patho/PCT exam 6

Secondary Adrenal Insufficiency - Treatment

"Stress dose" glucocorticoid therapy Acute illness or minor outpatient procedure-related stress: Chronic supraphysiologic steroid use: ~3x maintenance glucocorticoid dose Addison's Disease: no need to alter mineralocorticoid replacement Septic shock glucocorticoid dosing: Hydrocortisone 200 mg/day 50 mg IV Q6H Acute Respiratory Distress Syndrome (ARDS) dosing: Methyprednisolone 1 mg/kg/day continuous infusion ≥ 14 days IV steroid therapy used in adrenal insufficiency should be weaned and not stopped abruptly · To help out patients and know if they have a minor surgical procedure then they are gonna be a little extra stressed. If not getting exogenous then we are reliant on exogenous then we may need to beef up the dose a little in response to that event. When our patients become septic we can provide stress produced steroids. In general if you have a patient you adequately fluid rescustated, these patients can be profoundly. 200 mg per day to mimic the body's response during physiologic stress. Wean patients off IV therapy more slowly.

clubbing

(hypertrophic osteoarthropathy) - bulbous enlargement of end of finger or toe; levels of severity; seen with decreased oxygenation (bronchiectasis, CF, pulmonary fibrosis, lung abscess, and congenital heart disease; sometimes lung cancer)

ARDS development

1) alveolocapillary damage by highly acidic gastric content, toxic gases or chemical mediators of systemic disorders (sepsis, trauma, etc) 2) neutrophils adhere to injured capillary endothelium and marginate through the interstitium into the air space, which is filled with protein rich edema fluid 3) there is sloughing of both the bronchial and alveolar epithelial cells; protein ruch hyaline membranes form on the basement membrane 4) in the air space, alveolar macrophages secrete cytokines; IL1, 6, 8, and 10 and TNF alpha which act locally to stimulate chemotaxis and activate neutrophils. IL1 can also stimulate the production of extracellular matrix by fibroblasts 5) neutrophils can release oxidants, proteases, leukotrienes, and other proinflammatory molecules such as platelet activating factor (PAF), ROS 6) the influx of protein rich edema fluid into the alveolus leads to the inactivation of surfactant 7) this leads to impairment of gas exchange, decreased lung compliance, and increased pulmonary arterial pressure · Can see strong membrane formed by proteins and death cells with covid on the tissue and can see a drastic difference.

what factors lead to patient winding up in an emergency room with severe exacerbation?

1. an atopic response to an allergen due to a combo of genetic predispositions that lead to the inappropriate immune response 2. non-atopic factors (cold air, exercise) can contribute 3. then, given the presence of asthma, further factors such as viral infection or increased allergen level. all these factors could be involved simultaneously · Increase in airway resistance, FEV, decrease in expiratory flow, increased work of breathing, respiratory functional muscles have changed, arterial blood gazes, bronchial hyperresponsiveness, mucus plugging, etc. continuation and manifestation and elevated respiratory heart rates and such. Decreased level of oxygen characterized with prolonged expiration and inflamed lungs. Between episodes, pulmonary function could be normal. Another condition close to asthma is allergic rhinitis.

pathological stages of ARDS

1. the initial stage is the exudative stage, characterized by diffuse alveolar damage 2. the second stage of proliferation develops after 10-14 days, characterized by resolution of pulmonary edema, proliferation of type II alveolar cells, squamous metaplasia, interstitial infiltration by myofibroblasts, and early deposition of collagen 3. some patients progress to the third stage of fibrosis, characterized by obliteration of normal lung architecture, diffuse fibrosis, and cyst formation · Initial stage is associated with edema and diffuse capillary damage. Second stage is usually developed in 10-13 days and is characterized by resolution of pulmonary edema. Can see deposition of collagen. Some progress to the third stage

Treatment Overview

1.Infection control measures 2.Initiate antibiotics targeted at C. difficile 3.Discontinuation of all unnecessary antimicrobial therapies or change to "low risk" •Antibiotic stewardship 4.Discontinue other contributing agents · Number 1 the patient needs to be put in isolation with contact precautions, need to glove and gown up. They get 40% less visitations from healthcare workers. D/C PPIs, get off high risk to low risk antibiotics

Infection Control Measures Society of Healthcare Epidem. of America (SHEA)

1.Patient isolation in a single room - preferably with a bathroom 2.Strict contact precautions 3.Terminal room cleansing with 1:10 bleach 4.Avoidance of rectal thermometers 5.Soap & water (+ scrubbing) for hand washing 6.Antibiotic stewardship & control

Cushing's Syndrome - Treatment Options

1st line: Surgical resection of pituitary/other tumor Adjunct, Pre-operative, or Palliative Pharmacotherapy Steroidogenesis inhibitor therapy - ↓ cortisol production Ketoconazole, levoketoconazole Metyrapone Osilodrostat Etomidate (IV) Adrenolytic therapy - ↓ cortisol production Mitotane Coricotroph tumor-directed therapy - ↓ tumor ACTH production Cabergoline Pasireotide Glucocorticoid receptor antagonist Mifepristone · Main thing we can do is take patient to surgery to get the tumor out. But we use pharmacotherapy in the perioperative context and not everybody can go to the OR in that patients could be too old or too frail. Can use steroidogenesis inhibitors to slow down production. Main problem with ketoconazole are the side ffects and levoketoconazole doesn't really solve that problem and doesn't have an obvious benefit in regards to therapy. Upside could be less frequent dosing required. Metyrapone is another steroidogenesis therapy but is an older therapy . osilodrostat is another steroidogenesis inhibitor and targets 11 beta hydroxylase and has same side effects as metyrapone. Does have twice a day dosing. Another drug class we have to work with would be adrenolytics. Mitotane is the chemotherapy equivalent of these agents. We also sometimes have tumor involvement so when we use some of our dopamine agonists or sosmatostatin analogs, bc there are dopamine binding sites on these tumors, if we bind those sites we can slow the production of ACTH. Can try to bind those receptors on the tumors and slow down ACTH production.

asthma epidemiology

25.1 million people, 5.1 million children most common chronic disease in children and incidence is rising boys have higher incidence but often overgrow the problems. more girls begin to develop asthma as teenagers or later, so that among the 25-35 yr old groups, asthma in women is more than twice that of men morbidity/mortality decreased in past decreased due to improved management primary cause of death from inadequate assessment of airway obstruction/therapy higher prevalence in AA and hispanics; puerto ricans asthma rate is 50% higher than non-hispanic black people. socioeconomic factors could be important

COPD epidemiology and etiology

4th leading cause of death in US significant increase in prevalence over past decades primary cause is cigarette smoking (active and passive) however all smokers do not get genetic forms and other environmental exposures also

A 65 year old man presents to the emergency department with symptoms of abdominal pain, diarrhea with >7 water stools daily and a fever (101.3F) for the past 3 days. Home medications include lisinopril 10mg PO daily for HTN, metformin 500mg PO BID for diabetes, ciprofloxacin 500mg PO BID (day 15 of 28) for prostatitis, omeprazole 20mg PO daily for GERD. His CBC is remarkable for a WBC = 30,000cells/mm3 (21% bands). SCr is 1.7mg/dl which is elevated from his baseline of 1.1mg/dl. Our 65 year old patient is diagnosed with CDI via EIA Toxin A&B. He is admitted to the medical ward with stable hemodynamics (eg BP, heart rate). Recall his lab values: WBC = 30,000cells/mm (21% bands) and SCr is 1.7mg/dl. What medication(s) would you discontinue or hold in our patient? A.Omeprazole B.Metformin C.Ciprofloxacin D.Lisinopril

A and C Could switch to H2RA bc it is not as high a risk. May switch patient to Bactrim

cyanosis

A bluish discoloration of the skin and mucous membranes by desaturated hemoglobin (5 g/dl or more). it can be caused by decreased arterial oxygenation (low PaO2), pulmonary or cardiac right to left shunts, low cardiac output, cold environment or anxiety an insensitive indicator of respiratory distress in adults: presented only in case of severe hypoxemia. lack of cyanosis doesn't mean that oxygenation is notmal (severe anemia, CO poisoning). central cyanosis (decreased Hb sats in arterial blood) is seen in buccal mucous membranes and lipd. peripheral cyanosis (slow blood circulation in fingers and toes) is best seen in nail beds

asthma

A chronic lung disease that inflames and narrows airways: contraction of the smooth muscles, edema, and mucous secretion bronchi tend to be involved, although the problems can extend down into the bronchioles recurrent episodes of wheezing, breathlessness, chest tightness, and coughing, particularly in the night or early morning hyperresponsiveness of airways with variable obstruction to airflow - reversible with treatment most attacks short lived with complete recovery numerous cellular elements involved: mast cells, eosinophils, T cells, macrophages, neutrophils, and epithelial cells subbasement membrane fibrosis may occur in some patients · Asthma is still a chronic condition. Chronic lung disease that inflames and narrows airways. In asthma there is a contraction of muscles in the walls and there is inflammation and production of mucus. Usually the bronchi are affected but some problems might exist in bronchioles. Characterized by chest tightness and weakness. Airways characterized by hyperresponsiveness to irritating factors. Most asthma attacks are short with complete recovery and is associated with inflammation of airways and membrane fibrosis may occur in time.

patient case A 65 year old man presents to the emergency department with symptoms of abdominal pain, diarrhea with >7 water stools daily and a fever (101.3°F) for the past 3 days. Home medications include lisinopril 10mg PO daily for HTN, metformin 500mg PO BID for diabetes, ciprofloxacin 500mg PO BID (day 15 of 28) for prostatitis, omeprazole 20mg PO daily for GERD. His CBC is remarkable for a WBC = 30,000cells/mm3 (21% bands). SCr is 1.7mg/dl which is elevated from his baseline of 1.1mg/dl. Patient is admitted to a medical ward. What risk factors does this patient have for CDAD? A.Age B.PPI use C.Metformin use D.Long-term ACE inhibitor use E.Fluoroquinolone therapy

A, B, E · Patient case: biggest risk factor for this patient is recent cipro treatment for prostatitis, look back to see if this was avoidable or not. If patient got 2 weeks of cipro for a UTI they could have gotten nitrofurantoin for, then that is a risk factor. Omeprazole may alter gut microbiome bc it of increasing ppi but this mechanism isn't exact bc omeprazole acts in the stomach. C diff most at risk in average patient of 60 years old but even higher risk factor if you're 75 versus 65. Severe bc WBC above 15,000. Serum Cr is 1.5 times baseline which also categorizes him as severe.

Treatment by Severity of Initial Occurrence

ACG versus IDSA/SHEA guidelines Non-Severe Disease ACG- Vancomycin 125mg PO QID x 10 days Alternatives: Fidaxomicin 200mg PO BID x 10 days Metronidazole 500mg PO TID x 10 days IDSA/SHEA- Fidaxomicin 200mg PO BID X 10 days Alternatives: Vancomycin 125mg PO QID X 10 days Metronidazole 500mg PO TID x 10 days Severe disease ACG- Vancomycin 125mg PO QID x 10 days Alternative: Fidaxomicin 200mg PO BID x 10 days Surgery may be indicated IDSA/SHEA- Fidaxomicin 200mg PO BID x 10 days Alternative: Vancomycin 125mg PO QID x 10 days Severe/complicated disease (Note, ONLY place you see combination tx recommended): ACG- Vancomycin 125 (up to 500mg) PO QID x 10 days + Metronidazole 500mg IV Q8h ± Vancomycin 500mg in 500ml PR QID Surgery may be indicated IDSA/SHEA- Vancomycin 125 (up to 500mg) PO QID x 10 days + Metronidazole 500mg IV Q8h ± Vancomycin 500mg in 500ml PR QID Surgery may be indicated · Need to know dose for oral vanc- 125 mg po QID but you will see some people use 250 or 500. The concentrations you get 125 are 50-100x the MIC of C diff so going above that doesn't manage any better. No reason to go up on the vanc dose and we will give 1 exception to that. Fidaxomicin is recommended by the IDsa and dosing is the same for every patient and is a twice daily drug. Duration of therapy is 10 days. o The clinical cure between the two drugs (vanc and fidaxomicin) are the same. o Recurrence rates are lower with fidaxomicin than with vanc o Financial toxicity is much greater with fidaxomicin than vanc (costs a lot lol it's about $1200 while vanc is in the low $100 range) if patient is high risk enough, try fidaxomicin. If not, can do vanc. Meds to bed where every c diff patient gets their meds before they leave bc a lot of pharmacies need PA's or don't stock fidaxomicin. o Fidaxomicin doesn't seem to destroy the other gut bugs as much as oral vanc does. Seems microbiome can heal quicker when on oral fidaxomicin than on oral vanc o Fidaxomicin doesn't have data for critically ill so don't use in critically ill · Severe/complicated patients get the oral treatment plus IV. Using combo therapy outside of severe ICU cases does not do anything other than increase side effects and cost. Does not decrease recurrence or improve clinical cure. We use 2 different routes based on concern that what if oral vanc doesn't make it to the colon very quickly? Use 2 different routes to hope at least 1 drug will make it to the colon fast enough. Most complicated patients have an ileus.

Cushing's Syndrome - Etiology

ACTH-Dependent Cushing's Syndrome Pituitary gland is over-producing ACTH Pituitary adenoma (Cushing's Disease) Tumor located outside the pituitary secreting ACTH "Ectopic" ACTH secretion from lung, pancreas, or thyroid Overproduction of ACTH leads to increased cortisol ACTH-Independent Cushing's Syndrome Adrenal adenoma Adrenal carcinoma Tumor stimulates adrenal cortex to increase cortisol Iatrogenic Cushing's Syndrome Excessive pharmacologic glucocorticoid supplementation Intravenous glucocorticoids Methylprednisolone Hydrocortisone Oral glucocorticoids Prednisolone Prednisone Hydrocortisone Dexamethasone Infrequently: Inhaled, Intranasal, Intra-articular, and Topical Glucocorticoids · ACTH dependent and independent. The pituitary is where ACTH comes from so unfortunately some people can develop tumors in the pituitary which leads to overproductions of ACTH and lead to a hypercortisol state. Some tumors can secrete ACTH as its product which acts on the adrenals to cause production of cortisol in excess quantities. Adrenal themselves can overproduce it which can get tumors in the adrenal glands which can stimulate excess cortisol production. · IV glucocorticoid therapy has bigger problems than oral and rarely even our less systemically administered dosage forms like any sort of inhalation of corticosteroids. Also drug interactions can cause increased levels. Strong inhibitors of 3A4 can lead to increased levels of even topical formulations

ALLERGEN IMMUNOTHERAPY - AIT (DESENSITIZATION) side effects and Ci

ADMINISTRATION: SC, usually in two phases: 1) Induction phase - weekly doses; beginning dose is very low, then increased gradually to maintenance dose. 2) Maintenance phase - dose every 3-4 weeks, usually for 3-5 years. PREPARATIONS: single or multiple allergen extracts, standardized or nonstandardized SIDE EFFECTS: injection site reactions, systemic reactions from mild rhinitis to severe reactions such as anaphylactic shock (within 30 minutes) and cardiopulmonary arrest. CI: severe or uncontrolled asthma; concomitant use of β-adrenergic antagonists · Can't use AIT for those with extremely severe asthma bc it could be detrimental. Also can't give to those on beta blockers bc they might not respond well. Either need to be off the beta blocker or just don't do it

Hypoaldosteronism - Etiology & Treatment

Etiology Consequence of Addison's Disease Consequence of adrenal tumor removal Zona glomerulosa damage Treatment Mineralocorticoid supplementation Fludrocortisone 0.1-0.3 mg daily

Areas of Research & Development for CDI

•Oral beta-lactamases •Vaccine

Adrenal Hormones

Adrenal Cortex Hormones: Mineralocorticoids Aldosterone Glucocorticoids Cortisol Androgens Testosterone Estradiol Adrenal Medulla Hormones: Catecholamines Epinephrine Norepinephrine The adrenal glands are located above the kidneys and produce quite a few hormones

Pharmacokinetics of CSs

Absorption -orally effective (also available as IV, topical) Distribution -over 90% bind to plasma proteins (CBG and albumin) Metabolism: ▪Reduction of the 4-5 double bond. ▪Reduction of the 3-ketone to 3-hydroxyl derivative, forming THC in the liver. ▪A-ring reduced steroids are conjugated through the 3-hydroxyl group with sulfate or glucuronide in the liver and some in the kidney. ▪Synthetic steroids with an 11-keto group (cortisone and prednisone), must be enzymatically reduced in the liver to 11β-hydroxy derivative to be active. ▪In hepatic failure steroids that do not require enzymatic activation (e.g., hydrocortisone or prednisolone) should be used. Excretion- sulfate and glucuronides esters are excreted in urine. · Hydrocortisone is basically cortisol and shows both gluco and mineral corticosteroid effects. Prednisone needs to be metabolized prednisolone while prednisolone is the active form. If there is some impairment we need to activate prednisone to prednisolone. If patient has liver impairment they basically can't impair it. Methylprednisolone and beyond are the stronger ones. No mineralcorticoid effect in betamethasone or dexamethasone. They reduce immune system and increase WBC and risk of side effects like insomnia, peptic ulcer.

Primary Adrenal Insufficiency- Etiology & Clinical Signs

Addison's Disease Autoimmune destruction of adrenal cortex Tuberculosis Other Clinical Signs Low cortisol, aldosterone, androgen levels High levels of CRH and ACTH · Addison's disease is like the type 1 diabetes of the adrenal. The whole adrenal cortex is shut down. Tuberculosis can also damage the adrenals.

Adrenal Hypofunction - Clinical Presentation

Addison's Disease: Fatigue & malaise N/V/D/Anorexia Dehydration Weight loss Hypoglycemia Hyponatremia Hypotension Hyperpigmentation on skin exposed to friction Hyperkalemia HPA Axis suppression: Fatigue & malaise N/V/D/Anorexia Dehydration Weight loss Hypoglycemia Hyponatremia Hypotension or normotension No hyperpigmentation Eukalemia Have loss of production of both cortisol and aldosterone. Can have more of an issue with regard to hypotension although hypotension can occur as secondary adrenal insufficiency but we see a lot of electrolyte abnormalities. Looking at clinical profiles

comparison of duodenal, oral vanc, and vanc + bowel lavage

Age Duodenal FMT (n=16): 73 ± 13 Oral Vancomycin (n=13): 66 ± 14 Vancomycin + Bowel Lavage (n=13): 69 ± 16 Median CDI recurrences Duodenal FMT (n=16):3 (1-5) Oral Vancomycin (n=13): 3 (1-4) Vancomycin + Bowel Lavage (n=13): 2 (1-9) Previous vancomycin taper Duodenal FMT (n=16): 10 (62%) Oral Vancomycin (n=13): 8 (62%) Vancomycin + Bowel Lavage (n=13): 6 (46%) PPI use Duodenal FMT (n=16): 13 (81%) Oral Vancomycin (n=13): 10 (77%) Vancomycin + Bowel Lavage (n=13): 11 (85%) BI/NAP1 027 strain Duodenal FMT (n=16): 3 (23%) Oral Vancomycin (n=13): 1 (11%) Vancomycin + Bowel Lavage (n=13): 0

ATLAS score

Age, Treatment with antibiotics, Leukocytes, Albumin, Serum creatinine Age 0 points: < 60 years 1 point: 60 - 79 years 2 points: > 79 years Concurrent systemic antibiotics (>1 day) 0 points: No 1 point: --- 2 points: Yes WBC count 0 points: < 16,000 1 point: 16,000-25,000 2 points: > 25,000 Albumin 0 points: > 3.5g/dL 1 point: 2.6 - 3.6 g/dL 2 points: < 2.6 g/dL Serum creatinine 0 points: < 120 mmol/L 1 point: 121-179 mmol/L 2 points: > 180 mmol/L •Jacobson, et al. investigated ATLAS score to predict cure and recurrence in 245 patients receiving metronidazole, vancomycin or both. •48% of patients had severe disease; 71% taking concomitant antibiotics •**Significant negative correlation between ATLAS score & cure rates but not recurrence. •A median ATLAS score of 2 was associated with a cure rate of 88.2%. •Miller, et al. found that cure rates decreased to < 80% with ATLAS scores of > 4. ATLAs score isn't great bc you would have to score every single day so they aren't useful. But it gives you a rating scale for how aggressive you should be

Laboratory Evaluation: Aminotransferases

Aspartate aminotransferase (AST) Also known as serum glutamic-oxaloacetic transaminase (SGOT) Alanine aminotransferase (ALT) Also known as serum glutamic-pyruvic transaminase (SGPT) ¡Enzymes highly concentrated in liver; levels in serum become elevated in acute and chronic liver disease ¡Highest elevations in acute viral, ischemic, or toxic (including drug) injury (example: >/= 10 times upper limit of normal) ¡Chronic disease and cirrhosis usually present with less severe elevations or even normal levels · Do tests of aminotransferases to see why the person is tired. ALT is more specific for the liver. They are highly concentrated there and can be elevated in acute and chronic liver disease.

Which of the following are proper infection control measures for patients with CDI? A.Strict use of alcohol based hand sanitizer on room entry and exit B.Patient isolation in single room with bathroom C.Use of rectal thermometer only with proper sanitization D.Cleaning of room post-discharge with 1:10 bleach solution

B and D · C diff need physical hand washing bc alcohol sanitizer only moves spores around. Terminal cleaning of room for those going into procedure while getting procedure

COUGH SUPPRESSANTS (ANTITUSSIVES) Benzonatate (Tessalon Perles®)

Benzonatate (Tessalon Perles®) • A local anesthetic that acts peripherally by anesthetizing the receptors located in the respiratory passages, lungs, and pleura to reduce the cough reflex. Side effects • Dizziness • Dysphagia • Severe allergic reactions have been reported in patients allergic to para-aminobenzoic acid (PABA), a metabolite of benzonatate · Benzonatate is a local anesthetic but neverrrrr chew on it because the whole mouth will go numb. Has to be swallowed. If anyone is allergic to PABA be careful because this is in the structure.

Hyperaldosteronism - Etiology & Treatment

Bilateral adrenal hyperplasia (BAH) Aldosterone receptor antagonists Spironolactone Eplerenone Potassium-sparing diuretics Amiloride Aldosterone-producing adenoma (APA) Surgical removal of adenoma Glucocorticoid remediable aldosteronism (GRA) Low-dose glucocorticoids Dexamethasone 0.5 mg daily Prednisone 2.5-5 mg daily · Adrenals themselves can develop hyperplasia and lead to excess aldosterone production. Spironolactone can cause gynecomastia and if it does switch to eplernone. More palliative than curative. (treatin symptoms rather than getting rid of underlying problems). Solution is to get the tumor out. Genetic disorder can lead to enzyme becoming sensitive to ACTH. Any exposures to ACTH c auses aldosterone levels to go up so the main way to treat is to supplement with glucocorticoids to push ACTH levels down.

Definitions of CDI

CDI case *CDAD = C. difficile associated diarrhea: patient w/ symptoms of diarrhea or toxic megacolon confirmed by positive assay or histopathologic/ endoscopic evidence of colitis Recurrent disease: repeat episodes within 8 weeks, provided previous symptoms resolved Relapse: Return of symptoms <2 weeks after initial presentation

Pathways of corticosteroid biosynthesis

CYP11A1: cholesterol side-chain cleavage enzyme 3β-HSD: 3β-hydroxysteroid dehydrogenase CYP17: steroid 17α-hydroxylase CYP21: steroid 21-hydroxylase CYP11B2: aldosterone synthase CYP11B1: steroid 11β-hydroxylase · Pay attention to the numbers on each carbon because the enzymes have names that relate to the site where they will put the enzymes on it. Cholesterol has 27 carbons so as it loses side chain, it changes to a 21 carbon structure which are the precursors for androgen. · Have CYP11A1 which is cholesterol side chain cleavage enzyme and produces pregnenalone. Everything starts with cholesterol and then we have a path that ends up with androgens. End up with main focus of cortisol and see 3 hydroxyl groups with one on 11, one on 17, and one on 21. Then there is a ketone group. The enzymes involved include CYP17 and a 17 hydroxylase. Takes care of changing the position 3 from hhydroxy to ketone. That 17 hydroxyl is placed by the mediation of CYP17. CYP21 places the hydroxy group on carbon 21. We have mineralocorticoid which needs hydroxylase in 21 and in 11 and nothing on 17. An aldehyde group in aldosterone and happens in presence of CYP11B2 which is aka aldosterone synthase which only exists in glomerulosa layer and leads to production of aldosterone. Have 11 hydroxylation in presence and also have 18 carbon hydroxylation which later hydroxylizes to aldehyde group.

Cushing's Syndrome Clinical Presentation

Central weight gain Facial rounding Hirsutism Hump on upper back Severe fatigue Muscle weakness Bone fractures High blood pressure Anxiety, Irritability, Depression Infections Diabetes Decreased concentration and memory · Facial rounding aka moon face, severe fatigue, muscle weakness, bone fractures bc of osteoporotic.

Cushing's Syndrome Treatment Algorithm

Combination Therapy: • Adrenal Enzyme Inhibitors • Ketoconazole 200 mg TID ↓ • Titrate Ketoconazole to 400 mg TID ↓ • Add Metyropone 250 mg TID ↓ • Increase Metyropone to 4 grams/day ↓ • Consider Mitotane

Adrenal Hypofunction - Diagnosis

Corticotropin (cosyntropin) stimulation ("stim") test Administration of synthetic ACTH (cosyntropin) Assessment of adrenal cortisol production response General procedure Check morning serum cortisol Administration of 1 mcg or 250 mcg cosyntropin Check cortisol level 30-60 minutes later Interpretation & diagnosis of AI Post-cosyntropin cortisol <18 mcg/dL Post- vs. Pre- cosyntropin change (∆) in cortisol <9 mcg/dL · Can try to give patient ACTH to see if that can increase cortisol production.

Adrenal Insufficiency (AI)

Definition: Decreased glucocorticoid (cortisol) production presenting as acute deterioration in health status Associated with absolute hypotension (systolic blood pressure <100 mm Hg) or relative hypotension (systolic blood pressure ≥20 mm Hg lower than usual) Marked resolution of hypotension within 1 hour after parenteral glucocorticoid administration and improvement in clinical symptoms over a period of 2 hours AI may be chronic or acute Acute adrenal crisis is a medical emergency Hypotension, shock and death can result Most common etiologies: Primary AI: Addison's disease Secondary AI: abrupt glucocorticoid discontinuation (HPA axis suppression) Other etiologies: septic shock, acute respiratory distress syndrome (ARDS) · Adrenal insufficiency where adrenals are not producing enough cortisol and is dangerous if BP starts to thaw. Can see BP starting to run 20 mmHg lower or more than is usual for a patient. Can confirm adrenal insufficiency by giving steroids and seeing if we have a compensatory resolution in response to corticosteroid therapy. Can become a medical emergency and some can walk around with low or mild adrenal insufficiency. Primary adrenal insufficiency is an assault on the adrenals that causes them to stop functioning. Can also precipitate adrenal crisis when HPA axis has essentially shut down endogenous natural production of cortisol. Putting patients through stressful situations can also lead to profound and life threatening adrenal insufficiency.

ANTI-IgE THERAPY

Effects of IgE: • IgE plays a central role in allergic asthma • Activates high-affinity receptors (FcεRI) on mast cells, increasing release of histamine and other mediators. • Activates low-affinity receptors (FcεRII, CD23) on other inflammatory cells causing chronic inflammation. Anti IgE therapy where T helper T cells release IL4 and IL13 and they have receptors on the B lymphocytes where IgE is produced and can have a fast response and a slow response. The fast response is going to be on the mast cells where they sit on the receptors. There are inflammatory mediators that sit on the B cells. Knowing this, IgE is a great target and if we stop it here then we won't have those responses

Normal Physiologic Adrenal "Stress Response"

Elevated levels of circulating inflammatory cytokines Increase in CRH and ACTH secretion Physiologic production of cortisol under stress 200-350 mg/day of endogenous cortisol Equivalent to 200-350 mg/day exogenous hydrocortisone Normally, serum cortisol is 90% bound to corticosteroid binding globulin, which facilitates its entry into the tissues by way of glucocorticoid receptors, where it downregulates cytokine production · Extreme physiologic stress can cause adrenal insufficnecy is bc cortisol is our stress hormone so when we gegt into a stressed situation it churns out 10 times the normal cortisol. Equibrilates to about 200 mg we need to supplement a patient with to mimic this response. If a patient has high levels of circulating cytokines then we see increase of certain levels. Cortisol is normally 90% bound ot cortisol binding globulin where out of the cells it can have its effects to slow down inflammation and cytokine production. Gonna have higher cortisol levels throughout the bloodstream. At the same time we are not having the functional benefit we normally get

Secondary Adrenal Insufficiency - Etiology & Clinical Signs

Etiology Hypothalamic Pituitary Adrenal (HPA) axis suppression Abrupt withdrawal of glucocorticoid supplementation Abrupt withdrawal of progestins (medroxyprogesterone acetate, megestrol acetate) Acute Stress: critical illness, infection, or trauma Pharmacologic agents Mirtazapine Ketoconazole Phenytoin Rifampin Clinical signs of secondary adrenal insufficiency (AI) Decreased ACTH, cortisol, and androgen levels Normal aldosterone levels · When we abruptly withdraw supplementation, that is primary adrenal. Secondary occurs when we abruptly withdraw corticostraoid therapy and negative feedback loop ahs been going but shuts production of axis from producing endogenous cortisol

Secondary Adrenal Insufficiency - Etiology

Etiology Hypothalamic Pituitary Adrenal (HPA) axis suppression Critical illness, infection, or trauma Pharmacologic agents Mirtazapine Ketoconazole Phenytoin Rifampin Etiology: Pharmacologic agents → secondary AI Mirtazapine Ketoconazole Rifampin Phenytoin, phenobarbital Treatment: if possible, discontinue offending agent Recommend alternative therapy · Try to remove the offending agent and offer alternative therapy.

adrenal insufficiency

Etiology: Primary adrenal insufficiency (Addison's disease) ◦ Adrenal cortex is destroyed (autoimmune; TB) ◦ Medications causing primary adrenal insufficiency: ➢ Inhibitors of cortisol synthesis (ketoconazole) ➢ Accelerators of cortisol metabolism (phenytoin, rifampin, phenobarbital) Secondary adrenal insufficiency ◦ Decreased ACTH secretion ◦ Mineralocorticoid levels are normal since the RAAS controls the zona glomerulosa not ACTH. ◦ Medications causing secondary adrenal insufficiency: ➢ Exogenous administration of GCs (major cause) ➢ Mirtazapine and progestins (medroxyprogesterone acetate and megestrol acetate) Tertiary adrenal insufficiency o Caused by hypothalamic disorders disrupting CRH secretion · Adrenal insufficiency is hypofunction and primary is called addison's disease and the adrenal cortex is destroyed potentially to disease. Some medications may be preventing the synthesis of cortisol like ketoconazole used for a hypercortisol situation. We can have secondary is ACTH is decreased causing adrenal insufficnecy bc there are no stimulators so no production. Mineral corticoids not affect by HP axis bc that is regulated elseswhere. Secondary basically affect the HP axis and cause adrenal insufficiency bc it is not in the gland itself.

