Download Antiparasitic Agents

Antiparasitic Agents
I.
Parasitic Infections
a. Spread via travel
b. #1 disease is protozoal (malaria)
c. General considerations
i. Over 1 billion people have a parasitic infection
ii. Usually found in developing countries where there is little financial
incentive to market new drugs
d. Protozoal infections
i. Amebiasis
1. An intestinal disease caused by Entamoeba histolytica
2. Found in the US too
3. causes dysentery, diarrhea, nausea, tenderness and
enlargement of liver
4. also and extra intestinal form (liver)
5. different forms are transmitted differently
a. trophozoid: motile form and a cyst form
i. infectious
1. protected fro the environment
b. can have carriers
ii. Giardiasis
1. an intestinal disease caused by Giardia lambila
2. more common
3. self limiting
a. doesn’t need to be treated
4. called backpackers diarrhea
5. carried by wild animals
6. presents as diarrhea and cramps
a. the bodies attempt to flush the bug out of the body
7. no extra intestinal form
iii. Trichomoniasis
1. a protozoal infection caused by Trichomonas vaginalis
2. common
3. causes vaginitis
a. can be many things
b. effects the genital/urinary tracts
4. females have symptoms but not the male
5. transmitted through sexual acts
6. over 180 million people world wide have the infection
iv. Leshmaniasis
1. very uncommon in the use
a. one form: L. Mexicana
II.
i. Found in Mexico and some parts of Texas
2. Spread by the sand fly
3. It can infect many areas/body parts
4. Cause lesions an death
5. Has an extra intestinal form
6. Symptoms: fever, diarrhea, cough, enlarged liver an s spleen
v. Trypanosomiasis
1. systemic protozoal infections caused by Trypanosoma cruzi
(American trypanosomiasis or Chigas’ disease) and
Trypanosoma bruci (African trypanosomiasis or sleeping
sickness)
2. 50 million Africans at risk for developing the disease
3. organism can penetrate into the heart and cause a heart
attack
4. spread by tsetse fly in Africa and the kissing bug (Chigas’)
vi. Pneumocystis
1. an infection seen in immune compromised individuals
caused by Pneumocystis carinii and organism with
morphology somewhere between a protozoa and a fungi
a. no ergosterol—difficult to classify
2. on of the 3 major secondary disease in immunocompromised
patients
vii. Malaria
1. a systemic infection caused by any of four Plasmodium
a. P. flaciparum (very deadly), P. vivax, P. malariae, or P.
ovale
b. Most serious world wide disease
viii. Cryptosporidiosis
1. parasitic org found in immunocompromised patients
Drug therapy for protozoal infections
a. Treatment of amebiasis, giardiasis, trichomonias and cryptosporidiosis
i. Metronidazole (Flagyl, Metryl, Satric)
1. water soluble
2. HCl salt
3. MOA: Unsure
a. May produce a super oxide radical anion (diradical)
b. Nitro group picks up an electron and enters the
reductive state forming a hydroxyl amine.
c. The electron is then transferred to O2 forming a super
oxide radical anion who can from a reactive oxygen
species such as hydrogen peroxide
d. The reactive oxygen species is though to attach to
DNA leading to lethal fragmentation of the DNA
4. Metabolism:
a. prodrug that under goes hydroxylation (active
compound) and then glucuronide conjugation
i. Conjugates found in the urine
ii. Form off of either alcohol
iii. Inactive
b. Oxidation to an active compound
5. Therapeutic application
a. Resistant strains of amebidisis and trichomonas
b. Should not be taken during the 1st trimester
i. Carcinogenic/ mutagenic in mice
6. Side effects
a. Metallic taste, abdominal pains
b. Causes a disulfuram like effect
ii. Tinidazole
1. not available in the US
2. derivative of metronidazole
iii. Diloxanide furoate (Furamide)
1. available from the CDC
2. under goes degradation in the GI tract to form Diloxanide
(active compound)
3. metabolized to the glucuronide (inactive)
4. prescribed for asymptomatic amebiasis
a. not useful for extraintestinal amebiasis
iv. Nitazoxahide (Alina)
1. prodrug
2. appeared a few weeks ago
3. not carcinogenic or mutogenic
4. the nitro group is important for activity
a. required fro the redox reactions
5. thiazole
6. used against
a. G. intestinalis and T. vaginalis which are resistant to
metrondiazole
b. E. histolytica
c. Cryptosporidium parvum
d. H. Pylori
e. And some helminthes
7. MOA: nitazoxahide and Tizoxanide (active compouind) are
prodrugs which are activated by electron transfers from
PFOR (pyruvate: ferredoxin oxido reductase)
a. Effects NADH
III.
