Renal / Hepatic Flashcards
Kidneys:
1. What is the main function of nephrons?
- First, the ________(afferent/efferent) arteriole delivers blood into the glomerulus where the Bowman’s capsule lies. Substrates with a MW <40,000 will pass through, which are typically what kinds of substances?
- If substance does NOT pass through the Bowman’s capsule, it will exit the kidney back into the blood via the _______(afferent/efferent) arteriole.
- How is glomerular filtrate rate (GFR) assessed?
- Regulate Na and water which regulates blood volume, blood pressure, and pH
- Afferent;
-Substances w/ MW <40,000: most drugs, water, electrolytes (what does NOT pass: proteins, protein-bound drugs) - Efferent
- When kidneys are damaged, some albumin can pass through the glomerulus –> amount of albumin in urine is used to estimate GFR
Kidneys:
1. Once substances are filtered through the glomerulus, they enter the proximal tubule which does what?
- Next the substance can enter the Loop of Henle. Explain the functions of the descending loop and ascending loop.
- Next the substance can enter of the distal convoluted tubule which regulates what?
- Finally, where does urine go?
1.
-Major source of initial filtering of Na, Cl, Ca, and water to reabsorb back into the blood along
-Regulates blood pH through exchanges of hydrogen and bicarbonate molcules
-Main point of absorption in general –> can absorb many other substances (ex. glucose, amino acids, vitamins, urea, choline)
2.
-Descending loop: reabsorbs water into blood (NOT Na and Cl which increases their concentration in the filtrate)
-Ascending loop: Na and Cl ions reabsorbed into blood (NOT water UNLESS antidiuretic hormone = ADH or vasopressin is present –> anti-diuresis effects if present)
- Regulates K, Na, Ca, and pH (less reabsorption than initial parts of nephron)
- Through the collecting duct which can make any final adjustments of electrolytes and aldosterone acts on to increase Na and water reabsorption (increases BP, blood volume) –> ureter –> bladder –> urethra
Drug-induced nephrotoxicity
1. What are risk factors to renal toxicity?
- What drugs are specifically associated with renal toxicity?
Risk factors:
-Decreased renal blood flow (dehydration, hypotension, heart failure)
-Preexisting kidney disease
-Increased age
-Multiple concurrent nephrotoxic medications (especially at frequent and/or large doses)
Nephrotoxic Medications:
-Anti-infectives: amionglycosides, amphotericin B, polymyxins, vancomycin
-Others: cisplatin, cyclosporine, tacrolimus, loop diuretics*, radiographic contrast dye/constrast media, NSAIDs
- Associated w/ AKI due to excessive volume loss
Explain how BUN, SCr, and CrCl can reflect kidney function
Blood Urea Nitrogen (BUN) - the amount of nitrogen in the blood that comes from urea, a waste product of protein metabolized that is excreted by the kidneys
-As BUN increases, kidney function decreases –> OTHER things can increase too (ex. dehydration)
Serum Creatinine (SCr): water product of muscle metabolism mostly filtered from the glomerulus
-As SCr increases, kidney function decreases
-Normal Range: 0.6-1.3 mg/dL
Creatinine Clearance (CrCl): estimates kidney function with SCr, but may change on muscle mass (ex. frail pts with low muscle mass may have decreased SCr leading to overestimation and wrong dosing)
-NOT preferable in: young children, kidney failure, or unstable renal function that fluctuates
Define AKI, CKD, and ESRD along with potential causes
Acute Kidney Injury (AKI): sudden, temporary loss of kidney function
-Precipitating factors: drugs, dehydration (reflected by BUN:SCR > 20:1)
Chronic Kidney Disease (CKD): progressive loss of function over time measured by GFR or CrCl and degree of albuminuria
-Most common causes: HTN and DM
-Other causes: polycystic kidney disease, infections (ex. HIV, HepB, HepC), renal artery stenosis, nephrotoxic medications
End-Stage Renal Disease (ESRD): total, permanent kidney failure where fluid and waste accumulate and dialysis or transplant will be needed
CKD is confirmed when a pt has either a eGFR <____mL/min/1.73m2 OR albuminuria equivalent to a urine albumin excretion rate (AER) >/= _______mg/24 hours or urine albumin-to-creatinine ratio (UAC) >/= ______mg/g.
How long must these values have been occurring for to be considered CKD as opposed to AKI?
60; 30; 30
Must occur for 3 months at least
CKD recommendations in HTN
-What is the BP goal?
-What drugs are considered first line and when are they recommended?
-What should be monitored?
SBP < 120mmHg if tolerated (lower than the general ACC/AHA <130/80mmHg target)
Drugs: ACEI or ARB due to inhibition of renal-angionetensin-aldosterone system (RAAS) causing efferent arteriolar dilation
-Ultimately reduces glomerular pressure, decreases albuminuria, and delays progression to ESRD by reducing kidney workload
-Recommended when albuminuria present in pt
Monitoring: SCr and K 2-4 weeks after intiation and maximize dose if K is normal
-Normal SCr increase of up to 30% (if increases further, D/C)
-ACEIs and ARBs should NEVER be used together due to similar MOA which will increase hyperkalemia risk
-Avoid K supplements and salt substitutes with KCl
CKD Recommendations in DM: What drugs are helpful?