Secondary Adrenal Insufficiency - Etiology

Etiology: Critical illness, infection, or trauma Impaired adrenal "stress response" 50% decrease in corticosteroid-binding globulin leads to tissue resistance to cortisol and higher serum free [cortisol] Decreased downregulation of cytokines in the tissues → pro-inflammatory state Excess serum free [cortisol] leads to a decrease in CRH, ACTH, and cortisol production via negative feedback → Secondary Adrenal Insufficiency · Get into a proinflammatory state and can cause ACTH levels to go down through negative feedback.

Secondary Adrenal Insufficiency - Etiology& Treatment

Etiology: HPA Axis Suppression Exogenous glucocorticoid exposure requirement is not well-defined Anticipate in any patient taking for >3 weeks: > 30 mg/day hydrocortisone > 7.5 mg/day prednisone > 0.75 mg/day dexamethasone Has occurred in patients taking higher doses for ~5 days 50 mg/day prednisone Prevention/treatment: slow tapering glucocorticoids, if HPA axis suppression anticipated · Any time we continue doses for longer than 3 weeks, that is when we need to worry about it and need to taper doses until we stop. Can give for COPD exacerbation for like 5 days or so. If going longer than 3 weeks need to taper

Hyperaldosteronism

Etiology: Primary hyperaldosteronism (Conn's syndrome) ▪Usually caused by bilateral adrenal hyperplasia and aldosterone producing adenoma of the zona glomerulosa. ▪Most common cause of secondary HTN. Secondary hyperaldosteronism ▪Excessive stimulation of zona glomerulosa with high PRA (↑RAAS) due to low blood volume or low blood flow to kidney (renal artery stenosis),↑K + , ↓Na+ , cirrhosis, and HF. Symptoms: ↓K+ , ↑Na+ , weakness, HTN, tetany, polyuria, polydipsia, and alkalosis (hyperaldosteronism) · Hyperaldosteronism if primary is Conn's syndrome and could be due to some sort of hyperplasia or tumor in zona glomerulosa and can cause secondary hypertension. Increased renin, maybe hyponatremia or hyperkalemia etc. when sense by the RAAs system that sodium is low or aldosterone is high, it increases sodium to get it back to normal. So RAAS system is really controlled with this. We see hypertension, tetany bc of potassium, weakness, and some alkalosis potentially. Lose acid which will lead to metabolic alkalosis happening.

ICS preparations Fluticasones and mometasone

Fluticasone propionate (Flovent HFA®-aerosol, Flovent Diskus®-powder, ArmonAir RespiClick®- aerosol powder) ➢↑ First pass metabolism (↓SE) (t1/2=8 hrs) Fluticasone Furoate (Arnuity Ellipta®-aerosol powder) ➢Has a higher binding affinity for the lung GR than propionate ester. ➢Has the longest duration of action (t1/2=24 hrs) Mometasone furoate (Asmanex®-aerosol HFA, aerosol powder) · Flovent is very commonly used and comes in different formulations such as capsules or inhalers. High first pass metabolism here and length of effect is different here. Longer action for fluticasone furoate. Arnuity ellipta is a powder with a long binding affinity and is more selective to the receptor.

Adrenal hyper-function

Excess GC secretion: Cushing's syndrome ◦ ACTH-dependent: ◦ Cushing's disease: pituitary adenoma ◦ Ectopic ACTH-producing tumor ◦ Ectopic CRH-producing tumor ◦ ACTH-independent: ◦ Adrenal-secreting tumor Excess MC secretion ◦ Conn's syndrome Excess androgen secretion: ◦ Masculinization · In adrenal hyperfunction we have excess glucocorticoid secretion so we have increased cortisol. 2 different types like ACTH dependent and ACTH independent. Cortisol works under the influence of ACTH. If we don't ehave enough ACTH we expect low cortisol. That is why it is ACTH dependent. Cushing's disease is where we have a tumor in our pituitary gland and tumor cells will produce too much ACTH. With the ACTH we have increased tumor production. A tumor in the anterior pituitary causes lots of ACTH. Cushing's syndrome is overproduction of cortisol. Also see ectopic ACTH producing tumor which means the tumor producing ACTH is not in the anterior pituritary which is somewhere other than the adrenal. Or it could be ectopic CRH producing tumor. Most likely they have to remove the tumor and is an ACTH independent tumor. Excess MC secretion is when we have too much aldosterone.

Fidaxomicin Cost Effectiveness

Extend Trial 364 patients, Age > 60 years, 86 European hospitals Extended-pulsed fidaxomicin (200 mg PO BID D1-5, then QD alternate days on D 7-25) vs vancomycin 125 mg PO capsules, QID D1-10 Clinical cure 30 days after end of treatment Fidaxomicin acquisition costs are > than those of vancomycin Reduced recurrence rate with extended-pulsed fidaxomicin makes more effective and less costly treatment than vancomycin for 1st line tx of CDI in older patients Cost-Effectiveness Analysis Evaluating Fidaxomicin vs Oral Vancomycin for the Treatment of Clostridium difficile Infection in the United States 629 patients, Age > 16 years, 52 sites in US and 15 sites in Canada Fidaxomicin 200 mg PO Q12H vs vancomycin125mg PO Q6 Incremental cost/quality-adjusted life-years (QALYs) from the payer perspective While acquisition costs are greater, fidaxomicin is a cost-effective alternative for the treatment of CDIs under most scenarios examined

Adrenal Hypofunction Disorders

Glucocorticoid Disorders: Inadequate cortisol Primary Addison's disease Secondary HPA axis suppression Mineralocorticoid Disorders: Inadequate aldosterone Hypoaldosteronism · Can also see too little of adrenal function which can cause problems as well including addison's disease and can also precipitate HPA axis suppression and patients who underproduce aldosterone

Rates of cure without relapse at 10 weeks

FMT-related ADE: Belching: (3/16), 19% 81.3% for first infusion of donor feces 30.8% with vanc 23.1% with vanc with bowel lavage

FUTURE DEVELOPMENTs and resistance

FUTURE DEVELOPMENTS: To dissociate the DNA-binding effect of CS (mediates adverse effects) from the inhibitory effect on transcription factors such as NF-κB (mediates anti-inflammatory effect). CORTICOSTEROID RESISTANCE: • Patients with severe asthma • Smokers • Patients with COPD and cystic fibrosis ➢Resistance might be due to a reduction in HDAC2 expression Scientists are working to reduce those effects and lead to agents that are anti-inflammatory. Patients with severe asthma and smokers might not respond, COPD and CF may not respond, and some resistance might be due to either reduction of HDAC2 or maybe just not responding

Treatment by Recurrence of Infection

First recurrence: •Tapering or pulsed-dose vancomycin for patients after an initial course of fidaxomicin, vancomycin, or metronidazole •Fidaxomicin after an initial course of vancomycin or metronidazole Second or further recurrence: •FMT - can be delivered via colonoscopy, capsules, or enema •Can repeat FMT for patients experiencing a recurrence of CDI within 8 weeks of an initial FMT · 20-25% of patients have recurrence. Treating c diff while also on another antibiotic makes it very challenging. Some will get them stuck in a cycle and are on oral vanc for a long time and a lot of those patients will require a fecal transplat and are highly effective. Can either be capsules or a slurry that can be given during colonoscopy or slurry for tube down stomach. Can retry what we already have.

LEUKOTRIENE RECEPTOR ANTAGONISTS (LTRAS) Genetic considerations:

Genetic considerations: • Polymorphism of the gene's promoter (ALOX5) can affect the patient's response to LTRAs treatment. • Patients with at least one wild-type allele (5/5 or 5/4) respond better to LTRA treatment. • Gene study can identify those who respond to montelukast. Uses: Prophylaxis of asthma and seasonal allergic rhinitis. • Montelukast is safely used in children as young as 6 months old. Zafirlukast in patients ≥5 years of age. • The cys-LT1 receptor antagonists have NO ROLE in the therapy of COPD. · Also some genetic considerations such as some patients may be better responders. Singulair is safe for ages as young as 6 months. These have no role in COPD

inadequate cortisol

Glucocorticoid Disorders Inadequate cortisol Primary Addison's disease Secondary HPA axis suppression

Adrenal Hyperfunction Disorders

Glucocorticoid Disorders: Excess cortisol Cushing's Syndrome ACTH-dependent ACTH-independent Iatrogenic Mineralocorticoid Disorders: Excess aldosterone Primary aldosteronism Bilateral Adrenal Hyperplasia (BAH) Aldosterone-Producing Adenoma (APA) Glucocorticoid Remediable Aldosteronism (GRA) Secondary aldosteronism · Some patients can develop excess cortisol syndromes like ACTH dependent and independent and iatrogenics. Can also overproduce aldosterone.

excess cortisol

Glucocorticoid Disorders: Excess cortisol Cushing's Syndrome ACTH-dependent ACTH-independent Iatrogenic

Addison's Disease - Chronic Treatment

Glucocorticoid supplementation "Physiologic" dosing in AM or BID to mimic diurnal cortisol secretion 2/3 dose in AM and 1/3 dose in PM Hydrocortisone 20 mg 1 2 8-12 hrs Prednisone/Prednisolone 5 mg 4 1 18-36 hrs Methylprednisone 4 mg 5 0 18-36 hrs Dexamethasone 0.75 - 1 mg 20-30 0 36-64 hrs Mineralocorticoid supplementation Fludrocortisone 0.05-0.2 mg daily · For addison's we have little to no function of the adrenals and need to supplement both glucocorticoid therapy and mineralocorticoid therapy. A physiologic dose for treatment of addison's disease would be these. Want to dose 2/3 in the morning and 2/3 at night. Fludrocortisone is our aldosterone analog we can supplement with

Prevention of Chronic Glucocorticoid-Related Sequelae Glucocorticoid-related osteoporosis

Glucocorticoid-related osteoporosis Risk factors Low body mass index Parental history of hip fracture Current smoking ≥3 alcoholic drinks per day Higher daily glucocorticoid dose Higher cumulative glucocorticoid dose Intravenous pulse glucocorticoid usage Declining central bone mineral density measurement Onset within 1st 3 months of therapy Maximum effect on bone mineral density after 6 months · Most people can get away with not needing bisphosphonates but depends onn how at risk the patient is and how their bone loss plays out. Opportunistic infection prevention prophylaxis with low doses of antiviral and antibacterial agents t prevent events from happening. Unless you have another reason to be on opportunistic infection prophylaxis, you don't have to use it for certain use.

Glucocorticoid-related osteoporosis prevention

Glucocorticoid-related osteoporosis prevention Supraphysiologic doses >3 months: Calcium 1,200 -1,500 mg daily Vitamin D 800-1,000 IU daily Chronic glucocorticoid therapy Risk stratification: low, medium, and high Risk depends on dose, duration of steroids Therapy: alendronate, risedronate, zoledronic acid, teriparatide Opportunistic infection prevention Highest risk populations: chemotherapy and organ transplant Prophylactic antibiotics and/or antiviral therapy

Other Indications for Glucocorticoid Therapy

Head/CNS Brain or spinal cord tumor- related edema Exacerbations of multiple sclerosis Dental inflammation Heart/Lungs Pericarditis Asthma COPD exacerbations Gastrointestinal Ulcerative colitis Crohn's disease Joints Rheumatoid arthritis Refractory osteoarthritis Gout flares General Inflammatory processes Others... · Patients with brain or spinal cord injuries to reduce inflammation, dental applications, COPD exacerbations, lots of GI uses for corticosteroids especially the more inflammatory. Also in the world of arthritis and gout and everything

Antibiotics as Risk Factors

High Risk: l Clindamycin* l 2nd & 3rd Generation Cephalosporins lFluoroquinolones l Carbapenems lPenicillins (+BLI) Low(er) Risk: l Tetracyclines l Vancomycin l Metronidazole l Linezolid l Nitrofurantoin l SMX/TMP (maybe ↑) •*Historically - clindamycin greatest association with CDAD • Overall use has decreased over last 20-30 years (relation?) · Need to understand high versus low risk antibiotics. Clindamycin is historically the biggest antibiotic risk factor for c diff. clindamycin acts on gram negatve anaerobes which make up most of the gut so it wipes out the normal gut flora but doesn't cover c diff so it leads to c diff. don't need a lot of clinda to get C diff. penicillin with beta lactamase inhibitor like zosyn, augmentin, etc. if patient is at risk for c diff do lower risk. The lower risk drugs actually can be used to treat c diff. nitrofurantoin is low risk bc it only concentrates in the urine so it doesn't kill the gut. Drugs that don't really kill the gut are lower risk · *high risk factor will be previously of whatever (ex: previous c diff infection for c diff, previous endocarditis infection for endocarditis, etc)*

Commonly Used GC & MC Agents Generic (brand): GC: MC: Duration of action:

Hydrocortisone or cortisol (Cortef)-IV/PO/Top 1 2 S Cortisone (Cortone)-PO 0.8 2 S Prednisone (Deltasone)-PO 3.5 1 I Prednisolone (Orapred)-PO 4 1 I Methylprednisolone (Medrol)-IV/IM 5 0 I Triamcinolone (Kenalog)-IM/Top 5 0 I Fludrocortisone (Florinef)-PO 10 125 I Betamethasone (Celestone)-IM/Top 25 0 L Dexamethasone (Decadron)-IV/IM/Top 30 0 L

Aldosterone Deficiency (Hypoaldosteronism)

Hyporeninemic hypoaldosteronism: ◦ Patients with renal disease. ◦ Volume expansion ◦ Exogenous MCs Pseudohypoaldosteronism ◦ Resistance to the action of aldosterone. Symptoms: ↑K + , ↓Na+ , ↓BP, may develop metabolic acidosis. · If we always have aldosterone expansion we will have hypoaldosteronism. Low aldosterone leads to low blood pressure

Normal Adrenal Physiology

Hypothalamus ----CRH---> Anterior Pituitary ----ACTH---> Adrenal Cortex ----Cortisol ---->(Androgens) CRH = Corticotropin Releasing Hormone ACTH = Adrenocorticotropic Hormone · Bc pharmacotherapy ties in with physiology, essentially when our body sense it needs to make some cortisol it has a loop triggered by the hypothalamic pituitary adrenal axis. It is going to the brain. Hormones that signal the adrenals are gonna be happening in the brain. Anterior pituitary responds to CRH by producing ACTH which tells adrenal cortex to make some cortisol. Once we have enough cortisol on board then the negative feedback slows production for awhile. Then the adrenal production of cortisol goes down.

COMBINATION PREPARATIONS (INHALED)

ICS/LABA ▪ Fluticasone propionate/salmeterol (Advair®) -for COPD/asthma ▪ Budesonide/formoterol (Symbicort®)-for COPD/asthma ▪ Mometasone/formoterol (Dulera®)- for asthma ICS/ultra-LABA ▪ Fluticasone furoate/vilanterol (Breo Ellipta®)-for COPD/asthma ICS/LAMA/LABA: used for patients with severe asthma or asthma-COPD overlap. ▪ Fluticasone furoate/umeclidinium/vilanterol (Trelegy Ellipta®): First FDA approved triple combination inhaler used for COPD with once daily dosing. · Some combo products like ICS laba and should be able to easily identify what are the ingredients here. Salmeterol is a LABA. Some have indications for both COPD and asthma but we cannt use LABA alone in asthma. ICS/ultra-LABA likely given once a day due to the ultra LABA. Trelegy elliptra has all 3

ANTI-IL-5 THERAPY

IL-5 • Secreted by TH-2 cells . • Responsible for the growth, differentiation, recruitment, activation, and survival of eosinophils. Anti-IL-5 and anti-IL-5 receptor (IL-5Rα) antibodies • Inhibit eosinophilic inflammation and airway hyper-responsiveness in patients with asthma. · IL5 is secreted by mast, ILC2, and Th2 cells and then goes to sit on its receptor on eosinophils and such. It is an inflammatory mediator. Can act on this through agents that bind to IL5 or agents that bind its receptor. Can prevent eosinophilic inflammation

interstitial lung disease and idiopathic pulmonary fibrosis

ILD and pulmonary fibrosis are general terms to described inflammatory and fibrotic disorders of lung tissue (interstitium). there are over 100 known causes of interstitial lung disease and pulmonary fibrosis, which include familial and genetic disorders, inhaled substances, infections, meds, and connective tissue diseases. bc ILD result in a stiff and noncompliant lung, they are commonly classified as fibrotic or restrictive lung disorders idiopathic pulmonary fibrosis (IPF) is an ILD characterized by chronic inflammation, accompanied by an uncontrolled healing response that causes progressive scarring or thickening (fibrosis) of tissues between the lung's alveoli. the cause of IPF is unknown, although the body's own immune response seems to play a major role. recent data suggest approximately 28 cases per 100,000 population. the usual age at diagnosis is between 40 and 70, but often there is X-ray evidence of disease two to five years before the diagnosis is made. the disease affects more men than women · A final result of ILD is a stiff lung. Uncontrolled helium response that causes thickening. Collagen can be used to fix some injury, reason can exist and be chronic in nature. Evidence for this disease can start a few years before dialysis and more affects men than women.

IPF diagnosis and treatment

ILD/IPF diagnostics: -it has become significantly more accurate as a result of thoracoscopy, a minimal access procedure that uses small incisions and video endoscopic instruments to view the chest IPF treatment (symptomatic and to reduce progression): -to reduce inflammation, scarring, and thickening of tissue (corticosteroids and cytotoxics) -new FDA approved drugs to treat pulmonary fibrosis are available (pirfenidone, nintedanib) -lung transplantation has been successful as a treatment of last resort

Iatrogenic Cushing's Syndrome treatment

If possible, discontinue causative agent and substitute alternate therapy Slowly taper glucocorticoid therapy Goal: prevention of hypothalamic Pituitary Adrenal Axis (HPA) suppression with glucocorticoid withdrawal · Iatrogenic cushing's we want to stop the causative agent and figure out how to substitute something else. Don't abruptly stop corticosteroid therapy. Gotta taper the doses so slowly taper off unnecessary therapy and try to allow HPA axis time to recover and resume normal endogenous function before we pull of exogenous or therapeutic corticosteroids.

PREPARATIONS ICS

Inhalational agents (ICS): Introduced to reduce the side effects of oral steroids. Beclomethasone dipropionate-BDP (QVAR RediHaler®-aerosol): Prodrug Budesonide (Pulmicort®-aerosol suspension, Pulmicort Flexhaler®-aerosol powder): ↑ First pass metabolism (↓SE) Ciclesonide (Alvesco®-aerosol): Prodrug ➢Prodrugs are activated in the lung by esterases. Some dosage forms are inhalational and we want it to go straight to the site of action and don't want it to be absorbed systemically and have other side effects. Most of these agents are inhalational. Beclomethasone and ciclesonide need to be activated to active form by esterases. With budesonide we have increased first pass metabolism which is a good thing bc if it gets absorbed systemically, we want it to be metabolized or deactivated so we don't see the side effects of it.

Steroidogenesis Inhibitors ketoconazole

Ketoconazole LFTs should be monitored at baseline, every 1-2 weeks initially, and then monthly FDA safety alert 07/2013 recommends using only when the potential benefits outweigh the risks because of the risk of hepatotoxicity, certain arrhythmias (e.x. QT prolongation), , and adrenal insufficiency Screen for concomitant PPI therapy, which can greatly decrease ketoconazole bioavailability An acidic environment is required for conversion to absorbable soluble salt · The order is a litte different for a male patient bc ketoconazole can reduce testosterone. So instead of starting with ketoconazole for males we can try metyrapone first. Vice versa happens for women so metyrapone is not first line. Goal is to get patients on both of these as they work synergistically. Follow urine free cortisol levels to evaluate. · Do worry about hepatotoxicity so we monitor LFTs at baseline and then monthly thereafter. Use ketoconazole to slow down the adrenals and can cause adrenal insufficiency. Important to screen for concomitant PPIs bc we have to have an acidic environment available for ketoconazole to be absorbed.

Inhibitors of Steroidogenesis

Ketoconazole (Nizoral®) Levoketoconazole (Recorlev®)-New! Metyrapone (Metopirone®) Mitotane (Lysodren®) Etomidate (Amidate®) Osilodrostat (Isturisa®)-New! · Inhibitors of steroidogenesis where ketoconazole is an antifungal to prevent the synthesis of ergosterol which is necessary for cell wall synthesis. Levoketoconazole is new.

probiotic examples

Lactobacillus sp. 1-16 billion CFU (Dose may vary) Culterelle®, Flora-Q™ Saccharomyces boulardii 5 billion live cells Florastor® 250 mg BID Bifidobacterium longum, infantis, breve 1-10 billion viable cells daily Align®

THERAPEUTIC EFFECTS OF GCs

Leak is reduced, impact mucosecretion, COPD can also respond (maybe not as significant as asthma) and also help in pulmonary diseases

Iatrogenic Cushing's Syndrome

Long-term administration of "supraphysiologic" glucocorticoid dose What is physiologic? Normal 24-hour secretion of cortisol = approximately 20 mg Hydrocortisone: exogenous glucocorticoid most equipotent to cortisol "Physiologic" daily dose of hydrocortisone is 20 mg daily Hydrocortisone 20 mg Prednisone/Prednisolone 5 mg Methylprednisone 4 mg Dexamethasone 0.75 - 1 mg Drug interactions that ↓glucocorticoid clearance Potent CYP 450 3A4 inhibitors Disease states that ↓glucocorticoid clearance Hepatic disease, renal disease, increasing age Malnutrition, hypothyroidism, pregnancy Pharmacologic agents Progestins Medroxyprogesterone acetate Injectable hormonal contraceptive (DepoProvera®) Megestrol acetate Appetite stimulant used in chronic illness (HIV, Cancer) · Patients taking long term doses of glucocorticoids art supraphysiologic levels which means body normally produces 20 mg of cortisol but the pharmacologic agent like 20 mg of hydrocortisone is the same as the body's natural cortisol per day. Hydrocortisone is not the only corticosteroid though. · Strong 3A4 inhibitors put us at risk for developing iatrogenic syndrome bc of reduced clearance. There are also some disease states to reduce glucocorticoid clearance. Megestrol acetate for those having a hard time keeping on weight.

NINTEDANIB (OFEV®)- Tyrosine Kinase Inhibitor

MOA- Inhibitor of multiple receptor tyrosine kinases (RTKs): • Fibroblast growth factor receptors (FGFRs) 1,2, and 3 • Vascular endothelial growth factor receptors (VEGFRs) 1,2 and 3 • Platelet-derived growth factor receptor (PDGFR) α and β It binds competitively to the ATP binding pocket of the above receptors to block intracellular signaling necessary for proliferation, migration and transformation of fibroblasts. ➢Improves the quality of life, slows the progression of lung fibrosis and the decline of lung function, and reduces the rate of exacerbations in individuals with mild and moderate IPF. ADME: • Low oral bioavailability (first pass metabolism) • High protein binding • Substrate of P-gp and CYP3A4 (watch for drug interaction) • Fecal/biliary excretion. SIDE EFFECTS- Nausea, diarrhea, GI toxicity (including perforation), headache, hypothyroidism, decreased appetite and weight loss, elevated liver enzymes, arterial thromboembolic events (including MI), and bleeding. · Ofev will reduce or inhibit the growth factors. They all have this ATPP binding pocket and prevent fibrosis of the tissue while slowing the progress of the disease. · Ofev also has low *bioavailability and can be improved with food* and we need to check for drug interactions. 62% will develop diarrhea. Check the LFTs and another important consideration is the bleeding and thromboembolitic events. But if not taken, patients will eventually need a lung transplant.

ALLERGEN IMMUNOTHERAPY - AIT MOA

MOA: Allergen binds to a subset of dendritic cells to induce the formation of Treg cells, modulating T- and B-cell responses and inhibiting the migration of E, B, and MC to tissues and release of their mediators. Treg cells: • Secrete: IL-10 and TGF-β • Suppress Th2 cells • Regulate B cells: induction of IgG4 (IL-10 mediated) and IgA (TGF-ẞ mediated) and suppressing IgE which leads to down-regulation of allergic response. • IgG4 antibody blocks allergen-induced IgEdependent histamine released by basophils · AIT works through giving low doses of an allergen so that the immune system can become desensitized to that allergen. Induces Treg cells which secrete IL10 and TGF beta which regulate the Th2 cells which are the cells we don't want to get activated bc they produce IL4 and 13. Treg cells have inhibitory effect on this activation to reduce the amount of IgE being produced here while increasing IgG4. Gradually, the immune system will be desensitized to that allergen. Given weekly first and then gradually is less frequently injected

HUMANIZED MONOCLONAL ANTIBODIES TARGETING IL-5 Reslizumab (CINQAIR®)- IV

MOA: IL-5 antagonist (IgG4 kappa), inhibits the bioactivity of IL-5 by blocking its binding to the α chain of the IL-5 receptor complex expressed on the eosinophil cell surface. It binds to the soluble IL-5. Uses: severe asthma in adult patients who are not responding to primary therapies. Dose: 3 mg/kg IVI q 4 wks (weight based) Price: 100 mg/10 mL, $111.84 per mL ADR: Oropharyngeal pain, risk of anaphylaxis · Resolizumab is a weight based dose and is for adult patients for those not responding to primary therapies. Price is high and side effects are not too bad and with all of these biologics think of shock or hypersensitivity so expect anaphylaxis or hypersensitivity.

Osilodrostat (Isturisa®)-PO FDA approved in 2020

MOA: Inhibition of 11 ẞ-hydroxylase (CYP11B1) the enzyme responsible for the final step of cortisol biosynthesis in the adrenal gland. Indication: used in patients with Cushing Disease who are not a candidate for pituitary surgery or who have failed the surgery. Dosage forms: 1, 5, and 10 mg tablets (each 10 mg tablet is $570.00) Dosing: start with 2 mg bid with or without food (lower in hepaic impairment). Titrate by 1-2 mg twice daily every 2 weeks. Typical maintenance dose is 2-7 mg bid. If patient tolerates 10 mg bid but cortisol target is not achieved, increase by 5 mg bid every two weeks to maximum dose of 30 mg bid. ADR: adrenal insufficiency and hypocortisolism, headache, diarrhea, vomiting, nausea, fatigue, edema (fluid retention), arthralgia, QTc interval prolongation, HTN, hypokalemia (increased aldosterone precursors, might need use of MR antagonist), flu like symptoms, and androgenic effects. Monitor: Cortisol levels, serum K and Mg levels, renal and liver function tests, ECG, BP, assess for edema and adrenal insufficiency . ADME: ▪ Vd about 100 L, low protein binding ▪ Metabolized by multiple CYP enzymes (CYP3A4, CYP2B6 & CYP2D6). ▪ Excreted through urine (90%) · Osilodrostat works on cyp11B1 and is more selective working toward the last steps of cortisol synthesis and is better tolerated. Tablet with different strengths Side effects watch for qtc prolongation and hypokalemia bc of increased aldosterone and such. · Bc of risk of Qt prolongation we should monitor potassium and magnesium. · These drugs all work in different areas. Summary slide is on blackboard

LEUKOTRIENE SYNTHESIS INHIBITORS Zileuton (ZYFLO®)-PO

MOA: Inhibition of 5-lipoxygenase (5-LO) In COPD: ↑LTB4 (chemoattractant for neutrophils and eosinophils); 5-LO inhibitors could potentially be effective in COPD . Therapeutic effect: prophylaxis and chronic treatment of asthma in adults and children over the age of 12. Side effect: Hepatic dysfunction, neuropsychiatric events (sleep disorders, behavioral changes). CI: Active liver disease · Zileuton inhibits the 5-LO and can be for prophylaxis or chronic treatment of asthma for ages over 12. Technically, in COPD scientists found an increase in leukotriene D4 so in the future there may be a place for this is COPD. But right now it is just for asthma. Contraindicated in active liver disease due to its mechanism of metabolism.

