Renal & Hepatic Drugs Flashcards
What is the role of the kidney?
A - Acid-Base Balance Control
W - Water balance
E - Electrolytes
T - Toxins (removal)
B - BP
E - Erythropoietin
D - Activates Vit D
What are the stages of AKI?
Stage 1 - Creatinine rise of 26 micro mol + in 48 hr OR rise of 50-99% from baseline within 7 days
Stage 2 - 100-199% creatinine rise from baseline within 7 days
Stage 3 - 200%+ creatinine rise from baseline within 7 days
Is creatinine clearance a good assessment of AKI?
Its all we have but it does lag behind - about 24 hours from what is actually happening - so it is an estimate
When can an ACEI cause AKI?
When combined with diuretic + ibuprofen
Why do NSAIDs cause kidney problems?
They cause vasoconstriction leading to acute tubular necrosis or acute interstitial nephritis.
This is because prostaglandins dilate afferent arterioles = normal glomerular perfusion.
NSAIDs block prostaglandins = decreases perfusion to the kidneys = AKI.
Which antibiotic is nephrotoxic?
Aminoglycosides - cause direct tubular toxicity
What to ACEIs and ARBs do to the kidney?
Cause vasodilation of the efferent arteriole - causing acute tubular necrosis.
Why do diuretics cause AKI?
They can cause volume depletion leading to reduced renal perfusion resulting in acute tubular necrosis.
When are diuretics more likely to cause AKI?
Upon initiation
After dose increase
Or secondary to dehydration - e.g. D&V or hot day
How does omeprazole cause AKI?
It can cause acute interstitial nephritis
When the kidney senses low blood flow it produces renin. What is the end result of this enzyme being produced?
Renin - cleaves angiontensinogen (liver) into AGT1. ACEs (lungs) cleave this into AGT2. AGT causes vasoconstriction of capillaries = increased BF to the kidneys.
AGT2 also stims pituitary to release ADH - this affects the kidneys to inc water reabsorption - inc BV and BP.
AGT2 also stims adrenal cortex to release aldosterone - makes DCT inc Na reabsorption - which means more water is reabsorbed - again inc BP.
How do ARBs work?
They stop AGT binding to AGT2 receptors - therefore stopping the effect of vasoconstriction, and the release of aldosterone and ADH.
Why is hyperkalemia a potential side effect of ACEIs?
Naturally the RAAS system encourages reabsorption of Na+ - which is at the expense of K+ being released into the urine.
If ACEIs block this - it means less K+ is released into the urine = hyperkalaemia.
What is the difference between morphine and oxycodone when prescribing for patients with renal injury?
Morphine (and codeine) should not be used in renal impairment as their metabolites accumulate in the kidney causing nephrotoxicity.
Oxycodone can be safely used in kidney injury but may need dose adjustment.
How is the half-life of drugs affected by renal impairment?
It is prolonged
What can you do to prescribe drugs in patients with renal impairment?
Reduce the dose (interval remains the same)
Increase the dosing interval (so the dose remains the same)
Which drugs should you be especially careful about when you have a kidney impaired patient?
Antibiotics inc
Vancomycin
Gentamycin
Tazocin
Cetfazidime & Penicillin V - can cause neurotoxicity and altered consciousness.
Ciprofloxacin and Macrolides - can cause nausea if the dose is too high
Any drug with a narrow therapeutic index
Any drugs that are renally excreted (aminoglycosides, digoxin)
Drugs in which their active metabolites are renally excreted (morphine)
What should you do to Digoxin in patients with renal impairment?
Loading dose remains unchanged and the maintenance dose is reduced.
How can absorption of drugs be affected in severe renal disease?
May have reduced absorption due to vomiting, diarrhoea and GI oedema. Can get altered motility and increased gastric pH.
How is distribution of drugs affected in Ps who have severe renal disease?
Oedema / ascite = can increase the volume of distribution, whereas dehydration can decrease this.
Can get reduced plasma protein binding - due to excess protein loss/alteration caused by uraemia.
Tissue binding can be affected - can get displacement from binding sites by metabolic waste products.
How is metabolism of drugs affected by reduced kidney function?
Kidney = major site of insulin metabolism - therefore insulin requirements are often reduced.
Reduced conversion to active Vit D.
