Kidney + liver Flashcards
define nephrotoxicity
rapid deterioration in kidney function as a result of medications and chemicals
List types of nephrotoxic drugs and intoxicants
- prescribed drugs
-OTC
-herbal remedies
-Food products
-recreational drugs
-imaging agents
-moulds + fungi
-cancer therapeutics
-antibiotics
-some metals e.g. lead and mercury
e.g. Vancomycin, Mitomycin, NSAIDs, ACEi, ARBs, radiocontrast
Explain why not all nephrotoxic drugs affect patients equally
- some patients are more susceptible due to genetics
-patients have different metabolism and excretion of compounds
Discuss how drug characteristic e.g. solubility, structure, and charge can effect nephrotoxicity
solubility - may cause acute crystalline ppt in DCT if insoluble in urine + made worse by reduced urinary flow rates + excessive drug dosing e.g. methotrexate
structure - need to slowly rehydrate individuals because cell swelling can occur with drugs such as dextran.
charge - drugs with positive charge e.g. polycationic aminoglycosides are attracted to negatively charge PCT membrane phospholipids which facilitates drug binding to receptor complexes.
Explain how patient characteristics can effect whether a drug is nephrotoxic to them
- what their blood volume is
- electrolyte imbalance
- infection
- age, ethnicity, sex
- co-morbidities
-dehydration
-AKI + CKD
-nephrotic syndrome
-genetics + mutations
Explain how kidney structure and function determines nephrotoxicity
volume repletion
loading doses
phase 1 reactive oxygen species
ischemia of cells
transporters for uptake of drugs
Explain the aetiology of common causes of impaired kidney function including polycystic Kidney disease
what are the causes of AKI
- prerenal - impairment of blood supply to kidneys from volume depletion or drugs such as NSAIDs
- intrinsic - impairment within kidney’s blood vessels, glomeruli + tubules can happen from immune response, damage due to antibiotics or heavy metals or infection
-postrenal - obstruction of the urinary collecting system e.g. swelling of blood vessels leading to ischaemia or obstruction such as kidney stones.
what are risk factors of AKI
- poor fluid intake
- dehydration
-drugs
-infection
-trauma
-rhabdomyolysis
-volume depletion
-hypotension
-low cardiac output
what is the pathophysiology of AKI
sudden decrease in kidney function due to reduced urine output, urine retention or fluid overload.
what are the complications and management of AKI
diagnosis based on serum creatinine or urine output
fluid overload e.g. oedema - loop diuretics e.g. furosemide
dehydration - fluid resuscitation
metabolic acidosis - sodium biocarbonate
Hyperkalaemia (emergency) - when >7mmol/L more prominent T wave use of calcium gluconate to antagonise the membrane excitability, redirect K+ from blood to cells using insulin + glucose, salbutamol, sodium biocarbonate, haemodialysis.
Find the underlying cause
if infection - antibiotics
if obstruction - remove or empty bladder
if toxic drugs - stop taking.
describe the causes and risk factors of chronic kidney disease
-disease
-injury
-ageing
-hypertension
-hyperglycaemia
-hyperlipidaemia
-renal infections
-post-renal obstruction
-drugs e.g. NSAIDs
what is the pathophysiology of chronic kidney disease?
progressive, irreversible loss of nephrons due to disease, injury or ageing.
early - primary insult –> nephron number decreases –> increase in glomerular pressure –> vasodilation of surviving nephrons–> homeostasis–> keeps happening causes glomerular sclerosis
what are the complications and management of chronic kidney disease?
what is the mechanism of action for chelating agents used for kidneys?
