Protein Synthesis Inhibitors

TCs are incompatible with what two things

1. Co-administered multivalent ion-rich antacids & hematinics (blood forming components containing Fe3+) 2. Concomitant consumption of dairy products rich in calcium ions (milk/food) = contraindicated

What two tetracyclines have H at R3?

1. Doxy 2. Mino

Which TCs are *less* likely to cause nephrotoxity? Why?

1. Doxycycline 2. Minocycline *No OH at R3

R2-R4 are what type of groups?

1. H 2. OH 3. Methyl CH3

What are the two insolubility issues caused by chelation?

1. Inconvenient for the preparation of solutions 2. Interferes with blood levels on oral administration

What tetracyclines have an OH at R4?

1. Oxy 2. Doxy

What three tetracyclines have an OH at R3?

1. Tetra 2. Oxy 3. Demeclo

What tetracyclines have an H at R4?

1. Tetra 2. Demeclo 3. Mino

Epimerization slide

4-Epitetracycline (INACTIVE) Full N means INACTIVE. Solid is BAD

What will the compound look like that can cause potential kidney damage

4-Epitetracycline (inactive from Epimerization) can also lose -OH group and form toxic products *Look for a full-shaded N, Missing OH, and a double bond

Anhydrotetracycline

6 OH can be gone and the water is lost with the OH *Much deeper in color Forms conjugated double bond

How can TC cause phytotoxicity?

Absorb light Cause erythema on exposure to sunlight (RED)

Acid catalyzed dehydration slide

Acid and minus H20 See deeper color and know drug is losing activity Discard if discolored bc not active drug!

What is the difference in the structure of Tetracycline compared to Oxytetracycline

Add OH group on R4

Phototoxicity slide

All can cause but mono and doxy have less chance

Why are TCs given as hydrochloride (HCL) salts?

Although TCs are considered neutral aka Amphoteric they are slightly basic and that is why they are made as strong acid salts

How can you tell TCs have undergone Acid catalyzed dehydration

C-6 -OH is lost to form anhydro-TC and double bond is formed *dashed line is still there

Distribution of TC is wide including the saliva bone, nail, teeth, and fatty tissue (Minocycline). One is the one place TC does NOT distribute to

CSF

Which TC has intermediate lipophilicity, halogen (↑ photosensitive), resistance common

Demeclo

Phototoxicity is the worst with what TCs? Why?

Demeclo *Adding a Chloride or halogen conjugated double bond carbon have higher chance of causing Phototoxicity

R1 with a Cl is what tetracycline?

Doxy

Which TC has intermediate lipophilicity, widely used, well absorbed PO, once a day

Doxy

Phototoxicity is seen less with with TCs?

Doxy and Mino

What are the most common types of TC used? Why?

Doxy and Mino - most common because of excellent PK

________ absorption not affected by food

Doxy/Mino

ethylenediaminetetra-acetic acid (EDTA)

EDTA chelates with ions, thus chelation with TCs is less pronounced and water solubility is higher Takes care of calcium (di or trivalent cations) Not a drug; no therapeutic effect

What problem does Demeclocyclin have?

Halogens can increase photosensitivity Resistance is common

TC are not used with dairy products or antacids

KNOW THE EXCEPTIONS (Sodium, Potassium)

At equilibrium, the mixture may have equal amounts of active and inactive compound

Lose 50% of the drug Old TC preparations can lose ~half of their potency by this process

Chelation slide

Milk or dairy products, Antacids (Zn, Ca ions) M = metal ion decrease solubility

Which TC does NOT contain an OH in the structure

Mino

Which TC is most lipophilic, widely used, well absorbed PO, once a day

Mino

Which TCs do not have dehydration problem but will still have epimerization problems? Why?

Mino and doxycycline No OH at R3

Which drugs have less potential to cause kidney damage?

Mino and doxycycline. All have potential to cause kidney damage but with new ones less because do not have OH in structure

Rank the TC from the most lipophilic to the least lipophilic

Mino>Doxy>Dem>TC>Oxy

More CNS side effects are seen with

Minocycline

Which TC is used for CNS and prostate infections?

Minocycline

What is the *most Lipophilic* TCs

Minocycline *Good pharmacokinetics: half life and more penetration into different tissues - CNS infection, prostate gland infections

R1 of N(CH3)2 is what tetracycline?

Minor

TCs are acid, basic, or neutral?

Neutral - Amphoteric (both acidic and basic groups)

Will sodium antacid be a problem with TC?

No -Sodium is monovalent so this is a solution -Potassium will also not be an issue Need to be di or trivalent ions to bind and cause chelation

What compound is lost through chelation in TCs, leading to even more reduced solubility?

OH

With TC there is a worry about solubility if taken oral drug and food interacts with drug and if food is milk and ions such as antacids. What type of ions do they have to be to reduce absorption?

Only di or trivalent ions and binds and reduces the absorption

Which TC is the Most hydrophilic, mainly IM (parenteral) Excellent Gram-negative coverage

Oxy

Rank the TC from the most hydrophilic to the least hydrophilic

Oxy>TC>Dem>Doxy>Mino

What Aantimicrobials that target the 50S ribosome is BOTH CIDAL and STATIC?

