pharmacology of anti-parasite drugs

Question 1

what are the two classes of parasites of people?

Answer 1

1. Macroscopic parasites:
   - Taenia species (tapeworms) - Enterobius (pinworm)
   - Pediculus (head louse)
2. Microscopic parasites:
   - Entamoeba (amebiasis)
   - Giardia (beaver fever)
   - Trichomonas (trichomoniasis)
   - Plasmodium (malaria) Prevention:
   To what extent can control be achieved without drugs ?

Question 2

what is Taenia saginata and Taenia solium

Answer 2

Taenia saginata: beef tapeworm - by eating raw beef

Taenia solium: pork tapeworm - by eating raw pork

• flat and segmented
• live in river - will go with the flow until anchored to GI tract

Question 3

what is the life cycle of Taenia saginata/Taenia solium?

Answer 3

Question 4

info slide

Answer 4

Question 5

what are the structures at the anterior end of tapeworm for attachment to wall of small intestine

Answer 5

Question 7

what are cestocidal drugs?

Answer 7

cestodes = tapeworms

1. praziquantel
2. niclosamide

Question 8

praziquantel pharmacokinetics and moa

Answer 8

Chemistry & pharmacokinetics:
- synthetic isoquinoline derivative
- systemic bioavailability ~80% after oral dosing within small intestine
Action: (exact mechanism unknown)
- binds to parasite integument → focal vacuolization
- influx of Ca2+ causes muscle contraction (in seconds)
- impaired function of hooks and suckers at anterior end:
→ paralysis, dislodgement, death

Question 9

praziquantel clinical uses and adverse reactions

Answer 9

Clinical uses:
- effective against most cestode infections (drug of choice)
- safe and effective as single oral dose
- swallow without chewing (bitter taste → retching/vomiting)
Adverse reactions:
- mild, transient reactions = common (e.g. nausea, headache, abdominal discomfort)

Question 10

niclosamide pharmacokinetics and moa

Answer 10

Chemistry & pharmacokinetics:
- salicylanilide derivative
- minimally absorbed from gastrointestinal (GI) tract
Action:
- rapidly kills scolex + segments of adult tapeworms
- mechanism of action:
* inhibition of mitochondrial anaerobic phosphorylation of ADP results in ↓ ATP production

Question 11

niclosamide clinical uses and adverse reactions

Answer 11

Clinical uses:
- second-line choice for treatment of Taenia saginata and Taenia solium
- single oral dose effective
- cheap and readily available in many parts of world
Adverse reactions:
- minor GI complaints rarely encountered - nausea, vomiting, diarrhea

Question 12

prevention of reinfection of Taenia saginata and Taenia solium

Answer 12

• start cooking your beef
• start cooking your pork

Question 13

Life cycle of Enterobius vermicularis (pinworm)

Answer 13

Question 14

what is Enterobius vermicularis transmission and clinical presentation?

Answer 14

• most common nematode infection in temperate countries
  Transmission:
• female parasite on perianal skin → pruritus
• eggs → hands → ingestion
• eggs sticky + can survive long periods in environment
• contamination of nightclothes / bedding
• eggs → wide dispersal in bedrooms / house
  Clinical presentation:
• most frequent in school age children
• most infections asymptomatic, high risk of reinfection
• itching → irritability, incontinence, weight loss

Question 15

how to minimize risk of infection of enterobius vermicularis and drug of choice for treatment?

Answer 15

Minimise risk of infection:
- personal hygiene – handwashing, fingernail cleaning, regular bathing
- keep bedrooms scrupulously clean + dust free
- bed linen / nightclothes – change and launder frequently
Treatment:
- Drugs of choice: mebendazole, pyrantel

Question 16

mebendazole chemistry and pharmacokinetics and moa

Answer 16

Chemistry & pharmacokinetics:
- benzimidazole (broad spectrum activity against endoparasites)
- administered orally - less than 10% absorbed (want it in the gut)
- tablets should be chewed (maximized dispersion in GIT)
MOA:
- binds to β-tubulin (parasite specific):
* inhibits polymerisation to microtubules:
→ inhibits parasite motility, glucose uptake, cell division
- slow kill → expelled in feces (within day or two)
- efficacy varies with gastro-intestinal (GI) transit time (diarrhea decreases efficacy, transit time is quicker)

