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Pharmacy Stage 2 > Chemistry-Harburn > Flashcards

Chemistry-Harburn Flashcards

1
Q

what does a bacteria need to keep itself alive? what do antibiotics do to these?

A

outer membrane to keep itself together
DNA -information and be able to copy it to keep that information,and needs to transcribe that info to mRNA to copy it, need to be able to translated into proteins> protein used in cell.
needs essential metabolites e.g. folic acid.

> > > > > antibiotics attack these systems.

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2
Q

Describe the cell wall/membrane structure differences of gram positive and negative bacteria

A

Gram positive- CELL WALL ON OUTSIE, ONE MEMBRANE INSIDE CELL WALL:
>thicker peptidoglycan layer in cell wall than gram(-)
>teichoic acid in cell wall
>lipoteichoic acid in cell wall
>proteins in cell wall (Including glycoprotein antigen determinants)
>phospholipid bilayer forms cell membrane
>penicillin binding proteins on cell membrane
>porins on cell membrane
>(if beta-lactam antibiotics resistant) secreted Beta-lactamase on outside of cell.

Gram negative-OUTER MEMBRANE, CELL WALL, PERIPLASMIC SPACE, INNER MEMBRANE:
>phospholipid bilayer forms both cell membrane
>proteins on outer membrane
>more porins on outer membrane than gram(+)
>lipopolysaccharides on outer membrane
>thinner peptidoglycan layer in cell wall than gram(+)
>more penicillin binding proteins on inner membrane than gram(+)
>more porins on inner membrane than gram (+)
>(if beta-lactam antibiotics resistant) secreted Beta-lactamase in periplasmic space

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3
Q

Draw structure of -Lactam.

A

WEEK 5 ANTIBIOTICS LECTURE 1 (harburn)

draw like square 4 membred cyclic amide ring, double bond oxygen to ring on bottom left corner, N part of the ring on bottom right corner.

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4
Q

Which is the most up to date Beta-lactam antibiotic?

A

Monobactam . its very specific.

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5
Q

What do Beta-lactams do?

A

inhibition of the bacterial cell wall synthesis.

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6
Q

what is good about Beta-lactams being a 4-membered ring of a cyclic amide?

A

4 membered ring less stable than 6 membered rings as it is more strained because the sp3 orbitals don’t perfectly overlap. Therefore, Beta-lactams are energetically primed to open the ring- to release ring strain. Amides can be hydrolyzed to open the ring - (amine or suplphur or oxygen nucleophile can ring open it).

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7
Q

Are beta-lactams usually from natural sources?

A

yes. naturally developed by the microorganisms themselves. but some are semi synthetic
its thought that because of this, the bacteria use these as chemical weapons against other bacteria or other microorganisms.

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8
Q

Name some beta-lactams

A

penems, carbapenems, cefems, monobactams,

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9
Q

Name 2 penems which also contain Beta-lactamase inhibitors.

A

Co-amoxiclav
Tazocin

-(2 drugs in one medicine. the inhibitors prevent resistance of beta-lactam resistant bacteria.)

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10
Q

Describe the synthesis of bacterial cell wall/ peptidoglycan.

A

peptidoglycan:
heteropolymer of 2 sugar units: N-acetylmuramic acid and N-acetylglucosamine.
N-acetylmuramic acid untis have a peptide chain coming off them.
Last step of cell wall synthesis- peptide chains linked together by cross links (catalysed by transpeptidase) to give a net-like formation.

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11
Q

What happens when you can stop the net- like formation of peptidoglycan?

A

if you stop that from forming , when bacteria pressurises itself, it has holes in it, would undergo lysis and push cytosol out of the cell.

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12
Q

Penicillin inhibits transpeptidase from forming crosslinks between peptide chains of peptidoglycan. Explain how the crosslink is formed.

A

LOOK AT DIAGRAM IN WEEK 5 ANTIBIOTIC HARBURN LECTURE SLIDE 12.