Sodium-glucose cotransporter 2 (SGLT2) inhibitors if eGFR >20
-Demonstrated a reduction in CV events and/or CKD progression
-If unable to use medication or requires additional glycemic control: GLP-1 receptor agonist
Finerenone: non-steroidal mineralcorticoid receptor antagonist that can decrease CKD progression and CV risk as well which can be added to SGLT2i and max-tolerated ACEI or ARB in eGFR >25, albuminuria, and normal K levels
CKD: drugs that may require decreased dose or increased dosing interval
-Anti-infectives
-CV drugs
-GI drugs
-Others
Anti-infectives:
-Aminoglycosides (increase dosing interval primarily, due to nephrotoxicity)
-Beta-lactams ABXs (exceptions: nafacillin, oxacillin, ceftriaxone) - seizure risk
-Fluconazole
-Quionolones (except: moxifloxacin) - seizure risk
-Vancomycin
CV Drugs: LMWHs (enoxaparin), rivaroxaban, apixiban, dabigatran - bleeding risk
GI drugs: H2RAs (CNS risk), metoclopramide (EPS risk)
Others: bisphosphonates, lithium (NTI that is almost 100% renally cleared), cyclosporine, tacrolimus
CKD: drugs that are CI in CKD when:
-CrCl <60mL/min
-CrCL <50mL/min
-CrCl <30mL/min
-eGFR <30mL/min
-Others that have no CrCl specified cutoff
CrCl <60mL/min: nitrofurantoin (NOT effective)
CrCl <50mL/min:
-Tenofovir disoproxil fumarate containing products (Complera, Delstrigo, Stribild**, Symfi),
-Voriconazole IV (NOT from drug, but due to VEHICLE)
CrCl <30mL/min:
-Tenofovir alafenamide-containing products (Biktarvy, Descovy, Genvoya, Odefsey, Symtuza)
-NSAIDs
-Dabigatran* (for DVT/PE)
-Rivaroxaban*
eGFR <30mL/min: SGLT2 inhibitors, metformin**
Others: meperidine (seizure risk)
*Medication has indication-specific recommendations
**For treated patients, do NOT start TX if CrCl <70mL/min
***For treated patients, do NOT start TX if eGFR </=45
What are complications of CKD and why?
Increased PO4 - kidneys do NOT excrete as well
Decreased vitamin D and Ca - kidneys do NOT activate vitamin D which helps with Ca absorption
–> BOTH send signals to increase parathyroid hormone (PTH) which signals to reabsorb Ca++ (in chronic: Ca+ reabsorbed from bones which can cause bone fractures)
Hypercalcemia can be caused from chronic PTH levels, which can lead to calcium deposits in the eyes, lungs, heart, or blood vessels increasing risk of stroke
Decreased erythropoietin: produced by kidneys that signals to bone marrow to produce RBCs (anemia from chronic CKD)
Hyperphosphatemia in CKD: General Treatment
-What are DDIs with the treatmenet options?
Treatment:
-Nonpharm: restrict diet (dairy products, chocolate, soda, nuts)
-Phosphate binders: binds phosphate to the intestine to have less absorbed into blood
Phosphate binder types:
1. Aluminum based - aluminum hydroxide (LAST line: due to potency and toxicity, used no longer than 4 weeks and often in hospital setting)
2. Calcium-based - considered first line (calcium acetate > calcium carbonate)
3. Aluminum- and calcium-free: can be more expensive)
-Iron-based: sucroferric oxyhydroxide, ferric citrate
-Lanthanum carbonate
-Sevelamer carbonate (dialysis or not) and sevelamer hydrochloride (dialysis only)
DDIs: levothyroxine, quinolones, tetracyclines, oral bisphosphonates –> SEPARATE
Aluminum hydroxide:
-MOA
-ROA
-Administration
-AVEs
-Monitoring
MOA: phosphate binder for hyperphosphatemia
ROA: suspension
Administration: take WITH MEALS (if meal missed, skip)
AVEs: ALUMINUM INTOXICATION (CNS and bone toxicity: confusion, seizures, osteomalacia), constipation, nausea
Monitoring: treatment duration limited to 4 weeks due to toxicities
-Ca, PO4, PTH, s/sx of aluminum toxicity
Calcium-based phosphate binders:
-Drugs/Brands
-Administration
-AVEs
-Monitoring
Drugs: calcium acetate (Calphron, Phoslyra - D/C), calcium carbonate (Tums)
Administration: take WITH MEALS (if meal skipped, skip)
AVEs: HYPERCALCEMIA (especially with Vitamin D supplementation), CONSTIPATION, nausea
Monitoring: Ca, PO4, PTH
-Calcium acetate binds more dietary phosphorus than calcium carbonate
Iron-based phosphate binders
-Drugs/Brands
-Administration
-AVEs
-Warnings
-Monitoring
Drugs: sucroferric oxhydroxide (Velphoro), ferric citrate (Auryxia)
Administration: take with MEALS (if meal skipped, skip)
AVEs: diarrhea, discolored (black) fecers, constipation (ferric citrate)
Warnings: iron absorption with ferric citrate (dosage reduction of IV iron may be needed), store out of reach with children to prevent accidental overdose
Monitoring: PO4, PTH
-Ferric citrate: iron, ferritin, TSAT