Question 17

mebendazole clinical uses and adverse reactions

Answer 17

Clinical uses:
- approved for pinworms (+ roundworms, whipworms, hookworms)
- for pinworms – treat twice at 2-week interval
Adverse reactions:
- short-term therapy – nearly free of adverse effects (abdominal pain, nausea, diarrhea = infrequent)
- embryotoxic + teratogenic in animals – contraindicated in pregnancy

Question 18

pyrantel chemistry and pharmacokinetics and moa

Answer 18

Chemistry & pharmacokinetics:
- tetrahydropyrimidine
- poorly absorbed from GI tract  activity within GI tract
Action:
- “nicotinic anthelmintic”
- acts selectively at neuromuscular junction of parasite on
nicotinic acetylcholine receptors:
→ release of acetylcholine + inhibition of acetylcholinesterase
→paralysis (very rapid paralysis of parasite)→ expulsion

Question 19

pyrantel clinical uses and adverse effects

Answer 19

Clinical uses:
- approved for pinworms (+ roundworms, hookworms)
* narrower spectrum of activity than mebendazole
- for adult pinworms only – treat twice at 2-week interval
Adverse reactions:
- adverse effects = mild (rare for this particular drugs), transient: nausea, vomiting, diarrhea

Question 20

what is pediculus capitis?

Answer 20

head louse - lays eggs on hair called nymph - needs blood from scalp

Question 21

Life cycle of Pediculus capitis

Answer 21

• entire life cycle on head
• nymphs and adult lice feed on human blood
• egg to 1st nymph = 8-9 days (for eggs to hatch)
• egg to adult = 18-21 days (right in time for 2nd treatment)
• survive <2 days away from scalp at room temperature

Question 22

Pediculus capitis clinical presentation, transmission and epidemiology

Answer 22

Clinical presentation:
- itchy head – Note: many children = asymptomatic
- adult lice + eggs (nits) on hair
– most easily seen behind ears / back of neck
Transmission:
- mainly by direct head-to-head contact
- uncommon via combs, hairbrushes, hats etc
Epidemiology:
- most common in children in childcare and elementary schools
- not a sign of poor hygiene (affects everyone)
- all socioeconomic groups affected

Question 23

how do you treat Pediculus capitis?

Answer 23

1. Permethrin
2. Malathion

Question 24

Treatment of Pediculus capitis: what is permethrin moa and pharmacokinetics?

Answer 24

1. Permethrin:
   - drug class = synthetic pyrethroid:
   – synthetic derivative of the insecticide pyrethrin (applied topically)
   – obtained from Chrysanthemum plant Action and pharmacokinetics:
   - causes voltage-gated sodium channels to remain open → membrane depolarisation → rapid paralysis
   - absorption through skin = minimal
   - rapidly degraded to inactive metabolites in liver (typically pretty safe)
   - resistance to permethrin in ~50% head lice in USA

Question 25

what are some suggestions when treating Pediculus capitis?

Answer 25

- neither drug is significantly ovicidal (i.e. do not kill eggs) - more than one application is typically required – retreat at 10-11 day interval - treat bed mates at the same time - examine and treat infested household / close contacts at the same time - manual removal of nits after successful treatment is helpful, e.g. with fine-toothed nit comb

Question 26

Treatment of Pediculus capitis If living lice on scalp 24+ hours after treatment?

Answer 26

– incorrect use of drug – hatching of lice eggs after treatment – reinfestation – drug resistance Adverse reaction: - itching/mild burning sensation of scalp → inflammation of skin in response to agents – can persist for many days after lice are killed

Question 27

what are cestocidal drugs?

Answer 27

drugs used to treat tapeworms

Question 28

what are microscopic parasites?

Answer 28

- Entamoeba (amebiasis) - causes potential lethal disease (intestinal disease) - Giardia (beaver fever) - intestinal disease very closely related to Entamoeba just not lethal - Trichomonas (trichomoniasis) treatment for all three is similar, trichomoniasis means they have infection and disease

Question 29

what are antiprotozoal drugs?

Answer 29

- Protozoa = eukaryotes: * metabolic processes more similar to those of human host than prokaryotic bacterial pathogens * less easily treated than bacterial infections - May cause significant toxicity in host – especially cells with high metabolic activity

Question 30

what is amebiasis?