Electron pair from glycine of one peptide chain transfers to D-alanine of the next peptide chain. This D-alanine transfers the electron pair to the next D-alanine below it. That D-alanine takes the electron pair and is removed from the chain.
THIS WHOLE REACTION CATALYSED BY TRANSPEPTIDASE.

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13
Q

Explain transpeptidase mechanism of action.

A

week 5 antibiotic harburn lecture slide 13. diagram.

1) Lysine residue with charged amine side chain (NH3+)
- important in forming salt bridge with charged carboxylic acid (CO2-) which stabilizes the peptide on bringing it into the enzyme>allows reaction to happen as peptide is in close enough vicinity now.

2) Serine residue with OH side chain.
- important because a lone pair of electrons from the Oh gets transferred to D-Alanine of the first peptide chain, then electron pair transfers to the next D-Alanine along which takes the electron pair and is removed from the peptide.

3) Second peptide chain comes. e- pair from glycine on second peptide is transferred to D-Ala, which is transferred again to reform the OH of the serine residue side chain. PEPTIDE CROSS-LINK NOW FORMED.

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14
Q

What are the 2 important residues on transpeptidase which allow it to catalyse cross-linking of peptide chains of peptidoglycan?

A

1) Lysine residue with charged amine side chain (NH3+)
- important in forming salt bridge with charged carboxylic acid (CO2-) which stabilizes the peptide on bringing it into the enzyme>allows reaction to happen as peptide is in close enough vicinity now.

2) Serine residue with OH side chain.
- important because a lone pair of electrons from the Oh gets transferred to D-Alanine of the first peptide chain. Reaction has started.

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15
Q

Explain penicillin mechanism of action.

A

1) Lysine residue with charged amine side chain (NH3+)
- important in forming salt bridge with charged carboxylic acid (CO2-) which stabilizes the penicilin on bringing it into the enzyme>allows reaction to happen as penicillin is in close enough vicinity now.

2) Serine residue with OH side chain.
- a lone pair of electrons from the Oh gets transferred to the double bonded O of lactam ring and then again to open up the B- Lactam ring.

3) Covalent bond holding b-lactam in place and v strong salt bridge- keeping penicillin there-irreversible. Umbrella effect created: peptide chains cant come in and also blocking H20 from hydrolyzing the covalent bond.

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16
Q

Because of ring opening of Beta-Lactams, what are the 2 different ways a patient can get adverse drug reactions from Beta-Lactams?
List some adverse drug reactions.

A
  1. Occurring immediately (IgE mediated responses)
  2. Delayed reaction (T cell mediated responses)

e. g.
- Hives (Urticaria)
- Steven-Johnson syndrome
- Acute exanthematic pustulosis
- Anaphylaxis

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17
Q

How can Beta-Lactams cause hypersensitivity in patients?

A

ring opening can occur easily in vivo because Beta lactam ring can be cleaved by lots of things: acid, base, metal ions (as long as theres some water) or by nucleophiles. Or can ring open itself
»serum binding, binds to proteins and a covalent adduct called a Hapten carrier is formed.
Haptens are minute molecules that elicit an immune response only when attached to a large carrier such as a protein»hypersensitivity from immune response.

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18
Q

List some drug interactions with BeTA-lactams.

A

• Penems and Valproic Acid:
Increased clearance in Valproate> seizures
• Possible interaction with combined oral contraceptives:
>Gut flora (bacteria) assists in the deconjugation of estrogen metabolites>releasing ethinylestradiol >Facilitates reabsorption from duodenum/jejunum
>Estrogen passes to liver>conjugation to simple sugar&raquo_space;>‘Enterohepatic Shunt’> recycling
• Methotrexate:
Competition for excretion in kidney tubules
• Wafarin:
Increase/Decrease anticoagulation (possible CYP interaction)

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19
Q

Beta - lactam resistance can occur in bacteria. Examples?

