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Drug Action I > Block 1 - Cystic Fibrosis + PAH Physiology > Flashcards

Block 1 - Cystic Fibrosis + PAH Physiology Flashcards

1
Q

What is the cause of CF?

A

Mutation in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) caused by autosomal recessive inheritance

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2
Q

Where is CFTR located? What does it coded for?

A

Chromosome 7. Codes for cAMP that regulates Chloride channel as well as other electrolyte regulations

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3
Q

What is an autosomal disease?

A

Mode of inheritance of genetic traits located on the autosomes (22nd chromosomes)

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4
Q

What is the life expectancy of CF patients?

A

+50 since 2020

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5
Q

What is primary cause of CF deaths?

A

Lung disease

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6
Q

How many mutations listed on the CFTR mutation database?

A

1601

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7
Q

What is the mot common CFTR mutations? What class is it?

A

∆F508 Class II

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8
Q

What is the outcome of ∆F508 mutation?

A

Causes loss of the amino acid phenylalanine -> defecting protein folding within the Golgi apparatus/ER and degradation of the CFTR protein prior to reaching the cell surface

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9
Q

What are the outcomes of Class III-IV GF genes?

A

Produce fully processed CFTR proteins that are either non-functional or only partially functional

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10
Q

Describe the mechanism of CFTR mutation Class II?

A
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11
Q

Describe the normal function of chloride channels?

A

Agonist binds to channel that increase cAMP and PKA -> inducing phosphorylation of CFTR at the R domain -> ATP binding and degradation occurs NBD

Channels mainly help with chloride conductance

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12
Q

What are the 2 membrane domains of the ion channel?

A
  1. 2 nucleotide binding domains
  2. regulatory domain
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13
Q

What is the CFTR protein? What does it effect?

A

Protein that spans the membrane and acts a s channel, controlling the movement of chloride from cell to cell (sweat glands, lung, pancreas)

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14
Q

How does the CFTR protein affect other ionic functions in the body?

A
  1. Affects channel activation of K+ and Na+ channels via NBD
  2. Affects channels involved in ATP transport and much secretion
  3. Mediates transport of biocarb
  4. Interaction with epithelial NA+ channel
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15
Q

How do ionic channels change in patients with CF?

A

Loss of function affecting Cl-, K+, Na+, HCO3-

Functions are tissue specific

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16
Q

What are organs that affected by CF? Which one is the most prominent site?

A
  1. Lungs
  2. GI
  3. Liver
  4. Skin
  5. Pancreas
  6. Repro
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17
Q

Describe how CF affects the skin giving sweat its saltiness?

A
  1. Defective CFTR protein traps Cl- outside cell
  2. Cl- binds to positively charged ions preventing them from crossing channels
  3. Epithelial sodium channel activity in sweat ducts decrease
  4. NaCl forms in high amount which is test in the sweat test
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18
Q

How do you diagnose CF?

A

Sweat test

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19
Q

How is the sweat test conducted?

A
  1. Pilocarpine is placed under the electrode pad to stimulate sweating
  2. Saline is on the other
  3. Mild electric current passes between electrodes and sweat is collected
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20
Q

What is the normal sweat chloride?

A

0-40

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21
Q

What is borderline and positive sweat chloride?

A

40-60, 60-165

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22
Q

How do you screen for CF in newborns?

A

Measure immunoreactive trypsinogen (IRT) in blood

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23
Q

How does CF affect the lungs and exocrine tissue?
How does it differ from normal function?

A

Epithelial sodium channels regulate Na+ transport are normally inhibited CFTR, however, abnormal protein increase its activity -> Increased Na+ transport across membrane

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24
Q

What is the outcome of increased Na+ absorption into the cytosol?

A

Water follows Na+ dehydrating the mucus

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25
Q

How many CF patient die of lung infections?

A

> 95%

26
Q

What is the primary goal for CF therapy?

A

Treat the problems associated with lung function

27
Q

How does CF affect the liver? 5 ways

A
  1. Increased mucus viscosity
  2. Decreased mucociliary clearance
  3. Mucus plugging and tracheobronchial tree dilation
  4. high rates of infection
  5. Hostital admissions due to declining FEV-1
28
Q

What is infection caused by in CF?

A

Colonization with virulent/resistant strains

29
Q

How does colonization occur?

A

Static mucus providing optimal environment for growth -> tissue destruction

30
Q

What are the common bacteria fund in sputum of CF?

A

Staphylococcus aureus
Haemophilus influenzae
Pseudomonas aeruginosa

31
Q

What are some characteristics of Pseudomonas aeruginosa?

A
  1. Very virulent and highly resistant
  2. Antibiotic QD
  3. Generates a biofilm, protecting bacteria from inhaled antibiotics
32
Q

What is a recessive genetic disorder?

A

Both parents are carriers and each contributes an allele to the embryo

33
Q

What group of people are more susceptible to inheriting CF?