IV.
b. Essential for anaerobic energy metabolism (an
electron transfer reaction)
8. Tizoxanide is further conjugated with glucuronide to an
inactive compound
9. Both nitazoxahide and tizoxanide have an NO2
Treatment of leishmaniasis
a. Sodium stilbogluconate (pentostam)
i. Available from the CDC
ii. Diglucuronic with heavy metal
1. Sb = antimony
2. increases the affinity for sulfhydro groups
3. not very selective for pathogenic organisms
iii. MOA: unknown, but it may inhibit (up to 90%) glucose catabolism
resulting in decreased levels of ATP and GTP
b. Pentamidine
i. See below
Treatment of pneumocystis (PCP)
a. Common in immunocompromised
b. Has no ergosterol so it is not a true fungus
c. Sulfamethoxazole/trimethoprim (Bactrim, Septra)
i. Interferes with THF reduction
ii. DDS + trimethoprim interferes with PABA incorporation
1. used as a backup
d. Pentamidine (Pentam 300 and Nebupent)
i. Binds to the AT regions in DNA and inhibits Type 2 topoisomerase
in mitochondria DNA
1. H-bonds to DNA
2. cross links the two strands so that they cannot unwind
3. the amidine group donates reacts with the extra electrons on
the nitrogen
ii. available IV or aerosol
1. good since PCP is a lung condition
iii. 50% of patients on IV have toxic reactions
1. correlates to the rate of injection
2. breathlessness, tachycardia, dizziness
3. may be due to histamine release
iv. poor CNS penetration
v. high water solubility
e. Atovaquone (Mepron)
i. Used as a back up drug
ii. Inhibits mitochondrial respiratory chain
1. ubiquinone reductase inhibitor
V.
a. important for electron transport and may be
cytochrome BC1
iii. administered orally
iv. poor absorption
1. better when administered with a fatty meal
v. highly bound to plasma protein
vi. excreted unchanged
Treatment of Trypanosomiasis
a. Suramin sodium
i. Introduced in the 1020’s
ii. Drug of choice for non CNS African trypanosomiasis
iii. MOA: none proven
1. Inhibits dihydrofolate reductase
2. Inhibits thymidine kinase
3. Inhibits glycolytic enzymes
iv. Water soluble
v. Poorly absorbed
vi. Given IV
vii. Does not cross the blood brain barrier
1. limits used b/cause you can’t treat the active from of the
disease
viii. bound to plasma protein
ix. prophylactic
b. Pentamidine
i. Used for east African sleeping sickness
ii. Useful only in the early stages of the disease
iii. Does not penetrate the BBB
c. Eflornithine (Ornidyl, DFMO)
i. Derivate of ornithine
1. ornithine normally is decarboxylated by ornithine
decarboxylase to purtrescine and then spermine which leads
to cell division
ii. a poly-amine
iii. forms a Schiff base
iv. MOA: competes for ornithine decarboxylase
1. irreversible
2. yields a loss of HF
3. ODC attacks at the CHF of a decarboxylated compound
causing the loss of the last F then it cleaves the pyridoxyl-5phosphate and permanently attaches so the enzyme can not
carry out it’s proper reaction
v. Suicide substrate
VI.
