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URI > Renal pharmacology > Flashcards

Renal pharmacology Flashcards

1
Q

List the different classes of drug that influence renal function

A
  • Carbonic anhydrase inhibitors
  • Loop diuretics
  • Thiazides
  • Aldosterone antagonists
  • Triamterene and amiloride
  • Osmotic diuretics
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2
Q

What are the different groups that diuretics can be split into?

A
  • Those acting specifically on cells of nephron by interfering with sodium transport from within tubules (except spironolactone)
  • Osmotic diuretics
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3
Q

What is the renal effect on half life of a drug?

A

Tubular reabsorption means longer half life as stays in body longer

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4
Q

What are diuretics?

A

Drugs that increase rate of urine flow and excretion of Na+ and water from the filtrate

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5
Q

Broadly, how do diuretics carry out their function?

A
  • Decrease reabsorption of Na+ (and usually also Cl- from filtrate)
  • Secondary to excretion of Na+ (natriuresis) have increased water loss (follows by osmosis)
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6
Q

When would diuretics be needed?

A
  • Oedema (cardiac, hepatic or renal origin)
  • Acute renal failure (restimulate renal function)
  • Forced diuresis to remove toxins
  • Correct specific ion imbalances
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7
Q

How do osmotic diuretics work?

A

Drugs of high osmolarity that draw water into the tubule via osmosis

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8
Q

What feedback mechanism is important for diuretic effect?

A
  • Tubuloglomerular

- Inverse relationship between GFR and Na+ concentration at macula densa

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9
Q

What causes tolerance to diuretics?

A
  • Increase in plasma angiotensin, renin and aldosterone
  • Compensatory activity in other parts of nephron
  • Decreased efficacy due to increase in RAAS
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10
Q

What might cause resistance to diuretics?

A
  • Reduced activity of kidney (age)
  • Competitive inhibition of tubular secretion (NSAID)
  • Haemodynamic changes (low GFR due to low blood pressure)
  • Increased renal NaCl reabsorption (hyperactivity of aldosterone disease)
  • Drugs competing with excretion diuretics, reduce effect and reduce diuretic effect
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11
Q

What is the main type diuretic used in vet med?

A

Loop diuretics

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12
Q

Where do carbonic anhydrase inhibitors exert their action?

A

Proximal tubule

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13
Q

What is the function of carbonic anhydrase?

A
  • Catalyses reaciton of H+ and HCO3- to H2O and CO2
  • Are absorbed, dissociate back to H+ and HCO3-
  • Thus carbonic anhydrase supplies the H+ ions needed for the Na+ H+ antiport in order to reabsorb sodium
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14
Q

How does carbonic anhydrase inhibitor exert its action?

A
  • Leads to deficiency of intracellular H+, less Na+ reabsorbed
  • Na+ still out alongside bicarbonate on basolateral side
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15
Q

What is the effect of bicarbonate loss through action of carbonic anhydrase inhibitor?

A
  • Acidosis
  • Increase in H+
  • Self limiting
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16
Q

What are carbonic anhydrase inhibitors commonly used to treat?

A
  • Glaucoma
  • Epilepsy
  • Benign intracranial hypertension
  • Altitude sickness
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17
Q

Where do loop diuretics exert their action?

A

Thick ascending limb of loop of Henle

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18
Q

What is the action of loop diuretics?

A
  • Inhibit liminal transport of sodium ini the NaK2Cl pump
  • Thus strong diuretic effect
  • Loss of Na, Cl and water
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19
Q

How do loop diuretics get into the tubule?

A
  • Strongly bound to plasma protein so do not pass directly into glomerular filtrate
  • Secreted in proximal convoluted tubule by organic acid transport mechanism
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20
Q

What are the beneficial haemodynamic effects of loop diuretics, prior to the onset of diuresis?

A
  • Vasodilation increasing renal blood flow

- Thus increases renal perfusion and lessens fluid retention

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21
Q

Where do thiazides exert their action?

A

Distal tubule (proximal part)

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22
Q

What is the effect of thiazides?