A

Caucasians

34
Q

How does CF affect the liver?

A
  1. Accumulation of thickened mucus in the bile ducts -> cirrhosis
  2. Retention of biliary secretion and chronic cholecystitis
  3. Second leading cause
35
Q

How can CF affect the pancreas?

A
  1. Accumulation of mucus in ducts leading to decrease in function and secretion of enzymes
  2. Limitation of chloride-bicarb exchangers -> retention of enzymes and destruction of tissue
36
Q

What enzymes are secreted by the pancreas and what do they digest?

A
  1. Trypsin and chymotrypsin (protein)
  2. Amylase (carbs)
  3. Lipase (fats)
37
Q

What causes CFRD?

A

Damage to islet cells decrease insulin secretion that regulates blood glucose

38
Q

How is the GI affected by CF?

A
  1. Decrease in water secretion causing constipation and thickens mucous
  2. Lack of digestive enzymes
39
Q

What are the outcomes of lacking digestive enzymes?

A

Inability to properly absorb nutrients and ADEK leading to malnutrition or caloric loss

40
Q

How is the Reproductive system affected by CF in men and women?

A

Men: 97% infertility
Women: 20% infertile, thickened mucus, malnutrition

41
Q

What are the major presentation of CF?

A
  1. Salty skin
  2. Malnutrition
  3. Sinus polyps
  4. Male infertility
  5. Constipation
  6. CFRD
  7. SOB
42
Q

What is PAH?

A

Abnormal elevation in PAP and secondary right ventricular failure

PAP greater than 25 at rest and 30 with exercise

43
Q

What is the normal PAP?

A

8-20 mmHG at rest

44
Q

What are the classes of PAH? What how are they classified?

A
  1. PAH
  2. PAH owing to left heart disease
  3. PH secondary to chronic hypoxemia (COPD)
  4. Chronic thrombosis-embolic pulmonary HTN (CTEPH)
  5. Miscellaneous (extrinsic compression of pulmonary arteries)
45
Q

What are characteristics of Group 1 PAH

A

Primary
1. Relatively rare disease between 20-40
2. No racial preference
3. Common in women than in men

46
Q

What are the characteristics of Group 2-5 PAH?

A

Secondary: Due to pulmonary malfunction, cardiac malfunction, drugs, and cor pumonale

47
Q

Define cor pulmonale?

A

Enlargement of right ventricle secondary to any underlying cardiac or pulmonary disease (COPD)

48
Q

What is the life expectancy of untreated PAH?

A

3 years

49
Q

What are the symptoms of Class 1 PAH?

A
  1. w/o a resulting limitation of physical activity
  2. Not a cause of symptoms
50
Q

What are symptoms of Class 2 PAH?

A
  1. A slight limitation of physical activity
  2. Comfortable at rest, but physical activity may cause symptoms
51
Q

What are symptoms of Class 3 PAH?

A
  1. Marked limitation of physical activity
  2. less than ordinary symptoms
52
Q

What are symptoms of Class 4 PAH?

A
  1. Inability to carry out any physical activity without symptoms
  2. Signs of right heart failure
53
Q

What are common symptoms of early stage PAH?

A
  1. Dyspnea
  2. Fatigue
  3. Near syncope
  4. Chest pressure
  5. Palpitations
  6. Leg edema
54
Q

What causes PAH? Where does it occur?

A

Smaller blood vessels come more resistant to blood flow, the right ventricle is under stress to pump to lung

55
Q

What are the underling problems of PAH?

A
  1. Weakening of the lining of the lung’s blood vessels causing blood leakage
  2. Leakage cause constrict of smooth muscle -> thickening and hypertrophy of the arteriole
  3. Inflammatory mediators -> vasocontriction
  4. Fibroblast proliferation
  5. Constriction of BV increase BP choke BF between lungs and heart
56
Q

What causes right ventricular dysfunction in PAH?

A
  1. Pul Arterioles narrow and pressures increase -> RV works harder
  2. RV enlarges and pump less to heart leaving less blood in LV
57
Q

What is the primary cause of PAH death?

A

Long term pressure -> RV HF -> death

58
Q

What are the key signaling pathways that are disrupted by PAH?

A
  1. Nitric oxide
  2. Prostacyclin and thromboxane A2
  3. Endothelian-1
59
Q

What physiologically worsens PAH?

A
  1. Impaired vasodilation from decreased PGI2 production reducing NO synthase eNOS function
  2. Vasoconstrictive and mitogenic effects of upregulated ET1 signaling
60
Q

Describe how the PGI2 signaling factors contribute to PAH pathology?

A
61
Q

Describe how the NO signaling factors contribute to PAH pathology?

A
62
Q

Describe how the ET1 signaling factors contribute to PAH pathology?

A

Drug Action I (32 decks)

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