Absorption of which of the following antimalarial drugs increases with food intake?
Ans. a (Mefloquine) (Ref. KDT 6'h/787; Goodmann Gilllman Pharmacology, Chapter 39). Psychosis and seizures occur rarely, and mefloquine should not be prescribed to patients with neuropsychiatric conditions, including depression, generalized anxiety disorder, psychosis, schizophrenia, and seizure disorder. Antimalarial drugs 1. Suppressive (to avoid infection) 2. Therapeutic (eliminate erythrocytic) 3. Radical cure (elimination exoerythrocytic) 4. Gametocidal (destruction of gametocytes) Successful treatment is accomplished with chloroquine followed by primaquine. Chloroquine therapy is suppressive, therapeutic, and gametocidal, whereas primaquine eliminates the exoerythrocytic form. MEFLOQUINE # Like quinine and chloroquine, this quinoline is active only against the asexual erythrocytic stages of malarial parasites. # It has been the antimalarial prophylactic agent of choice for much of the tropics because it is usually effective against multidrug-resistant falciparum malaria and is reasonably well tolerated. # Mefloquine's mode of action is similar to that of chloroquine. # The presence of food significantly enhances the rate and extent of absorption. # About 98% of the drug binds to protein. # Mefloquine is excreted mainly in the bile and feces; no dose adjustment is needed in persons with renal insufficiency. # Adverse effects: - Mefloquine should be used with caution in individuals participating in activities requiring alertness and fine-motor coordination (e.g., driving, piloting aircraft, operating machinery, and deep-sea diving). - Sleep abnormalities (insomnia, abnormal dreams) have occasionally been reported. - Halofantrine must not be given simultaneously with or <3 weeks after mefloquine because a potentially fatal prolongation of the QTc interval on electrocardiography may occur. - Caution should be exercised with regard to concomitant antiretroviral therapy, since mefloquine has been shown to exert variable effects on ritonavir pharmacokinetics. - Women of childbearing age are encouraged to practice contraception during malaria prophylaxis with mefloquine and for up to 3 months thereafter. ATOVAQUONE # Absorption after a single oral dose is slow, erratic, and variable; increased two- to threefold by fatty food; and dose- limited above 750 mg. CHLOROQUINE # It has marked, rapid schizontocidal and gametocidal activity against blood forms of P. ovale and Plasmodium malariae and against susceptible strains of P. vivax and P. falciparum. # It is not active against intrahepatic forms (P vivax and P ovale). # Hydroxychloroquine, a congener of chloroquine, is preferred to chloroquine for the treatment of autoimmune disorders because it produces less ocular toxicity when used in high doses. # Chloroquine can be administered intravenously, but excessively rapid parenteral administration can result in seizures and death from cardiovascular collapse. # About half of the drug is excreted in urine, but dose not reduced for persons with acute malaria and renal insufficiency. ARTEMISININ DERIVATIVES (THE NOVEL ANTI-MALARIALS) # Artesunate, artemether, arteether, and the parent compound artemisinin are sesquiterpene lactones derived from the wormwood plant Artemisia annua. (Chinese drugs). # These are rapidly effective against multidrug-resistant falciparum malaria and are at least as effective as and considerably safer than quinine or quinidine. # These agents are at least ten-fold more potent in vivo than other antimalarial drugs and presently show no cross- resistance with known antimalarials; thus they have become first-line treatments for severe falciparum malaria in areas where multidrug resistance is a major problem. # Artemether appears to be effective for the treatment of schistosomiasis and is being evaluated for community-based treatment programs. # When these agents are used alone, recrudescence may occur. LUMEFANTRINE # Has marked blood schizontocidal activity against a wide range of plasmodia