A

Penicillinse (Beta lactamase)

MRSA (methicillin resisitant Staphylococcus Aureus)

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20
Q

Why is there stability problems with penicillin, especially the original penicillins?
How does this lead to reduced bioavailability, or inactivity?

A

problem with penicillins in acid (e.g. stomach acid) especially original ones (e.g. benzylpenicillin)-
c6 side chains can interact and open up the ring
>hydrolysable easily through series of mechanisms involving the C6 side chain>giving products which are not active. Original ones used to be injected because too low bioavailability because of this problem.
help this problem:
> selectively change R group to something which is electron withdrawing prevents hydrolysis reactions taking place. Or something charged which would help with bioavailability.

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21
Q

What is one of the original penicillins with very low bioavailability?

A

benzylpenicillin

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22
Q

The original penicillins e.g. benzylpenicillin , have very low bioavailability of the intact drug due to being easily hydrolysed and being changed into inactive products. How can you improve the absorption of intact drug?
How can you make the drug more longer acting?

A

absorption of intact drug only 15-30% for benzylpenicillin befcause of quick breakdown

replacing R groups with electron withdrawing and charged increases availability of INTACT drug :
electron withdrawing better
charged better
electron withdrawing AND charged: much better
one way to get around beta lactamases is if u bulk up the molecule. steric blocks. Beta-lactamase cant get in to hydrolyse the beta lactams.
»»>higher absorption of intact drug.

electron withdrawing+ charged- more absorption :)
more lipophilic R groups more protein binding>longer acting….so its an interplay with what u want.

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23
Q

Co-amoxiclav and Tazocin contain Beta lactams and Beta lactamase inhibitors, to get aroud Beta lactamases without being hydrolysed. Name another way to get around Beta- Lactamases.

A

one way to get around beta lactamases is if u bulk up the molecule. steric blocks. Beta-lactamase cant get in to hydrolyse the beta lactams.
»»>higher absorption of intact drug.

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24
Q

What class of antibiotics is Vancomycin? WHat is it used for and where does it come frpm?

A

Glycopeptides ,
used to treat MRSA- NARROW spectrum bactericidal(can kill narrow range of bacteria)
produced by Streptomyces orientalis from India/Borneo

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25
Q

Mechanism of vancomycin?

A

-targets pbp but CAPS the actual chain. ,Vancomycin recognizes and binds to the two D-ala residues on the end of the peptide chains inhibiting them from binding to pbp and creating the cross links

  1. Fixed conformation of hexapeptide -hexopeptide backbone
  2. Contain H bond donor/HBond Acceptor groups on aglycone to form FIVE H-Bonds to terminal D-ala-D-ala 3. Inhibits a number of processes by forming ‘Protective Layer’
  3. D-ala-D-ala held in deep cleft within Vancomycin- TRANSPEPTIDASE/PBP cant bind to the D-ala/ therefore cant form cross links.
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26
Q

Explain mechanism of vancomycin dimerization on themselves. - THEY DO THIS TO DIM

A

2 vancomycin molecules attached to a -D-ala-D-Ala sequence each, can dimerize with the 2 vancomycin molecules hydrogen bonding to each other.
Head to tail .
Four hydrogen bonds .
Steric shield to Transglycosidase and Transpeptidase enzymes.

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27
Q

What class of antibiotics is Teichoplanin? whats it used for and produced from what? How does it work??

A

GLYCOPEPTIDES.
-to treat Gram(+) bacteria (narrow spectrum bactericidal, less toxic than vancomycin).
- Produced by Actinoplanes teichomyceticus
-works similar to vancomycin. has same hexopeptide backbone. H bonds to outside of peptidoglycan wall. alkyl chain also gives extra bond (lipophilically) to cell membrane.
so mores stable.

28
Q

Glycopeptides usually injected so can see side effects v quickly. List some adverse drug reactions of glycopeptides.

