Lecture 2 Pharmacology of Anti-Parasitic Drugs Kumar PHARMACOLOGY of ANTI-MALARIA DRUGS

Lecture 2 Pharmacology of Anti-Parasitic Drugs Kumar

PHARMACOLOGY OF ANTI-MALARIA DRUGS: PLASMODIUM SPECIES THAT CAUSE HUMAN MALARIA: CHLOROQUINE (& AMODIAQUINE): Plasmodium  One cycle COMMENTS  Drug of choice for both treatment and prophylaxis falciparum o Infection ceases spontaneously < 4 wk  Rapidly and almost completely absorbed oral administration  Responsible for most serious complications  Acidic in nature/DNA and deaths SPECTRUM  Blood schizonticide – all 4 strains  Most likely to become drug resistant  Gametocide – P. vivax, P. ovale and P. malariae Plasmodium  One cycle MOA  Exact pharmacological mechanism still debated but malariae o Infection ceases spontaneously < 4 wk o Changes in metabolic pathway & inhibits reproduction Plasmodium  Dormant hepatic stage (hypnozoite) vivax  Relapses occur 1. Parasite digests host cell’s hemoglobin to obtain essential AAs  Not very common in African population 2. Large amounts of heme is released  toxic to parasite Pkasmodium o Lack duffy hemokine receptor on 3. Normally, parasite polymerizes heme to non-toxic hemozoin ovale endothelial cells which transport a. Chloroquine prevents polymerization to hemozoin – parasite into human body accumulation of heme  lysis of parasite & host RBC ADRs  Pruritis (common) PARASITE LIFE CYCLE:  Give after meals to reduce nausea and other GI symptoms  1. Anopheline (females) mosquito initiates infection Hepatic and permanent eye damage (prolonged use) CAUTIONS 2. Sporozoites invade liver  Chlorouine can precipitate acute attacks of psoriasis and porphyria (hereditary blood disorder) 3. Shizonts mature in liver into then released to invade RBCs  Anti-diarrheal agents (kaolin and calcium/magnesium o Hypnozoite remains dormant in liver containing antacids) interfere with absorption 4. Clinical illness 5. Gametocytes develop in RBCs before taken up by mosquitoes QUININE: DRUGS  Quinine – first effective txt/reserved in cases of resistance CLINICAL PRESENTATION:  Quinidine – dextrorotatory stereoisomer of quinine SYMPTOMS  Symptoms result from antigens released  Mefloquine – synthetic derivative ONSET from the RBCs after invasion by merozoites COMMENTS  Alkaloid derived from bark of cinchona tree – used since 1820 Symptoms may appear up to ≥ 30 days after  Rapidly absorbed orally, widely distributed in body tissues a trip to an area with malaria  Individuals with malaria have higher plasma drug levels SYMPTOMS  Fever and flu-like illness (shaking, chills, SPECTRUM  Blood schizonticide against all 4 species headache, muscle aches, tiredness)  Gametocidal against P. vivax and P. ovale  Nausea, vomiting, diarrhea may also occur o Not active against liver stage parasites  Anemia and jaundice because of loss of RBCs MOA  Exact pharmacological mechanisms unknown!! IF  Can result in mental confusion, seizures, ADRs UNTREATED coma, kidney failure, and death  Cinchonism (tinnitus, headache, nausea, dizziness)  Flushing and visual disturbances (common)  Hypoglycemia (insulin release) CLASSIFICATION OF MALARIA:  Hypersensitivity reactions (rash to bronchospasm) MILD  Non-specific febrile illness  Hematologic abnormalities (hemolytic anemia) MALARIA  Terminated by antimalarial treatment or by  Blackwater fever (rare), hemolysis, hemaglobinuria host responses CAUTIONS  Quinine should not be given with mefloquine SEVERE  1% of cases (most are P. falciparum)  Quinine can raise plasma levels of warfarin and digoxin MALARIA  Severe anemia  shock, ↓awareness MEFLOQUINE  Caution in hepatic dysfunction, pregnancy, lactation   Cerebral impairment impaired consciousness, seizures  may lead to long- term neurological deficits MALARONE:  Hypoglycemia, coagulopathies COMMENTS  Becoming the product of choice for prophylaxis  Combination of two drugs CLASSIFICATION OF ANTI-MALARIAL DRUGS: M ATOVAQUONE  Tissue/blood schizonticide against all 4 species SCHIZONTICIDES  Tissue – eliminate developing or O  Parasite mitochondrial electron transport inhibitor dormant liver forms A  Not very effective by itself against malaria  Blood – act on erythrocytic parasites PROGUANIL/  Tissue/ blood schizonticide against all 4 species GAMETOCIDES  Kill sexual stages and prevent PYRIMETHAMINE  Selectively inhibits plasmodial dihydrofolate transmission to mosquitos reductase (key enzyme in synthesis of folate) o Don’t affect clinical symptoms  Appears to synergistically enhance the effect of COMMENTS  No single agent eliminates hepatic and atovaquone on mitochondrial membrane potential ABOUT ANTI- erythrocytic stages ADRs  Headache and abdominal pain are possible MALARIAL DRUGS  Few drugs prevent infection  Can result in strange or vivid dreams  Drugs prevent clinical disease CAUTION  Avoid in patients with severe renal impairment  No prophylaxis is fully protective

