Renal Flashcards
What is the glomerular filtration rate?
The volume of fluid filtered from the renal glomerular capillaries into bowman’s capsule per unit time
How do the kidneys regulate body fluid composition?
By producing urine tailored to the body’s requirements at any time
How do reabsorption and secretion occur at a normal rate?
Renal blood flow and GFR are controlled to maintain fairly constant over moderate changes in arterial BP
What is clearance?
The removal of substances from the plasma and their excretion in urine
Give an example of something that is never cleared and something that is fully cleared from the body
Glucose - zero clearance
Para-aminohippuric acid - fully cleared
What is the clearance equation?
Cx = Ux . V / Px
Cx - clearance of x
Ux - conc of x in urine
V - urine flow rate
Px - conc if x in plasma
What happens when a solute is fully cleared?
The volume of plasma which flow into the kidneys is the same as the clearance of that solute
How is PAH used to test the body’s ability to clear substances?
It is injected into the plasma
Wait one hour
Measure the conc in arterial plasma and urine and the urine flow rate of the hour
Then use the equation
Why is renal blood flow not measured?
RBCs are not present in the plasma or the urine and the Ppah and Upah already omit these
How would you calculate renal blood flow?
RBF = RPF x (1 / 1- Hct)
RBF - renal blood flow
RPF - renal plasma flow
Hct - haematocrit
What criteria must be met in order to test the clearance function of the kidneys?
1) substance must be freely filtersble in the glomeruli
2) substance must be neither reabsorbed nor secreted by the tubules
3) substance must not be synthesised, broken down, nor accumulated by the kidney
4) substance must be physiologically inert
What two substances are routinely used to test clearance?
Insulin
Creatinine
How do you determine clearance when using inulin or creatinine?
Urine is collected over a 24hr period to determine flow rate
The conc of inulin/creatinine is taken from the urine
The conc of inulin/creatinine is taken from a blood sample
What is a normal GFR for men?
90-140 mL/min
What is a normal GFR for women?
80-125 mL/min
Why is determining GFR using clearance important?
It helps diagnose and monitor renal disease
Can help determine how the kidneys handles particular solutes - are they reabsorbed or secreted etc
Is important in the design of clinically useful drugs
How do you calculate the filtered load?
Fx = GFR x Px
What is the transport rate?
The difference between what was filtered and what was in urine
Why is transport rate significant?
Whether it has a positive or negative sign allows you to determine whether a substance was reabsorbed or secreted
How is creatinine concentration determined in a urine sample?
1mL or urine sample
1mL of creatinine standard
To both add 1mL of picuric acid and 1mL of NaOh
Wait ten minutes
Use colorimeter on both
Du is the optical density of the urine sample
Ds is the optical density if the standard what calculation do you use to find the creatinine conc in the 200mL urine sample?
(Du x Ds) x 0.1 x 200 / 15
= 1.33 (Du x Ds)
Why do you get a diuresis with 700mLs of water?
…
What is pharmacodynamics?
What drugs do to our bodies
What is pharmacokinetics?
What our bodies do to the drug
What does pharmacokinetics depend on?
Absorption
Distribution
Metabolism
Excretion
What is the therapeutic window?
A dose between what is toxic and the minimal does at which there is a therapeutic effect
What is absorption?
The journey of a drug from where it administered to the blood plasma
Where are drugs absorbed?
The gut
Skin
Muscle
CSF
Lungs
What is distribution?
It’s presence in body fluid compartments and fat
What are the two forms of drugs?
Bound and unbound (free in solution)
Which form of drug achieves the clinically useful effect?
The unbound form
How is drug distribution achieved?
Through the circulatory system
Highly vascular areas allow rapid distribution: the heart, liver, kidneys
Less vascular areas have a slower distribution: peripheral tissues like fat and skeletal muscle
Do drugs distribute equally around the body?
No, some drugs are water soluble (atenolol) and stay the blood and interstitial fluid, while others are fat soluble (fentanyl) and will concentrate in fats
Where can drugs be metabolised?
GI tract
Kidneys
Lungs
Liver
How are drugs metabolised by the liver?
Must enter a hepatocyte (cross the plasma membrane), liver enzymes will then make them inactive
Hydrophobic drugs are more easily metabolised by the liver because of this
How are hydrophilic drugs metabolised?