Lanthanum carbonate
-Brand
-MOA
-Administration
-AVEs
-Warnings/CIs
-Monitoring
Brand: Fosrenol
Administration: take WITH MEALS (if meal skipped, skip); comes as chewable tablet –> CHEW THOROUGHLY (reduces risk of GI AVEs, but also increases surface area to help with phosphate binding)
AVEs: N/V/D, constipation, abdominal pain
Warnings/CIs:
-Warnings: GI perforation
-CIs: GI obstruction, fecal impaction, ileus
Monitoring: Ca, PO4, PTH
Sevelamer carbonate and Sevelamer hydrochloride:
-Brand
-Administration
-Differences between the salts
-AVEs
-Warnings
-CIs
-Monitoring
Brands: sevelamer carbonate (Renvela), sevelamer hydrochloride (Renagel)
Administration: take WITH MEALS (if meal skipped, skip)
Salts:
-Carbonate: can be used in dialysis pts or not
-Hydrochloride: dialysis only
AVEs: N/V/D (20%), dyspepsia, constipation, abdominal pain, flatulence, meetabolic acidosis (with sevelamer hydrochloride)
Warnings:
-Reduced absorption of vitamin D, E, and K and folic acid
-Tablets can cause dysphagia and get stuck in esophagus –> consider powder if difficulty swallowing
-Metabolic acidosis in sevelamer HYDROCHLORIDE (Cl may decrease bicarbonate levels)
CIs: bowel obstruction
Monitoring: Ca, PO4, HCO3, Cl, PTH
-Both can lower total cholesterol and LDL by 15-30%
CKD: Vitamin D deficiency and secondary hyperparathyroidism
-Pathophysiology
-General TX
Kidneys are unable to hydroxlyate vitamin D into active form 1,25-dihydroxy vitamin D which hypocalcemia stimulates PTH release
-Vitamin D3 (cholecalciferol): synthesized in skin after UV light expsoure
-Vitamin D2 (ergocalciferol): from dietary sources
Treatment:
-Earlier stages may be able to take vitamin D supplements (D3, but still need to be activated)
-Vitamin D analogs reserved foe later stages of CKD (4 and 5) with progressive hyperparathyroidism which increase Ca absorption from gut, increasing Ca and lowering PTH
-Calcitriol: active form of vitamin D3
-Paricalcitriol and doxercalciferol: newer vitamn D analogs that cause less hypercalcemia than calicitriol
-Cinacacalcet: mimics the actions of Ca on parathyroid gland which increases sensitivity of Ca receptors reducing PTH (used in dialysis ONLY)
Vitamin D Analogs:
-Drugs/Brands
-MOA
-Administration
-TX
-AVEs
-Warnings/Cis
-Monitoring
Drugs: calcitriol (Rocaltrol), calcifediol (Rayaldee), doxercalciferol (Hectorol), paricalcitol (Zemplar)
MOA: vitamin D analogs that increase Ca absorption in the gut, increasing serum Ca and lowering PTH
-Calcifediol: prodrug of calcitriol
Administration: take with food or shortly after meal to decrease GI upset (calcitriol)
TX: CKD later stages (3-5), dailysis
AVEs: hyperphosphatemia, N/V/D
Warnings/Cis: HYPERCALCEMIA (newer analogs: doxercalciferol and paricalcitol cause this less), vitamin D toxicity
Monitoring: Ca, PO4, PTH, 25-hydroxy vitamin D (calcifediol)
Cinacalcet:
-Brand
-MOA
-TX
-AVEs
-Warnings
-CIs
-Monitoring
Brand: Sensipar
MOA: mimics actions of Ca on parathyroid hormone to increase sensitivity of receptors to decrease PTH production
TX: dialysis pts
AVEs: N/V/D, HA, anorexia, constipation, weakness, myalgia, URTIs
Warnings: HYPOCALCEMIA (caution in hx of seizures, QT prolongation), GI bleeding, decreased bone turnover
CI: HYPOCALCEMIA
Monitoring: Ca, PO4, PTH
Etelcalcetide:
-Brand
-MOA
-TX
-AVEs
-Warnings
-Monitoring
Brand: Parsabiv
MOA: mimics actions of Ca on parathyroid hormone to increase sensitivity of receptors to decrease PTH production
TX: dialysis pts
AVEs: MUSCLE SPASMS, PARESTHESIA, N/V/D
Warnings: HYPOCALCEMIA, worsening HF, GI bleeding, decreased bone turnover
Monitoring: Ca, PO4, PTH
CKD: Anemia
-Pathophysiology
-General TX (see anemia flashcards for in-depth)
Kidneys do NOT produce erythropoietin (EPO) as much which stimulates RBCs from bone marrow and inflammatory state
Treatment:
-Erythropoiesis-stimulating agentes (ESAs): act like EPO to produce more RBCs (epoetin alfa, darbepoetin alfa), but have RISKS (elevated BP and thrombosis) –> only when Hgb <10 g/dL (D/C or hold if Hgb exceeds 11g/dL)
-ESAs only effective with adequate iron stores (assess iron, ferritin, and TSAT levels) –> may need to give IV iron at dialysis center
-Daprodustat (Jesduvroq): ORAL ESA indicaeted for CKD pts who have been receiving dailysis for at least four months
CKD: Hyperkalemia
-Pathophysiology
-Other contributing factors
-Symptoms
Potassium is NOT excreted as well through kidneys (primarily excreted through gut and kidneys)
