Renal replacement and drugs Flashcards
1
Q
What are the 6 classses of diuretics
A
Osmotic diuresis
Carbonic anyhydrase inhibitors
Aldosterone antagonists
ENaC channel antagonists
Loop diuretics
Thiazide diuretics
2
Q
What is an osmotic diuretic? What are 2 side effects? How does it work?
A
- Mechanism - unresorbable but fully filtered solute acts by increasing the osmolarity of the tubular fluid and therefore reducing the osmotic gap between fluid and intersititum; thereby reducing the effect of urine concentration mechanisms as fluid is not able to effectively move out of the tubule down a concentration gradient
- Example: Mannitol
- Side effects:
◦ Hypotension
◦ Hypokalaemia
3
Q
Where do carbonic anhydrase inhibitors work? What is their mechanism> Side effects?
A
- Site: proximal convoluted tubule
- Mechanism: Block the enzyme carbonic anhydrase on PCT cell surface and within PCT cells
◦ Decreased re-absorption of bicarbonate and sodium increasing tubular fluid and osmolality - Example: acetazolamide
- Side effects
◦ Metabolic acidosis
◦ Hypokalaemia
4
Q
Where do loop diuretics act
A
sodium-chloride-potassium cotransporter inhibition in the thick ascending LOH
5
Q
What is the MOA of loop diuretics?
A
Disruption fo the counter current multiplier system by decreasing absorption of ions from the loopof Henle into the medullary intersittium thereby decreasing the osmolarity fo the medullary intersitital fluid and its concentration ability, in addition to impairing reabsorption fo sodium the key determinant of fluid osmolality
6
Q
What are side effects of loop diuretics
A
◦ Hypotension
◦ Hypokalaemia
◦ Metabolic alkalosis - hypochloraemia
7
Q
Thiazide diuretics site of action and mechanism
A
- Site of action: DCT sodium and chloride co-transporter
- Mechanism of action: sodium and chloride transporter inhibition increasing sodium delivery to the distal nephron, preventing reabsorption of urinary water by reducing the tubulo-medullary osmotic gradient
8
Q
What are side effects of hydrochlorothiazide
A
- Side effects: hypokalaemia, hyponatraemia, gout flares, vasodilation
9
Q
Aldosterone receptor antagonists act where? WHat is the MOA?
A
- Site of action: Collecting duct + DCT
- Mechanism of action: block aldosterone receptors
◦ Leads to reduced ENaC channel expression, reduced Na/K exchange on basolateral surface and reduced hydrogen ion secretion in the DCT leading to reduced sodium reabsorption and higher tubular sodium content
10
Q
What are side effects of aldosterone antagonsits
A
◦ Hyponatraemia
◦ Hyperkalaemia
◦ Metabolic acidosis - Type 4 RTA
◦ Gynaecomastia
11
Q
What are non aldosterone receptor antagonists? MOA? Side effects?
A
- Site of action: ENaC channel blockade
- Mechanism of action: Reduced sodium reabsorption, therefore reduced tubulo-medulary osmotic gradient
- Example: Amiloride
- Side effects: hyponatraemia, hyperkalaemia
12
Q
Define dialysis
A
is the separation of particles in a liquid based on their ability to pass through a membrane - this process occurs through filtration and diffusion.
13
Q
What is haemofiltration? What is it based on?
A
14
Q
How is ultrafiltration manipulated
A
◦ Positive pressure is increased in blood through blood pump increasing flow through the dialyzer; but additionally return pressure as seen below if elevated will increase clearance also
◦ Negative pressure applied to the dialysate side by the machine
15
Q
What is transmembrane pressure? How would you calculate it?
A
16
Q
Convective flux means what?
Equation
A
the mechanism by which solutes pass through the membrane is haemofiltration
= ultrafiltration rate x solute concentration in plasma x sieving coeffcient
17
Q
What is a sieving coefficient
A
Ratio of specific solute concentration in ultrafiltration/mean plasma concentration in the filter
18
Q
What are the factors affecting clearance in haemodialysis
A
- Pressure difference - primary control variable
- Permeability of the dialysis membrane and resistance to flow
- Oncotic pressure difference - not maniuplated
- Reflection coeffiicient
19
Q
What is the equation determining flow in haemodialysis
A
Fick’s law
20
Q
Define diffusion
A
spontaneous movement of substances from a higher solute concentration to a lower solute concentration
21
Q
What enhances the efficacy of dialysis mechanisms rather than haemofiltration mechanisms
A
Countercurrent
22
Q
Each substances clearance by haemodialysis is governed by
A
◦ Each substance’s clearance will be a reflection of
‣ Concentration difference - increased difference increases clearance, which can be manipulated through reduced concentrations in dialysate fluid of substances to be cleared; and is maximised through countercurrent flow of dialysate fluid
‣ Individual solute characteristics e.g. molecular weight, shape/size and charge will influence
23
Q
Total clearance in haemodialysis is a function of?
