Principles of Anti-pathogen Chemo Flashcards
Pathogen
A living agent that causes disease (pathology)
Not - asbestos, tobacco, chemical pollutants, allergens
Viruses
Particles bound by a protein coat (sometimes with a lipid envelope) containing a genome (RNA or DNA) that invadex other cells in order to replicate.
Generally <0.1um in size.
Examples - HIV, influenza, measles, small pox, yellow fever.
Bacteria
Prokaryotic cells (no nucleas), bound by a celk membrane and a cell wall (2 membranes in Gram negative bacteria)
Generally 1-5um in size
Examples - myobacterium tuberculosis, staphlycoccus, streptococcus.
Protozoa
Eukaryotic single cells (membrane bound organelles) bousnd by a single membrane.
Generally 5-20um in size
Examples - plasmodium, toxoplasma, trypanosoma, giardia.
Helminths
Eukaryotic multicellular organisms
Individual cells arranged into organs, covered by tegument (strong coating, protects from drugs and adverse conditions).
Size varies from 0.2mm to >1m.
Examples - tape worm, filarial worm, schistomes, nematode worms.
Selectivity is the central concept of chemotherapy
Drug must kill parasite but not host
Something may be really tpxic hut is acceptable as long as it kills target cell/organism before host.
Key examples -
Atoxyl treats trypanosomiasis, still makes host sick just not dead.
Salvarsan - treats syphilis, heaking arsenic
Pentavalent antimony drugs - leishmaniasis
Cancer drugs.
Chemotherapeutic drugs exploit the differences between the host and the invading microorganism or between a normal cell and a cancer cell.
Therapeutic index
Minimum curative dose as a fraction of the max dose tolerated by patient.
Chemotherapy
The use of chemicals, either natural or synthetic, to kill, or inhibit growth of an infectious agent or growth of malignant cells. Applicable to - Malignancies Bacteria Protozoa Viruses Fungi Helminths Ectoparasites
Selective toxicity in cancer chemo
Cancer cells are too similar to normal host cells, therefor side effects are more common and accepted than in an infectious or degenerative disease.
Pharmacokinetics of chemotherapy
Must be retained at levels which kill the pathogen for long enough, without harming the host.
Must be able to reach the pathogen, be that via blood, CNS, extravascularly or intracellularly.
Orally available drugs must…
Survive acid pH of stomach
Cross intestinal epithelium
Reach therapeutic levels in target organs and remain long enough to kill the pathogen (ie must not be removed in urine,bile,saliva,breath,faeces etc or altered to an inactive metabolite).
Some organs are difficult to reach ie brain, usually a good thing but makes them a difficult drug target.
4 step drug development
- Target identification
- Target validation
- Identification of hit ckmpounds as inhibitors
- Optimisation of leads to improve pharmacology and toxicology
Target validation
Involves the verification that a target is primarily responsible for the theraputic activity of a proven drug.
To be validated as a drug target the putative target must be shown to be essential and susceptible to selective inhibition in vivo.
Development of antimicrobials can be much cheaper than other drug development
Microbes differ genetically from their hosts and are therefor replete with potential targets.
In addition to targets being unique to pathogens, other conditions can favour hitting targets within pathogens.
For example -
Protekns common to host and pathogen can be non-Essen in host but essential in pathogen. Differences in the context of a protein can alter its suitability as a drug target.
Why do very toxic substances selectively kill pathogen and not host?
- Selective activation
- Selective detoxification by host cell (turns drug into inactive metabolite)
- Selective target (unique to pathogen, different importance in pathogen, different stability of target protein, drug has higher affinity for parasitic enzymes than host enzymes)
- Selective accumulation in pathogen (active uptake hy pathogen, active efflux by host cell.
