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Transcript
FUN2: 10:00-11:00
Scribe: Brittney Fain
Tuesday, December 9, 2008
Proof: Marjorie Hannon
Dr. El Kouni
Pharmacology
Page 1 of 6
Parasitic Diseases
I. Introduction [S1]: Today will talk about parasitic diseases. It is a very big problem in the world today. The global
prevalence exceeds 50% and it is increasing. Most of the parasitic diseases, like ascaris, are ignored because their
effect on the human health is not as dramatic as other diseases (AIDS). However some of these diseases cannot be
ignored like malaria because about 1.5 million people are being killed by malaria. Also in the clinic resistance is
developing and there is a lack of new drugs being developed to combat malaria.
II. Top 10 human parasites (table) [S2]
a. This is an old slide. It needs to be updated. This is to give you an idea of the parasitic disease.
b. The table is thousands per year.
c. In the case of ascaris there are about 900 million infections but only 20,000 deaths per year. (it’s not very
problematic). Then there is the hookworm that infects about 800 million and results in approximately 55,000
deaths per year.
d. Malaria infects about 800 million and kills 1.5 million every year.
e. Schistosomiasis is the second worst parasitic disease and it has approximately 750,000 deaths per year.
f. These numbers are increasing. Most of the life cycles of the parasites are related to water and due to the
increase in irrigation and projects in under developed countries we are seeing greater prevalence of these
diseases.
III. Chemotherapy of Parasitic Diseases [S3]
Side Note: He will focus on Malaria and Schistosomiasis because these diseases cause the most deaths per year.
a. We are talking about Chemotherapy for parasitic diseases because we do not have any vaccines for them.
b. For example, in the case of Schistosomiasis it changes the antigen on its surface every 24-48 hours so by the
time the body recognizes the foreign pathogen it no longer exists in the body in that form. For this reason the
parasite can stay in the body for 40-50 years. (Why we cannot create vaccines for these diseases)
c. We do not have many drugs or new drugs.
d. New drugs are still needed for the treatment of diseases caused by trypansosomes including Chaga disease.
We really do not have any effective drugs against them except the (Inaudible at 4:10) drugs, which are quite
toxic.
e. Looking for new drugs for malaria as well because of the increased resistance the disease has to the old drugs.
f. Just as an example scientists have looked at a quarter of a million drugs in the last 20 years and only one new
drug, halofantrine (inaudible 4:36, but according to the internet: “Halofantrine is a new blood schizontocidal
drug used for the treatment of multidrug-resistant falciparum malaria”) has been used and even it
has shown some cross resistance.
g. Most of the drugs we have today have been discovered by chance because little is known about the
biochemistry, physiology, and molecular biology of the parasite.
IV. Antihelmintic Drugs [S4,S5,S6,S7]
a. Helminthes are worms and can be divided into 3 categories:
i. Trematodes (flukes) example: schistosomes
ii. Nematodes (roundworms) example: ascaris
iii. Cestodes (flatworms) example: tapeworms which can live in the intestine and be meters long in length
b. Most of the antihelmintic drugs attack energy metabolism because most of their energy comes from glucose.
They also attack the neuromascular coordination because the parasite has to remain in a certain part of the
body like in the case of schistosomes which live in the portal veins. They need strong muscles to remain in
place. The other one is microtubular function which is important in cell division. Most parasites either divide
rapidly or they lay large numbers of eggs.
c. There are 3 classes of drugs:
i. Benzimidazoles
ii. Avrimectins
iii. Miscellaneous
V. Mode of action of Benzimidazoles [S8]
a. Inhibition of Glucose transport
b. Inhibition of Fumarate reductase (related to energy function)
c. Interruption of microtubular functions (related to cell division and replication)
VI. Mebendazole [S9]
a. Most commonly used benzimidozole
b. Has a broad spectrum against cestodes (flatworms) and nematodes (roundworms)
c. These are not satisfactory against strongyloids and hydatid diseases
i. These diseases are becoming important in AIDS patients.
