Among most common diseases of man
Developing countries especially afflicted
Jet/military travel increase relevance to US
Spreading from tropics to Northern latitudes
Entameba histolytica (Amoebic disease)
20% of US may carry - esp eleemosynary inst.
Trichomoniasis -- repro. tract
Giardiasis
Trypanosomiasis
Leishmahiasis
Balantidium coli
Malaria -- Plasmodium spp.
toxoplasmosis
Isosporosis
coccidia -- self-limiting disease in man
diarrheas - bismuth salicylate
NO immunization
Chemotherapy
Worldwide
highest morbidity & mortality of any disease
Resurgence
Plasmodium falciparum
Plasmodium malariae
some merozoites stay in liver and reproduce
Plasmodium vivax
Plasmodium ovale
Bite by Anophlene female mosquito with SPOROZOITES in salivary gland
Sporozoites to liver where they become primary tissue SCHIZONTS
Schizonts mature and rupture releasing
TISSUE MEROZOITES w/in 5-16 days
Merozoites reenter liver if P. ovale or P.vivax
Cause delayed attacks
Asexual portion of cycle
ALL P. falciparum leave liver
RBCs rupture, release merozoites which reenter RBCs
Rupture releases debris which causes clinical signs
Several cycles possible before mosquito bites and takes on
gametocytes (sexual form)
Mosquito bites carrier patient
Gametocytes enter mosquito where 'sexual' form begins
Attack asexual forms of parasite
Available in US
Chloroquine [Aralen]
Mefloquine [Lariam]
Hydroxychloroquine [Plaquenil]
Pyrimethamine [Daraprim]
Pyrimethamine - sulfadoxine [Fansidar]
Quinine sulfate (p.o.)
Quinine HCl (parenteral)
Quinine gluconate (iv)
Sulfadiazine
Tetracycline
Doxycycline
Clindamycin
For P. ovale & P. vivax
Eliminate ALL asexual forms
Eliminate ALL exoerythrocytic forms
Relapse if insufficient treatment
Primaquine
Eliminate all asexual and exoerythrocytic forms
Primaquine
Toxic, controversial
SUPPRESSIVE prophylaxis (Field" / "Clinical" prophylaxis)
Inhibit erythrocytic stage to prevent clinical attacks
Drugs -- 2 wks before to 8 wks after trip
Other 4-aminoquinolines
Not fully explained
Can't explain rapid schizonticidal action
free F-IX,breakdown product of hemoglobin digestion by parasite, is toxic to cells
causes lysis of RBC and intracellular parasites
Parasite can sequester F-IX to protect self
Chloroquine binds F-IX to prevent sequestration, but allow F-IX lyse cells
Inhibit parasite's proteases that digest hemoglobin
Chloroquine is weak base that accumulates in acid lysosomal compartments of parasite where digestion occurs
Drug of choice for ACUTE ATTACKS (erythrocyctic stage
(All four Plasmodium spp.)