Why do you need to beware of ultra metabolisers of drugs with kidney impairment?
Because more drug is reduced, more quickly - which can have even greater toxic effects if the kidney impaired.
How can you work out clearance in a renally impaired patient?
The fall in renal drug clearance is reflective of the decline in the number of functioning nephrons.
E.g. a 50% reduction in eGFR reflects a 50% decline in renal clearance.
What is a natriuretic?
Diuretic that increases Na excretion
What is a kaliuretic?
A diuretic that increases K+ excretion
What is an aquauretic?
A diuretic that increases water excretion
How does ADH work?
Secretion of ADH increases the number of AQP2 channels in DCT and CD = increased amount of water reabsorbed.
What effect does alcohol have on ADH?
Inhibits the release of ADH - thus the volume of urine increases.
What effect does nicotine and morphine have on ADH?
Increases ADH release and therefore reduces the volume of urine produced.
What is demeclocyline used for? Why?
Used for SIADH (syndrome of inappropriate ADH release) - is an ADH antagonist in the CD - means more water excreted as a result.
What percentages of water are absorbed at the following places in the kidney?
How do loop diuretics work?
Act on Na/K/2Cl (NKCC2) cotransporter in ascending limb LOH - causing inc loss of Na, K, Cl and Water.
What are loop diuretics used to treat? Why?
Used to clear peripheral oedema and acute pulmonary oedema.
Used because they are more powerful than other diuretics.
Give one example of a loop diuretic.
Furosemide
How long do furosemide effects last for?
6 hours
What are the SEs of loop diuretics?
Hypokalaemia
Ototoxicity (NKCC1 in inner ear)
Dehydration
Renal impairment
Low Na, Ca, Mg
Increased uric acid = inc gout
Why do loop diuretics cause hypokalaemia?
They inc Na+ in the distal tubule - where it is exchanged for K+ which is then excreted = hypokalaemia.
How do thiazide diuretics work?
Inhibit the Na/Cl co-transporter in the distal tubule = inc loss of Na, K, Cl and H2O.
What are thiazide diuretics used for?
Mild oedema and hypertension (good effect on BP - has secondary effect of vasodilation)
Also - urinary tract stones (can prevent stone formation)
Nephrogenic diabetes insipidius
How long do thiazide diuretics last for?
Up to 24 hours
Name one thiazide diuretic
Bendroflumethiazide
How do thiazide-like diuretics work?
Activate Kate channel in smooth muscle of TVs = dilation
Name a thiazide-like diuretic
Indapamide
What are the possible side effects of thiazides?
Hypercalcaemia - they increase the absorption of Ca = inc blood levels
Low - Na, K, H+, Mg
Increased urate (gout)
Increased glucose (diabetes)
Increased lipids (liver disease)
How do aldosterone antagonists work?
Reduces Na channels in DCT - means less Na and therefore less water reabsorbed
Do aldosterone antagonists affect K+ levels?
No they are K+ sparing (unlike loop diuretics)
Name a drug that is an aldosterone antagonist.
Spironolactone
Eplerenone
When is spironolactone used?
Is a weak diuretic
Used in Ps with poor LV function or post MI (especially in acute HF)
First line - hyperaldosteronism and cirrhosis, add on for resistant HT
What are the side effects of spironolactone?
Impaired renal function
Hyperkalaemia
Metabolic acidosis
Gynaecomastia, testicular atrophy
Name an osmotic diuretic
Mannitol
How does mannitol work?
Is a non-reabsorbable solute that is given IV - increases the water in circulating plasma and urine by osmosis.
Why is mannitol not used for hypertension?
Because it increases blood volume - therefore increases BP
How long do the effects of mannitol last for?
6-8 hours
What is mannitol used for?
Cerebral oedema - sucks the fluid out of the brain and back into the blood - thereby lowering intra-cranial pressure
What is the cause of pre-renal disease?
Reduced perfusion to the kidneys through the afferent arteriole
What percentage of AKIs are due to a pre-renal cause?
55-60%
What causes an AKI?
A sudden decrease in glomerular filtration rate due to imbalance between pressure gradient from afferent capillaries and the pressure in Bowman’s space
What are the possible causes of pre-renal disease?