Streptogramin Quinupristin/dalfopristin

Doxycycline has good absorption, distribution, half life and once a day dosing

T

T/F Discolored old TCs should be discarded

T

T/F TC can cause nephrotoxicity

T

T/F TC cross the placenta and are CI in pregnancy

T

T/F TC does not have much metabolism

T

T/F Tetracyclines is the class where tetracycline is the drug itself

T

T/F The salts of polyvalent metal ions (Fe2+, Ca2+, Mg2+, Al3+) are all quite insoluble at neutral and basic pHs

T

T/F Multivalent ions decrease solubility of TC

T. Be careful NOT monovalent ions!

T/F Old TC preparations can lose ~half of their potency by this process

T. Discard old formulations because lose potency! Solution is not as active, not the drug itself!

T/F TC leads to a progressive and, essentially, permanent discoloration in which, in advanced cases, the teeth are even brown

T. Do NOT give to children (age 6-12 years) Cosmetically unattractive (but no deleterious except in extreme cases)

T/F TCs require slightly acid pH

T. If basic or neutral it is bad for solubility

T/F Food interacts with TC

T. Milk, iron, calcium, antacids decrease absorption of TC

T/F OH is not a good group at R3

T. Nephrotoxicity

Tetracyclines (TCs) slide

TC is 4 ring structures fused together; it is a reduced form of naphthacene; we see 6 double bonds which means 12 hydrogens can be attached there and we call it "dodecahydronaphthacene." don't be confused with the name Naphthacene Tetracycline are reduced forms of naphthlacene Dodeca - means 12 4 ring and only the last ring is benzene Dodecahydro (12H being reduced)

Why does TC have more affinity for the bones, which the teeth are the most visible

Teeth contains Ca2+ and TC can bind

Which TC has PO-irregular blood levels, absorption ↓50% with food/milk

Tetra

Oral dose absorption varies for

Tetracycline

T/F What is the oldest drug in the class that is not used orally

Tetracycline -decrease absorption with food

Which Antimicrobials that target the 30S ribosome are bacterioSTATIC

Tetracyclines (TCs) Tetracycline (Sumycin®) OxyTC (Terramycin®) Doxycycline (Adoxa®, Doryx®) Minocycline (Minocin®) Glycylcyclines Tigecycline (Tygacil®)

Why are *Aminoglycosides* bacteriCIDAL

They cause the bacteria to form faulty proteins which causes the bacteria to die Others are mostly bacteriostatic

Will Magnesium Hydroxide be a problem with TC?

Yes. MgOH2

TCs: Physico-chemical Properties slide

double bonds can absorb light Can cause brown teeth in children Dash N!!!! Full solid that is not TC > drug is unstable and inactive

Between pH 2 & 6, tetracyclines undergo

epimerization *we want acid pH (2-6) is much better because then we will have more solubility means less pain at injection site

What is given with the drug to reduce painful injections?

ethylenediaminetetra-acetic acid (EDTA)

TCs absorption affected by

food

TCs are generally given as

hydrochloride (HCL) salts

R1 is what type of group?

hydrogen (H) or lipophilic group

TCs are partially reduced ____________ ring system

naphthacene

What is the pH you want for more solubility and less pain at injection site?

pH 2-6

Intensification of discoloration with time is said to be a

photochemical process

Tetracycline is mostly reabsorbed leading to

renal elimination

Patient should be advised to be cautious about such exposure for at least first few doses to avoid potentially severe

sunburns

TCs are ______ colored compounds

yellow

How can you solve the problem of chelation with TCs?

Give a monovalent ion OR space them out from the drug

If concomitant oral therapy with TCs and incompatible metal ions must be done, what is the solution to reduce chelation?

Give ions 1 hour before or 2 hours after TCs

Doxycycline removed OH from R3 and replaced with a

H

Injectable formulations contain ethylenediaminetetra-acetic acid (EDTA) and are buffered at comparatively ______ pH levels

acidic

The ______ functions of the TCs are capable of forming salts through chelation with metal ions such as Fe2+, Ca2+, Mg2+ & Al3+

acidic

The _____-stereochemisty of the dimethylamino group is essential for activity

alpha

What ribosomes do humans have compared to bacteria?

*70 Bacteria* (odd) -50 -30 *80 Humans* (even) -60 -40

Which group of Antimicrobials Targeting the 30S ribosome are bactericidal?

*Aminoglycosides* - CIDAL Streptomycin Tobramycin (Nebcin®, TOBI®) Gentamicin (Garamycin®) Amikacin (Amikin®) Kanamycin Neomycin *The rest of the 30S are STATIC

TCs: Chemical Structure slide

*Do not need to know position of each group

T/F TCs are soluble drugs

F. Because of its amphoteric nature, these are not much soluble. We have to worry about solubility because when I take oral drug because if it is not soluble then it cannot be absorbed efficiently.

T/F If a patient is taking NaHCO3 and doxycycline together, sodium in the antacid can chelate with the drug and decrease its absorption.

F. Antacids and TC interact but talking about monovalent antacid Na+ NOT calcium or magnesium

T/F Doxycycline contains no OH

F. Doxycycline has OH and 5 position/R4 and Minocycline has NO OH

What is the problem with eating spinach with TC

F. Iron in spinach. Drug comes out of solution and cannot be absorbed. *Lose drug activity and absorption

T/F Oxytetracycline is the least hydrophilic

F. MOST hydrophilic *only parenteral and good gram negative coverage

T/F Anhydrotetracycline is an active drug of Tetracycline

F. Not active *Look for OH missing and double bond formed

Why can TCs cause painful injections?

Forms insoluble Ca2+ complexes (within body)