Contributing factors:
-Medications (ACEIs/ARBs; K-sparing diuretics, aliskiren, canagliflozin, drosperinone-containing COCs, K-containing IV fluids, K supplements, Bactrim, cyclosporine, tacrolimus, everolimus)
-High urine flow
-Negatively charged ions in distal tubule (bicarbonate)
-Insulin deficiency in DM
**Diet does NOT usually affect because offset by insulin
Symptoms: often asymptomatic, but can cause muscle weakness, bradycardia, and fatal arrhythmias
CKD: Hyperkalemia TX
- Stabilize the heart: calcium gluconate (preferred) > calcium carbonate
-does NOT decrease K, but stabilized myocardial cells to prevent arrythmias
-IV route, onset: 1-2 minutes - Move K intracellularly: onset of 30 minutes
-Regular insulin IV: given w/ dextrose to prevent hypoglycemia, but can be used alone if BG >/=250
-Sodium bicarbonate IV: when metabolic acidosis present
-Albuterol, nebulized: monitor for tachycardia and chest pain - Remove K
-Loop diuretics (typically furosemide): IV onset of 5 minutes; eliminates K IN URINE
-Hemodialysis: immediate once started, but takes several hours to setup/complete; other methods usually used in conjunction
-Potassium binders (sodium polystrene sulfonate, patiromer, or sodium zirconium cyclosilicate)
**Always D/C potassium source as well
Sodium polystyrene sulfonate
-Brand
-MOA
-ROA
-Onset of action
-AVEs
-Warnings
-DDIs
Brand: SPS, Kayexalate
MOA: potassium binder
ROA: PO or PR
Onset of action: 2-24 hours
AVEs: N/V/D, constipation
Warnings: GI NECROSIS (increased risk when with sorbitol), electrolyte imbalances (hypernatremia, hypokalemia, hypomagnesemia, hypocalcemia), fecal impaction
DDIs: can bind with other oral medications (check for DDIs)
Patiromer
-Brand
-MOA
-ROA
-Onset of action
-AVEs
-Warnings
-DDIs
Brand: Veltassa
MOA: potassium binder
ROA: PO
Onset of action: 7 hours
AVEs: CONSTIPATION, nausea, diarrhea
Warnings: can worsen GI motility, HYPOMAGNESEMIA
-Delayed onset may limite life-threatening hypekalemia
DDIs: binds to many oral drugs; separate by at least 3 hours before or after
Sodium zirconium cyclosillicate
-Brand
-MOA
-ROA
-Onset of action
-AVEs
-Warnings
-DDIs
Brand: Lokelma
MOA: potassium binder
ROA: PO
Onset of Action: 1 hour (generally preferred in hyperkalemia due to quicker onset)
AVEs: peripheral edema
Warnings: can worsen GI motility, edema, contains sodium (may need to adjust dietary intake)
DDIs: can bind to other drugs; separate by at least 2 hours before or after
CKD: Metabolic Acidosis
-Why can metabolic acidosis occur in CKD?
-TX
Metabolic acidosis occurs because the ability of the kidney to reabsorb bicarbonate in CKD decreases
TX: replace serum bicarbonate when <22 mEq/L
-Sodium bicarbonate: Na overload can cause fluid retention, monitor levels and caution in HTN or CVD
-Sodium citrate/citric acid solution (Cytra-2, Oracit): metabolized to bicarbonate by livr (not as effective in liver failure), monitor Na levels
Dialysis: Types
-Hemodialyis (HD): blood is filtered through dialyzer and infused back into patient which takes about 3-4 hours per session usually three times a week
-Peritoneal dialysis (PD): dialysis solution usually containing glucose is pumped into peritoneal cavity (the abdominal cavity surroounding the internal organs) which is left in the abdomen to “dwell” for a period of time to allow waste product and electrolyte exchange then drained; repeated QD at home by pt
-Continous renal replacement therapy (CCRT): 24-hour dialysis therapy typically in acute settings for AKI and fluid overload
Factors that affect drug removal during dialysis
-Drug properties: MW (smaller molecules more readily removed), Vd (larger Vd less likely to be removed), protein-binding (higher binding less likely to be removed)
-Dialysis membrane: high influx have larger pore size which removes more than low influx
-Blood flow rate (higher rate increases drug removal over given time)
What is hepatitis and its causes? What is the general recommendations for screening and vaccinations?
Inflammation of the liver
Causes:
-Most common = viruses (hepatitsis A-E mostly A/B/C; herpes virurses; cytomegalovirus; Epstein-barr; adenoviruses)
-Alcohol
-Certain drugs
-Autoimmune diseases
-Other infections
Screenings: one-time for HBV and HCV for anyone of 18 yo and older (repeat if at enhanced risk, screening at each pregnancy)
Vaccinations: HBV for all adults
Compare Hepatitis A, B, and C in terms of:
-Acute or Chronic
-Transmission
-Vaccine for prevention?
