Renal Flashcards
Functional unit of the kidney
Nephron, each kidney has roughly 1x10^6 nephrons
Types of nephron and their location
Cortical (85%), majority in cortex
Juxtamedullary (15%), majority in medulla
5 distinct regions of the nephron
Bowman’s capsule
Proximal convoluted tubule
Loop of henle
Distal convoluted tubule
Collecting duct
Structures that make up the renal corpuscle
Bowman’s capsule
Glomerular capillaries
Juxtaglomerular apparatus and its functions
Distal convoluted tubule and glomerular afferent arteriole
Autoregulation, renin release (salt water balance)
Functions of nephron
Renal corpuscle filters initial blood to form filtrate / ultrafiltrate / tubular fluid
Tubular system (cortical and medullary) controls concentration and content of urine
Blood supply to the nephron
Glomerular capillary bed (within bowman’s capsule)
Peritubular capillary bed (wraps around remainder of nephron)
Functions of the blood supply to the nephrons
Glomerular - high hydrostatic pressure (60mmHg) for filtration
Peritubular - low pressure (20 mmHg) for reabsorption and secretion
Outline vasa recta
Peritubular capillaries wrap around loop of henle and provide O2 and nutrients to innermost regions of medulla
Cardiac output to the kidneys
25%,
Important role in cleaning blood and homeostasis
Outline the filtration fraction
20% of plasma that enters glomerular capillaries is filtered, 19% reabsorbed, 1% excreted externally
Remaining 80% leaves via efferent arteriole and is returned by Peritubular capillaries to systemic circulation
Define glomerular filtration rate
Volume of fluid entering bowman’s capsule per unit time
Outline process of ultrafiltrate formation
Fluid driven from capillaries into bowman’s capsule, across glomerular filter by capillary hydrostatic pressure
Efferent arterioles smaller than afferent, maintaining pressure
Structure of glomerular filter
Glomerular capillaries separated from podocytes by basement membrane
Mesangial cells provide structural support and are contractile
Characteristics of the glomerular capillary membrane
Endothelium- very charged glycoproteins repel anionic proteins
Podocytes have filtrations slits
Normally all contents of plasma except trace amounts of plasma proteins appear in filtrate
How can GFR be altered
Kf (filtration coefficient)
Starling forces by patho/physiological conditions / drugs
State the ways in which capillary hydrostatic pressure can change
Constriction of afferent / efferent arterioles
Outline the impact of constriction of afferent arteriole on GFR
Increase renal vascular resistance, decrease renal vascular resistance
Decreases intraglomerular pressure and GFR
Outline the impact of changes in colloid osmotic pressure on GFR
Decrease in protein concentration (hypo proteinaemia), increase in GFR
Outline the impact of changes in bowman’s space pressure on GFR
Increase in bowman’s space pressure by renal stone, decrease in GFR
Outline the impact of changes in Kf on GFR
Increase in Kf via drugs or conditions, decrease in GFR
Outline the use of insulin as an indicator of GFR
Freely filtered, not reabsorbed / secreted / metabolised
No effect on renal toxic
Easily measured in urine
Mass filtered = mass excreted
Function of the kidneys
Filter and excrete waste products
Control water and electrolyte balance
Location of kidneys
Retroperitoneal
T12- L3
R kidney usually lower due to presence of liver
State the layers encasing the kidneys from deep to superficial
Renal capsule
Perirenal fat
Renal fascial (and suprarenal glands)
Pararenal fat (mainly posterolateral)
Outline structure of the kidneys
Renal parenchyma split into outer cortex and inner medulla
Cortex extends into inner medulla, creating renal pyramids
Outline internal structure of kidneys
Apex of pyramids - renal papilla
In middle of pyramids - minor calyx
Base of pyramids - major calyx
Connection of pyramids - renal pelvis
Renal pelvis attached to ureter
Outline the arterial supply of the kidneys
R and L renal arteries (L1-2), enter at hilum at split
R renal artery (crosses IVC posteriorly) slightly longer due to aorta being left of midline
Venous drainage of the kidneys
R and L renal veins
State the equation for GFR, using insulin clearance
GFR = (UI x V)/ Pl
UI- urine conc of insulin
V - urine flow rate
Pl- plasma conc of insulin
