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4th Year Unseen Exam > Antibiotics - Chemistry > Flashcards

Antibiotics - Chemistry Flashcards

1
Q

Which antibiotics as responsible for interfering with DNA topoisomerases?

A

Fluoroquinolone such as ciprofloxacin, Quinolone

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2
Q

Which antibiotics are responsible for interfering with folic acid synthesis?

A

Sulfonamides, trimethoprim

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3
Q

Which antibiotics damage DNA?

A

metronidazole

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4
Q

Which antibiotics interfere with the 50S ribosomal subunit?

A

Chloramphenicol, clindamycin, linzolid, macrolides (azithromycin, clarithromycin)

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5
Q

Which antibiotics interfere with the 30S ribosomal subunit?

A

Aminoglycosides, gentamicin, neomycin, tetramycin, tetracyclines

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6
Q

Which antibiotics interfere with cell wall synthesis?

A

Peptidoglycan: glycopeptides such as vancomycin

Peptidoglycan cross linking: penicillins

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7
Q

What is the difference between gram negative and gram-positive bacteria?

A

Gram negative have a secondary cell wall, with more lipids outside. They are harder to treat due to this cell wall structure, which is harder to penetrate

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8
Q

Describe B lactams

A

They have a 4 membered amide structure, which is prone to being opened

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9
Q

How do B lactams work? Describe the process compared to the normal process

A

Normally, serine of the transpeptidase enzyme binds to peptide chain, another peptide chain comes in and binds and this forms the peptide chain. In the presence of penicillin, the b lactam ring enters the pocket and covalently binds, the second peptide chain is unable to come in and form the cross link in the peptide chain

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10
Q

Describe the B lactam adverse drug reactions

A 
anaphylaxis
uricaria
steven-johnson syndrome (painful rash)
hives
penicillin sensitivity - the free sulfide unit can exchange with cysteine which is a large protein, which stimulates an immune response
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11
Q

List and discuss drug-drug interactions with b lactams

A

Valproic acid - increased clearance leads to seizures
methotrexate - competition for excretion by the kidney
Warfarin - can increase/decrease effect, so monitor

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12
Q

Discuss drug resistance specific to b lactams

A

beta lactamase produced by bacteria opens the beta lactam ring, and so penicillin is useless. Co-amoxiclav and piperacillin + tazobactam are beta lactamase inhibitors and therefore prevent this resistance

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13
Q

Bacteriostatic or cidal - penicillin

A

bactericidal

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14
Q

What is the purpose of side chain changes in penicillins and discuss how different side chains can impact the structure-activity relationships?

A

To affect the hydrolysis and effectiveness of the drug. bulkier groups prevent beta lactamase from entering. Electron withdrawing side chains will pull electrons away from the ring, and therefore it will be less prone to hydrolysis/degradation. Positively charged side chains lead to increased absoprtion

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15
Q

Give an example of a glycopeptide

A

Vancomycin

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16
Q

How do glycopeptides prevent cell wall synthesis?

A

Large structures, with an alkyl chain anchor which keeps it anchored to bacterial cell membranes. They form a protective layer to inhibit a number of processes in the building of the cell wall. Dimerisation between glycopeptides takes place and forms a protective shield

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17
Q

Bacteriostatic or cidal - glycoproteins

A

bacteriacidal

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18
Q

List and discuss adverse drug reactions associated with glycopeptides

A 
They are mainly IV events, due to IV events
Anaphylaxis 
red man syndrome
hypotension 
puritus
dyspnea
uritacaria
ototoxicity
nephrotoxicity
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19
Q

Describe the process of translation of mRNA

A

The 30s ribosomal subnuit binds at the 5’ end of the mRNA and moves in the 3’ direction. At the start codon, the tRNA and the 50s Ribosomal subunit attach, this continues along the mRNA with the 50s Ribosomal subunit bringing in the corresponding tRNA as the 30s ribosome moves along the sequence, producing the protein, until it reaches the stop codon

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20
Q

Describe the process of drugs blocking protein synthesis by binding to the 30S ribosomal subunit

