, Adrenaline, Heparin, Prostacyclin, Pentoxyphylline,Hyperbaric oxygen, Cyclosporin A.

·       Seizures

·       Renal failure- Up to 30% of nonimmune adults infected with P.falciparumsuffer acute renal failure. Consider peritoneal/hemodialysis if patient remains oliguric/anuric after adequate rehydration. Give isotonic saline till CVP is at 15cm of H2O

·       Hemoglobinuria (blackwater fever)-Blaclkwater fever is the passage of dark, colored urine. This condition is caused by hemolysis, hemoglobinemia and the subsequent hemoglobinuriaand hemozoinuria.

·       Noncardiogenic pulmonary edema- This affliction is most common in pregnant women andresults in death in 80% of cases.

Management :

 ·       Keep patient upright, raise head end.

·       High conc. Of oxygen, may even consider mechanical ventilation.

·       Frusemide, 40 mg IV, can increase upto 200 mg, if no response.

·       ICU care, O2 PEEP, ventilation, haemodynamic support.

·       If due to overhydration stop all IV fluids, use Frusemide, withdraw 250 ml of blood byvenesection.

·       Profound hypoglycemia- Hypoglycemia often occurs in young children and pregnant womenand is often difficult to diagnose since adrenergic signs are not always present and since stupor may already there.

·       Patients at risk for the above- serious diseases, children, pregnant women and those onQuinine/Quinidine therapy.

Management : 50 ml 50% glucose at clinical suspicion followed by IV infusion of 5-10% dextroseclose monitoring of glucose

·       Lactic Acidosis- This occurs when the microvasculature becomes clogged with P.falciparum.If venous lactate level reaches 45 mg/Dl, a poor prognosis is very likely.

·       Hemolysis resulting in severe anemia and jaundice. If PCV<20% consider transfusing freshWB/packed cells.

·       Bleeding (coagulopathy)

Prognosis:

 ·       Most uncomplicated malaria patients show marked patients show marked improvementwithin 48h after the initiation of treatment and are fever-free after 96h. For pregnant women and children, see Special Concerns section below.

Special Concerns (WOMEN and CHILDREN)

 ·       PREGNANT women, especially primagravid women, are up to 10 timesmore likely to contract malaria than non-gravid women. Gravid women who contract malaria also have greater tendency to develop severe malaria. Unlike malarial infection in non-gravid individuals , pregnant women with P.vivax are at high risk for severe malaria and those and those with P.flaciparum have a greatly increased predisposition for severe malaria as well. Ifa pregnant woman becomes infected, she should know that many of the antimalarial and antiprotozoal drugs used to treat malaria are safe for use during pregnancy for both the mother and the fetus. Therefore, they should be used since the benefits of these drugs out- weigh the risks associated with leaving the infection untreated.

·       In children, malaria has a shorter course, often progressing rapidly to severe malaria. Children are more likely to present with hypoglycemia, seizures, severe anemia and sudden death but much less frequently develop renal failure, pulmonary edema or jaundice. Cerebral malaria leaves between 9-26% of children with neurologic sequelae but of these about half resolve completely with time. Most antimalarials are very effective and safe in children, provided that the proper dosage is administered and it is common for children torecover from even severe malaria much faster than adults. 

INDICATIONS FOR PARENTERAL THERAPY

 ·       Failure to retain drugs due to vomiting

·       Cerebral Malaria

·       Multiple complications

·       Peripheral Asexual Parasitemia>/=5%

STEPS IN MANAGEMENT

 ·       Hospitalize

·       Parasitic Index-need for exchange transfusion

·       Recheck daily

CONSIDER EXCHANGE TRANSFYUSION IF PARASITIC INDEX > 10%

RESISTANCE OF PARASITE TO DRUG--------------- WHEN TO SUSPECT/DIAGNOSE?

DRUG USED

Qunine Dl HCl 10 mg/kg (max. 600 mg) diluted in 300 ml dextrose over 1-2 hrs. Followed by 10 mg/kg/8 hrly

Switch over to oral quinine S04, 10 mg/kg TID x 3-7 days

CHLOROQUINE SENSITIVE P.FALCIPARUM

 Rx:- Tab CQ. 150 mg base (250 mg each) 4 tabs stat followed by 2 of same 6 hours later followed by4 tabs (1 bdx2 days)

CHLOROQUINE RESISTANT

Quinine SO4 + Doxy 100 mg bd x 7d/ Clinda 900 mg TIDx 3 D/Metakelfin (Pyritmethamine 25 MG+ Sulfadiazine 500 MG) 4 TIDx5 D/Tetracycline 250-500 mg 4 times a day x 7D/ 3 tabs of Fansidar stat ORMefloquineORHalofantrineORArtemetherORArtesunate

Px FOR P.VIVAX CQ+ Primaq.

ELIMINATION OF GAMETOCYTES

For P.Malariae, ovale, vivax                                                  -- Chloroquine For P. Falciparum       -- Primaquine

CHEMOPROPHYLAXIS

 If chloroquine sensitive area :

·       Chloroquine 500 mg/week --- Starting 1 wk before exposure and continuining 4 wks after

If Chloroquine resistant area :

·       Mefloquin 25 mg/wk OR

·       Doxy 100 mg/day Starting 2 days before, Cont. 4 weeks after Primaquine on returning home if significant exposure.

Pregnancy--------------------- Chloroquine only.