CROMOLYN / NEDOCROMIL

MOA: Mast cell stabilizer, preventing histamine release. • Cromolyn sodium- long-term control of asthma; prevents exercise-induced bronchospasm (not for acute attack) • Nedocromil sodium-similar to Cromolyn • Used in children >2 years of age and adults. • Reduce symptomatic severity and the need for bronchodilator. • Poorly absorbed into the systemic circulation and have little toxicity but are not as potent or as effective as ICS. • SE: Hypersensitivity, bad taste · Mast cell stabilizer where this has low absorption in pediatrics so it has a good safety profile. leave a bad taste after use

ANTI-IL-4 THERAPY Dupilumab (DUPIXENT®)-SC

MOA: a human monoclonal IgG4 antibody that inhibits IL-4 and IL-13 signaling by binding to the IL4Rα subunit and inhibiting IL-4 and IL-13 cytokineinduced inflammatory responses. Use: • Asthma: Add-on maintenance treatment of moderate to severe asthma in ≥6 years of age (eosinophilic phenotype or corticosteroid dependent). • Atopic dermatitis (Eczema) ADVERSE EFFECTS: Ocular effects (conjunctivitis and keratitis) Dose: 400-600 mg then 200-300 mg q 2wks. Cost: Prefilled syringe: $1753.44 (200 mg/1.14 mL) $999.46 (300 mg/2 mL)!!! · Anti IL4 is another mediator for inflammation. Dupixent is an antibody that binds to the subunit which is similar in both receptors for IL4 and 13. It is a receptor blocker rather than blocking IL4 and 13 themselves. Can also be an add on treatment for moderate to severe asthma. These are all related to eosinophilic asthma. · Remember the ocular effect of dupixent with conjunctivitis and keratitis. Very pricey so you always have to check if this is covered by insurance

HUMANIZED MONOCLONAL ANTIBODIES TARGETING IL-5RΑ Benralizumab (FASENRA®)-SC

MOA: a humanized afucosylated monoclonal antibody (IgG1 kappa), binds to the α unit of IL-5 receptor(IL-5Rα) on the surface of eosinophils and basophils. This results in reduction of eosinophils and basophils through antibody-dependent cell-mediated cytotoxicity (ADCC). Dose: 30 mg SC q 4 wks x 3, then 30 mg SC q 8 wks. Use: severe eosinophilic asthma in patients aged ≥12 yrs. ➢Has oral GCS sparing effect. · shock or hypersensitivity so expect anaphylaxis or hypersensitivity. · Benralizumab is an antibody against the receptor itself for IL5. Ra in the name indicates it sits on receptor alpha. Antibody dependent cell medicated cytotoxicity where it sits on the receptor and then attracts natural killer cells and macrophages to cause cytotoxicity and destroys eosinophil sitting there. Fixed dose and first is 4 weeks then 8 weeks and as young as 12 years of age and reduce the need

OMALIZUMAB (XOLAIR®)

MOA: a humanized monoclonal antibody that binds the IgE in circulation and blocks the binding of IgE to high-affinity IgE receptors (FcεR1) on mast cells preventing their activation by allergens. ➢It does not inactivate the IgE that is already bound to its receptor. Effect: ↓ Bronchial inflammation Administration: SC to patients ≥6 yrs with positive IgE skin tests Dosing: Based on body weight & pretreatment serum IgE level (150- 375 mg q 2-4 wks) Side effects: injection site reaction, ↑ risk of infections, headache, anaphylaxis (after initial use) and cancer (low risk) Uses: treatment of moderate to severe recurrent asthma. • It reduces the requirement for oral and ICSs and markedly reduces asthma exacerbations. • Can also be used for allergic rhinitis • Cost: $660 per 75 mg (0.5 mL) · Omalizumab is a monoclonal antibody and is injected bc PO administration would lead to disintegration. Binds IgE in the circulation but if IgE is already sat on its receptor then it won't work. Basically reduces bronchial inflammation. Given SC for patients over 6 and positive for IgE skin tests. Then they would be dosed based on the titer of IgE. The range would be 150-375 mg every 2-4 weeks. Can be used for recurrent asthma and can hopefully reduce amount of oral or inhalational corticosteroids. Less corticosteroids is better. Very expensive though

β2 ADRENERGIC AGONISTS

MOA: activation of the Gs-AC-cAMPPKA pathway →↓Ca , ↓ MLCK Other effects: ↓ Inflammatory mediators release from mast cells. ↓ Microvascular leakage ↑ Mucus secretion Recruitment of GRs to regulatory regions of DNA. Inhibit ACh release · Side effects are something we consider so we might have some side effects. Also consider the method of delivery. By mouth absorbs systemically so we expect some adverse effects. Try to focus on the area of disease such as the lungs. · Beta adrenergic agonists work on the GPCR and is a stimulatory G protein and is involved in adenyl cyclines and can eventually lead to activation. If you decrease it it will help with dilation. Can also have the same effect if we reduce constriction. Result is decreasing calcium and leads to bronchodilation effect. Some added benefits are not just through that mechanism but also reduces inflammatory mediators released from mast cell. Can induce histamine release as well. Could also decrease microvascular leakage. Mucus secretion we want to be decreased but doesn't happen with a beta agonist. Clears better than mucus that is secreted. Have a synergistic effect with glucocorticoids. Glucocorticoids also help with vagal receptor development. Beta 2 agonists can also inhibit the release of acetylcholine which increases bronchoconstriction. If acetylcholine is reduced, it is helpful. Beta 2 agonists can also reduced acetylcholine from the nerves.

MUSCARINIC ANTAGONISTS

MOA: competitively inhibit the action of acetylcholine at M3 receptors on airway smooth muscle cells via M3 -Gq-PLC-IP3 -Ca2+ pathway. ➢Cause bronchodilation (less potent than β2 agonists) ➢Inhibit mucus secretion • Have no effect on mast cells, microvascular leak, or the chronic inflammatory response. • Less effective against bronchoconstriction induced by histamine and LTs. · Muscarinic agents can inhibit the action of acetylcholine or can sit on airway receptor and induce pathway. G protein coupled receptor potential as well. Acetylcholine can affect calcium. Bronchodilation effect we see is not as potent as beta 2. Can have bronchodilatory effect and becomes more potent. Could increase secretion with acetylcholine so these agents decrease mucus secretion or can be cleared faster but no control over the amount of secretion.

GLUCOCORTICOIDS

MOA: corticosteroids enter target cells and bind to GRs in the cytoplasm. The steroid-GR complex moves into the nucleus, where it binds to specific regulatory region in the DNA, resulting in increased (or decreased) transcription of the gene, with subsequent increased (or decreased) synthesis of the proteins. · Glucocorticoids are the main and most potent anti-inflammatory drugs.

PHOSPHODIESTERASE 4 INHIBITORS

MOA: selective inhibition of PDE4 • Relax smooth muscle and inhibit inflammatory cells through an increase in cellular cAMP and could be useful as an anti-inflammatory treatment in both asthma and COPD. ➢ PDE4 has 4 subfamilies: • Inhibition of PDE4D: vomiting • Inhibition of PDE4A and PDE4B: anti-inflammatory effects. SIDE EFFECTS: GI tract disturbances (diarrhea, nausea), weight loss, headache, behavioral changes (anxiety, depression, insomnia, and suicidal thoughts). · There is one PDE4 inhibitor and is particularly for COPD exacerbation and is more of a last line agent to prevent hospitalization. · 4 subfamilies for PDE4 where A and B are specifically anti-inflammatory. Also blocks the D1 to cause GI side effects like vomiting. Can see some behavioral changes like suicidal thoughts

HUMANIZED MONOCLONAL ANTIBODIES TARGETING IL-5 Mepolizumab

Mepolizumab (NUCALA®)- SC MOA: IL-5 antagonist (IgG1 kappa), inhibits the bioactivity of IL-5 by blocking its binding to the α chain of the IL-5 receptor complex expressed on the eosinophil cell surface. It binds to the soluble IL-5. Uses: severe asthma in patients ≥ 6 years of age who are not responding to primary therapies. Dose: 100 mg SC q 4 wks ADR: Headache, injection site reactions, back pain, and weakness. Has risk of anaphylaxis. Price: 100 mg/mL, $3545.68 per mL · 2 agents target IL5 and these are mepolizumab and resilizumab. · Mepolizumab is an antagonist is IL5 itself. Safety information may get updated as we have clinical trials and such. So far it is 6 years. So far injection site reactions and price is insaneeeeeee

Steroidogenesis Inhibitors: metyrapone and etomidate

Metyrapone Not readily available in the U.S. but can be obtained from manufacturer (Novartis) for compassionate use. Price is $216 per 18 capsules Etomidate Only available as IV therapy Would need to be used as low-dose infusion to quickly decrease cortisol levels in patients with acute/severe hypercortisolism symptoms or in patients who cannot take oral medications Initial dose: 0.04 to 0.05 mg/kg/hour IV · Etomidate for acute lowering for those who can't take oral.

Glucocorticoid Receptor Antagonist

Mifepristone (Investigational therapy) MOA: receptor affinity is 18-fold higher than cortisol Approved for treating Cushing's disease with ACUTE Complications (e.x severe hyperglycemia) who failed surgery or are not surgical candidates. Potent antiprogestin and therefore, an abortifacent & contraindicated in pregnancy Side-effects: hypokalemia, elevated blood pressure, and endometrial hyperplasia. Initial Dose: 300 mg daily Mifepristone is a glucocorticoid receptor antagonist as last ditch action. Binds receptors to block cortisol from binding and having normal effects in the body

inadequate aldosterone

Mineralocorticoid Disorders Inadequate aldosterone Hypoaldosteronism

Adrenolytic Therapy

Mitotane Affects mitochondria in adrenal cortical cells and causes adrenal cortical atrophy Initial dose: 500 mg PO BID Corticotroph tumor- directed therapy Cabergoline (Investigational therapy) Dopamine agonist that binds to D2 receptors expressed on corticotroph tumor cells Reduces tumor cells' secretion of ACTH, which reduces cortisol production Initial Dose: 0.5 mg once weekly or twice weekly Pasireotide (Investigational therapy) Somatostatin analog that binds somatostatin receptors on corticotroph tumor cells to reduce their secretion of ACTH, resulting in less cortisol production Side-Effects: hyperglycemia (inhibits insulin secretion and decreases incretin response) Initial Dose: 0.6 mg subcutaneously BID · Mitotane is our adrenolytic and reduces mitochondria in adrenal cortex. May atrophy. · Pasireotide same idea where tumor is producing ACTH ectopically and we can slow that if we bind somatostatin receptors on the surface of the tumor.

Additional therapies for CDI

Nitazoxanide Active versus many protozoan infections Rifaximin "Chaser" after completion of vancomycin course Could be considered for recurrent infection Cholestyramine Binds toxins A/B ALSO binds oral vancomycin and metronidazole Probiotics Some data supports decrease in antibiotic associated diarrhea, but doesn't really work for CDI If used, prefer multiple species formulation Caution in immunocompromised IVIG 200-500 mg/kg x 1-6 doses Rifampin In largest study, INCREASED mortality

C diff severity of disease

Non-severe WBC<15,000 cells/mm3 and SCr<1.5x pre-CDI level Serum albumin ≥3 g/dL or WBC ≤ 15,000 cells/mm3 and absence of abdominal tenderness Severe WBC >15,000 cells/mm3 or SCr >1.5x pre-CDI level *Age mentioned, but not spec. Serum albumin <3 g/dL PLUS WBC > 15,000 cells/mm3 or abdominal tenderness Severe/ Complicated (Critically Ill) Hypotension or shock, ileus, megacolon Attributable to CDI: Admission to ICU, hypotension, T >38.5°C, ileus/abdominal distention, MS changes, WBC > 35,000 or <2,000, lactate >2.2 mmol/L, or EOD · We do need to know how to characterize by severity of disease. Can look at other things and determine the type of treatment we should use. We have 2 different guidelines and they represent different things. IDSA and ACG compete and are not the same. Nonsevere means they don't have elevated white count or SCr. Severe is opposite and can be so severe that they now have organ damage. If patient is on dialysis we can't use SCr values, eliminate that altogether. *If admitted to the ICU bc of C diff you are severe/complicated*. This is important bc treatment for severe/complicated is very different. Only other exception would be if patient has an ileus that blocks passage of things.

COUGH SUPPRESSANTS (ANTITUSSIVES) opioid analgesics dextromethorphan

OPIOID ANALGESICS (e.g., codeine, hydrocodone) MOA: bind to G-protein coupled mu opioid receptors (MOR) in the NTS, may also have actions on cough receptors in the airways and decrease the sensitivity to airway stimuli to induce cough. • Antitussive effect occurs at lower doses than required for analgesic effects. • Potential for addiction with chronic use. • Side effects: sedation, constipation DEXTROMETHORPHAN MOA: Centrally acting N-Methyl-D-Aspartate (NMDA) receptor antagonist, may also antagonize MOR. • Poorly effective, abuse potential, less sedation and constipation than codeine • Hallucinations at high doses (more common in children) · Can suppress coughing through acting on mu receptors and such. But expect side effects with opioids such as dependence, constipation, etc. another option is dextromethorphan and one side effect in pediatrics is hallucinations so we wouldn't want to use.

Inhibitors of ACTH Secretion

Pasireotide ▪ Signifor®-SC ▪ Signifor LAR®-IM Cabergoline (Dostinex®)-PO · Inhibitors of ACTH secretion we can try to inhibit ACTH secretion and inhibit production of steroids. Can also block the receptors that cortisol sits on. If producing then last chance would be to stop site of action · Focusing on anterior pituitary and one agent works on receptors, some steroidal genesis inhibitors, and etc. first group is really 2 members that are inhibiting ACTH secretion.

Steroid Tapers - Purpose

Purpose: Prevent adrenal insufficiency or adrenal crisis when decreasing dose or discontinuing glucocorticoid therapy Prevent rebound of pro-inflammatory mediators and inflammatory symptoms that could recur if glucocorticoids are stopped abruptly · Gotta taper bc of the HPA axis shutting down. In terms of treatment for inflammation we taper to prevent rebound of symptoms or inflammation. Taper a lot more slowly for HPA axis suppression to allow for production to normalize in the body

petrosal sinus drainage

Petrosal sinus drainage we get level

Effects of GCs (Cortisol)

Physiologic effects ◦ Influencing cell function, release of insulin, or glucagon ◦ Permissive effects (vascular response to NE) Metabolic effects ◦ Serum glucose↑(inhibit glucose uptake by cells except brain and heart) ◦ Lipolysis (TG →fatty acid + glycerol) ◦ Gluconeogenesis Catabolic and anti-anabolic effects ◦ In lymphoid and connective tissue, muscle, peripheral fat, skin and bone (causing osteoporosis; reduce growth in children) Anti-Inflammatory and immunosuppressive effects ◦ ↓ inflammatory cytokines (IL-1, IL-6, TNF-α) ◦ COX-2 inhibition Protection against damage of stress Other effects: insomnia, peptic ulcer, ↑RBC, PLT & WBC ➢Demargination · Cortisol has some physiologic effects where it influences cell function, insulin, and glucagon. If we increase cortisol, glucose goes up (any corticosteroid/glucocorticoid causes this) and can lead to hyperglycemia and functions as a sort of insulin antagonist. Has some permissive effect regarding vascular response. Has some permissive effect for vasopressors. As it increases the glucose levels in the blood, it expresses in important cells. See decreased glucose in muscles. If we want the brain and heart to get all the energy. It breaks down the lipid/proteins bc it is trying to find amino acids to change them also to glucose. · Corticosteroids cause bone resorption so in children need to weigh risks versus benefits. When we think about glucocorticoids think hyperglycemia and calming down the immune system so that the organ is not rejected. Even inhibit COX2 and production of some prostaglandins. Advise to take with food, big breakfast, can be more sensitive to H pylori infection as well. Demargination is the reason why when we give steroids it causes white blood cells to go up. WBCs are attached to the vasculature and a protein called L selectin keeps WBC attached to vasculature but becomes disattached and apparently this L selectin that keeps it bound and then we have the WBC. This L selectin doesn't last forever as shedase is the enzyme that destroys it so it needs to be replaced. Cortisol prevents creation of L selectin so WBC ends up in the bloodstream not attached to the vasculature. Even if we give prednisone we will see a transient increase in our blood cells.

Steroid Tapers - Procedure

Procedure: No exact science Examples: 14 day prednisone taper: Prednisone 60 mg PO x 5 days Prednisone 40 mg PO x 5 days Prednisone 20 mg PO x 2 days Prednisone 10 mg PO x 2 days Medrol dose pack · Steroid tapers have no exact science to them and depends on what dose we are starting with and the reason for tapering and how quickly we can go. Rebound inflammation is a faster taper. Medrol dose packs are built in with a taper. For HPA reduce by 1 mg every 2 weeks.

AGENTS FOR TREATMENT OF IPF

Recent anti-fibrotic drugs for IPF (2014) • Pirfenidone (Esbriet®) Tyrosine Kinase Inhibitor: • Nintedanib (Ofev®)

Adrenal Cortex

Secretes steroid hormones: ➢Glucocorticoids (cortisol) ➢Mineralocorticoids (aldosterone) ➢Androgens · In the adrenal cortex we have 3 steroid hormones being secreted. Have to look int

Aldosterone Antagonists

Spironolactone ▪Eplerenone Use: Primary hyperaldosteronism (Conn's syndrome) • Short-term preoperative treatment of primary hyperaldosteronism . • Long-term maintenance therapy for patients with aldosteroneproducing adrenal adenomas who are not candidates for surgery. • Long-term maintenance therapy for bilateral micro- or macronodular adrenal hyperplasia (idiopathic hyperaldosteronism). • Patients should maintain on a low salt diet. · Use aldosterone antagonists if we have too much aldosterone. Can be used in primary hyperaldosteronism (conn's syndrome). Can't use for addison's disease bc it is adrenal insufficiency. But conn's has too much aldosterone

Cushing's Syndrome - Diagnosis

Step 1 - Confirm ↑ [cortisol]: Midnight plasma [cortisol] 24 hr Urine Free [cortisol] (UFC) Late-night salivary [cortisol] Dexamethasone suppression test Administration of 1 mg at 11pm, followed by 8am fasting plasma [cortisol] Step 2 - Determine Etiology: Plasma [ACTH] CT or MRI to screen for tumors · In a patient who's HPA axis is functioning normally, we should see a drop of cortisol levels following that dose. If we don't see that, it tells us that the negative feedback loop isn't working. If we see elevated ACTH it can signify elevated ACTH syndrome

Hypoaldosteronism - Clinical Presentation

Symptoms Weight loss Gastrointestinal disturbances Dizziness, lightheadedness Salt-craving Signs Severe postural hypotension Hyponatremia Hyperkalemia Hyperchloremic metabolic acidosis May cause complete heart block · Hypoaldosteronism patients how low blood pressure and severe postural hypotension. May be salt craving, not retaining fluid so maybe fluid weight loss, not retaining sodium, if patient has addison's disease or tuberculosis can precipitate damage to this area, then we can use mineralocorticoid syndrome. With addison's disease we need to supplement on mineralo and glucocorticoid side to replace aldosterone in addition to cortisol

Hyperaldosteronism - Clinical Presentation

Symptoms Muscle weakness Fatigue Paraesthesias Headache Signs Hypertension Muscle tetany Excessive thirst ↑aldosterone-to-renin ratio(ARR) Excessive urination Hypernatremia Glucose intolerance Hypomagnesemia Hypokalemia · Hyperaldosteronism can lead to sodium and fluid retention in the body so leads to hypertension. Also excessively thirsty and excessive water retention leading to excessive urination. Hypernatremia and bc of exchange in the kidneys, high level of sodium usually leads to compensatory hypokalemia and hypomagnesemia. Should see a set aldosterone renin ratio.

Adrenal Crisis - Symptoms

Symptoms of Adrenal Crisis: Nausea and vomiting Abdominal pain Hypoglycemia, hyponatremia Hypotension Hypovolemic shock Delirium, obtundation

systemic GCs

Systemic Agents: • Hydrocortisone (IV) • Methylprednisolone (IV or PO) • Prednisone (PO) • Prednisolone (PO) · Systemic options in case of severe exacerbation then inhalation is not enough.

Anti-TSLP Therapy Tezepelumab (Tezspire®)-SC

Tezepelumab (Tezspire®)-SC First in class! MOA:A human monoclonal antibody (IgG2λ) that binds and inhibits the actions of a thymic stromal lymphopoietin (TSLP) • TSLP is a key epithelial cytokine occupying an upstream position in the asthma inflammatory cascade. • Blocking TSLP reduces inflammatory biomarkers and cytokines such as eosinophils, Ig E, IL-5, and IL-13 Use: Asthma: Add-on maintenance treatment in adults and children ≥ 12 to improve severe asthma symptoms that are not controlled by their current asthma medicine. ▪ Not for acute bronchospasm. ▪ Not limited to a specific type of severe asthma. ▪ Administered once every 4 weeks. ▪ Parasitic infections should be treated before starting Tezepelumab. · Tezepelumab is a human monoclonal antibody inhibiting TSL. It is in the upper stream of everything we have discussed. Kind of has control over everything released. Not specific for eosinophilic asthma and is upstream in the asthma anti-inflammatory cascade so it is general rather than blocking one type of inflammatory disease. · Tezspire is an add on maintenance and for now is for ages 12 and above. None of these antibodies are for acute treatment. It is not limited to a specific type of severe asthma so you can give it for any type of severe asthma. Apparently if there is any parasitic infection, there is an immunologic response in the body for the TSL system. So prior to use, we need to ensure any parasitic infection is treated.

Adrenal Disorders Summary

The HPA axis regulates endogenous glucocorticoid and mineralocorticoid production Disorders resulting from adrenal hyper- or hypo- function are associated with significant sequelae Excess exogenous glucocorticoid supplementation can lead to Cushing's Syndrome Secondary adrenal insufficiency can result from HPA axis suppression or critical illness Acute adrenal insufficiency is a potentially life-threatening emergency Exogenous glucocorticoid therapy is associated with many side-effects and tapering may be used to minimize HPA axis suppression and rebound of symptoms being treated with the glucocorticoid

PREPARATIONS Short Acting Muscarinic Antagonists (SAMA)

The onset of bronchodilation is relatively slow with maximal effect 30- 60 min after inhalation. Lasts 6-8 hrs. Ipratropium bromide (Atrovent®): quaternary ammonium derivative of atropine, can be used as an inhalational bronchodilator due to its poor absorption and poor entry into CNS. SABA/SAMA: ▪ Albuterol/ipratropium (Combivent®) ▪ Used in COPD ▪ Off-label use in acute asthma · SAMA can have effect in 30-60 minutes. Very important agent is Atrovent (ipratropium bromide) and are antagonists of acetylcholine like atropine is. But we don't use atropine bc of side effects passing through BBB and having CNS effects. These agents we use are quaternary amines making ammonium positive making it more difficult to cross BBB or get into central circulation. Have a combo of SABA and SAMA in COPD or in acute asthma attacks.

General Pharmacotherapy Pearls:

The stepwise treatment approach may differ for male vs. female patients Ketoconazole reduces testosterone & causes hypogonadism & impotence in men, so not first line for men; start with metyropone for men Metyrapone can increase production of androgens & cause hirsutism in women, so not first line for women; start with ketoconazole in women These drugs may be combined to work synergistically (although there are limited data evaluating triple therapy with ketoconazole + metyrapone + mitotane) Escalation of therapy should follow assessment of urine free cortisol levels and symptom management · In general for treating cushing's we can start there and titrate the dose to add on metyrapone. Consider adding mitotane as well

THEOPHYLLINE

Theophylline: elixir, ER tab, cap, IV MOA: • Competitively blocks adenosine receptors inhibiting the release of histamine and other mediators from mast cells. • Nonselective inhibitor of cAMP PDE (PDE3: airway; PDE4: inflammation) • Enhancement of histone deacetylation • Increases the release of IL-10 • Promotes apoptosis of granulocytes SIDE EFFECTS: headache, N&V (inhibition of PDE4), anxiety, tremor, insomnia, GI upset, diuresis, tachycardia. High dose: seizures (central A1 antagonism) and fatal arrhythmias (inhibition of cardiac PDE3 and A1 receptors). ADME • Rapidly and completely absorbed • Metabolized in liver (CYP1A2) • Reduced clearance (↑ toxicity): neonates, elderly, HF, liver disease, acute pulmonary edema, fever over 102°F, high carb/low protein diet, CYP1A2 inhibitors (fluconazole, macrolides) and following smoking cessation. · Theophylline is available in different formulations but competitively blocks receptors. One way is through adenosine and another through PDE. Also enhances histone deacetylation. Can prevent inflammatory mediator production and IL10 is increased. Granulocytes are a problem and if we can cause cell death in these cells that is beneficial to prevent cytokine release and also promotes apoptosis. Caffeine citrate we see caffeine being used. · High dose makes even worse risk and have to monitor therapeutic levels somewhere between 5-50. Be aware of conditions for reduced clearance · Theophylline is used for pulmonary diseases and is a culmination of many effects. Can inhibit the release of histamine and other mediators. Works on PDE3 and helps with bronchodilation and PDE4 works with inflammation. Can inhibit both PDE's. can enhance histone deacetylation and help with inflammation by histone deacetylation and increase IL-10 and IL-10 is a very anti-inflammatory cytokine. There's also apoptosis of granulocytes and release of cytokines are decreased. · Side effects can be similar to the effects after drinking coffee and high dose can cause seizures or arrhythmias and we consider theophylline as a narrow therapeutic index so we need to monitor levels. Goes through CYP1A2 and watch for groups with reduced clearance. Smoking increases metabolism of the drug but stopping smoking leads to decreased clearance.

CYS-LEUKOTRIENES (LTC4, LTD4, and LTE4)

Two ways to interrupt the leukotriene pathway: 1. Inhibition of 5-LO, preventing LT synthesis 2. Inhibition of the binding of cys-LT to its receptor on target tissues, preventing its action. · When we look into mast cells and eosinophils, these can induce release of leukotrienes and can make eosinophils to release arachidonic acid and then metabolized to cysteinyl leukotrienes which sit on the Cys-LY receptors and cause bronchoconstriction, mucosecretion, etc which we don't want. So we can use a receptor blocker to prevent these from sitting on their receptor or we can prevent the synthesis of these leukotrienes.

Adverse Effects of Glucocorticoid Therapy

Weight gain Fluid retention Electrolyte disturbances Hypernatremia HPA Axis Suppression Iatrogenic Cushing's Syndrome Gastric irritation Hypertension Glucose intolerance Muscle wasting Cataracts Glaucoma Psychiatric issues Dermatologic issues Osteoporosis Immunosuppression Others... · Corticosteroids cause all kinds of nasty side effects. Electrolyte disturbances, iatrogenic syndrome, using corticosteroids iin patients that are hospitalized are more at risk for a stress ulcer so we may need stress ulcer prophylaxis. High glucose levels and such.

FDA Regulatory actions due to DILIMarketed drugs: 1995-2012

Withdrawals: Bromfenac Troglitazone Pemoline Ximelgatran** Lumaricoxib** Warnings: Acetaminophen Leflunomide Nefazodone Nevirapine Pyrazinamide/rifampin Terbinafine Valproic acid Zifirlukast Atomextine Interferon 1b/1a Saquinavir Infliximab Bosentan Telithromycin Erlotinib Natalizumab (kava) (lipokinetix) Special Use: Trovofloxacin Felbamate Tolcapone · Telithromycin is relative to a z pack which *exam question real class name of azithromycin is an azalide*. Has a slightly different structure than normal macrolides. Drug induced hepatotoxicity is not common but gotta go by how severe the risk is. No way we risk the liver even if it is less than 1% of a chance. Valproic acid also causes hepatitis.

LEUKOTRIENE RECEPTOR ANTAGONISTS (LTRAs)

Zafirlukast (ACCOLATE®)-PO Montelukast (SINGULAIR®)-PO MOA: competitive antagonism of cys-LT1 receptors present on airway smooth muscle, mast cells, basophils, and eosinophils. Therapeutic effects: inhibition of LT-mediated bronchoconstriction and the influx of eosinophils into the lungs and mast cells/basophils into the nasal mucosa. ➢Their anti-inflammatory actions are weaker than GCs SIDE EFFECTS: • Headache, dyspepsia, gastroenteritis • Systemic eosinophilia (rare) • A rare vasculitis (Churg-Strauss Syndromeassociated with allergy and asthma) • Hepatic dysfunction (monitor LFT) • Neurophsychiatric (NP) events including depression, suicidal thoughts and suicide (boxed warning) · The LTRAs block the receptor and inhibit bronchoconstriction and such. · A rare vasculitis can occur and is mostly reported with singulair. Would need to stop the drug and reevaluate if need be. Boxed warning includes neuropsychiatric events.

tests of pulmonary function: diffusing capacity (DLCO)

a measure of the rate of gas diffusion across the alveolocapillary membrane carbon monoxide or oxygen is used in this test it is measured how much carbon monoxide is taken up by the blood and dividing this amount by the pressure gradient across the alveolocapillary membrane helium is often added to the gas mizture to obtain a simultaneous measurement of residual volume (RV), functional residual capacity (FRC), and total lung capacity (TLC) ventilatory maneuvers similar to those of spirometry a decreased diffusing capacity can be the result of an abnormal ventilation-perfusion ratio or an actual diffusion effect diffusing capacity is decreased in individuals with emphysema

obstructive pulmonary diseases

airway obstruction that is worse with espiration the common sympotm is dyspnea the common sign is wheezing increased work of breathing ventilation/perfusion mismatching decreased forced expiratory volume in one second (FEV1) the most common are asthma, chronic bronchitis, and emphysema. bc many individuals have both chronic bronchitis and emphysema, these diseases together often named COPD asthma is more acute and intermittent than COPD, even though it can be chronic · Obstructive characterized by decreased expiratory volume and FEV is usually decreased more and have significant problems. Chronic bronchitis and emphysema and frequently co-exist. Asthma is more acute and intermittent compared to COPD.

kidneys and adrenal glands in adrenal physiology

aldosterone ----increased sodium and water retention---> kidneys and adrenal glands <-----angiotensin II · The adrenal cortex is responsible for producing aldosterone. When we have enough fluid volume on board, our baroreceptors are doing fine but as soon as we are in a fluid state we have angiotensin II and aldosterone produced as a consequence to help body hold on to sodium and water. When we retain water our fluid volume status in blood stream goes up. Once hemodynamic stability is restored, then the feedback shuts everything down in terms of aldosterone to prevent BP from continuing to rise.