-General treatment
Hepatitis A:
-Acute only
-Fecal-oral transmission (typically improper handwashing or ingestion of contaminated food/water)
-Has vaccine
-Supportive care as TX (usually self-limiting)
Hepatitis B:
-Acute or chronic
-Blood or bodily fluid transmission (sexual activity, sharing contaminated needles, perinatal transmission from mother to newborn)
-Has vaccine
-TX: PEG-IFN (inteferon alfa) or NRTI (tenofovir or entecavir)
Hepatitis C:
-Acute or chronic
-Blood transmission
-NO vaccine
-TX: Direct Acting Antivirals (DAAs) combination (2-3)
Hepatitis C: Treatment
TX is in general complex due to different recommendations for six different genotypes and guidelines should be consulted
General TX:
-Direct-Acting Antivirals (DAA) combination of 2-3 (choose ones with different MOAs) usually for 8-12 weeks
-Second line TX: adding ribavarin (RBV)
-PEG-INF (interferon alfa) NO longer recommended due to sucess of DAAs (DAAs typically able to CURE hepC)
DAAs for Treatment-Naive Patients:
-Glecaprevir/pibrentasvir (Mavyret) for 8 weeks
-Sofosbuvir/velpatasvir (Epclusa) for 12 weeks
Direct Acting Antivirals (DAAs) for Hepatitis C:
-Drugs/Brands/MOA
-Administration
NS3/4A Protease Inhibitors (PIs): “-previr” (glecaprevir, grazoprevir, voxilaprevir)
NS5A Replication Complex Inhibitors: “-asvir” (elbasvir, ledipasvir, pibrentasvir, velpatasvir)
NS5B Polymerase Inhibitors: “-buvir” (sofosbuvir)
Administration: take with food (Protease Inhibitors and Grub -> PIG “Take with food”)
Direct Acting Antivirals (DAAs) for Hepatitis C: General AVEs, Warnings, BBW, and Monitoring for ALL DAAs
AVEs: WELL-TOLERATED (HA, fatigue, diarrhea, nausea)
Warnings: potentially serious DDIs, rapid decrease in HCV viral load can improve glucose metabolism (hypoglycemia)
BBW: RISK OF REACTIVATING HBV (test ALL pts before starting)
Monitoring: LFTs (including bilirubin), HCV-RNA
DDIs: Have lots –> always check package labeling of each one
-ALL: strong inducers of CYP3A4 (carbamazepine, oxcarbazepine, phenobarbital, pehyntoin, rifampin, rifabutin, St. John’s Wort), most increase statin concentrations (myopathy risk), decrease BG with inuslin and other DM medications
Sofosbuvir:
-Brand by itself
-Brand when added to ledipasvir
-Brand when added to velpatasvir
-Brand when added with velpatasvir and voxilaprevir
-MOA
-TX
Sofosbuvir (Sovaldi)
Sofosbuvir/ledipasvir (Harvoni)
Sofosbuvir/velpatasvir (Epclusa)
Sofosbuvir/velpatasvir/voxilaprevir (Vosevi)
MOA: NS5B Polymerase
TX: HCV (NOT effective as monotherapy-> most common Harvoni and Epclusa)
-Epclusa: used for all six genotypes
Sofosbuvir:
-Administration considerations
-Warnings/CIs
-DDIs
Administration: protect from moisture –> dispense and keep in original container
Warnings/CIs:
-Vosevi: rare cares of liver failure typically with baseline impairment
-CI: Vosevi concurrent use with rifampin, Epclusa with PPIs
DDIs:
-Sofosbuvir-containing regimens cause serious symptomatic bradycardia with amiodarone
-Ledipasvir: avoid or minimize acid-suppressing therapy (PPIs NOT recommended with Epclusa; H2RAs take at the same time or separated by 12 hours –> famotidine ; antacids: seperate by 4 hours)
What is the booster that can be found in HCV drugs, and why is it important?
Ritonavir - found in Technivie (ombitasvir/paritaprevir/ritonavir) and Viekira (dasabuvir/ombitasvir/paritaprevir/ritonavir)
Is pharmacokinetic booster, but also LOTS of DDIs
-Specifically CI with ethinyl estradiol
Counseling: How to take
-Viekira Pak
-Viekira XR
Viekira Pak: co-packaged formulation (has ombitasvir/paratiaprevir/ritonavir together to take QD and dasabuvir separately as BID)
Viekira XR: 3 tablets ONCE daily with meal
Mavyret:
-Generic
-MOA
-ROA
-Administration
-TX
-Warnings
-CIs
-DDIs
Generic: glecaprevir/pibrentasvir
MOA: NS3/4a protease inhibitor (glec) + NS5a replication complex inhibitior (pib)
ROA: PO
Administration: take WITH FOOD
TX: HCV
Warnings: rare cases of liver failure (typically when pt has baseline impairment)
CI:
-Moderate-severe hepatic impairment (Child-Pugh class B or C)
-Hx of hepatic decompensation
-Coadministration with rifampin (decreases serum concentration of Mayvret) or atazanavir (increases serum concentration of Mayvret)