State the equation of eGFR using creatinine clearance
eGFR = ([U]CR x V) / [P] CR
V - urine flow rate
[U]CR - urine conc of creatinine
[P] CR- plasma conc of creatinine
Define renal plasma flow
Amount of plasma that perfumes the kidneys per unit time
State the purpose of renal plasma and renal blood flow measurements (RPF and RBF)
Indicators of renal health
RPF can be used to estimate RBF
Outline the relationship between renal plasma flow (RPF) and glomerular filtration rate (GFR)
The greater, the greater
Outline the method to estimate renal plasma flow
Mass excreted (of indicator substance) = mass (of indicator substance) delivered to kidneys
Give an example of an indicator used to estimate renal plasma flow
Para - aminohippuric acid (PAH), freely filtered and secreted
Outline the movement of para-aminohippuric acid (PAH) with regards to the nephron
Enters glomerular capillaries, some filtered and most leaves via efferent arteriole
PAH secreted out of Peritubular capillaries and into tubular lumen via transporters on proximal tubule
State the equation regarding clearance of para aminiohippuric acid (PAH)
Total mass PAH excreted = total mass PAH presented to kidney
= (plasma conc) x (plasma vol / unit time)
= RPF
= 600mL/min
State the condition in which all para-aminohippuric acid (PAH) is secreted from Peritubular fluid to proximal tubule
Tubular transport maximum (Tm) not exceeded, low plasma concentrations of PAH
Define filtration fraction
Proportion of plasma that forms filtrate
State the equation linking filtration fraction, glomerular filtration rate and renal plasma flow
FF = GFR/ RPF
= 120/600
= 20%
State the relationship between filtration fraction and collie pressure
The greater, the greater
Hence greater forces for tubular reabsorption at proximal tubule
Define haematocrit
Proportion of blood volume occupied by RBCs
Outline the amount of blood and plasma received at the kidney per minute
Cardiac output = 5L / min
Kidney receives 20-25% of output
= 1300ml blood or 600ml plasma / min
Mechanism of autoregulation by the kidneys
Occurs between arterial blood pressure of 90-180 mmHg
Ensures fluid and solute excretion remains constant during normal changes in arterial BP
Outline the myotonic mechanism which changes afferent arteriolar resistance
Afferent arteriole contracts in response to pressure and stretch
Outline the tubuloglomerular feedback mechanism which changes afferent arteriolar resistance
Increase of NaCl in filtrate detected by macular densa of juxtaglomerular apparatus
Causes contraction of afferent arteriole via adenosine / ATP
Vasoconstriction of afferent arteriole reduces blood getting into glomerular capillaries which decreases GFR
State the make up of the juxtaglomerular apparatus
Macula densa (of loop of henle - distal convoluted tubule junction) and granular / juxtaglomerular cells (of afferent arteriole)
Summarise the pathway of the autoregulation mechanisms in response to increased BP
Increased RBF and GFR triggers myogenic mechanism and tubuloglomerular feedback
Mechanisms trigger afferent arteriolar contraction (through pressure / stretch and adenosine / ATP production) causing decrease in capillary hydrostatic pressure
Decrease in RBF and GFR
State the factors affecting renal blood flow (RBF) and glomerular filtration rate (GFR)
Vasoconstrictors (sympathetic nerves, angiotensin II)- decrease
Vasodilators (prostaglandins, PGE2, PGI2)- increase
Outline the mechanism in which vasoconstrictors influence renal blood flow (RBF) and glomerular filtration rate (GFR)
Activation by decreased BP
Efferent arteriole more sensitive to AgII than afferent (at low concs), therefore will dominate and help maintain GFR in presence of hypotension
Outline the process in which NSAIDs and COX inhibitors may exacerbate vasoconstriction
Drugs block synthesis of prostaglandins, interfering with preservation of RBF
If RBF already low, excessive vasoconstriction and ischaemia may lead to renal tubular necrosis
State conditions / situations in which the renal threshold for glucose is exceeded, causing glucose excretion in urine
Untreated diabetes mellitus
Hyperthyroidism
Fanconi syndrome
Familial renal glucosuria
Pregnancy
Drugs
State the equation linking filtered glucose load, GFR and plasma glucose conc
Filtered glucose load = GFR x plasma
Glucose conc