Conditions caused by pulmonary disease or injury

an abnormal ventilation-perfusion ratio is the most common cause of hypoxemia. the normal Va/Q is 0.8 to 0.9 because perfusion is somewhat greater than ventilation in the lung bases 1) if blood passing through the pulmonary capillaries is exposed to less O2 than normal, Va/Q ratio is low 2) mismatching of this type is called shunting and occurs in asthma (it causes bronchoconstriction), pulmonary edema, and pneumonia (alveoli are filled with liquid). poor perfusion of well ventilated portions of lungs (high Va/Q ratio) resulting in wasted ventilation 3) the result is a decrease in PaO2. the most common cause is pulmonary embolus. an area where alveoli are ventilated but not perfused is termed alveolar dead space

allergic rhinitis (hay fever)

an allergic disorder characterized by an exaggerated immune response to pollen and other substances nose typically first site of exposure to air borne particulate matter foreign material conecntrated in lymph tissues at back of throat eliciting production of antibodies allergen interaction with IgE bound to mast cells immediate and late phases -release of various chemical mediators; sneexing/itching due to stimulation of vagus; histamine induces rhinorrhea and obstruction; leukotrienes and kinins contribute -4-8 hours later inflamed mucosa becomes hyperresponsive to additional cytokines from mast cells and Th lymphocytes- individual more sensitive reacting to smaller amounts of allergen · Allergic rhinitis or hay fever is pretty common and unfortunately associated with seasonal and contact of pollen. Flows to asthma. Nose is typically first site of exposure and this reaction happens in the nose. Foreign materials in lymph tissue and forced production of specific antibodies. Interaction with IgE and such. Similarity with asthma. Is a release of various chemical mediators and such. 6 hours later between 4 and 8 there is inflammation of mucus due to additional cytokines and lymphocytes. Like stage 1 and 2 of asthma but located in our nose and throat and lungs aren't affected

clinical presentation of IPF

areas of opaqueness on imaging weight loss, cyanosis, pulmonary HTN/cor pulmonale classic restrictive lung disease with reduced TLC, FRC and RV decreased lung compliance FVC and FEV1 reduced bc of decreased TLC with normal or increased FEV1/FVC lung volumes progressively decrease with lung stiffness work of breathing increases; rapid and shallow decreased ventilation causes reduction in V/Q ratio resulting in decreased diffusion capactiy blood gas normal or hypoxemic with respiratory alkalosis extent of disease determined by gas exchange measurements at rest and during exercise testing · Most important criteria is reduction of TLC

Atopic asthma

atopic (extrinsic) asthma: a combination of a genetic predisposition and environmental factors causes certain individuals to respond to certain antigens with hyperallergic (atopic) response the antigen here is usually called an allergen. the most common are from house dust mites, cockroaches, dogs, cats, rodents, molds and fungi · Asthma can be generated by dust mites, cockroaches, pollen, etc. first step with an allergen is our respiratory system is in contact with an allergen. This pollen constricts epithelium and can be cleared by mucus transport and another scenario could be taken by dendritic cells which can present the antigen and present some epigenic epitopes and generated by T cells and immune response. If not a response to asthma, lympthocytes are involved and in the case of asthma, different subtypes are involved. Both types of lymphocytes are involved in immune response and response is abnormal bc of genetic and other factors that can create a shift in the TH2 response. Can produce interleukin 5 which activate eosinophils and can induce production of alpha L 9. Ig E is recognized in allergen and epitopes presented by dendritic cells and then the IgE can present on surface of mast cells and deals with mast cell accumulation and production can induce swelling. Mast cells are already ready to produce a pro inflammatory mediator causing swelling and inflammation so if contact is repeated it can be responsible very quick and pretty strong. Different factors can precipitate this and could be a viral infection. Some other factors like nitrogen dioxide from cars and such.

values measured by spirometry

look at slide

pathogenesis of pulmonary fibrosis

look at slide · Microscopic energy can lead to pulmonary fibrosis and causes could be irritants or infection

pain

can be originated in pleurae, airways, or chest wall pleural pain is the most common and usually sharp or stabbing in character causes of pleural pain: infection, inflammation, pulmonary tissue death (infarction), caused by pulmonary embolism. it's accelerated after cough, individuals with tracheitis or tracheobronchitis may have central chest pain, appeared after coughing. it must be differentiated from cardiac pain. pulmonary HTN can cause chest pain during exercises, which is often mistaken for chronic anina. pain in the chest wall is muscle pain or rib pain caused by inflammation

allergic rhinitis epidemiology/etiology

can be associated with several medical conditions 40-50% of asthmatics have classified as seasonal and perennial epidemiology/etiology -very comon; 6th most prevalent in US -inflammatory response of nasal mucous membrane due to IgE mediated response -determined by genetics and exposure to allergens; typically family history involved · Allergic rhinitis is very common and inflammatory response can be due to Ig mediated response and could be predisposed to it.

lung diseases: general discussion

classified as acute/chronic, obstructuve/restrictive, infectious/noninfectious either due to impaired gas exchange pr increased work of breathing disorders are major causes of morbidity and mortality - incidence of some are increasing many chronic disorders are preventable lung has numerous non-respiratory functions

sugns/symptoms of pulmonary disease: cough

cough- an important reflex that helps clear the airways of inhaled material, excessive secretion of abnormal substances initiated mostly in the larynx and in the tracheobronchial tree by both mechanical and chemical receptor stimulation. just a few in the distal bronchi and alveoli that allows to accumulate secretions other cough receptors are located at in the external auditory canal, diaphragm, pericardium, pleura, and stomach stimulation of cough receptors is transmitted centrally through the vagus nerve, and central modulation of this reflex can be influenced by opiates and serotinergic agents acute cough (usually 2-3 weeks, but in case of some viral infections -7- 8 weeks). most frequently the result of upper respiratory infections, allergic rhinitis, acute bronchitis, pneumonia, CHF< pulmonary embolus chronic cough in non-smokers is almost always caused by postnasal drainage syndrome, asthma, or GERD. in smokers chronic bronchitis is the most common cause. lung cancer must also be considered up to 33% of patients taking ACE inhibitors for CV disease develop chronic cough that resolves with D/C of the drug

hemoptysis

coughing up blood or bloody secretions. it's bright red and has alkaline pH. most common in bronchiectasis, lung cancer, bronchitis, and pneumonia, TB. cause: injury to the lung parenchyma, rupture of pulmonary vessels (inflammation, injury). evaluation: bronchoscopy combined with CT

clinical manifestations chronic bronchitis

decreased exercise tolerance, wheezing, SOB, productive cough copious sputum and frequent infections FEV1 and FVC reduced with increased FRC, RV decreased alveolar ventilation - hypoxemia and hypercapnia

tests of pulmonary function: arterial blood gas analysis (ABG)

direct analysis of the pH and gas concentrations in the arterial blood information about gas exchange and acid base status. acidosis (low pH), alkalosis (high pH), ventilatory alterations and decreased PaO2 can be tested accurately only by this method oximetry can be used to monitor oxygen saturation once the arterial blood gas analysis has accurately measured PaO2, but does not measure PaCO2 or pH

signs/symptoms of pulmonary disease: dyspnea

dyspnea - person feels short of breath; synonyms: SOB, breathlessness, difficulty breathing, respiratory distress, breath hunger normal conditions: exercises (short-term); extremely high elevation; medical conditions: acute: low blood pressure, respiratory conditions (asthma, pulmonary embolism, inhalation of foreign object, poisonous gas), allergies, trauma to the chest wall, panic attack, GERD chronic: heart diseases (heart attack, CHF, arrhythmias), lung diseases (COPD, lung HTN, pneumonia, interstitial lung disease), anemia, obesity mechanisms: it is believed that dyspnea results when a "mismatch" occurs between the afferent and efferent signals in CNS: such as when the need for ventilation (afferent signaling) is not being met by physical breathing (efferent signaling) orthopnea: a type of dyspnea caused by the horizontal position, which redistributes body water, causes pressure on the diaphragm and decreases the efficiency of respiratory muscles evaluation: assessment of airways, breathing, and circulation. evaluation of the degree (modified borg scale or mMRC scale), blood tests (D dimer, brain natriuretic peptide), imaging (chest X-ray, tomography)

COPD: emphysema

emphysema is a permanent enlargement of lung air spaces distal to the terminal bronchioles (respiratory bronchioles, alveolar ducts and alveoli are affected). it is characterized b the destruction of their walls without fibrosis, and destruction of lung parenchyma with loss of elasticity · Can talk about COPD and emphysema and is permanent enlargement of bronchioles. Fibrosis is not typical for this. Don't need to remember the subtypes just know that alveoli and respiratory bronchioles can be affected. Sometimes it can affect just alveolar sacs or both. Some respiratory bronchioles can be stronger affected by alveoli. Some respiratory bronchioles and others can be affected as well. Can happen if toxins or smoke inflame the airway and leads to production of inflammatory cytokines that increase airway permeability. The activity of these proteases are inhibited by normal anti proteases. Activated by alpha 1 trypsin. Proteases can take lead and start tissue destruction. As a result, expiration can become difficult and we have air trapping.

signs/symptoms of pulmonary disease: abnormal breathing patterns

eupnea (normal breathing) is rhythmic and effortless (8-16 breaths per min with a short expiratory pause with each breath, and occasionally a deep breath: 10-12 per hour). in response to different oxygen demand, the rate, depth, regularity and effort could be changes. an example: Kussmaul respiration (hyperpnea) after strenuous exercises: very large tidal volume, slightly increased ventilatory rate, and no expiratory pause. patterns of breathing automatically adjust to minimize the work of respiratory muscles obstructed breathing (increased resistance: COPD)- slow rate, large tidal volume, increased effort, and prolonged inspiration or expiration. a whistling sound is often present restricted breathing (decreased compliance: pulmonary fibrosis)- small tidal volumes, rapid ventilatory rate (tachypnea) Cheyne-Stokes respirations: alternate periods of deep and shallow (15-60 sec) breathing. results from any condition that slows the blood flow to the brain stem, which in turn slows impulses to the respiratory centers of the brain stem

pulmonary fibrosis

excess fibrous tissue; scar tissue after active disease (ARDS, TB) or by inhalation of harmful substances (coal, dust, asbestos); cause: disregulated repair process resulting in chronic inflammation, alveolar epithelialization, and myofibroblast proliferation; decreased lung compliance and gas diffusion

pulmonary edema

excess water in the lung; caused by 1) increased pulmonary cap pressure due to elevated left atrial pressire 2) fluid movement from capillaries due to damaged capillary endothelium 3) inability to remove excess fluid due to blockage of lymphatic vessels

clinical definition of ARDS

first defined by AECC in 1994 as the acute onset of hypoxemia (arterial partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2) </= 200 mm Hg) with bilateral infiltrates on frontal chest radiograph, with no evidence of left atrial hypertension and acute lung injury (ALI) was defined using similar criteria, but having PaO2/FiO2 </= 300 mmHg a panel in 2011 developed the Berlin Definition of ARDS using a consensus process. the Berlin definition require all four criteria's tp be present for diagnosis of ARDS 1) timing: respiratory symptoms must have begun within one week of a known clinical insult, or the patient must have new or worsening symptoms during the past week 2) chest imaging: bilateral opacities consistent with pulmonary edema must be present on a chest radiograph or CT scan, which is not fully explained by pleural effusions, lobar collapse, lung collapse, or pulmonary nodules 3) origin of edema: the patient's respiratory failure must not be fully explained by cardiac failure or fluid overload. an objective assessment (ex: ECG) to exclude hydrostatic pulmonary edema is required if no risk factors for ARDS are present 4) oxygenation: a moderate to severe impairment of oxygenation must be present, as defined by the PaO2/FiO2 ratio

Atopic Asthma Pathogenesis

following its introduction into the body, the antigen (allergen) is taken up for processing by dendritic cells. however, instead of typical activation of protective immune response (T cells in particular TH1, B cells, macrophages), a specific type of T cells: TH2 cells are predominantly activated. as a result, a specific set of cytokiness is released and the B cells release IgE, setting in motion the secretion of a set of regulatory molecules that significantly promotes inflammation that leads to airway hyper-responsiveness another precipitating factor, such as viral infection, can lead to a serious exacerbation. many factors can increase the response, such as nitrogen dioxide from cars, tobacco smoke, ozone, pollution etc

acute respiratory distress syndrome (ARDs) epidemiology/etiology

fulminant form of respiratory failure- acute lung inflammation and diffuse alveolocapillary injury manifested by hypoxia and stiff lungs due to increased pulmonary vascular permeability represents an acute response to diverse provoking trigger factors and etiologies, resulting in bilateral lung opacities on radiography and hypoxemia can result from systemic or pulmonary insults no clear definition of clinical manifestations; include hypoxemia, pulmonary edema and altered pulmonary hemodynamics patients with aspiration pneumonia and sepsis at highest risk; numerous other risks 200,000 patients per year in the US 30-40% mortality rate; decreasing with improved treatment many return to normal lung function (variable) · ARDS presents acute response to trigger factors of etiologies and in x ray we can see bilateral lung stuff due to accumulation and is associated with hypoxemia. Clinical minfestation could vary and the characteristic is hypoxemia and pulmonary edema and changes to pulmonary hemodynamics.

Mifepristone (Korlym® )

glucocorticoid receptor antagonists ▪A synthetic steroid, at low doses blocks progesterone receptors. ▪At high doses blocks the effect of cortisol at the glucocorticoid receptor (GCR) antagonizing the effects of cortisol on glucose metabolism. ▪It secondarily increases endogenous ACTH and cortisol levels by blocking feedback regulation of the HPA axis. MOA: Causes stabilization of the hsp-GCR complex and inhibition of the dissociation of the mifepristone-bound GCR from the hsp chaperone proteins. ▪Long acting (↑ Protein Binding), metabolized in liver (major substrate of CYP3A4). ▪Causes generalized GC resistance. ▪Use: control hyperglycemia secondary to hypercortisolism in patients with endogenous Cushing's syndrome who have DM-2 or failed surgery or not surgical candidate. ▪Side effects: Hypokalemia (cortisol's effect on MC receptors), HTN, headache, edema, N & V, arthralgia, endometrial hyperplasia, vaginal bleeding and risk of infection. ▪Contraindication: pregnancy. · Mifepristone is the only glucocorticoid receptor antagonist and was used for the termination of pregnancy but it can antagonize the effect of cortisol. As it stops the effect of cortisol we might still see elevated levels of ACTH too. · Long acting, can be used to control hyperglycemia. Can have some mineral corticoid effects too to cause hypokalemia. Vaginal bleeding bc it caused abortion

COPD: chronic bronchitis

hypersecretion of mucus and chronic productive cough for at least 3 months a year (usually winter months) for at least 2 consecutive years incidence is increased in smokers (up to 20 fold) and even more in workers exposed to air pollution most commonly in middle aged men inhaled irritant initially induce inflammation in the larger bronchi, but eventually all airways are involved edema and hyperplasia of submucosal glands; excess mucus secretion and accumulation due to impaired cilia activity pathogenic bacteria become embedded in mucus and reproduce rapidly that increase inflammation and thickening of bronchial walls persistent inflammation and recurrent infection leads to bronchospasm and permanent narrowing of the airways Chronic bronchitis is hypersecretion of mucus and is associated with cold weather. Associated with proliferation of goblet cells. Associated with hyperplasia of goblet cells. Incidence has increased in smokers especially in workers involved with lung pollution. Eventually all airways are involved and is characterized with edema and hyperplasia and impaired cilia activity. Become embedded in mucus and infection can lead to bronchospasm and narrowing of airways.

pulmonary thromboembolism

incidence not known VTE/PE increases with age higher risk in multiple traumas and lower extremity orthopedic surgeries prolonged immobility thrombus the usual cause of embolism; PE in >50% of those with DVT impact and clinical manifestations dependent on extent of blood flow obstruction

asthma: end result of pathophysiologic process

increase in airway resistance decrease in FEV1 and FEV1/FVC, PEF hyperinflation of lungs increased work of breathing altered respiratory muscle function changes in elastic recoil V/Q mismatch altered arterial blood gases bronchial hyperresponsiveness, airway remodeling, mucous plugging

hypercarbia

increased carbon dioxide in arterial blood (increased PaCO2) caused by hypoventilation of the alveoli. there are 6 causes: 1) depression of the respiratory center by drugs, infection, or trauma 2) diseases of spinal cord 3) diseases of the neuromuscular junctions or respiratory muscles themselves 4) thoracic cage abnormalities (chest injury, congenital deformity) 5) large airway obstruction (tumors, sleep apnea) 6) increased work of breathing or physiologic dead space (emphysema)

clinical manifestations of emphysema

increasing dyspnea with minimal cough pursed lip breathing to aid expiration reduced FEV1, FVC, FEV1/FVC ratio, anf FEF TLC, FRC and RV inceased - air trapping gas diffusion is reduced - blood gases do not change until severe stage reached · Air trapping is typical for emphysema and gas diffusion is reduced. Primary cause is cigarette smoking and genetic forms and environmental exposure can be exposed

bronchiolitis

inflammation/obstruction of the small airways or bronchioles; usually diffuse; most common in children; in adults usually occurs with chronic bronchitis or with viral infection (RSV) or toxic gases; can decrease V/Q ratio (hypoxemia)

COPD pathophysiology

look at slide These conditions frequently happen together and affect both bronchi and alveoli. Deals with proliferation of mucus cells but is defective immune response to infections and eventually may cause fibrosis and pulmonary hypertension. Final result is obstruction of airways and such. Chronic cough and predisposition to pneumonia and can lead to right sided heart failure

Idopathic Pulmonary Fibrosis (IPF)

interstitial lung disease involving parenchyma diagnosed with onset of worsening exertional dyspnea, persistent nonproductive cough, inspiratory crackles IPF is most common and serious of ILDs; survival rate low and death within 3-5 years of diagnosis etiology: -risk factors of smoking, exposure to particulate matter; farming, viral infections -strong genetic components: mutations in surfactant protein genes and telomerases -classic interaction of genetic and environmental factors · Risk factors include smoking and there are mutations and surfactant proteins found and is typically classic for genetic and environmental factors.

SAMA structures

ll are N positive and the hydroxyls are important for attachment to the receptor.

FVC maneuver

look at slide

cushing's syndrome suspected

look at slide

interpretation of PFT

look at slide

section through the alveolar septum

look at slide

types of pleural effusion

look at slide

typical changes in the static lung volumes and capacities in obstructive and restrictive lung

look at slide

COPD: emphysema etiology

look at slide proposed to be caused by unregulated activity of extracellular proteases secreted from inflammatory cells this is a response to chronic exposure to cigarette smoke or other inhaled irritants linked to an imbalance between neutrophil serine proteases, particularly neutrophil elastase and their inhibitor- alpha 1 antitrypsin extracellular proteases cause the breakdown of alveolar walls and collapse of small airways the loss of elastic recoil and structural support leads to air trapping, hyperinflated lungs, decreased airflow rate on expiration · Elastic recoil typically expels air out but if air trapping then it prevents alveoli bc of lack of elastic recoil to push out. Elastase inhibitor could be serpin. 2 different branches of activity could be mutations in the gene and if there are some mutations, z allele is the worse one associated with significant dysfunction of the protein. Can be hypermobility of alpha protein and then elastase can be produced at a high level and cause emphysema. Smoking tobacco where tobacco causes irritation of the bronchial tree and induces elastase activity by immune cells and also in activation of alpha antitrypsin.

clinical manifestations of COPD

look at slide · Breathing can help recover a deficit which is why they are called pink puffers. Barrel chest is classic but coughing not super common. Hypoxemia is stronger and in tissues can result in condition where people become blue which is why they are blue bloaters. In time, a pink puffer can become a blue bloater. Prolonged expiration is typical for both people. Pink puffer happens late in course and can work with blue bloater.

IgG Levels in CDAD

look at slide for figure · If you don't have good antibodies against c diff you are more at risk

diagnosis and treatment algorithm

look at slide lol i am lazy

obstructive and restrictive flow volume loops

look at slides

LFT Effects of Statins: Clinical Trial Experience

look at slide· Transaminitis is not common and quite frankly is not that different from placebo. But it takes years to determine if person had liver failure. RCT didn't identify this bc they are designed for efficacy not side effects.

hyperaldosteronism

mineralocorticoid disorders: Excess aldosterone Primary aldosteronism Bilateral Adrenal Hyperplasia (BAH) Aldosterone-Producing Adenoma (APA) Glucocorticoid Remediable Aldosteronism (GRA) Secondary aldosteronism

pathogenesis of IPF

multiple pathways of abnormal healing, progressive fibrosis and scar formation injury and apoptosis of alveolar epithelium followed by loss of type I pneumocytes and injury to basement membrane leading to abnormal epithelial cell growth release of growth factors from fibroblasts and myofibroblasts which have enhanced proliferative capacity scarring due to increased collagen and ECM tyrosine kinase activation via various growth factors induces apoptosis and ECM production ER stress and surfactant protein misfolding may contribute hallmark histopathologic changes seen with progression significant alterations in ventilation and gas exchange

structure of the upper airway

nose, mouth, jaw, oral cavity, pharynx (naso, oro, and, laryngo) and larynx -main functions: warm, filter, and humifdify air as it enters · Laminar flow when coming just straight through. Slows down with contact through nasal concare. Ring like muscular tube connects all parts of the nasal and oral cavity and can be separated to the nasopharynx, oropharynx, and laryngopharynx. Now point of interest with the oropharynx where the structure consists of a system ofo cartilage to support the structure. Can cover the space and prevent fluid from coming through the respiratory system.

PREPARATION Long-Acting Muscarinic Antagonists (LAMA)

onset is 1-3 hrs Approved for maintenance therapy of COPD and severe asthma • Tiotropium (Spiriva®)-Kinetic receptor selectivity (dissociation: M3 slowly; M2 fast) • Aclidinium bromide (Tudorza Pressair®)-bid; kinetic selectivity Glycopyrrolate (or glycopyrronium) bromide (Seebri Neohaler®)-bid • Umeclidinium bromide (Incruse Ellipta®)-qd · LAMA onset is 1-3 hours. These agents can have a role in maintenance therapy for copd and severe asthma. Pay attention to the kinetic receptor selectivity and we have the M3 and M2. If Ach sits on M3 we have bronchoconstriction but we block this and then acetylcholine cannot sit on M3. Acetylcholine can go to M2 and reduce its own release. If it stimulates M2 it induces its own release. We prefer to have the M2 available. These scientists have found that these agents have kinetic stability to attach to m3. M3 detach slowly and m2 detach quickly which makes Ach able to stimulate and slow down its own release by binding to M2 instead of M3. This is the principle of kinetic selectivity.

non-atopic (intrinsic) asthma

patients skin prick is negative and total serum IgE conc withint the normal range. a non-antigenic factor may be involved. one of the most common is the onset of exercise. other exampels are breathing cold air or tobacco smoke there is less familial association than for atopic form in the hyper-responsive airways in non-atopic asthma, afferent neurons are stimulated by the stimulus involved. this begins a reflex, which occurs either locally or via the CNS, that leads to contraction of smooth muscle and secretion by submucosal glands recently scientific evidence challenged the dualistic concept of extrinsic and intrinsic asthma. inflammatory cytokines IL4, IL5, and IL13 in bronchial biopsies were similar in both these types of asthma, leading to the concept that these types have similar patterns with activation TH2 cells, mast cells and infiltration of eosinophils. Moreover biopsies, obtained from non-atopic asthmatics showed enhanced expression of high affinity IgE receptor, probably due to the local IgE synthesis in airways Recent scientific evidence in non-atopic asthma where there are interleukins and systemic IgE in lung tissue meaning maybe we didn't catch the effect of non-atopic asthma.

gravity, pulmonary blood flow and ventilation-perfusion ratio

perfusion exceeds ventilation in the bases of the lungs, and ventilation exceeds perfusion in the apices of the lungs. the adequacy of the matching of these two variables is evaluated by ventilation-perfusion ratio or V/Q is 0.8 V/Q ratio decreases from the apex of the lung to the base of the lung

bronchiectasis

persistent abnormal dilation of the bronchi; (obstruction of airway with mucuous plug, atelectasis, infection/inflammation, CF, TB, systemic diseases such as rheumatologic diseases, IBD, AIDS)

ADVERSE EFFECTS OF ICS

pharyngeal irritation coughing dry mouth oral fungal infections (thrush) systemic effects are rare · As we use the spray, it may deposit in vocal cords so could have some irritation, coughing, dry mouth. Corticosteroids decrease the immune system so it gives a change for fungal and other opportunistic infects.

Pleural Abnormalities

pneumothorax: partial or complete pulmonary collapse - a collection of air within pleural space. it destroys the negative pressure of the plerual space. P. types: spontaneous p: -primary (idiopathic or simple pneumothorax) due to ruptured subpleural apical blebs; risk factors: family history, male gender, slim tall stature, smoking, homocystineuria -secondary (a complication of underlying lung disease producing blebs, bullae or cysts --> rupture) traumatic p: (injury) tension p: (life threatening variant of p. characterized by progressively increasing pressures within the chest. may occur with any p. types mentioned above -Pleural effusion- fluid in pleural space; several types; can cause compression atelectasis and displace mediastinal contents. pleural pressure remains negative

ARDS clinical manifestations

rapid shallow breathing initially alkalosis due to hyperventilation work of breathing increases bc of the decrease in compliance cause by alveolar filling and collapse dyspnea and hypoxemia hypoxemia worsens despite oxygen therapy metabolic acidosis bc of the increased work of breathing and cellular hypoxia fluffy infiltrates on chest radiographs if treatment is not effectice, respiratory acidosis develops and further hypoxemia results in hypotension, decreased cardiac output and death

hypoxemia

reduced oxygenation of arterial blood (reduced PaO2) (hypoxia - reduced oxygenation of cells in tissues) 4 causes: 1) decreased O2 content of inspired gas 2) hypoventilation (lack of neurologic stimulation) 3) diffusion abnormalities (emphysema, fibrosis, edema) 4) ventilation-perfusion mismatch (asthma, chronic bronchitis, pneumonia, ARDS, atelectasis, shunting, arteriovenous malformation, congenital defects)

respiratory system

responsible for oxygen and CO2 exchange in the body functionally can be divided into two parts: the conducting airways, and the respiratory tissues of the lungs the conducting airways include the nasal passages, mouth and nasopharynx, larynx, and tracheobronchial tree the lungs are the functional structures of the respiratory system. the lung lobules consist of the respiratory bronchioles, alveoli and pulmonary capillaries the lungs are incased in thin double layered serous membrane called pleura. the pressure in the pleural space is negative to the alveolar pressure, prevents lungs from collapsing the nervous system controls the movement of respiratory muscles and adjust the rate of breathing so that is matches the needs of the body during various level of activity

pulmonary tests

spirometry: to measure forced expiration which is affected by diffuse pulmonary disease diffusing capacity (DLCO): rate of gas diffusion across the alveolocapillary membrane arterial blood gas analysis (ABG): for individuals with suggested or diagnosed pulmonary disease. analysis of pH (acidosis/alkalosis, ventilatory alterations, decreased PaO2) chest rediographs: help to detect lung disease in asymptomatic individuals

atelectasis

the collapse of part or all of a lung by blockage of the air passages (bronchus or bronchioles) or by pressure on the lung 1) obstructive -occurs from a blocked airway (mucus plug, foreign body, tumor inside the airway, general anesthesia (affects exchange of lung gases, which can cause alveoli to deflate) 2) nonobstructive -occurs from pressure from outside the lung (pleural effusion, pneumonia, pneumothorax, tumor)

aspiration

the drawing of a foreign substance, such as gastric contents or food, into respiratory tract during inhalation cause: reduced tongue control, abnormal swallow reflex, neurological and esophageal disorders, throat surgery, dental problems. A. often occurs in individuals with decreased consciousness; effects vary; usually see function with acids; loss of surfatant is possible and lung becomes noncompliant and edematous

3 phases in asthma

the first early phase begins in the first hour. mast cells release inflammatory paracrines such as histamine and particularly leukotrienes. this causes inflammatory changes you would expect in airways -contraction of smooth muscle -edema in all layers of the airway wall -more mucus secretion the second phase begins in 4-6 hours. now cytokines play an important role. there is continued inflammation, but now with infiltration of cells, such as mast cells and often eosinophils. airways become hyper-responsive, a key characteristic of asthma the third phase: finally, over weeks and months, in addition to the inflammation and infiltration by cells there is airway remodeling, which produces visible histological changes in the airways: -walls of the airways thicken, with more submucosal tissue, including capillaries -basement membrane of the epithelium thickens -goblet cell hyperplasia · Early stage of asthma where sensitization happens and abnormal allergic response is generated and mast cells contact with allergen and cause inflammatory changes and edema. Second phase is 46 hours and cytokines begin activity and promote inflammation and associated and airway becomes hyperresponsive. Provides visible airway remodeling in the third phase. Basically we see a thickening of the middle layer of the bronchi and described as airways that happens bc of remodeling and proliferation of cells. Asthma exacerbation could be environmental or genetic factors and cold air or exercises. Viral infection is pretty potently promoting this condition.

mechanics of breathing

the lung and chest wall have elastic properties that permit equation during inspiration and return to resting volume during expiration elastic recoil (ER) is the easy way with which lungs rebound after been stretched by inhalation. it permits passive expiration, eliminating the need for major expiration muscles. if it's damaged (for instance in emphysema) the accessory muscles of expiration are used a) balance between the outward recoil of the chest wall and inward recoil of the lungs occurs at the resting level, at the end of respiration. b) during inspiration, contraction of respiratory muscles, assisted by chest wall recoil, overcomes lung recoil c) at the end of inspiration, the muscle contraction maintains lung expansion d) during expiration, respiratory muscles relax, allowing elastic recoil of the lungs to deflate the lungs lung compliance is a measure of the lungs ability to stretch and expand (distensibility of elastic tissue). low compliance indicates a stiff lung (one with high elastic recoil) and can be thought of as a thick balloon- this is the case often seen in fibrosis. high compliance indicates pliable lung (one with low elastic recoil) and can be thought of as a grocery bag- this is the case often seen in epmphysema lung compliance described the change in lung volume that can be accomplished with a given change in respiratory pressure it is determined by the elastin and collagen fibers of the lungs, its water content and surface tension the elastin fibers are easily stretched and increase the ease of lung inflation, while the collagen fibers resist stretching and make lung inflation more difficult in interstitial lung disease and pulmonary fibrosis, the lungs become stiff and non-compliant as the elastin fibers are replaced with scar tissue. pulmonary congestion and edema produce reversible decrease in pulmonary compliance overstretching the airways, as occurs in emphysema causing the elastic components to lose their ability to recoil, making the lung easier to inflate but more difficult to deflate due to its inability to recoil an important factor in lung compliance is the surface tension in the alveoli. it develops at the interface between liquid film and alveolar air due to the stronger interaction between liquid molecules than air molecules. excess surface tension in the alveoli makes lung inflation more difficult

tests of pulmonary function: chest radiographs

the most common examination of the pulmonary system in case of asthma or emphysema air trapping in alveoli can be detected in case of pneumonia or pulmonary edema- consolidation of lung tissue abscess or TB produces cavities different cancerous changes can be detected as nodules often allow to detect asymptomatic pathological changes

respiratory failure

two out of three clinical indicators: 1) PaO2 less than 60 mmHg 2) PaCO2 greater than 50 mmHg 3) signs of acute respiratory distress (tachypnea, the inability to lie supine without becoming SOB, sweaty, intercostal muscles restractions or abdominal muscle contraction during inhalation)

V/Q ratio: practical implications

ventilation is compromised in pneumonia, asthma, COPD, pulmonary edema. as a result, V/Q ratio is significantly decreased in these diseases absolute pulmonary shunt- perfusion but no ventilation (V=0) in some area of the lung: V/Q = 0 in COPD in addition to reduced ventilation, perfusion is also reduced (damage of pulmonary blood vessels at the late stage of the disease) perfusion is compromised in pulmonary embolism. V/Q = infinity. affected area is named "absolute dead space"

clinical manifestations of asthma

wheezing, cough and dyspnea elevated respiratory and heart rates onset characterized by chest tightness and nonproductive cough prolonged expiration hyperinflated lungs end of episode characterized by cough with thick, stringy mucus pulmonary function test is normal between episodes

chest wall restriction

when chest wall is deformed, immobilized or made heavy by fat; the work of breathing is increased; ventilation may be impaired due to a decreased in tidal volume; causes: obesity, MSK abnormalities (kyphoscoliosis, ankylosing spondylitis, deformity by depression of the sternum, neuromuscular disease)

MOA of ACTH on Cortisol-secreting Cells in The Inner Two Zones of The Adrenal Cortex

· ACTH finds GPCR which is a stimulated g protein coupled to adenylate cyclase to produce cAMP and eventually cholesterol ester hydrolase is activated by phosphorylation with protein kinase A which changes cholesterol esters to free cholesterol to form cortisol, androgens, and such.

