Basics Of Chemotherapy- Anti Malaria’s And HIV Treatment Flashcards
What are considered to be parasites when it come to chemotherapy
Bacteria, Protozoa, viruses, helminths, fungi and cancer cells
What is the principle mechanism of action when it comes to chemotherapy
We try to identify a qualitative or quantitative difference in the bio chemical machinery between the host and parasite, which when exploited by a selective drug results in a cytotoxic effect to the parasite but not the host
What e variations are there on the theme of chemotherapy
A) That the target is completely absent on the host leading to no cytotoxic effect
B) The target is present on the house but there is a significant difference in the structure between the host and parasite target. To the extent that a selective drug for the parasitic target can be selectively modulated
C) The target of our drug is found in both the parasite and the host however the host contains an escape mechanism a.k.a. an alternative pathway which protects against the target being modulated in the host the compensatory mechanism is absent in the parasite
What is the therapeutic index
It evaluates safety it measures the degree to which we can find differences between the parasites by chemical machinery and that of the hosts can have a major effect on our drug
What is the therapeutic index in humans
Therapeutic index = TD 50/ ED50
What is the therapeutic index in animals
Therapeutic index = LD 50/ ED 50
What does ED 50 mean/ represent 
ED 50 represents the median effective dose a.k.a. is the dose that produces the therapeutic affect in 50% of the population
What does TD 50 represent
TD 50 is the median toxic dose a.k.a. is the dose that produces the toxic affect in 50% of the population
What does LD 50 represent
LD50 is the medium lethal dose is those that produces the lethal effect and 50% of the population
What does it mean when we have a high therapeutic index
A high therapeutic index indicates a safe drug a.k.a. the therapeutic window in which we can see a beneficial effects of a drug without any toxic effect is a large
Name two problems of chemotherapy
A) whilst bacteria and protozoa have many differences viruses have fewer differences but in cancers they are essentially derived by the host cell ( we look for quantitative differences- uncontrollable proliferation)
B) development of resistance ( adaptation/mutation)
What does the first class of target in chemotherapy represent
Class one represents bio chemical reactions which are involved in energy production they are usually not targeted by therapeutic agents and they are fundamental for self biology glycolysis is an example 
What does the second class at target in chemotherapy represent
The second class of targets are bio chemical reactions which are involved in the small molecule synthesis. A number of therapeutic drugs against malaria etc. target these mechanisms biosynthesis of amino acids is an example
What does class three of the targets of chemotherapy represent
Class three represents bio chemical reactions which involve macromolecule production a.k.a. polymers for example the bio synthesis of DNA. These bio chemical reactions are a good source of targets for the generation for chemotherapeutic agents
What are the three lifecycles of malaria
A) exo-erythrocyticcycle. (prior to infection ot liver cells. )
B) erythrocytic cycle (infection of erythrocytes ) -involves schizont and the rupture of them causing re infection of erythrocytes
C) sporogonic cycle (mosquito stages)
What is the main cellular consequences of malaria due to
Lysis of erythrocytes
What is uncomplicated malaria
A patient who represents with symptoms of malaria and a positive parasitological test but with no features of severe malaria
What is severe malaria
Severe malaria occurs when infections are complicated by serious organ failures or abnormalities in the patient’s blood or metalbolism
What are malaria relapses
Malaria relapses are associated with those species of malaria which at the lifecycle stage within the liver the parasite is dormant until reactivated which causes reinfection of erythrocyte leading to symptoms
What does drug treatment response depends on
Malarial species and strains, drug metabolism, side effects, hosts immunity
What are the purposes of drug treatment for malaria
To protect and prevent infection, cure established infection, prevent malaria transmission
What is one major mechanism of action that anti-malarial drugs take
They interfere with the folate pathway
What drugs can be used to interfere with the folate past week and what do they do
Note that the malaria parasite synthesises folate whereas the host does not synthesize it this accounts for a qualitative difference in bio chemical pathways between the host and the pathogen
Usually Sulphonamides and sulphones target dihydropteroate synthetase ( rely on the fact that malaria synthesises folate and the host doesn’t)
Proguanil and pyrimethamine targets dihydrofolate reductase in the parasite (rely on the different sensitivity of malaria and host dihydrofolate reductases to antagonists)
What is another major pathway that anti malarial drugs interfere with
The heme catabolism
Choloroquine and Quine target another qualitative difference between malaria and host, that of heme catabolism.
