Antimalarial Drugs

Plasmodia Life Cycle and Prophylaxis

The treatment of malaria Malaria Malaria is an infectious parasitic disease affecting humans and other animals. Most commonly transmitted via the bite of a female Anopheles mosquito infected with microorganisms of the Plasmodium genus. Patients present with fever, chills, myalgia, headache, and diaphoresis. Plasmodium/Malaria is targeted at different stages of the Plasmodium life cycle Cycle The type of signal that ends the inspiratory phase delivered by the ventilator Invasive Mechanical Ventilation:

• Human liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy stage: targeted with tissue schizonticides
• Human blood stage: targeted with blood schizonticides
• Gametocyte stage: targeted with gametocides 
• Human liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy dormant stages: Hypnozoites Hypnozoites Plasmodium/Malaria can form in P. ovale P. ovale A species of protozoan parasite causing malaria. It is the rarest of the four species of Plasmodium infecting humans, but is common in West african countries and neighboring areas. Plasmodium/Malaria and P. vivax P. vivax A protozoan parasite that causes vivax malaria. This species is found almost everywhere malaria is endemic and is the only one that has a range extending into the temperate regions. Plasmodium/Malaria infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease and are targeted with primaquine or tafenoquine.

Treatment consists of 3 steps:

1. Identification Identification Defense Mechanisms of the infecting Plasmodium species
   • P. falciparum P. falciparum A species of protozoa that is the causal agent of falciparum malaria. It is most prevalent in the tropics and subtropics. Plasmodium/Malaria is the most severe; can cause anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types and cerebral malaria Cerebral malaria A condition characterized by somnolence or coma in the presence of an acute infection with Plasmodium falciparum (and rarely other Plasmodium species). Initial clinical manifestations include headaches; seizures; and alterations of mentation followed by a rapid progression to coma. Pathologic features include cerebral capillaries filled with parasitized erythrocytes and multiple small foci of cortical and subcortical necrosis. Plasmodium/Malaria
2. Identification Identification Defense Mechanisms of drug susceptibility of the infecting Plasmodium
   • Determined by geographic origin of infection
3. Patient’s clinical status
   • Avoid the same drug for treatment if it was used prophylactically

Malaria Malaria Malaria is an infectious parasitic disease affecting humans and other animals. Most commonly transmitted via the bite of a female Anopheles mosquito infected with microorganisms of the Plasmodium genus. Patients present with fever, chills, myalgia, headache, and diaphoresis. Plasmodium/Malaria prophylaxis Prophylaxis Cephalosporins and prevention

• Centers for Disease Control and Prevention (CDC) prophylactic regimens are based on a traveler’s geographic region.
• Travelers should consult local guidelines (will vary from country to country and with seasons)
• Principles of prevention
  • Chloroquine: first choice in areas without resistant P. falciparum P. falciparum A species of protozoa that is the causal agent of falciparum malaria. It is most prevalent in the tropics and subtropics. Plasmodium/Malaria
  • Mefloquine: first choice in areas with chloroquine-resistant P. falciparum P. falciparum A species of protozoa that is the causal agent of falciparum malaria. It is most prevalent in the tropics and subtropics. Plasmodium/Malaria
  • Doxycycline or Malarone® (atovaquone + proguanil): in areas with multidrug-resistant malaria Malaria Malaria is an infectious parasitic disease affecting humans and other animals. Most commonly transmitted via the bite of a female Anopheles mosquito infected with microorganisms of the Plasmodium genus. Patients present with fever, chills, myalgia, headache, and diaphoresis. Plasmodium/Malaria
  • Primaquine: in terminal prophylaxis Prophylaxis Cephalosporins of P. vivax P. vivax A protozoan parasite that causes vivax malaria. This species is found almost everywhere malaria is endemic and is the only one that has a range extending into the temperate regions. Plasmodium/Malaria and P. ovale P. ovale A species of protozoan parasite causing malaria. It is the rarest of the four species of Plasmodium infecting humans, but is common in West african countries and neighboring areas. Plasmodium/Malaria