A 
Mainly associated with adverse infusion events: 
• Anaphylaxis 
• Hypotension 
• Dyspnea 
• Urticaria (hives) 
• Red Man Syndrome 
• Pruritus 
• Thromocytopenia 
• Nephrotoxicity 
• Auditory Nerve Damage 
• Ototoxicity
29
Q

Explain how vancomycin resistance

A

D-ala replaced with D-lactic acid>changes H bonding of vancomycin.
removes H bond. cant bind, cant block pbp from binding. From mutations.

30
Q

Name some antibiotics which inhibit protein synthesis (translation)>

A

> Aminoglycosides: Gentamicin, Neomycin, Tobramycin, Amikaicin
Tetracyclines: Demeclocycline, Doxycycline, Lymecycline, Minocycline, Oxytetracycline, Tigecycline >Macrolides: Clarithromycin, Erythromycin, Fidaxomicin, >Chloramphenicol
Lincosamides: Clindamycin
Oxazolidinone: Linazolid

31
Q

Know transciprtion translation.

A

look at last year notes- paper in black folder.

32
Q

Aminoglycosides are Isolated from various organisms. Explain chemistry of aminoglycosides

A

H bonds and ionic salt bridges.
aminoglycosides positively charged.
phosphate backbone 16S ribosomal DNA portional of 30S subunit is negatively charged&raquo_space;>so aminoglycosides bind to the 16S ribosomal DNA in 30S by ionic salt bridge and H bonds.&raquo_space;>causes
• Conformational change occurs in the peptidyl A site on binding of aminoglycoside
>Mistranslation of RNA template and selection of incorrect amino acid.

33
Q

How does aminoglycoside resistance develop in bacteria?

A
  • Most commonly due to bacterial elaboration of Resistance Transfer Factor mediated enzymes à Acetylation, Phosphorylation, Adenylation
  • lots of different amine groups on aminoglycosides. so if u change it u change the way it binds. >Prevents ribosomal binding
34
Q

Aminoglycoside drug interactions?

A

• β-Lactam Antibiotics
e.g.»» Co-administration of Gentamicin and β-Lactam causes reaction with each other à Acylation.

can ring open the carbonyl of beta-lactams because aminoglycosides are nucleophile.
>efficacy for both drugs go down.
Can give both together just have to increase dose when given together.

35
Q

Which bacteriostatic broad spectrum antibiotics can be used against gram positive and negative bacteria, and is usually prescribed after Beta lactams? HINT: First isolated from Streptomyces aureofaciens.

A

tetracyclines.

36
Q

Describe the structure of tetracyclines, and how this enables them to function as a protein synthesis inhibitor (antibiotic).

A

4 rings
2 faces, one is polar lots of OH and carbonyls etc so can form lots of H bonds
the other face- less polar , more hydrophobic.
different substitution patterns on ‘X’ offers different antiabacterial activities for different bacteria. Critical functional groups on ‘Southern’ and ‘Eastern’ faces
»allows them to bind to sugar phosphates of 16S rRNA in 30S ribosome subunit, preventing aminoacyl-tRNA from binding into A site. This stops further addition of amino acids and also protein release.
-Binding to sugar phosphate backbone Involves Magnesium ion .

(NOTE: More than one binding site )

37
Q

Why are tetracyclines restricted when used? what do they have issues with?

A
  • resistance
  • stability
  • toxicity,
  • photodegradable- problems with colouring (e.g. can cause teeth staining)
  • drug epimerisation
  • drug dehydration problems.

that’s why restricted when used.

38
Q

Tetracycline- Drug Interactions ?

A

tetracyclines can bind metal ions especially metal2+ ions . Thats why binds to Mg2+, however it can bind to other Metal 2+ ions like Ca2+. problem:
• Incompatible with multivalent ion rich antacids
• Consumption of dairy products rich in Ca2 (e.g. milk) contraindicated
• Can complex with Ca2+ from teeth/bones and can also cause teeth staining (avoid in children)
• Incompatible in acidic/basic conditions

39
Q

Tetracyclines resistance problem due to…

A

overuse in animal husbandry of young animals

40
Q

Explain Tetracyclines Drug Epimerisation problem.