Answer 30

Infected with this parasite but they also got the disease (intestinal disease) Entamoeba histolytica - most common to kill you - 500 million people infected globally (W.H.O.) - asymptomatic (can affect other people) ↔ diarrhea ↔ bloody diarrhea - 110,000 deaths per year globally - more common in poor socioeconomic communities

Question 31

Life cycle of Entamoeba histolytica and the clinical manifestations of infection in people

Answer 31

Question 32

Entamoeba histolytica Clinical presentations

Answer 32

Clinical presentations: - asymptomatic intestinal infection - mild to moderate colitis (present with diarrhea) - severe intestinal infection (dysentery - fresh blood in feces) - ameboma (pseudotumoral lesion) - liver abscess / other extra-intestinal infection

Question 33

Chemotherapy for E. histolytica - Amebicidal drugs

Answer 33

a) Luminal amebicides (only against cysts and throphs in the lumen): → parasites in bowel lumen b) Systemic amebicides (don't get rid of intestinal infection): → parasites in intestinal wall & liver - can go elsewhere in the body c) Mixed (luminal and systemic) amebicides: → parasites in bowel lumen, intestinal wall & liver

Question 34

Mixed amebicide - metronidazole is the choice for what?

Answer 34

Mixed amebicide of choice for Entamoeba histolytica - kills trophozoites, not cysts Also extensive use in treatment of: - Giardia lamblia - Trichomonas vaginalis - anaerobic cocci - anaerobic gram-negative bacilli - pseudomembranous colitis ↔ Clostridium difficile

Question 35

metronidazole chemistry and pharmacokinetics

Answer 35

- nitroimidazole - administered orally – readily absorbed: * extensive tissue distribution ↔ simple diffusion * therapeutic levels in vaginal and seminal fluids, saliva, cerebrospinal fluid - metabolism ↔ hepatic oxidation by mixed-function oxidase, then glucuronylation - metronidazole + metabolites excreted in urine - rate of plasma clearance ↓ if impaired liver function - simultaneous treatment with inducers of hepatic mixed- function oxidase (e.g. phenobarbital) → enhanced metabolism - drugs that inhibit hepatic mixed-function oxidase (e.g. cimetidine) → prolonged excretion

Question 36

metronidazole moa and adverse effects

Answer 36

Mechanism of action: - some anaerobic protozoal parasites – lack mitochondrial activities for generating ATP + disposing of electrons - instead: * ferredoxin-like, low redox potential, electron-transport proteins: → can transfer electrons to nitro groups of metronidazole → cytotoxic reduced products (bind to DNA + proteins) Adverse effects (high dose most likely to see side effects): - nausea, vomiting, headache, abdominal cramps, metallic taste in mouth – all occur commonly (take with food) - nausea & vomiting if alcohol ingested simultaneously - mutagenic in bacteria: * best avoided in pregnant or nursing women

Question 37

metronidazole clinical uses

Answer 37

Amebiasis (E. histolytica): - drug of choice for treatment of diarrhea/dysentery - not reliably effective for luminal parasites * must be used with luminal amebicide: → iodoquinol (unknown mechanism of action) → paromomycin (not as commonly used) – aminoglycoside

Question 38

what are luminal amebicides used for and what is the drug of choice for its infection?

Answer 38

Used: (i) after treatment of invasive intestinal or extra-intestinal amebic disease (ii) for treatment of asymptomatic infections (for travel) Iodoquinol: - drug of choice for asymptomatic luminal infections - active against luminal stages (trophozoites + cysts) - side effects = rash, diarrhea, dose-related peripheral neuropathy (including rare optic neuritis) - long-term use should be avoided

Question 39

what are metastatic infections

Answer 39

(usually hepatic abscesses) - need to kill parasites within liver abscess + intestinal wall + intestinal lumen - high dosage of metronidazole used to eliminate trophozoites in liver abscess & intestinal wall (not gut lumen) - followed by iodoquinol: * to treat intestinal infection + prevent further amebic liver abscesses

Question 40

Life cycle of Giardia lamblia

Answer 40

- most common intestinal parasitic infection of people - no tissue development

Question 41

what is Giardia lamblia (“beaver fever”) and the drug of choice for its infection?