Forms a chelate complex with a metal ion forming a strong stable ring structure when binding with a polydentate. Kf/formation constant helps to determine the stability.
what is the mechanism of action of phosphate binding agents used for the kidneys?
phosphate binding agents - form insoluble compounds in the GI tract so they cannot be absorbed into the body, so they are excreted out. e.g. Calcium acetate, calcium carbonate, aluminium salts
what is the mechanism of action of thiazide diuretics used for the kidneys?
promotes diuresis, blocks Na/Cl transporter –> inhibits reabsorption of Na and Cl ions –> increases elimination of water from the body
what is the MOA of calcimetic agents
mimic action of calcium on tissues, binds at allosteric site acts on calcium sensing receptors e.g. Cinacalcet
what does alfacalcidol do?
promote calcium homeostasis and bone metabolism
an analogue of vit D3 (Vit D3 gets hydroxylated at C25, then further at 24 or 1 alpha. Those with renal failure cannot perform alpha 1 hydroxylation so are given alfacalcidol
advantages of sustained/controlled release
- reduces the dose frequency
-minimal fluctuations for desired therapeutic effect
-reduced side effects
-reduce total drug
discuss the different types of modified drug release
delayed release - drug released some time after administration (enteric coated+pulsatile)
extended release - prolonged release to reduce dose freq(sustained + controlled)
targeted release - inc conc of medication in some parts of the body (passive + active targeting)
key points of controlled drug release
delayed - enteric coated protects from gastric acid or patient from irritation. Pulsatile released based on repeated succession of pulses at time intervals.
extended sustained - maintains rate of drug release over sustained period but not at a constant rate - prolong time in therapeutic range. Only oral
extended controlled - drug released at nearly constant rate + Cp independent of biological environment. Variety of dosage forms e.g. transdermal systems.
How do the two types of diffusion controlled release mechanisms work?
Matrixes - Monolithic where drug molecules diffuse through pores or between chains.
Reservoirs - drug released from an insoluble polymeric semi - permeable membrane that encapsulates the drug e.g. a transdermal patch (membrane controlled).
How does osmotic drug delivery mechanism work?
polymer - controlled release agent swells and releases the drug. Usually from absorbing water or bodily fluids
How does dissolution/degradation mechanism of drug delivery work?
Biodegradable polymers
degrade by natural processes either the surface erodes or the bulk.
How does responsive controlled drug release mechanism work?
responds to a stimuli e.g. pH or electrical current that allow for the drug to be released
describe the various gastroretention systems
advantages and disadvantages of targeted drug delivery
how are drugs cleared from the kidneys and liver
how are drugs targeted to be delivered to the kidneys and liver
provide examples for site-specific drug delivery systems
what are the transmission routes of hepatitis B and C?
Blood, sexual or vertical (mother)
outline the pathogenesis hepatitis B
- asymptomatic - incubation period 4-12 weeks replicates in hepatocytes without symptoms
- acute phase - HBV detected in plasma –> T -cell response causes hepatocellular necrotic damage. Early response - cytokines released no cytolytic effect. Late response causes liver damage and inflammation. Can resolve on its own within 6 months.
Pathophysiology of hepatitis B
After chronic phase (6 months)
- CD8 T cell response fails and liver necrosis and inflammation occurs.
-causes cirrhosis of the liver and leads to permanent scaring –> hepatocellular carcinoma
-HBV is an oncovirus so can lead to cancer transformation –> hepatocellular carcinoma
what are the clinical manifestations of hepatitis B?
-pre-icteric phase : fever, nausea, serum alt levels rise
-icteric phase: (3-10 days) jaundice, systemic symptoms, enlarged liver
-resolution phase: icteric symptoms resolve + fatigue may last
How do you manage and treat hepatitis B?
target the reverse transcriptase using anti-HBV drugs
resemble natural nucleosides and terminate viral DNA by incorporation into the viral DNA.
e.g. Lamivudine, Entecavir, Telbivudine
Use of Peg-IFNalpha - 2a - pegylated derivatives of interferon alpha help to boost the immune system.
patients should be monitored every 6 months for viral load and renal function.
desired outcome HBV undetectable levels to prevent disease progression. Treatment usually lifelong
How do you manage and treat hepatitis C?
