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Drugs and Disease > Drug Targeting and Resistance > Flashcards

Drug Targeting and Resistance Flashcards

1
Q

What is drug targeting?

A

Is ensuring that your inhibitor has a very high affinity for the target (enzyme)

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2
Q

What is drug resistance?

A

Is the result of mutations in the target (enzyme)

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3
Q

What are some factors that need to be considered when considering if your drug will reach the target cell?

A

Oral or parenteral administration
Metabolism by liver, plasma enzymes etc. (is it stable?)
Excretion in the kidneys
Segregation in specific tissues, binding to plasma proteins
Blood-brain barrier; placenta; blood-testes barrier etc.

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4
Q

What are some blockages that prevent the drug entering the target cell?

A

Lipophillic or hydrophilic
Transporters, channels
Multidrug resistance proteins (ABC transporters)

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5
Q

What are the ways to cross the plasma membrane?

A

Diffusion
Facilitated diffusion
Active transport

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6
Q

What molecules can get across by diffusion?

A

Highly lipophilic molecules only (not water soluble)
Not specific: Enters any cell
Wide distribution may mean higher dosage and toxicity
High lipophilicity also means increased penetration across blood brain barrier and similar
Absorption through skill may be possible

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7
Q

What is an example of molecules that can cross through diffusion?

A

Example: steroids

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8
Q

What is facilitated diffusion mediated by?

A

Transport proteins

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9
Q

What compounds usually pass through in facilitated diffusion?

A

Hydrophobic compounds

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10
Q

What is specific targeting?

A

Enters only cells expressing appropriate

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11
Q

What is equilibrative?

A

Allows the passage across the plasma membrane until there is equilibrium between intracellular and extracellular concentrations

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12
Q

What can intracellular concentration never be higher then in facilitated diffusion?

A

Plasma concentration

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13
Q

What is active transport mediated by?

A

Transport proteins

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14
Q

What is active transport depend on?

A

Energy dependent

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15
Q

What is concentrative?

A

Continues to ‘pump’ the substrate into the cell even against high concentration gradient

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16
Q

How can intracellular concentration differ to plasma concentration in active transport?

A

Can grossly exceed plasma concentration

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17
Q

What does the increased intracellular concentration increase?

A

Specifity and keep required plasma concentrations low

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18
Q

What are transporters characteristics?

A

Highly specific
Concentrative if energy dependent
Equilibrative if not energy dependent
Cause of resistance if lost

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19
Q

What do transporters define?

A

What molecules reach the intracellular target
What concentrations are achievable within the parasite/target cell
How fast the drug is taken up
Drug resistance and cross-resistance

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20
Q

What is active transport?

A

The combination of high affinity and high rates of uptake requires energy

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21
Q

What direction is active transport?

A

Uni-directional and accumulates substrates in the cell above the gradient

22
Q

What is an example of active transport?

A

Pentamidine given at 1 nanometer accumulates to mM inside trypanosomes

23
Q

What are the 3 types of active transport?

A

ATP dependent
Using sodium gradient
Using proton-motive force (H+ gradient)

24
Q

What is ATP dependent active transport dependent on?

A

Ion pumps
P-glycoproteins
Multi-drug resistance (mdr) proteins

25
Q

What is sodium gradient active transport dependent on?

A

High affinity mammalian transporters

Usually expressed in specialised tissues

26
Q

What is proton-motive force active transport dependent on?

A

Most protozoan transporters

27
Q

What does the BBB consist of?

A

BBB consists of brain capillary endothelial cells, connected by tight junctions, plus astrocytes

28
Q

What does the composition of the BBB do?

A

Keeps many unwanted substance and pathogens out but essential nutrients still need to be taken into the brain: specific transporters

29
Q

What are transporters in the BBB?

A

Mostly active and uni-directional

30
Q

What do efflux pumps do in the BBB?

A

Severely limit the ingress of drugs

31
Q

What are the most potential causes of drug resistance?

A 
Mutation of the target protein
Loss of the target
Overexpression of the target
Overexpression of pathway bypassing target
Loss of enzyme activating prodrug
Detoxification with elevated levels of glutathione etc. 
Expression of ABC transporters
Loss of transporters
32
Q

What does expression of ABC transporters rely on?

A

MDR

P-glycopoprotein

33
Q

How can loss of transporters occur?

A

Mutations
Gene deletions
Loss of expression

34
Q

What is an example of mutation of target?

A

Benzimidazoles as anthelminthics
Most widely used anthelmintics
Thiabendazole (1961). Later analogues reduced toxicity
Widely used in human and veterinary medicine
Effective against most intestinal and systemic nematodes (roundworms) and cestodes (tapeworms) and some trematodes (flukes)

35
Q

How does this mutation occur?

A

High affinity, but irreversible binding to beta-tubulin
This cases ultra structural changes to intestinal cells of nematodes and to the tegument of cestodes
Disruption of cytoskeleton
Inhibition of microtubule-mediated vesicular transport

36
Q

What are microtubules?

A

13 proto-filament strands

37
Q

What are proto-filaments?

A

Made up of strings of alpha-beta hetero-dimers

38
Q

What does binding to beta-tubulin prevent?

A

Tubule elongation

39
Q

What is normal tubule elongation?

A

alphabeta: alphabeta:alphabeta etc

40
Q

What does benzimidazole treatment lead to?

A

Tubule capping and degredation

41
Q

What do macrolides inhibit?

A

Including erythrocmycin

Inhibit protein synthesis by binding to 23 S ribosomal subunit

42
Q

How is resistance associated by alterations to target?

A

Methylation of rRNA

Plasmid-encoded methyl transferase

43
Q

How is resistance by reduced cellular concentration?

A

Plasmid-encoded efflux pump

44
Q

What is arsenical resistance in trypanosomes?

A

Tyrpanosoma brucei spp cause sleeping sickness
Are transmitted by the tsetse fly
Sleeping sickness is treated with the organo-arsenic compound melarsoprol

45
Q

What can melarsoprol resistance be the result of?

A

Detoxificarion plus-extrusion
Loss of uptake into parasite
Combination of both

46
Q

What does Melarsoprol (MelB) enter the parasite through?

A

P2 adenosine transporter

47
Q

What does MelB form?

A

Adduct with trypanothione (MelT)

48
Q

What is the adduct exported by?

A

TbMRPA (ABC transporter)

49
Q

What is the most common mechanism?

A

ABC-transporter-mediated efflux

50
Q

What is non-expression of (uptake) transporters?

A

Unlikely to be result of loss-of-function mutations
Heterologous population followed by selection → survival of non-expressors → relapse with resistant cancer
Individual differences between people

Drugs and Disease (25 decks)

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