TTC ....Macrolide ppt.pptxTTC ....Macrolide ppt.pptxTTC ....Macrolide ppt.pptxTTC ....Macrolide ppt.pptx

1. Tetracyclines antibiotics

2. Important notes on Tetracyclines:
 MOA: Protein synthesis inhibitor by inhibiting the initiation of translation by
binding to the 30S ribosomal subunit and tetracyclines chelate Mg+2 ions
(required for TTC to bind to ribosomal binding site) due to keto-enol
tautomerism, which is essential for chelation.
 Spectrum of activity: (wide range of Gram-positive and
Gram-negative bacteria, anaerobes, atypical pathogens, spirochetes,
obligate intracellular bacteria, as well as protozoan parasites).
Especially: Tigecycline: extended spectrum to the resistant bacteria to
other TTC class members.
 Acid and base sensitivity:
 All are Acid sensitive (give anhydro TTC)
Except (drugs with no 6 OH):1. Doxycycline 2. Minocycline 3. Tigecycline
 All are Base sensitive (give iso TTC)
Except (drugs with no 6 OH): 1. Doxycycline 2. Minocycline 3. Tigecycline
 Bacteriostatic

3.  Route of administration: (Drugs that can be taken orally in stomach
hyperacidity):
Doxycycline
Minocycline
 Parenteral prodrug of tetracycline: (Rolitetracycline) used in serious
bacterial infection and will be hydrolyzed in vivo to the parent tetracycline.
 C/I: in pregnancy, lactation and for Childs (less than 8 years of age).
 Phototoxicity: Tetracyclines with a C-7-chlorine (Chlortetracycline).
 Specific uses: Acne.
 Generations of tetracyclines:
1st generation
TTCs
Tetracycline, Rolitetracycline, Chlortetracycline,
xytetracycline.
2nd generation
TTCs
Doxycycline, Minocycline.
3rd generation
TTCs
Tigecycline.

4. Tetracyclines
Case 1
Rk a15-year-old adolescent girl with a severe case of acne, come to your community
pharmacy with a prescription for oxytetracycline. Upon consulting her patient profile
card, you find she also has a gastric hyperacidity disorder that causes intermittent
distress sever enough to warrant medication with an antacid (Mylanta, which contain
both aluminum hydroxide and magnesium hydroxide, is her OTC drug of choice).
Compliance has been a problem with this woman when taking medication in the past,
and she claims she ‘’just does not remember to take her pills when she is supposed to’’.
Answer the following questions about TTCS.
A. Tetracycline B. Rolitetracycline C. Oxytetracycline
D. Doxycycline E. Chlorotetracycline F. Tigecycline

5. Question 1:
1.Discuss the potential drug-drug interaction between any of tetracycline
structure and the Mylanta taken intermittently by this patient. What
professional advice would you provide if both drugs needed to be taken?
The correct answer is:
 Stable chelate complexes are formed by tetracyclines with many metals
including Ca+2, Mg+2, and Fe+2 forming very water insoluble chelates. This
property explains their impaired absorption in presence of milk and antacids
containing calcium, magnesium and aluminum.
 My advice: don’t take the 2 drugs together, but it is better to separate them by
3 hours.

6. Question 2:
2.From all of the previous drugs select the newly approved derivative
belong to the Third generation of tetracyclines.
The correct answer is:
Drug no. F (Tigecycline).

7. Question 3:
3.Which tetracycline structure would be most stable in this patient stomach
during hyperacidity and why?
Select one drug which is unstable in strong acidic medium and diagram the
mechanism of acid-catalyzed drug decomposition and show the final inactive
product that could form.
The correct answer is:
Drug D and F is the stable derivatives due to the lack of 6-OH group.
N.B: Tigecycline taken by IV not by oral route….

8. Question 4:
4. What is the effect of change the orientation (Epimerization) of position 4 in
drug 1- Tetracycline.
The correct answer is:
 Formation of Epitetracyclines is much less active than the natural isomerism
solution of intermediate acidic pH range (pH 4).
 Epi-anhydro-TTC: causing kidney toxicity (results from expired TTC)
(prevent metal reabsorption).

9. Question 5:
5.What is the effect of encircled group in the drug B- Rolitetracycline?
The correct answer is:
 Aminomethylation of amide nitrogen (N-pyrrolidinomethyl) produce
more water soluble and less irritant derivative (prodrug) than the
parent for injectable products (IV or IM) in serious bacterial
infection and will be hydrolyzed in vivo to the parent tetracycline.

10. Case 2
A 54-year-old woman was presented to hospital with a one-month history of
intermittent, burning epigastric abdominal pain that was moderately severe in
intensity. The physician checked her medical history and found that she is a
peptic ulcer patient, and she had multiple endoscopies which showed positive
results of presence of Helicobacter pylori. The doctor prescribed her a
combination therapy for oral administration consisting of two antibiotics
clarithromycin and a member of tetracycline class.
A.Rolitetracycline B.Oxytetracycline
C.Minocycline D.Tetracycline

11. Question 1:
1. Predict the member of tetracycline class prescribed orally in this case?
Justify your answer.
The correct answer is:
 Drug no C (minocycline)
 Other drugs have 6-OH group which is unstable in strong acidic medium and
undergo acid-catalyzed drug decomposition to anhydro TTC.
Question 2:
2. What is the mechanism of action of the selected drugs combination
therapy?
The correct answer is:
 Additive antibacterial action by inhibiting bacterial protein synthesis through
dual mechanisms:
1st one: binding reversibly to the P site on the 50S subunit of the bacterial
ribosome by clarithromycin.
2nd one: minocycline binds to the 30S ribosomal subunit and prevents the
amino-acyl tRNA from binding to the A site of the ribosome and chelates
Mg+2 ions (required for TTC to bind to ribosomal binding site) due to
keto-enol tautomerism.