vi. Human cells can produce ODC rapidly but the bug can not so the
drug has somewhat selective effects
vii. Poor oral absorption
viii. Zwitterionic
ix. Given IV and PO
x. Specturm of activity
1. Tb. gambinese
a. Early and late
2. not effective against Tb. rhodesiense
d. Nifurtimox
i. Available from CDC
ii. Contains a nitrofuran
iii. MOA: generate ractive oxygen species
1. NO2 is the source of the electrons that it transfers to the O2
2. Damages lipid portion of the cell membrane
3. damages the DNA
4. inhibits trypanothione reductase
iv. Drug of choice for Chigas’ disease (acute)
e. Melarsoprol
i. Available from the CDC
ii. Has arsenic at the center of the compound
iii. Developed in the 1040s
iv. MOA: As has high affinity for sulf hydrol groups present in several
key trypanosoma enzymes
1. trapanothione reductase
2. pyruvate kinase
3. phosphofructokinase
v. administered IV
vi. poorly absorbed
vii. enters the CNS
viii. drug of choice for late stage menigoencephalitic trypanosomasis
1. active against Tb. rhodesiense and Tb. gambinese
ix. very serious side effects
1. 3-5% death
2. convulsions, cerebral edema, coma and encephalopathy
Malaria
a. Patients are non symptomatic when the bug is in the liver (Preerythrocytic stage)
b. 300-500 million people have a clinical case of malaria
c. 1.5-2.5 million deaths per year
d. only the female mosquito bites
e. disease foun di n all warmblooded animals
f. difficult to control
g. Tertian or quatrain malaria
i. the symptoms occur every 3rd or 4th day
h. Drugs:
i. Quinine
1. original compound
2. entered into the London Pharmacopia about 1677
3. used the bark of the cincona tree
4. resistance has developed
5. developed quinacrine in 1934
a. closely related to quinine
6. chloroquine is the mainstay of treatment today
a. the best anti-malarial
b. developed in the 1940’s
7. quinoline nucleus is important for the compound
8. MOA:
a. intercalculation into DNA
i. Requires a flat molecule
ii. Dose needed is much higher than the
therapeutic dose
iii. Probably not the MOA
b. Ferriprotoporphyrin iX (FP9)
i. Very possible
ii. Because plasmodium degrades erythrocytes
for amino acids
iii. Also produces hemozin (contains FP9)
1. very toxic except when bound to protein
iv. chloroquin can also bind (very toxic)
c. weak base hypothesis
i. plasmodium lysosome pka is about 4.8 – 5.2
ii. anti malarial forms salt and increases the pH
iii. plasmodium’s digestion of the hemoglobin is
diecreased
iv. reasonable MOA
9. Resistance
a. Increased drug efflux
b. Increased Cyp 450 activity
10. Threepudic Application
a. Active against erythrocytic plasmodium
i. Erythrocytic schizonticide
ii. Quinine
1. metabolized via Cyp 3A4 to a di-hydroxyl compound with
poor activity
iii. Choloroquine (Aralen)
iv.
v.
vi.
vii.
viii.
1. metabolized via dealkalytion via CYP 450 to an active
compound
Mefloquine (Lariam)
1. CF3 protects against metabolism (bug can’t hydrolyze)
2. derivative of quinine
3. effective against resistant strains
4. suppressive prophylactic
5. has neuro-psychiatric side effects as well as GI disturbances,
cardiovascular and skin effects
6. Metabolsim: the alchohol is oxidized and converted to a
ketone and then COOH
a. Inactive
Halofantrine (Halfan)
1. metabolized via dealkylation to the active agent
a. removal of a butyl group
2. good for resistant organisms
3. back up agent
4. useful for cholorquine resistant P. falciparius
5. Side effects: lengthens the QT interval
Pyrinethamine (Daraprim, Fansidar)
1. contains a sulfer drug (Fansidar)
2. structure is similar to trimethoprim
3. inhibits DHF reductase and THFA synthesis
4. used in combination with sulfa drugs
a. sequential blocking
Proguanil
1. prodrug that undergoes oxidation and cyclization to
cycloguanil (active)
2. similar to trimethoprim
a. not an aromatic ring
3. melarone = Atovaquone an dProguanil
4. erytholytic shizontacide
Artemisinin
1. started as a natural product
a. all have an O-O peroxide
2. not on the market yet
3. kills through free radical oxidative mechanism
a. membrane oxidation
4. therapeutic application: gametocytocidal agent
a. prevents the spread of the disease