Adrenal Gland

· Adrenal gland sits atop the kidneys and the medulla is where we have the catecholiamines. The cortex has different layers which is where our focus is. Remember GFR with the glomerulus outside, then the follicularis, then the reticularis.

Bronchodilation can be achieved by all the following mechanisms EXCEPT: a) Increasing the rate of intracellular c-AMP synthesis. b) Decreasing the degradation of c-AMP by inhibition of phosphodiesterase. c) Inhibition of muscarinic M3 receptors. d) Stimulation of adenosine receptors.

· Bronchodilation can be achieved by all except: D bc it causes bronchoconstriction

etiology of adrenal insufficiency

· Can be atrophy of adrenal gland and as it stimulates there is no production. With addison's disease patients have weight loss, fatigue, myalgia, and heart is even small bc they have chronic hypertension and heart becomes small. Triggers like stress, trauma, and surgery can take them to crisis. Patient with addison's disease they are at risk for crisis bc they are there. These patients may have hyperpigmentation and increased ACTH bc of no activity in the adrenal cortex.

etiology

· Etiology slide will be on exam. We have CRH from hypothalamus where we are producing ACTH and go into cortex and when we have cortisol we have negative feedback to reduce ACTH and CRH. Too much cortisol should have a negative impact and reduce those 2. In cushing's disease, there is a tumor constantly producing ACTH which stimulates the adrenal cortex to produce cortisol so we see some hypertrophy in the adrenal gland. Have that cortisol production which has negative feedback on those 2 and CRH is gonna calm down an the amount of ACTH will decrease producing ACTH but tumor is not responding to negative feedback so ACTH level is not going to be reduced with the negative feedback. In ectopic ACTH the tumor is in the lung here (just not in the pituitary) and it produces ACTH which affects adrenal gland and produces cortisol. Cortisol is increased and gives negative feedback and works on the axis to decrease ACTH and CRH. In the meantime, ACTH level is high so the axis is working but the source of ACTH is somewhere else bc it is still stimulating the glands. How much ACTH is being released from the adrenal pituitary gland. Tumor in the adrenal cortex is an adrenal adem=noma and is ACTH independent and leads to too much cortisol which does negative feedback to the axis to calm it down and doesn't work to decrease cortisol bc the tumor itself is producing it

Patient Case #1: SG is a 55 year-old female with increasing darkening of the skin on her knees and elbows, dizziness upon standing, excessive fatigue, nausea, occasional vomiting and progressive weight loss over eight months prior to presentation. Vitals: BP = 98/60 mmHg, HR = 106 bpm Labs: Na+=136 (L), Cl- =100, K+=5.3 (H), CO2=22, BUN=12, SCr=1.0, Glucose = 69 (L) 1. What is the most likely etiology of SG's symptoms? A. Hyperaldosteronism B. Addison's disease C. Cushing's disease D. Aldosterone-producing adenoma (APA)

· Case 1: patient has Addison's disease and needs both A and C (fludrocortisone and hydrocortisone) bc they need gluco and mineralocorticoid therapy. For part 2 shes overtreated the adrenal insufficiency. Low BP and low sodium clues into low aldosterone. The low glucose levels clues into low cortisol levels. *Darkening of skin on knees and elbows when ACTH levels when they get high cause darkening of skin on high friction areas*. Fludrocortisone as the mineralocorticoid and then the hydrocortisone is a physiologic replacement dose and provides cortisol supplementation. In part 2 shes developing cushingoid type reaction and is over treated adrenal insufficiency (iatrogenic). In terms of dex dose, we recommend C, 0.75 mg QAM bc it represents a dose reduction and bc dex is usually dosed once daily. 30 mg of hydrocortisone = 1.125 mg of dex. If reducing dose to 20 mg then 0.75 is an equivalent dex dose.

Patient Case #4 MR is a 36 year old female with asthma who has recently seen her doctor because she has poor control of her symptoms after getting a new cat. Her physician provided her with the following prescription: Prednisone 60 mg x 5 days, then 40 mg x 3 days, then 20 mg x 3 days, then 10 mg x 3 days 7. Which of the following actions would be most appropriate? a. A steroid taper is required for all patients experiencing an asthma exacerbation to prevent symptom rebound b. The patient can receive a 5-day steroid burst without taper since adrenal axis suppression is unlikely c. The daily prednisone does not exceed the "physiologic" dose of 5-7.5 mg dosed every other day to minimize adrenal axis suppression risk

· Case 4 answer is B.

Patient Case #5 LM is a 24 year old female with rheumatoid arthritis. Her physician tells you than he plans to prescribe Prednisone 10 mg daily for 1 year before he plans to gradually taper her off. 8. Which other orders should you check her medication profile for to prevent adverse effects of chronic steroids? A. Insulin B. Calcium supplementation C. Vitamin D supplementation D. Opportunistic infection prophylaxis with Bactrim® E. All of the above F. B and C only

· Case 5 answer is F (B and C only)

Physiologic Cortisol Circadian Rhythm

· Cortisol follows a circadian rhythm. See peak at 9 am in the morning. Main one is acrophase which is our maximum level of cortisol around 9ish. Then we have 2 other peaks around noon and another around 6 pm. The lowest one is midnight or 1 in the morning and is called nadir which is our lowest level of cortisol and is when we are supposed to sleep. If you change a night shift, the whole circadian rhythm is messed up.

cushing's syndrome

· Cushing's has too much cortisol and will present with moon face bc of fluid retention and redistribution of fat in the body. Also central obesity and buffalo hump is a typical sign. Stretch marks or striae is a hallmark bc it destroys the connective tissue and loss of muscle tone and blood pressure will increase and retain water and sodium to increase the blood pressure. Might even develop diabetes and does the opposite of insnulin and can cause acne or excessive hair growth bc overproduction can also cause adrogen production. Easily bruising, problems with menstruation, osteoporosis, etc. tiredness, sleep. Memory problem and some mood problems and insomnia · Hyperpigmentation characteristic of ectopic tumors · Evaluate each step to see where the problem is. If we want to consider if the patient has cushing syndrome or not the first thing we want to do is check the cortisol. Midnight salivary level should be lowest so if it is high then it could be a problem. There is inferior petrosal sinus sampling as well. A dexamethasone suppression test challenges the ACTH axis. By giving an exogenous corticosteroid we are challenging the axis. Cosyntropin is an analog of ACTH and has enough part of the ACTH to have physiologic effects but no action. Insulin tolerance test looking at a stressor.

LFT Recommendations for Statins

· Don't memorize the exact recommendations. We monitor LFTs for statins are what we need to know.

Regulation of the Hypothalamic-Pituitary-Adrenal (HPA) axis

· HPA axis where in presence of any stress, it stimulates release of some neurotransmitters and stimulates anterior pituitary gland to release ACTH which then simulates the adrenal cortex to produce cortisol. Ccortisol when produced can have negative feedback on these two sources in the axis itself. Can control the release of CRH and ACTH.

Mechanism of Anti-inflammatory Effects of GCs

· Have the corticosteroid there, finds its receptor, enters the nucleus, and finds the corticosteroid binding protein. NFkappaB is an inflammatory cytokine and these are produced by going in and uncoiling the DNAse. When an acetyl group is attached to DNA it opens up the coil and that becomes available for gene transcription. If we remove that acetyl group it will go back in and coil up again. Histone deacetylase will remove the acetyl group and coil the DNA back so it won't be available for corticoids.

HPA axes & immune inflammatory network

· In presence of distress we have release of neurotransmitters. GABA is also inhibitory. There is another component involved and that is the immune system. Cortisol production can also be initiated by the immune system and cytokines can also stimulate the HPA axis and stimulate cortisol. It can also have negative impact on the immune system through negative feedback by cortisol look at slide

MOA of GCs (Cortisol)

· Main MOA of glucocorticoids applies to all the glucocorticoids. Examples are prednisone and such and MOA is the same. Cortisol binds to the corticosteroid binding globulin, goes in, finds its receptor, and such. When steroid comes in, it finds and attaches to its receptor and causes a conformational change. The steroid attached to the receptor will find another unit and become a dimer. This dimer will go into the nucleus and finds a glucocorticoid response element and produces the proteins which causes the response to our stress hormone or cortisol.

Muscarinic antagonists MOA

· Muscarinic antagonists have no effect on mast cells and no effect on microvascular lead or release of histamine or leukotrienes and specifically work on the M3. Can cause bronchoconstriction or work on airway epithelium

What medication(s) would you start in our patient? A.Metronidazole 500mg PO TID x 10 days B.Vancomycin 125mg PO four times daily x 10 days C.Fidaxomicin 200mg PO BID x 10 days D.Culturelle® 16 billion CFU PO BID x 10 days

· Need to know dose for oral vanc- 125 mg po QID but you will see some people use 250 or 500. The concentrations you get 125 are 50-100x the MIC of C diff so going above that doesn't manage any better. No reason to go up on the vanc dose and we will give 1 exception to that. Fidaxomicin is recommended by the IDsa and dosing is the same for every patient and is a twice daily drug. Duration of therapy is 10 days.

Patient Case #2: GM is an 18 year old male with a minor case of contact dermatitis. The physician wants to start a 5 day course of therapy with prednisone 20 mg daily. 5. What steroid taper do you recommend? A. 20 mg on day 1, 20 mg on day 2, 15 mg on day 3, 10 mg on day 4, 5 mg on day 5, then stop B. 20 mg on day 1, 15 mg on day 2, 15 mg on day 3, 10 mg on day 4, 5 mg on day 5, then stop C. 20 mg on day 1, 15 mg on day 2, 10 mg on day 3, 5 mg on day 4, 5 mg on day 5, then stop D. A steroid taper is not necessary in this situation; it is not likely that the patient would develop adrenal axis suppression after 5 days of therapy

· Patient case 2: D where we don't necessarily need a steroid taper since not on therapy for 3 weeks.

Patient Case #3: AS is a 35 year old female admitted to the trauma ICU with pulmonary contusions and multiple fractures s/p motor vehicle accident. Her PMH is significant for Ulcerative Colitis. She has received adequate fluids throughout her hospitalization and is adequately hydrated. Home medication list: Prednisone 20 mg daily Vital signs: BP = 86/61 mmHg, HR = 112 bpm, Temp = 98.6⁰F, All cultures = (-) Labs: Na + = 137, K+ =4.6, Cl- = 102, CO2=26, BUN=15, SCr=0.9 6. How should this patient's glucocorticoid therapy be managed while she's in the ICU?

· Patient case 3 we should give her more steroids based on critical illness needing a stress dose. Hydrocortisone 50 mg IV q6h for anyone in ICU critically ill. In that situation we would stop the prednisone but would want to transition back as we prepare for discharge

RAAS and aldosterone

· RAAS controls mineralcorticoids like aldosterone. If we have any changes in blood pressure or sodium level then we will have to adjust the glomerular cells that will sense low BP and stimulate release of renin and angiotensin 1 and 2 and have vasoconstriction and production of aldosterone. Sodium will be retained and sodium and water increase potassium will decrease. All these changes will happen with aldosterone and will try to bring the BP up. BP will go up especially with vasoconstriction and that is how RAAS controls secretion of aldosterone.

Physiologic diurnal secretion of cortisol

· Surge in cortisol between 6-8 am and then there is a second spike around 6-8 pm. (2/3rds in the morning, 1/3rd at night)

structures of the lower airway

· Trachea has 20 cartilege rings subdivided into segmental bronchi and can see that cartilage is kind of moving out and we see formation of small round alveoli and then divided into alveolar ducts. Sacs interconnected with each other with support of spores of form and densely surrounded by capillary system. Oxygenated blood can then circulate throughout the body.

long term glucocorticoid use

· With long term use of exogenous glucocorticoids, if we give too much prednisone to the patient, it can lead to decreased amount of ACTH and such and if we stop giving prednisone to that patient, then there is no production of cortisol. With ACTH coming back to the normal range, cortisol will start being produced. Which is why we need to wean someone off if they are on it for months

What's in the Pipeline? Astegolimab

• A human IgG2 monoclonal antibody selectively inhibiting interleukin (IL)-33 receptor. • IL-33 is released in response to irritants, viral infection and allergens and act on variety of cells via its receptor ST2. • IL-33 participates in asthma pathogenesis upstream from Th2 pathways • Administered SC every 4 weeks • Proposed for patients suffering from severe asthma who do not respond to currently available biologic agents. • Phase 2b trial: 40% reduction in asthma exacerbation. · Astegolimab targets IL33 and is at phase 2B, don't need to memorize but it has a new target

Cushing's Syndrome - Treatment

• ACTH-Dependent Cushing's Syndrome • Pituitary adenoma (Cushing's Disease) • metyrapone, pasireotide, mifepristone, cabergonline, mitotane • "Ectopic" ACTH secretion from lung, pancreas, or thyroid • metyropone, ketoconazole ± mifepristone, mitotane • ACTH-Independent Cushing's Syndrome • Adrenal adenoma • ketoconazole • Adrenal carcinoma • mitotane ± metyrapone, ketoconazole\ · For ACTH dependent we have a pituitary one and can use an antagonist and when we have ectopic secretion from a tumor we can consider those options. For adrenal adenomas there are things to support

Systemic effects (with large doses) of ICS

• Adrenal suppression • Growth suppression in childrenuse the lowest dose, use spacer • Osteoporosis • Metabolic abnormalities (Glu, INS, TGs) • Psychiatric disturbances (euphoria, depression) • Risk of PNA • Dermal thinning and skin capillary fragility- common in elderly patients. • Cataract and glaucoma · Risk of pneumonia where once they develop pneumonia, you shouldn't give corticosteroids. Dermal thinning and skin capillary fragility seen in pneumonia

HUMANIZED MONOCLONAL ANTIBODIES (BIOLOGIC AGENTS)

• Anti-IgE • Omalizumab (Xolair®) • Anti-IL-5 • Mepolizumab (NUCALA®) • Reslizumab (CINQAIR®) • Anti-IL-5Rα • Benralizumab (FASENRA®) • Anti-IL-4 • Dupilumab (DUPIXENT®) • Anti-TSLP (New class!) • Tezepelumab · There are also inflammatory mediators and we can target these through biologics which are antibodies against these mediators. IgE comes into play in allergic asthma. Also have anti IL5 and also anti IL5 receptor alpha which is a different class

MANAGEMENT OF IPF

• GCS (prednisone) and IS therapy (azathioprine or cyclophosphamide) have not shown any benefits. • An oxidant-antioxidant imbalance may contribute to the pathogenesis of IPF, but the use of an antioxidant, N-acetyl cysteine (NAC), has not shown any benefit. • IPF patients have a high prevalence of GERD and a retrospective study of IPF patients receiving GERD treatment increased length of survival and reduced evidence of fibrosis. · IPF is a progressive disease where lung tissue has increased fibrosis and involves scarring of the lungs, it is irreversible. Eventually when it gets really bad, they go for a lung transplant bc the tissue is not useable anymore. For a while, there were no options until in 2014 we had 2 agents approved to slow the progression of IPF

β2 RECEPTOR POLYMORPHISMS

• Genetic variations in β2 receptors • Common variant is Gly16Arg. • A single nucleotide polymorphism (SNP) has been identified that changes the amino acid code at position 16 from glycine to arginine. • Patients with the homozygous Arg16Arg variant have more frequent adverse effects and a poorer response to SABAs than heterozygotes or Gly16Gly homozygotes. • Pharmacogenomic studies of asthma treatment are an active focus of research, as an approach to the development of "personalized therapy. · People with Arg16 could develop more adverse side effects and if not responding well so it may be because of genetics.

PIRFENIDONE (ESBRIET®)

• Has combined anti-inflammatory, antioxidant, and anti-fibrotic effects • Can significantly improve FVC in patients with IPF MOA: unknown ↓Fibroblast proliferation ↓Fibrosis associated proteins & cytokines ↓ Collagen formation (due to TGF-β & PDGF- fibrogenic mediators) ↓ Accumulation of inflammatory cells ➢Primarily metabolized by CYP1A2 (avoid smoking) SIDE EFFECTS • GI disorders (nausea, diarrhea, abdominal pain) • Photosensitivity rash • Elevated liver enzymes • Decreased appetite, and weight loss · Esbriet has a combo effect, and its MOA is not exactly known but it reduces a lot of different factors that make the tissue more fibrotic and less useable. · Esbriet is metabolized by 1A2 so smoking is strongly rrecommended against. GI side effects could be very severe leading people to stop taking it. *Taking with food decreases the absorption and bioavailability*. It isn't super safe but it is all we have

PREPARATIONS (INHALED) Long Acting β Agonist (LABA)

• Highly lipid soluble; duration of action 12 hours; used for maintenance therapy • In COPD: alone or in combination with LAMA or ICS. • In asthma: only with an ICS. Formoterol fumarate (Perforomist®)-racemic; full agonist; fast onset (3 minutes); may induce tolerance Arformoterol tartrate (Brovana®)-R,R formoterol, ↓ CV effect Salmeterol (Serevent Diskus®)-INH powder; slow onset (30 minutes); partial agonist · Long acting ones are like formoterol. These 3 agents are LABA and are highly lipid soluble which makes them longer acting. Bc it is lipid soluble it is longer acting. Arfomoterol is the R enantiomer of formoterol and can be used in COPD or asthma. Can never use by itself in asthma. Perforomist is a full agonist and this can impact the side effects. Has a fast onset. Can be used also for rescue bc it should be used in 1-5 minutes bc onset of action is 3 minutes. Can use formoterol as a rescue inhaler as well but mainly for maintenance. Advantage bc patient can use same inhaler for maintenance or rescue. Salmeterol was one of the first on the market LABA and has inhalation of pwder and onset is 30 mins but cannot be used as rescue. · LABA pneumonic is For Sale

Control of Adrenocortical Secretion

• Hypothalamic-pituitary-adrenal (HPA) axis controls the production of glucocorticoids (GC) and adrenal androgens. • The renin-angiotensin-aldosterone system (RAAS) is the main regulator of the production of mineralocorticoids (MC). · Main thing that regulates adrenocorticoids are cortisol and there is the HPA axis. HPA is hypothalamic pituitary adrenal axis which regulates production of cortisol and has some control of androgens too. Mineralocorticoid aldosterone is regulated by the RAAs system which controls release of aldosterone

MUSCARINIC ANTAGONISTS in COPD

• In COPD: anticholinergic drugs as effective as or even superior to β2 agonists. • Vagal tone is the only element of airway obstruction in COPD which can be reversed by muscarinic antagonists. • Reduce air trapping and improve exercise tolerance in patients with COPD · In COPD they have an important role bc that is one mechanism that is reversible with COPD which is a progressive disease. We can slow down progression but can't control it or reverse it. In COPD the bronchioles are constricted but when you use muscarinic antagonists it can be less restricted. Can have short acting muscarinic agents.

ANTI-LEUKOTRIENES

• Leukotriene Synthesis Inhibitors • Zileuton • Leukotriene Receptor Antagonists (LTRAs) • Zafirlukast • Montelukast · Zileuton inhibits the synthesis and then 2 agents which block the receptor.

DRUG INTERACTIONS OF ROFLUMILAST

• Metabolized by CYP3A4 and CYP1A2. • Co-administration with strong CYP450 inducers (rifampin) or strong CYP450 inhibitors is not recommended. Contraindication: hepatic impairment. ➢ Use of inhaled PDE4 inhibitors with the idea of reduced systemic absorption and adverse effects has not been effective.

SYMPATHOMIMETICS

• Non-selective • Epinephrine (INH)- α, ẞ1 , ẞ2 stimulator • Indirect-acting • Ephedrine: norepinephrine release (α and ẞ1 stimulator) • Longer acting and less potent than epinephrine ➢Systemic effects (HR↑, BP↑) ➢Should only be used as a last resort · Sympathomimetics can be non-selective and not respond to therapy. Epinephrine mimics the effects of the sympathetic system. Epinephrine works on alpha beta 1 and 2. The focus of pulmonary effect is on beta 2. In the meantime it also works on other receptors. Can cause vasocontriction so that would be a side effect. Beta 1 stimulation increases so we expect some tachycardia with it. As long as we use non-selective agents there are some side effects with it.

PREPARATIONS (INHALED) Short Acting β Agonist (SABA)

• Onset: 1-5 minutes, last 2-6 hrs • First-line for acute attacks of asthma (symptom relievers) and • May be co-administered with a short acting muscarinic antagonist in acute, or severe attacks. o Albuterol (Ventolin®, Proventil®, Proair® HFA) 50:50 R(-) and S(+) o Levalbuterol (Xopenex®) (R-(-)isomer of albuterol, ↑cost) o Terbutaline (Brethaire®)-inhaler discontinued o Metaproterenol (Alupent®)-inhaler discontinued o Pirbuterol (Maxair®)-discontinued (contained CFC) · Can have short acting beta agonists and can be referred to as SABA. From a beta agonist, we expect it to work as quick as possible. Onset of action matters bc onset is within 1-5 minutes and can last anywhere from 2-6 hours. If using for symptom relief or rescue inhalers, it has to be short onset of action. Not for maintenance but for helping to relieve that attack. Can be coadministered with a short acting antagonist. Albuterol is an example. HFA is the propellant that pushes the ingredient out of the container. Used to have CFCs which were damaging the ozone layer and the montreal agreement where countries banned CFC and so instead they started using HFA's. albuterol is a racemic mixture and is 50/50 R and S. found that the R(-) is the active ingredient and can work well enough with less side effects bc S(+) have some cardiac side effects like tachycardia. Not much advantage to it compared to albuterol. Be selective on who gets the S(+).

Roflumilast (Daliresp®)

• Oral product used for maintenance treatment of severe COPD • Reduces incidence of exacerbations • Has little effect on symptoms and lung function • Diarrhea, headaches, and nausea limit its efficacy · Roflumilast can be for severe COPD and is for preventing exacerbation of COPD. Is a last resort and prevents patient from coming back to the hospital.

USE OF GCS

• Prophylaxis of moderate to severe asthma (symptom controllers) • Allergic rhinitis (nasal spray) • Acute episodes of asthma and AECOPD (systemic) • Less significant anti-inflammatory effect in COPD. · Can be used for asthma, allergic rhinitis with like a nasal spray such as flonase, can be used for acute episodes of exacerbation and especially with COPD they can be used systemically. Have to give 5 days of high dose prednisone. In COPD the anti-inflammatory effect is like as in asthma. Anticholinergics are reversible in COPD.

ANTI-INFLAMMATORY EFFECT OF GCS

• Suppression of AP-1 and NF-κB by two mechanisms: • Directly binding to the coactivator, inhibiting histone acetyltransferase (HAT) • Recruiting histone deacetlyase (HDAC2), which reverses histone acetylation, leading to the suppression of activated inflammatory genes. · Anti-inflammatory drugs are the maintenance therapies and are not for acute attack. They are considered controllers. MOA involves binding to the glucocorticoid receptor and the complex would move to the nucleus and proteins would detach and 2 molecules of the steroid receptor would dimerize. Some may be inflammatory versus non-inflammatory and synthesis happens after it is non-inflammatory.

ADVERSE EFFECTS OF ẞ2 AGONISTS:

• Tachycardia • QT interval prolongation • Skeletal muscle tremor • Hypokalemia • Restlessness and insomnia • Tachyphylaxis & tolerance • Metabolic effects (↑Glucose) · Can see tachycardia bc beta 1 agonist (non-selective), can also stimulate some beta receptors in the atrium, or reflex tachycardia where beta 2 acts through vasodilation where following vasodilation we could have reflex tachycardia. Can also cause hypokalemia by pushing potassium into cell (potentially via increased insulin release). Restlessness and insomnia potentially bc of central effects it can have like tachyphylaxis and tolerance. Some metabolic effects with high tolerance. Beta 2 receptors have been studied for a long time and apparently there is a single nucleotide polymorphism.

ADME of Muscarinic Antagonists

• The tertiary ammonium derivatives (atropine, revefenacin) get absorbed rapidly, cross BBB, and have more side effects. • The quaternary ammonium compounds (ipratropium, tiotropium, glycopyrrolate, aclidinium and umeclidinium) have poor systemic absorption, do not cross BBB, and have better tolerability. • Most of the drugs administered by inhalation is swallowed. Most of the swallowed drug is appeared in the feces. • After inhalation, maximal response is seen over 30-90 minutes. • Onset of action of LAMAs: 1-3 hours, persists ≥24 hours, suitable for once daily dosing.

METHYLXANTHINES

• Theophylline, theobromine, and caffeine. • Affect CNS, kidney, and cardiac and skeletal muscle as well as smooth muscle. • Theophylline is the most selective in its smooth muscle effects. • Caffeine has the highest effect on CNS. · Methylxanthines basically have a methyl group in the structure. Have effects in CNS, kidney, cardiac, skeletal, and smooth muscles. Between these 3, theophylline is more selective towards the effects on the smooth muscle. Caffeine has more effect in CNS. Can see shaky hands, tachycardia, GI motility, frequency in urinating, etc.

SIDE EFFECTS OF MUSCARINIC ANTAGONISTS

• Well-tolerated due to poor absorption • May cause dry mouth, urinary retention, nasopharyngitis, upper respiratory tract infection and GI disturbances. CNS effects: Headache, dizziness and blurred vision. CV: tachycardia • Unpleasant bitter taste is reported with ipratropium • Risk of glaucoma in elderly, when ipratropium bromide is nebulized using a face mask. ➢Use with caution in patients with renal failure, prostatic hypertrophy, urinary retention, or glaucoma · Side effects of muscarinics include anticholinergic effects like blurred vision, constipation, urinary retention, etc. have to watch for at risk patients such as those with renal failure, urinary retention, glaucoma, etc. use with caution bc patients can worsen the situation. Recommended to use a mouth device instead of face mask

PREPARATIONS (INHALED) Ultra-Long Acting (ultra-LABA)

• onset 30 min; duration ≥ 24 hours • once daily • Used for COPD Indacaterol (Arcapta Neohaler®) Olodaterol (Striverdi Respimat®) Vilanterol-only in combination · Ultra-LABA we have 3 agents. Vilanterol has to be used in combo only. Expect use to be once a day and can be used for COPD. Not used in asthma. Pneumonic is VIOLIN. ViOlIn (vilanterol, olodaterol, indacterol)

probiotics

•Data is primarily in pediatrics but there are 3 uses: •Pediatrics, antibiotic associated diarrhea, and C. difficile associated diarrhea •Probiotics reduced the duration of diarrhea by ~ 24 hours in diarrhea that lasted ≥4 days •More research is needed to determine which particular probiotic regimen would be of best benefit •Multiple strains taken multiple times daily* •Caution use in immunocompromised hosts

Additional Important Questions: How would you respond...

•"Let's restart his loperamide today as well to decrease the amount of watery stools." •"We should restart his levofloxacin to complete a full 10-day course for his CAP." •"Let's add rifampin therapy for synergy in this critically ill patient." •"When should we recheck C. difficile toxins?" •"Our patient cannot get CDAD after this round of antibiotics because he is being treated with an active antibiotic (metronidazole or vancomycin)." •"Should we monitor vancomycin levels from oral medication?" •"Should we lengthen the course of therapy for CDI if the patient is receiving concomitant antibiotics, such as cefepime?" •"Our patient has a history of 2 recurrent CDI and now she needs Augmentin (amoxicillin/clavulanate) for a sinus infection. What should we do?"

Introduction to Fecal Transplant

•"Transplanting" feces to establish a new, healthy gut microbiome to control overgrowth of pathogenic bacteria •First described in 1958 humans •Prevalent use in Canada, Europe

Recurrence/Relapse Risk Factors

•20-25% of patients will fail initial therapy •Each relapse further increases risk for future relapses •Risk factors: •Previous recurrence •Age (>60, further >75) •Immunocompromise •*Concurrent antibiotics* •PPI tx? - RF for initial disease, thought to be for recurrence

clinical presentation of C diff

•Acute onset •Watery diarrhea (could be >10 per day) •Leukocytosis •May be acute & extreme (e.g. >30K possible) •Abdominal cramping •Complications/Extensive disease •Pseudomembraneous colitis •Colonic damage · Clostridioides difficile is after antibiotics and antibiotics destroy normal gut microbiome and becomes opportunistic. Infects in the colon because it likes a higher pH. 90% of the time due to exposure to antibiotics. This is watery diarrhea and patients report between 6 and 12 watery stools per day. Could have a really high spike in WBC and is an acute leukocytosis where somebody could be cruising along (normal WBC 6-10 thousands) and the next day theyre at 20,000. When this accompanies diarrhea, C diff should be in mind. Can get pseudomembranes which is like a yellow plaque and look like play doh has been caked in someones colon and represents colonic tissue that is no longer viable. Very serious complication almost always attributed to C diff and happens in 2-5 cases of C diff.

General Risk Factors for CDAD

•Antibiotic exposure •PPI exposure •Infection control •Patient specific factors: •Alterations in normal gut flora •Use of gastric acid suppression therapies (PPIs especially) •Age (elderly) •Immunosuppression -antitoxin A IgG levels •Immunosuppressant therapy? •Compromise of intestinal peristalsis = decrease elimination of organism & toxins

Hemolytic uremic syndrome

•Direct toxin effect on endothelial cells •Triggers platelet aggregation & resulting microthrombi •Primarily affects the kidney •Treatment •Supportive care primarily

Oral Vancomycin: What do we use?