A

in presence of a base or if put in aqueous solution, can release a proton from C-4,
this chiral centre is key for its activity, so changing it will reduce its activity. Reprotonation can take place from the top or the bottom of the molecule
• Reprotonation from the top regenerates Tetracycline
• Reprotonation from the bottom produces inactive 4-Epietracycline
>if put in aqueous system, it will equilibrate - At equilibrium, the mixture nearly consists of equal quantities of the two diastereomers- that’s why if u give particular dose, u have to give twice the dose as half of it will be the inactive diastereomer.

41
Q

Explain tetracycline dehydration reaction problems. How they can lead to nephrotoxicity ?

A
  • Most natural tetracyclines have tertiary and benzylic OH at C-6 >comes off
  • Has ideal geometry for acid catalysed dehydration >carbocation is very stable as its a benzyl carbocation. hide positive charge over lots of centres.
  • Resulting product biologically inactive and deeper in colour .
  • Can also get dehydration then isomerisation, or isomerisation then dehydration»> All can arrive at 4-Epianhydrotetracycline which is (also inactive) and nephrotoxic - causing less reabsorption of materials from tubular fluid ànd can be fatal
  • Tetracyclines with no C-6 OH groups can’t dehydrate àre free of this toxicity
42
Q

Tetracyclines adverse effects?

A
  • Tooth Staining
  • Phototoxicity – most notibly with C7-Cl (visible absorber)
  • Kidney damage
  • Nausea
  • Vomiting
  • Diarrhea
  • CNS effects (vertigo, dizziness)
  • Distinguish imperfectly between bacterial 70S and mammalian 80S ribosomes
  • Inducers of CYP> increase metabolism therefore dose may need adjustment (can cause azotemia)
  • Typically administered orally due to thrombophlebitis
43
Q

What are macrolides? give an example of one too.

are macroldies bacteriocidal or static?

A

e.g. erythromycin -has broad scale activity.
eg Clarithromycin, Erythromycin, Fidaxomicin
-bacteriostatic
-cultured rather than made synthetically.
-composition: sugar untis, c5 untis which r joined together in enzymatic cascade.
-macrolides inhibits translocationn by binding to 23S rRNA in the polypetide exit tunnel adjacent to the peptidyl tRNA centre in the 50S ribosomal subunit&raquo_space;Inhibit ribosomal protein biosynthesis&raquo_space;»prevents growing peptide from becoming longer.

44
Q

Explain why how macroldies are synthesed is clinically important.

A

mainly packaged up
to be either proddrugs or to be more water soluble
-hydrochloride salts (erythromycin hydrochloride)- make things more water soluble
-ethyl succinares (erythromycin ethylsuccinate) - esters- act as prodrugs bc ester is hydrolysed within the body therefore releasing the active drug.
normally ferment them up then do semi-synthesis.

The amine with 2 CH3s on it , when in body gets metabolised and 2 CH3s come off»> metabolyssed by CUP3A4 into nitrosoalkane formed
»this radical is metabolized by CYP 3A4 (this enzyme transforms 50% of all drugs) once metabolized and radical forms, that radical forms complex w the enzyme and enzyme is destroyed&raquo_space;»drug interactions.
»nitrosoalkane can form another radical»>lead to toxicity.

45
Q

Macrolides drug interactions?