d. It inhibits glucose uptake causing glycogen depletion and death
e. Inhibits microtubule synthesis
FUN2: 10:00-11:00
Scribe: Brittney Fain
Tuesday, December 9, 2008
Proof: Marjorie Hannon
Dr. El Kouni
Pharmacology
Page 2 of 6
VII. Albendazole [S10]
a. Newest and most promising of them all
b. Effective against larval and adult stage of nematodes
c. Causes degeneration of the intestine and tegument (skin) cells
d. Important effective against hydatide disease
e. Important drug now because it is effective against almost all of the nematodes and against some of the
cestodes
VIII. Thiabendazole [S11]
a. Broad spectrum benzimidazole against nematodes
b. Drug of choice for treating strongyloidiasis
c. Ovicidal and larvicidal (kills eggs and larva)
d. Activity against saprophytic and pathogenic fungi
e. Has antipyretic, anti-inflammatory, and analgesic properties
f. Inhibits fumarase reductase (effect on energy metabolism)
IX. Ivermectin [S12]
a. Ivermectin is a relatively new drug
b. This is a natural product found from the bacteria Streptomyces avermitilis that the Japanese found in the soil on
a golf course
c. Newest class of nematocides
d. Effective against endo and ectoparasites (parasites found in and on the body)
e. Does anyone know why this was first used in the states?
i. Answer: Heart worm (Dog)
ii. They gave the some of the money they made to the WHO which took the drug to Africa and found it was
effective against sleeping sickness and River blindness-- in some villages in Africa almost every one above
16 is blind.
f. This is very effective and they have found large amounts of digested ivermectin in the dung of animals treated
with this drug.
g. Important: Ivermectin is NOT effective against trematodes or cestodes but IS effective against nematodes.
(Remember, albendazole is effective against nematodes).
h. The difference between the two classes of parasites is in their effects on muscle coordination (GABA verses
cholinesterases).
i. Ivermectin is effective against nematodes because it potentiates the release and binding of GABA at the
post synaptic site at the neuromuscular junction. On the other hand it is not effective against trematodes
and cestodes because acetyl cholinesterase not GABA controls their muscle coordination.
X. Niclosamide [S13]
a. This is effective against cestodes
b. Effects energy metabolism
c. Powerful taeniacide on contact
d. Insoluble in water and not absorbable from the GI tract
e. By touching the cestode it kills it. No pharmacodynamic action because it is excreted completely
Student question: What did you say about touching the cestodes?
Answer: Powerful on contact which means the drug has to be in the vicinity of the parasite
f. It kills on contact with the parasite. It is rapidly and quantitatively excreted (urine 25-30%, the rest in the feces)
XI. Schistosomiasis [S14,S15,S16]
a. In WW II the most common disease among the GI’s in Asia
b. 1.5 billion people are exposed
c. Affects 200 million people worldwide
d. Prevalence about 40-60%
e. Almost everybody (95%) at one time or another was infected in these regions
i. If you go to the schools in rural areas of Egypt almost 95% of the kids have this disease
f. Kills nearly 750,000 people per year
g. Schistosomiasis is caused by 3 or 4 species
i. Schistosoma mansoni (mostly in South America)
ii. Schistosoma hematobium (mostly Africa and some overlap in other areas)
iii. Schistosoma japonicum (mostly found in Far East)
**See Map for picture
XII. Pathogenesis of Schistosomiasis [S17,S18,S19]
a. Causes hepatic fibrosis, portal hypertension, and bladder cancer
i. Bladder cancer is the most common cancer in Egypt because of the prevalence of this parasite.
FUN2: 10:00-11:00
Scribe: Brittney Fain
Tuesday, December 9, 2008
Proof: Marjorie Hannon
Dr. El Kouni
Pharmacology
Page 3 of 6
b. The pictures are to show the clinical signs that may occur in an individual with schistosomiasis.
i.Very enlarged spleen and very enlarged liver. In these kids there is no way to treat them because the
damage at this point is irreparable. The symptoms are due to the accumulation of eggs in the liver.
XIII. Praziquantel [S20,S21,S22]
a. Made by Merck in the old days
b. Effective against all of the trematodes
c. Albendazole, Ivermectin, and Praziquantel were considered the Pencillins of parasitic diseases. In Africa it was
suggested that the population should be treated with these 3 drugs.
d. Newest and most effective drug
e. First drug to treat all of the species of Schistosomiasis (most drugs only treat one of the species)
f. One or two pills can eradicate the disease
g. Causes severe destruction of the parasitic tegument
h. Do not know the defined action of this drug it seems that prepares for the destruction of the tegument by the
body’s immune response. They found this out by working with mice. The drug prepares the worm to be
attacked by the body’s humoral immune response.
i. It causes muscle contraction and paralysis in the parasite
j. Important: Synergestic with the host humoral immune response
**WE REALLY NEED TO KNOW WHAT THE DRUG IS USED FOR AND GENERAL MECHANISM
XIV.
