Cystic Fibrosis Past Paper PDF (2024-2025)

CLIN PHARM 182 PHARMACOTHERAPY OF PULMONARY AND GASTROINTESTINAL DISEASES AY 2024-2025 - 1ST SEMESTER DR. DARYL E. MAGNO, RPH, PHARM.D. (MELLIT.)｜ LECTURE # 6｜10/07/2024 CYSTIC FIBROSIS...

CLIN PHARM 182 PHARMACOTHERAPY OF PULMONARY AND GASTROINTESTINAL DISEASES AY 2024-2025 - 1ST SEMESTER DR. DARYL E. MAGNO, RPH, PHARM.D. (MELLIT.)｜ LECTURE # 6｜10/07/2024 CYSTIC FIBROSIS Conductance - allows the movement from the OUTLINE other membrane I. CYSTIC FIBROSIS Regulator - the one moving the membrane A. Genetics Chronic, progressive, and frequently fatal genetic B. Epidemiology (inherited) disease of the body’s mucus glands C. Pathophysiology D. Clinical Presentation Primarily affects the respiratory and digestive systems in i. Sweat Glands children and young adults. ii. Pancreatic Involvement iii. Gastrointestinal Involvement GENETICS iv. Hepatic Involvement v. Genitourinary Involvement Cystic fibrosis is a recessive disease vi. Bona And Joint Involvement In recessive versus dominant, it depends on how many vii. Pulmonary Involvement copies of gene defect that the child will acquire or inherit II. DIAGNOSIS from their parents. A. Immunoreactive Trypsinogen (IRT) B. Pilocarpine Iontophoresis Test ○ Dominant: even just one copy of gene defect, we will C. DNA Analysis manifest the disease III. GENERAL APPROACH TO TREATMENT ○ Recessive: the child has to have a copy of both gene A. Nonpharmacologic Therapy i. Nutritional Parameters defect from both mom and dad B. Pharmacologic Therapy i. Airway Clearance Techniques a) Bronchodilation b) Airway Hydration Therapy c) Dornase Alfa d) Mechanical Methods ii. Anti-Inflammatory Therapies a) NSAIDs b) Macrolides c) Corticosteroids iii. Anti-Infective Therapies a) β-Lactam Antibiotics b) Aminoglycosides c) Prophylactic (Oral Or Inhaled) Antibiotics iv. Lung Transplantation C. Pharmacologic Therapy For Extrapulmonary Disease i. Pancreatic Insufficiency a) PERT b) Vitamin Supplementation c) Fertility And Contraception ii. Diabetes a) Insulin Figure 1. Genetics iii. Novel Therapies EXAMPLE (If both parents are carriers). Bb X Bb CYSTIC FIBROSIS B = normal gene It is a disease whose name doesn’t necessarily describe b = gene defect (CFTR) the actual disease itself (cyst = fluid-filled sac and fibrosis In the example, both parents are carriers. B b = multiple scars). B BB Bb ○ The name was taken from the pancreas where this b Bb bb was originally discovered. 2nd column, 2nd row [BB]: One of the child might be Cystic fibrosis is actually a description of disease from completely normal, it carries both the normal genes of the different organs. parents Autosomal recessive disorder caused by a single gene 3rd column, 2nd row [Bb] & 2nd column, 3rd row [Bb]: mutation on the long arm of chromosome 7 The other one could be a carrier because it contains your ○ This gene defect is what we call Cystic Fibrosis gene defect but he wouldn’t have cystic fibrosis because he only has one gene defect. Transmembrane Conductance Regulator (CFTR) 3rd column, 3rd row [bb]: The child receives both gene Transmembrane - the movement of one defects from mom and dad so he will have cystic fibrosis, membrane to another which is a 25% chance. BULANTE, DELA ROSA, MARTURILLAS, MELLA, TAGALICUD 1  CYSTIC FIBROSIS EPIDEMIOLOGY In cystic fibrosis, this is 2x or 3x times higher Birth prevalence than in regular person ○ 1 in 3,000 Caucasians ○ One diagnostic test for cystic More prevalent fibrosis is a sweat gland test ○ 1 in 13,000 Latin Americans This dysregulation of chloride and sodium ○ 1 in 15,000 African Americans also applies in different parts of the body ○ 1 in 31,000 to 100,000 Asian descent where CFTR is found (e.g., lungs, pancreas, Very rare liver) Expected survival: 49 years NOTE. ○ Survival period was less before becomes longer as CFTR is the gene regulator of our chloride channel medicines are being discovered PATHOPHYSIOLOGY CF is caused by mutations in the CFTR gene There are about 2,000 identified mutations in the CFTR gene which leads to abnormal channels but most of these mutations are very rare. ○ Usually, less than 10 mutations frequency of just greater than 1% ○ The most common mutation is the DF508 The descriptions in the table below is based on how the mutation affect the CFTR CLASS EXAMPLE MUTATION DESCRIPTION I G542X No functional CFTR made II DF508 Defective protein processing III G551D Defective regulation IV D1152H Defective conduction Figure 2. Difference between a normal CFTR channel and a mutant V A455E Reduced functional CFTR CFTR channel Table 1. Mutations of CFTR gene CLINICAL PRESENTATION A dysfunctional or absent CFTR has different effects on NOTE (Table 1). different organs, resulting in the multiorgan clinical