A
Increasing surface area —> increased clearance and vice versa
‣ Reduced thickness of membrane —> increased clearance
‣ Porosity of the membrane
‣ Increased temperature
24
Q
How is blood flow through a dialysis circuit determined
A
- Blood flow (Q) = (Pa-Pv)/R
◦ Pa = access pressure
◦ Pr = return pressure
◦ R = circuit resistance
25
What factor affects access and return pressure in a dialysis circuit?
◦ Set blood pump speed
◦ Vascular access device properties
◦ Pressure at access points - arterial, central venous pressure
26
When describing resistance in a dialysis circuit what factors are important
As resistance is occurnig within a set of tubing it is determined to an extent by Hagen Pouseulle equation
* Resistance = 8nL/πr4 where
◦ n = viscosity,
‣ 3.5 - 5.5 cP and depends on
* Haematocrit
* Blood protein and lipid content
* Temperature
* Pre and post replacement fluid
* Fahraeus Lindquist effect where blood becomes less viscous in smaller vessels (<0.5mm diamtre) because of RBC deformation
◦ π = 3.14,
◦ r = radius
‣ vascular access
‣ filter deisgn
‣ Circuit dimensions
‣ Clot or fibrin
‣ Anticoagulant strategy
◦ L = length - generally 3.5m
27
What is the Limitation of using a Hagen Pousieulle equation to describe resistance in a dialysis circuit?
Blood vessels are elastic and contrcatile rather than rigid tubes
Blood flow often turbulent within dialysis machines
Poisuelles law is constant flow - this is pulsatile
Blood is a non newtonian fluid
28
What are the two mechanisms of fluid removal in a dialysis machine
1. Osmosis
2. Ultrafiltration
29
How does osmosis work in a dialysis machine
◦ Movement of FLUID (solvent) across a semipermeable from an area of LOWER solute concentration to an area of HIGHER solute concentration.
◦ When a solvent passes through a membrane, the process is called osmosis. (semipermeable)
30
Solute removal mechanisms in a dialysis machine?
Diffusion
Convection
31
What is convection in reference to dialysis?
◦ Osmosis is when a solvent passes through a membrane. The frictional forces between solutes and water molecules will pull dissolved substances along, a process known as bulk flow or solvent drag.
◦ Important for movement of small solute (urea, creatinine). Elimination via bulk flow is independent of solute concentration gradients across membranes
◦ Transport dependent on Starlings forces
‣ Transmembrane pressure determined by blood flow to the membrane and oncotic pressure; and flow is subsequently influenced by porosity
32
When does renal dysfunction result in clinical symptoms - what % of loss
50-75% of function must be lost as existing nephrons excrete additional water and electrolytes increasing their filtration and reabsorption
33
If you were to subclassify the effects of advanced renal failure how would you do so
Water
Electrolytes
Acid Base
Endocrine
Drug handling
Proteins
Creatinine
34
How does renal failure affect water balance
Generally high ECF
- Hypervolaemia may occur if oliguric renal failure
* Reduced GFR --> reduced filtration, reduced capacity for reabsorption (ATN) and therefore reduced excretion --> water retention
* Chronic AT2 + aldosterone + ADH proudction --> increased retention
◦ Renal responsiveness to vasopressin and aldosterone decreases so the ability to regulate body fluid volume and osmolality is also decreased
* In some circumstances ATN --> low plasma volume
35
How is control of osmolality influenced by renal failure
