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Med Chem Exam 1
Terms in this set (139)
If the N1 substitution contains a EWG, what happens?
increased activity and improved pharmacokinetics
When the antimicrobial agent is more toxic to a pathogen than to the host it is called...
Comparative distribution is...
accumulation (from differences in surface area, differences in transport, the "hairiness" of plants, ect.)
Comparative biochemistry is...
certain metabolic pathways may be absent from one species but present in another
Comparative cytology is...
plants have cell walls, animals do not
Prontosil is active ____________
How is Prontosil activated?
Antibacterial Sulfonamide basic structure
Sulfonamide Azo Dyes (like prontosil) are active in vivo because..
they are metabolized to the active form by breaking the Azo bond (N=N) in the liver
Uses of Sulfonamide Antibacterial Agents? (6)
UTIs, Burn therapy, Ophthalmic infections, Prophylaxis of rheumatic fever, Crohn's disease/Ulcerative colitis, AIDS - pneumonia prophylaxis
UTIs are treated with a Sulfonamide in conjunction with....
Trimethoprim is a...
dihydrofolate reductase inhibitor
Sulfonamide Functional Group basic structure
Sulfonamides as a pharmacological agent can be 3 things...
1. aniline substituted sulfonamides
2. prodrugs metabolized to sulfanilamide
3. non aniline derived sulfonamides
mafenide is a ________________________ type of sulfonamide pharmacological class
Sulfonamides are (acidic/basic)
the pKa value always refers to the pKa of the...
The pKa for the sulfonamide refers to the loss of the proton from the ___________ nitrogen
A sulfonamide is (basic/acidic), so the pKa for the sulfonamide refers to the loss of the proton from ________-
The more forms a structure has makes it more..
If a sulfanilamide has a heterocyclic ring attached to the N-1 position, what happens?
It is an EWG and it doubly activated the proton, thus it lowers the pKa of the N-1 proton (more acidic compound)
If urine pH > pKa for a sulfonamide, then it (will/will not) form crystals in the urine
will not (ionized - salt form - soluble in urine)
If urine pH < pKa for a sulfonamide, then it (will/will not) form crystals in the urine
will (unionized - not soluble in urine)
What are 4 methods to reduce crystal formation in the urine with sulfonamides?
1. increase urine flow
2. raise urine pH
3. use sulfonamide with lower pKa value
4. mix sulfonamides to reach the total dose
If pH > pKa for an acid, then it is (ionized/unionized)
If pH < pKa for an acid, then it is (ionized/unionized)
What is the Henderson-Hasselbalch equation for an acid?
pH = pKa + log [I]/[U]
When a sulfonamide is in its ionized form the N1 nitrogen has...
a negative charge
When a sulfonamide is in its unionized form the N1 nitrogen has...
How could you counsel a patient to raise their urine pH
increase vegetable intake
T or F: Increasing urine flow increases solubility
Sulfonamides are (bacteriocidal/bacteriostatic)
Sulfonamides act as a ________________ inhibitor
What enzyme do Sulfonamides inhibit?
dihydropteroate synthase is used in bacteria for biosynthesis of _________________ and ______________
folic acid derivatives, thymidine
Sulfonamides are a competitive inhibitor by competing at the active site with __________________ so that it can't incorporate into folic acid
PABA (p-aminobenzoic acid)
T or F: Efficacy of sulfonamides cannot be reversed by adding significant quantities of PABA
False (Adding a lot of PABA can reverse the efficacy of sulfonamides)
By inhibiting dihydropteroate synthase and the biosynthesis of thymidine, bacteria cannot ____________
Bacteria and protozoa (can/cant) biosynthesize folate coenzymes
Humans (can/cant) biosynthesize folate coenzymes
Where do humans get folic acid?
Can bacteria use folic acid from the host?
No, it is not absorbed across the cell wall
What enzyme does Trimethoprim inhibit?
dihydrofolate reductase (the bacterial isoform)
T or F: The structures of PABA and Sulfanilamide are very similar
Trimethoprim (is/isn't) selective for the bacterial enzyme dihydrofolate reductase
is (100,000x more than human)
What is the optimum ratio of Sulfamethoxazole: Trimethoprim?
