Renal pharmacology Flashcards
List the different classes of drug that influence renal function
- Carbonic anhydrase inhibitors
- Loop diuretics
- Thiazides
- Aldosterone antagonists
- Triamterene and amiloride
- Osmotic diuretics
What are the different groups that diuretics can be split into?
- Those acting specifically on cells of nephron by interfering with sodium transport from within tubules (except spironolactone)
- Osmotic diuretics
What is the renal effect on half life of a drug?
Tubular reabsorption means longer half life as stays in body longer
What are diuretics?
Drugs that increase rate of urine flow and excretion of Na+ and water from the filtrate
Broadly, how do diuretics carry out their function?
- Decrease reabsorption of Na+ (and usually also Cl- from filtrate)
- Secondary to excretion of Na+ (natriuresis) have increased water loss (follows by osmosis)
When would diuretics be needed?
- Oedema (cardiac, hepatic or renal origin)
- Acute renal failure (restimulate renal function)
- Forced diuresis to remove toxins
- Correct specific ion imbalances
How do osmotic diuretics work?
Drugs of high osmolarity that draw water into the tubule via osmosis
What feedback mechanism is important for diuretic effect?
- Tubuloglomerular
- Inverse relationship between GFR and Na+ concentration at macula densa
What causes tolerance to diuretics?
- Increase in plasma angiotensin, renin and aldosterone
- Compensatory activity in other parts of nephron
- Decreased efficacy due to increase in RAAS
What might cause resistance to diuretics?
- 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
What is the main type diuretic used in vet med?
Loop diuretics
Where do carbonic anhydrase inhibitors exert their action?
Proximal tubule
What is the function of carbonic anhydrase?
- 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
How does carbonic anhydrase inhibitor exert its action?
- Leads to deficiency of intracellular H+, less Na+ reabsorbed
- Na+ still out alongside bicarbonate on basolateral side
What is the effect of bicarbonate loss through action of carbonic anhydrase inhibitor?
- Acidosis
- Increase in H+
- Self limiting
What are carbonic anhydrase inhibitors commonly used to treat?
- Glaucoma
- Epilepsy
- Benign intracranial hypertension
- Altitude sickness
Where do loop diuretics exert their action?
Thick ascending limb of loop of Henle
What is the action of loop diuretics?
- Inhibit liminal transport of sodium ini the NaK2Cl pump
- Thus strong diuretic effect
- Loss of Na, Cl and water
How do loop diuretics get into the tubule?
- Strongly bound to plasma protein so do not pass directly into glomerular filtrate
- Secreted in proximal convoluted tubule by organic acid transport mechanism
What are the beneficial haemodynamic effects of loop diuretics, prior to the onset of diuresis?
- Vasodilation increasing renal blood flow
- Thus increases renal perfusion and lessens fluid retention
Where do thiazides exert their action?
Distal tubule (proximal part)
What is the effect of thiazides?
Inhibition of sodium reabsorption and promotion of potassium secretion
What are the benefits of thiazides?
- 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
Why are thiazides better tolerated than loop diuretics?
- Loss of volume not as strong
- No rebound effect
- Reactivation of RAAS
How do thiazides exert their action
- Bind to Cl- site of distal tubular Na+/Cl- cotransport system, inhibiting its action
What are triamterene and amiloride?
Potassium sparing diuretics
Where do triamterene and amiloride exert their action?
Distal convoluted tubules and collecting duct
How do triamterene and amiloride exert their action?
- Block ENaC channels preventing uptake of Na+
- Little effect on potassium
Where do aldosterone antagonists exert their action?
Collecting ducts
How do aldosterone antagonists work as diuretics?
- 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
What is the effect of aldosterone antagonists?
- Decrease sodium and chloride reabsorption, decrease potassium and calcium excretion
Where do osmotic diuretics carry out their function?
- Parts of nephrone freely permeable to water
- Proximal tubule
- Descending limb of LoH
- Collecting tubules
How do osmotic diuretics carry out their function?
- Are large, pharmacologically inert substanes, that can get into ultrafiltrate
- Increase osmolarity of filtrate
- Water drawn into urine to maintain osmotic balance
What is the result of using osmotic diuretics?