A

Drug binds at the 30S, protein synthesis is blocked as tRNA cannot be incorporated into the chain

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21
Q

Describe the process of drugs blocking protein synthesis by binding to the 30s ribosomal subunit

A

Drug binds at the 30s, leads to the incorporation of an incorrect amino acid and a nonsense protein

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22
Q

Which drugs inhibit protein synthesis, list and give examples of each

A 
Aminoglycosides - gentamicin
Tetracycline - doxycyline, tetracycline
macrolides - azithromycin, clarithromycin
Chloramphenicol
Lincosamide - clindamycin
Ozalidiione
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23
Q

How do aminoglycosides inhibit protein synthesis?

A

They bind to the 16S ribosomal subunit on the 30s ribosome and impair the proof reading function of the ribosome, which leads to a conformational change on the peptidyl site. This leads to the mistranslation of RNA and the incorrect amino acid being selected

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24
Q

How does aminoglycoside resistance occur?

A

Resistance factor mediated enzymes prevent ribosomal binding

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25
Q

What drug interactions occur with aminoglycosides?

A

Coadministration with beta lactams can lead to an acylation reaction

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26
Q

Are aminoglycosides bacteriostatic or cidal

A

bacteriocidal

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27
Q

How do tetracyclines inhibit protein synthesis?

A

They bind to the 30s ribosomal subunit and prevent tRNA binding.

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28
Q

Are tetracyclines bacteriostatic or cidal?

A

bacteriostatic, they are broad spec and usually prescribed after b-lactams

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29
Q

Describe and discuss the structure of tetracyclines

A

4 ring structure - tetracyclic, planar, potentially teratogenic, aromatic stacking.
OH groups bind to Mg2+ and can push electrons back and forthe

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30
Q

What happens when tetracyclines are dehydrated?

A

benzoylic oh at c6 becomes conjugated and produces a blue discolouration
can absorb UV light

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31
Q

List and discuss drug interactions with tetracyclines

A

Can complex calcium, so avoid dairy products and in young children (teeth/bones)

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32
Q

List and discuss adverse effects of tetracyclines

A 
tooth staining
phototoxicity
kidney damage - in acid
nausea
vomitting
diarrhea
CNS effects
Some cross over with human cells
CYP inducers increase metabolism
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33
Q

How do macrolides inhibit protein synthesis?

A

They bind to the 23s rRNA polypeptide exit tunnel in tRNA in the 50S ribosomal subunit. Prevents the peptide from growing longer as it inhibits translocation

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34
Q

Are macrolides bacteriostatic or cidal?

A

Bacteriostatic

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35
Q

List and discuss drug interactions with macrolides

A

Metabolised by CYP3A4, can cause rhabdomylosis and changes the clearance of other drugs such as statins, benzodiazepenes (increased area under the curve), neuroleptics, theophylline, carbamazepine, anti-arrythmics

36
Q

How does chloramphenicol inhibit protein synthesis?

A

Inhibits protein synthesis by binding to the 50s ribosomal subunit, and prevents binding og the next charged tRNA. Binds through h bonding and the interaction with Mg2+

37
Q

Bacteriostatic or cidal - chloramphenicol

A

Bacteriostatic

38
Q

List and discuss drug interactions with chloramphenicol

A

inhibits CYP, so increased plasma levels of: TCA, SSRI, antiepileptics, PPI, antifungals, macrolides, CCB, clopidrogrel, gliclazide, propanolol

39
Q

How do lincosamides inhibit protein synthesis?

A

binds to the 50s ribosomal subunit, preventing the binding of tRNA. Prolongs the effects of neuromuscular blocking drugs. Their similarity to macrolides and chloramphenicol mean that they should not be given together

40
Q

Is clindamycin bacteriostatic or cidal

A

static. (lincosamide)

41
Q

How do oxazolidinones inhibit protein synthesis?

A

They bind to the 50S ribosomal subunit and prevents the formation of the iniation complex with 30s. Inhibits at an early stage, less resistance problems.