DDIs: do NOT use with select statins (atorvastatin, lovastatin, simvvastatin), select protease inhibitors (atazanavir, darunavir, lopinavir, ritonavir), cyclosporine (>100mg/day), or ethinyl estradiol (>20mcg/day)
Zepatier:
-Generic
-MOA
-ROA
-TX
-Warnings
-CIs
-DDIs
Generic: elbasvir / grazoprevir
MOA: NS5a replication complex inhibitor (elb) + NS3/4a protease inhibitor (grazo)
ROA: PO
TX: HCV
-Screening for NS5A polymorphism is recommended when treating genotype 1a
Warnings: increases ALT (>5 ULN) at or after 8 weeks of TX, rare cases of liver failure
CI:
-Moderate-severe hepatic impairment (Child-Pugh class B)
-Hx of hepatic decompensation
-Use w/ strong CYP3A4 inducers, OATP1B1/3 inhibitors, or efavirenz
DDIs: do NOT use with efavirenz, cyclosporine, or select protease inhibitors (atazanavir, darunavir, lopinavir, tipranavir), NOT recommended with tacrolimuz, ertavirine, Stribild, Genyovya, modafanil, nafcillin, ketonazole, bosentan
Ribavirin (RBV):
-MOA
-ROA
-TX
-AVEs
MOA: inhibits replication of RNA and DNA virsues
ROA: PO
TX: HCV (NEVER as monotherapy)
AVEs: fatigue, HA, insomnia, anxiety/mood changes, N/V/D. anorexia, myalgia, hypothyroidism, alopecia
Ribavirin (RBV):
-CIs
-BBW
-Monitoring
-DDIs
CIs:
-PREGNANCY, women of childbearing age who do NOT use contraception reliably, male partenrs of pregnant women –> AVOID pregnancy 6-9 months after completion w/ at least 2 forms of effective contraception during and post-TX follow up
-Hemoglobinopathies
-CrCl <50mL/min (capsule)
-Autoiummune hepatitis
BBW: TERATOGENIC, HEMOLYTIC ANEMIA (mostly within first two weeks of initiation and can worsen leading to cardiac death and MI) –> avoid in unstable or significant cardiac disease
“RIBA”:
-R: Renal (CrCl <50mL/min)
-I: In combination only
-B: Birth defects
-A: Anemia: hemolytic (primary toxicity)
Monitoring: CBC w/ differential, PLTs, electrolytes, LFTS/bili, HCV-RNA, TSH, monthly pregnancy tests
DDIs:
-Can increase hepatotoxic effects of NRTIs (lactic acidosis)
-Zidovudine: can increase risk and severity of anemia w/ RBV
Inteferon Alpha
-Brand
-MOA
-ROA/Dosing frequency
-TX
Brand: Pegasys (pegylated intefron-alpha-2a)
MOA:
-Inteferons: natural cytokines w/ antiviral, antiproliferative, and immunomodulatory effects
-Pegylated (PEG-IFN-alpha): added polyethylene glycol to PROLONG HALF LIFE
ROA/Frequency: SQ weekly
TX: Chronic HBV monotherapy
-Sometimes added to HCV regimen
Peglyated inteferon-alfa-2a:
-AVEs
-Warnings
-CIs
-BBW
-Monitoring
AVEs: CNS EFFECTS (fatigue, depressoin, anxiety, weakness), GI UPSET, INCREASED LFTS (5-10x UNL), mild alopecia,
-NEEDS pre-treatment w/ APAP and antihistamine: FLU-LIKE SYNDROME (fever, chills, HA, malaise) 1-2 hours after administration
Warnings: MYLEOSUPPRESSION, CV events, visual disorders (decreased vision, retinopathy), endocrine disorders (hypo/hyperthyroidism, hypo/hyperglycemia), pancreatitis, skin rxns
CI: autoimmune hepatitis, decompensated liver disease in cirrhotic pts, infants/neonates
BBW: can cause or exacerbate NEUROPSYCHIATRIC, AUTOIMMUNE, ISCHEMIC, or INFECTIOUS disorders
Monitoring: CBC w/ differential, PLTs, LFTs, uric acid, SCr, electrolytes, TGs, thyroid fxn tests, serum HBV-DNA levels
-Stop or reduce dose based on: ANC, PLTs, CrCl
Inteferon products:
-What are these products used for if its alpha or beta?
-Are inteferons curative?
Alpha: HBV, HCV, some cancers
Beta: mutilple sclerosis (MS)
NOT CURATIVE
Nucleoside Reverse Transcriptase Inhibitors (NRTIs) for Hepatitis B:
-MOA
-What should be screened before usage?
-For ALL NRTIs: AVEs, BBW, dose adjustments
MOA: inhibit HBV replication by inhibition HBV polymerase, resulting in DNA chain termination
Screening prior to use: HIV –> some also have activity for HIV, BUT two NRTIs are recommended to minimize risk of HIV antiviral resistance
AVEs: GI upset, rash, increased LFTs
BBW:
-LACTIC ACIDOSIS and SEVERE HEPATOMEGALY W/ STENOSIS (can be fatal, downgraded to warning for both tenofovir formulations and lamivudine)
-EXACERBATIONS of HEPB once D/C
-Can cause HIV resistance
Dose Adjustments: when CrCl <50mL/min: decrease dose or frequency (except: Vemlidy)
Which NRTIs are approved for HBV?
