Pharmacology Flashcards
what are the drugs that act on the kidneys
diuretics
vasopressin receptor agnoists and antagonists
SGLT2
Uricosuric drugs
what are the main functions of diuretics
increase urine flow, normally by inhibiting the reabsorption of electrolytes (mainly sodium salts) at various sites in the nephron
what is the golden rule in water balance physiology
Where sodium goes water follows
how do diuretics work fundamentally
water follows sodium
normally 90% of sodium reabsorbed so water follows
diuretics decrease sodium absorption, decreasing water reabsorption
thus increasing urine flow
how can the volume of urine excreted in due to diuretics be affected
where on the nephron is being affected
what are diuretics used to treat
conditions where there is an increase in the volume of interstitial fluid i.e. oedema causing tissue swelling
what does oedema result from
an imbalance between the rte of formation and absorption of interstitial fluid
what forces dictate fluid movement from the capillary circulation and the interstitial fluid
a.k.a. the Starling forces
driving water out of the capillary
- capillary pressure
driving water into the capillary
- capillary osmotic/oncotic pressure
Pressure in interstitial fluid
- does not have much of a driving force
Osmotic/oncotic pressure of the interstitial fluid
- again not much driving force
what is the capillary osmotic pressure derived from
plasma proteins
- mainly albumin
what is the formation of interstitial fluid proportional to
(Pc - Pi) - (πp - πi)
(osmotic pressure inside the capillary - osmotic pressure outside the capillary i.e. interstitial)
what causes oedema in relation to starling forces
increase Pc or decrease πp
what diseases cause this
the nephrotic syndrome
congestive heart failure
hepatic cirrhosis with ascites
what will the glomerulus not let pass through and what is it when this goes wrong
large plasma protein
- it is kept in the capillaries of the glomerulus
the nephrotic syndrome
what is the nephrotic syndrome
disorder of glomerular filtration, allowing protein (largely albumin) to appear in the filtrate (proteinuria)
when is proteinuria normal
under conditions of intense exercise
what does the urine look like in proteinuria
frothy
what happens as a result of the nephrotic syndrome
decreased plasma volume
Decreased πp (oncotic pressure)
increase in formation of interstitial fluid
what does the increase in interstitial fluid cause
oedema
↓blood volume
↓ cardiac output
how does a decrease in blood volume and CO eventually lead to oedema
activation of RAAS >> Na+ and H20 retention >> ↑Pc, ↓ πp (increase in pressure in the capillary and decrease in osmotic pressure) >> Oedema
what does congestive heart failure arise from and what does it cause in relation to kidneys
from reduced cardiac output.
renal hypoperfusion activates the renin-angiotensin system
how does congestive heart failure cause pulmonary and peripheral oedema
Expansion of blood volume contributes to increased venous and capillary pressures which, combined with reduced πp causes oedema
how does hepatic cirrhosis with ascites cause oedema
Increased pressure in the hepatic portal vein, combined with decreased production of albumin, causes loss of fluid into the peritoneal cavity and oedema (ascites)
what are the major steps of sodium reabsorption
- Na+ (passive Cl- absorption)
- Na+/H+ exchange (blocked by carbonic anhydrase inhibitors)
- Na+/K+/2Cl- co-transport (blocked by loop diuretics)
- Na+/H+ exchange (blocked by carbonic anhydrase inhibitors)
- Na+/Cl- co-transport (blocked by thiazide diuretics)
- Na+/K+ exchange (blocked by potassium-sparing diuretics)
where do the steps of sodium reabsorption occur
Steps 1 +2 - Proximal convoluted tubule
Step 3 - Thick ascending limb of the loop of Henle
Step 4 + 5 - Distal convoluted tubule
Step 6 - Collecting tube
how to diuretics shift oedema
increased output of water and salt
blood leaving the kidney is hemoconcentrated (volume reduced)
plasma protein concentration goes up
oncotic pressure goes up
blood goes back to the periphery with greater oncotic pressure
it can suck fluid out of interstitial space and help mobilise oedema
when might a potassium-sparign diuretic be added
when a loop diuretic and thiazides are already being used and hypokalaemia needs to be corrected
where is the site of action of many diuretics (thiazides, loop, potassium sparing) and what does this mean
apical membrane of the tubular cells
i.e. the membrane facing the lumen
that the diuretic must be in the filtrate to reach its site of action
how can diuretics get into the filtrate
glomerular filtration (for drug not bound to plasma protein)
secretion via transport process in the proximal tubule (most important one)
what are the two transport systems that diuretic that can get them into filtrate
The organic anion transporters (OATs) – transport acidic drugs (e.g. thiazides and loop agents)
The organic cation transporters (OCTs) – transport basic drugs (e.g. triamterene and amiloride)
what is the principle marker for renal plasma flow
PHA
what does secretion result in in relation to diuretics and what does this contribute to
i.e. molecules moving against concentration gradient
concentration of diuretic in the filtrate being higher than that in blood
contributes to pharmacological selectivity i.e. only work in the kidney which we need