In malaria the enzyme harm polymerase breaks down free haem to hemozoin
Whereas in the host heme oxygenase is used. ( into iron, co, bilirubin)
What is Artemisinin
It is a drug that has a little resistance is isolated from sweet wormwood and is used in combination therapy mode of action is complex and relies on artemisinin activation/ metabolism- it’s activated in digestive vacuole of the malaria parasite by the mechanism in hemoglobin breakdown
What diseases give a natural resistance to malaria
A) sickle cell anemia
B) thalassemia
C) glucose 6 phosphate dehydrogenase deficiency
These have been shown to have a certain amount of protection for individuals with the disease against malaria this is due to the dysfunctional erythrocyte function this occurs in the erythrocytes in individuals with these diseases, Aretha site has a little appetizing environment for the malarial pathogen
What are the main events that occur in HIV infection
A) Fusion of HIV to the wholesale surface this happens by the GP 120 proteins on the HIV molecule finding to the city for receptors on the host molecule this fusion is also aided by a Co Receptor on the lymphocyte.
B) HIV RNA, reverse transcriptase, integrase and other viral proteins enter into the host cell
C) viral DNA is formed by reverse transcription
D). Viral DNA is transported across the nucleus and integrates into the host DNA
The integrated DNA then becomes reactivated and new viral RNA is used as genomic RNA and makes viral proteins
E) The gnu viral proteins and viral RNA accumulates at the cell surface and a gnu immature HIV molecule forms, the virus is released
Viral protease cleaves new poly proteins to create mature infectious virus.
What is a nucleoside
It is the base and a sugar
What is a nucleotide
It is a bass a sugar and a phosphate
What are the purine bases
Adenine and guanine 
What are the pyramidine bases
Uracil, thymine, cytosine
What are the two types of reverse transcriptase inhibitors
Nucleotide reverse transcriptase inhibitors and non-nuclear side reverse transcriptase inhibitors
Both of these drugs inhibit the conversion of HIVRNA to HIV DNA by the enzyme reverse transcriptase this enzyme is encoded for by the viral genome human cells do not convert RNA to DNA and therefore this enzyme is not present therefore this enzyme represents a qualitative difference between host cells and virally infected lymphocytes
What are the main features of nucleoside reverse transcriptase inhibitors
They are analogues of naturally occurring nucleosides the major difference is the modification of the ribose ring plus the removal of a hydroxyl molecule this result in the inability to add new triphosphate nucleotides to the structure
What is the mechanism of action of nucleoside reverse transcriptase inhibitors in HIV
The nucleoside transcriptase inhibitor can act as a substrate to reverse transcriptase I said can insert the triphosphate AZT into the elongating viral DNA chain causing termination and preventing viral replication
AZT is converted to the triphosphate nucleotide form once inside the cell- carried out by kinases
What about the structure of non-nucleoside reverse transcriptase inhibitors
Their structure varies
What is the mechanism of action of a non-nucleoside reverse transcriptase inhibitors in HIV
They act on the P51 subunit of reverse transcriptase, and can be considered as three fingered. Between the thumb and the first finger we find the catalytic site and also a binding region for the inhibitor.between the second finger and the thumb we find RNASE site which breaks down RNA. HIV RNA enters the molecule and the complementary DNA molecule is synthesised and as it exists the molecule the RNA itself is broken down by the RNASE, essentially RNA enters the enzyme while the DNA exists. The Inhibitors bind to their binding site and inhibit this reaction
A problem with NNRTI
Is that because their binding site is not within the catalytic site a number of mutations can occur in the enzyme that can lead to the resistance of these drugs and this can happen relatively rapidly.
How do integrase inhibitors work
Integrase represents a qualitative difference Between host and parasite - raltegravier
HIV protease inhibitors what do they do
Prevents the cleavage of these structural proteins and thus their assembly thus resulting in the inability for a HIV viral protein to mature - indinavir