A

• Clarithromycin, Erythromycin, Fidaxomicin
• Responsible for significant drug interactions
• Metabolised by CYP 3A4 into nitrosoalkanes
>CYP 3A4 responsible for 50% biotransformation of all therapeutic agents
> Then complex with the enzyme
>Destruction of the isoenzyme
>Subsequently affecting the metabolism of all drugs metabolised by CYP 3A4 (»
vast differences like
raised areas under the curves, half lives, elimination etc.)
• Benzodiazepines – Raised AUC, half life, elimination
• Neuroleptics (Clozapine) – seizures, dysrhythmia
• Statins – rhabdomyolysis
• Theophylline – unpredictable
• Carbamazepine – toxic levels
• Anti-arrhythmics – Quinidine clearance decreasedd

46
Q

Explain what chloramphenicol is.

A
  • natural product which has 2 Cl in it- unique.> Unusual chlorinated derivative, diol (2 OHs), and chiral centres
  • bacteriostatic
  • looks v similar to an aminoacylated nucleusoide/ tRNA>how it binds into same pocket.

> Inhibits protein synthesis through binding to 50S at the peptidyl transferase centre A site preventing binding of next charged tRNA

-unusually toxic- possibily due to nitro group which can get metabolised into radical.

  • Binding through H-bonding and interaction with Mg2+ in catalytic site
    >diol OH OH to MG2+
  • broken down by bacteria using acetyltransferase enzymes>can no longer bind Mg2+
  • typically used topically > ear infection ,conjunctivitis

-unusually good half life .
in aqueous conditions also stable
just not in heat or light.

-Binds to same region as Marcrolides and Lincosamides

47
Q

chloramphenicol drug interactions

A 
•chiral centres >could get diastereomers
• Inhibits CYP 2C19 and 3A4 –slows metabolism 
• Elevated plasma levels of: 
Tricyclic antidepressants 
Selective serotonin reuptake inhibitors 
Antiepilectic drugs 
Proton pump inhibitors 
Azole antifungals 
Macrolide antibiotics 
Calcium channel blocking agents 
Clopidrogel, Gliclazide, Propanolol, Tetrahydrocannabinol
48
Q

What is Lincosamides?

A

e.g. Clindamycin
natural
• Similar mechanism of action as Macrolides
• Binds to the 50S rRNA of the large bacterial ribosome subunit
• Prolong the effects of neuromuscular-blocking drugs
• Its similarity to the mechanism of action of Macrolides and Chloramphenicol means they should not be given simultaneously, as this causes antagonism and possible cross-resistance

49
Q

What is Oxazolidinones?

A

e.g. Linezolid
• new synthetic class of antibiotics
• Bacteriostatic/bacteriocidal against Gram (+)
• Inhibit protein synthesis by binding to 50S preventing both subunits coming together>blocking formation of the functional initiation complex including N-formylmethionine- tRNA, the 30S subunit, mRNA and initiation factors
• Distorts the binding site for initiator tRNA which overlaps both 30S and 50S
• Inhibits much earlier stage of translation so has less resistance problems
• Competes with Chloramphenicol in binding studies with the 50S unit but does not have the same mode of action

50
Q

Oxazolidinones drug interactions?

A

• dont take with selective serotonin reuptake inhibitors (SSRIs) bc Linezolid acts as weak monoamine oxidase inhibitor, can cause Serotonin Syndrome with SSRIs
• Caution with other sympathomimetic drugs eg pseudoephedrine
• Rare but serious side effects:
Myelosuppression (reduced red blood count)
Peripheral neuropathy (nerve damage)
Lactic acidosis (changes in blood pH)
• Possible due to interaction with mitochondrial function

51
Q

what are quinolones/fluoroquinolones?