Lecture 2 Pharmacology of Anti-Parasitic Drugs Kumar PHARMACOLOGY OF ANTI-MALARIALS (CONTINUED) :

DOXYCLINE: RESISTANCE:

COMMENTS  Tetracyline antibiotic CHLOROQUINE  P. falciparum (common), P. vivax (↑) SPECTRUM  Blood schizonticide – all 4 strains  Mutations in a putative drug transporter  Not active against liver stage parasites have been suggested MOA  Inhibits protein synthesis by binding to 30S ribosomal subunit  Reversed by combination with certain ADRs  GI symptoms (NVD) drugs (ex// chlorpheniramine)  Candida vaginitis (more likely in immunocompromised pts) QUININE  P. falciparum (common in some areas in  Photosensitivity MEFLOQUINE South East Asia) CAUTIONS  Should be given cautiously to patients with myasthenia gravis PRIMAQUINE  P. vivax (New Guinea, SE Asia) o Works through acetylcholine receptors  Avoid during pregnancy and children under 8 PROPHYLAXIS: o Retards skeletal bone growth BITES  Prevent mosquito bites o May cause tooth discoloration o Insect repellants, insecticides, nets CARIBBEAN /  Malorone or chloroquine PRIMAQUINE: C. AMERICA COMMENTS  Drug of choice for eradication of dormant liver forms of BORDER AREAS  High prevalence of multidrug-resistant P. vivax and P. ovale OF THAILAND falciparum malaria SPECTRUM  Tissue schizonticide – all 4 strains  DOXYCYCLINE  Active against hypnozoite of P. vivax and P. ovale OTHER AREAS  Mefloquine or malarone  Gametocide – all 4 strains MOA  Pharmacological mechanism unknown TREATMENT:  Hydroxychloroquine is synergistic CHLOROQUINE  P. malariae, vivax, ovale & falciparum ADRs  Nausea, epigastric pain, abd. cramps, headache (infrequent) (non-resistant infections)  Cyanosis due to hemolysis or methemoglobinemia PRIMAQUINE  Used in subsequent treatment of vivax  Leukopenia, agranulocytosis, leukocytosis, cardiac arrhythmias and ovale malaria to eradicate dormant CAUTIONS  Avoid in granulocytopenia or methemoglobinemia hepatic stage (hypnozoite)  Avoid in myelosuppressive drugs (ex// quinidine) QUININE (PO)  Plus doxycycline or clindamycin  Avoid in pt w/ glucose-6-phosphate dehydrogenase deficiency QUINIDINE (IV)  Falciparum malaria from most areas (resistant form)

PHARMACOLOGY OF ANTI-PROTOAZOALS:

