Diuretics Flashcards
LO
- To be able to describe and discuss the mechanisms and pharmacology of blood volume control
- Angiotensin-Renin control system
ACE inhibitors
ANP
- Diuretics
Multiple classes/sites of action
- To be able to describe and discuss the therapeutic benefits of pharmacological interventions in control of blood volume
Pharmacological interventions to modify salt/ water balance are beneficial in what?
- Heart failure
- Hypertension
nb. reduced perfusion compromises kidney function- vicious cycle
What does kidney function require?
good perfusion at sufficient blood pressure
What does circulation require?
Control of blood volume and ionic concentrations in order to produce appropriate blood pressure to ensure sufficient tissue perfusion
Tell me the overview of volume regulation and the enzymes involved?
Tell me the overview of ACE inhibitor in volume regulation
Give an example of an ACE inhibitor?
Tell me its side effect?
ACE inhibitors
Tell me where the atrial natriuretic peptide is released from and in response to what?
Released from atrial mycocytes in response to atrial stretch (particularly in embryonic and in congestive heart failure)
What does the Atrial natriuretic polypeptide counteract?
Renin/ Angiotensin
How many receptor types of Atrial natriuretic peptide are there?
Three receptor types
What does the Atrial natriuretic peptide relax and reduce?
- Relaxes Vascular smooth muscle – resistance down
- Reduces Renin secretion (so less angiotensin II)
- Reduces Aldosterone secretion
What is the pharmacological target of the Atrial natriuretic peptide ?
Pharmacological target is degradation via Neutral Endopeptidase to enhance ANP effects – drugs can be both Endopeptidase and ACE inhibitors
What is the function of the kidney?
Blood filtration, loss of materials of MW <50kDa, ~10% of blood vol
What does the kidney secrete/ remove?
The kidneys remove from the blood the nitrogenous wastes such as urea, as well as salts and excess water, and excrete them in the form of urine. This is done with the help of millions of nephrons present in the kidney.
Secretion – eg. organic acids
What type of things does the kidney reabsorb?
Reabsorption - Uptake of ions and glucose
What are normal GFR value in the kidney?
GFR -Normal values 120±25 mls/min = 7litres per hour - (ca.10% of perfusion flow)
Label this diagram for the gross anatomy of the urinary system
Roughly how much cardiac output do the kidneys recieve at rest?
about 20% (ca. 1 litre/min)
Label this diagram of the kidney?
What is the functional unit of the kidney?
Nephron
Label this diagram of the nephron
What can ANS innervation modify?
filtration pressure and hence rate
Label this nephron diagram
What features do the glomerular capillaries contain?
Tell me the mechanism to urine function by the kidney?
- Na+ gradient generated by Na+/K+ pump of proximal tubule epithelial cell walls is used to drive reabsorption of glucose, amino acids
- Osmotic gradient leads to H2O reabsorption – ca. 50%
- Mainly paracellular H2O in proximal tubule
Urine formation is done in 3 main steps:
1. FILTRATION
2. REABSORPTION
3. EXCRETION
Tell me about kidney filtration
During filtration, blood enters the afferent arteriole and flows into the glomerulus where filterable blood components, such as water and nitrogenous waste, will move towards the inside of the glomerulus, and nonfilterable components, such as cells and serum albumins, will exit via the efferent arteriole. These filterable components accumulate in the glomerulus to form the glomerular filtrate.
Normally, about 20% of the total blood pumped by the heart each minute will enter the kidneys to undergo filtration; this is called the filtration fraction. The remaining 80% of the blood flows through the rest of the body to facilitate tissue perfusion and gas exchange.
Tell me about reabsorption in the kidney
The next step is reabsorption, during which molecules and ions will be reabsorbed into the circulatory system. The fluid passes through the components of the nephron (the proximal/distal convoluted tubules, loop of Henle, the collecting duct) as water and ions are removed as the fluid osmolarity (ion concentration) changes. In the collecting duct, secretion will occur before the fluid leaves the ureter in the form of urine.