Metrifonate (Bilarcil) [S23] SKIPPED SLIDE
XV. Oxamniquine (Vansil, Mansil) [S24]
a. Vansil and Mansil are the names found in the pharmacy
b. A tetrahydroquinoline compound
c. Effective against S.mansoni in the Americas and W. Africa (effective against only 1 species)
d. Not very effective against North and East Africans strains this it is important to consider what regions you are in
when determining the right drug to administer.
e. The mechanism of action is not well defined.
f. Proposed to inhibit nucleic acids and protein synthesis
g. We do not know the action of most drugs used against parasitic diseases
XVI.
Antiprotozoal Drugs [S25]
a. Most of these drugs came from metallo-organic drugs.
b. A German scientist was working on small pox. He started using dyes. He also tried using arsenics. Merck and
other companies used to be textile companies in the old days. They were making dyes for the textiles. Once
these drugs were discovered this changed everything.
XVII. Sodium Antimony Gluconate [S26]
a. Effective against leishmaniasis
b. Leishmaniasis is one of the diseases that we do not really have a good drug for it.
c. Mechanism of action is not known they think it probably works by inhibition of phosphofructokinase and energy
depletion
d. Binds to SH groups of proteins and forms thioantimonties
e. Very soluble in water and distributes throughout the extra cellular volume
f. Administered by slow i.v. injections
i. If you do it intermuscular then it is very painful
ii. If you do it fast then you can damage the veins
XVIII. Metronidazole [S27]
a. Very effective against trichomoniasis, amoebiasis, and giardiaisis (very prevalent disease here)
b. What you really need to know here is reduced form binds covalently to guanine and cytosine residues in DNA.
This causes the DNA to lose its helical structure and breakdown.
c. Problems with this drug, is it has CNS nervous system effect and neutropenia involvement. These are reasons
why you should be careful when administering this drug
XIX.
Iodoquinol [S28]
a. A halogenated 8-hydroxyquinoline derivative
b. Effective against amoebiasis
c. Eradication of cysts in patients with active bowel disease
d. Alternative to tetracycline for treatment of Balantidium coli dysentery
e. Mechanism of action unknown
HE REPEATEDLY SAID WE WILL NEED TO KNOW WHAT DRUGS ARE USED FOR WHAT DISEASES
XX.
PAROMMYCIN [S29]
a. Structure (can be found in book)
XXI.
The top 10 human parasites [S30]
FUN2: 10:00-11:00
Scribe: Brittney Fain
Tuesday, December 9, 2008
Proof: Marjorie Hannon
Dr. El Kouni
Pharmacology
Page 4 of 6
a. Giving the slide to us again to show the prevalence of malaria and the number killed by this disease.
XXII. Malaria
a. Occurs in more than 100 countries. You do not see this disease in the U.S. The reason for this is we do not
have the intermediate host for the parasite in the U.S. You do not see very many parasitic diseases in the
northern or colder countries because the intermediate host cannot live in the cold weather.
XXIII. Geographic distribution of malaria [S32]
a. This shows the areas where malaria is prevalent
i. Shows the high risk areas. (areas are those that are chloroquine-resistant P. Falciparum (most lethal
species of malaria) If you go to these high risk areas need to have a drug to treat these species of malaria.
XXIV. Malaria Transmission [S33]
a. There are four species of malaria:
i. Plasmodium falciparum
ii. Plasmodium malariae
iii. Plasmodium vivax
iv. Plasmodium ovale
b. You should be familiar with these.
c. [S34, 35] The mosquito has the macrogametes of the malaria in their intestine. It develops into an oocyst which
has what we call sporozoites. These sporozoites are in the salivary glands of the mosquito when the mosquito
bites someone, the sporozoites are released into the person’s body.
d. All of the types of malaria go to the liver and stay there until they divide asexually to form merozoites. In the
liver there are two things that can happen:
i. In the case of falciparum and malariae, all of the parasites in the liver will rupture and go into the
bloodstream where they affect red blood cells. There they divide and some become merozoites and thus
when the mosquito is sucking on the patient’s blood, the merozoites can go into the mosquito and begin the
cycle again.
ii. In the case of vivax and ovale, some of the parasites stay in the liver and are called hypnozoites. These
can rupture at any time.
e. This is why it is very important that when you are prescribing drugs for malaria that you know what species you
are treating and what stage it is in.
XXV. Malaria Pathogenesis and Pathology [S36]
a. These are the symptoms of malaria:
i. Shaking chills, high fever, headache, severe sweating, and the liver and spleen are often involved.