State the equation linking glucose, excretion, urine flow (V) and urine glucose conc
Glucose excretion = urine (V) x urine glucose conc
State the equation linking glucose reabsorbed, glucose filtered and glucose excreted
Glucose reabsorbed = glucose filtered - glucose excreted
State the equation linking filtered glucose load, GFR and plasma glucose conc
Filtered glucose load = GFR x plasma glucose conc
State the plasma solute concentration of Na+
135-145 mmol/ L
State the plasma solute concentration of K +
3.5 - 5.0 mmol /L
State the plasma solute concentration of Cl-
100-106 mmol/ L
State the plasma solute concentration of HCO3-
21-28mmol/L
State the plasma solute concentration of H+
37-43mmol/L
State the plasma solute concentration of glucose
3.9-5.6 mmol/L
State the plasma solute concentration of protein
60-84 g /L
Outline how the concentration of constituents of plasma solute and ultrafiltrate differ
Similar due to free movement through filtration barrier
Except protein, held back by filtration barrier so very low concentrations in ultrafiltrate
State the approximate GFR in a normal 70kg person
120ml / min
State the approximate RPF in a normal 70kg person
600 ml / min
State the approx PVC in a normal 70kg person
40%
State the approximate RBF in a normal 70kg person
1 L/min
State the approx cardiac output in a normal 70kg person
5L/min
Outline the histology of the epithelial cells of the nephron and the corresponding Peritubular capillaries
Tubular epithelium with basolateral membrane facing Peritubular fluid and apical / luminal membrane facing lumen of nephron
Peritubular fluid separates nephron and capillary
Tight junctions between epithelial cells
State the transport pathways between epithelial cells of the nephron and Peritubular capillaries
Transcellular / transepithelial transport across cells
Paracellular transport - between cells
Outline the function of Na + / K + ATPase pumps in the basolateral membrane of the nephron
Pump Na+ out in exchange for K+, creating Na+ conc
Promotes movement of Na+ to move from lumen to peritubular fluid via tubular epithelium
Outline the function of the peritubular capillaries with regards to reabsorption
Hydrostatic pressure in Peritubular capillaries is low ( 10 mmHg), facilitating reabsorption from Peritubular fluid
Increased colloid osmotic pressure favours this
Outline the reabsorption that takes place at the proximal convoluted tubule
Bulk - 60-70% of filtered load of Na+, H2O, Cl-, K+ and other solutes, and nearly all filtered glucose and amino acids are reabsorbed, coupled with Na+ reabsorption
Outline the properties of the proximal convoluted tubule which prevents build up of significant osmotic gradients
Leaky tight junctions between tubular epithelial cells
Presence of aquaporin -1 (membrane proteins acting as H2O channels)
Peritubular fluid = isometric with plasma
Outline the transport of Na+, glucose, AAs and PO4 from the proximal convoluted tubule to peritubular fluid
Na+ readily enter epithelial cells, crossing apical membrane from tubular lumen, down gradients created by Na+ pump on the basolateral membrane
Other molecules move via symptom treatment with Na+
State the 4 mechanisms by which Na+ enters the tubular epithelium from the tubular lumen via the apical membrane
Na+ / H+ exchange
Coupled with entry with glucose, AAs and PO4 via symporters
Membrane channels
Passive through tight junctions into lateral space
Outline the transport of HCO3- from the proximal convoluted tubule to peritubular fluid
H+ +HCO3-, forms carbonic acid
Dissociates due to CA into CO2 and H2O
CO2 and H2O move into tubular epithelium and are converted back to H+ and HCO3- by CA
HCO3- transported to peritubular fluid via Na+ transporter in basolateral membrane
H+ continues to move between cell and lumen
Outline the adaptations to the transport of HCO3- under alkalotic conditions
Excrete more filtered HCO3- into urine and reabsorb less
Outline the adaptions to the transport of HCO3- under acidic conditions
Production of new HCO3- (normal system is already close to capacity)
Outline the transport of H2O from the proximal convoluted tubule to peritubular fluid
Via leaky tight junctions
Via aquaporin 1 (AQP1) channels in apical and basolateral membranes
Reabsorbed by osmotic pressure grad due to Na+ reabsorption