- Tenofovir disoproxil or alafenamide
- Entecavir
- Adefovir
- Lamivudine (Epivir HBV) - Epivir for HIV (dosing different)
Tenofovir disoproxil fumurate (TDF) and tenofovir alafenamide (TAF):
-Brands
-MOA
-ROA
-Administration
-TX
Brands: Viread (TDF), Vemlidy (TAF)
MOA: NRTIs
ROA: PO
Administration: protect from moisture (dispense only in original container)
TX: preferred therapy in HBV; in combo w/ HIV therapy (TAF)
Tenofovir disoproxil fumurate (TDF) and tenofovir alafenamide (TAF):
-Differences between salts
-AVEs
-Warnings
-DDIs
Salt differences: increased RENAL TOXICITY with TDF
AVEs: N/D, HA, abdominal pain, fatigue, depression, increased LFTs, LIPID ABNORMALITIES (increased with TAF)
Warnings: renal toxicity including AKI and/or FANCONI SNYDROME (inadequate absorption in proximal renal tube), DECREASED BMD
TeNOFovir: “NOF” = Nephrotoxic, Osteoporosis, Fanconi syndrome
DDIs: do NOT use TAF w/ oxcarbazepine, phenytoin, phenobarbital, rifampin, and St. John’s Wort; do not use TAF or TDF w/ adefovir (increased virologic failure and side effects)
Entecavir:
-Brand
-MOA
-ROA
-Administration
-TX
-AVEs
Brand: Baraclude
MOA: NRTI
ROA/Administration: PO OES (2 hours before or after meal –> food reduces AUC by 18-20%)
TX: HBV (prefererd treatment), combo in HIV
AVEs: ascites, increasd LFTs, hematuria, nephrotoxicity, hyperglycemia, glycosuria
Lamivudine:
-Brand for HBV TX
-MOA
-AVEs
-BBW
-DDIs
Brand: Epivir HBV
MOA: NRTI
AVEs: HA, N/V/D, fatigue, insomnia, myalgia, increased LFTs, pancreatitis (rare)
BBW: do NOT use Epivir HBV for HIV treatment (lower doses which can result in HIV resistance)
DDIs: Bactrim can increase lamivudine levels
Adefovir:
-Brand
-MOA
-ROA
-TX
-AVEs
-BBW
-DDis
Brand: Hepsera
MOA: NRTI
ROA: PO
TX: HBV
AVEs: HA, weakness, abdominal pain, dyspepsia, nephrotoxicity
BBW: caution in pts with renal impairement or at risk of renal toxicity (includding concurrent nephrotoxic drugsd and NSAIDs)
DDIs: do NOT use with tenofovir due to increased risk of virologic failure and side effects
Cirrhosis:
-Define
-Causes
-Symptoms
-Complications
Cirrhosis: advanced fibrosis (scarring) of the liver
Causes: most common are Hepatitis C and alcohol
Symptoms: N/V/D, anorexia, pain in upper right quadrant of abdomen, jaundice of skin and eyes, darkened urine, paler stool from decreased bile
Complications: portal HTN, gastroesophageal varices, ascites, hepatic encephalopathy
Liver Function Tests: what labs are abnormal in:
-Acute liver toxicity, including from drugs
-Chronic liver disease (ex. cirrhosis)
Acute liver toxicity: increased AST and ALT (liver enzymes: normal range of 10-40 U/L)
Chronic liver disease:
-Increased: AST/ALT, Alk Phos, Tbili, LDH (lactate dehydrogenase), PT/INR (bleeding risk)
-Decreased: albumin
-Overtime with damaged liver cells, AST and ALT can look normalized or go down
Liver Function Tests: what labs are abnormal in:
-Alcoholic liver disease
-Hepatic encephalopathy
-Jaundice
Alcoholic liver disease: AST will be about double of ALT; increased gamma-glutamyl transpeptidase (GGT)
Hepatic encephalopathy: increased ammonia
Jaundice: increased Tbili (total bilirubin)
Child-Turcotte Pugh (CTP) or Child-Pugh Classification AND the Model for end-stage liver disease (MELD)
Child-Pugh/CTP: assessment of severity of liver disease (likelihood of complications, surgical outcomes, and survival)
-Class A (mild) <7
-Class B (moderate) 7-9
-Class C (severe): 10-15
MELD: assess likelihood to die in next three months and often for eligibility for liver transplant (higher score the worse ranging from 0-40)
Natural products and hepatic function:
-What can help?
-What is hepatotoxic?
Milk thistle: limited efficacy, but not harmful (mild diarrhea and some DDIs)
Hepatotoxins: Kava, comfrey
-Many –> important to look into (Liver Tox website)
Drug-induced liver injury (DILI):
-What is the primary treatment?
-What is the dosing for APAP?
-What drug class should be avoided in cirrhosis that can lead to decompensation?
Primary TX: D/C offending drug (typically when LFTS >3x UNL –> especially when >150)
APAP: for pts w/ cirrhosis, <2g/day
Drug class to avoid in cirrhosis: NSAIDs
What drugs have a BBW for hepatotoxicity?
-APAP (high dosage, acute or chronic): fairly safe if dosed appropriately
-Amiodarone
-Isonazid, ketoconazole (PO)
-Methotrexate
-Nefazodone
-Neviripine
-NRTIs
-Propylthiouracil
-Valproic acid
-Zidovudine
Alcohol-associated liver disease (ALD):
-Complications
-How does chronic ALD change the pathophyiosolgy?