Hypovolaemia -
- haemorrhage
- GI loss (D&V)
- renal loss (diuretics)
- skin & mucous membrane loss
- third space loss (pancreatitis, hypoalbuminaemia)
Decreased cardiac output (heart disease, pul HT, systemic vasodilation, drugs)
Renal vasoconstriction (NOR, liver disease, sepsis, hypercalaemia)
Renovascular disease (atherosclerosis, thrombus, renal artery dissection)
Drugs that impair GFR by affecting afferent and efferent arterioles (ACEIs, NSAIDs, diuretics, ARBs, cyclosporin, tacrolimus)
Which drugs can cause acute tubular necrosis?
ABs - Vancomycin, Acyclovir, Gentamycin
Organic solvents (ethylene glycol, toluene)
NSAIDs
ACEIs
Chemo agents - Cisplatin & Ifosfamide
Immunosuppressants - Cyclosporin / Tacrolimus, IV IG
Radiocontrast
What do ahminoglycosides, amphotericin B and cisplatin all do to the kidneys?
Cause direct toxicity to the PCT cells = tubular cell toxicity
What do NSAIDs and Rifampicin do to the kidneys?
Cause inflammation of the interstitial = interstitial nephritis
What do Acyclovir and Ampicillin do to the kidney?
Cause crystal toxicity - precipitation of crystals in the renovascualr and renal tubules
What does the kidney do in hypoperfusion. How do ACEIs interfere with this?
Kidney in hypo perfusion - constricts the efferent arteriole to cause back flow of blood in the kidney.
ACEIs - prevent this from happening
What are the symptoms of pre-renal AKI?
Severe dehydration -
- sunken eyes
- dry skin
- decreased skin elasticity
- dry mouth and eyes
- tachycardia
- orthostatic hypotension
How long does a renal injury need to persist before it is termed chronic kidney disease?
More than 3 months
What does pre-renal injury do to the kidney?
Reduces blood flow causing ischaemia in the PCT = acute tubular necrosis
How is AKI staged?
Depending on the serum creatinine levels
Stage 1 = 1.5-1.9x reference value or inc > 0.3mg/dl
Stage 2 = 2.0-2.9 reference range
Stage 3 = >3.0x reference value OR inc ?4.0mg/dL
What is GFR?
A measure of the amount of fluid that filters through the glomerular membrane per unit of time.
What affects GFR?
The filtration pressure at the glomerulus
The permeability of the glomerular membrane
SA of the glomerular membrane
What are the main causes of CKD?
DM (1&2)
Uncontrolled HT
What is the staging of CKD?
Stage 1 - normal function - eGFR 90+
Stage 2 - mild loss of function - eGFR 60-89
Stage 3 - moderate loss of function - eGFR 45-59 (3A) and 30-44 (3B)
Stage 4 - severe loss of function - eGFR 15-29
Stage 5 - kidney failure - eGFR <15
What is the problem with using creatinine to monitor CKD?
Once the eGFR goes below 60-50% - the creatinine rises incredibly high - but before this point there isn’t much change in creatinine levels. Therefore it doesn’t predict CKD in Stage 1 or most of Stage 2.
When do Ps become symptomatic with reduced kidney function?
When GFR becomes <15%
Which types of renal vascular disease can be a pre-renal injury?
Renal artery stenosis
Renal artery thrombosis
Also - renal artery aneurysm, atheroembolic renal disease
What are the investigative signs of AKI?
Elevated urea and creatinine
Elevated serum K
ABG - metabolic acidosis, dec pCO2, normal O2, decreased HCO3 (P will hyperventilate to blow off CO2 - hence low CO2)
What is the initial management of AKI?
Stop all nephrotoxic drugs
Appropriate fluids
Maintain sufficient BP (MAP >80)
ABs for sepsis if needed
Renal replacement therapy (if fluid overload, hyperkalaemia, metabolic acidosis, uraemia)
What is the normal serum potassium levels?
3.5-5.5
What does blood and protein in the urine indicate?
That the glomerular membrane isn’t working
How is proteinuria linked to CKD?
It increases the progression rate of CKD as protein is nephrotoxic to the tubules. Increased proteinuria is associated with faster decline in renal function.
What does
- bleeding from the kidney
- bleeding from the lower renal tract
indicate?