Facilitated by oncotic pressure and low hydrostatic pressure in capillaries
Outline the mechanism of solute drag
Free and passive oncotic flow of H2O results in solutes being carried through to be reabsorbed
Outline the transport of K+, Cl- and urea from the proximal convoluted tubule to peritubular fluid
K+ via solvent drag
Cl- via paracellular and transcellular transport
Urea via paracellular and transcellular transport after concentration due to H2O movement
Outline the structure of the loop of henle
Descending thin limb
Ascending limb (initially thin, then thick)
Outline the nature of the descending thin limb with regards to H2O and other solutes
Highly permeable to H2O due to AQP1
Less permeable to NaCl and urea, movement is largely passive
Outline the nature of the ascending limb with regards to H2O and other solutes
Impermeable to H2O
Na+, Cl- and K+ reabsorbed, mainly at thick limb
Thin limb involved in passive reabsorption
Outline the function of Na+ / K+ ATPase pumps in the basolateral membrane of the thick ascending limb
Pump Na+ out in exchange for K+, creating Na+ concentration gradient
Promotes movement of Na+ to move from lumen to peritubular fluid via tubular epithelium
Outline the function of symporter proteins on the apical membrane of the thick ascending limb
Move Na+ and 2 Cl- across membrane into epithelial cells, down concentration gradient
Outline the movement of Na+ from the lumen to the Peritubular fluid
Into epithelial cells via symporter proteins on the apical membrane
Into peritubular fluid via Na+ pumps on basolateral membrane
Outline the movement of Cl- from the lumen to the Peritubular fluid
Into epithelial cells via symporter proteins on apical membrane
Into peritubular fluid via Cl- channels on basolateral membrane
Outline the movement of K+ from the lumen to the Peritubular fluid
Into epithelial cells via symporter proteins on apical membrane
Into peritubular fluid via K+ channels on basolateral membrane
Mainly diffusion back into lumen, creating +ve charge within lumen
State the driving force behind paracellular transport of +vely charged ions
Diffusion of K+ from epithelial cells back into lumen, creating +ve charge within lumen
Outline the function of Na+ / H+ antiporters on the apical membrane of the thick ascending limb
Secretion of H+ into lumen from epithelial cells
Used to reabsorb HCO3- into the lumen
State the consequences of salts moving out of the thick ascending limb without the accompaniment of H2O
Osmolality (dilution) of tubular fluid
Interstitial fluid becomes hyperosmotic, important in renal concentrating mechanism
Outline the nature of the tubular fluid arriving at the early distal tubule
Further reduction in volume
Hyperosmotic with respect to plasma due to reabsorption of salts
Function of early distal tubule
Continues active dilution, reabsorption of salt without water causes osmolality to fall further
Mechanisms functioning at the early distal tubule
Continues active dilution, reabsorption of salt without water causes osmolality to fall further
Mechanisms functioning at the early distal tubule
Na+ pumps drive transport of many solutes
Na+ /Cl- symporter transports into epithelial cells from lumen
Cl- channels allows Cl- to leave epithelial cells and into peritubular fluid
Ca2+, Mg2+ and K+ reabsorption
H+ excretion via Na+ / H+ exchange or H+ pump
State the target of drug action of thiazides
Na+ / Cl- protein symporter transporter
State the function of principal cells
Reabsorb Na+ and H2O
Secrete K+
State the function of the intercalated cells
Regulate acid base balance due to high intracellular concs of carbonic anhydrase
State the location from which aldosterone is released from
Zona glomerulosa of adrenal cortex
State the effects of aldosterone on solute handling in the late distal tubule and cortical collecting duct
Enhances Na+ and K+ reabsorption in principal cells
Enhances H+ secretion in intercalated cells
Outline the methods by which aldosterone enhances Na+ reabsorption in principal cells
Increased number and activity of apical Na+ channels
Increased activity of basolateral Na+ pump
Outline the methods by which aldosterone enhances K+ reabsorption in principal cells
Increased number and activity of apical K+ channels
Increased activity of basolateral Na+ pump
Increased Na+ reabsorption