Tell me about secretion in the kidney?
During secretion some substances±such as hydrogen ions, creatinine, and drugs—will be removed from the blood through the peritubular capillary network into the collecting duct. The end product of all these processes is urine, which is essentially a collection of substances that has not been reabsorbed during glomerular filtration or tubular reabsorbtion.
Urine is mainly composed of water that has not been reabsorbed, which is the way in which the body lowers blood volume, by increasing the amount of water that becomes urine instead of becoming reabsorbed. The other main component of urine is urea, a highly soluble molecule composed of ammonia and carbon dioxide, and provides a way for nitrogen (found in ammonia) to be removed from the body. Urine also contains many salts and other waste components. Red blood cells and sugar are not normally found in urine but may indicate glomerulus injury and diabetes mellitus respectively.
Tell me about the filtration step and how ATP is consumed by the Na+/K+ pump
In the ascending loop of loop of Henle, what does Na and Cl reabsorption require?
Na/K/2Cl co-transporter and energy
Tell me about the Na/K/2Cl co-transporter?
- The Na-K-Cl cotransporter (NKCC) is a protein that aids in the secondary active transport of sodium, potassium, and chloride into cells
- In humans there are two isoforms of this membrane transport protein, NKCC1 and NKCC2, encoded by two different genes
- NKCC1 is widely distributed throughout the human body; it has important functions in organs that secrete fluids. NKCC2 is found specifically in the kidney, where it serves to extract sodium, potassium, and chloride from the urine so that they can be reabsorbed into the blood.
Tell me about the NKCC2
- where is it found?
- where does it reside?
- Whats its role?
NKCC2 is specifically found in cells of the thick ascending limb of the loop of Henle and the macula densa in nephrons, the basic functional units of the kidney.
Within these cells, NKCC2 resides in the apical membrane abutting the nephron’s lumen, which is the hollow space containing urine.
It thus serves both in sodium absorption and in tubuloglomerular feedback.
Tell me about the countercurrent mechanism in the loop of henle?
what is it?
- Counter current mechanism driven by active extrusion of Na produces hypertonic conditions in medulla
- This can be used to create hypertonic urine by regulating water permeability of collecting duct – regulated by ADH
Countercurrent multiplication in the kidneys is the process of using energy to generate an osmotic gradient that enables you to reabsorb water from the tubular fluid and produce concentrated urine. This mechanism prevents you from producing litres and litres of dilute urine every day, and is the reason why you don’t need to be continually drinking in order to stay hydrated.
nb. not the same as countercurrent exchange
Overview of diuretics
What is the equation for clearance
What is the effect of diuretic drugs on the kidney?
Diuretic drugs increase urine output by the kidney (i.e., promote diuresis).
Tell me the mechanism by how diuretic drugs work in the kindey?
diuretic drugs increase urine output and this is accomplished by altering how the kidney handles sodium.
If the kidney excretes more sodium, then water excretion will also increase.
Most diuretics produce diuresis by inhibiting the reabsorption of sodium at different segments of the renal tubular system
Name 5 different diuretics which can be taken?
- Carbonic anhydrase inhibitors
- Osmotic diuretics
- Thiazide diuretics
- Loop diuretics
- K+ sparing diuretics
Tell me how the loop diuretic works
Loop diuretics inhibit the sodium-potassium-chloride cotransporter in the thick ascending limb
This transporter normally reabsorbs about 25% of the sodium load; therefore, inhibition of this pump can lead to a significant increase in the distal tubular concentration of sodium, reduced hypertonicity of the surrounding interstitium, and less water reabsorption in the collecting duct.
This altered handling of sodium and water leads to both diuresis (increased water loss) and natriuresis (increased sodium loss).
- Act on thick ascending limb
- Block Na/K/2Cl co-transporter preventing Na gradient driven reabsorption of K+.