with lower recrudescence rate. # The pharmacokinetic properties of lumefantrine are reminiscent of those of halofantrine, with variable oral bioavailability, considerable augmentation of oral bioavailability by concomitant fat intake, and a terminal elimination half-life of ~4 to 5 days in patients with malaria. Properties of Antimalarial Drugs Drugs Pharmacokinetic properties Antimalarial activity Minor toxicity Major toxicity Quinine, quinidine Good oral and IM absorption (quinine); CI and Vd reduced, but plasma protein binding (principally to a1 acid glycoprotein) increased (90%) in malaria; quinine t1/2: 16 h in malaria, 11 h in healthy persons; quinidine t1/2: 13 h in malaria, 8 h in healthy persons Acts mainly on trophozoite blood stage; kills gametocytes of P. vivax, P. ovale, and P. malariae (but not P. falciparum) : no action on liver stages Common "Cinchonism": tinnitus, high- tone hearing loss, nausea, vomiting, dysphoria, postural hypotension; ECG QTc interval prolongation (quinine usually by <10% but quinidine by up to 25%) Rare: Diarrhea, visual disturbance, rashes Note: very bitter taste Common: Hypoglycemia Rare: Hypotension, blindness, deafness, cardiac arrhythmias, thrombocytopenia, hemolysis, hemolytic-uremic syndrome, vasculitis, Cholestatic hepatitis, neuromuscular paralysis Note: Quinidine more cardiotoxic Chloroquine Good oral absorption, very rapid IM and SC absorption; complex pharmacokinetics; enormous Cl and Va (unaffected by malaria); blood concentration profile determined by distribution process in malaria; t1/2: 1-2 months As for quinine but acts slightly earlier in asexual cycle Common: Nausea, dysphoria, pruritus in dark-skinned patients, postural hypertension Rare: Accomodation difficulties, keratopathy, rash Note: Bitter taste, well tolerated Acute: Hypotensive shock (parenteral), cardiac arrhythmias, neuropsychiatric reactions Chronic Retinopathy (cumulative dose, > 100 g), skeletal and cardiac myopathy Amodiaquine Good oral absorption; largely converted to active metabolite desethylamino- quine As for chloroquine Nausea (tastes better than chloroquine) Agranulocytosis; hepatitis, mainly with prophylactic use Mefloquine Adequate oral absorption; no parental preparation; t1/2: 14-20 days (shorter in malaria) As for quinine Nausea, giddiness, dysphoria, fuzzy thinking, sleeplessness, nightmares, sense of dissociation Neuropsychiatric reactions, convlusions, encephalopathy Tetracycline, doxycycline Excellent absorption; t1/2: 8 h for tetracycline, 18 h for doxycycline Weak antimalarial activity; should not be used alone for treatment Gastrointestinal intole- rance, deposition in growing bones and teeth, photosensitivity, moniliasis, benign intracranial hypertension Renal failure in patients with impaired renal function (Tetracycline) Halofantrine Highly variable absorption related to fat intake; t 1/2: 1-3 days (active desbutyl metabolite t1/2: 3-7 days) As for quinine Diarrhea Cardiac conduction disturbances; QTc interval prolongation; potentially lethal ventricular tachyarrhyyhmias Artemisinin & derivates (artemether, artesunate) Good oral absorption, slow and variable absorption of IM artemether Artesunate and artemether biotransformed to active metabolite dihydroartemisinin; all drugs eliminated very rapidly; t 1/2 :1 h Broader stage specificity and more rapid than other drugs; no action on liver stages; kills all but fully mature gametocytes of P falciparum Reduction in reticulocyte count (but not anemia) Anaphylaxis, urticaria, fever Pyrimetha- mine Good oral absorption, variable IM absorption; t1/2: 4 days) For blood stages, acts mainly on mature forms: casual prophylactic Well tolerated Megaloblastic anemia, pancytopenia, pulmonary infiltration Proguanil (chlorogua- nide) Good oral absorption: biotransformed to active metabolite cycloguanil; t1/2: 16 h: biotransformation reduced by oral contraceptive used and in pregnancy Casual prophylactic; not used alone for treament Well tolerated; mouth ulcers and rare alopecia Megaloblastic anemia