how can OA- enter the cells in OATs and where does it happen
by either diffusion (only a little), or in exchange for α-ketoglutarate (α-KG)
at basolateral membrane
how is α-KG transported in the cell
(against a concentration gradient) via a Na+-dicarboxylate transporter
how does the OA- enter the lumen at the apical membrane
via either leaving on multidrug resistance protein 2 (MRP2), or in exchange for α-KG via OAT4
where is the sodium and potassium channel always found
the BASOLATERAL membrane
NEVER the apical
how can sodium move into the cell and what is it coupled with
via the NaDC
coupled with α-ketoglutarate (α-KG)
what does NaDC allow
build up of α-ketoglutarate (α-KG) inside the cell
how can α-ketoglutarate (α-KG) go back into the interstitial fluid
in exchange for organic ions
how organic ions get into the tubular cell
what is a problem with using a thiazide diuretic
it competes with uric acid for transport at OATs causing plasma urate increase predisposing to gout
how can Organic cations (OC+) get into the cell at the basolateral membrane
either by diffusion (if they are uncharged) or OCT (both driven by negative potential of cell interior and against a concentration gradient)
how does OC+ exit the apical membrane and enter the lumen
by facilitated diffusion via multidrug resistance protein 1 (MRP1)
OR
in exchange for hydrogren ions on an antiporters system (OCTN)
what does the antiporter system allow
allows protons from the tubular fluid to come back into the cell in exchange for organic cation going out of the cell
what does the antiporter system mean for sodium reabsorption
sodium comes in
proton goes out
some proton come back in
allow OC+ to be placed in the lumen
MOA of loop diuretic
- drives direction of sodium, potassium and chloride all in the same direction out of the lumen
- goes into the cytoplasm of the tubular cell
- ratio is 1 sodium to 1 potassium to 2 chlorides (2 +ve ions and 2 -ve ions so electroneutral process)
- sodium exported across membrane through the Na+/K+ ATPase and adds sodium to the interstitium
- potassium can be move out the cell on K+/Cl- co-transporter OR can leak back into the lumen via potassium channel
- some of the chloride moves out of the K+/Cl- co-transporter AND some leaves basolateral membrane via a Chloride ion channel
where do loop diuretics work and what do they work on
in the thick ascending limb of the loop of Henle
work on Triple transporter (Na+/K+/2Cl- co-transporter; NKCC2)
what is a problem with MOA of loop diuretics
it is an electroneutral reaction but there is an uncompensated leak of potassium back into the lumen
- adds positive charge into the lumen
what are the principle loop diuretics drugs
furosemide and Bumetanide
where is the site of action of a loop diuretic drugs and there effect
Inhibit the Na+/K+/2Cl- carrier by binding to the Cl- site and thus:
- Decrease the tonicity of the interstitium of the medulla
- Prevent dilution of the filtrate in the thick ascending limb
- Increase the load of Na+ delivered to distal regions of the nephron (causing K+ loss)
- Increase excretion of Ca2+ and Mg2+
what extra effect do loop diuretics have that is helpful in heart failure
indirect venodilator action
- blood return to heart reduces
- helps shift pulmonary oedema
when are loop diuretics used
To reduce salt and water overload associated with - HF, pulmonary oedema, chronic kidney failure
increase urine volume in acute kidney failure
Tx hypertension when in conjunction w/ renal failure
reduce acute hypercalcaemia
side effects of loop diuretics
Potassium loss producing low serum potassium levels (hypokalaemia)
shift in acid-base towards alkaline side (metabolic alkalosis)
Decreased volume of circulating fluid (hypovolaemia) and hypotension
Depletion of calcium and magnesium
Increased plasma uric acid (hyperuricaemia) i.e. gout
what causes metabolic acidosis as a side effect of loop diuretics
increased H+ secretion from intercalated cells in collecting tubule
where do work Thiazide diuretics
distal tubule of loop of Henle
MOA of thiazide diuretics and effects of this
Inhibit the Na+/Cl- carrier by binding to the Cl- site and thus:
- Prevent the dilution of filtrate in the early distal tubule
- Increase the load of Na+ delivered to the collecting tubule (causing K+ loss)
- Increase reabsorption of Ca2+
principle drugs of thiazide diuretics
Bendroflumethiazide
Hydrochlorothiazide
what additional effect do thiazide diuretics contain
indirect, vasodilator action
- makes them suitable to use in conjunction to treat hypertension
what are thiazide diuretics used to treat
mild heart failure
hypertension
severe resistant oedema (w/ loop diuretic)
Renal stone disease
side effects of thiazide diuretics
Hypokalaemia Metabolic alkalosis Hypovolaemia and hypotension Depletion of magnesium (NOT CALCIUM) Hyperuricaemia i.e. gout Male sexual dysfunction Impaired glucose tolerance
where does potassium loss in loop and thiazide diuretics occur
late distal and collecting tubule
how does potassium loss in loop and thiazide diuretics occur
1 - Increased Na+ load produces enhanced reabsorption of Na+
2 - Resulting charge separation makes lumen more negative and depolarizes the lumenal vs. basolateral membrane
3 - Increased driving force on K+ across the lumenal membrane leads to enhanced secretion of K+.
