CF- Austin

Define each of the following:

• autosomal

• exocrinopathy/exocrine glands

• CFTR

• mucolytic

• corrector

• potentiator

• amplifier

CF is an…

a. autosomal dominant exocrinopathy

b. autosomal recessive exocrinopathy

c. sex-linked exocrinopathy

b. (exocrinopathy means effecting the exocrine glands, which are glands that secrete)

What gene is responsible for CF?

cystic fibrosis transmembrane conductance regulator (CFTR)

What is CFTR responsible for?

• anion channel that transports chloride and bicarb

• regulates amount and composition of exocrine gland secretions

Describe the pathophysiology of CF:

• what happens to the airways?

• what happens to the pancreas?

• what are some other exocrine tissues effected?

• airways—> secretions obstruct small/medium airways

  • result: breeding ground for bacteria

• profound damage to the pancreas—> obstructed ducts, impaired flow/production of digestive enzymes

  • result: chronic malabsorption, poor growth, fat-soluble vitamin deficiencies

• other tissues affected:

  • liver (bile ducts)

  • intestines

  • reproductive organs

  • musculoskeletal

  • CNS

CF airway is characterized by aggressive ___________-induced inflammation driven by chronic respiratory infection.

neutrophil

What is the tx class for mucus in CF patients?

mucolytics, secretolytics, and mucoregulators

Answer the following about Dornase alfa:

• is it a mucolytic, secretolytic, or mucoregulator?

• what type of enzyme?

• MOA

• ADRs

• mucolytic

• recombinant human deoxyribonuclease I (rhDNase)

• MOA: enzyme that selectively cleaves DNA, reduces sputum viscosity by hydrolyzing DNA to promote clearance of secretions

• ADRs:

  • voice alteration

  • pharyn/laryngitis

  • rhinitis

What route of admin is 1st line for antibacterials in CF?

inhaled formulations (duh)

What oral and IV agents are also used for antibacterial tx in CF?

• fluoroquinolones

• aminoglycosides

• vancomycin

What is the MOA and 2 key effects of aminoglycosides (-mycin/micin)?

• MOA—> binds 16S rDNA of 30S subunit

• effects:

  1. misreading of mRNA= premature termination and incorporation of incorrect amino acids

  2. inhibition of initiation= stuck at the start codon

What is the spectrum of activity of aminoglycosides (-mycin/micin)?

• active against:

  • G- aerobes

    • INCLUDING PSEUDOMONAS

• inactive against:

  • G+

  • anaerobes

  • facultative anaerobes

  • mycobacterium

What are the 3 significant toxicities associated with aminoglycosides?

What is the BBW?

1. nephrotoxicity—> may be reversible

2. ototoxicity—> irreversible

3. neuromuscular blockage (serious side effect where muscle contraction is inhibited, potentially leading to respiratory paralysis)

BBW: nephrotoxicity, ototoxicity, pregnancy

What is the spectrum of activity of Aztreonam?

• active against:

  • G- bacteria

    • INCLUDING PSEUDOMONAS

• not active against:

  • G+ bacteria

  • anaerobes

Aztreonam is safe to use in what allergy?

penicillin/cephalosporin allergy

Answer the following about Polymyxins (Colistin):

• what are polymyxins?

• MOA

• Main toxicities?

• polymyxins—> cationic peptide detergents produced by Bacillus

  • polymyxins B and E are used clinically

  • polymyxin E is colistin

• MOA: surface-active amphipathic agents

  • BACTERICIDAL against G-

  • interacts with and disrupts membrane phospholipids

• toxicities:

  • nephrotoxicity and neurotoxicity

Pancreatic insufficiency in CF is supplemented with enzymes from animals (pigs).

What are the contents of pancreas enzymes supplemented?

• lipase: fats

• protease: proteins

• amylase: carbs

How are pancreatic enzymes dosed?

• know this

based on LIPASE/grams of fat ingested

ADRs of pancreatic enzymes:

• GI (pain, n/v/d/c)

• HA

MOA of a CFTR CORRECTOR.

• drug examples?

• SAR considerations

• ADRs

KNOW THIS. (maybe except for SAR considerations)

increase # of functional CFTR at cell surface—> act as chaperones during protein folding to increase trafficking to cell surface

• drugs: lumacaftor, tezacaftor, elexacaftor

• SAR considerations: R stereochemistry, para acidic group on distal ring, difluoromethoxy group

• ADRs:

  • chest discomfort

  • GI (n/d/pain)

  • HA

  • respiratory (cough, congestion)

  • increased transaminases

MOA of a CFTR POTENTIATOR.

• drug examples?

• ADRs

KNOW THIS.

keep channel open to increase chloride transport

• drugs: ivacaftor

• ADRs:

  • GI (n/d/pain)

  • HA

  • URI

  • nasal congestion/ nasopharyngitis

MOA of a CFTR AMPLIFIER.

• drug examples?

KNOW THIS.

increase production of CFTR

• drugs: nesolicaftor (in development still)

Which of the following correctly describes tobramycin (in monotherapy)?

A. May be effective against MRSA; potential ADR tendon rupture

B. May be effective against MRSA; potential ADR neuromuscular blockade

C. May be effective against Pseudomonas; potential ADR tendon rupture

D. May be effective against Pseudomonas; potential ADR neuromuscular blockade

D.

Which of the following drugs prevents CFTR misfolding?

A. Ivacaftor

B. Lumacaftor

C. Nesolicaftor

D. None of the above

B.