Pancytopenia, pulmonary infiltration Primaquine Complete oral absorption; active compound not known; t1/2 : 7 h Radical cure; eradicates hepatic forms of P. vivax and P.ovale; kills all stages of game- tocyte development of P. falciparum Nausea, vomiting, diarrhea, abdominal pain, hemolysis, methemo- globinemia Massive hemolysis in subjects with severe G6PD deficiency Atovaquone Highly variable absorption related to fat intake; t1/2: 30-70 h Acts mainly on trophozoite blood stage None identified None identified Lumefantrine Highly variable absorption ralated to fat intake; t1/2: 3-4 days As for quinine None identified None identified Chloroauine-Sensitive Malaria P. falciparum Chloroquine P. malariae Chloroquine P vivax Chloroquine plus primaquine P. ovale Chloroquine plus primaquine Chloroquine-Resistant Malaria # Prophylaxis: Mefloquine: backup drugs: doxycycline, atovaquone-proguanil # Treatment: quinine, either doxycycline, clindamycin, or pyrimethamine Drug Side effects Contraindications and Cautions Chloroquine, hydroxychloroquine G1 distress, pruritus, headache, dizziness, hemolysis Avoid in psoriasis Mefloquine NVD, dizziness, syncope, extrasystoles, CNS, Psychiatric effects (rare) Avoid in seizures, psychiatric disorders, and in cardiac conduction defects Primaquine GI distress, headache, dizziness, neutropenia, hemolysis Avoid in pregnancy, G6PD defi, and autoimmune disorders Quinine GI distress, cinchonism, CNS effects, hemolysis, hematotoxicity Avoid in pregnancy Also Know: Drugs, whose absorption is decreased by food intake Drugs, whose absorption is increased by food intake Penicillin Griseofulvin Phenytoin Rifampicin Digoxin Spironolactone Erythromycin Itraconazole Levodopa Mefloquine Tetracyclines Important Food-Drug Interactions Drugs Food Food-Drug Interactions WARFARIN High-protein diet Raises serum albumin levels, decreases in international normalized ratio (INR) Vegetables containing vitamin k Interferes with effectiveness and safety of warfarin therapy Charbroiled Decreases warfarin activity Cooked onions Increases warfarin activity Cranberry juice Elevated INR without bleeding in elderly patients Leafy green vegetables Thromboembolic complications may develop Charbroiled Decrease warfarin activity MONOAMINE OXIDASES Tyramine-containing food Hypertensive crisis PROPRANOLOL Protein-rich food Serum level may increase ACE INHIBITORS Empty stomach Absorption is increased CALCIUM CHANNEL BLOCKERS Grapefruit juice Increases bioavailability ANTIBIOTICS Dairy products Calcium complexes with some antibiotics and prevents their absorption - reduced bioavailability ACETAMINOPHEN Pectin Delays both absorption and onset NSAIDS Alcohol Increases risk of liver damage or stomach bleeding Beverages c max and auc0-alpha significantly increased THEOPHYLLINE High-fat meal and grapefruit juice Increases bioavailability Caffeine Increases risk of drug toxicity ESOMEPRAZOLE High-fat meal Bioavailability was reduced CIMETIDINE with food(any type) Increases bioavailability ISONIAZID Plants, medicinal herbs, leanolic acid Exerts synergistic effect CYCLOSERINE High fat meals Decreases serum concentration ATORVASTATIN Grapefruit juice Increases toxicity - rhabdomyolysis risk GLIMEPIRIDE With breakfast Absolute bioavailability ACARBOSE At start of each meal Maximum effectiveness MERCAPTOPURINE Cow's milk Reduces bioavailability TAMOXIFEN Sesame seeds Inducing regression of established mcf-7 tumor size but beneficially interacts with tamoxifen on bone in ovariectomized athymic mice LEVOTHYROXINE Grapefruit juice Delays absorption Note that alcohol should not be consumed with any drug, but some alcohol-drug interactions are more serious than others. Patients taking psychoactive substances - whether it's SSRIs, anaesthetics, anticonvulsant drugs, or some analgesic preparations - are likely to exhibit worsening side effects if taken with alcohol. Respiratory depression is, for example, more likely in patients taking hypnotics (and many other drug classes).
Mefloquine
Artesunate
Chloroquine
Amodiaquine