Harvoni OD - HCV polymerase inhibitor
Zepatier OD - HCV protease inhibitor
Epclusa OD - HCV polymerase inhibitor
Mavret TDS - HCV protease inhibitor
what is the location and structure of components on the urinary system?
consists of: inferior vena cava, adrenal gland, aorta, renal artery, renal hilum, renal vein, kidney, ureter, lilac crest, uterus, urinary bladder, urethra
what are the structure, blood supply, nerve supply and function of the kidney?
functions of kidneys:
- regulate blood volume
-removal of urea from bloodstream
-conserve nutrients
-regulate acid-base balance
-regulate blood pressure
-calcium homeostasis
-production of erythropoeitin and renin
Blood and nerve supply:
Aorta –> renal artery–>segmental artery–>interlobular artery –> arcuate artery –> cortical radiate artery –> Afferent arteriole –> glomerulus –> efferent arteriole–> peritubular capillaries –> cortical radiate vein –> arcuate vein –> interlobular vein –> renal vein –> inferior vena cava
describe regulation of micturition
urinary bladder stretches –> afferent impulses from stretch receptors to simple spinal reflex or brain.
Promotion of micturition when: increased parasympathetic activity, decreased sympathetic activity, decreased somatic motor nerve activity –> Detrusor muscle contracts, internal + external sphincter open
Inhibition of micturition when: Goes to brain, pontine storage centre, acts on three spinal efferents –> decreased parasympathetic activity, increased sympathetic activity, increased motor nerve activity
explain the anatomy of a nephron in relation to the formation of urine
glomerulus –> bowman’s capusle (glomerular filtration) –> PCT (tubular reabsorption + secretion) –> loop of henle –> DCT –> collecting tubule –> collecting ducts –> calyces –> renal pelvis –> ureter –> urinary bladder –> urethra.
explain the 3 processes of urine formation
Filtration (blood to nephron tubules)
Tubular reabsorption - passive and active returning material to blood from filtrate e.g. glucose, Na+, HCO3-
Tubular secretion - removing material from blood to filtrate e.g. urea
describe the regulation of water, acid, base and electrolyte balance in the kidney
water - controlled by ADH released by posterior pituitary in response to low blood volume or high osmolarity (Na).
acid + base - HCO3- combines with H+ to form H2CO3, carbonic anhydrase converts H2CO3 into H2O and CO2. This regulates urine and blood pH
electrolyte - symporters and transporters help to move electrolytes such as Na.
liver disease symptoms
Early stages/compensated:
- bruising
-fatigue
-abdominal pain
-loss of appetite
- weightless + muscle wasting
- dark urine
- N + V
-spider navi
-disturbed sleeping patterns
decompensated:
- jaundice
- ascites - build up of fluid in abdomen
-coagulopathy - bleeding risks
-increased infections
-encephalopathy - confusion
-increased sensitivity to drugs + alcohol
symptoms of liver cirrhosis - liver failure
- Jaundice (increased bilirubin causes yellow colour) can cause itchiness and pale stools
- Encephalopathy:
Wernicke’s - caused by thiamine deficiency
Hepatic - caused by build up of toxins in the blood e.g. nitrogen compounds increases permeability of BBB.
can cause sleep disturbances, motor problems, behavioural changes
-Coagulopathy:
prolonged clotting times, low PLT, prolonged prothrombin time
symptoms of cirrhosis - portal vein hypertension
- Ascites: portal vein clot + increased resistance in blood flow due to scarring and pushes fluid into abdominal space causing bloating and pain. Na and water retention and splanchnic vasodilation.
-Spontaneous bacterial peritonitis: Bacterial infection in patient abdomen due to ascites causes fever, increased HR, chills
-variceal haemorrhage: dilated veins in oesophagus + abdomen bodies way of reducing BP in hepatic portal vein. contributes to encephalopathy as blood by-passes the liver and can lead to bust haemorrhage. Blood in vomit + stool.