Answer 41

- two life-cycle stages (i) trophozoite (ii) cyst - infection ↔ ingestion of cysts: usually in water - people-specific and zoonotic genotypes (animal infections wont infect people) - many infections = asymptomatic, severe diarrhea can occur Drug of choice = metronidazole: - dosage much lower than for amebiasis – better tolerated - treatment typically not used for asymptomatic infections – self clearance - only treat giardia if your sick completely different from the other one because it is deadly - can induce resistance - very seasonal late summer early fall - when we are out and about, children under 10 are most at risk and 20-39 years of age - most likely to be travelling inc infection

Question 42

Risk factors for Giardia infection in humans:

Answer 42

– Ingesting contaminated drinking water* (ppl travelling often drink unfiltered water) – Children in child care settings – Close contact with infected persons – Swallowing contaminated recreational water (e.g. pools) – Taking part in outdoor activities (e.g. camping) – Contact with infected animals – Men who have sex with men

Question 43

what is Trichomonas vaginalis and life cycle

Answer 43

Parasites reside in: - female lower genital tract - male urethra + prostate Does not have cyst form - does not have environmentally resistant form - Trophozoite replicates by binary fission - Does not survive in external environment

Question 44

how does Trichomoniasis affect men and women and how is it treated?

Answer 44

- one of most common sexually transmitted diseases, in North America >8 million new cases/year women = asymptomatic ↔ highly symptomatic * vaginal discharge * vulvar itching * discomfort during urination, occasionally dysuria men = usually no signs or symptoms * urethral discharge, burning sensation post urination Treatment: - metronidazole = drug of choice: * single and multiple dose regimens * single dose typically more effective ↔ compliance - metronidazole-resistant infections → treatment failure - repeat treatment at higher doses - systemic treatment preferred to topical therapy ↔ multifocal nature of infection - simultaneous treatment of sexual partner = important

Question 45

Should people with asymptomatic Entamoeba histolytica infections be treated?

Answer 45

yes - they can become sick and this can kill unlike other parasites

Question 46

Should people with asymptomatic Giardia lamblia infections be treated?

Answer 46

no - usually self clearing, we dont wanna over use metronitozole bc it is broad spectrum and can cause resistance

Question 47

Should asymptomatic Trichomonas vaginalis infections be treated?

Answer 47

yes - unknowling pass it onto others and readily transmissable and can inc susceptibility to other sti’s

Question 48

Blood smear - Plasmodium falciparum

Answer 48

causes malaria

Question 49

Global impact of malaria

Answer 49

- Endemic (risk) in 106 countries - Approximately 0.5 billion people infected each year - >1 million people die every year: * most under the age of 5 years * mostly within Africa - In Africa, one child dies every 30 seconds - In Zambia, ~20% of babies do not live to see their fifth birthday because of malaria - Disease of poverty (easily preventable though lack financial)

Question 50

what is malaria and ist life cycle?

Answer 50

- Plasmodium falciparum (nastiest of them), Plasmodium vivax, Plasmodium malariae, (Plasmodium ovale) - P. falciparum → most serious disease + death - Drug resistance = major prophylactic and therapeutic problem Life cycle: Note: Only erythrocytic parasites (damage to rbc is what makes people sick not anything else) → clinical illness

Question 51

Falciparum malaria Clinical disease:

Answer 51

- incubation period generally 9-14 days * headache, pain in back and limbs * anorexia, nausea * fever, chills * anemia(common in young children - they dont have as many rbc as we do) - cerebral malaria = severe disease * usually ill for 4-5 days with fever - can be dead in 5 days very quick * slowly lapse in to coma → +/- convulsions * mortality = ~15-20%

Question 52

Plasmodium life cycle

Answer 52

Question 53

malaria - drugs that eliminate:

Answer 53

drugs that eliminate: a) liver stages = tissue schizonticides (drug kills parasite that is asexually dividing in liver) b) Erythrocytic stages = blood schizonticides (drug kills parasite that is asexually dividing in rbc) c) sexual stages = gametocytes Effective chemoprophylactic agents (what you give ppl to stop from getting sick): * kill erythrocytic parasites before grow in numbers → disease

Question 54

what is the treatment of people with clincial malaria?

Answer 54

1. P. falciparum + P. malariae: - one cycle of multiplication in liver (then leaves liver to rbc): * liver infection ceases in less than 4 weeks - elimination of erythrocytic parasites cures infection 2. P. vivax + P. ovale: - dormant hepatic stage (hypnozoite) - not killed by most drugs (some parasites get dormant in liver not good) - must eliminate both erythrocytic + hepatic parasites

Question 55

how do you prevent malaria?