A

Inhibition of sodium reabsorption and promotion of potassium secretion

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23
Q

What are the benefits of thiazides?

A
  • Act on different sites of renal tubule than other diuretics so can be combined with loop diuretic or potassium sparing diuretic in treating refractory fluid retention
  • Better tolerated than loop diuretics
  • Reduce Ca2+ excretion limiting osteoporosis
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24
Q

Why are thiazides better tolerated than loop diuretics?

A
  • Loss of volume not as strong
  • No rebound effect
  • Reactivation of RAAS
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25
Q

How do thiazides exert their action

A
  • Bind to Cl- site of distal tubular Na+/Cl- cotransport system, inhibiting its action
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26
Q

What are triamterene and amiloride?

A

Potassium sparing diuretics

27
Q

Where do triamterene and amiloride exert their action?

A

Distal convoluted tubules and collecting duct

28
Q

How do triamterene and amiloride exert their action?

A
  • Block ENaC channels preventing uptake of Na+

- Little effect on potassium

29
Q

Where do aldosterone antagonists exert their action?

A

Collecting ducts

30
Q

How do aldosterone antagonists work as diuretics?

A
  • Cell impermeable to Na+ in absence of aldosterone
  • Inhibit effect of channels and inhibit production of proteins that stimulate those channels
  • Spironolactone competes with aldosterone at its receptor site causing mild diuresis and potassium retention
31
Q

What is the effect of aldosterone antagonists?

A
  • Decrease sodium and chloride reabsorption, decrease potassium and calcium excretion
32
Q

Where do osmotic diuretics carry out their function?

A
  • Parts of nephrone freely permeable to water
  • Proximal tubule
  • Descending limb of LoH
  • Collecting tubules
33
Q

How do osmotic diuretics carry out their function?

A
  • Are large, pharmacologically inert substanes, that can get into ultrafiltrate
  • Increase osmolarity of filtrate
  • Water drawn into urine to maintain osmotic balance
34
Q

What is the result of using osmotic diuretics?

A
  • Decreased concentration of Na+ in lumen (more water)

- Thus decreased reabsorption of sodium

35
Q

What are some negative effects of thiazides?

A
  • Increase in urinary frequency
  • Erectile dysfunction
  • Potassium loss
  • Impaired gucose tolerance
  • Hyponatraemia
36
Q

Explain the paradoxical effect of thiazides in diabetes insipidus

A
  • Reduce volume of urine by interfering with production of hypotonic fluid in distal tubule
  • Reduce ability of kidney to excrete hypotonic urine
37
Q

How are thiazides excreted?

A

By tubular secretion

38
Q

When are aldosterone antagonists used?

A
  • With K+ -losing diuretics to prevent K+ loss
  • Heart failure
  • Primary hyperaldosteronism
  • Secondary hyperaldosteronism
  • Resistant essential hypertension
39
Q

What are some negative effects of aldosterone antagonists?

A
  • Hyperkalaemia
  • Should not be used with K+ supplements, ACE inhibitors, angiotensin receptor antagonists or beta-adrenoceptor antagonists
  • GI disturbances
  • Gynaecomastia, mentrual disorders, testicular atrophy
40
Q

What are some unwanted effects of triamterene and amiloride?

A
  • Mainly hyperkalaemia
  • Dangerous in patients with renal impairment or receiving other drugs increasing plasma K+
  • GI disturbances
  • Triamterene in kidney stones
41
Q

What are some unwanted effects of diuretics?

A
  • Transient expansion of extracellular fluid volume (risk of precipitating left ventricular failure)
  • Hyponatraemia
  • Headache, nausea, vomiting
42
Q

What are some unwanted effects of loop diuretics?

A
  • Excesive Na+ and water loss (hypovolaemia and hypotension)
  • Hypokalaemia
  • Metabolic alkalosis
43
Q

What are the 3 fundamental processes that account for renal drug excretion?