Outline the method by which aldosterone enhances H+ secretion in intercalated cells
Stimulates H+ - ATPase pump
State the potential fates of disturbed aldosterone levels
Hyperaldosteronism (aldosterone excess) - metabolic alkalosis, hypokalaemia
Hypoaldosteronism (type 4 renal tubular acidosis)- hyperkalemia
Outline the production of diuresis, in the absence of ADH
Tubular fluid entering distal tubule always hyposmotic to plasma
Late distal tubule and collecting duct have low permeability to H2O
Outline the production of antidiuresis in the presence of ADH
Increases permeability of late distal tubule and collecting duct by increasing stimulation of AQP2 on the principal cells
Water exits the lumen by osmosis into interstitial fluid
Functions of ADH
Regulation of urine and extracellular fluid osmolality
Outline the urea permeability of the nephron, in the absence of ADH
Restricted to proximal tubule and inner medulla
Outline the urea permeability of the nephron in the presence of ADH
ADH dependent urea transporter on apical membrane in inner medullary collecting duct concentrates urea
Urea diffuses out of lumen and into medullary interstitium
Purpose of urea reabsorption
Maintains osmotic gradient between interstitium and collecting duct lumen
Urea diffuses into tip of loop of henle and is recycled
Outline the regions of the nephron with low urea permeability in the absence of ADH
Descending thin limb
Ascending thick limb
Distal tubule
Collecting duct
Relationship between urea permeability and ADH
Proportional
Relationship between H2O permeability and ADH
Proportional
Disorders of ADH secretion / response
Diabetes insipidus - polyuria , polydipsia
SIADH ( syndrome of inappropriate section of ADH - hyponatremia)
Nocturnal enuresis (bed wetting)
Location of the adrenal gland
Superomedially to the upper pole of each kidney
Describe the relationships of the right adrenal gland
Posteriorly- diaphragm
Inferiorly- kidney
Medially - vena cava
Anteriorly - hepato-renal pouch and bare area of the liver
Describe the relationships of the left adrenal gland
Postero-medially: crus of the diaphragm
Inferiorly: pancreas and splenic vessels
Anteriorly: lesser sac and stomach
Arterial supply of the adrenal gland
Superior adrenal arteries - from inferior phrenic artery
Middle adrenal arteries- from aorta
Inferior adrenal arteries from renal arteries
What is the venous drainage of the right adrenal
Via one central vein directly into the IVC
What is the venous drainage of the left adrenal
Via one central vein into the left renal vein
Why are diuretics so important
Important cardiovascular drugs
Management of CHF
Antihypertensives
A/C (D) guidelines
A: ACE inhibitor
C: Ca2+ channel inhibitor
D: diuretic
What are the different types of diuretics
Osmotic agents
Loop diuretics
Thiazides
Potassium sparing agents
What are osmotic diuretics
Eg mannitol
Pharmacologically inert
Freely filtered in bowmans capsule
Increased osmolality of tubular fluid in PCT and loop of henle
Reduce passive reabsorption of H2O
Used in cerebral oedema (increases osmolality and removes fluid from the brain)
What are loop diuretics
Eg furosemide
High ceiling bc powerful diuretic effect
Causes 15-25% of filtered Na+ to be excreted
Block Na+ / 2Cl- / K+ symporter of thick ascending limb
Reduces hyperosmotic interstitium
Risk of dehydration
How do loop diuretics work
Reduce the ability of the loop to concentrate urine by preventing creation of a hypertonic interstitium in the medulla
Increases Na+ delivery to DCT
- promotes K+ loss (risk of hypokalameia)
Decreases Na+ entry into macula densa
- promotes renin release
Uses of loop diuretics
CHF- reduce pulmonary oedema, 2’ to LVF and peripheral oedema
Venodilators - iv rapid effect in acute LVF
Renal failure - to improve diuresis
What are thiazides
Moderately powerful diuretics Act on DCT Blocks Na+/Cl- cotransporter Inhibit active Na+ reabsorption and accompanying Cl- Reduce circulating Cl- Used in mild / moderate heart failure - 2nd line in hypertension
Renally excreted / secreetd by weak acid transporter in PCT before acting on DCT
What is hypokalaemia
K+ loss -> caused by kaliuresis
2’ to loop diuretics, thiazides
How does aldosterona cause hypokalaemia
Acts on mineralcorticoid receptor (intracellular) -> goes to the nucleus and determines which genes are expressed.