Trimethoprim prevents reduction of __________ to __________
FH2 to FH4
An antibiotic that is bacteriostatic means..
it prevents the growth and reproduction of bacteria
An antibiotic that is bacteriocidal means...
it kills bacteria
T or F: Sulfonamides are broad spectrum
true (Gram + and Gram - could be inhibited)
5 ways bacteria may become resistant to sulfonamides
Increased PABA production
2. Alteration of binding affinity to pathway enzymes
3. Decreased permeability of the bacteria cell membrane
4. Active efflux of sulfonamide (drug pumped out of bacteria cell)
5. R-factor transferring resistance to other bacteria
What happens if you modify the N4 group on a sulfonamide?
Loss of activity (unless its a prodrug)
(Sulf) The aniline N and sulfonyl group must be ________
(Sulf) If you exchange the SO2-NH with a sulfone, what happens?
it retains antibacterial activity
(Sulf) If you exchange the SO2-NH for a CO-NH2 what happens?
greatly decreases activity (S -> C = loss of activity)
(Sulf) If the N1 substitution contains a EWG, what happens?
increased activity and improved pharmacokinetics
(Sulf) If the N1 is disubstituted, what happens?
loss of activity (except where NH can be regenerated in vivo)
Maximal antibiotic effect is seen in sulfonamides with a pKa of....
6.7 - 7.4
Which sulfonamide has the most active antibacterial effect?
Sulfamethazine (in the range of pKa 6.7-7.4)
Which sulfonamide has the
chance of crystalluria?
Sulfisoxazole (lowest pKa of 5.0, more ionized, in the salt form, more soluble, no crystals)
Which Sulfonamide is the most toxic (most prone to cause crystalluria)?
Sulfamethazine (highest pKa = 7.4)
What are 3 toxicities and side effects of sulfonamides?
, hematologic, crystalluria
What are some examples of hypersensitivity?
Stevens-Johnson syndrome, skin eruptions, allergic myocarditis, photosensitization
What are some examples of a hematologic issue?
agranulocytosis, aplastic anemia, hemolytic anemia, patients with glucose-6-phosphate dehydrogenase deficiency
Most sulfonamides are quickly absorbed and are well distributed, except what 2 cases?
for topical burns, for ulcerative colitis and to reduce bowel flora
Most sulfonamides are found in the urine within _______ minutes
What form of sulfonamide is not active?
protein bound fraction (sulfonamide is bound to plasma proteins - inactive; higher dose is needed to compensate for some drug bound)
What form of sulfonamide is active?
At pH 7.4, increased lipid solubility = ____________ protein binding
If two sulfonamides have similar pKa values, the ________ substituent with the most ___________ group has the greater effect on protein binding
If N4-acelayted metabolites are more protein bound, then they are excreted (faster/slower)
N4-acetate metabolites exhibit a _________ lipid solubility leading to _____________ protein binding
(Sulf) N4-acetates are (active/inactive)
N4-glucuronides are (active/inactive)
T or F: You can have unmetabolized drug in the urine
If you could pick a sulfonamide to use and want to ensure no crystallization, you would pick one with a (higher/lower) pKa
lower (pH>pKa to make it ionized)
Sulfonamides for ophthalmic preparations are in the ___________ _________
salt form (ionized)
Sulfonamides for burn therapy are in what form? Why?
ionized form, to keep them from being absorbed systemically so they will stay on the skin
People used ____________________ for IBD until newer drugs came about that were 100% not absorbed in the GI
Tetracyclines are _______________ antibiotics
Tigecycline is marketed as a _______________ class of drug
Tetracyclines are very sensitive to logP at C___ and C____
C6 and C5 (but more so at 6)
What portion of a tetracycline is basic?
N(CH3)2 (on C4-alpha)
What portion(s) of a tetracycline are acidic?
phenolic enone system from C-10 to C12, trione system from C-1 to C-3
What is the glycine part of Tigecycline?
Which 2 tetracyclines have 6 chiral centers? Why?
oxytetracycline and doxycycline, they have a 5alpha-OH group
At pKa 20, would you see the keto or enol form?
keto (on the left)
At pKa 2.8-3.3, would you see the keto or enol form?
enol (on the right)
Tetracyclines are _____________ and exist mainly as ______________
For oral administration of tetracyclines, what is usually used?
Solution tetracyclines with amphoteric salts will crystallize out of aqueous solution unless...
excess acid is used to stabilize it
Insoluble salts of tetracyclines are formed with ____________ and _________________ ___________ to help what?
divalent, trivalent, metals, localize where you want it (ex: topical use)
When tetracycline is epimerized at intermediate pH and the proton is attached from behind, what compound is formed? Active or inactive?
