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Macrolides
Macrolides1
43
Pharmacology
Professional
10/25/2011

Additional Pharmacology Flashcards

 


 

Cards

Term
Erythromycin - Disadvantages (3)
Definition

       Derived in 1952 from Saccharopolyspora erythrea (Philippines)

       Disadvantages

       Poor bioavailability – Not very acid stable; gets degraded in the stomach

       Drug interactions

       Four times a day dosing – Problem with patient compliance

Term
Macrolides (4)
Definition
  • Erythromycin
  • Clarithromycin
  • Azithromycin
  • Telithromycin (historical interest only)
Term
In what ways did clarithromycin and azithromycin improve over erythromycin?
Definition

       Pharmacokinetics – Better bioavailability; better dosing (twice or even once a day); more acid stable

       Spectrum of activity (slightly) – more potent against some of the Gram +

       Drug interactions (mainly azithromycin)

Term
Mechanism of action
Definition

       Inhibition of protein synthesis

       Binds to Domain V of the 23s rRNA

       Part of the 50S ribosomal subunit

Term
[image]
Definition

Exit tunnel – for the growing AA chain. Macrolides block the exit tunnel, and the ribosome eventually dissociates and protein synthesis ceases. This prevents the growth of the bacteria.

Azithromycin can bind in two molecules at this site (versus one molecule for most macrolides)

Term
[image]
Definition
Macrolide prototype
Term
Static
Definition
  • Reversible
  • Stops growth
  • Immune system does the killing
Term
Cidal
Definition
  • Irreversible
  • Damages cell leading to death
  • Direct cell death
  • Good for immunocompromised patients, whose immune systems may not be capable of doing the killing
Term
Are macrolides static or cidal?
Definition
  • Both static and cidal
  • Dose, site, organism dependent
Term

Spectrum of activity - good

(HHMM...)

Definition
  • atypicals
  • H. influenzae
  • M. catarrhalis
  • H. pylori
  • Mycobacterium avium
Term
Spectrum of Activity - moderate
Definition
  • S. pyogenes
  • S. pneumoniae (telithromycin>macrolides)
Term
Spectrum of Activity - poor
Definition
  • staphylocci
  • enteric GNRs (azithromycin>clarithromycin)
  • anaerobes
  • enterococci
Term

Gram positive spectrum of activity

(SSoP)

Definition

       Staphylococcus aureus

       Resistance has become common

       MRSA are very likely to also be resistant to macrolides

       Streptococcus pneumoniae

       May be used for respiratory tract infections, CAP

       Resistance has become common

       Macrolides commonly used against S. pneumoniae

       Other Streptococci

       Variable activity against S. pyogenes

       Modest activity against Viridans Streptococci

       Macrolides not very good here

       Poor Enterococcus activity

Term
Gram negative spectrum of activity
Definition

       Helicobacter pylori

 

       Moraxella catarrhalis

 

       Haemophilus influenzae

 

       Erythromycin is unreliable

 

       Campylobacter jejuni – diarrhea-type symptoms; may lessen duration by a few days

 

       Neisseria gonorrhoeae

 

       Neisseria meningitides – possible prophylaxis

 

       Bordetella pertussis

 

       Poor coverage of Enterobacteriaceae

 

       Respiratory disease, peptic ulcer disease, STDs

Term
Spectrum: Miscellaneous
Definition

 

-          Poor anaerobic coverage

 

-          Macrolides excel in coverage of atypicals

 

        Mycoplasma

 

        Chlamydia

 

        Legionella

 

        Mycobacterium avium complex

 

Term
Mechanisms of Resistance - Two main methods
Definition

-          Efflux

        Mediated by mefA/E gene

        Affects macrolides only

        Can go from narrow spectrum to broader spectrum

-          Target site modification

        Mediated by erm gene

        Affects macrolides, clindamycin, and streptogramins

        MLSB – Macrolide, Lucosamide (ex. Clindamycin), Streptogramins

Term
Mechanisms of Resistance (image)
Definition
[image]
Term

Resistance in S. pneumoniae

Definition

-          About 15-30%

        <5% in early 1990’s

-          Efflux > Methylation in US

-          Methylation conveys higher levels of resistance

-          Z-pak for respiratory infections; its overuse has driven up resistance

Term
Macrolide preparations - Erythromycin
Definition

â—¦       Base (tabs) – has enteric coating to help it get through the stomach to the small intestine

â—¦       Stearate salt (tabs)

â—¦       Ethylsuccinate (tabs, chew-tabs, liquid)

â—¦       Estolate (tabs, capsules, liquid)

â—¦       Gluceptate (IV) – IVs can cause intense burning at the injection site

â—¦       Lactobionate (IV)

Term
Macrolide preparations - Clarithromycin
Definition

â—¦       Tabs, ER tabs, suspension

â—¦       No IV formation

Term
Macrolide preparations - Azithromycin
Definition

 

—  least amount of drug interactions of the macrolides

 

â—¦       Tabs, suspension, IV

 

â—¦       Z-max – Sustained release for CAP and URIs. Good for TB patients, you watch them take their medication

 

Term
Pharmacokinetics (image)
Definition
[image]
Term
Pharmacokinetics - Absorption
Definition

       Food decreases the absorption of erythromycin (except estolate and ethylsuccinate form)

       Clarithromycin and azithromycin may be taken with or without food.

       Decreases GI side effects

       Azithromycin capsules should be no food 

Term
Pharmacokinetics - Distribution
Definition

       Excellent tissue penetration

       Produce high intracellular concentrations in several different cells (leukocytes, macrophages)

       Poor CSF penetration – They are very hydrophilic, but can get into CSF tissue. Can be used for treatment failures with other drugs.