MRNA and aldosterone induced proteins produced -> Na+ channels inserted into basolateral membrane : Na+ reabsorbed so K+ is lost
What are potassium sparing diuretics
- aldosterone receptor antagonists
Na+ channel blockers (on DCT) - weak diuretics but in combo w K+ losing agents may reduce K+ loss
ACEi cause hyperkalaemia so may negate effects of K+ losing diuretics
What are aldosterone (mineralocorticoid) receptor antagonists
Eg spironolactone
- antagonise aldosterone receptors
- prevent insertion of Na+ pumps and channels
- used in 1’/2’ hyperaldosteronism
- used in CHF to block aldosterone actions on heart
What are sodium channel blockers
Eg amiloride / triamterene
Block luminal Na+ channels in late DCT and CD
Na+ no longer retained at expense of K+
What is renoprotection
Diabetes associated with renal nephropathy
Cause of chronic renal failure
ACEi slow renal damage, advocated in nephropathy/ diabetes + hypertension
- block inappropriate RAAS activation
How to counsel a patient for taking diuretics
Best taken am (so sleep isnt disturbed by needing to urinate) Pt will experience increased urine flow Pt should avoid excess salt in diet May cause postural hypotension Thiazides: may uncover / worsen diabetes Thiazides / LD may worsen gout NSAIDs may reduce effect of LD - electrolytes should be monitored
Mechanism of action of spironolactone
Is an aldosterone antagonist
Inhibition of the mineralocorticoid receptor in the cortical collecting ducts interferes with excretion of potassium so can cause hyperkalaemia
Side effect: breast tissue growth
Which diuretic causes abnormally tall T waves on ECG
Spironolactone
Dietary advice for chronic kidney disease
Diet low in protein, phosphate, potassium and sodium
Protein- a source of ammonia which is normally excreted by the kidney (but less so in CKD)
Phosphate- can complex with calcium to cause renal stones
Sodium - increases blood pressure, which damages the kidney further
Potassium - not well excreted by failing kidneys and can cause cardiac arrhythmia
How do you maintain acid base balance
1) buffers
2) ventilation
3) renal regulation of H+ and HCO3- (slow)
What are the sources of H+ gain
From CO2 in tissue (aerobic respiration) - forms carbonic acid which then dissociates
- metabolism of protein and other organic molecules
- loss of HCO3- in diarrhoea
- loss of HCO3- in urine
What are the sources of H+ loss
H+ + HCO3- -> H2O + CO2 (CO2 excreted through lungs)
- utilising H+ in metabolism of organic anions
- loss of H+ in vomitus
- loss of H+ in urine
What are the buffers
Combine with H+ to form HB in acidosis and vice versa to maintain body pH
- HCO3- (intra and extracellular)
- phosphates, Hb
How do the kidneys maintain homeostasis
- excrete ‘ reabsorption H+
- phosphate / ammonia buffers
- regulate plasma [HCO3-]
- excretion of filtered HCO3-
- addition of new HCO3- to blood
What happens in acidaemia in the kidneys
High plasma [H+]
- increase H+ secretion (add new HCO3- to blood) -> decreases plasma [H+]
How can reabsorption in the proximal tubule affect an alkalosis
Less HCO3- reabsorbed helps alkalosis
- can’t help acidosis because working at max HCO3-
Reabsorption (1 HCO3- reabsorbed for 1 HCO3- filtered)
No net gain of HCO3-
What is ammoniagenesis
Creation of new ammonia to act as a buffer in the excretion of H+ ions in urine, and new HCO3- is added to the blood
What is ammonium / diffusion trapping
NH4+ transported across apical membrane into tubular fluid but nephron membrane has limited permeability: travels around the nephron in the tubular fluid until the thick limb which is permeable
What is the effect of aldosterone on the late DCT / CCD
1) stimulates Na+ reabsorption (principle cells) to maintain electroneutrality
2) stimulates K+ secretion (principle cells)
3) stimulates H+ secretion (intercalated cells) also b/c stimulates H+ATPase .: 1’ aldosterone excess of 2’ hyperaldosteronism -> metabolic alkalosis
Why are diuretics so important
Important cardiovascular drugs - management of CHF - antihypertensives - A/C (D) guidelines A: antihypertensives C: Ca2+ channel inhibitor D: diuretic
What do diuretics do
- increase Na+ secretion (natriuresis)
- Na+ flowed osmotically by H2O
- decrease ECF / plasma vol
:- reduces oedema and BP
What is natriuresis
Excretion of sodium
What are the different types of diuretics
Osmotic agents
Loop diuretics
Thiazides
Potassium sparing agents
What are osmotic diuretics
Eg mannitol
Pharmacologically inert
Freely filtered in bowman’s capsule
Increases osmolality of tubular fluid in PCT and loop of henle