When tetracycline is epimerized at intermediate pH and the proton is attached to the top, what compound is formed? Active or inactive?
If tetracycline is epimerized under acidic conditions, there will be what amounts of tetracycline and epitetracycline?
equal amounts of each isomer
If tetracycline is epimerized at neutral pH, the epi form can account for ___________% of the mixture. Why?
90%, it is a zwitterion which is more stable
Tetracyclines that have a OH at the ________ position can be attacked by acids and bases causing loss of activity leading to anhydrotetracycline
Which two tetracyclines can be attacked by acids (and one by bases) to form anhydrotetracycline?
tetracycline and methcycline
The beta position is _________
The alpha position is __________
A strong acid on tetracycline or methcycline could cause what?
dehydration involving the C6 beta hydroxyl and the C5a alpha hydrogen
Tetracycline and Methcycline under acidic degradation form anhydrotetracycline because it is __________ driven
Anhydrotetracycline is _____________
toxic (to liver)
The breakdown products anhydrotetracycline and anhydro-4-epitetracycline can lead to what syndrome?
What can you expect from a person with Fanconi-like Syndrome? why?
vomiting, polyuria, polydipsia, proteinuria, acidosis, glycosuria, and gross aminoaciduria. Because you cannot absorb these things back into your body so they will be excreted out (happens about 1 month after treatment)
If tetracycline is in basic conditions, a reaction between the ____________ and _______________ result in a (active/inactive/toxic) product
C-6 OH, C-11 Carbonyl, inactive
In order to have a
tetracycline antibiotic, you must remove the ___________
C-6 beta OH
Methcycline is only metabolized to a toxic product in _________ conditions
Tetracyclines can also form ____________ which are water insoluble and impair tetracycline absorption
What do tetracyclines interact with to form chelates?
divalent and trivalent metals (Ca, Mg, Fe, Al)
Tetracycline chelates are water (soluble/insoluble) and impair....
Tetracyclines affinity for Ca causes them to deposit in bones and teeth as __________________
tetracycline-calcium orthophosphate complexes
Tetracyclines are distributed into __________, meaning the fetus (is/isnt) susceptible
Tetracyclines are (bacteriocidal/bacteriostatic)
How do tetracyclines enter the bacterial cell? What does it require?
passive diffusion and active transport that requires ATP and Mg
How do tetracyclines work?
Bind 30S subunit, preventing the attachment of aminoacyl-tRNA from binding
The selective toxicity of Tetracyclines against bacteria is dependent on....
the bacterias ability to transport tetracyclines
Bacterial resistance of tetracyclines can happen what 4 ways?
1. Loss of ability to actively transport TCNs
2. Presence of TCN-binding proteins at cell surface
3. Synthesis of bacterial proteins which associate with the ribosomes to allow protein synthesis to continue in the presence of bound TCNs
4. Active efflux of TCN-Mg complexes
Both aminoacyl tRNA and TCNs require ____________ to bind to the ribosome
T or F: Tetracyclines are the broadest spectrum of any known antibacterial agents
Tetracyclines are (fully/incompletely) absorbed
If a tetracycline derivative has fewer than four rings....
it is inactive
(TCNs) If you replace the amide at C2 with any other functional group...
it is inactive
(TCNs) Monoalkylation of the amide at C2...
decreases activity with increasing size
(TCNs) The dimethyl amino at C4....
must be present and have alpha stereochemistry
(TCNs) If you remove the dimethyl amino at C4...
(trans/cis) ring fusion is necessary for tetracyclines
(TCNs) Alkylation at ___________ abolishes activity
(TCNs) At what Cs can you substitute that are less sensitive and may increase activity
5, 5a, 6, 7, 9
(TCNs) If you add a EWG or EDG on the D ring, what happens?
increase in activity
(TCNs) Removal of the 6-betaOH increases the...
partition coefficient (more lipophilic)
Doxycycline and Minocycline have:
____ protein binding
____ renal clearance
increased protein binding
lower renal clearance
(TCNs) if you have a polar substituent at C5 or C6, then the partition coefficient...
Lipophilic substituents __________ the partition coefficient
TCNs are excreted in (higher/lower) concentration in the urine
Doxycycline and Minocycline also exhibit a ____________ DOA
The hyclate salt increases what?
The hyclate salt helps...
eliminate acid/base instability
What is the hyclate form?