Blood Schizonticides, Tissue Schizonticides, and Gametocides

Blood schizonticides

• Chloroquine
  • Mechanism of action: prevents polymerization of heme and intracellular heme is toxic to the parasite
  • Mechanism of resistance Resistance Physiologically, the opposition to flow of air caused by the forces of friction. As a part of pulmonary function testing, it is the ratio of driving pressure to the rate of air flow. Ventilation: Mechanics of Breathing:
    • Plasmodia develop membrane transporters to eject intracellular heme.
    • P. falciparum P. falciparum A species of protozoa that is the causal agent of falciparum malaria. It is most prevalent in the tropics and subtropics. Plasmodium/Malaria develops a transporter for chloroquine itself, coded by the P. falciparum P. falciparum A species of protozoa that is the causal agent of falciparum malaria. It is most prevalent in the tropics and subtropics. Plasmodium/Malaria chloroquine transporter (pfcrt) gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics.
  • Side effects at low doses:
    • Gastrointestinal (GI) disturbances ( nausea Nausea An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. Antiemetics, cramping, diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea)
    • Skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions rash Rash Rocky Mountain Spotted Fever
    • Headaches
  • Side effects at high doses:
    • Severe skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions reactions
    • Peripheral neuropathies Neuropathies Chédiak-Higashi Syndrome, toxic psychosis, retinal and auditory damage
    • Myocardial depression
    • May precipitate porphyria attacks
• Quinine
  • Mechanism of action: combines with dsDNA, prevents strand separation, blocks replication and transcription Transcription Transcription of genetic information is the first step in gene expression. Transcription is the process by which DNA is used as a template to make mRNA. This process is divided into 3 stages: initiation, elongation, and termination. Stages of Transcription
  • Used in chloroquine-resistant P. falciparum P. falciparum A species of protozoa that is the causal agent of falciparum malaria. It is most prevalent in the tropics and subtropics. Plasmodium/Malaria
  • Often combined with doxycycline or clindamycin Clindamycin An antibacterial agent that is a semisynthetic analog of lincomycin. Lincosamides, used to shorten the duration and limit Limit A value (e.g., pressure or time) that should not be exceeded and which is specified by the operator to protect the lung Invasive Mechanical Ventilation toxicity Toxicity Dosage Calculation
  • Toxicity Toxicity Dosage Calculation:
    • Cinchonism (GI distress, headache Headache The symptom of pain in the cranial region. It may be an isolated benign occurrence or manifestation of a wide variety of headache disorders. Brain Abscess, vertigo Vertigo Vertigo is defined as the perceived sensation of rotational motion while remaining still. A very common complaint in primary care and the ER, vertigo is more frequently experienced by women and its prevalence increases with age. Vertigo is classified into peripheral or central based on its etiology. Vertigo, blurred vision Blurred Vision Retinal Detachment, tinnitus Tinnitus A nonspecific symptom of hearing disorder characterized by the sensation of buzzing, ringing, clicking, pulsations, and other noises in the ear. Objective tinnitus refers to noises generated from within the ear or adjacent structures that can be heard by other individuals. The term subjective tinnitus is used when the sound is audible only to the affected individual. Tinnitus may occur as a manifestation of cochlear diseases; vestibulocochlear nerve diseases; intracranial hypertension; craniocerebral trauma; and other conditions. Cranial Nerve Palsies)
    • Hemolysis in G6PD G6PD Pentose Phosphate Pathway deficient patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship
    • Blackwater fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever ( intravascular hemolysis Intravascular hemolysis Hemolytic Anemia)
• Mefloquine
  • Chemically related to quinine
  • Mechanism of action: creates toxic heme particles in food vacuoles
  • First-line agent: taken weekly (4 weeks before and 1 week after)
  • Toxicity Toxicity Dosage Calculation:
    • GI distress, skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions rash Rash Rocky Mountain Spotted Fever, headache Headache The symptom of pain in the cranial region. It may be an isolated benign occurrence or manifestation of a wide variety of headache disorders. Brain Abscess, dizziness Dizziness An imprecise term which may refer to a sense of spatial disorientation, motion of the environment, or lightheadedness. Lateral Medullary Syndrome (Wallenberg Syndrome)
    • Nightmares
    • May cause cardiac conduction defects and seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures at high doses