GIARDIASIS: AMEBIASIS: NOTES  Also called “backpacker’s diarrhea” and “beaver fever” CAUSE  Caused by Entamoeba histolytica o Infects a number of animal species, including beavers o Fecal-oral spread  One of the most common parasite infections worldwide o Use of night soil (crop fertilization w/ human waste)  Spread by fecal-oral contamination  Two-stage life cycle: CAUSE  Caused by Giardia lamblia 1. Cysts (infective form, shed in fees)  Two-stage life cycle: 2. Trophozoites (causes disease in duodenum) 1. Cysts (infective form, shed in fees) SX  10% of world population infected but only 1/10 infected 2. Trophozoites (causes disease in duodenum) individuals get clinical disease a. Trophozoites move to colon & can spread in  Symptoms 2-6 weeks post infection bloodstream to liver, lung and brain o Disrupts protective mucus layer on colonic mucosa  Commonly water-borne (resistant to chlorine) and survives o Bleeding epithelial ulcerations cause colitis well in cold mountain streams ACUTE  Malaise, severe abd. pain, fever, wt loss SX ACUTE  Incubation period 1-2 weeks  Profuse bloody diarrhea  Gradual onset of long-lasting mild diarrhea CHRONIC  Ameboma – collection of edematous (2-4 weeks) granulation and fibrous tissue in intestinal  GI distress (nausea, vomiting, malaise, lumen  pain, obstruction flatulence, cramping, steatorrhea)  Liver abscesses (5 mo after infection)  Significant weight loss CHRONIC  Loose stool may wax and wane (months) TRICHOMONIASIS:  10-20% weight loss CAUSE  Caused by Trichomonas vaginalsi  Malaise, fatigue, depression  Commonly sexually transmitted disease o Infects squamous epithelium of the genital tract AMERICAN TRYPANOSOMIASIS = CHAGAS DISEASE SX WOMEN  50% asymptomatic carriers CAUSE  Caused by Trypanosoma cruzi  Vaginal discharge, pruritis, irritation o Southern US to southern Argentina MEN  Usually asymptomatic SX ACUTE  Often asymptomatic  Non-gonococcal urethritis & prostatitis CHRONIC  30-40% of cases – irreversible heart and GI tract lesions TREATMENT OF PROTOZOAN INFECTIONS: GIARDIASIS Metronidazole CRYPTOSPORIDIOSIS AMEBIASIS  Luminal = iodoquinol CAUSE  Caused by Cryptosporidium parvum  Tissue = metronidazole  Transmitted via fecal-oral route  Liver = metronidazole then paramomycin SX  Diarrhea, abd. pain and (less frequently) vomiting CHAGAS DISEASE  Nitroimidazoles (ex// benznidazole)  Disease is usually self-limiting (resolves in a few weeks) TRICHOMONIASIS  Metronidazole  Severe life-threatening disease in immunocompromised pts CRYPTOSPORIDIOSIS  No effective drug treatment

Lecture 2 Pharmacology of Anti-Parasitic Drugs Kumar

PHARMACOLOGY OF ANTI-PROTOZOANS (CONTINUED):

METRONIDAZOLE IODOQUINOL: NOTES  Nitroimidazole NOTES  Luminal amebicide used with metronidazole  Active against protozoans and anaerobic bacteria  90% of drug is retained in intestine & excreted in feces o Kills trophozoites but not cysts MOA  Unknown  Effectively eradicates intestinal & extra-intestinal tissue infxns ADRs  Diarrhea and GI distress MOA  A prodrug that needs to be activated in susceptible organism  Rash, pruritus  Enters the cell by diffusion and exerts its cytotoxic effects by D/C  Persistent diarrhea signs of iodine toxicity producing free radicals o Dermatitis, urticaria, pruritus, fever o Reduction of metronidazole is thought to create a concentration gradient that favors the increased uptake to the drug and promotes formation of metronidazole radicals  The reduced intermediates are highly reactive and causes DNA fragmentation and eventually cell death ADRs  Headache, nausea, dry mouth or a metallic taste  Disulfiram-like effect, nausea and vomiting can occur if alcohol is ingested during therapy CAUTION  Avoid in pregnant or nursing women

CHEMOTHERAPY OF HELMINTHIC INFECTIONS:

HELMINTHIC INFECTIONS: PYRANTEL PAMOATE & LEVAMISOLE:  3 families of worms cause human disease: nematodes, cestodes, trematodes SPECTRUM  Broad-spectrum (pin worm, round worm, hookworm)  Number of pharmacologically diverse agents employed to txt helminthic infxn MOA  Depolarizing neuromuscular blockers o Worms have nicotinic receptors which are ROUNDWORMS (nematodes): pharmacologically different from mammalian nicotinic receptors Pinworm or  Most common cause of infestation in N. America (child)  Pyrantel is also a cholinesterase inhibitor seat worm  Lives in cecum of large intestine