Reduce passive reabsorption of H2O
Used in cerebral oedema (increases osmolaltiy and removes fluid from the brain)
What are loop diuretics
Reduces ability of loop to concentrate urine by preventing creation of an hypertonic interstitium in the medulla
- increases Na+ delivery to DCT
- promotes K+ loss (risk of hypokalaemia)
- decreases Na+ entry into macula dense - promotes renin release
Kidney becomes refractory (less responsive) to LDs for some hours after use (regimen: o.d)
What are the uses of loop diuretics
CHF
- reduce pulmonary oedema, 2’ to LVF and peripheral oedema
Venodilators
- iv, rapid effect in acute LVF
Renal failure
To improve diuresis
What are thiazides
Moderately powerful diuretics eg chlorothiazide, chlorthalidone
Act on DCT (less important for Na+ balance)
Blocks Na+ /Cl- cotransporter
- inhibits active Na+ reabsorption and accompanying Cl-
- reduce circulating volume
Used in mild / moderate heart failure
2nd line in hypertension
Renally excreted / secreted by weak acid transporter in PCT before acting on DCT
How does aldosterone cause hypokalaemia
Acts on mineralocorticoid receptor (intracellular) -> goes to the nucleus and determines which genes are expressed
- mRNA and aldosterone induced proteins produced -> Na+ channels inserted into basolateral membrane
Na+ reabsorbed so K+ is lost
What are potassium sparing diuretics
Aldosterone receptor antagonists
- Na+ channel blockers of DCT
- weak diuretics but in combination with K+ losing agents may reduce K+ loss
- ACEi cause hyperkalaemia so may negate effects of K+ losing diuretics
What are aldosterone (mineralocorticoid) receptor antagonists
Eg spironolactone
- antagonise aldosterone receptors
- prevent insertion of Na+ pumps and channels
- used in 1’/2’ hyperaldosteronism eg ascites
Used in CHF to block aldosterone actions on heart
What are sodium channel blockers
Eg amiloride / triamterene
Block luminal Na+ channels in late DCT and CD
Na+ no longer retained at expense of K+
What is renoprotection
Diabetes associated with renal nephropathy -> cause of chronic renal failure
ACEi slow renal damage, advocated in nephropathy / diabetes + hypertension
- block inappropriate RAAS activation
How to counsel a patient for diuretics
Best taken morning so sleep isn’t disturbed by needing to urinate Pt will experience increased urine flow Avoid excess salt in diet May cause postural hypotension - thiazides may uncover or worsen diabetes - thiazides / LD may worsen gout - NSAID may reduce effect of LD Electrolytes should be monitored
What is hyponatremia
Deficiency of sodium
Common
What is hypernatremia
Excess sodium
Common
What causes hyponatremia
Usually H2O retention
- Advanced renal failure or inability to suppress secretion of ADH
- Effective circulating volume depletion
- Syndrome of inappropriate ADH secretion
- Hormonal changes (cortisol deficiency, hypothyroidism)
- primary polydipsia (excessive thirst, often schizophrenic) - Renal osmostat
Treatment of hyponatremia
Water restriction, increase salt intake / diuretics
Depends on severity and cause
Aggressive treatment can cause central pontine myelinolysis
What is pseudohyponatremia
Artefactually low serum [Na+] b/c volume displacement but hyperlipidaemia or hyperproteinaemia
Can be caused by hyperosmolar state eg hyperglycaemia in uncontrolled diabetes
What is hypernatraemia
Less common than hypo b/c thirst is main defence mechanism against it
- v rare in alert pt w access to water and normal thirst
Found in pt over 60 (bc ability to create concentrated urine is worse)
What are the causes / treatment of hypernatremia
Mainly H2O loss (diabetes, fever + impaired thirst)
Na+ retention eg administration of hypertonic NaCl or NaHCO3
H2O out of cells -> decrease in brain vol, lethargy, seizures, coma
Tx: decrease Na+, increase H2O
How is K+ balance regulated
ECF [K+] controlled by:
- uptake of K+ into cell
- renal excretion and extrarenal losses
- abnormalities can cause hypo / hyperkalaemia
Why is the distribution of K+ important
Affects membrane potential
Transcellular shifts more important for Sx than external shifts
ICF K+ affects protein and glycogen synthesis
Only small [K+] ECF but small changes affect tissue excitability
Dietary K+ intake can’t be rapidly excreted renally
What happens if K+ distribution increases
Depolarises membrane -> more excitable - persistent depolarisation inactivates Na+ channels : membrane excitability decreases : impaired cardiac conduction / mm weakness
What happens is K+ distribution decreases
