pharmacology of anti-parasite drugs Flashcards
what are the two classes of parasites of people?
- Macroscopic parasites:
- Taenia species (tapeworms) - Enterobius (pinworm)
- Pediculus (head louse) - Microscopic parasites:
- Entamoeba (amebiasis)
- Giardia (beaver fever)
- Trichomonas (trichomoniasis)
- Plasmodium (malaria) Prevention:
To what extent can control be achieved without drugs ?
what is Taenia saginata and Taenia solium
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
what is the life cycle of Taenia saginata/Taenia solium?
info slide
what are the structures at the anterior end of tapeworm for attachment to wall of small intestine
what are cestocidal drugs?
cestodes = tapeworms
- praziquantel
- niclosamide
praziquantel pharmacokinetics and moa
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
praziquantel clinical uses and adverse reactions
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)
niclosamide pharmacokinetics and moa
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
niclosamide clinical uses and adverse reactions
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
prevention of reinfection of Taenia saginata and Taenia solium
- start cooking your beef
- start cooking your pork
Life cycle of Enterobius vermicularis (pinworm)
what is Enterobius vermicularis transmission and clinical presentation?
- 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
how to minimize risk of infection of enterobius vermicularis and drug of choice for treatment?
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
mebendazole chemistry and pharmacokinetics and moa
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)
mebendazole clinical uses and adverse reactions
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
pyrantel chemistry and pharmacokinetics and moa
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
pyrantel clinical uses and adverse effects
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
what is pediculus capitis?
head louse - lays eggs on hair called nymph - needs blood from scalp
Life cycle of Pediculus capitis
- 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
Pediculus capitis clinical presentation, transmission and epidemiology
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
how do you treat Pediculus capitis?
- Permethrin
- Malathion
Treatment of Pediculus capitis: what is permethrin moa and pharmacokinetics?
- 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
what are some suggestions when treating Pediculus capitis?
- 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
Treatment of Pediculus capitis If living lice on scalp 24+ hours after treatment?
– 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
what are cestocidal drugs?
drugs used to treat tapeworms
what are microscopic parasites?
- 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
what are antiprotozoal drugs?
- 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
what is amebiasis?
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
Life cycle of Entamoeba histolytica and the clinical manifestations of infection in people
Entamoeba histolytica
Clinical presentations
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
Chemotherapy for E. histolytica - Amebicidal drugs
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
Mixed amebicide - metronidazole is the choice for what?
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
metronidazole chemistry and pharmacokinetics
- 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
metronidazole moa and adverse effects
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
metronidazole clinical uses
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
what are luminal amebicides used for and what is the drug of choice for its infection?
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
what are metastatic infections
(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
Life cycle of Giardia lamblia
- most common intestinal parasitic infection of people
- no tissue development
what is Giardia lamblia (“beaver fever”) and the drug of choice for its infection?
- 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
Risk factors for Giardia infection in humans:
– 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
what is Trichomonas vaginalis and life cycle
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
how does Trichomoniasis affect men and women and how is it treated?
- 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
Should people with asymptomatic Entamoeba histolytica infections be treated?
yes - they can become sick and this can kill unlike other parasites
Should people with asymptomatic Giardia lamblia infections be treated?
no - usually self clearing, we dont wanna over use metronitozole bc it is broad spectrum and can cause resistance
Should asymptomatic Trichomonas vaginalis infections be treated?
yes - unknowling pass it onto others and readily transmissable
and can inc susceptibility to other sti’s
Blood smear - Plasmodium falciparum
causes malaria
Global impact of malaria
- 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)
what is malaria and ist life cycle?
- 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
Falciparum malaria Clinical disease:
- 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%
Plasmodium life cycle
malaria - drugs that eliminate:
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
what is the treatment of people with clincial malaria?
- 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 - 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
how do you prevent malaria?
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
how is permethrin used to prevent malaria?
- 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
what is the clinical uses and pharmacokinetics of chloroquine and what happens with a parasite in rbc
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
chloroquine moa
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
chloroquine resistance and adverse effects
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
mefloquine clinical uses and resistance?
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
mefloquine pharmacokinetics and moa
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
mefloquine adverse reactions and cautions
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
doxycycline uses
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
doxycyline action and adverse effects
Action:
- inhibits protein synthesis – as in bacteria
- blood schizonticide
- not active against liver stages
Adverse effects:
- infrequent gastrointestinal symptoms
- photosensitivity