(Enterobius  Female worm lays eggs on perineum at night vermicularis) o Eggs hatch in duodenum PIPERAZINE: o Egg deposition  perineal, perianal, vaginal SPECTRUM  Alternative for round worm and pin worm irritation  scratching and secondary infection MOA  γ-aminobutyric acid (GABA) receptor agonist  Fecal-oral route of spread (poor hygiene)  GABA receptor is a chloride channel found on worm  Infestation usually lasts only 4-6 wks muscle membrane Hook worm  Second most common infestation in N. America o Opening chloride channel hyperpolarizes (Necator  Eggs hatch into larvae that live in soil muscle and results in paralysis and expulsion americanus o Larvae enter thru pores, hair follicles, intact skin of live worms and o Travel through bl(Sood to lung alveolar capillaries Ancylostoma o Climb bronchial tree  swallowed with secretions Duodenale) o Mature worms attach to small intestine and feed IVERMECTIN: on blood SPECTRUM  A semisynthetic macrocyclic lactone actinomycete  Infestation occurs without symptoms  Streptomyces avermitilis for round worms  Over time, iron deficiency anemia & malnutrition MOA  Tonic muscle paralysis Round worm  Infection by ingesting contaminated food or soil  Agonist for a glutamate-gated chloride channel (Ascaris o Opening chloride channel hyperpolarizes lumbricoides) muscle and results in paralysis and expulsion Whipworm  Tropical diseases (children) of live worms (Trichuris  Infection by ingesting contaminated food (whipworm) trichiura)  Infects from soil by penetrating skin and replicates PRAZIQUANTEL: Threadworm within host to cause multiple cycles of infection SPECTRUM  Used for fluke & flatworm infestations (Strongyloides (threadworm) MOA stercoralis)  Increases intracellular calcium  Possibly acts on the calcium-induced calcium release Trichinella  Eating undercooked meat (particularly pork) (CICR) channel in sarcoplasmic reticulum of muscle (Trichinella  Larvae mature in intestine to worms o Same site that caffeine acts on spiralis)  Adult worms invade muscle and heart  Results in paralysis, dislodgement, and death  Causes pain, dysfunction and ocassionally death

FLATWORMS/TAPEWORMS (cestodes) MEBENDAZOLE & ALBENDAZOLE: SPECTRUM  Beef tapeworm (Taenia saginata)  Eating undercooked meat Synthetic compounds discovered in the 1960s  Broad-spectrum oral anti-helmintics against Pork tapeworm (Taenia solium)  Worms confined to intestine nematodes (round, hook, pin, and whip worms) Fish tapeworm (Diphyllobothrium latum)  Pork tapeworm  brain MOA  Bind to β-tubulin (higher affinity for β-tubulin in worms than mammals) FLUKES (trematodes)  Inhibit microtubule synthesis leading to damage of Schistosomiasis  Primarily affects tropical regions worm intestinal lining (Schistoma haemotobium, (Caribbean, S. America, etc)  Results in failure of glucose uptake and worm death mansoni, japonicum)  Infected snails spread to fresh water (by starvation)  Infection involves liver, spleen and GIT

Lecture 2 Pharmacology of Anti-Parasitic Drugs Kumar CHEMOTHERAPY OF HELMINTHIC INFECTIONS:

TREATMENT: MAJOR ADRs: WORM DRUG OF CHOICE DRUG MAJOR SIDE EFFECTS Roundworm Pyrantel (Mebendazole) Pyrantel pamoate / mebendazole Mild and mainly GI symptoms Whipworm Pyrantel (Mebendazole) Levamisole Disulfiram-like effect Hookworm Pyrantel (Mebendazole) Piperazine Sedation (high dose) Threadworm Invermectin Ivermectin Drowsiness, dizziness, GI symptoms Pinworm Pyrantel (Mebendazole) Praziquantel Headache, dizziness, drowsiness Tapeworms Praziquantel Flukes Praziquantel