They require specific transport proteins to enter the liver
But these drugs are at least partly excreted unchanged
What are prodrugs?
These are modified by the liver to for the pharmacologically active molecule
E.G perindopril to perindoprilat
What are the two phases of metabolism?
Phase 1: catabolic
Phase 2: anabolic
Where are liver metabolising enzymes found?
Embedded in the smooth endoplasmic reticulum
What is the important system for drug metabolism?
The cytochrome P450 (CYP) system
How are drugs excreted?
Biliary excretion
Faeces
Respiration
Kidneys
How does clearance determine the dosage of a drug?
The higher the rate of clearance the higher the dosage must be
The slower the clearance rate the lower a dosage can be and still maintain a therapeutic concentration
What is the rate of excretion in the kidneys determined by?
Drug filtration
Secretion
Reabsorption
What part of the drug will be filtered by the glomerulus?
Only the unbound drug
What are two examples of drugs that even when unbound will not be filtered at the glomerulus?
Warfarin and Heparin
They are too big even when unbound
What is secretion?
When a substance is secreted from the blood into the renal tubules
How are organic acids secreted?
They are transported in their anionic form against the electrochemical gradient by OAT family proteins
How are organic bases secreted?
They are transported in their cationic by OCT family proteins
Give an example of a drug that is transported by OAT
Penicillin
Give an example of a drug that is transported by OCT
Morphine
How can the therapeutic effect of a drug be prolonged
By taking agents that block tubular secretion alongside the drug
Does reabsorption increase or decrease the concentration of drug in the tubular lumen?
It decreases it as the drug is reabsorbed back into the bloodstream
What factors affect drug reabsorption?
Urine flow rate
Lipid solubility
Ionisation of the drug
Can lipid soluble drugs be excreted by the kidneys?
Not well as they cross the tubular membrane
Why are polar drugs excreted well?
They cannot cross the tubular membrane
Will ionisation if drug increase or decrease it’s reabsorption?
It will decrease it
What happens to drugs that are weak acids?
In alkaline urine they will become anionic and their excretion will increase
What happens to drugs that are weak bases?
In an acidic urine they will become cationic and their excretion will increase
What is ion trapping?
The charged form of the drug remains in the tubules and more it is excreted
How can pH of urine be changed to favour certain drug excretion?
Antacids are a good way of changing urine pH to become more alkaline and favour the excretion of acids
What is the Henderson-Hasselbalch equation?
PH = pKa + Log10 [A-] / [HA]
What is the defence of H+ concentration?
Buffers
Respiratory regulation
Renal regulation
Describe the buffer graph
pH is the y-axis
Acid added is LHS
Alkali added is RHS
pH = pKa where the line crosses the y-axis
It is a sigmoidal curve
Give two examples of buffers for respiratory regulation of pH
Carbonic acid
Haemoglobin
Give the steps of respiratory regulation of pH
Decrease in pH
Chemoreceptors detect this
Signal to respiratory centre
Increase minute volume
Decrease PaCO2 (breathing out)
There’ll be an increase of pH
Give the steps of renal regulation of pH
Increase in H+
Kidneys will:
- increase H+ secretion and excretion
- increase HCO3- reabsorption and decreased excretion
These will decrease H+
At what point is reabsorption highest in the nephron?
PCT - massive reabsorption
DCT - fine adjusted reabsorption and secretion
Collecting duct - adjusted water reabsorption
What are important pH values to know?
Normal - 7.4
Acidosis - <7.35
Alkalosis - >7.45
What is respiratory acidosis?
The retention of carbonic acid, increased PCO2
What is metabolic acidosis?
Increased non-carbonic acids, decreased PCO2 and decreased HCO3-
What do diuretics do and how do they work?
They increase urine volume
By increasing water excretion, by excreting more sodium
What diuretics work by causing a natriuresis?
Thiazides
Loop
Potassium sparing
Where do thiazide diuretics work?
The DCT
How do thiazide diuretics work?
By binding to the Cl binding site of the Na+/Cl- cotransporter
Inhibiting it’s activity and increasing excretion if Na+ and Cl-
What sort of effect do thiazide diuretics have on BP?
They have a hypotensive effect
Due to the decrease in blood volume
Give an example of a thiazide diuretic
Hydrochlorothiazide
Give two example of loop diuretics
Furosemide
Bumetanide
How do loop diuretics work?