Answer 55

Counselling of people: - ↑ resistance of parasites to drugs - no chemoprophylactic regimen is 100% protective - prevent mosquito bites: * insect repellents * insecticides * appropriate clothing * bed nets, ideally impregnated with insecticide, e.g. permethrin Chemoprophylaxis recommendations (C.D.C.): - chloroquine – if only chloroquine-S parasites - mefloquine – most malarious areas - doxycycline – if high prevalence of multidrug-resistant falciparum malaria

Question 56

how is permethrin used to prevent malaria?

Answer 56

- Synthetic version of natural insecticide (see head lice) - Used on nets as mosquito repellent + insecticide - Residual activity for 2 weeks to 6 months - In environment, binds to soil and biodegraded in 1-20 weeks - ~5.5 lives can be saved each year for every 1000 children protected with insecticide-treated bed nets

Question 57

what is the clinical uses and pharmacokinetics of chloroquine and what happens with a parasite in rbc

Answer 57

Clinical uses – Drug of choice for: - chemoprophylaxis IF chloroquine-S parasites in area * e.g. Caribbean, Central America west of Panama canal * taken weekly per os - treatment of – chloroquine-S Plasmodium falciparum Pharmacokinetics: - synthetic 4-aminoquinoline – for oral use - rapidly absorbed and distributed to tissues * blood schizonticide - no activity against liver parasites - dealkylated by hepatic mixed-function oxidase system (highly metabolized by liver) * parent drug + metabolites → urine Parasite in red blood cell: - digests host hemoglobin → (i) essential amino acids (ii) heme = toxic to parasite - polymerizes heme → hemozoin * sequestered in food vacuole

Question 58

chloroquine moa

Answer 58

unclear, but: - drug concentrated in parasite’s acidic food vacuole - prevents polymerization of heme (by binding to heme) into hemozoin - oxidative damage → lysis of parasite + red blood cell

Question 59

chloroquine resistance and adverse effects

Answer 59

Resistance: - very common in P. falciparum (e.g. Africa, Asia, South America) - mutations in membrane transporter thought to be responsible Adverse effects: - minimal at low doses for chemoprophylaxis - nausea, vomiting, blurred vision – higher doses - dosing after meals ↓ adverse effects

Question 60

mefloquine clinical uses and resistance?

Answer 60

Clinical uses: - recommended chemoprophylactic drug in areas with: - chloroquine-R Plasmodium falciparum - taken weekly per os - treatment of – chloroquine-R Plasmodium falciparum Resistance: - uncommon except in regions of Southeast Asia with high rates of multidrug resistance - associated with resistance to quinine and halofantrine, not chloroquine

Question 61

mefloquine pharmacokinetics and moa

Answer 61

Pharmacokinetics: - synthetic 4-quinoline methanol – chemically related to quinine - given orally – well absorbed - extensive distribution in tissues – eliminated slowly Action: - blood schizonticide – P. falciparum - no activity against hepatic stages or gametocytes - mechanism of action – concentrated in parasite by unknown mechanism * may inhibit heme polymerization * final result = membrane damage

Question 62

mefloquine adverse reactions and cautions

Answer 62

Adverse reactions (toxicity a concern): Weekly dosing for chemoprophylaxis: - neuropsychiatric toxicities – much publicity - nausea, vomiting, dizziness - sleep and behaviour disturbances - frequency of serious adverse effects no higher than other anti-malarials ? Cautions: - contraindicated – history of epilepsy, psychiatric disorders Note: risks of mefloquine use must be balanced with risk of contracting falciparum malaria

Question 63

doxycycline uses

Answer 63

Clinical uses: - standard chemoprophylactic drug in areas of: * Southeast Asia with multidrug-R parasites (including mefloquine-R) * administered daily per os - for treatment – should not be used as a single agent as slow action: * commonly used for treatment of P. falciparum in conjunction with quinidine or quinine: - allows shorter + better tolerated course of these drugs

Question 64

doxycyline action and adverse effects

Answer 64

Action: - inhibits protein synthesis – as in bacteria - blood schizonticide - not active against liver stages Adverse effects: - infrequent gastrointestinal symptoms - photosensitivity