       Azithromycin has longest WBC half-life and highest concentration

       Allows concentration of drug at site of infection 

       Average tissue half-life is 2-4 days

       Therapeutic concentrations in tissue 5 days or more after completion of therapy

       Serum concentrations suffer as a result

       Use in primary bacteremia is questionable

Term
Pharmacokinetics - Metabolism
Definition

       CYP450 system substrates

       Erythromycin and clarithromycin are inhibitors of CYP enzymes

 

HEPATIC METABOLISM

Term
Drug interactions
Definition

       Theophylline

       Erythromycin or clarithromycin may be associated with increased levels of theophylline

       Theophylline used to be used for asthma (not so much anymore)

       Type I antiarrhythmic drugs:

       Disopyramide, quinidine, procainamide

       Erythromycin enhances the effects of these agents and should be used with extreme caution.

       At high concentrations, antiarrhythmics can actually become proarrhythmics

       Antacids:  decrease absorption of azithromycin

       Warfarin

       Increase in anticoagulant effect

       Carbamazepine

       Inhibition of carbamazepine’s metabolism

       May lead to toxic levels

       50% reduction in dose may be necessary

       Monitor carbamazepine serum concentrations

       Digoxin

       May increase digoxin levels leading to toxicity

       Cyclosporine

       May increase cyclosporine levels leading to toxicity

Term
Therapeutic Uses
Definition

       Respiratory tract infections

       CAP

       Potential empiric use

       Excellent agents when atypicals are suspected

       Streptococcal pharyngitis

       Erythromycin is an alternative to PCN/Cephs

       Acute exacerbations of chronic bronchitis (AECB)

       Clarithromycin and azithromycin may be better due to likelihood of H. influenzae

       Sexually Transmitted Diseases

       Azithromycin as 2g single dose will cover N. gonorrhoeae and C. trachomatis

       Peptic Ulcer Disease

       Clarithromycin in combo with other antibiotics and acid suppressants

       Cat scratch fever (Bartonella henselae)

       Whooping cough (Bordetella pertussis)

       Lyme Diseases (Borrelia burgdorferi)

       Mycobacterium avium complex (MAC) – Protozoal infection, but macrolides will cover it

       Treatment

       Prophylaxis (CD4<50 in HIV patients)

Term
What is clarithromycin good for?
Definition
H. pylori-induced GI ulcer disease (when used in combination with other drugs and acid-suppressive agents)
Term
What is azithromycin good for?
Definition
Upper and lower respiratory tract infections, chlamydia, atypical mycobacterial infections, and traveller's diarrhea.
Term
Adverse effects
Definition

       Gastrointestinal

       Abdominal pain (1-12%)

       diarrhea (1-10%)

       nausea (2-8%)

       Erythromycin stimulates GI motilin

       Mild elevation of liver enzymes 

       Central Nervous System

       Mild headache or dizziness

       Dose-related hearing loss or tinnitus with high doses (reversible)

       Hypersensitivity Reactions

       Anaphylactic reactions (rare)

       Cardiovascular

       QTc prolongation and torsades de pointes

Term
Precautions
Definition

       Pregnancy:

       Azithromycin and erythromycin: Category B

       Animal studies show no risk, but human studies not adequate or animal toxicity but human studies show no risk

       Clarithromycin: Category C

       Animal studies have shown an adverse effect on the fetus/ no adequate studies in humans

Term
Anti-inflammatory and Immunomodulatory Properties
Definition

-          Activity in addition to antimicrobial effect

        First seen in type of bronchiolitis

-          Limit production of pro-inflammatory cytokines

-          Reduce neutrophil chemotaxis

-          Decrease sputum and mucus production

Term
Role in Cystic Fibrosis
Definition

-          Reduced exacerbations

-          Increased time to exacerbation

-          Decreased toxins

-          Inhibition of biofilms and quorum sensing

-          Daily or MWF

-          Reservoir for resistance? Especially H. influenza

Term
Drug interaction
Definition
Macrolides are potent inhibitors of the drug-metabolizing CYP450 enzymes
Term
Diabetic Gastroparesis
Definition

 

Diabetic Gastroparesis

 

-          Azithromycin’s side-effect can actually help here, to decrease gastroparesis. It increases gastric emptying by about 50%

 

-          Delayed gastric emptying

 

        Fullness

 

        N/V

 

        Bloating

 

-          Motilin-receptor agonist

 

        Second line

 

        Erythromycin

                           -   Before meals

 

Term
What are the unique properties of macrolides?
Definition
They have anti-inflammatory and immunomodulatory properties.
Term
Which conveys a higher level of resistance, efflux or methylation?
Definition

methylation

(Efflux>Methylation in the US)

Term
How do macrolides penetrate tissues?
Definition
They can get into the white blood cells to get carried to the site of infection.
Term
Do macrolides enter the CSF?
Definition

No, they exhibit poor CSF penetration (they are very hydrophilic drugs)

They pass the CNS "somewhat" - not very well.

Term

Erythromycin:

 

Bioavailability?

Elimination?

Half - life?

Definition
  • Bioavailability = 18 - 45%
  • Elimination = Partially unchanged in bile
  • Half-life = 1 - 2 hours

You don't have to adjust doing for impaired renal funcion (CrCl <30)

Term

Clarithromycin:

 

Bioavailability?

Elimination?

Half-life?

Definition
  • Bioavailability = 50 - 55%
  • Elimination = Primarily renal
  • Half-life = 4 - 7 hours
Term

Azithromycin:

 

Bioavailability?

Elimination?

Half-life?

Definition
  • Bioavailability = 35 - 40%
  • Elimination = Unchanged in bile, 20% unchanged in urine
  • Half-life = 29 - 96 hours

You don't have to adjust dosing for impaired renal function (CrCl <30)

Term
How are macrolides metabolized?
Definition
Hepatic
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