Tissue schizonticides

• Primaquine  
  • Tissue schizonticide and gametocide
  • Used in conjunction with a blood schizonticide
  • Mechanism of action: forms quinoline-quinone metabolites that act as oxidants
  • Eliminates dormant liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy stages ( hypnozoites Hypnozoites Plasmodium/Malaria) of P. vivax P. vivax A protozoan parasite that causes vivax malaria. This species is found almost everywhere malaria is endemic and is the only one that has a range extending into the temperate regions. Plasmodium/Malaria and P. ovale P. ovale A species of protozoan parasite causing malaria. It is the rarest of the four species of Plasmodium infecting humans, but is common in West african countries and neighboring areas. Plasmodium/Malaria
  • Toxicity Toxicity Dosage Calculation:
    • GI distress, headaches
    • Methemoglobinemia Methemoglobinemia Methemoglobinemia is a condition characterized by elevated levels of methemoglobin in the blood. Methemoglobin is the oxidized form of hemoglobin, where the heme iron has been converted from the usual ferrous (Fe2+) to the ferric (Fe3+) form. The Fe3+ form of iron cannot bind O2, and, thus, leads to tissue hypoxia. Methemoglobinemia, toxicity Toxicity Dosage Calculation in G6PD-deficient patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship (hemolysis)
    • Contraindicated in pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care

Gametocides

• Kill sexual stages and prevent transmission to mosquitoes

Gametocidal + schizonticidal:

• Quinine: gametocidal against P. vivax P. vivax A protozoan parasite that causes vivax malaria. This species is found almost everywhere malaria is endemic and is the only one that has a range extending into the temperate regions. Plasmodium/Malaria and ovale 
• Primaquine: gametocidal against P. falciparum P. falciparum A species of protozoa that is the causal agent of falciparum malaria. It is most prevalent in the tropics and subtropics. Plasmodium/Malaria, malariae, ovale, and vivax

Artemisinins and Antifolate Drugs

Artemisinins

• Blood schizonticides
• Not used as monotherapy to prevent resistance Resistance Physiologically, the opposition to flow of air caused by the forces of friction. As a part of pulmonary function testing, it is the ratio of driving pressure to the rate of air flow. Ventilation: Mechanics of Breathing
• Only drugs effective against quinine-resistant strains
• Mechanism of action: accumulate in protozoan food vacuoles, and once metabolized, release Release Release of a virus from the host cell following virus assembly and maturation. Egress can occur by host cell lysis, exocytosis, or budding through the plasma membrane. Virology toxic free radicals Free radicals Highly reactive molecules with an unsatisfied electron valence pair. Free radicals are produced in both normal and pathological processes. They are proven or suspected agents of tissue damage in a wide variety of circumstances including radiation, damage from environment chemicals, and aging. Natural and pharmacological prevention of free radical damage is being actively investigated. Ischemic Cell Damage
  • Rare adverse effects of nausea Nausea An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. Antiemetics, vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia, and diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea
  • No increase in congenital Congenital Chorioretinitis problems or stillbirths in women taking these drugs
• Short half-lives and not used for malaria Malaria Malaria is an infectious parasitic disease affecting humans and other animals. Most commonly transmitted via the bite of a female Anopheles mosquito infected with microorganisms of the Plasmodium genus. Patients present with fever, chills, myalgia, headache, and diaphoresis. Plasmodium/Malaria prophylaxis Prophylaxis Cephalosporins
• Artesunate IV: treatment of severe malaria Severe malaria Plasmodium/Malaria
• Artemether-lumefantrine: CDC recommended for uncomplicated malaria Uncomplicated malaria Plasmodium/Malaria treatment in adults and children weighing ≥ 5kg
  • Not to be used in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship on mefloquine prophylaxis Prophylaxis Cephalosporins  
• Halofantrine: Active against all 4 plasmodium malarial species
  • Not available in the United States
  • Not recommended by the CDC due to adverse cardiac events
  • Contraindicated in pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care
• Dihydroartemisinin-piperaquine: not available in the United States and not recommended by the CDC due to widespread resistance Resistance Physiologically, the opposition to flow of air caused by the forces of friction. As a part of pulmonary function testing, it is the ratio of driving pressure to the rate of air flow. Ventilation: Mechanics of Breathing