42
Q

List and discuss drug interactions with oxazolidinones

A

Acts as a weak monoamine oxidase inhibitor, caution with SSRIS and pseudoephedrine

43
Q

Which drugs bind to the 50S ribosomal unit?

A

oxalidinones - methianine
lincosamides - clindamycin
chloramphenicol
macrolides - clarithromycin

44
Q

Which drugs bind to the 30S ribosomal unit?

A

Tetracyclines - doxycycline

Aminoglycosides - gentamicin

45
Q

Which drugs inhibit nucleic acid transcription and replication?

A

Quinolones and fluoroquinolones - levofloxacin, ofloxacin.

46
Q

What is the function of DNA gyrase?

A

DNA gyrase catalyses double strand DNA cuts. Catalyses the supercoiling of DNA

47
Q

What is the function of DNA topoisomerase?

A

Unties the daughter molecule

48
Q

How do fluoroquinolones and quinolones inhibit nucleic acid transcription and replication?

A

They stabilise the cut DNA by DNA gyrase, DNA cannot be supercoiled as they bind to the cut bases by base stacking which leads to cell death

49
Q

Are fluoroquinolones bactericidal or bacteriostatic?

A

bactericidal. They inhibit replication by stabilising the complex formed between DNA and topoisomerase

50
Q

List and discuss nucleic acid transcription and replication inhibitors adverse drug reactions

A

nausea, vomitting, dyspepsia, abdo pain, diarrhea, headache, rashes, blood disorders, HERG blockade, dermatological side effects, phototoxicity, CNS effects

51
Q

List and discuss nucleic acid transcription and replication inhibitors drug interactions

A

Can complex metal ions, theophylline, can inhibit CYP1A2, can cause reduced digoxin metabolism

52
Q

Which drugs cause injury to plasma membranes?

A

Polymixin b

53
Q

Is polymyxin B grame -ve or gram +ve active

A

Gram -ve

54
Q

How does polymyxin B cause injury to plasma membranes?

A

Binds to phosphate groups in bacterial membranes which leads to changes in pressure and liquid leaks out of cells

55
Q

What cautions are associated with polymyxin B?

A

They are neuro/nephro toxic

56
Q

Which drugs inhibit the synthesis of essential metabolites? Bacreriostatic or cidal?

A

Sulfonamides and trimethoprim eg co-trimoxazole, dapsone. Bacteriostatic

57
Q

How do sulphonamides inhibit the synthesis of essential metabolites?

A

They act as competitive inhibitors of dihydropteroate synthetase, which blocks they synthesis of tetrahydrofolate in bacterial cells

58
Q

How does trimethoprim inhibit the synthesis of essential metabolites?

A

It is a direct inhibitor of dhyrdofolic acid

59
Q

What cautions are associated with sulphonamides

A

They have a high pKa and are prone to crystalluria, therefore they can cause kidney damage

60
Q

describe and discuss sulfonamide classes

A

rapidly absorbed/excreted: sulfisoxazole, sulfamethoxazole
orally absorbable

Poorly absorbed - bowel active:
sulfasalazine

topical - burns sulfacetamide

61
Q

What is trimethoprim found to be useful for/ what has it been found to be typically not useful for?

A

AIDs: pcp prophylaxis, UTI, Conjuctivitis.

Typically not useful in strep infections, UC

62
Q

What adverse drug reactions are associated with sulphonamides/trimethoprim?

A

5% of patients have hypersensitivity, drug fever, skin rashes, photosensitivity, allergic myocarditism anaphylaxis
crystalluria - advise 2-3l of fluid intake
competition for plasma protein binding site increased with warfarin concentration

63
Q

Via which bonds do sulfonamides bind to the active site?

A

H bonding, ionic bonding, van der waals bonding

64
Q

Describe the structure of methenamine

A

A formaldehyde which will crosslink anything with an amine in it

65
Q

How does methenamine have an antimicrobial effect?

A

Used for disinfection of acidic urine. Is a low molecular weight polymer of ammonia and formaldehyde and under mildly acidic conditions converts to starting materials

66
Q

Why/how does methenamine have so many drug-drug interactions?