Hyperpolarises membrane -> less excitable in cardiac myocytes membrane excitability increases b/c removal of normal inactivation of Na+ channels
Impaired cardiac conduction / mm weakness
What is the influence of insulin (glucagon) on K+
Increases K+ uptake into cells: activates Na+ / K+ ATPase
What is the influence of catecholamines on K+
Beta-2 receptors; increase K+ uptake into cells; activates Na+/K+ ATPase
What is the influence of plasma K+ concentration on K+
Increased K+ in plasma -> K+ movement into cells
Decrease K+ in plasma -> K+ moves out of cells
What are the consequences of hypokalaemia
Often no Sx or if more severe non specific Sx
- Muscle weakness / paralysis (inc gut)
- Cardiac arrhythmias
- Rhabdomyolysis
- Renal dysfunction
What are the causes of hyperkalaemia
Usually pt with renal failure
- Increased intake of oral salt or IV
- Movement from cells into ECF
- Decreased urinary excretion
What are the consequences of hyperkalaemia
Mm weakness / paralysis (sustained depolarisation inactivates Na+ channels :. Decreased excitability)
Cardiac arrhythmias
Hyperkalaemia treatments
- Antagonism of membrane actions
- Ca2+ restores membrane excitability - Increase K+ entry into cells
- Removal of excess K+
What is referred pain
Perception of visceral pain some way away from the organ involved
Doesn’t accurately represent where the problem is
Signal from several areas of the body often travel through the same nerve pathway
What is the relevance of the viscera
Innervated mostly only by autonomic nerves :. Visceral pain conducted along afferent autonomic nn (can only enter CNS where sympathetic / parasympathetic motor fibres leave)
Sensory info from viscera may be involved with reflex activity of elicit pain
What is the difference between somatic and visceral pain
Somatic is epitomised by pain arising from the skin, many modalities, sensitive, well localised, often sharp, many sensory receptors
Visceral has fewer sensory endings, often in smooth muscle, poorly localised, dull, heavy or gripping, may be referred
What is visceral pain
From internal organs
Mild discomfort of indigestion
Agony of a renal colic
Reproductive life
Common cause to seek medical intention
Viscera insensitive: crushing / cutting / burning
Viscera sensitive: stretching / contraction
What are visceral afferent fibres
No peripheral synapse (unlike visceral efferent)
Joins a spinal nn, enter CNS along dorsal nerve root
- cell body found in dorsal root ganglion
- enters spinal cord at T1-2 (sympathetic motor outflow), S2-4 (parasympathetic outflow)
What is the mechanism of referred pain
Not known
Nociceptors from several locations converge on a single tract
Pain signal from skin more common (high sensory input)
Brain associates activation of pathway with pain in skin
Examples of referred pain
Appendix: RLQ, U
Bladder: lower abdomen, upper thighs
Diaphragm: shoulders
Oesophagus: along sternum, L upper thorax
Heart: base of neck, L jaw, L shoulder and arm
Intestines: back (backache / sharp pain in back), U
Kidneys: posterior costovertebral angle, radiating forwards around the flank
Liver: R shoulder
Pancreas: directly behind pancreas, LLQ, U
Spleen: L shoulder, upper 1/3 of arm
Ureter: costovertebral angle radiating to lower abdomen, testicles, inner thigh
Routes of excretion
Expired air Urine Bile Sebum / sweat Breast milk
How does excretion in the bile work
Active transport process for highly polar compounds
Minor route for unmetabolised drug
Major route for drug metabolites
May be alternative route of excretion of polar drugs in patient with renal impairment
Possibility of enterohepatic re circulation
What are the consequences of enterohepatic re circulation of drugs
Prolongation of drug action
Localisation of drug action
Why are NSAIDs contraindicated with methotrexate
B/c competition for secretion (blocked by salicylate) :. Less secreted so toxicity increases
How should you prescribe in renal impairment
Choose short acting agents
Gentamicin: increase dosage interval
- choose non renally excreted alternative
Some drugs must be avoided eg meteor in
Some require renal excretion to act :. Ineffective in renal impairment
How do you prescribe if a patient is on dialysis
Excretion will be altered by the membrane permeability
Consult a specialist
Describe the effects of excretion of drugs in milk
Limited evidence
Amount of drug relates to pharmacokinetics
Could have effect on baby
BNF:
Drug used with caution / contraindicated
Present in milk but not known to be harmful
Not known to be harmful