12. Question 3:
3. What is the effect of the removal of the encircled hydroxyl group in drug no
B?
The correct answer is:
 Increase lipophilicity and activity
 Increase stability in acidic and basic mediums by preventing formation of
anhydro TTC in strong acidic medium & iso TTC in basic medium.
Question 4:
4.Classify the provided drugs according to their generation.
The correct answer is:
 1st generation TTCs: A-Rolitetracycline, B- Oxytetracycline, D- Tetracycline.
 2nd generation TTCs: C- Minocycline.
Isotetracycline (inactive)

13. Case 3
A 66-year-old diabetic hypertensive patient presents with painful foot wound.
His wound seems red and swollen. After examination, it is diagnosed as a soft
tissue infected diabetic ulcer caused by resistant staphylococcus aureus
bacteria. The doctor prescribes him an antibacterial agent
intravenous infusion.
Examine the following drugs then answer the questions below.
given by
A. Tetracycline B. Doxycycline
C. Minocycline D. Tigecycline

14. Question 1:
1.Suggest the drug of choice in this case? Why?
The correct answer is:
The drug of choice is (D) tigecycline.
As it is approved to treat complicated skin, soft tissue infections caused by
resistant bacterial strains.
Question 2:
2.What is the effect of the encircled group in drug (D)?
The correct answer is:
This large 9-t-butyl-glycylamido group makes steric hindrance which
renders the molecule highly active against bacterial strains that exhibit
tetracycline resistance mediated by efflux or ribosomal
protection.

15. Question 3:
3.What is the mechanism of action of these drugs?
The correct answer is:
TTCs are bacteriostatic.
They inhibit protein synthesis by binding to the 30S subunit of ribosomes and
preventing aminoacyl-tRNA from binding, which stops the further addition of
amino acids to the growing protein chain and chelate Mg+2 ions (required for TTC
to bind to ribosomal binding site) due to keto-enol tautomerism.

16. Macrolides antibiotics

17. Important notes on Macrolides:
 MOA: protein synthesis inhibitor by binding to 50S ribosomal subunit.
 Spectrum of activity: gm +ve bacteria mainly & (Roxith+ Azithr+Clarith)
broad spectrum (+ve, -ve and atypical).
 Bacteriostatic
 Route of administration: can be taken orally (except erythromycin not
used in hyperacidity). But erythromycin required being in ester or salt
prodrugs to mask its bitter taste and improve its oral absorption.
(as Estolate: N-lauryl sulfate salt of the propionic ester of erythromycin)
 Specific uses:
Upper respiratory tract infections.

18. Macrolides
Case 1
Tw is a 14-year-old boy with a history sensitive stomach. He was sent to the
hospital and diagnosed in a local emergency room with ‘’walking pneumonia’’.
The physician prescribed Drug (A) 250 mg twice daily. TW after that suffered
from nausea, vomiting, abdominal cramps and diarrhea. The pharmacist
advised him with two alternatives, drug B and drug C that produce minimal to
negligible gastrointestinal upset. Please answer the following questions.
A. Erythromycin B. Azithromycin C. Clarithromycin

19. Question 1:
1.Discuss mechanism of action of these three macrolides (A-C).
Mode of action:
The macrolides selectively bind to a specific site on the 50S ribosomal
subunit to prevent the translocation step of bacterial protein synthesis.
Spectrum of activity resembles that of penicillins and they act mainly against
gram - positive infections.

20. Question 2:
2. Mention (drawing not necessary) the instability of drug 1 under acidic conditions.
The correct answer is:
The instability of erythromycin in acidic media arises from a facile intramolecular cyclization
in which the hydroxyl group at C-6 adds to the carbonyl group, forming a 6, 9-hemiketal that
undergoes irreversible dehydration. Participation of the hydroxyl group at C-12 in a second
intramolecular cyclization yields the 6, 9; 9, 12-spiroketal, either through the intermediate
anhydro hemiketal or directly from erythromycin.
 These products are pharmacologically inactive.

21. Question 3:
3. What problems can you foresee from this limited medication history?
The correct answer is:
He suffers from sensitive stomach and this erythromycin cause abdominal cramps
and is unstable in acid media. He may take any drug to treat nausea and vomiting or
shifts to other macrolide analog.
Question 4:
4. What is the effect of insertion of the encircled group in drug B & C?
The correct answer is:
Formation of Semi-synthetic derivatives to prevent the intramolecular reactions so
increases the acid stability of the provided derivatives with marked reduced GI side.
Also, for drug B (Azithromycin) it increases the duration of action so that it can
be taken once daily.

22. Case 2
G.S 40 year old woman with a history of gastric hyperacidity suffered
from early infection of β-lactamase producing streptococcus bovis (gm
positive bacteria). Doctor prescribed an oral antibacterial drug.
A. Erythromycin Ethylsuccinate B. Roxithromycin C. Erythromycin

23. Question 1:
1. Predict the member of macrolide class prescribed orally in this case?
Justify your answer.
The correct answer is:
 Drug B (Roxithromycin).
 Replacement of position no 9 ketone group (present in drug no A & C) that is
responsible for the intramolecular cyclization in strong acidic condition, so
increases the acid stability in this case that have a history of gastric
hyperacidity.

24. Question 2:
2.What is the different structure features between drugs no A & C?
The correct answer is:
Erythromycin ethyl succinate ester is less soluble in water so decreased
bitterness of erythromycin and suitable for oral administration (has better
oral absorption).