A

because it will crosslink anything with an amine in it

67
Q

How do nitroimidazole antibiotics work?

A

They are prodrugs which are reduced in cells to give radicals which are toxic. The exact mechanism of action is unclear, believed to passively enter the cell, cause a radical cascade.

68
Q

What are some key interactions with nitroimidazole antibiotics? Discuss

A

Alcohol - due to generation of radical, warfarin, phenytoin, carbemazepine

69
Q

What are nitroimidazole antibiotics typically used for?

A

anaerobic bacteria and anaerobic infections such as c.diff. H.pylori and gram -ve infections

70
Q

What is the usual first line treatment for TB?

A

2 antibiotics for 6 months: isoniazid and rifampicin

2 additional antibiotics for the first 2 months: pyrazinamide, ethambutol

71
Q

What is the usual second line treatment for TB?

A

aminoglycosides, polypeptides, fluoroquinolones

72
Q

How can all the TB drugs be used together?

A

They all act on different mechanisms

73
Q

How do rifamycins work?

A

They are semi-synthetic antibiotics with broad spectrum activity

74
Q

Discuss the structure of rifampicin and how it works

A

It is an orally active compound, active against gram -ve and +ve bacteria and mycobacteria. (TB). It has an alphatic chain which forms a bridge between adjacent portions of aromatic moiety. Targets bacterial DNA dependent RNA polymerase, binding tightly to the subunit of the enzymes. Inhibition of DDRP leads to blocking of chain formation in RNA synthesis.

75
Q

Discuss the structure-activity relationship of rifampicin

A

Rifampicin is structurally locked with an aromatic centre, if the ring is opened, this will lead to deactivation. A reduction in double bonds will lead to a decrease in activity

76
Q

How does altering the ring structure of rifampicin impact activity

A

opening the ring will deactivate it

77
Q

How does altering the side chain of rifampicin affect it’s activity

A

Reducing the amount of double bonds will lead to a decrease in activity

78
Q

Why do fast metabolizers need a dose adjustment with isoniazid?

A

Because it is metabolised to inactive metabolites

79
Q

How does isoniazid work?

A

Inhibits cell wall synthesis via mycolic acid. It is a prodrug activated through an oxidation reaction. Reaction of INH and INHA is involved in mycolic acid production

80
Q

Describe mycobacteria

A

They are made up of peptidoglycan and arabinan, which is a polymer of a sugar. + specific lipids. There is an intensely deep lipid layer outside of the cell, which makes TB hard to treat. High lipid content means high log p, so they are resistant to acids, alkalis and disinfectant

81
Q

How does pyrazinamide work?

A

It crosses cell membranes by passive diffusion and converts to pyrazine acid at ph 5.4 or lower. Can lower the pH of immediate surroundings, which means that bacteria are unable to grow. If pyrazinic acid is kicked out of the cell, hydropyrazinic acid re-enters, acidises the cytoplasm and this leads to lethal disruption of membranes

82
Q

How does ethambutol work?

A

Inhibits arabinozyl transferase, causes damage to cell wall and allows for improved penetration of the other drugs

83
Q

How do cephalosporins work?

A

Inhibit cell wall synthesis. They are packaged up IV as to be stabile they are bulky.

84
Q

Discuss the pros and cons of cephalosporins?

A

cons - polar due to side chain which means they are difficult to purify, they have low potency, treat UTIs where it is concentrated in the urine. NOT absorbed orally

pros - no-toxic, lower risk for allergic reactions, more stable in acids/against beta lactams

85
Q

Discuss 1st generation cephalosporins

A

They are more active than penicillins vs gram-ve and less likely to cause allergic reactions. cefalexin can be given orally. Useful in penicillin allergy

86
Q

Discuss 2nd generation cephalosporins

A

they have a better spectrum of activity and greater resistance to b lactamase

87
Q

Why is ceftazidine used for meningitis

A

because it has the ability to cross the blood brain barrier

4th Year Unseen Exam (17 decks)

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