- Decreased concentration of Na+ in lumen (more water)
- Thus decreased reabsorption of sodium
What are some negative effects of thiazides?
- Increase in urinary frequency
- Erectile dysfunction
- Potassium loss
- Impaired gucose tolerance
- Hyponatraemia
Explain the paradoxical effect of thiazides in diabetes insipidus
- Reduce volume of urine by interfering with production of hypotonic fluid in distal tubule
- Reduce ability of kidney to excrete hypotonic urine
How are thiazides excreted?
By tubular secretion
When are aldosterone antagonists used?
- With K+ -losing diuretics to prevent K+ loss
- Heart failure
- Primary hyperaldosteronism
- Secondary hyperaldosteronism
- Resistant essential hypertension
What are some negative effects of aldosterone antagonists?
- Hyperkalaemia
- Should not be used with K+ supplements, ACE inhibitors, angiotensin receptor antagonists or beta-adrenoceptor antagonists
- GI disturbances
- Gynaecomastia, mentrual disorders, testicular atrophy
What are some unwanted effects of triamterene and amiloride?
- Mainly hyperkalaemia
- Dangerous in patients with renal impairment or receiving other drugs increasing plasma K+
- GI disturbances
- Triamterene in kidney stones
What are some unwanted effects of diuretics?
- Transient expansion of extracellular fluid volume (risk of precipitating left ventricular failure)
- Hyponatraemia
- Headache, nausea, vomiting
What are some unwanted effects of loop diuretics?
- Excesive Na+ and water loss (hypovolaemia and hypotension)
- Hypokalaemia
- Metabolic alkalosis
What are the 3 fundamental processes that account for renal drug excretion?
- Glomerular filtration
- Active tubular secretion
- Passive reabsorption across epithelium
Describe glomerular filtration in the excretion of drugs
- Only molecules below 20kDa
- Plasma albumin cannot pass through
- Most drugs pass barrier freely
- If bound to albumin, only free drug filtered
Describe active tubular secretion in renal excretion of drugs using organic anion transportes
- Transports acidic drugs in negatively charged anionic form
- Transports drug molecules against electrochemical gradient
- Therefore reduces plasma concentration to nearly 0
Describe active tubular secretion in renal excretion of drugs using organic cation transport
- Handles organic bases in protonated cationic form
- Facilitates transport down electrochemical gradient
Where does the majority of renal drug elimination occur? Why?
- Proximal tubule
- 80% of drug delivered to kidney presented to carrier
Why do drug interactions occur with respect to the kidney?
- Many drugs compete for the same transport systems
- May lead to prolonging of action of another as prevents tubular secretion
Describe passive diffusion across the tubular epithelium in renal secretion of drugs for excretion
- 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
Describe the excretion of lipid soluble drugs
Excreted poorly
Describe the excretion of polar drugs of low tubular permeability
- Remain in lumen
- Become progressively concentrated as water is reabsorbed
- E.g. digoxin
How does the ion trapping effect relate to drug excretion?
- 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
Explain how the ionisation of a drug affects the renal elimination
- 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
What are aminoglycosides?
Antibiotics of complex chemical structure
- Gentamycin, streptomycin, amikacin, tobramycin, neomycin
How do aminoglycosides work?
Inhibit bacterial protein synthesis
Describe the structure of aminoglycosides
- Polycations = highly polar
Describe the elimination of aminoglycosides
Almost entirely by glomerular filtration in kidney
What can be caused by aminoglycosides if renal function is impaired?
- Rapid accumulation
- Increase in toxic effects e.g. ototoxicity and nephrotoxicity that are dose related
Describe nephrotoxocity with aminoglycosides
- 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
Describe nephropathy in relation to analgesics
- Following long term high dose regimes of NSAIDs
- Often irreversible
What are the main ways in which a drug can affect the rate of renal excretion of another?
- Altering protein binding and hence filtration
- Inhibiting tubular secretion
- Altering urine flow and/or urine pH
Explain the consequences of inhibition of tubular secretion on a drug
- 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
Explain the consequences of altering urine flow and pH on secretion of a drug
- 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