Lowers fever w/in 24-48 h
No parasites in blood by 48-72 h
NOT GOOD for latent tissue schizonts (hypnozoites)
Will NOT remove exoerythrocytic organisms
Only antimalarial ok for pregnant women
Many P. falciparum resistant
Systemic amebic liver abscesses
Primarily PO
Use parenterally (e.g., im) when --
Severe nausea is produced by po chloroquine
Potential for questionable absorption
Severe infection
Usually MILD
upset, nausea, and diarrhea
rash and pruritus
headache
reversible decreased accomodation
Dizziness, nausea
Decreased vision
Hypotension -->
Abnormal ECG pattern
Retinopathy
Circulatory failure
Convulsions
Respiratory and cardiac arrest
Death
Highly concentrated in liver and kidney
use with caution when these are impaired
Patients with neurologic disorders usually suffer greater incidence & intensity of side effects
From bark of Cinchona tree of S. America
Spanish 1633, described "fever tree"
Mefloquine only successful derivative
Mechanism may resemble chloroquine
Usually given orally, but can be given iv
Much more toxic than chloroquine
Direct nerve toxicity
headache
nausea
cardiovascular system
skeletal muscle
gastrointestinal system and pancreas
indicated only for chloroquine resistant P. falciparum
Much less toxicity than quinine
500 mg/week for 1 year, no overt toxicity in adults
mild nausea and vomiting
dizziness
some disorientation and depression
8-aminoquinoline
Do not confuse with pyrimethamine
Tissue schizontocide
Radical cure of exoerythrocytic forms
Prophylaxis
Administered ONLY orally
Marked interindividual variation in elimination
half-life, 3-6 hours
methemoglobinemia
abdominal pain
hemolysis
Associated with glucose-6-phosphate Dehydrogenase (G6PDH) deficiency
G6PDH deficiency --> Decr. NADPH formation -->
Decr. reduction of G-SS-G to 2 GSH
GSH is needed to keep H2O2 low
NADH methemoglobin reductase deficiency
Self-limiting. Older RBCs most susceptible
Primarily vaginal infections - T. vaginali
Persistent - extravaginal foci
Signs -- wet inflammed vagina
strawberry" cervix
Thin, yellow, frothy malodorous discharge
Males reprod. tract may be asymptomatic, Treat anyway!
Metronidazole [Flagyl] First trichomonocide. (See below)
Povidone-iodine [Betadine]
Amicrine --
For local use, need adjuvants (e.g., wetting agents) to increase penetration
Wetting agents
Restore vaginal acidity
Highly effective against many protozoans
T. vaginalis
Entamoeba Histolytica -- symptomatic amoebic dysentery
Giardia spp.
Effective against some bacteria that are obligate anaerobes
NOT good for other causes of vaginitis, e.g.., candidosis
Selectively toxic against anaerobes and microaerophilic organisms
Nitro group is REDUCED to reactive intermediates
Nitro radical anions, nitroso-, hydroxylamino- products undergo reactions with cellular components that lead to cytotoxicity. May include DNA strand breakage.
Acts as an electron "sink" that deprives organisms of reducing equivalents needed for energy production. This is an older view.
Selectivity derives from fact that anaerobes maintain reductive environment whereas host cells have oxidative environment.
Administered orally
Distributed widely throughout body tissues
Cleared primarily by liver via oxidative metabolism.
Low -- few serious reactions clinically
Nausea, anorexia, diarrhea, epigastric pain, and cramping may occur
Disulfiram-like reaction when given ethanol is consumed
Carcinogenicity/mutagenicity
Mutagenic in Ames test
Carcinogenic in laboratory studies in mice and rats. Not in hamsters. Nonetheless, should be reserved for cases with positive diagnosis of infection with susceptible organisms.
This drug is a member of a family of drugs that have been specifically disallowed for use in food producing animals by FDA/CVM because they have been shown to cause cancer in some models.
What should one do with a stud bull with Trichomoniasis?
Amprolium
Eimeria -- cattle
CORID
AMPROL PREMIX
Lynn'95
Decoquinate
Eimeria coccidia in chickens, cattle, goats
a quinolone derivative
Lynn'95
Lasalocid
Ionophore
for coccidia in cattle, sheep, poultry
BOVATEC Feed additive
Lynn'95
Metronidazole -- not approved for vet use
FLAGYL
Trichomonas vaginalis, Giardia lamblia -- dogs
Entamoeba histolytica -- amoebic dysentery
Dog 100 mg/kg well tolerated
higher doses cause tremors, weakness, ncoordination, ataxia.
causes pulmonary tumors in mice and
increased incidence of various neoplasms in rats, esp mammary
Lynn '95
Monensin
COBAN & RUMENSIN
coccidiosis
Na & K ionophore for poultry and cattle -- can be fatal to horses
inhibits mitrochondrial function
Lynn'95
Quinacrine
ATABRINE
Not FDA approved for vet use, but is used on Giardia, Taenia, and Diphyllobothrium infestations
Lynn'95
Sulfadimethoxine
ALBON
coccidia in small animals
Lynn '95
Sulfamethazine -- coccidia
Sulfaquinoxaline -- coccidia in poultry, cattle, sheep