As renal failure progresses juxtamedullary nephrrons are lost so the concentration variance of urine becomes reduced to the point it cannot be changed and body regulation of osmolality is greatly impaired
36
How does renal failure affect electrolytes
◦ Hyperkalaemia - failure to excrete potassium in distal tubule/failed filtration
◦ Hyperphosphataemia —>causes hypocalcaemia (hypercalcaemia can occurr as delayed phenomenon secondary to tertiary hyperparathyroidism)
* Sodium relatively preserved
◦ Increased water relative to sodium can occur leading to relative hyponatraemia --> decreased osmolality
- Generally the reduced reabsorption balances out the increase
37
How is acid base status influenced by advanced renal failure
Preserved until 70-80% function lost, then non linear urate, PO4 and H+ increase
80mmol/day of non volatiles require excretion
‣ Renal failure leads to progressive acidosis due to loss of buffering ability and limiting urinary pH of 4.5
‣ Reduced ability to excrete acids
‣ Reduced ability to reabsorb bicrabonate - leading to reduced bicarbonate and a reduced capacity to compensate for metabolic acidosis by increased ammonium secretion
‣ Normal (from failure of renal acidification mechanisms) or high anion gap (due to accumulation of non volatile acids) metabolic acidosis
◦ Loss of renal compensation of respiratory acid/base disturbances
38
How does advanced renal failure affect proteins
1. Damage to glomerular membrane can lead to loss
2. Increased ECF so become diluted
3. Increasing acidosis leads to change in function
4. Accumulation of protein waste products (urea) leads to encephalopathy and pericarditis
39
What are the endocrine effects of advanced renal failure 3
* Decreased production of Erythropoietin —> anaemia
* Thrombocytopenia due to decreased Thrombopoetin (Along with PLT dysfunction due to hyperuraemia)
* Renal conversion of 25-hydroxy Vit.D to 1,25,-dihydroxy Vit D promotes GI reabsorption of Ca lost in renal dysfunction (due to Hyperphosphataemia as well as renal damage) leading to hypocalcaemia and hypophosphataemia
◦ Secondary hyperparathyroidism --> tertiary hyperparathyroidism --> hypercalcaemia
* Indirect neuroendocrine changes
◦ Especially early in renal failure Renin release from JG cells in ischaemic areas due to reduced renal salt delivery with RAAS activation increasing fluid retention and hypertension
◦ RAAS plays a pathogenic role in the progression
40
Define dialysate
* Dialysate is the fluid medium used to exchange solutes with the blood in a dialysis filter
41
What is effluent
effluent is everything which comes out of the filter even though it may be unchanged
42
What Physiological characteristics are sought in renal replacement fluids
‣ Physiological concentration of electrolytes - resembling a healthy human
* Na 140
* Buffer 35-45mmol/L
* Ca 2mmol/L
* Mg 1mmol/L
* Glucose 6mmol/L
* Zero potassium - is often however added to bags, 20mmol per 5L (4mmol/L)
* Zero phosphate -hence phosphate replacement may be required
43
What buffer is used in renal repplacement fluids most commonly
bicarbonate
44
What are the pros and cons of bicarbonate as a buffer in dialysate
Pros - physiological
Cons - shelf life, bacterial colonisation, reacts with Ca and Mg
45
What options other than bciarbonate are there for buffers in dialysate?
Lactate - peritoneal dialysis, metabolised by the liver. Slightly acidic but cheaper and more stable
Citrate
Acetate
46
In CVVD what is the pH of dialysate? What replacement fluid is used?