Kidney = glomerular disease
Lower renal tract = tumours / stones / catheter
What is cocoa cola urine (muddy brown & foamy) a sign of?
Nephritic syndrome - contains blood, protein and fat.
What is the difference between nephrotic and nephritic syndrome?
Nephrotic = loss of protein into urine
Nephritic = loss of blood into urine
Where does renal disease start from in terms of kidney anatomy?
From the glomerulus - before this is “pre-renal” disease
Name some causes of renal disease
Small vessel disease within the kidney
Glomerular disease
Acute tubular injury / necrosis
Acute interstitial nephritis
Intra-tubular obstruction
How does inflammation affect the glomerulus?
Inflammatory mediators and Ig deposition + factors from Tcells causes effacement of podocytes (flattening) - the barrier breaks down and allows proteins and RBCs to pass through.
Can get thickening of the glomerular capillary wall
What are the two types of immune disease of the glomerulus?
Type II - ABs attack the glomerulus itself (IgG and IgM) –> Diffuse proliferative glomerulonephritis
Type III - antigen-antibody complexes from elsewhere get trapped in to the glomerulus and trigger an inflammatory cascade –> membranous glomerulonephritis
What causes small vessel disease in the kidney?
Vasculitis
Thrombosis
Atherosclerosis (HT and DM can cause)
How does atherosclerosis affect the kidney?
Arteries in become thickened and narrowed - reduced BF to the glomerulus –> mesangial proliferation - these secrete ECM = glomerulosclerosis.
Causes haematuria with variable proteinuria
How does DM affect the kidney?
Excess glucose - sticks to plasma proteins - causes thickening of BM in efferent arteriole = obstruction = dilation of afferent arteriole and inc pressure in glomerulus. Over time = hyper infiltration injury.
Mesangial cells proliferate - secrete ECM - glomerulus becomes thickened = nodular glomerulosclerosis.
What is the difference between hypertensive and diabetic glomerulonephropathy?
Diabetic is more nodular
Hypertensive - is more widespread
What is the triad of nephrotic syndrome?
Proteinuria (lost in urine) => oedema
Low albumin (liver produces more - SE = inc cholesterol production)
Oedema
Ass features = high cholesterol and tendency to thrombosis (anti-thrombin lost in the urine)
What is the cause of nephrotic syndrome?
Leaky kidneys - podocyte damage = basement membrane lets through big molecules = reduced colloid osmotic pressure of the blood.
Activates RAAS and albumin is lost.
What are the signs of nephritic syndrome?
Haematuria (CC urine)
Proteinuria (not enough to lower serum albumin though)
Hypertension (fluid retention)
Reduced urine output
Raised creatinine levels
What is the cause of nephritic syndrome?
Inflammation which disrupts the glomerular basement membrane
How can you tell the difference between nephritic and nephrotic syndrome?
What can cause acute tubular necrosis?
Ischaemia (low BP, sepsis, D&V or bleeding) or toxins (ABs, chemo, contrast)
What is the pathophysiology of ATN?
Initial event –> hypoxia in the tubule = inflammatory response and cells die. This causes obstruction to the tubule - forces pressure back into the glomerulus and leakage into the interstitium. Eventually blood flow is restored, cellular repair and proliferation occurs, there is a restoration of tubular integrity and improvement in renal function.
Which cells are most affected by ATN?
Corticomedullary neurone - they have the most precarious blood supply.
What is interstitial nephritis?
What causes it?
Inflammation of the mesangium of the kidney
Drugs (ABs, Diuretics & NSAIDs) - 70%
Infection - 15%
AI disorders - SLE and Sarcoid
How does AKI present clinically?
Urea and creatinine retention in the blood
Non-nitrogenous waste products
Disordered electrolytes, acid-base and fluid homeostasis
What are the indications for urgent renal replacement therapy?
Uncontrollable fluid overload
Uncontrollable severe metabolic acidosis
Uncontrollable hyperkalaemia
Uraemia pericarditis / encephalopathy
Poisoning (ethylene glycol, lithium, NSAIDs)
Name 3 types of renal replacement therapy
Haemodialysis
Peritoneal dialysis
Renal transplant
What is Autosomal Dominant Polycystic Kidney Disease (ADPKD)?
How does it present?
P born with normal kidneys - but gradually then increase in size and number of cysts, with a progressive decline in renal function.