-portal vein thrombus:
how do you treat acute alcohol withdrawal
-Use NICE the CIWA-Ar protocol (based on symptoms, score >11 suggests severe and assessed every 1-2 hours.
- Diazepam 20mg PRN (PO) when CIWA-Ar >11 (benzodiazepine)
- Diazepam 10mg PRN (PR) if the patient has a seizure
- Adrenaline 1:1000 (IM) if patient has anaphylactic reaction to pabrinex.
How do you treat + manage encephalopathy?
Wernicke’s (vit B deficiency):
Acute management
Pabrinex (IV or IM) 2 pairs TDS 5 days, then 1 pair OD (make sure patient isn’t on any thiamine whilst using)
Prophylaxis:
Thiamine (PO):
Mild - 50mg-100mg daily
severe - 200mg - 300mg daily (divided doses for both)
Hepatic (build up of nitrogen compounds):
prophylaxis:
Lactulose 30-50ml TDS aim for 2-3 stools per day (less time for ammonia to be reabsorbed into the circulation)
Rifaxamin 550mg BD (reduces production and ammonia reabsorption) used alongside lactulose.
How do you treat portal vein hypertension
reduces ascites, abdominal varices and portal vein thrombi
- Propranolol - 40mg BD (max 160mg BD)
-Carvedilol (unlicensed indication) - 6.25mg daily
How do you treat coagulopathy?
vitamin K OD (PO or IV) 10mg stat for max 5 days + monitor prothrombin time and signs of bleeding
hold anticoagulants
How do you treat ascites?
managed with diuretics to remove fluid build-up or drain in severe cases
Spironolactone 100mg-400mg OD
monitor Cr + K+ + weight
How do you treat spontaneous bacterial peritonitis (SBP)?
No pen allergy:
Tazocin (IV) 4.5g TDS
non - severe pen allergy:
Cefotaxime (IV) 2g TDS
Metronidazole (IV) 500mg TDS
severe pen allergy:
Co-trimoxazole (IV) 960mg BD
Metronidazole (IV) 500mg TDS
Gentamycin (IV) 5mg/kg OD
Prophylaxis:
1st line: co-trimoxazole (PO) 960mg OD
2nd line: Ciprofloxacin (PO) 500mg OD
How do you treat oesophageal + abdominal varices?
endoscopic intervention e.g. variceal band ligation (prevents bleeding)
If rupture does occur:
Terlipressin (IV) 1mg -2mg QDS max 72 hrs (vasopressin analogue –> vasoconstriction)
kept in the fridge
medications to avoid in Werneck’s encephalopathy (vit B deficiency)
medications that cause constipation e.g. opioids + slow gut motility
medications to avoid in hepatic encephalopathy (nitrogen build up to brain)
medications that sedate e.g. analgesics, opioids, gabapentiniods, antipsychotics, sedatives, benzos, sleeping tablets
medications to avoid in coagulopathy/varices
anticoagulants + antiplatelet treatment e.g. NSAIDs, aspirin
medications to avoid due to ascites (fluid overload)
drugs that cause fluid retention e.g. steroids, NSAIDs, CCBs
medications to avoid due to lowered drug metabolism
drugs that are metabolised by the liver or secreted in bile unchanged.
medications to avoid due to decreased protein synthesis
drugs with high protein - binding potential = increased risk of toxicity e.g. phenytoin, prednisolone
medications to avoid due to hepatotoxicity
Methotrexate, sodium valproate, amiodarone etc.
Patient finds dose toxic at lower doses
risk factors for NAFLD
obesity, impaired glucose reg, T2 diabetes, hypertension, hyperlipidaemia, FHx, endocrine disorders, drugs, other liver conditions, obstructive sleep apnoea
what complications can occur in NAFLD
- same as alcoholic liver disease
- increased risk of HTN, CKD, type 2 diabetes, impaired glucose regulation, CVD