- Therefore, lose K+ and H2O
Label the sites of action of diuretics
Give an example of a loop diuretic
Furosemide
Tell me about osmotic (solute) diuretics and give an example
- eg. Mannitol,
- Non-metabolizable enters tubule and via osmotic effects prevents reabsorption of water
- Water movement largely paracellular in proximal tubule
Tell me about carbonic anhydrase inhibitor diuretics and provide an example
- eg. Acetazolamide, reduce reabsorption of bicarbonate
- Na gradient drives H+ efflux into tubule,
- Combines with HCO3- via Carbonic anhydrase to produce CO2 and H20 (lost)
- CO2 into epithelial cell combines with H20 in cell to produce HCO3- and H+ via Carbonic anhydrase
- HCO3- plus Na+ via cotransporter to blood
- Hence, normally reabsorb Bicarb and H2O
Carbonic anhydrase inhibitors inhibit the transport of bicarbonate out of the proximal convoluted tubule into the interstitium, which leads to less sodium reabsorption at this site and therefore greater sodium, bicarbonate and water loss in the urine. These are the weakest of the diuretics and seldom used in cardiovascular disease. Their main use is in the treatment of glaucoma.
Proximal tubule- carbonic anhydrase inhibiting diuretics
Ascending limb of loop of Henle: NA/K/2Cl co-transporter blocked by “loop diuretics”
Tell me about Thiazide diuretic and give an example
- Eg. bendrofluazide
- Act on distal convoluted tubule
- Block Na/Cl co-transporter
- Increase Na and K loss
Thiazide diuretics, which are the most commonly used diuretic, inhibit the sodium-chloride transporter in the distal tubule. Because this transporter normally only reabsorbs about 5% of filtered sodium, these diuretics are less efficacious than loop diuretics in producing diuresis and natriuresis. Nevertheless, they are sufficiently powerful to satisfy many therapeutic needs requiring a diuretic. Their mechanism depends on renal prostaglandin production.
Distal convoluted tubule: Na Cl co-transporter blocked by “thiazide diuretics
Tell me the normal impermeability of the collecting duct
Collecting duct normally:
- Impermeable to water in absence of ADH (aquaporins)
- Impermeable to Na in absence of Aldosterone (eNaC)
Give two examples of K+ sparing diuretics
- Aldosterone blockers
- eNaC blockers
Tell me about aldosterone blockers
Aldosterone Blockers (K+ sparing but weaker diuresis)
eg. Spironolactone, limited action via blocking intracellular Aldosterone receptors prevent upregulation of eNaC
Tell me about eNaC blockers
eNaC Blockers
- antagonise Aldosterone effects (K+ sparing)
- eg. Amiloride, reduces Na reabsorption and K+ loss
Give two examples of drugs that block the effects of aldosterone, and what each specifically blocks
Name an ACE inhibitor
Diuretic structures- overview and evolution
Summary of diuretics
Extra information of K+ sparing diuretics
Unlike loop and thiazide diuretics, some of these drugs do not act directly on sodium transport.
Some drugs in this class antagonize the actions of aldosterone (aldosterone receptor antagonists) at the distal segment of the distal tubule.
This causes more sodium (and water) to pass into the collecting duct and be excreted in the urine.
They are called K+-sparing diuretics because they do not produce hypokalemia like the loop and thiazide diuretics.
The reason for this is that by inhibiting aldosterone-sensitive sodium reabsorption, less potassium and hydrogen ion are exchanged for sodium by this transporter and therefore less potassium and hydrogen are lost to the urine
Other potassium-sparing diuretics directly inhibit sodium channels associated with the aldosterone-sensitive sodium pump, and therefore have similar effects on potassium and hydrogen ion as the aldosterone antagonists.
Their mechanism depends on renal prostaglandin production.
Because this class of diuretic has relatively weak effects on overall sodium balance, they are often used in conjunction with thiazide or loop diuretics to help prevent hypokalemia.