XXVI. Plasmodium Falciparum [S37]
a. This is the most lethal and causes 80 % of the cases.
b. Cause cereberal malaria, renal failure, hemolytic anemia, and most often causes death
c. Duration of the infection is the shortest
i. People that have malaria have these cycles of shaking, sweating, and relaxing. This is related to the cycle
of the blood cells. When the cells ruptures you have the shaking and fever as a result of your immune
system then when they infect another cell then you start sweating and start to feel better. The cycle
repeats itself. In the case of this species this has a very short infection period
d. The liver stage releases 2.5-20 times more merozoites in comparison to the ovale and other species.
e. In the case of p. malariae they only infect older erythrocytes and p. vivax infects only young erythrocytes.
f. p. falciparum can invade a red blood cell at any stage of development this causes the species to have high
parasitemia (number of blood cells infected with the parasite.)
XXVII. Lifecycle of Malaria [S38]
a. Skipped
XXVIII. Recurrence of malaria [S39]
a. In the case of malaria can have relapse or recrudescence need to understand these to determine the proper
treatment
b. Relapse only occurs in P. Vivax and P. Ovale infections
i. Why does relapse occur in these species? Because some cells reside in the liver
c. Relapse can also occur by reinfection from activated hypozoites (which are in the liver)
d. Difference in relapse and recrudescence is that in the case of relapse you see reinfection after good treatment
of the disease
e. Recrudescence can occur in P. falciparum parasites reappear in the blood because you have resistance in
falciparum when you have low parasitemia you don’t realize this until the resistance builds up and you can see it
again as an infection.
XXIX. Goals of Chemotherapy in Malaria [S40]
a. When you are using drugs for malaria you need to determine your goal
FUN2: 10:00-11:00
Scribe: Brittney Fain
Tuesday, December 9, 2008
Proof: Marjorie Hannon
Dr. El Kouni
Pharmacology
Page 5 of 6
b. In areas that have resistance use prophylaxis
i. Clinical and Casual
c. Also have Cure: two types suppressive and radical
i. Suppressive: when infection is in blood and you want to get rid of it
ii. Radical: want to completely clear the body from all of the malaria parasites
d. Difference between Ovale/Vivax and Malariae/Falciparum
i. In the case of malariae and falciparum you can kill all the parasites in the body by using drugs that are
effective against the red blood stages.
ii. In the case of ovale and vivax you have to kill the red blood stages and the ones that are in the liver.
He is just giving us the terminology in case we hear it
XXX. Prophylaxis of malaria [S41]
a. Clinical Prophylaxis
i. Using drugs effective against asexual blood stages
ii. Destroys blood stages
b. Casual Prophylaxis
i. Using drugs effective against tissue stages
ii. Prevents initiation of blood stages (kills parasite before entering blood stage)
XXXI. Types of Antimalarial Drugs [S42]
a. Different drugs affect different stages of the blood cycle.
b. Blood Schizontocides: act on asexual erythrocytic stages
c. Tissue schizontocides: act on exoerythrocytic stages within the liver
d. Gametocidal drugs: Destroy the sexual forms of the parasite and prevent the transmission by vectors
e. Sporonticidal drugs: inhibit the development of oocysts on the stomach wall of the infected mosquito.
XXXII. Antimalarial Drugs [S43]
a. Can be described according to their mechanisms of actions into two classes
i. Undefined (mechanism unknown) these are the quinolines (mainly have this type)
ii. Well Defined (DHFR inhibitors)
XXXIII. What determines the type of drug? [S44]
a. Purpose of chemotherapy: whether it is prophylaxis or cure
b. The type of infection (what type of malaria)
XXXIV. Quinolines [S45]
a. All except primaquine, are fast acting against erythrocytic stages
b. Reach high concentrations selectively with the parasite
c. Sequestered quickly by resistant strains
XXXV. Proposed mechanism of quinolines [S46]
a. When you are having the red blood stage affect by the hemzoin the following happens
i. The stages digest the hemoglobin to provide themselves with essential amino acids. The hemoglobin
digestion release haem which if soluble is toxic. The parasites detoxify haem by incorporating it into the
insoluble and crystalline malaria pigment (hemzoin) by the haem polymerase.
ii. The quinolines work by inhibiting the haem polymerase which means the parasite cannot convert to the
insoluble, crystalline form.