A

-synthetic
Levofloxacin, Ofloxacin
>first one: Naldixic acid 1960s
> Second generation in 1980s -Fluoroquinolones
• Inhibit replication and transcription of bacterial DNA by stabilizing the complex formed between DNA and topoisomerases -so while DNA being chopped, the quinolones stops the chopped DNA segments from resealing itself
• Gram (+) 1000 fold selectivity for bacterial enzyme over human cells. Gram (-)target is complex between DNA and DNA Gyrase
>Topoisomerase IV more important to Gram (+) and DNA Gyrase more important to Gram (-)
• Using energy generated by ATP hydrolysis, DNA is wound about itself as a supercoil
• In the absence of ATP reversal takes place relaxing the molecule
• It must be partially unwound for cell to access genetic information
• Reversibility allows for changes to be:
-Stored properly
-Unwound
-Replicated
-Repaired
-Transcribed
these enzymes r inhibited:
• DNA Gyrase alters the conformation of DNA by: catalysing double strand cuts, passing uncut portion through the gap, resealing the molecule
• DNA topoisomerase IV unties enchained daughter molecule

> > > > Inhibition of either or both makes cells DNA inaccessible > cell death&raquo_space;>.bactericidal

52
Q

what is function of DNA Gyrase? (its an enzyme within the class of topoisomerase enzymes)

A

catalyses negative supercoiling of circular DNA:

1) stabilizes positive node
2) both strands of segment at back of DNA coil is cut
3) unbroken segment passes through the gap/break, broken segment is resealed but at the front of the coil> negative supercoil

53
Q

how do are fluoroquinolones more advanced than first generation quinolones?

A

Fluorine associated w changing the polarizability of the molecule> so when it comes up to membrane, does it help get it through the membrane?
also change lipophilicity of molecule
>better cell penetration

54
Q

What is the purpose of the COOH and O in quinolones?

A

to bind Mg2+

55
Q

quinolones adverse drug reactions?

A

• Nausea/Vomiting • Dyspepsia • Abdominal pain • Diarrhea • Headache • Rashes • Blood disorders • HERG blockade • Dermatological side effects (phototoxcity à superoxide radicals • CNS effects

56
Q

if 2 quinolones come together on either side of the 2 PIECES OF DNA, what happens?

A

overlay on top of each other and form H bonds between aromatic systems»>helps hold them together

((like a sandwich with dna in middle))

57
Q

Quinolones and Fluorquinolones: Drug Interactions?

A
  • Can complex metal ions e.g. mg2+,ca2+– antacids
  • Theophylline– phosphodiesterase inhibitor>metabolised by N-demethylation by CYP 1A2»Some quinolones inhibit CYP1A2 causing increased serum levels
  • Digoxin– should be treated with caution as some quinolones may reduce gut floral growth à reduction in metabolism of digoxin in active form)
58
Q

what is polymyxin B?

A

e,g, Collistin
injury to plasma membrane
• Last line of treatment (2016 resistance in pigs detected, China)
• Produced by fermentation of Bacillus polymyxa
• Gram (-) active
• Binds to phosphate groups in bacterial membranes disrupting integrity:
lots of amine grouos - positively charged in physiological pH, forming like a net of positive charge over the top of the membrane
>will interact with it bc phospholipid heads r negatively charged»
This weakens the membrane, membrane more loose and permeable. can cause permeations in the plasma membrane>forming porins.
other molecules can get in easier>so polymyxin B can be used in conjunction w other drugs/antibiotics.
• IM/IV as sulfate for treatment of Pseudomonas aeruginosa
• Precaution warranted as neuro and nephro toxic

59
Q

What is a primary and secondary metabolite?

A

primary metabolite- keeps an organism alive like oxygen, amino acids, glucose, PABA
secondary metabolite- gives advantage to an organism e.g. something chemical defense mechanism, or something that makes u more camoflauged etc.

60
Q

2 antibiotics, Sulfonamides and Trimethoprim, inhibit synthesis of essential metabolites. explain more about them.

A

Sulfonamides and Trimethoprim: Co-trimoxazole, Dapsone, Trimethoprim
• Bacteriostatics
first one- Prontosil(1935)
• Act as competitive inhibitors of dihydropteroate synthetase
• Block the biosynthesis of tetrahydrofolate in bacterial cells
• Co-trimoxazole= Trimethoprim + Sulfamethoxazole
look in Alistair lecture, better explaning.