Class I: CFTR is not functioning at all Class II: Abnormal intracellular processing of the key manifestations of CF. proteins Class III: Defective regulation of the channel ORGAN MANIFESTATION Class IV: Abnormal conduction of chloride through the Insufficiency channel Pancreatic Pancreatitis Class V: Reduced function of CFTR Abnormal glucose tolerance** Diabetes mellitus** Biliary cirrhosis Choletithiasis: gallstones Defective coding for CFTR Hepatobiliary Choletithiasis ○ Inhibits the normal regulation of ion transport in and Biliary obstruction out of the cell on the apical surface of secretory Meconium ileus* intestinal epithelial cells Meconium ileus equivalent**obstruction by putty-like Intestinal Rectal prolapse Usually, the sodium ion is followed by the Gastroesophageal reflux faecal material in the cecum or chloride ion and is reabsorbed by the CFTR but Appendiceal abscess terminal ileum some of it will go out of your skin → sweat Nasal polyps -all head sinuses infected (hence, salty sweat) Pansinusitis** -widened airways -> build- However, with a defective CFTR, there is no Respiratory Bronchiectasis** up mucus Pneumothorax -cough up blood from other reabsorption that will happen in your lumen → Hemoptysis** parts increased number of sodium chloride in your Delayed puberty** sweat (sweat with high levels of salt). Reproductive Infertility** The process is a highly negatively charged ** much more common in adults than in infants lumen which leads to an increased salt Table 2. Clinical Manifestations of Cystic Fibrosis content in your sweat gland. This process is what you call a Transepithelial potential difference BULANTE, DELA ROSA, MARTURILLAS, MELLA, TAGALICUD 2  CYSTIC FIBROSIS SWEAT GLANDS ○ Result from the inspissation of intestinal secretion and Defect in the reabsorption of electrolytes incomplete digestion of intestinal content High salt content in sweat Inspissation - process of increasing the viscosity Basis for diagnostic sweat chloride test of a fluid, or even of causing it to solidify, typically by dehydration Distal intestinal obstruction syndrome ○ can be developed at any age outside of neonatal period (meconium ileus equivalent) GERD: clinical manifestation for gastrointestinal involvement ○ Children are screened and treated (if diagnosed) Figure 3. Difference between a normal sweat gland and a CF sweat gland PANCREATIC Exocrine and endocrine functions are affected by cystic fibrosis Figure 4. Meconium ileus RECALL. Pancreatic enzymes are normally secreted into your HEPATIC bicarbonate rich fluid from the pancreatic duct. CFTR ○ Located on the apical surfaces of the cells lining the Loss of CFTR function inhibits secretion of digestive intrahepatic and extrahepatic bile ducts and enzymes and bicarbonates into your duodenum gallbladder ○ Resulting in ductal obstruction Facilitate ion transport Accumulation of enzymes (lipase, protease, and amylase) CFTR dysfunction = abnormal Chloride (Cl–) efflux across resulting in digestion of pancreatic tissue cells → Reduction in water and sodium movement into the ○ Results to multiple scars in your pancreas → cystic bile fibrosis ○ Decrease in volume and flow of bile → stasis and Poor digestion of fats and to a lesser extent, proteins and biliary tree obstruction intestine impairment of bile flow from the liver to the small due to blockage of the biliary duct carbohydrates Chronic obstruction = inflammation → Characterized by steatorrhea (fatty stool), decreased characteristic lesion of your focal biliary cirrhosis absorption of fat-soluble vitamins (Vitamin A, D, E, K), Liver disease malnutrition (low BMI), and failure to thrive ○ develops in the first decade of life Progressive destruction affects endocrine function ○ Significant liver disease: usually seen in 25% of ○ Glucose intolerance children with cystic fibrosis In most cases, it is much more common to adults like 75% (or at least 50%) of patients with cystic GENITOURINARY fibrosis will actually have DM. Early aggressive insulin therapy is given to RECALL. patients in order to have better clinical outcomes. Principle: Where salt is, water follows Gene defect of CFTR = there is no reabsorption/no flow of salt = no water → thicker liquid in the body → GASTROINTESTINAL obstruction of vas deferens Meconium ileus occurring in 20% of newborns with cystic fibrosis ○ Meconium ileus – Intestinal obstruction at birth BULANTE, DELA ROSA, MARTURILLAS, MELLA, TAGALICUD 3  CYSTIC FIBROSIS MALE NOTE. Illustration shows how CFTR affects the lungs: 98% with CF are infertile secondary to in utero obstruction of the vas deferens A: Normal airway epithelial with functional CFTR CFTR found in the apical surface of epithelial cells of the lungs FEMALE Higher prevalence of infertility B: Defective CFTR ○ Production of thick and tenacious cervical mucus Causes reduced periciliary liquid and loss of mucociliary clearance → accelerated ion transport → increased Sodium (Na+) reabsorption → BONE AND JOINT increased oxygen consumption and hypoxic CF patients have low bone mineral density, slower rate of gradients in the airways bone formation, accelerated rate of bone loss and arthritis Impaired mucociliary clearance → accumulation of ○ Insufficient intake and absorption of Vitamins D and mucus within the airway causing airway obstruction K needed in bone development CF patients: have terminal arthritis symptoms C, D, E: Hypoxic gradient ○ 1-2% of patients would have persistent symptoms Increased use of oxygen → Hypoxic gradient Anaerobic bacteria like P. aeruginosa thrive in the ○ Recurring symptoms of pain lungs → Infection PULMONARY F: Neutrophil-mediated chronic inflammatory response Where CF makes a big effect P. aeruginosa infection → results to neutrophil-mediated chronic inflammatory response The principal cause of repeated hospitalizations → release of reactive oxygen species and proteases to kill the bacteria → damage airways The depletion and dehydration in the lungs caused by CFTR gene defect leads to: 1. difficulty in breathing; and, 2. gives an anaerobic environment for bacteria to thrive and cause infection Reduces Airway Surface Layer (ASL) ○ ASL is a thin film of liquid in the airways surfaces contain antimicrobials, antioxides, proteases, and other substances to make sure that your lung is free from any other pathogens It is one of the lung defense mechanisms that maintains a pathogen-free environment in the lower airways of normal lungs ○ ASL removes invading microbes by moving mucous gel toward the mouth In a normal person: during infection, ASL coughs off invading microorganism as phlegm → give them a mucolytic agents and NOT cough suppressants to expel the phlegm In a patient with CF: CFTR defect reduces ASL → Results in marked thickened mucus and impaired mucociliary clearance Continued mucus hypersecretion → mucus plugging and airway obstruction There is high reabsorption of Sodium (followed by water) → thicker liquid in the lungs and the thicker it gets, the harder it is to expel → airway obstruction Causes alkalization of intracellular organelles and accumulation of ceramide ○ Increased susceptibility to infection P. aeruginosa ○ P. aeruginosa thrives in this environment Figure 5. How CFTR affects the lungs secretes a ceramidase capable of cleaving the N-acyl linkage of ceramide to generate fatty acids and sphingosine BULANTE, DELA ROSA, MARTURILLAS, MELLA, TAGALICUD 4  CYSTIC FIBROSIS DIAGNOSIS GENERAL APPROACH TO TREATMENTT 1. Immunoreactive Trypsinogen (IRT) Test Goals of Therapy a. Screening test 1. Address nutritional, gastrointestinal, pulmonary and 2. Pilocarpine Iontophoresis Test psychosocial concerns a. Confirmatory test 2. Prevent and treat infectious disease 3. DNA Analysis a. Confirmatory test NONPHARMACOLOGIC THERAPY IMMUNOREACTIVE TRYPSINOGEN (IRT) Achieve and maintain normal weight for adults and Newborn screening normal growth for children. Measures trypsinogen in the blood ○ Manage GI and pulmonary symptoms ○ Produce in pancreas usually carried into the small ○ Monitor nutrient and energy intake intestine ○ Addressing psychosocial and financial issues ○ Infant with CF We want to achieve this because there is the failure of there is obstruction of enzymes from pancreas to absorption of essential vitamins, there's no breakdown of the small intestine → might go back to the blood food for our CF patients ○ Mucus blocks transport of trypsinogen Mucus blocks the ducts from pancreas into the NUTRITIONAL PARAMETERS small intestine → accumulation in blood Age appropriate body mass index (BMI) method should ○ This can be detected and measured since infants be utilized to assess weight and height have increased IRT levels in their blood Better FEV1 status at about 80% predicted or above was associated with BMI % at 50th percentile or higher NOTE. If IRT is done (as a screening test) and tests CYSTIC FIBROSIS FOUNDATION positive, confirmatory tests, namely, pilocarpine iontophoresis test and DNA analysis test, would be done RECOMMENDATIONS Children and adolescents aged 2–20 years ○ recommends that weight for stature assessment uses PILOCARPINE IONTOPHORESIS TEST the BMI percentile method and those children and Also known as sweat chloride test adolescents maintain a BMI at or above the 50th Uses only a small area on the forearm percentile Previously, patients were wrapped in plastic to induce ○ They need to be more than the 50th percentile of the more sweat production general population ○ Safer and reduces the risk of hyperpyrexia Children diagnosed