pH is 7.4
No replacement fluid used
Therefore the rate of alkalinisation is dependent on the buffer concentration in the dialysate, dialysis flow rate
47
In CVVH what is the pH of replacement fluid
pH 8 post filtration
The ultrafiltrate as effluent has the same pH as the incoming blood and the blood returning to the patient is a combination of both these
There is no dialysate
48
What is the difference between dialysate and replacement fluid
None
49
Why would you give replacement fluid pre filter
Maximum dialysis dose is limited by blood flow rate, and if too much fluid is removed then it degrades the filter --> so this increases you blood flow rate
Clearance of solute smight be slower though however urea clearance higher as increases urea movement out of cells
Prolongs filter life
50
Post dilution advantages for replacement fluid
Clearance of small molecules dependent on diffusion is greater (greater concentration gradient)
Less replacement fluid
51
Cons of post dilution replacement fluid
Clearance of middle molecules is proportional to ultrafiltration rate so unaffected
Maximum dose of dialysis limited by blood flow rate, and max ultrafiltrtion rate is 25% so limits flow
Lifespan of filter shorter
52
What is the determinant of small molecule removal in haemofiltration
Concentration difference
53
What is the determinant of middle molecule clearance in haemofiltration
Ultrafiltration rate
54
What is the membrane surface area of a dilaysis memebrane
2 metres squared for high volume haemofiltration
55
What pharmacokinetic and pharmaceutic factors affect drugs being dialysed
1. How much free drug is actually in plasma
- Small Vd
- Protein binding
2. Molecular size - >15kDa poorly dialysed
56
What sized particles for drugs affects dialysis
◦ Small molecules <500 daltons freely diffuse
◦ Molecules >15kDa poorly dialysed - proteins, heparins,monoclonal antibodies
57
What dialysis factors affect drug removal
* Dose/flow rates
◦ Reduced flow rates reduce clearance
‣ High flux haemodialysis more rapid clearance compared to lower flux Haemoperfusion or CRRT
* Membrane permeability
* Timing
58
What drugs can be dialysed
A's
- ASpirin
- Antibiotics - aminoglycosides, metronidazole, carbapenams, cephalosporins, penicillins
- Atenalol + sotalol
- Alcohols including ethylene glycol and methanol
Barbituates
Sodium valproatye
Lithium
metformin
Methotrexate
Theophylline
59
Drugs not removed at all by dialysis
Digoxin
Gliclizide
Beta blockers
Benzo
Phentyoin
CTA
Warfarin
60
Define ultrafiltration
* Ultrafiltration - filtration through a semipermeable membrane where smallTransmmenbrna particles and macromolecules are selectively permeable and therefore separated from body fluid water. It is driven by pressure gradient
61
Define diffusion
* Diffusion - solute transport across a semi permeable membrane generated by a concentration gradient
62
Define convection
* Convection - bulk flow of solute across a semi permeable membrane together with solvent in a manner dependent on transmembrane pressure and membrane characteristics
63
Define transmembrane pressure
hydrostatic pressure gradient across the membrane
64
Define sieving coefficient
a measure of equilibrationbetween concentrations of two mass transfer streams. Describes the efficiency of solute removal by ultrafiltration depending on properties of membrane and rate of ultrafiltration
◦ = ultrafiltration concentration / blood concentration
◦ Determinants - molecular size, protein binding, charge, size and number of pores in the filter membrane
65
Explain the concept, equation, and utility of the sieving coefficient
66
What is the sieving coefficient for urea
0.96
67
What is the sieving coefficent for urate
0.96
68
What is the sieving coefficient for Cr
0.96
69
What is the sieving coefficent for phosphate
0.96
70
What is the ultrafiltration coeffiicent
ltrafiltration coefficient (KUF) is the permeability of membrane to water per unit of pressure and surface area
‣ Typical filter 10-25 ml/h/mmHg/m^2
71
What is the ultrafiltration coeffiicent equation
72
What is the ideal membrane for haemofiltration
73
Filtration fraction
Ultrafiltration rate/PLASMA blood flow rate
74
What is the ideal filtration fraction in haemofitlration
0.25 if haematocrit 0.3
75
What is a typical pre filter BP
* Pre filter BP 120-100mmHg
* Post filter BP 50-40
* Pressure from 60-70
* Effluent pressure -20 to -70
* TMP average 100-150
76
What is a ypical post filter Bp
* Pre filter BP 120-100mmHg
* Post filter BP 50-40
* Pressure from 60-70
* Effluent pressure -20 to -70
* TMP average 100-150
77
What is a typical pressure drop across a dialyiss circuit
* Pre filter BP 120-100mmHg
* Post filter BP 50-40
* Pressure from 60-70
* Effluent pressure -20 to -70
* TMP average 100-150
78
What is a typical effluent pressure
* Pre filter BP 120-100mmHg
* Post filter BP 50-40
* Pressure from 60-70
* Effluent pressure -20 to -70
* TMP average 100-150
79
What isa typical transmembrane pressure
* Pre filter BP 120-100mmHg
* Post filter BP 50-40
* Pressure from 60-70
* Effluent pressure -20 to -70
* TMP average 100-150
80
What is the diffusability coefficient proportional and inversely proportional to
* Proportional to
◦ Gas constant, absolute temperature
* Inversely proportional to
◦ Viscosity of solvent
◦ Radius of particles - which we assume based on calculations from molecular weight assuming everything is a perfect sphere
◦ Number of particles per mole of solute