They inhibit the Na+/2Cl-/K+ cotransporter by binding to the Cl- site
What effect do loop diuretics have?
They reduce blood pressure by reducing blood volume and have a vasodilators effect
What is a side effect of both thiazide and loop diuretics?
The loss of potassium
Na+ reabsorption and K+ secretion are linked
Creates an electrochemical gradient favouring K+ secretion
Give examples of potassium sparing diuretics
Amiloride
Triamterene
Spironolactone
How do amiloride and triamterene work?
They block Na+ channels that normally facilitate the passive diffusion of Na+
How does spironolactone work?
It is an aldosterone antagonist
It competes with aldosterone for its intracellular receptors
Rank the order of diuretics from most useful to least
Loop
Thiazide
Potassium sparing
How do osmotic diuretics work?
They reduce water reabsorption along the nephron
What are osmotic diuretics used to treat and why?
Emergency treatment of cerebral oedema
Increased intraoccular pressure
By increasing plasma osmolarity but do not enter the eye or brain allowing water to be drawn out
What type of hypertension are thiazide diuretics used to treat?
Uncomplicated hypertension
They are better tolerated while also reducing the risk of stroke or heart attack
When are loop diuretics used to treat hypertension?
When dealing with resistant hypertension alongside other hypertension drugs
How does the distribution of cardiac output change as a result of heavy exercise?
Increased blood flow to skeletal muscle
Decreased blood flow to renal and splanchnic circulations
Account for the increase in skeletal muscle blood flow in response to exercise
Sympathetic vasodilator fibres
Changes as a result of increased metabolism:
- increased H+, CO2, and temperature
- low PO2
What are the mechanisms behind the change in blood supply to the kidneys?
Renal arteries and arterioles are innervated by sympathetic nerve fibres which elicit vasoconstriction
RAS - renin-angiotensin system
What happens during the renin-angiotensin system?
Liver - Angiotensinogen
+
Kidney - Renin
=
Angiotensin l
+
Lungs - Angiotensin converting enzyme
=
Angiotensin ll
What does angiotensin ll do?
Vasoconstriction
Increased aldosterone secretion
Increased ADH secretion
Increased thirst
How does the GFR change as a result of exercise?
During heavy exercise GFR is reduced
There is sympathetic nervous innervation
How would you measure the GFR change as a result of exercise?
Clearance of inulin/creatinine
What is proteinuria?
Increased rate of protein excretion
Usually 20-30 mins after stopping exercise - 70-80% VO2 max
What is proteinuria caused by?
Increased permeability of filtration membrane
Reduced elastic charge
Reduced reabsorption of proteins by renal tubules
What is haematuria?
Increased excretion of RBC
Caused by mechanical trauma to the glomerulus
What are the benefits of increased ADH release during exercising?
Increased water reabsorption
Vasoconstriction
Glycogenolysis is increased - releasing more glucose
The renin angiotensin system and exercise
1) muscular activity - sweating
2) reduces plasma volume and blood flow to kidneys
3) this stimulates renin release from the kidneys then l converts to ll
4) angiotensin ll stimulates release of aldosterone from adrenal cortex
5) this increase Na+ and H2O reabsorption
6) plasma volume increases and urine production decreases
after several days of exercise
Why is plasma lost to the interstitial fluid?
As BP increases so does capillary hydrostatic pressure
As active muscle produces metabolic waste products these increase intramuscular osmotic pressure and attract fluid
Sweat is formed from interstitial fluid, as it decreases in volume more plasma fluid will move into tissues
Why is haemoconcentration a good thing?
Increasing the concentration of electrolytes and blood proteins will increase haematocrit and increase of the Hb content per mL of blood
How does the plasma volume stay constant after the init drop while exercising?
ADH and Aldosterone
Oxidative metabolic processes in active muscle produce water
Why is it the respiratory system that responds to acidosis during exercise?
The respiratory system responds in seconds, the renal system would take hours or even a day to have a significant effect
There is also an increased respiratory rate
Give three methods that are used to increase RBC
Erythropoietin
Blood doping
Hypoxic tent
Why is advantageous to train athletes at high altitudes?
Increased Hb and haematocrit
Increased VO2 max
Increased time to exhaustion
Why would athletes consider taking diuretics?
To lose weight to meet a certain category
As a masking agent - will dilute the presence of a different banned substance in their urine