•Dosage forms? •Capsules •Firvanq® •Powder for oral solution (requires reconstitution) •Can we use IV formulation, orally? •Cost concerns?

diagnosis tools for CDAD

•Clinical suspicion based on clinical presentation & risk factors Glutamate dehydrogenase EIA Common C. diff antigen; Step 1, must then do EIA or PCR for Step 2 to know if toxigenic Sensitivity: 85-100 Specificity: 70-80 EIA (A or A/B) Detects Toxin A and B; Rapid and inexpensive Sensitivity: ~75, repeat test common Specificity: 95-98 Cell culture cytotoxin assay Not routinely done, highly specialized Sensitivity: >95 Specificity: 90-95 Real-time PCR for Toxin B (NAAT) Detects toxin in genes typically Toxin B, but can be both; results in hours Sensitivity: >95 Specificity: 80-100 Stool toxin culture Not routinely done, highly specialized Sensitivity: >95 Specificity: 80-100 Typing Not routinely done but identifies BI/NAP1 strain · Cannot culture c diff. c diff has to be detected by other mechanisms. The toxin most present with c diff is toxin b so we can screen for toxin b. EIA is an enzyme immunoassay to test for either toxin a and B or just toxin B. sensitivity is lower for EIA than others but if negative we would repeat the test but now some use EIA and not repeat bc they only want the important ones bc pcr is so senstivie it will pick up recovery from C diff and goes on hospital report card and the hospital has to reimburse the patient bc it is the hospital's fault if hospital acquired. Enzyme aminoassay detects toxin production. Glutamate dehydrogenase (GEH) is present in all c diff so it is used as a screening tool and if positive they'll hunt for toxins or do PCR to confirm. GEH could be positive bc of c diff that isn't producing toxins but we don't want to treat it if there are toxins. Also can do PCR which is very very sensitive. Need to be aware of 3 diagnostic tools (EIA, GEH, PCR). But you need to have at least 3 watery stools before you are even tested for c diff (the 3 stools are within a day)

Therapy in Severe/Complicated CDI

•Combination therapy •Vanc PO vs. Vanc PO + metronidazole IV combo in critically ill •Retrospective analysis, single center, N=88 patients •In-hospital mortality: 36.4% monotherapy vs. 15.9% combo therapy (p<0.05) **Outside of ICU, combination therapy ONLY increases ADEs, so not recommended •What about rectal vancomycin? •Outcomes mixed but no definitive studies •Some risks associated with PR vancomycin •Appropriate delivery •Metabolic acidosis from 0.9% NS in colon (rare) •Perforation •May consider in addition to combo therapy in severe/complicated cases especially when ileus suspected · IV vanc is not on this list bc *IV vancomycin does not get to the colon*. Iv metronidazole does get to the colon. Vanc has a topical effect (runs down the gut to coat the colon). Avoid oral metro unless you really have to use it. · Fidaxomicin is also oral topical effect and only concentrates in the gut. Is technically macrocyclic but is almost identical to a macrolide antibiotic. If you have a patient with a severe macrolide allergy we may want to avoid on.

OpenBiome

•Commercially available product used by many institutions •Donors are screened for numerous communicable diseases and colonization of MDROs

Recurrence/Relapse of CDI

•First line therapy often vancomycin (avoid metronidazole) •Fidaxomicin an option? •Bezlotoxumab? •Pulse dosing or tapering of vancomycin over 6 - 8 weeks •One example: See prior chart •Additional alternatives for multi-recurrence include adjunctive tx. •Fecal transplant may be best option with multi-recurrence

Treatment of NPO Patient

•Intravenous metronidazole has reports of both success & failures -Theoretically hepatic re-circulation of metronidazole should achieve good concentrations in the gut -IV vancomycin should be avoided •Vancomycin PR enemas -250-500mg QID in 500 - 1000 cc •Addition of IV metronidazole to PR vancomycin •IVIG •Colectomy May be considered as an indication for NG placement

E. coli 0157:H7

•Major serotype of EHEC •Highly virulent •Severe complications •Death from hemorrhagic colitis or hemolytic uremic syndrome (HUS) •Lower ID than other E. coli (perhaps 10²) •Outbreaks •Undercooked ground beef •Petting zoos, contaminated drinking water (water fountains), other vegetables (spinach) •Reportable condition to DHEC in SC •62 cases of shiga toxin producing E. coli in SC from 2010-20131

New monoclonal antibody therapy: Bezlotoxumab (MK-6072)

•Monoclonal antibody - Toxin B •Actoxumab - Toxin A •RCT evidence MODIFY I 1452 pts, 19 countries Age ~65 years Bezlotoxumab 10mg/kg x 1 IV infusion vs actoxumab 10mg/kg x 1 IV infusion vs both (all plus SOC) 12-week CDI recurrence Bez: 17.4% Placebo: 27.6% (P=0.0003) Bez+Act no more effective Actox alone not effective ADE similar to placebo (mostly GI) MODIFY II 1168 pts, 17 countries Age ~67 years Bez 10mg/kg x 1 IV infusion vs both (all plus SOC) 12-week CDI recurrence Bez: 15.7% Placebo: 25.7% (P=0.0003) Bez+Act no more effective Actox alone not effective ADE similar to placebo (mostly GI) •Not used as monotherapy •Should only be used in conjunction with antibacterial drug treatment for CDI (i.e., adjunct therapy) •Timing of administration •Administer at any time during CDI antibiotic treatment (per package insert) •However, in clinical trials, 94% of participants received bezlotoxumab within 6 days of initiation of antibiotic treatment. •Outpatient vs. inpatient •Caution in CHF •In patients with a history of CHF, higher rate of heart failure (12.7% vs. 4.8%) and mortality (19.5% vs. 12.5%) in patients treated with bezlotoxumab vs. placebo · Last option would be bezelotoxumab and is novel and available for bacteria. Starts with b bc it targets toxin B. bezlotoxumab is only given as an adjunct to another standard therapy and typically given as oral adjunct or monotherapy. Could also be a one time IV infusion which needs to occur while you're getting the other antibody and give during that 10 day course of vanc or fidaxomicin. Should really give this outpatient bc it is not really reimbursed in hospital. Reduces recurrence significanctly but does not increase clinical cure. In some of the studies clinical cure went up 4%. Significant warning for heart failure patients. Patients with underlying heart failure had increasing exacerbations and higher mortality so don't give in heart failure. Thought to have negative effects on the heart directly

Proper Dose of Oral Vancomycin

•N=13 •Matrix & liquid formulations •Concentrations consistently at least 50-1000x above MIC50/90=1mcg/mL •Significant variation between pts. •Vanc concentrations increased as stool became more formed

Vancomycin vs. Metronidazole Focus on Mild Disease

•National cohort study of Veterans with initial mild disease •Mild disease= WBC < 15 cells/mm3 and SCr < 1.5 mg/dL within 7 days of CDI treatment •Observational comparative efficacy analysis, N= 115 propensity-score matched pairs < 65 yo, Vanc vs. MTR •No significant difference in: •30-day all-cause mortality (HR 0.29, 95% CI 0.06-1.38), •Recurrence (HR 0.62, 95% CI 0.26-1.49), or •Failure (HR 0.50, 95% CI 0.23-1.07) •Metronidazole may be an appropriate treatment option for initial mild disease in patients < 65 years old.

Treatment of CDAD

•Oral route preferred •Decision to initiate based on clinical signs and a (+) test Metronidazole: 500mg PO/IV TID x 10 days Non-severe aka mild disease (as alternative) Dysgeusia, Disulfiram Rxn, Neurotoxicity Vancomycin: 125mg PO QID (may increase up to 500mg QID if critically ill) x 10 days Taper: Vancomycin 125mg PO QID for 21 days, then 125mg PO BID for 7 days, then 125mg PO QD for 7 days, then 125mg PO 3x weekly for 7 days, then 125mg PO 2x weekly for 7 days, then 125mg PO once weekly for 7 days. First line for non-severe or severe Taper is for recurrence Mild GI possible Fidaxomicin: 200mg PO BID x 10 days High-risk of recurrence (Can be used in mild, moderate or severe as first line) Typically benign Macrolide allergy? · Could do pulse dosing or tapered dosing where instead of 10 days we may do that for a week then taper (2 times a day for a week, 1 time a day for a week, etc) to break cycle of recurrence and allow for some gut healing. Or 3 times a week for 6-8 weeks.

Fidaxomicin Allergy

•Postmarketing surveillance identified 12 cases of hypersensitivity reactions •Rash, facial swelling, dyspnea, angioedema, purpuric rash •Fidaxomicin labeling revised to include information on possible hypersensitivity reactions •Fidaxomicin is a macrolide •3 of the 12 reports indicate previous reaction to macrolide

Vancomycin vs. Metronidazole Focus on Severe Disease

•Retrospective analysis 460 hospitals, 20 million cases (16th European ID & Clin Micro 4/07) •Clinical cure not reported - BUT significant difference in length of stay, mortality, & ICU time (favoring vancomycin) •RCT, N=172 pts. Vancomycin vs. MTR •Mild disease = MTR 90% vs. V 98% (p=0.518) •*Severe disease = MTR 76% vs. V 97% (p=0.02)* •Severe CDI = vancomycin as primary therapy

toxins in C diff

•Toxin A (tcdA) •Toxin B (tcdB) •Present in majority of toxigenic strains •Binary toxin •Unknown true impact, although presence may increase other toxin release •Ribotyping (aka certain "strains" of C. difficile) •May impact severity of disease, transmissibility •BI/NAP-1 O27 strain - example of well described "hypervirulent" strain...although debatable · Toxin A and toxin B where some c diff have both of these but these are the toxins that cause the watery diarrhea and colitis. Basically all of them express toxin B.

summary of c diff

•Wash your hands = soap & water...and scrub for CDI prevention •Gastroenteritis primarily self-limiting, viral •Antibiotics indicated in protracted illness and/or IC host •CDI Risk factors = Antibiotic exposure, PPI exposure, age •CDI Treatment •Vancomycin is now recommended generally as first line therapy in all patients - although Bookstaver believes metronidazole CAN be used in certain cases of mild disease •Combination therapy not warranted outside of the ICU, then it should be used •Mild disease is perhaps a byproduct of sensitivity of PCR testing •Antibiotic stewardship is a primary way to reduce CDI incidence especially in high-risk individuals

COMBINATION INHALERS LAMA/LABA:

▪ Aclidinium/Formoterol (Duaklir Pressair®-aerosol powder): bid ▪ Glycopyrrolate/indacaterol (Utibron Neohaler®-capsule): bid ▪ Glycopyrrolate/formoterol (Bevespi Aerosphere®): bid ▪ Tiotropium/olodaterol (Stiolto Respimat®): qd ▪ Umeclidinium /vilanterol (Anoro Ellipta®-aerosol powder): qd · Be familiar with, no need to memorize the combo products. Be able to identify which is LABA and which is LAMA and how frequently they will be used. Would expect once a day.

Toxicity of GCs

▪ Could be due to long term use at supra-physiological doses. ▪ These effects include fluid and electrolyte abnormalities, hypertension, hyperglycemia, increased susceptibility to infection, peptic ulcers, osteoporosis, myopathy, behavioral disturbances, cataracts, and growth retardation in children. · In hepatic failure our choices are hydrocortisone and prednisolone

Levoketoconazole (Recorlev®)-PO

▪ FDA approved December 30th, 2021 ▪ 150 mg tablet ▪ 2S, 4R enantiomer of ketoconazole ▪ More potent steroidogenesis inhibitor than its racemic mixture, ketoconazole, inhibiting CYP11B1 (11 βhydroxylase), CYP11A1 (cholesterol side-chain cleavage enzyme), and CYP17A1 (17 αhydroxylase). ▪ Used for treating endogenous hypercortisolemia in adults with Cushing syndrome for whom surgery is not an option or has not been curative. ▪ Warning: Hepatotoxicity; QT interval prolongation ▪ Drug-drug interactions! ▪ Not approved for treatment of fungal infections Levoketoconazole is recent and is a combination of the enantiomers. Recently came and FDA approved in 2021. Po med and see the targets as CYP11B1 and CYP17.and can be used for cushing syndrome for whom surgery is not an option or the surgery didn't have the outcome we wanted. First line is surgery, this is a second option.

Revefenacin (Yupelri®- solution for nebulizer)

▪ First once daily nebulized LAMA. ▪ High lung selectivity. ▪ It competitively and reversibly inhibits M3 receptors in bronchial smooth muscle. ▪ Rapidly absorbed, metabolized via hydrolysis of the primary amide to carboxylic acid. Elimination t1/2 is 22-70 hours. ▪ Indicated for maintenance treatment of COPD. · Revefenacin is highly selective and gets metabolized and indication is for maintenance of COPD.

Aminophylline-IV

▪ Salt of theophylline: theophylline ethylenediamine (2:1) ▪ Improved water solubility (25 mg/mL IV solution vs 0.8 mg/mL) ▪ Shorter action than theophylline ▪ Theophylline dose is 79% of aminophylline dose. ▪ IBW is used for dosing (theophylline distributes poorly into body fat). ▪ Narrow TI, monitor levels (therapeutic levels: 5 to 15 mcg/mL) USE of methylxanthines: control of symptoms in asthma and COPD, either alone or in combination with ICS. · Aminophylline is in IV formulation. Solubility is really low for theophylline so a better option is aminophylline. It has improved solubility and now we can have concentration as 25 mg/ml. this is preferred for IV formulation but duration of action is a little shorter. Use ideal body weight for dosing bc it doesn't have good penetration.

WARNINGS & PRECAUTIONS with beta 2 adrenergic antagonists

▪ β2 adrenergic agonists should be used with caution in: ▪ Hyperthyroidism ▪ Severe cardiac disease (arrhythmia and hypertension) ▪ Diabetes ▪ Hypokalemia ▪ Hx of seizure ▪ Patients taking β-blockers (non-selective) or monoamine oxidase inhibitors. ▪ Avoid LABA monotherapy in patients with asthma ▪ Prolonged bronchodilation masks symptoms of bronchial inflammation, increasing the risk of life-threatening and fatal asthma exacerbations. · Be cautious with hyperthyroidism and if there is cardiac disease bc of potential for tachycardia. Hypokalemia could worsen it bc of pushing potassium into cell. Or MAOI bc they affect metabolism of beta 2 agonists bc they are very similar to catecholamines. Avoid LABA monotherapy bc they can mask symptoms of bronchial inflammation leading to increased risk of life threatening asthma exacerbation.

Diagnostic Tests Assessing The HPA Axis

▪24-hour urine cortisol ▪Midnight salivary cortisol level ▪The plasma ACTH level ▪Inferior petrosal sinus sampling ▪Dexamethasone suppression test ▪Cosyntropin (ACTH 1-24) test (stimulation) ▪Insulin tolerance test (ITT) · Cushing starts with a 24 hour urine. If elevated we have to look into plasma ACTH or give dexamethasone suppression test and look into an adrenal tumor situation. Compare these with each other and see the thought process. Cortisol will decrease 50% and can still have some decreased effect and can guide you if there is cushing's disease and best way is removing the tumor. Even a high dose of dexamethasone will not suppress it bc ACTH was coming from another location

Metyrapone (Metopirone®)-PO

▪A selective inhibitor of CYP11B1 (11-beta hydroxylase) ▪Metyrapone is used in diagnostic test of HPA axis. ▪Off label use: to treat the hypercortisolism due to inoperable adrenal neoplasms or tumors ectopically producing ACTH. ▪Chronic use causes: hirsutism and HTN (elevated levels of 11- deoxycortisol/11-deoxycorticosterone that have MC activity) · Metyrapone is for hypercortisolism and can cause some hirsutism. Whatever is before that is going to build up and produce more androgen or mineralocorticoid.

Mineralocorticoids (MCs)

▪Aldosterone is the most important MC in humans ▪Deoxycorticosterone (DOC) is a precursor of aldosterone (unlike aldosterone ACTH primarily controls its production). ▪Fludrocortisone, a synthetic CS, is the most prescribed salt-retaining hormone with low GC effects. ▪MCs promote the reabsorption of Na+ from the distal part of the distal convoluted renal tubule and from the cortical collecting tubules, excreting K+ and H+ . ▪Excessive levels of aldosterone produced by tumors or overdosage with synthetic MCs lead to hypokalemia, metabolic alkalosis, increased plasma volume, and HTN. MOA: Bind to mineralocorticoid receptor (MR) in the cytoplasm of target cells, especially principal cells of the distal convoluted and collecting tubules of the kidney. ▪ Increase the expression of Na+ /K+ -ATPase and the epithelial sodium channel (ENaC). ▪ MCs are specific to the kidneys due to presence of the enzyme 11β-hydroxysteroid dehydrogenase type 2, which converts cortisol to cortisone, so only MC effect will be seen and not GC effect. ▪ Cortisone has reduced GC activity in the kidneys.

Etomidate (Amidate®)-IV

▪An anesthetic and sedative agent ▪At sub-hypnotic doses inhibits CYP11B1 activity ▪Is the only parenteral medication available in the treatment of severe Cushing's syndrome ▪May cause muscle spasm and pain at injection site. ▪Off label use: to treat hypercortisolism when rapid control is required in a patient who cannot take oral medications. etomidate is IV for urgent situations if we want rapid control. Used for hypercortisolism.

CORTICOSTEROIDS

▪Can be used in adrenal insufficiency as a supplement for the deficiency (physiologic level) ▪The corticosteroids are grouped based on their relative GC and MC activities and duration of action. ▪Fludrocortisone has strong MC activity with minimal GC effect. ▪Categorized based on half-life: ◦ Short acting (8-12 hrs) ◦ Intermediate acting (12-36 hrs) ◦ Long acting (36-72 hrs) · Exogenous corticosteroids used for adrenal insufficiency and if we have hypo and not enough cortisol produced then we have to give exogenous glucocorticoids.

Ketoconazole (Nizoral®)-PO

▪In high doses, inhibits adrenal and gonadal steroidogenesis ▪Inhibits CYP17A1 (17α-hydroxylase). At higher doses inhibits CYP11A1, effectively blocking steroidogenesis in all primary steroidogenic tissues. ▪Best tolerated, most effective, but not FDA approved for CD. Oral absorption requires gastric acid. ▪Side effects: liver impairment, QTc prolongation. ▪Increased risk of drug-drug interaction by altering drug transport and metabolism through inhibiting P-GP and CYP3A4 · Inhigh doses, ketoconazole can inhibit adrenal and gonadal steroidogenesis and inhibits the cyp17A1 and also at higher doses inhibits CYP11A1 which cleaves the side chain. By doing that it can prevent the synthesis of all these mineralocorticoids. Would expect not producing androgen, mineralocorticoid, cortisol, etc. not selective so it may not be the best. Oral absorption of ketoconazole requires gastric acid. Very important for liver impairment and Qtc prolongation

Mitotane (Lysodren®)-PO

▪Is a steroidogenesis inhibitor and an adrenocorticolytic agent used to treat inoperable adrenocortical carcinoma. ▪It inhibits CYP11A1, CYP11B1, and CYP11B2 (aldosterone synthase) thereby reducing steroid synthesis. ▪Its cytolytic action is due to its metabolic conversion to a reactive acyl chloride by adrenal mitochondrial CYPs and subsequent reactivity with cellular proteins. ▪Onset of action takes weeks to months ▪Adrenal crisis may occur in the setting of shock or severe trauma and response to shock is impaired. Hydrocortisone replacement is advised in patients treated with mitotane. Adverse effects: ▪CNS toxicity: depression, dizziness, and ataxia (requires discontinuation and restart at lower doses) ▪GI disturbances: anorexia, diarrhea, N & V (use with antiemetics) ▪Vision changes: blurred vision, diplopia Pregnancy: ▪Potent teratogen ▪Long half-life (18 to 159 days) defer pregnancy up to 5 years post discontinuation of the drug. · Mitotane is an adrenolytic agent and kills the cells like a chemo drug. Can destroy the cells. Can affect all the ezymse listed and have a lot of side effects. Cytolytic actions bc in our body it changes to a reactive acyl chloride to react with the protons basically. Potential for adrenal insufficiency bc of cytolytic action . · Side effects like toxicity and vision changes and if patient has ataxia (loss of coordination) we need to hold the dose or restart with a lower dose. Some GI disturbances have been seen and can report blurred vision.

Pasireotide (Signifor®-SC; Signifor LAR®-IM)

▪LA somatostatin analogue with high affinity for SSTR5 ▪Activation of SSTR5 → inhibition of ACTH secretion→ ↓cortisol ▪FDA-approved for CD with over expression of SSTR5 ▪Adverse effects ▪GI discomfort (diarrhea, nausea, abdominal pain), hyperglycemia, gallstones, headache, HTN, peripheral edema, bradycardia, QTc prolongation, flu-like symptoms, and hair loss. ▪ Less side effects with the long-acting release formulation which is given IM every 28 days. · Pasireotide is in 2 formulations and is a PO medication. · Pasireotide is a somatostatin analog which works of multiple receptors of somatostatin 1-5 but this drug is preferential for somatostatin 5. Is a somatostatin analog with inhibitory. As activated it prevents release of ACTH. By inhibiting that we have less cortisol production. Is an FDA approved drug for acromegaly and cushing disease with over expression of SSTR5. So many side effects with it. Have to monitor carefully. Risk of Qtc prolongation and check liver enzymes. Side effects worse for SC bc it is short acting

ALLERGEN IMMUNOTHERAPY (AIT)

❖Prevention of hypersensitivity in patients with allergic rhinitis and asthma with minimal response or intolerance to symptomatic therapy or with high risk for morbidity upon exposure to allergen. ❖Administration of increasing doses of allergen to patients with evidence of specific IgE antibodies to induce immune tolerance. · If the patient has severe allergic reaction to asthma, we could desensitize these patients through AIT

EFFECTS OF GCS ON GENE TRANSCRIPTION

➢ Increasing the transcription of anti-inflammatory genes: ▪ Annexin-A1: Annexin A1 suppresses PLA2, blocking eicosanoid production, inhibiting the two main products of inflammation, PGs and LTs. ▪ β2-adrenergic receptor (potentiating the actions of β2 agonists) ▪ Cytokine: IL-10 ➢ Decreasing the transcription of many pro-inflammatory genes: Cytokines:IL-4, IL-5, IL-9, IL-13, TNF-α and GM-CSF. ▪ Inflammatory enzymes (COX-2) · NfKappa, glucocorticoids can bind to coactivator in transcription of these inflammatory genes and is not sitting directly on the DNA. Histone acetyltransferase uncoils the DNA and bind to coactivator and either have inhibitory effect or would recruit HDAC2 and would remove the group and could coil back the DNA to not be available for transcription. · Another impact is on annexin A1 and induces some protein synthesis. Annexin A1 is a phospholipase A inhibitor and is an inhibitor of phospholipase A1 and is involved in prostaglandins and leukotrienes. If you increase annexin A1 it prevents inflammatory mediators and works with beta agonists synergistically and has a potentiating effect on beta adrenergic receptors. Will also decrease transcription of some pro-inflmmatory genes. Work in so many different ways. Slide summarizes everything

Cabergoline (Dostinex®)-PO

➢A potent LA dopamine D2 receptor agonist used primarily to treat hyperprolactinemia. ➢Cabergoline binds the D2 receptors on pituitary corticotroph adenomas inhibiting the secretion of ACTH. ➢Off-label use in CD ➢Has a very long half-life (65 hrs), given once or twice weekly. ➢May cause nausea (give with food), headache, hypotension and dizziness. ➢Avoid use in patients suffering from psychosis · Cabergoline is for hyperprolactinemia but also can inhibit secretion of ACTH and attaches to receptors on the pituitary adenoma. Can sit on the receptor and reduce secretion of ACTH. Not FDA approved and given once or twice weekly with side effects of nausea, hypotension, dizziness. With nausea they recommend giving it with food.

BRONCHODILATORS

➢Bronchodilator: c-AMP • β2 adrenoceptor agonists (↑c-AMP) • PDE inhibitors (↓ c-AMP degradation) ➢Bronchoconstrictors: Acetylcholine (ACh), Leukotrienes (LTs), and adenosine • Inhibit bronchoconstriction • Leukotriene antagonists • Muscarinic antagonists • Adenosine antagonists · Anything that can increase cAMP can increase bronchodilation. By stimulating adenylate cyclase. Some mediatiors can cause bronchoconstriciotn and that includes leukotrienes, acetylcholine, and adenosine. Anything that can reduce these will be helpful. Theophylline can have a secondary mechanism by blocking the effects of adenosine.

Addison's disease

➢Symptoms: weight loss, fatigue, myalgia, fever, anemia, and chronic hypotension leading to small hearts due to decreased work of the heart. ➢Triggers (stress, trauma, infection, surgery) can result in severe hypotension and shock, which is an endocrine emergency called "Addisonian crisis". ➢Circulating ACTH levels are elevated (presenting with spotty pigmentation of skin creases) · Can be atrophy of adrenal gland and as it stimulates there is no production. With addison's disease patients have weight loss, fatigue, myalgia, and heart is even small bc they have chronic hypertension and heart becomes small. Triggers like stress, trauma, and surgery can take them to crisis. Patient with addison's disease they are at risk for crisis bc they are there. These patients may have hyperpigmentation and increased ACTH bc of no activity in the adrenal cortex.

AS, a 63 year old WF with copious bloody emesis §PMH: PBC (dx 2002); cirrhosis (dx 2019) §Meds: Nadolol 40 mg daily §HPI: Pt presents to emergency room with bright red blood emesis §Vitals: BP: 88/66 HR: 52 O2 Sat: 98% What next steps are indicated in AS now?

AS esophageal varices burst`

Laboratory Evaluation:"Cholestatic Pattern"

Alkaline phosphatase (alk phos) Gamma-glutamyl transferase (GGT) ¡Think bile flow problem (i.e.; it cannot get out of the liver and into the duodenum for eventual expulsion) §Primary biliary cirrhosis §Primary sclerosing cholangitis §Drug-induced cholestasis (example: estrogen, anabolic steroids) §Bile duct obstruction ¡Alk phos and GGT elevation not specific for liver (present in various tissues) §HOWEVER, alk phos elevation accompanied by GGT elevation is suggestive of hepatic disease · Cholestatic tests when elevated means there is a bile flow problem, have a backup in the system. Includes primary biliary cirrhosis and sclerosing cholangitis. Birth control pills can cause this. Bile duct obstruction like gallstones. These are not specific for the liver but are present in various tissues and those include the liver.

treatment of gastroenteritis

Causes: Viruses Rotavirus Norwalk virus Astroviruses Enteric adenovirus Treatment: •Primarily symptomatic care •ORT •Loperamide •In cases of severe, symptomatic dehydration or extreme ages IV rehydration may be required Causes: Parasites Giardia lamblia Entamoeba histolytica Cryptospordium Strongyloides Microsporidia Treatment: •Metronidazole •Albendazole •Nitazoxanide •Paromomycin Causes: Bacterial Campylobacter (most common bacterial cause) E. coli* Shigella sp. Salmonella Clostridium sp. Vibrio cholera Yersinia Treatment: •Primarily symptomatic care •Consider antibiotic therapy for the following indications: •Extended duration of illness (~4+ days) •Systemic symptoms for extended periods (typically >72 hours) (e.g. fever) •Unresponsive to symptomatic care •Severely immunocompromised •When antibiotics are indicated, options include: •Ciprofloxacin 250-500mg PO BID x 3-5 days (or 400mg IV) •SMX/TMP 1 DS PO BID x 3-5 days •Doxycycline 100mg PO BID •Macrolides (Azithromycin) (limited activity against some pathogens)

child pugh example

KD is a 65-year-old male who has been diagnosed with cirrhosis for the past 2 years. KD presents with mild ascites, esophageal and gastric varices with no bleeding, and no apparent encephalopathy. Pertinent laboratory values are: §total bilirubin 2.5 mg/dL (0.3-1.2) §albumin 2.9 g/dL (3.2-4.6) §prothrombin time 19.5 seconds (12.5-15.2) KD is currently having difficulty with overactive bladder and his physician is considering starting him on darifenacin. Based on the patient's Child-Pugh score and the following information from darifenacin's dosing information, what dose will you recommend for BT? · A is mild, B is moderate, grade C is severe. The example patient is greade B bc he has 9 points so he should be put on 7.5 mg daily instead of 15 mg

Quantification: MELD-Na

MELD= 9.57 × Loge(creatinine mg/dL) + 3.78 × Loge(bilirubin mg/dL) + 11.20 × Loge(INR) + 6.43 MELD-Na= MELD - (sodium [mEq/L]) - (0.025 x MELD x (140-sodium [mEq/L])) + 140 MELD Score Interpretation Score: 3-Month Mortality Rate: >/= 40 71.3% 30-39 52.6% 20-29 19.6% 10-19 6% <9 1.9% MELD-Na used by UNOS for allocation of organs for transplant · MELD is another quantification (model for end stage liver disease) and the sodium is bc it is now adjusted based on where someone's sodium level is. Adjusted for sodium is the version of MELD we see today. MELD doesn't usually play a role in drug dosing. MELD doesn't have as much as that subjectivity. There is no PT but instead they use a more normalized and consistent INR instead of the PT.

nonselective beta blockers

Nadolol (Corgard) 20-40 mg daily, Propranolol (Inderal) 20 -40mg BID Non-selective beta-adrenergic blocker Nonselective beta-adrenergic blockers reduce portal pressure by producing splanchnic vasoconstriction (beta2 effect) thereby reducing portal blood flow Carvedilol (Coreg) 3.125 mg BID Non-selective beta-adrenergic blocker and alpha-adrenergic blocker Nonselective beta-adrenergic blockers reduce portal pressure by producing splanchnic vasoconstriction (beta2 effect) thereby reducing portal blood flow ¡Titrate nadolol or propranolol every 2-3 days to resting heart rate of 55 to 60 beats per minute §Nadolol daily max: 160 mg (no ascites) or 80 mg (ascites) §Propranolol daily max: 320 mg (no ascites) or 160 mg (ascites) ¡Carvedilol should be titrated to 6.25 mg twice daily after 3 days (note: titration NOT guided by heart rate as with propranolol and nadolol) ¡Systolic BP should be monitored and always maintained above 90 mmHg ¡Monitoring of non-selective β-blockers in this population includes looking for bradycardia, hypotension, bronchospasm, hypoglycemia (especially in insulin-dependent diabetes), sx of HF, excessive sodium/water retention. ¡Endoscopic variceal ligation may be used instead of drug therapy in the case of medium/large varices and high risk of bleeding. We treat patients with esophageal varices and gastric varives with nonselective beta blockers for primary prophylaxis. The drugs we use are nonselective beta blockers like nadolol or propranolol or in the case of primary prophylaxis we could use carvedilol (but not for secondary prophylaxis) and has beta and alpha blocking properties. Also going to affect beta 2 and impacts the splanchnic vasculature. Know about titration and monitoring. Propranolol has to be twice a day but nadolol is once a day so they may be more compliant to this. Nadolol and propranolol we worry about increasing too much if they also have ascites bc it could make the ascites picture worse. Carvedilol is titrated regardless of heart rate. Any BP below 90 could lead to spontaneous bacterial infection. Systolic BP below 90 could invoke ascites