Due to AD mutation in PKD1
Presents in 3-4th decade as renal insufficiency, haematuria and hypertension, poss abdominal mass and flank pain
What is Autosomal Recessive PKD? (ARPKD)
Rare - multiple small cysts in cortex and medially originating from collecting ducts. Can also get liver cysts and fibrosis.
Ass with pulmonary hypoplasia
Presents in infancy
What is multi cystic kidneys?
Acquired cysts of the kidney - make sure you rule out cancer
Where is the demarcation for the source of post-renal disease?
Anything beyond the nephron
What is hydronephrosis?
Dilated infrarenal collecting system = excessive water in the kidney
What is the initial response of the kidney to an acute ureteric obstruction?
Get increased pressure in Bowman’s - causes reduced flow at macular dense - kidney releases renin to cause dilatation of the afferent arteriole to increase GFR.
What happens to the kidney after 90 mins of ureteric obstruction?
No further dilation of afferent arteriole can occur, GFR starts to decrease as no further compensation can occur.
After 4 hours - get afferent vasoconstriction, lack of perfusion of many glomeruli - causes of reduced colloid osmotic pressure and reduced tubular pressure. Get obstructive atrophy of the nephrons.
Excretion of urine doesn’t occur - K+ and H+ inc in the body causing arrythmias and acidosis.
Therefore urinary tract obstruction = EMERGENCY
What are the symptoms of a urinary tract obstruction?
Flank pain (colicky, loin to groin)
UTI symptoms
Pain after drinking
Haematuria
Exercise induce haematuria
What investigations should you do for suspected ureteric obstruction?
Renal bloods - U&Es
FBC
Prostate specific antigen
Urinalysis
Urine culture
Blood gases
USS
CT
DRE
What is the emergency treatment for acute ureteric obstruction?
Percutaneous nephrostomy - insert drain into kidney under IR.
What things can cause obstruction in the ureters and kidney?
Stones
Tumours
Strictures
Compression from lymph nodes, tumours, fibrosis
Enlarged prostate
What genetic disorder can cause lots of urinary tract stones formation?
Cystinuria - stones are made from cystine
What is the most common type of uric stone?
Calcium oxalate and phosphate
What are stones made from that are associated with gout?
Uric acid
What are stones called when caused by infect in the kidney?
Staghorn stones - Ca, Mg & NH3, P (triple phosphate)
What is ureteric colic described as?
Severe pain that comes in waves
Radiates from loin to groin
Increased frequency - can be blood in urine
P can also have N&V
What is urinary retention caused by?
Bladder outflow obstruction
What complications can you get from urinary retention?
Hyperplasia of the bladder wall
Diverticulum of the bladder
How do α blockers work? What are they used for? Name one.
They relax the neck of the bladder and smooth muscles within the prostate
Used to manage mild urinary retention
Tamsulosin
What type of receptors are found in the muscle of the urethra?
Α receptors (SS - NA)
What type of receptors are found within the bladder?
SS - β3 receptors (NA)
PSS - M3 receptors (ACh)
What drugs can be used to inhibit growth of BPH?
5 α reductase inhibitors
- Finasteride
- Dutasteride
How can drugs damage the kidney?
Altered intraglomerular haemodynamics
Tubular cell toxicity
Inflammation
Crystal nephropathy
Rhabdo
Thrombotic microangiopathy
Which drugs are associated with post-renal obstruction?
Anticholinergics
Mirabegron (Adrenergic Β3 agonist)
Indinavir (Antiviral drug used in HIV)
What happens when the liver is impaired?
Impaired drug metabolism - usually needs to be extensive disease for this to be clinically significant
Hypoproteinaemia
Reduced blood coagulation
Hepatic encephalopathy
Fluid overload
Hepatotoxic drugs
What tests indicate the synthetic capacity of the liver?
PT (inc INR) and dec albumin
Changes in PT / INR occur sooner than albumin
Which tests are the most indicative of liver function?
INR and albumin are more indicative than LFTs
Which drugs are hepatotoxic?
Paracetamol
Statins
Methotrexate
Phenytoin
Aspirin
Alcohol
What do you need to consider when prescribing in a P with hepatic or renal impairment?
How is absorption affected by liver disease?