Antifolate drugs

• Prophylaxis Prophylaxis Cephalosporins and treatment for multidrug-resistant P. falciparum P. falciparum A species of protozoa that is the causal agent of falciparum malaria. It is most prevalent in the tropics and subtropics. Plasmodium/Malaria 
• Mechanism of action: antimetabolites, block folic acid synthesis Synthesis Polymerase Chain Reaction (PCR)
• Proguanil
  • Inhibits protozoan dihydrofolate reductase Dihydrofolate Reductase Sulfonamides and Trimethoprim (DHFR)
  • Used in combination with atovaquone
• Pyrimethamine
  • Inhibits DHFR
  • Combination with sulfadoxine (Fansidar®) inhibits both dihydrofolate reductase Dihydrofolate Reductase Sulfonamides and Trimethoprim and dihydropteroate synthase Dihydropteroate Synthase An enzyme that catalyzes the formation of dihydropteroate from p-aminobenzoic acid and dihydropteridine-hydroxymethyl-pyrophosphate. Sulfonamides and Trimethoprim 
  • Not used in the United States
• Sulfonamides Sulfonamides A group of compounds that contain the structure so2nh2. Sulfonamides and Trimethoprim
  • Mechanism of action: inhibit dihydropteroate synthase Dihydropteroate Synthase An enzyme that catalyzes the formation of dihydropteroate from p-aminobenzoic acid and dihydropteridine-hydroxymethyl-pyrophosphate. Sulfonamides and Trimethoprim
  • Adverse reactions: skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions rashes Rashes Rashes are a group of diseases that cause abnormal coloration and texture to the skin. The etiologies are numerous but can include irritation, allergens, infections, or inflammatory conditions. Rashes that present in only 1 area of the body are called localized rashes. Generalized rashes occur diffusely throughout the body. Generalized and Localized Rashes, GI upset, hemolysis, kidney damage
  • Sulfadoxine-pyrimethamine: not used in the United States
  • Dapsone Dapsone A sulfone active against a wide range of bacteria but mainly employed for its actions against Mycobacterium leprae. Its mechanism of action is probably similar to that of the sulfonamides which involves inhibition of folic acid synthesis in susceptible organisms. It is also used with pyrimethamine in the treatment of malaria. Antimycobacterial Drugs: rarely used
• May combine pyrimethamine and sulfadoxine: synergistic effects through a sequential Sequential Computed Tomography (CT) blockade
• Toxicity Toxicity Dosage Calculation:
  • Skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions rash Rash Rocky Mountain Spotted Fever, GI distress
  • Contraindicated in pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care

Erythrocides and Miscellaneous Drugs

Erythrocides

• Atovaquone
  • Malarone® (atovaquone + proguanil)
  • Used as treatment and as once-daily prophylaxis Prophylaxis Cephalosporins
  • Is an alternative treatment for P. jiroveci infection
  • Mechanism of action: disrupt mitochondrial electron transport
  • Toxicity Toxicity Dosage Calculation:
    • Abdominal pains
    • GI effects
• Halofantrine
  • Active against erythrocytic forms of all 4 malarial organisms
  • Not used as a chemoprophylactic agent
  • High potential for cardiotoxicity: prolonged QT interval QT interval Electrocardiogram (ECG)
  • Embryotoxic: contraindicated in pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care

Miscellaneous drugs

• Doxycycline
  • Used for chemoprophylaxis Chemoprophylaxis Meningitis in Children for travelers
  • Unknown mechanism
• Amodiaquine
  • Inexpensive
  • Used extensively in the developing world
  • Used in fixed dosing with artesunate
  • Toxicity Toxicity Dosage Calculation:
    • Agranulocytosis Agranulocytosis A decrease in the number of granulocytes; (basophils; eosinophils; and neutrophils). Lincosamides and aplastic anemia Aplastic Anemia Aplastic anemia (AA) is a rare, life-threatening condition characterized by pancytopenia and hypocellularity of the bone marrow (in the absence of any abnormal cells) reflecting damage to hematopoietic stem cells. Aplastic anemia can be acquired or inherited, however, most cases of AA are acquired and caused by autoimmune damage to hematopoietic stem cells. Aplastic Anemia

Adverse Effects

Overview