Secondary prevention of variceal bleeding

Nadolol (Corgard) 20-40 mg daily, Propranolol (Inderal) 20 -40mg BID Non-selective beta-adrenergic blocker Nonselective beta-adrenergic blockers reduce portal pressure by producing splanchnic vasoconstriction (beta2 effect) thereby reducing portal blood flow ¡Combination of EVL with pharmacologic therapy considered most appropriate §EVL repeated every 1-2 weeks until obliteration ¡Pharmacologic therapy: nonselective β-blocker started as soon as day 6 from index event ¡Titrate every 2-3 days to resting heart rate of 55 to 60 beats per minute §Nadolol daily max: 160 mg (no ascites) or 80 mg (ascites) §Propranolol daily max: 320 mg (no ascites) or 160 mg (ascites) ¡Systolic BP should be monitored and always maintained above 90 mmHg ¡Monitoring of non-selective β-blockers in this population includes looking for bradycardia, hypotension, bronchospasm, hypoglycemia (especially in insulin-dependent diabetes), sx of HF, excessive sodium/water retention. · Need secondary prohlyaxis if they already had a bleed. Secondary we use a nonselective beta blocker but not carvedilol, just nadolol and propranolol. Ongoing monitoring with the endoscope and ongoing ligation. See EVL repeated every 1-2 weeks until everything that can be ligated off, have been.`

treatment of hepatic encephalopathy

Patients with HE should receive the maximally tolerated amount of protein (goal 1.2-1.5 g/kg/d) Patients with zinc deficiency should receive supplementation (typical dose of elemental zinc: 50 mg/day) Reduction of Nitrogenous Load from the Gut Lactulose (Enulose) 20 grams (30 mL) every 1-2 hours until evacuation occurs (at least 1-2 loose stools). Then dosing adjusted to achieve 2-3 soft bowel movements per day (typically 10-30 grams (15-45 mL) 2-3 times daily). Lactulose (Enulose) Osmotic laxative Removes nitrogenous waste through laxative effect; metabolized by microbiota in lower GI tract producing short-chain organic acids which inhibit growth of ammonia-producing bacterial further. Non-absorbable antibiotics: Rifaximin (Xifaxan) Rifaximin dosing: 550 mg po bid (in conjunction with lactulose) Higher cost but may be offset by less hospitalization and shorter lengths of stay Studied in combination with lactulose (90% in study on combo) More effective than lactulose alone Better tolerated Neomycin NOT first-line for HE Chronic use of neomycin can lead to irreversible ototoxicity (1-3% of dose absorbed so beware in patients with renal dysfunction) Considered as effective as lactulose but NOT first-line therapy for HE Lack of place in therapy now that rifaximin available Metronidazole (Flagyl) NOT first-line therapy for HE Neurotoxicity (peripheral neuropathy) caused by impaired hepatic clearance of the drug may be problematic Lack of place in therapy now that rifaximin available Rifaximin (Xifaxan) Antibiotic Inhibits bacterial RNA synthesis by binding to bacterial DNA-dependent RNA polymerase Metronidazole (Flagyl) Antibiotic Interacts with DNA to cause a loss of helical DNA structure and strand breakage resulting in inhibition of protein synthesis and cell death in susceptible organisms Neomycin Aminoglycoside antibiotic Interferes with bacterial protein synthesis by binding to 30S ribosomal subunits; ammonium detoxificant · Treat cirrhosis as if it is ammonia we are going after. Need to carefully minimize protein but not too much. Check zinc level and zinc can be used in these patients and see it like 15 mg a day. Lactulose removes nitrogenous waste and is metabolized by bacteria in gut producing short chain organic acids and lower ammonia in 2 ways. Used acutely and see at least 1-2 loose stools. Then adjust dose to maintain 2-3 soft bowel movements everyday and take between 10-20 grams 2-3 times per day. Rifaximin (xifaxan) inhibits bacterial RNA synthesis and reduces bacteria in the gut. Older antibiotics that are absorbed systemically can be problematic. Can lead to toxicities and same with metronidazole.

Spontaneous Bacterial Peritonitis: Prophylaxis

Primary Prophylaxis Scenario 1: Acute upper GI bleeding: ▪Ceftriaxone 1 g IV daily x 7 days Scenario 2: May consider long-term primary prophylaxis with ciprofloxacin 500 mg daily if ascitic fluid protein < 1.5 g/dL and at least one of the following is present: ▪SCr > 1.2 mg/dL ▪BUN > 25 mg/dL ▪Na <130 mg/dL ▪Child-Pugh Score > 9 with bilirubin > 3mg/dL Secondary Prophylaxis All patients who have survived an episode of SBP should receive long-term antibiotic prophylaxis with ciprofloxacin 500 mg daily · Think of secondary prophylaxis for SBP. Long term antibiotic therapy think of cirpo 500 mg daily indefinitely. If person has ascites and also has serum cr over 1.2 and such, then primary prohylaxis could be useful as well. Know about ceftriaxone and such for primary prophylaxis. Generally secondary prophylaxis is a lifetime

Assessment of Disease Severity: Scoring Systems

Ranson criteria: •Estimates the risk of life-threatening complications or death with acute pancreatitis •Assesses 11 variables from admission & at 48 hours after presentation •Score > 3 associated with severe disease APACHE II: •General severity of disease classification system for ICU patients •Calculated within 24 hours using 12 variables •Score > 8 is associated with severe disease Severe AP with organ failure or necrosis is associated with a 30% mortality · Ranson is specific for pancreatitis and it estimates the risk for life threatening complications.

treatment of SBP

STEP 1: Tap peritoneal fluid for culture and polymorphonuclear count (before starting abx) If ascitic fluid PMN counts are greater than 250 cells/mm3, empiric antibiotic therapy should be instituted. STEP 2: Community setting (diagnosed at admission or within 48 hours): cefotaxime* (Claforan) 2 g IV every 8 h recommended (AASLD) 3rd generation cephalosporin or piperacillin/ tazobactam** (EASLD) Duration: 5-7 days If ascitic fluid PMN counts are less than 250 cells/mm3, but signs or symptoms of infection exist, empiric antibiotic therapy should be initiated while awaiting culture results. Nosocomial setting (diagnosed >/= 48 hours after admission or hospital contact in last 90 days) and/or in presence of high MDRO rates: empiric choice should be carbapenems alone or in combinations with daptomycin, vancomycin, or linezolid STEP 3: If ascitic fluid PMN counts are greater than 250 cells/mm3, clinical suspicion of spontaneous bacterial peritonitis is present, and the patient has a serum creatinine greater than 1 mg/dL and blood urea nitrogen of greater than 30 mg/dL or total bilirubin greater than 4 mg/dL, 1.5 g/kg albumin should be infused within 6 h of detection and 1 g/kg albumin infusion should also be given on day 3. *3rd generation cephalosporin ** extended spectrum beta lactam · Step one culture to look for bacteria and account for eosinophilic neutrophils. When tap is done we look for PMN. Anything above 250 has a high indication of SBP. For step 2 we start empiric drug therapy. Currently have cefotaxime recommended. In the end, antibiotic would be expected to cover. If in community setting, we would give for 5-7 days. Step 3 is to look at PMN, count, wait for culture to come back to target therapy. Could also see utilization of albumin as well.

septra and diuretics

Septra: A 32-year-old man presented with epigastric pain. He had a previous episode of acute pancreatitis of undetermined cause 2 years earlier. The patient had taken trimethoprim (80 mg) and sulfamethoxazole (400 mg) twice daily because of acute urethritis 3 days prior to admission. No definite cause of acute pancreatitis could be identified on baseline studies. A thorough history-taking revealed that the patient had an episode of acute pancreatitis while taking trimethoprim (80 mg) and sulfamethoxazole (400 mg) twice daily for 2 weeks for prostatitis prior to the previous admission. Therefore, a cause-and-effect relationship between trimethoprim-sulfamethoxazole (TMP-SMX) and repeated episodes of pancreatitis was highly suggested. The patient was presumably diagnosed as TMP-SMX-induced pancreatitis. The final diagnosis was TMP-SMX-induced pancreatitis. Since drugs are rare causes of acute pancreatitis and the diagnosis of drug-induced pancreatitis is difficult to establish, we report this interesting case along with a review of medical literature Diuretics: •Suggested mechanisms of action for furosemide-induced acute pancreatitis include a direct toxic effect to the pancreas, diuretic-induced stimulation of pancreatic secretion, and ischemia. An experimental study demonstrated that a decreased volume of extracellular fluid lessens pancreatic blood flow, thereby leading to ischemia. •Two of the negative effects of hydrochlorothiazides are hypercalcemia and hyperlipidemia. Because hydrochlorothiazides cause increased calcium resorption from bone and increased levels of serum calcium, hydrochlorothiazides create an increased risk for acute pancreatitis. Hydrochlorothiazides also may be involved in the development of hyperparathyroidism that can lead to hypercalcemia and acute pancreatitis. Finally, hydrochlorothiazides can increase serum triglyceride levels, putting a patient at increased risk for acute pancreatitis.

Quantification: Child Pugh

Total bilirubin (mg/dL) 1: <2 (<34.2 mmol/L) 2: 2-3 (34.2-51.3 mmol/L) 3: >3 (>51.3 mmol/L) Albumin (g/dL) 1: >3.5 (>35 g/L) 2: 2.8-3.5 (28-35 g/L) 3: <2.8 (<28 g/L) Ascites 1: None 2: Mild 3: Moderate Encephalopathy (grade) 1: None 2: 1 and 2 3: 3 and 4 Prothrombin time (seconds prolonged) 1: <4 2: 4-6 3: >6 Grade A, <7 points; grade B, 7-9 points; grade C, 10-15 points. Usually used for drug dosing (when dosing info available for hepatic dysfunction) · Child pugh is a standardized way to determine how severe someone's disease is. If you do have drug dosing info based in liver dysfunction, it is probably based off of child pugh. Total bilirubin is important for its prognostic value and the T bili is one of the most objective things. If T bili is less than 2, person would get a score of 1 and so on. If albumin is more than 3.5 it is good bc liver is synthesizing. Ascites where if considered mild, they get a 2 and moderate is 3. Encephalopathy is how aware someone is and the more confused they are, the more likely they are having encephalopathy. Most drugs that have data on liver adjustment are usually based on child pugh score

ascites treatment

Treatment Initial therapeutic paracentesis should be performed in patients with tense ascites. Albumin infusion at a dose of 6-8 g/L of ascitic fluid removed recommended when volumes exceeding 5 L are removed Diuretic therapy: Spironolactone (Aldactone) 100 mg po daily with or without furosemide (Lasix) 40 mg po daily. Therapy can be titrated every 3-5 days (maintaining the 100:40 mg ratio) to reach adequate natriuresis and weight loss. Maximal doses are spironolactone 400 mg daily and furosemide 160 mg daily. STOP ETOH Sodium restriction of 2000 mg/d should be instituted as well as oral diuretic therapy. Diuretic-sensitive patients should be treated with sodium restriction and diuretics rather than serial paracentesis. Spironolactone (Aldactone) Aldosterone antagonist Competes with aldosterone for receptor sites in the distal renal tubules, increasing sodium chloride and water excretion while conserving potassium and hydrogen ions Furosemide (Lasix) Loop diuretic Inhibits reabsorption of sodium and chloride in the ascending loop of Henle and proximal and distal renal tubules, interfering with the chloride-binding cotransport system, thus causing increased excretion of water, sodium, chloride, magnesium, and calcium ¡Fluid restriction to < 1.5 L/day also used if serum sodium <120-125 mmol/L §Vaptans (example: tolvaptan) may be utilized as well though evidence lacking that this affects mortality, cirrhosis, or hepatorenal syndrome § DISCONTINUE drugs associated with sodium/water retention (example: NSAIDs) Diuretic therapy goals: ¡Goal is to achieve 78 mmol/day of sodium excretion (measured via 24-hr urine collection) ¡Random spot urine sodium concentration greater than potassium concentration (ratio > 1) correlates with this goal with 90% accuracy ¡Monitor for electrolytes, renal impairment, and gynecomastia · Some non-pharm and pharm ways to treat ascites. First could be paracentesis where they insert a needle and take out fluid from empty area in peritoneal cavity to take pressure off. also give albumin which is given between 6-8 grams of acidic fluid got pulled off from paracentesis. If they drink alcohol they need to stop, one of the most important things they can do. Sodium restriction to less than 2000 mg/day. Aldosterone antagonist causes holding on of potassium while loop loses potassium so this helps keep things normal while causing a diuresis. High dose of spironolactone where we start with 100 mg going to a max of 400 mg of spironolactone and 160 of Lasix. Important to keep ratio at 100:40 so we must adjust one if we adjust the other. · Fluid restriction is a part of it but we need to know we don't want to cause fluid to be held onto by other drugs. People with ascites should NOT be taking NSAIDs. Have a goal to achieve 78 mmol/day excretion of sodium.

loperamide misuse and abuse

look at slide

Pathophysiology of the Complications of Cirrhosis:Hepatic Encephalopathy

¡A metabolically induced functional disturbance of the brain, may be reversible §HE due to cirrhosis: Type C §Usually no precipitant identified and long-term treatment required §Possible Precipitants: ▪Constipation ▪GI bleeding, infection ▪Hypokalemia ▪Dehydration ▪Hypotension ▪CNS-altering drugs like benzodiazepines (flumazenil may be used) and narcotics ¡Thought to result from accumulation of gut-derived nitrogenous substances in the systemic circulation due to decreased hepatic functioning and shunting through portosystemic collaterals bypassing the liver ¡Nitrogenous waste in systemic circulation causes alterations of neurotransmission that affect consciousness/behavior ¡Ammonia most commonly cited culprit in the pathogenesis of HE §Other possible causes include: glutamine, benzodiazepine receptor agonists, aromatic amino acids, and manganese §Interventions to lower blood ammonia levels remain the mainstay of treatment for HE Hepatic encephalopathy where waste from liver (especially ammonia) and can lead to this. Can be not like themselves or even all the way to being comatose

Pathophysiology of the Complications of Cirrhosis:Ascites

¡Accumulation of an excessive amount of fluid within the peritoneal cavity §Most commonly occurring complication of cirrhosis §Infection: Spontaneous Bacterial Peritonitis (translocation of E coli, Klebsiella, pneumococci from gut to intraperitoneal space) 1.Portal hypertension activates vasodilatory mechanisms mediated by nitric oxide and prostacyclins 2.Splanchnic and peripheral arteriolar vasodilation result in drop in arterial pressure 3.Baroreceptor-mediated activation of RAAS, the sympathetic nervous system, and release of antidiuretic hormone occur in response to maintain normal BP 4.Sodium and water retention results 5.Ongoing splanchnic vasodilation increases splanchnic lymph production beyond capacity of lymph transport system leading to leakage of lymphatic fluid into peritoneal cavity 6.Persistent renal sodium and water retention, increased splanchnic vascular permeability, and lymph leakage combine to create sustained ascites in end-stage disease · Ascites is accumulation of excessive amount of fluid. Bacteria that are normally in the gut would get out and we could end up with SVP. · Portal HTN activates vasodilation bc body is trying to get more blood to liver to clean out toxins. End up with systemic reduction in BP which activates RAAS which tries to calmp down aldosterone and such. Have more and more lymph production and at some point can no longer stay in our GI system and leaks out into the belly. Have persistent renal water and sodium system.

Treatment of Variceal Bleeding: Goals

¡Adequate fluid resuscitation and hemodynamic stabilization §(Hgb goal of ~ 7 g/dL) ¡Prevention of infection ¡Control of bleeding ¡Preservation of liver function ¡Prevention of re-bleeding · She might need a transfusion if hemoglobin drops below 7. Want to preserve liver function and prevent re-bleeding

causes of cirrhosis

¡Alcoholism ¡Chronic hepatitis C* ¡Nonalcoholic fatty liver disease ¡Hemochromatosis ¡Wilson disease ¡Autoimmune hepatitis ¡Primary biliary cirrhosis ¡Primary biliary cholangitis ¡Budd-Chiari ¡Drug-induced liver injury (below list not all-inclusive): Isoniazid, macrolides, amoxicillin-clavulanate, nitrofurantoin, fluoroquinolones, amiodarone, nonsteroidal anti-inflammatory drugs, allopurinol, sulfasalazine, methotrexate, interferon-β, interferon-α, anti-tumor necrosis factor inhibitors, valproate,lamotrigine, phenytoin, carbamazepine, green tea extract *Hepatitis C becoming less of an important cause now that sustained virologic cure therapy options exist (example: ledipasvir-sofosbuvir (Harvoni®)) · We don't treat cirrhosis, we treat the symptoms · Liver function test is LFT but measures the markers · Child pugh scores the severity of cirrhosis. · Chronic alcoholism is still number 1 cause. As obesity increases and as metabolic syndrome increases, we have an increase also in certain causes of cirrhosis. Wilson's is when the body holds on to too much copper. Can have such a large impact from the drug. Cirrhosis is a chronic disease state. Usually can make a change before we go to that chronic disease state. Some drugs as common as augmentin and NSAIDs can lead to liver dysfunction. Amiodarone also causes it but this drug is used over a long period of time so we need lots of monitoring.

Primary prevention of variceal bleeding in patients with varices

¡All patients with cirrhosis should be screened for varices upon diagnosis ¡All patients found to have medium/large varices (and those with small varices and increased risk factors for bleeding such as red wale markings on varices and Child-Pugh class B or C) should receive prophylaxis therapy with a nonselective β-blocker

Treatment of Variceal Bleeding: Preventing Infection

¡Antibiotic Prophylaxis: Duration 7 days §Ceftriaxone (Rocephin) 1 g IV daily Ceftriaxone (Rocephin) Third generation cephalosporin antibiotic Inhibits bacterial cell wall synthesis causing lysis · To prevent infection we use a third generation cephalosporin. Guidelines are different bc if you look at different guidelines, it is given as a 1 gram IV infusion daily and has a very specific short term duration (only a week)

clinical presentation of cirrhosis

¡Asymptomatic to decompensated with ascites, spontaneous bacterial peritonitis (SBP), hepatic encephalopathy (HE), coagulopathy, or variceal bleeding ¡ ¡Other symptoms: §Anorexia and weight loss §Weakness and fatigue §Jaundice §Pruritis Could be asymptomatic to having serious side effects like ascites (fluid build up usually in abdomen), SBP which is whenever the fluid becomes infected, hepatic encephalopathy (swelling in the brain), could have variceal bleeding as well which involves dilated veins which are around the stomach and the esophagus.

Spontaneous Bacterial Peritonitis

¡Bacterial infection of the peritoneal fluid §Organisms translocated from the intestinal lumen into the bloodstream §Commonly Escherichia coli, Klebsiella pneumoniae, and Pneumococci ¡Potentially fatal complication of cirrhosis

Pathophysiology of the Complications of Cirrhosis:Portal Hypertension and Cirrhosis

¡Bleeding most likely when Hepatic Venous Pressure Gradient (HVPG) reaches 10 mmHg ¡Bleeding also predicted by Child-Pugh score, size of varices, and presence of red wale markings on varices ¡Rebleeding common following first occurrence with high mortality rate · HVPG is a test where the pressure can be measured inside the liver. Risk of bleeding can increase and bleeding can be predicted by child pugh score and the size of esophageal varices. Also red whale markings which can predict if someone had esophageal varices rupture and there is a high risk of death even at the first occurrence.

Laboratory Evaluation:Bilirubin

¡Conjugated bilirubin elevation §If elevated in presence of AST and ALT elevation, then sign of acute liver disease like hepatitis, toxicity, or ischemia §If elevated in presence of elevated alk phos, then sign of cholestatic liver disease ¡Unconjugated §Elevated in Gilbert's disease as well as hemolysis, ineffective erythropoiesis, hematoma resorption ¡In cirrhosis, total bilirubin (t bili) used for its prognostic value §Elevation indicates liver has lost ½ of its excretory capacity · Conjugated bilirubin concerned about total bilirubin aka T bili and is used bc of its prognostic value. Where it is elevated is useful for its prognosis. Could mean the liver loses half of its excretory ability/capacity.

Other Complications of Cirrhosis:Coagulation Defects

¡Decreased synthetic capability of liver leads to tenuous state of hemostasis because of: §Decreased levels of most clotting factors (not factor VIII) §Decreased levels of antithrombin III and protein C (natural anticoagulants) §Increased levels of factor VIII and von Willebrand factor (a blood glycoprotein and procoagulant) ¡Platelet count and function affected in cirrhosis: §Thrombocytopenia common but; due to von Willebrand factor, function increased ¡Fibrinolysis rebalanced by: §Increased levels of TPA and thrombin-activatable fibrinolysis inhibitor §Reduced levels of plasminogen and increased plasminogen activator inhibitor · When it comes to patients with cirrhosis, the liver is not able to make that stuff. Might have a decrease in clotting factors but not a decrease in factor 8. Can have a rebalancing in essence. If someone has an indication on being on an anticoagulant, having cirrhosis is

Other Complications of Cirrhosis: Hepatopulmonary Syndrome

¡Defect in arterial oxygenation caused by pulmonary vascular dilation that occurs in the presence of liver disease ¡Patients present with dyspnea on exertion, at rest, or both ¡Diagnosed based on the presence of arterial hypoxemia ¡Long-term management requires supportive therapy with supplemental oxygen · Hepatopulmonary syndrome can happen and this person is given supplemental oxygen

Pathophysiology of Cirrhosis

¡Hepatic stellate cells normally store vitamin A and maintain the matrix of the sinusoidal space of Disse ¡During cirrhosis, stellate cells become "activated" and initiate fibrosis which accumulates scar tissue in the sinusoidal space · When we talk about cirrhosis we talk about basic understanding of the pathophysiology. If the liver is normal, we talk about hepatocytes which are the work course of the liver. In cirrhosis as the liver tries to regenerate itself, it has fibrotic tissue being laid down. Instead of the liver regenerating itself normally, it begins to generate in nodules. They become arranged in a more disfigured, globulated thing

Laboratory Evaluation:Albumin and PT/INR

¡Markers of hepatic synthetic activity ¡Not specific to the liver, but utilized in quantifying systems §Child-Pugh: PT §MELD: INR · An acute acetaminophen OD would cause dramatic elevations whereas chronic is mild elevation. · Albumin is a protein that can change the way drugs are bound or unbound but it keeps fluid where it's supposed to be in the body to maintain normal plasma in our blood. PT INR is prothrombin time and international normalized ratio which measure clotting time. PT can become increased if liver can't make a certain thing. INR is normalized whereas PT can get all over the place.

Laboratory Evaluation:Platelets

¡Platelets should be checked when liver disease suspected ¡Should be evaluated before liver biopsy (bleed risk) · Thrombocytopenia (not enough platelets) can accompany cirrhosis

Hepatorenal Syndrome

¡Renal dysfunction without structural kidney damage §Result of renal vasoconstriction which occurs compensatorily due to peripheral arterial vasodilation § Discontinue drugs that decrease blood volume or cause vasodilation including diuretics, ACE-Is, ARBs ¡Liver transplant needed; bridge therapies include: midodrine (vasopressor) + octreotide (decreases splanchnic blood flow) + IV albumin (increases intravascular volume) · Hepatorenal syndrome where kidney's are not able to function bc vasoconstriction has clamped down he kidneys. People with hepatorenal syndrome tend to be kidney donors bc of compensatory mechanism. See octreotide used and IV albumin to increase intravascular volume.

Treatment of Variceal Bleeding: Controlling Bleeding

¡Vasoactive Drug Therapy plus Endoscopy ▪Octreotide is the preferred vasoactive agent employed in the medical management of variceal bleeding ▪Monitoring for octreotide: Side effects include hyperglycemia (monitor serum glucose), abdominal pain and vomiting, bradycardia (monitor HR), hypertension (monitor BP), arrhythmia (monitor EKG) ▪Endoscopy employing EVL is the primary therapeutic tool in the management of acute variceal bleeding (vasoactive drug therapy used in conjunction; vasoactive drug therapy should be instituted before endoscopy when possible) ▪Erythromycin 250 mg IV infused over 5 minutes 20 minutes before EVL used to empty stomach ▪Endoscopic injection sclerotherapy (EIS) may be used if EVL technically difficult ▪Transjugular intrahepatic portosystemic shunts (TIPS) are employed as salvage therapy in patients who have fail endoscopy and vasoactive drug therapy (increases incidence of encephalopathy...does not preserve hepatic function) Octreotide (Sandostatin) 50 mcg IV bolus then 50 mcg/h for 2-5 days Discontinue once bleeding stopped 24 hrs Somatostatin analog Mimics natural somatostatin by inhibiting serotonin release, and the secretion of gastrin, VIP, insulin, glucagon, secretin, motilin, and pancreatic polypeptide. Decreases splanchnic blood flow. · Octreotide is very effective in treating splanchnic blood flow. Dosing is given IV and given 50 mcg per hour after a 50 mcg bolus. Monitor for hyperglycemia, monitor for BP and such. Look at EKG. Octreotide is not all that is done, they are also concerned with bleeding due to suspicions of ulcer so they could also get a PPI especially if they haven't figured out the cause yet. EVL is also a primary regimen. Could also give erythromycin as 250 mg IV infusion before EVL bc that will cause evacuation of gastric contents so the erythromycin is used to empty the GI tract. If they can't do EVl they may try to burn or use a chemical on the varices. TIPS is last line when a stent is placed allowing blood to bypass the liver but TIPS can cause a buildup of toxicity if no blood is going to the liver.

summary of pancreas slides

· 2 main functions: endocrine and exocrine · Differences between acute and chronic: acute is sudden where amylase and lipase are elevated. Chronic is irreversible loss of endocrine and exocrine function. A lot more fatty stools and loss in chronic · Treatment regimens: fluids, pain, nutrition, and if needed insulin, antibiotics. Chronic treatment is a little different and a little more supportive: pain, insulin, patient needs to get to eating which is where pancreatic enzyme comes in.

AS, a 63 year old WF with jaundice §PMH: Primary Biliary Cirrhosis (dx 2002) §Meds: Actigall 600 mg BID §HPI: Noticed jaundice (yellow sclera and skin) beginning ~ 1 month ago. Subsequent liver biopsy noted fibrotic tissue and nodularity indicative of cirrhosis. What next steps are indicated in AS now?

· Anyone diagnosed with cirrhosis should be screened for varices upon diagnosis. Can see raised areas with abnormal blood flow which is what we look for in endoscopy

AS, a 63 year old WF with recent variceal bleed §PMH: PBC (dx 2002); cirrhosis (dx 2019) ; GI bleed (2022) §HPI: Pt presented to emergency room with bright red blood emesis. Underwent successful treatment with EVL, octreotide, and short-course ceftriaxone. §Vitals: BP: 142/88 HR: 76 What next steps are indicated in AS now?

· If bleed is actually happening we do octreotide bc it causes significant vasoconstriction. May give some blood (lower threshold). Also go down with scope to find the bleeding and use a ligation to stop it. Might see erythromycin used to empty the gut. Ceftriaxone is not used for a long period of time, used for short duration if that is all we know. Before she goes home, we need to talk about ongoing prophylaxis

Patient Case A 27yo female hiker is bitten by a deer tick presumed to carry Borrelia burgdorferi. She contacts her PCP who prescribed Doxycycline 100mg PO x 2 doses. She obtains the medications from a local pharmacy, and after a long day of hiking, she takes the medication. She noted that it felt as though the pill was stuck in her throat, drank some more water, and then retired to her sleeping bag for the evening. Several days later she awakens with sharp pains behind her sternum and has difficulty swallowing liquids/solids.

· Patient case has that pill esophagitis and can burn a hole in the esophagus and causes direct irritation. Be CAREFUL if patient has general trouble swallowing, try to find an alternative route or alternative drug

•Patient 1 •ALT - 400 (ULN = 40) •Alk P - 120 (ULN = 120) •TB - 1.3 (ULN = 1.2) •Calculate the ratio for both patients and classify as: •Hepatocellular •Cholestatic •Patient 2 •ALT - 120 •Alk P - 350 •TB - 3.5 •Ratio = (ALT/ULN) ÷ (Alk P/ULN)

· Ratio os 10 is hepatocellular, ratio of 1 is cholestatic. •Patient 1 •ALT - 400 •Alk P - 120 •TB - 1.3 •What type of DILI? •Ratio = (400/40) ÷ (120/120) = 10 Hepatocellular •Patient 2 •ALT - 120 •Alk P - 350 •TB - 3.5 •What type of DILI? •Ratio = (120/40) ÷ (350/120) = 1 •Cholestatic

AS, a 63 year old WF with abdominal distension and pain §PMH: PBC (dx 2002); Cirrhosis (dx 2019); Ascites (dx 2021) §Meds: Nadolol 40 mg daily, Furosemide 80 mg daily, Spironolactone 200 mg daily §HPI: Noticed increasing abdominal girth beginning ~ 2 weeks ago. Has progressed to significant protrusion and now painful. §SH: Denies EtOH. Confirms dietary sodium restriction. Confirms compliance with med regimen. §Vitals: BP: 102/78 HR: 60 Temp: 102 What next steps are indicated in AS now?

· Temperature could indicate SBP which is a potentially fatal complication. Typically caused by things in our gut.

AS, a 63 year old WF with worsening abdominal distension 6 months after initiating diuretic therapy for ascites who presents to the ER with acute esophageal variceal bleeding 2 days ago §PMH: PBC (dx 2002); Cirrhosis (dx 2019); Ascites (dx 2021) §Meds: Furosemide 80 mg daily, Spironolactone 200 mg daily, octreotide 50 mcg/hour, ciprofloxacin 500 mg BID §HPI: Noticed increasing abdominal girth beginning ~ 2 weeks ago. Has progressed to significant protrusion. Two days ago, while eating, began spitting up copious amounts of bright red blood. §SH: Denies EtOH. Confirms dietary sodium restriction. Confirms compliance with med regimen. §C7 (on admission): 140 105 1.2 136 4.2 23 10 §C7 (today): 120 98 3.2 98 6.2 23 32 what is happening in AS now?