A
  • Glomerular filtration
  • Active tubular secretion
  • Passive reabsorption across epithelium
44
Q

Describe glomerular filtration in the excretion of drugs

A
  • Only molecules below 20kDa
  • Plasma albumin cannot pass through
  • Most drugs pass barrier freely
  • If bound to albumin, only free drug filtered
45
Q

Describe active tubular secretion in renal excretion of drugs using organic anion transportes

A
  • Transports acidic drugs in negatively charged anionic form
  • Transports drug molecules against electrochemical gradient
  • Therefore reduces plasma concentration to nearly 0
46
Q

Describe active tubular secretion in renal excretion of drugs using organic cation transport

A
  • Handles organic bases in protonated cationic form

- Facilitates transport down electrochemical gradient

47
Q

Where does the majority of renal drug elimination occur? Why?

A
  • Proximal tubule

- 80% of drug delivered to kidney presented to carrier

48
Q

Why do drug interactions occur with respect to the kidney?

A
  • Many drugs compete for the same transport systems

- May lead to prolonging of action of another as prevents tubular secretion

49
Q

Describe passive diffusion across the tubular epithelium in renal secretion of drugs for excretion

A
  • Water reabsorbed as fluid traverses tubule
  • If drug freely permeable to drug molecules, 99% of filtered drug will be reabsorbed passively down resulting concentration gradient
50
Q

Describe the excretion of lipid soluble drugs

A

Excreted poorly

51
Q

Describe the excretion of polar drugs of low tubular permeability

A
  • Remain in lumen
  • Become progressively concentrated as water is reabsorbed
  • E.g. digoxin
52
Q

How does the ion trapping effect relate to drug excretion?

A
  • Basic drugs more rapidly excreted in an acid urine that favours charged form, thus inhibits reabsorption
  • Acidic drugs more rapidly excreted if urine is alkaline
53
Q

Explain how the ionisation of a drug affects the renal elimination

A
  • Fat soluble drugs metabolised in liver
  • First step: oxidation, reduction and hydrolysis
  • Second step: conjugation to allow inactive and polar products to be readily excreted in urine
54
Q

What are aminoglycosides?

A

Antibiotics of complex chemical structure

- Gentamycin, streptomycin, amikacin, tobramycin, neomycin

55
Q

How do aminoglycosides work?

A

Inhibit bacterial protein synthesis

56
Q

Describe the structure of aminoglycosides

A
  • Polycations = highly polar
57
Q

Describe the elimination of aminoglycosides

A

Almost entirely by glomerular filtration in kidney

58
Q

What can be caused by aminoglycosides if renal function is impaired?

A
  • Rapid accumulation

- Increase in toxic effects e.g. ototoxicity and nephrotoxicity that are dose related

59
Q

Describe nephrotoxocity with aminoglycosides

A
  • Consists of damage to kidney tubules
  • Pre-existing renal disease or conditions where urine volume is reduced increase chance
  • Concomittant use of other nephrotoxic agents
  • nephrotoxic action impairs own excretion
  • Reversible when remove
60
Q

Describe nephropathy in relation to analgesics

A
  • Following long term high dose regimes of NSAIDs

- Often irreversible

61
Q

What are the main ways in which a drug can affect the rate of renal excretion of another?

A
  • Altering protein binding and hence filtration
  • Inhibiting tubular secretion
  • Altering urine flow and/or urine pH
62
Q

Explain the consequences of inhibition of tubular secretion on a drug

A
  • Prolong action of drug
  • Enhance actions of substances that rely on tubular secretion for elimination (probenecid-like effect)
  • Inhibition of secretion of diuretics into tubular fluid (e.g. by NSAIDs) decreases their function
63
Q

Explain the consequences of altering urine flow and pH on secretion of a drug

A
  • Diuretics increase urinary excretion of other drugs and their metabolites
  • Loop and thiazide: increase proximal tubular reabsorption of lithium = lithium toxicity where treated with lithium carbonate
  • Effect of urinary pH on excretion utilised in treatment of salicylate poisoning, not cause of accidental interactions

URI (15 decks)

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