-Treatment
Complications: alcohol hepatitis (often associated w/ poor short-term survival), fatty liver (steatohepatitis), chronic hepaitits (w/ fibrosis or cirrhosis)
Chronic ALD: increased secretion of pro-inflammatory cytokines (TNF-alpha, IL-6, IL-8), oxidative stress, lipid peroxidation, and acetaldehyde toxicity
TX: alcohol cessation (liver may be able to regenerate depending on phase)
-BZDs: alcohol withdrawl (for mild: gabapentin, carbamazepine)
-Naltrexone, acamprosate, and disulfiram: prevent relapses
-Prevent malnutrition: vitamin A/D, thiamine (B1), folate, pyridoxine (B6), zinc
-THIAMINE: can prevent and TX Wernicke-Koraskoff snydrome (induces brain damage from lack of vitamin B1)
Portal Hypertension and Variceal Bleeding:
-Pathophysiology
-Acute treatment
-Prevention (primary and secondary)
Fibrotic tissue causes resistance to blood flow, increasing pressure in portal vein (portal HTN). Blood can back up and flow into smaller blood vessels with less pressure (ex. esopahgus and rectum) causing them to balloon out. Enlarged vessels (esophageal varices) can break open and result in bleeding.
Acute treatment: ocreotide (selective fore splanchnic vessels) or vasopression (nonselective)
-Non-medications: band liagation (band around vessel), sclerotherapy (injecting solution into vessel to force it to collaspse and close), stent placed in liver to direct flow
-ABXs: ceftriaxone or ciprofloxacin for up to 7 days may be given to prevent bacterial infections
Prevention (primary and secondary): non-selective beta-blocker (nadolol, propranolol) for lifetime (target HR: 55-60 bpm, SBP >/=90mmHg) –> do NOT use selective which focuses only on heart
-Carvedilol: has additional alpha-1 blocking effects to vasodilate intrahepatic circulation to decrease resistance and approved for primary prevention
Ocreotide:
-Brand
-MOA
-ROA
-TX
-AVEs
-Monitoring
Brand: Sandostatin, Sandostatin LAR Depot
MOA: analog of somatostatin, inhibiting vasodilatory hormones
ROA: IV
TX: variceal bleeding (selective to splanchnic/GI circulation)
AVEs: BRADYCARDIA, CHOLELITHAISIS, BILIARY SLUDGE, fatigue, HA, hyper/hypoglycemia, N/V/D, abdominal pain, dizziness, flatulence, constipation, injection site rxns, URTIs
Monitoring: BG, HR, ECG
Hepatic Encephalopathy (HE):
-Pathophysiology
-Symptoms
-Treatment
HE: hepatic insufficiency causes accumulation of gut-derived nitrogenous substance in the blood (ex. ammonia, glutamate)
Symptoms: musty odor of breath and/or urine, changes in thinking/confusion/forgetfullness, drowsiness, disorientation, mood changes, poor concentration, worsening handwriting, flapping hand tremor (asterixis), sluggish movements, coma
Treatment:
-Reduce ammonia levels by reducing animal protein intake (vegetable protein sources have lower calorie to nitrogen ratio)
-DOC: lactulose (nonabsorbable disaccharide that converts ammonia produced by intestinal bacteria to ammonium which is polar and cannot readily diffuse in blood and enhances diffusion of ammonia into colon for excretion)
-Add-on TX: rifaximin to inhibit activity of urease-producing bacteria, decreasing ammonia production (alternatively: neomycin - NOT preferred due to neurotoxicity OR metronizadole -NOT as preferred due to peripheral neuropathy)
Lactulose:
-Brand
-MOA
-ROA
-TX
-AVEs
-CIs
-Monitoring
Brand: Enulose, Constulose, Generlac, Kristalose
MOA: nonabsorbable disaccharide that converts ammonia produced by intestinal bacteria to ammonium which is polar and cannot readily diffuse in blood and enhances diffusion of ammonia into colon for excretion
ROA: PO, can make enema as well
TX: hepatic encephalopathy
AVEs: FLATULENCE, DIARRHEA, DYSPEPSIA, ABDOMINAL DISCOMFORT, dehydration, hypernatremia, hypokalemia
CI: low galactose diet
Monitoring: mental status, BOWEL MOVEMENTS, AMMONIA, fluid status, electrolytes
Ascites:
-Define
-Treatment options
-Complications
Ascites: fluid accumulation within peritoneal space
TX:
-Cirrhosis AND ascites: liver transplant
-Portal HTN: restrict Na intake to <2g/day, avoid Na-retaining medications (NSAIDs)
-Diuretic TX: spirinolactone monotherapy (suspension: CaroSpir is NOT therapeutically equivalent to oral tablets Aldactone) or in combo with furosemide (furosemide itself NOT recommended since it does NOT target aldosterone despite being a potent diuretic) –> when in combo, ratio of spirinolactone:furosemide 100:40mg to maintain K balance
-Severe: abdominal paracentesis (removal of fluids) –> addition of albumin recommended (6-8g per L of fluid removed) to prevent paracentesis-induced circulatory dysfunction and progression to hepatorenal syndrome
Complications:
-Spontaneous bacterial peritonitis (SBP): infection from ascitic fluid (see ID section, but general TX: ceftriaxone for streptococci and GNRs x5-7D or equivalent; secondary prophylaxis: one dose of Cipro or Bactrim)
-Hepatorenal Syndrome (HRS): renal failure from advanced cirrhosis with poor prognosis (prevention key due to high mortality rate) –> can be treated wtih vasoconstrictors such as terlipressin or norepinephrine in combo with albumin, ocreotide, or midodrine