61
Q

2 ways which sulfonamides work to inhibit synthesis of tetrahydrofolic acid?

A

1) PABA and sulfonamide has similar structure w similar groups, so can react with starting molecule (dihydropteroate diphosphate) like PABA does, forming a false metabolite, which cant be used in the reaction to form tetrahydrogolic acid
2) competes with PABA , competitively inhibiting (dihydropteroate synthase).

62
Q

explain 3 bonds which sulfonamides and PABA make with the active site of the dihydropteroate synthase , making them similar to each other and both able to fit into this enzymes active site

A

PABA:

1) H BOND WITH NH2 GROUP
2) VAAN DER WAALS WITH AROMATIC RING
3) IONIC BOND W COOH

SULFONAMIDE:

1) H BOND W NH2 GROUP
2) VAAN DER WAALS W AROMTIC RING
3) IONIC BOND W SO2=NR GROUP

63
Q

sulfonamide problems?

how to fix?

A

high pKa values prone to crystalluria(resulting kidney damage)
To avoid:
• Heterocyclic rings (e- withdrawing) are attached to the sulfonamide residue -LOWERS the pKa value (ionized - water soluble)
• Use more than one type of sulfonamide (Triple sulfa)
•forcing fluids are still in use to prevent this but not needed as much now bc Amount of each dose not reach a threshold amount leading to crystals

64
Q

trimethoprim looks v similar to dihydrofolic acid. why is this important in inhibiting tetrahydrofolic acidsynthesis?

A

trimethoprim inhibits dihydrofolate reductase (competitively) bc looks v similar to dihydrofolic acid

65
Q

Trimethoprim packaged up w other drugs.
explain for what.
uses of trimethoprim?
what not to use on?

A

Today these drugs alone or in combination with the antimetabolite trimethoprimhave found use in the following infections:
1. AIDS patient opportunistic infections treatment and prophylaxis
• Pneumocystis carinnipneumonia (PCP)
• Cerebral toxoplasmosis
2. UTI
3. Burn therapy – topicals
4. Conjunctivitis and other ocular infections 5. Chloroquine-resistant malaria – Sulfadoxine (Fansidar®)

• These drugs are generally NOT effective against:

  1. Streptococcal infections
  2. Prophylaxis in rheumatic fever recurrences
  3. Other bacterial infections
  4. Reduction of intestinal flora
  5. Ulverative colitis

• Largely replaced by other Antibiotics

66
Q

Sulfonamides and Trimethoprim: Adverse drug reactions

A
  • 5% of all patients have some degree of hypersensitivity
  • Drug fever, skin rashes, photosensitivity, allergic myocarditis, analphylaxis
  • Patients deficient in glucose-6-phosphate - hemolytic anemia
  • Crystalluriaif normal adequate fluid intake not sufficient (2-3 liters per day)
  • Competition for plasma protein binding sites increases warfarin concentrations

Biotransformations:
• With the exception of sulfonamides used for ulverative colitis and reduction of bowel flora - all sulfonamides and trimethoprim are absorbed quickly
• Protein binding ranges from 38% (sulfadiazine) to 76% (sulfisoxazole), and for trimethoprim (45%)
• Excreted as unchanged drug, N-acetyl and glucuronide derivatives
• Trimethoprim has 6 active metabolites
• Fixed dosages should not be used for patients with low creatinine clearance

67
Q

uses of sulfonamides:

A

Sulfonamides & Folate Reductase Inhibitor Classes:

1) Rapidly absorbed/excreted (oral absorbable)
• Short-Acting – Sulfisoxazole
• Intermediate-Acting – Sulfamethoxazole

2)Poorly absorbed (bowel active)
• Sulfasalazine

3)Topical - Burns
• Sulfacetamide, Silver sulfadiazine

4) Long-acting
• Sulfadoxine - Fansidar®

Pharmacy Stage 2 (8 decks)

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