Basics of Chemotherapy 1 - L9

What is Malaria

• it is a protozoa - unicellular prokaryote

• many protozoa that effect humans e.g Pasmodium falciparaum

• can be divided if tehy ahve an exo-erthretic stage or not

• Falaciparum is common in areas aroudn water e.g. Africa, eastern Asia and central America countries

what is the Malaria cycle

have the Sprogonic cyle → Only happens in Mosquitoes

Have the erythrocyte stage → damage to erythrocytes (resd blood cells) due to production of Schizonts which are produced through asexual reproduction called sporigony

Sproziotes (transferred form mosquitoes) infect liver cells and mature and then rupture erythrocytes which can then re infect other erythrocytes

can be transferred back to misquotes when they feed on host

Have exo-erythrocyte stage → some malaria have this stage involved infection of liver cells, happen prior to erythrocytic stage

erythrocytic stge is still the major stage for reproduction of schizonts

what is major consequence of malaria

lysis of erythrocytes / destruction of red blood cells

Diagnosis of Malaria

Uncomplicated malaria → fever, shivering, jaundice, joint pain, stomach issues…

Severe Malaria → associated with neurological conditions e.g. loose consciousness, coma, cerebral hemorrhaging and ever organ faliue

Relapsing Malaria → occurring with malaria that has a large stage in liver, parasites remain dormant in liver until reactivated, once reactivated infect erythrocytes leading to malaria symptoms

what is important in chemotherapeutic regimes

that the host has a good immune system as its used to help the destruction of parasite

some patients present malaria and HIV at the same time which is a problem

drug treatments for malaria have 3 objectives

1) give drugs before establish infection - prevent infection of individual

2) drugs to kill parasite

3) drugs to stop transmission

why has malaria been eradicated in most parts of Europe, China and North America

• due to irrigation of living spaces with mosquitoes, misquotes netting

• educating local people

• pesticides

what is the aim of chemotherapy

the target qualitative difference in the biochemistry of host and parasite and target these differences to then kill parasite

Folate pathway

• Folate important in synthesis of DNA from nucleotides

• humans get folate through diet

• Parasites also get folate from diet and synthesis

• Dihydropterate sythetase - use sulfonamides to inhibit this enzyme so cannot make folate

• can still get enzyme from environment so inhibit enzyme Dihydrofolate synthase (also in humans but different on molecule level)

• Drugs like trimethyprim (have small effect on human enzyme

• Promethyamine no effect on human version of enzyme

• So can combine the Dihydropteroate synthetase inhibitors (Sulphonamides) with dihydrofolate reductase inhibitors (specific for proteasome form ) to inhibit this pathway

Heme catabolism Pathway

• in HUMANS → free haem leading to activation of uxygen species which can eb harmful so is controlled by enzyme haem oxygenase breaks down free haem into iron, Carbon monoxide and bilurin

• In PARACITES → breask down haemaglobin as food sorce to relase AA, as tehy do this release toxic chemical heme, enzyem haem polymerase converes heme into hemozin which is a polymer of haem

• can used Chloroquinne and quinine to inhibit this enzyme Haem polymerase and cause no effect on humans

• now have some resistant strains

Artimisinin

• Important drug that has low rates of resistance

• Artmisinin is active when gets to digestive vacuole of paarsite whihc leads ot egneration of reactive oxygen species wich eveutually leads to death of parasite

• Artimistinin and Quinine are made form traditional chemicals that were used to treat malaria (like things that were found in plants )

so what are the main things that drugs attack in malaria

• folate pathway

• haem pathway

• mitochondrial interaction and development of reactive oxygen species

Relationship between diseases of erythrocytes and malaria:

diseases like sickle cell anemia and glucose 6 phosphate dehydrogenase deficiency has shown low levels of these people catching malaria

this is because these diseases affect erythrocytes making it a less habitable environment for malaria and so less likely to get infected

how ever these diseases have higher rates of contracting other things

different scenarios of drug interactions and their effects on a host and a parasite:

HIV infection

• HIV is positively stranded RNA

• It infects lymphocytes

• binds to CD4 protein using GP120 glycoprotein on HIV molecule

• binding causes interaction with Co-receptors call chemokine (type of GCPR)

• this then allows HIV to fuse with cell membrane allowing RNA, reverse transcriptase and intergrase enzyme to move into cell

• once in cell HIV RNA is transcribed into DNA through reverse tarscriptase

• Then moves to nucleus where integrated into DNA using enzyme integrase

• viral proetins then get tarscribed

• proteins accumilate around cell surafce where protease causes them to form viral particle

• then get released from lymphocytes into blood stream and infect other CD4 proteins

what is a nucleoside

Base + Sugar

base can be purine or pyrimidine

how to make a nucleotide form nucleoside

through addition of phosphate

in DNA backbone where is nucleotide added

• at 3’ hydroxly group

what were the first drugs used to treat HIV

they were Reverse transcriptase inhibitors

• this enzyme not present in humans as we do not convert RNA into DNA so a qualitative difference

what are the 2 types of reverse transcriptase inhibitors

• Nucleoside RT inhibitors

• Non-nucleoside RT inhibitors

Nucleoside RT inhibitors

• they remove OH group from ribose ring

• this means no DNA elongation can take place

• e.g. ATZ has a nitrogen group instead of a OH group

• when ATZ in cell gets converted into triphosphate nucleotide using host kinase

• now it is in right form to be used as a subsutare in the trascription of RT

• once its added ot the chain as no OH group elongation cannot contiues and it is then terminated and so no protein is formed

• DAN polymerase has a lower affinity to ATZ compared

Non- Nucleoside RT inhibitors

• can come in different shapes

• Reverse transcriptase enzyme is like a 3 fingered shape

• between first finger and thumb have catalytic site have NNRTIs biding site

• between thumb and second finger have RNA site, where RNA is broken down

• So when RNA comes in, it gets converted into complementary RNA DNA and leaves, the RNA then gets broken down by RNAase

• NNRTIs work by binding to there site and inhibiting the production of complementary RNA DNA

• mutations can occur causing resistance

• E.g. Nevirapine

Integrase inhbitors

• these drugs inhibit enzyme integrase which integrates RNA DNA into host DNA

• e.g Raltegravir

HIV protease inhibitors

• These drugs inhibit the cleave of structural proteins so do not get mature HIV

• e.g. Indinavire

SO overall have drugs that can :

• stop formation oh HIV DNA + HIV RNA

• can inhibit integrase enzyme

• can inhibit assembly of particle formation

• inhibit binding to lymphocyteè , targeted for CCR5 and CXCR4

  • prevent fusion

what is important in a clinical setting for optimum therapeutic utility

THAT YOU COMBINE DRUGS