XXXVI. Quinoline Antimalarial Drugs [S47]
a. These are the basic structures of the quinolines we know.
b. Also on this diagram is Quinine which was isolated first from bark in South America. It was then isolated in
France in 1820. It can be made chemically but is very expensive so it is extracted from natural resources.
c. Quinine is important in treatment in Malaria in South America and Africa. What is the most important drink the
British had in Africa? GIN AND TONIC because tonic has quinine in it.
XXXVII. Quinine [S48]
a. Major alkaloid from the cinchona (guina guina)
b. Effective against all four species of malaria
c. Gametocide against all four except mature P. falciparum
d. No significant effect on the liver stages
e. Most rapidly active drug against P. falciparum especially cholorquine-resistant strains
f. Need to be careful because large doses can cause hypoglycemia in severe malaria because of stimulation of
pancreatic B-cells and failure of glucogenesis
XXXVIII.
Quinidine [S49]
a. Diasteromer of Quinine
b. More active against P. falciparum
c. Should only be reserved for situations where quinine is not available
FUN2: 10:00-11:00
Scribe: Brittney Fain
Tuesday, December 9, 2008
Proof: Marjorie Hannon
Dr. El Kouni
Pharmacology
Page 6 of 6
d. Has stronger hemodynamic toxicity than quinine
e. Large doses can cause hypoglycemia in severe malaria
XXXIX. Chloroquine and Amodiquine [S50]
a. Chloroquine was the savior of the people with malaria
b. Was synthesized by the Nazis in Germany after the defeat of Germany it was hidden for a while and we did not
know about this drug until after the war was over
c. Rapid blood schizonticides against all species of malaria
d. Chloroquine is the drug of choice against sensitive P. falciparum
e. Enormous Vd (10-100L/kg) change your slide here it says 100-100 that is wrong) elimination t-half life is 2
months
f. Distribution rather than elimination determine the blood concentration
g. Treatment is a loading dose
h. Little or No toxicity at recommended doses
i. High doses can cause hypotension and cardiovascular toxicity
j. Can cause massive hemolysis in some individuals and lead to dark urine and renal failure
XL. Meflaouine [S51]
a. The most recent of all (maybe in the last 20 years now)
b. First new antimalarial drug to be clinically used in 10 years
c. Potent blood schizonticide
d. Was active against multi-drug resistant P. falciparum
e. Should only be given to patients resistant to chloroquine but this is not the case and it is being given to everyone
which is causing some to resistance to start occurring.
XLI.
Primaquine [S52, S53]
a. This is another quinoline but it has a different mode of action
b. This is very effective during the tissues stages of all four species of malaria
c. Drug of choice for RADICAL care of P.Vivax and P. ovale
d. At high doses causes anemia in most patients and leukopenia in some
e. Causes intravascular hemoglysis and anemia in G6PD deficiency as a result of oxidation stress
f. The oxidation can destroy the cell
g. Mechanism of toxicity
h. Oxidation stress can kill the cell and this is caused by the deficiency in G6PD
XLII.
Flow Chart [S54]
a. The two steps highlighted have been detected in malaria parasites
i. Know the mechanism of action of these drugs
1. In the first step can use sulfa drugs to inhibit this enzyme
2. Also have inhibitor for other enzyme in this pathway
ii. Want to use these two drugs together to minimize resistance
XLIII. Table [S55]
a. Couple of drugs most commonly used in malaria
b. It shows that the therapeutic index for these drugs are good
c. Used with sulfahydra drugs in the treatment of malaria
XLIV. Picture [S56]
a. This is one of the oldest treatments used for malaria and other protozoan diseases (toxoplasm)
b. Mefloquine + Sulfadoxine/Pyrimethamine triple combination
c. Toxoplasm for those in optometry can cause ocular diseases in adults
d. The sulfadoxine is the dihydropteroate synthase inhibitor, mefloquine is the potent blood schizonticide, and
pyrimethamine is the dihydrofolate reductase inhibitor
e. The trade name for this drug is Fansimef (has all three drugs in one tablet)
XLV. Artemissia [S57]
a. This is extracted from a Chinese herb and seems to be working very well
b. It does not have cross resistance to the quinolines
c. Been used quite a bit in China and WHO is starting to use it on a wider scale
XLVI. Halofantrine [S58]
a. This is in the book
b. One of the only drug screened in that quarter of a million that had some effect on malaria however if it is a
resistant strain then will be resistant to this drug as well.
c. Unfortunately resistant malaria is also resistant to this drug
KNOW WHICH DRUG IS USED FOR WHAT UNLESS YOU ARE GOING TO AFRICA OR ANOTHER HIGH RISK
AREA (END 54:25)