GI motility can be decreased - means rate of absorption is slower.
Is less first pass metabolism - therefore bioavailability will inc (more drug in less time than you should have) = inc chance of toxicity. Consider reducing dose for oral drugs metabolised in the liver.
Cirrhosis - oral drugs are distributed directly into systemic circulation
What does low volume of distribution mean?
That is a highly protein bound drug so it is retained in plasma.
E.g. Warfarin
What does medium volume of distribution mean?
They are water soluble but have low lipid solubility.
Means the drug distributes into the interstitial fluid but not cells.
Dose on ideal body weight.
E.g. Gentamicin
What does high volume of distribution mean?
Is fat soluble drug - distributes into the tissues.
E.g. Amiodarone
How is distribution affected by liver impairment?
Reduced albumin synthesis - can be problematic for protein bound drugs.
Ascites / oedema - can increase the Vd of water soluble drugs! (Gentamicin).
How does hyperbilirubinemia affect distribution?
Bilirubin binds to albumin - so if you have hypoalbumin and hyperbilirubinaemia - can get even less drug binding to protein.
How does liver impairment affect metabolism?
Metabolism decreases - due to less metabolic enzymes. (Due to reduced BF and functioning cell mass)
Therefore excretion also decreases, and the number of metabolites in the body will increase.
What does the liver do to lipid soluble drugs?
Makes them more hydrosoluble so they can be excreted in the urine.
How is creatinine affected by cirrhosis?
It is reduced.
The liver produces creatinine (a waste product of muscle metabolism) - cannot do this in cirrhosis.
Due to hypoperfusion of kidneys - the RAAS system is activated => more water absorption = therefore further dilution of the creatinine concentration.
Why do the kidneys receive less blood in cirrhosis?
Portal hypertension - means hat blood is diverted elsewhere = less circulating volume and renal perfusion.
Cirrhosis also causes systemic vasodilation - further decreasing renal perfusion.
What happens to pharmacodynamics of drugs with renal impairment?
Less excretion = exaggerate response, reduced effect and inc toxicity.
Which medicines do you need to be most careful of prescribing when there is hepatic or renal impairment?
Sedatives
Opiates
Diuretics
Anticoagulants
Nephrotoxic meds - aminoglycosides, NSAIDs
Which medicines disturb fluid/electrolyte balance?
NSAIDs
Corticosteriods
Diuretics
Which medicines may precipitate encephalopathy?
Diuretics
Sedatives
Opioids
Constipating meds (opioids, antimuscarinics, sedating antihistamines)
Which medicine is both hepatotoxic and nephrotoxic?
Methotrexate
Medicines which are metabolised by which reactions should be avoided in liver disease?
Oxidation
Reduction
Hydrolysis reactions
Do kidneys metabolise?
Yes
Why does uraemia impact drug effects on Ps more than Ps without uraemia?
In uraemia - the BBB is not protecting as well - allowing things to pass more than they should. Therefore more drugs will be able to pass through the BBB = increased sensitivity.
How can absorption be affected by renal disturbance?
Oral absorption can decrease
= with renal disease - can get higher production of ammonia in the GIT - changes pH.
CKD - can cause N,V &D - affects absorption
How is distribution affected by renal disturbance?
Hydration status can be affected - affects water soluble drugs.
Odema/ascites = inc Vd
Dehydration = dec Vd
Can also get hypoalbuminaemia - due to increased uraemia (or bilirubin in liver disease) both of which bind to albumin and decreasing the amount for the free drug to bind to.
Therefore can decrease Vd for protein bound drugs
How is digoxin affected by KD?
Is displaced from the tissues = therefore is reduced Vd and inc plasma concentration
What does the kidney metabolise?
Insulin
Vit D
How does kidney disease effect metabolism?
Can slow the metabolism of the liver.
Can also have reduced renal metabolism - important for insulin and Vit D.
What happens to renally excreted drugs in kidney impairment?
They will have a prolonged half-life as they can’t be excreted as quickly.
When should you think about dose adjusting drugs in renal impairment?
If >50% of the drug is renally excreted unchanged
If active metabolites are renally excreted
If there is a narrow therapeutic range
What are the two ways to do dose adjustment?
Vary the dose, keep the same interval
Vary the interval, keep the same dose