4 - Secreted K+ ‘washed away’ by increased urinary flow rate
5 - development of hypokalaemia (and metabolic alkalosis)
MOA of potassium sparing diuretics - Amiloride and Triamterene
Block the apical sodium channel and decrease sodium reabsorption
MOA of potassium sparing diuretics - Spironolactone and Eplerenone
Compete with aldosterone for binding to intracellular receptors causing:
1 - decreased gene expression and reduced synthesis of a protein mediator that activates Na+ channels in the apical membrane
2 - decreased numbers of Na+/K+ATPase pumps in the basolateral membrane
what do Spironolactone and Eplerenone competitively antagonise and where do they gain access to cytoplasm
the action of aldosterone at cytoplasmic aldosterone receptors
can access via the basolateral membrane
what actions do Spironolactone and Eplerenone have
increase excretion of Sodium
decrease excretion of potassium
what actions do Amiloride and Triamterene have and how do they get into the nephron
Block lumenal sodium channels in the collecting tubules.
enter nephron via the organic cation transport system in the proximal tubule
what are the clinical indications of potassium sparing diuretics
is in conjunction with other agents that cause potassium loss
what happens when potassium sparing diuretics by themselves
hyperkalaemia
what are potassium sparing diuretics also known as
Aldosterone antagonists
what are Aldosterone antagonists used in treatment for
Heart failure
Primary hyperaldosteronism (Conn’s syndrome)
Resistant essential hypertension
Secondary hyperaldosteronism (due to hepatic cirrhosis with ascites)
where is the major site of action of osmotic diuretics
proximal tubule
enter nephron nephron by glomerular filtration but are not reabsorbed
what is an osmotic diuretic
a type of diuretic that inhibits the reabsorption of water and sodium
e.g. mannitol
MOA of osmotic diuretic
increase the osmolality of the filtrate
decrease sodium reabsorption in the proximal tubule
when are osmotic diuretics used
- prevention of acute hypovolaemic renal failure
- raised inter cranial and intraocular pressure
what do carbonic anhydrase inhibitors do and what is an example of one
ncrease excretion of HCO3- with Na+, K+ and H2O
e.g. acetazolamide
what are carbonic anhydrase inhibitors used in
glaucoma and following eye surgery
prophylaxis of altitude sickness
what is aldosterone effects on the collecting tubule when it is secreted from the adrenal cortex
enhanced tubular sodium reabsorption and salt retention
what is ADH effects on the collecting tubule when it is secreted from the posterior pituitary
enhanced water absorption
what are the two types of diabetes insipidus
neurogenic diabetes insipidus
- lack of ADH secretion from the posterior pituitary
nephrogenic diabetes insipidus - - inability of the nephron to respond to ADH
how is neurogenic diabetes insipidus treated
Desmopressin
what is the function of vaptans
act as competitive antagonists of vasopressin receptors
what are the 3 vasopressin receptors and what do they do
V1A receptors mediate vasoconstriction
V1B not important
V2 mediate H2O reabsorption in collecting tubule
what happens when V2 receptors are blocked
excretion of water without accompanying sodium
thus raises plasma sodium concentration
when are vaptans used
Tolvaptan used in the Tx of SIADH
how does reabsorption happened in the proximal tubule via SGLT2
secondary active transport (apical membrane) and facilitated diffusion (basolateral membrane)
how does SGLT2 transport glucose
coupling it to Na+ influx glucose
what does inhibition of SGLT2 result in
glucosuria
decreases HbA1 c
weight loss
examples of SGLT2 inhibitors
Canagliflozin
dapagliflozin
what are the major prostaglandins synthesised by the kidneys
PGE2 - medulla
PGI2 - glomeruli
what do the prostaglandins of the kidney do and when are they synthesised
act as vasodilators
synthesised in response to ischaemia, mechanical trauma, angiotensin II, ADH and bradykinin
how do prostaglandins work on the GFR
- vasodilate the afferent arteriole
- renin released leading to angiotensin II that vasoconstrictor the efferent arteriole
- filtration pressure increases
how can NSAIDs precipitate acute renal failure
inhibit COX and can greatly decrease GFR in conditions where renal blood flow is dependant upon vasodilator prostaglandins
e.g. HF, liver cirrhosis
what 3 drugs in combination can cause acute renal failure
ACEI (or ARB), diuretic and NSAID
how is uric acid formed
catabolism of purines