· Titrate up by maintaining ratio of 100:40 up to max of 400 mg and 160 mg.

Endoscopic Variceal Ligation

· When they do endoscopy they can also treat varices through endoscopic variceal ligation where they grab the varices and tie it off to cause it to die so that it can't bleed.

Alanine Aminotransferase

•ALT 1st described in 1955 as a biomarker for acute myocardial infarction •Primarily located in liver •Also heart, kidneys, muscles, and pancreas · ALT is a liver function test which was initially for MI but we use it to establish liver dysfunction.

Clinical Presentation of Chronic Pancreatitis

•Abdominal pain radiating to the back •May be episodic initially, can progress •Steatorrhea •fatty stool •Azotorrhea •Excessive loss of protein in stool or urine •Weight loss •Insulin deficiency

Management of Chronic Pancreatitis: Basics

•Abstinence from alcohol •Dietary modification: •Small, frequent meals •Restriction of dietary fat (0.5gm/kg/d) if uncontrolled with enzyme supplementation •Enteral nutrition •only if unable to consume adequate calories, continued wt loss, complications, require surgery •Jejunal feeding preferred Avoid alcohol, need small frequent meals bc we don't have the enzymes for digestive function

Pancreatitis: Inflammation of the pancreas

•Acute Pancreatitis (AP) •Acute inflammation characterized by severe pain & elevations of pancreatic enzymes in the blood •Chronic Pancreatitis (CP) •Permanent damage to pancreatic structure & function due to progressive inflammation & long-standing pancreatic injury •Loss of exocrine / endocrine function · Acute pancreatitis is severe pain resulting from inability to digest food and may see elevated pancreatic enzymes. Chronic we have destruction and evevn necrosis and all loss of digestion and blood sugar regulation.

loperamide

•Anti-diarrheal (OTC) •Dose: 4 mg after the first loose stools, followed by 2 mg after each subsequent stool; maximum dose of 8 mg/day •Avoid use with bloody stools and fever, bacterial enterocolitis (caused by Salmonella, Shigella, Campylobacter) •Should typically be used for ~2 days

Inflammatory bowel disease

•Antibiotics •Oral contraceptives •Mycophenolate mofetil •Etanercept •Rituximab

Assessment of ADR (Naranjo Algorithm)

•Are there previous conclusive reports of this reaction? •Did the adverse event appear after the drug was given? •Did the adverse reaction improve when the drug was discontinued or a specific antagonist was given? •Did the adverse reaction reappear upon readministering the drug? •Were there other possible causes for the reaction? •Did the adverse reaction reappear upon administration of placebo? •Was the drug detected in the blood or other fluids in toxic concentrations? •Was the reaction worsened upon increasing the dose? Or, was the reaction lessened upon decreasing the dose? •Did the patient have a similar reaction to the drug or a related agent in the past? •Was the adverse event confirmed by any other objective evidence? •Answered as Yes, No, or Don't Know •Point values assigned (-1, 0, +1, +2) for each question •Scoring •Definite ADR: > 9 •Probable ADR: 5-8 •Possible ADR: 1-4 •Doubtful ADR: 0 · No perfect system to knowing if there is a problem. Classic example is the Naranjo algorithm. Gives you a score and if it is greater than 9 it is definite. But even if you score 9, it does not mean it is 100% definite. Shows the likelihood of a drug induced event

Mechanisms of Drug-Induced Diseases

•Autoimmunity •Idiosyncratic reactions •Disruption of Calcium homeostasis & cell membrane injury •Metabolic activation of CYP450 enzymes •Stimulation of apoptosis •Mitochondrial injury •Neoplastic disease •Direct tissue injury · Could have autoimmune processes, disruption of calcium, looking at enzymes of the liver, mitochondrial toxicity, neoplastic, etc.

azathioprine

•Azathioprine is widely used in Crohn's disease. •A major drawback is the occurrence of side-effects, especially acute pancreatitis. •Acute pancreatitis is rarely seen when azathioprine is used for other diseases than Crohn's disease. · Azathioprine can have a drug disease association of pancreatitis and rn this is only seen with crohn's disease

valproic acid

•Boxed Warning: Pancreatitis •Cases of life-threatening pancreatitis have been reported in both children and adults receiving valproate. •Some of the cases have been described as hemorrhagic with rapid progression from initial symptoms to death. Some cases have occurred shortly after initial use as well as after several years of use. The rate based upon the reported cases exceeds that expected in the general population and there have been cases in which pancreatitis recurred after rechallenge with valproate. In clinical trials, there were 2 cases of pancreatitis without alternative etiology in 2416 patients, representing 1044 patient-years experience. •Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that require prompt medical evaluation. If pancreatitis is diagnosed, valproate should ordinarily be discontinued. · Valproic acid has a boxed warning which is different from a side effect because a side effect could be anything anyone experiences while on trial but these could have absolutely nothing to do with the medication (ex: side effect of simvastatin most common is respiratory tract infection but this could be absolutely not important). BBW are the ones where physicians are VERY confident in the association. · Most mechanisms for medication caused acute pancreatitis are theories. We know about pancratic duct constriction bc it could be accumulation of a metabolite or some other reason for a blockage. A drug may not necessaril cause it itself, but it could cause an increase in lipids or calcium can predispose you to pancreatitis. Also reports of angioedema of the pancreas. · Valproic acid is an antiepileptic drug and has BBW of pancreatitis. This can be life threatening and must recognize if people have increased lipase we need to address it immediately. Some patients are hemmorrhagic with death. Pancreatitis is extremely rare to go from initial symptoms to death but that is why it is important to recognize when to refer. Number one way is that they have documented cases with those that have been re-challenged with the drug. In clinical trials there were 2 cases. Gold standard is the phase 3 RCT bc it minimizes bias. A phase 3 randomized controlled trial can minimize a side effect bc so much is controlled for it that C controls everything. If in the study, you get labs taken so many times that if amylase is even just a TINY bit high and asymptomatic, that person is taken OUT of the study because of how severe pancreatitis is and stopping this person from getting it allows us to prevent the pancreatitis here. need phase 4 bc you can't always identify everything that may ahpepn. *bolded paragraph is counseling for the patient*. If pancreatitis is diagnosed, valproic acid should be discontinued.

ACE-Inhibitor Bowel Angioedema

•Clinical presentation: •Abdominal pain, N/V, diarrhea •Can occur days to years after initiating ACE-I •Most commonly reported with lisinopril •Probably related more to frequency of prescribing · ACE-I can also cause angioedema. · Peroxide enema can cause extensive inflammation.

Diagnostic Imaging of Acute Pancreatitis

•Computed tomography (CT scan) •Ultrasound •Magnetic resonance imaging (MRI) · CT and other imaging to assess for presence of gallstones

Drug-Induced Liver Injury (DILI)

•Defined as: •Liver injury induced by drug/herbal •Leading to liver test abnormalities or dysfunction •With reasonable exclusion of competing etiologies · Drug induced liver could happen from a drug or supplement leading to liver test abnormalities and acute liver failure.

drug induced GI disorders

•Drug-induced gastrointestinal disorders can mimic conditions, such as inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) •Medications produce symptoms by: •altering GI physiology (eg, constipation induced by anticholinergic medication), •causing tissue toxicity and damage (eg, ulcers from non-steroidal anti-inflammatory drugs (NSAIDs)), •changing the intestinal microbiota (eg, antibiotics causing Clostridium difficile infection), •unknown mechanisms, such as with metformin. •The pharmacologically active compound, as well as the excipient (or packaging) of the tablet or capsule can cause problems. •Excipients, the fillers or 'vehicle' that transport the drug in a capsule or tablet, can potentially cause symptoms. •For example, small amounts of wheat starch containing gluten can potentially be harmful to patients with coeliac disease •Name the most common medication GI symptom: *N/V* · Meds induce symptoms by altering GI physiology. Working on cox 1, changing bacteria in stomach, etc. · Excipients can cause symptoms like how some drugs have gluten. Most common GI symptom is N/V

Diagnosis of Acute Pancreatitis

•Elevated pancreatic enzymes > 3x upper limit or normal (ULN) •Amylase/lipase levels peak within 24 hrs, return to normal over 8-14 days •Lipase is more sensitive/specific, may be elevated longer •Other laboratory abnormalities: •Leukocytosis •Hyperglycemia •Hypoalbuminemia •Hypocalcemia •Elevated C-reactive protein •Amylase: RR = 30 - 110 U/L oAn amylase blood test is used to diagnose or monitor a problem with your pancreas, including pancreatitis, an inflammation of the pancreas. oAmylase is an enzyme, or special protein, that helps you digest food. Most of your amylase is made in the pancreas and salivary glands. •Lipase: RR = 0-60 U/L oLipase is a protein (enzyme) released by the pancreas into the small intestine. It helps the body absorb fat. This test is used to measure the amount of the lipase in the blood. · May see increased white count, increased blood sugar, low albumin, low calcium, elevated C reactive protein bc this is a major inflammatory process

pancreatic endocrine functions

•Endocrine functions •Islets of Langerhans secrete: •Insulin •Glucagon •Somatostatin •serves to block the secretion of both insulin and glucagon from adjacent cells. •Insulin, glucagon, and somatostatin act in concert to control the flow of nutrients into and out of circulation. * Islets of Langerhans: groups of pancreatic cells secreting insulin and glucagon Pancreas is the size of a one-dollar bill Shaped like a leaf

Esophageal Disorders

•Esophageal disorders may be induced by •medications that alter peristaltic contractions (eg, by altering smooth or striated muscle function), •altering lower esophageal sphincter pressure, •decreasing saliva production, •causing direct esophageal damage through ulceration or predisposing to infection

acute pancreatitis

•Estimated >200,000 hospital admissions each year in the US •Acute pancreatitis characterized by: •Severe pain in the upper abdomen •Elevations in pancreatic enzymes (amylase/lipase) •Pathogenesis •Inappropriate activation & reduced elimination of trypsin •Leads to activation of other enzymes •Inflammatory response •Tissue damage •Progression beyond the pancreas (SIRS, multi-organ failure, death)

digestive enzymes

•Exocrine functions •Digestive enzymes •Proteolytic - trypsinogen, chymotrypsinogen, procarboxypeptidase, proelastase •Amylolytic - amylase helps digest carbohydrates •Lipolytic - lipase breaks down triglycerides to free fatty acids •Nucleolytic - ribonuclease, deoxyriboduclease •Trypsin inhibitor •Proteolytic enzymes are synthesized within acinar cells & activated in the lumen of the duodenum •Enterokinase converts trypsinogen to trypsin •Trypsin activates other proteolytic enzymes •Lipase, amylase, ribonuclease, deoxyribonuclease are secreted in their active forms · There are a LOT of neurohormonal processes controlling function. Main important ones: *amylase and lipase* bc we use these two clinically and observe them in labs. Number one symptom of pancreatitis will be pain with N/V. valproic acid is something that can cause 3 different types of nausea and vomiting which is why amylase and lipase are critical bc we have to know to see if they are elevated to indicate pancreatitis · Just bc we have inflammation in the pancreas, that inflammation can progress and could ultimately lead to death

pancreatic exocrine functions

•Exocrine functions •Produces 1-2 L/d of pancreatic fluid containing water, electrolytes, and enzymes for digestion •Bicarbonate secreted by centroacinar cells •Maintains appropriate pH for enzyme activity (~8.3) •Phases of exocrine secretion: •Cephalic - stimulated by sight/smell of food •Gastric - stimulated by gastric distention, rate of gastric emptying •Intestinal - stimulated by hormones (secretin & cholecystokinin) •Absorbed nutrient - directly stimulate pancreatic secretion · Exocrine is digestion and pancreas will produce pancreatic fluid which has water and pancreatic enzymes. Different phases as body prepares to eat

etiology of acute pancreatitis

•Gallstones •Small %chance progression to CP •Alcohol •Dose-dependent •increased, viscous secretions •premature activation of enzymes •14-41% chance to progress to CP •Other causes •Hypertriglyceridemia •Duct obstruction •Medications •Sphincter of Oddi dysfunction · Gallstones can cause acute pancreatitis and will involve surgery. Gallstones cause obstruction and can only treat it with surgery. Small chance that it could lead to chronic pancreatitis. Next big cause is alcohol and is dose dependent and makes those enzyme secretions really thick and creates an obstruction but we can't remove those surgically. Triglycerides increase in size and can't move through the ducts well and causes blockage. Need to do alcohol in moderation · Hepatitis patients with acute hepatitis can lead to severe N/V. look at LFT (liver function test) and AST to look for hepatitis for patient with severe N/V and not getting better. If they're fine, we start to look for pancreatitis. Every single drug we need to process in this way. Estrogens are controversial in that they do pancreatitis indirectly, could do this through the effect on triglycerides. Didanosine is not used anymore but is a nucleoside reverse transcriptase inhibitor used to treat HIV. Bactrim can also cause this. Others and the most common of this would be the diuretics (know #1, diuretics are a classic example). All the medications are so diverse that there really isn't any association between what causes these.

Management of Chronic Pancreatitis: Enzyme Supplementation

•Helps reduce pain •Limits/improves nutrient mal-absorption •Adult Dosing (based on lipase content) •500-2,500 units/kg/meal, take with food •Avg pt = 25,000 - 40,000 IU Lipase per meal + 10,000 - 20,000 IU Lipase for snacks •Side effects: hyperuricemia, nephrolithiasis, folic acid deficiency •Most preparations are enteric coated to prevent enzyme degradation by gastric acid •Dosing example: •Pancrealipase (Creon) •Enzyme dosing should begin with 500 lipase units/kg of body weight per meal for those older than age 4 years to a maximum of 2,500 lipase units/kg of body weight per meal (or less than or equal to 10,000 lipase units/kg of body weight per day), or less than 4,000 lipase units/g fat ingested per day. · We can actually give a patient enzymes and these have a very specific indication (chronic pancreatitis and even CF) but it can help with the exocrine function to digest food. To help with endocrine function we could give insulin. But with the enzymes they also help reduce pain. · Most of these enzymes are enteric coated and a common example is creon which includes all those enzymes. Dosed with 500 lipase units per kg *dose based on lipase*. · Don't memorize the pancreatic enzymes, just know the differences in the units and generally examples. We does on the *LIPASE* component. (look at slide for this table)

Phenotypes of Liver Enzyme Changes

•Hepatocellular •Ratio > 5 and ALT >2x ULN or baseline •Cholestatic •Ratio < 2 and Alk P > ULN •Mixed Ratio = (ALT/ULN) ÷ (Alk P/ULN) Acute liver necrosis Acetaminophen, INH, disulfiram Cholestatic hepatitis Amoxicillin-clavulanate Chronic hepatitis Phenytoin, INH Drug-induced AIH Nitrofurantoin, minocycline Steatohepatitis Amiodarone, valproate Fibrosis Methotrexate · Know that there are hepatocellular liver dysfunctions which are more severe han cholestatic.

pill esophagitis

•Hold-up in clearance of the pill from the esophagitisCaustic injury of locally released drug. •Tetracyclines •Bisphosphonates •Potassium chloride •NSAIDs •Iron · Pill esophagitis where it feels like an ulcer down your throat. Tetracyclines like doxycycline can cause it as well so they need to drink lots and lots of water to wash the pill down. Bisphosphonates they can't lay down for 30-60 minutes. Potassium chloride, NSAIDs, and iron can all do this

Fluid resuscitation

•IAP / APA recommended lactated ringers: 5-10 mL/kg/hr •mixture of sodium chloride, sodium lactate, potassium chloride, and calcium chloride in water. •ACG recommends crystalloids: 250-500 mL/hr •Goals (one or more of the following) •Heart rate < 120 beats/minute •Mean arterial pressure 65 - 85 mm Hg •Urinary output greater than 0.5 - 1.0 mL/Kg/h •Hematocrit 35-44% with transfusion of blood · In terms of fluid resuscitation, we typically can used LR in 5-10 ml/hr/kg which has a llot more electrolytes. Other organizations recommend crystalloids such as NS. Might not be as aggressive in fluid distribution if patient has something like heart failure. Definitely know fluid rescusitation. Want a heart rate less than 20 and MAP less than 65-85. We want UOP as 1 ml/kg/hr. hemoglobin x 3 is always hematocrit which we want at 35-44%. · Chronic is aggressive and unfortunately irreversible.

estrogen therapy

•In patients with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis. Consider discontinuation of treatment if pancreatitis occurs. •The second proposed mechanism is that pancreatic necrosis is induced by a hypercoagulable state. •A report stated that patients who had ever used hormone replacement therapy (HRT) had a 57% increase in the risk for acute pancreatitis compared with patients who had never used HRT. The authors analyzed data from 13,113 women who were current users of HRT at baseline, 3,660 past users, and 14,721 women who had never used HRT. •CMAJ 2014:186(5):338-344. · Estrogen therapy can be associated with elevations of plasma and triglycerides. Patients who had ever used HRT had an increased risk of acute pancreatitis

Pathophysiology of Cirrhosis: Eventual Results

•Increased splanchnic blood flow via vasodilation and varices formation and variceal bleeding •Hypotension and decreased systemic vascular resistance •Neurohormonal vasoactivity: Renin Angiotensin Aldosterone System and Nonosmotic Vasopressin Release •Ascites and Renal Dysfunction And... ¡Loss of hepatocyte function ¡Portal-systemic shunting which leads to hepatic encephalopathy The body realizes blood is not getting cleaned out so we must not be sending blood to the liver enough so we have increase in splanchnic blood flow and there is a vasodilation occurring and the body creates collaterals. That is where we end up with the creation of varices. Having all that vasodilation leads to a systemic hypotension and when the body sees blood pressure dropping, it kicks the RAAS into high gear and causes a build up of vasoconstriction to combat vasodilation. Then antidiuretic hormone leads to more fluid building up. Leads to us having ascites and leads to hepatorenal syndrome.

Pathogenesis of Chronic Pancreatitis

•Inflammation ----> •Cellular necrosis ---> fibrosis

Drug-Induced Microscopic Colitis

•Inflammation of the colon that is only visible with a microscope •Lymphocytic colitis: number of lymphocytes is higher, and the tissues and lining of the colon are of normal thickness •Collagenous colitis: layer of collagen, a threadlike protein, underneath the epithelium builds up and becomes thicker than normal •Other causes •Bacteria, viruses, genetic factors, bile acid malabsorption •Results in profuse, watery diarrhea •Medication causes: •SSRIs (particularly sertraline) •NSAIDs •Lansoprazole (& other PPIs) •Carbamazepine •Acarbose •Ticlopidine •Simvastatin · Could also have inflammation of the colon but this is different from C diff.

Dysphagia

•Inhibit striated muscle function: •Antipsychotics (dopamine antagonist) •often associated with parkinsonism •Alcohol •Inhibit smooth muscle function: •Anticholinergics (eg, tricyclic antidepressants) •Calcium channel blockers •Theophylline •Alcohol •Cause xerostomia: •Anticholinergics (eg, tricyclic antidepressants) •Opiates •Antipsychotics •Antihistamines Clonidine · Dysphagia is a swallowing problem which can lead to pneumonia if we aspirate things in terms of striated muscle function · Could also have dysphagia due to smooth muscle function. · Dry mouth as well

Intrinsic vs. Idiosyncratic DILI

•Intrinsic •Predictable •Dose-related •+ animal studies •High incidence •Short latency •Types: •Directly destructive •Indirect, metabolic •Cholestatic High Mortality Idiosyncratic: •Unpredictable •Not Dose-related •Not seen in animals •Low incidence, rare •Longer latency, variable •Types: •Immunoallergic •Metabolic •Mortality variable · Intrinsic we expect the drug to do this. An example would be acetaminophen bc we KNOW if you exceed 4 grams, Tylenol becomes predictable and is dose related. Idiosyncratic is like telithromycin where we don't know why it causes the liver disease and we can't prevent we only respond if they get it so we avoid.

Diagnostics of Chronic Pancreatitis

•Laboratory •Amylase/Lipase are usually normal •Deficiency develops due to loss of acinar cell function •Mal-absorption testing Fecal fat •Ultrasonography •Trans-abdominal •Endoscopic US •CT/MRI •ERCP · Big difference is that for chronic, amylase and lipase can be normal which tells us these are a better indication for acute than chronic.

Gastroesophageal reflux

•Lower esophageal sphincter pressure •Nitrates •Calcium channel antagonists •Dopamine/dopaminergic agents •Anticholinergics (eg, tricyclic antidepressants) •Progesterone •Methylxanthines (caffeine, theophylline) •Progesterone •Alcohol · Reflux is where we are refluxing acid and it causes esophagitis in a different way. Nitroglycerin can cause this, amlodipine and other calcium channel blockers,

Pharmacotherapy: Acute Pancreatitis

•Majority of cases , self-limiting disease that responds spontaneously without compilations •20% have a severe course of disease •Fluid resuscitation •Aggressive fluid resuscitation to correct volume depletion •Decrease risk of SIRS & organ failure •Rate & IVF choice patient specific •Lactated Ringers •Electrolyte replacement •Potassium, Magnesium, calcium •Hyperglycemia •Insulin •Nutrition Support •AP = catabolic state •Often patients mal-nourished (e.g., EtOH) •Severity •Mild AP - oral feeding once pain improving, +BS •Nutrition support if >1 week w/o nutrition •Enteral preferred •Pain management •Consider safety/efficacy •Lack of high-quality evidence •Parenteral opioid analgesics •Morphine/Hydromorphone •Meperidine •PCA •No evidence that antisecretory therapy relieve/prevent abdominal pain •Nausea/Emesis •Anti-emetics (promethazine, ondansetron) •NG aspiration/suction •Antibiotics •No role for prophylactic antibiotics in mild AP •Consider for severe/necrotic AP •Carbapenems, FQ + metronidazole, Pip/Tazo · Vast majority are self limiting assuming we remove the source · Have to give fluids to run fluids at certain rates. Would need to give fluids bc patients have severer N/V which can lead to hypovolemia which leads to kidney failure and the heart gets harmed. Want to give fluid therapy to decrease risk of organ failure and overall inflammation. No specific formulation but a lot use LR because we also want to replace electrolytes. If you don't have enough nutrition the body can go into a catabolic state. Patients could potentially be malnourished. Begin feeding once the pain has resolved and wait for positive bowel sounds. If we cannot get food into them within a week we need to do nutritional support. · Opiates have been traditionally used for pancreatitis. Ondansetron is typically for chemo or post op. pancreas can become infected and when it is we give broad spectrum systemic antibiotics.

diarrhea

•Metformin •Iron •Fibrates (less with fenofibrate) •Antibiotics (especially clavulanate) •ACE inhibitors •β-blockers •Lithium •Carbamazepine •NSAIDs •Furosemide •5-ASA •Proton pump inhibitors A lot of drugs cause diarrhea and antibiotics can cause both GI upset and C Diff (a superinfection caused by antibiotics that needs to be treated by another antibiotic). Tons cause constipation, also IBD.

Signs & Symptoms of Acute Pancreatitis

•Nausea/Vomiting •Abdominal pain •Gallstone pancreatitis has sudden onset with stabbing pain which may radiate to the back •Other causes pain may be less abrupt & poorly localized •Abdominal distention •Hypotension •Tachycardia •Low grade fever · Gallstones happen very suddenly with discomfort and distention and can progress to hypotension and tachycardia

complications of acute pancreatitis

•Necrosis •Diffuse or focal areas of non-viable pancreatic parenchyma •Pseudocyst •A collection of pancreatic fluids & tissue enclosed by fibrous or granulation tissue •Pancreatic abscess •A collection of pus in or adjacent to the pancreas · Could see necrosis, a cyst development which could lead to something like gallstones in terms of obstruction

Management of Chronic Pancreatitis: Chronic Abdominal Pain

•Non-narcotic analgesics - scheduled •Acetaminophen, NSAIDS, Tramadol •Oral narcotics •Typically reserved for severe pain, acute episodes •Non-narcotic modulators: SSRIs or TCAs •Potentiate the effects of opioid narcotics •Have a direct effect on pain · Want to use non-narcotics as possible. Can have some effects with non-narcotics.

Cost of LFT Monitoring

•Number of patients in US taking statins (2005): •30 million •LFT Cost: •$50 •Cost/year of Semiannual LFT Testing: •$3 Billion · LFT monitoring costs $50 per test and can cost $3 billion per year. Unfortunately this cost prevents people from measuring every single side effect so we need to keep an eye out

constipation

•Opiates •Anticholinergics •Iron •Antipsychotics •Verapamil •Levothyroxine •Cholestyramine

complications of chronic pancreatitis

•Pancreatic pseudocysts •Ascites •Portal hypertension with varices •Pancreatic cancer · Complications include cysts, ascites (which makes sense with portal hypertension bc we are losing protein which if we lose protein, it causes ascites), and pancreatic cancer

pancreatic function

•Pancreatic secretion in response to a meal occurs in 4 distinct but overlapping phases which are named based on the location of ingested food. •The four phases of pancreatic secretion are •cephalic, gastric, intestinal, and absorbed nutrient. •Crosstalk and inter-regulation is associated within the phases, thereby ensuring adequate, but not excessive, enzyme and bicarbonate secretion. •Each phase is regulated by a complex network of neural & humoral feedback mechanisms which help to maintain an optimal environment for food digestion and absorption. · Have to have these processes work in concert otherwise we could digest our own pancreas!!! If we don't cut the mechanisms off we could have some kind of digestion of yourself. If body is doing something like this, it is autoimmune. Without these mechanisms we start to hurt our own pancreas.

Melanosis (or Pseudomelanosis) Coli

•Pathophysiology •Dark pigment-laden macrophages within mucosal layer •Cause •Laxative abuse •Prognosis •Benign •Relationship with melanoma •None · Laxative abuse can lead to melanosis and change the colon. It is a serious consequence and can change the structure of the colon

pill esophagitis patho

•Pathophysiology: •Altered esophageal contractions •Altered LES pressure •↓ saliva production •Direct irritation •In > 50% of healthy patients, gelatin capsules remain in the esophagus > 5 min •Epidemiology •Unknown, often attributed to GERD •Appropriate treatment? •Withdrawal of offending drug •PPI and/or sucralfate suspension/slurry most common culprits: Antibiotics# 36% NSAID 35% Anti-hypertensives 12% Bisphosphonate 5% Ascorbic acid 3% Warfarin 3% Other drugs* 5% # Particularly tetracyclines *Ferrous sulfate, Potassium chloride, and chemotherapeutic agents · Pill esophagitis leads to decreased nutrition. Sucralfate may help coat the esophagus.

DILI Epidemiology

•Prevalence & incidence poorly defined •Estimated incidence •Between 1 in 10,000 to 1 in 100,000 •Detected primarily in post-marketing phase •Premarketing studies include 2000-5000 highly selected patients •Passive surveillance (e.g., MEDWATCH) only uncover 5-10% · Prevalence and incidence are poorly defined bc we measure with different things but if something is wrong with the pancreas we can identify it bc if you eat you have GI pain. For the liver, it takes a longgggggg time before you start having symptoms such as jaundice, confusion, etc. AST and LFT can be under the radar for many years. Primarily find it after drug is already on the market and FDA approved.

Chronic Pancreatitis (CP)

•Progressive & irreversible loss of exocrine/endocrine function •Etiology •Alcohol consumption = ~70% •Idiopathic = 20% •Other causes = 10% •Autoimmune diseases •Genetic abnormalities •Obstruction •Hyperparathyroidism · Clinical presentation would be excessive protein loss. Weight loss, insulin deficiency, changes in stool and urine related to protein and fat content

DILI Assessment Methods

•Roussel Uclaf Causality Assessment Method (RUCAM) •Similar to Naranjo algorithm •Specific for DILI assessment · Roussel uclaf is absolutely specific for intrinsic liver. Can have mild, acute, symptomatic, asymptomatic, etc.

DILI Clinical Presentation

•Spectrum of liver injury •Mild/Severe •Acute/Chronic •Symptomatic/asymptomatiic •Temporal relationship •Idiosyncratic reactions occur between 7-90 days

Gastroenteritis

•Syndrome of diarrhea or vomiting •Non-inflammatory infection in the upper bowel or inflammatory infection in the colon •Clinical Presentation: •Diarrhea •Amount varies based on severity •Bloody or non-bloody •Abdominal cramping •Nausea/vomiting •Dehydration •Malnutrition •Long-term diarrhea

medication causes of acute pancreatitis

•Valproic acid •Estrogens •Azathioprine/6-MP •Didanosine •Sulfamethoxazole/trimethoprim •Others •Thiazide diuretics •Furosemide •Corticosteroids •Opiates •Sulfasalazine •Sulindac •Cytarabine •Drug-induced acute pancreatitis based on theories extracted from case reports, case-control studies, animal studies, and other experimental data •Potential mechanisms include •pancreatic duct constriction •cytotoxic and metabolic effects •accumulation of a toxic metabolite or intermediary •hypersensitivity reactions •negative effects of drugs •hypertriglyceridemia and chronic hypercalcemia •localized angioedema effect in the pancreas •arteriolar thrombosis · Huge amount of drugs can cause pancreatitis. Usually a drug induced side effect is not gonna be from just one drug, usually will be because of multiple drugs.

Nausea and Vomiting

•Via tissue damage: •Potassium chloride •NSAIDs •Iron •Chemotherapeutic agents •Via chemoreceptors in the central nervous system: •Digoxin •Dopaminergic agents (eg, levodopa, bromocriptine) •Opiates •Digoxin Chemotherapeutic agents (eg, cyclophosphamide, cisplatin) · Can get N/V through tissue damage or CNS. Chemotherapy can cause both. Those with tissue damage we can take with food to coat the stomach

pancreas

•organ located in the abdomen •essential role = converting food into fuel for the body's cells •2 main functions: •Exocrine: digestion •Endocrine: regulates blood sugar · Pancreas is leaf shaped and about the size of a dollar bill and it does 2 main things: exocrine with digestion and endocrine to regulate blood sugar Pancreas in the abdomen and turns food into fuel. Overeating will lead to stomach pain. If we don't have pancreas exocrine function there will be extreme stomach pain bc it can't digest it