renal pharm Flashcards
outline the pathway of pharmacokinetics
- absorption (stomach, intestine if oral, SC, IM etc)
- distribution (blood)
- metabolism (liver/lungs)
- excretion (kidney, GIT?)
renal clearance of drugs is defined as
- volume of plasma containing the drug removed by the kidney per unit time
- calculated from plasma concentration, urinary concentration and rate of flow of urine
- varies greatly for different drugs (penicillin almost completely cleared from blood on a single transit through kidney)
what are the 3 fundamental processes of renal clearnace of drugs
- ultrafiltration: glomerulus = all solute plasma components
- secretion: proximal/distal tubule = H+, K+ uric acid and drugs
- resorption: proximal/distal tubule = glucose, amino acid, ions and water and passive reabsorption of lipophilic molecules (drugs)
explain how glomerular filtration impacts drug excretion
- drugs under 20kD will pass through glomerular capilaries into the filtrate
- most drugs are small and thus can cross glomerulus freely into tubular lumen
- however, heparin as a macromolecule is not renally cleared
- plasma albumin is largely impermeable, thus only free or unbound drug will be filtered, but a drug bound to albumin will have reduced clearance by filtration
- above is different if leaky (nephrotic syndrome)
explain how active tubular secretion is involved in renal excretion of drugs
- about 20% of renal plasma flow is filtered through the glomerulus
- thus 80% of the delivered drug will pass into the peri-tubular capillaries
- drugs can be transferred into tubular lumen by two independent and relatively non-selective carrier systems
- organic anion transporters for acidic drugs, against the electrochemical gradient
- organic cation transporters for organic basic drugs facilities down gradient
- potentially most effetive mechanism of renal elimination as can remove bound drug
- many drugs can compete for same transport system
explain how passive tubular resorption is involved in renal excretion of drugs
- drugs that cross membranes freely (small, lipid soluble) will be reabsorbed down the concentration gradient
- lipid soluble drugs are poorly excreted
- polar drugs remain in lumen and get progressively more concentrated as water is reabsorbed
- drug metabolites are often removed in this manner
- drug excretion is influenced by degree of ionisation and urinary pH1 creating an ion trapping effect
- acidic drigs are more rapidly excreted if urine is alkaline
- basic drugs are more reapidly excreted if urine is acidic
explain how aminoglycosides can damage the renal tubules
ca cause AKI in theory as renal tubular cells, particularly PCT, are vulnerable as they concentrate and reabsorb glomerular filtrate. they cause tubular cell toxicity by:
- acumulate in lysosome of PCT epithelial cells
- impair mitochondrial function thereby increasing oxidative stress and free radicals
- thus can interfere with tubular transport
- dogs are more sensitive than cats
before giving need to consider potential risk factors (dehydration) and consult IRIS for dose and duration
gentamycin
explain how NSAIDs interact with the kidney and cause damage to renal tubules
- kidney autoregulates intra-glomerular pressure by modulating the afferent and efferent arterial tone to preserve GFR and urine output
- prostaglandins normally dilate afferent arteriole
- NSAIDs are COXw inhibitors and thus BLOCK PG production
- thus NSAIDs may decrease blood flow to the kidneys and lack of oxygen would cause AKI
- ALSO cause AKI by inducing acute interstitial nephritis by inducing an immunological reaction after period of NSAID exposure leading to the presence of inflammatory cell infiltrate in the kidney interstitium
explain how renal dysfunction can impact renal excretion of drugs
- if GFR is low then drug clearance can be decreased
- drugs removed predominantly by renal excretion are libale to cause toxicity in elderly pts and those with renal dysfunction
- polar drugs remain in lumen and get progressively more concentrated
- if main route of elimination is kidney then these drugs need special care in patients with renal dysfunction
what are diuretics
- drugs that increase the rate of urine flow and excretion of Na+ and water from the filtrate
- the decrease the reabsorption of Na and usually Cl from the filtrate
- secondary to excretion of Na: increased water loss
under which circumstances may we need diuretics
- oedema
- acute renal failure
- forced diureses (intoxications)
- correct specific ion imbalances
list the different groups of diuretics
- osmotic diuretics
- loop diuretics
- thiazides
- amiloride
- spirolactone
what is the mechanism of action of osmotic diuretics
- pharmacologically inert substances
- compounds are filtered in glomerulus but cannot be reabsorbed
- the increase the osmolarity of the filtrate in PCT, descending limb and collecting ducts
- to maintain osmotic balance, water is retained in the urine
- the result is a decreased concentration of Na in the lumen (more water) and decreased reabsorption of Na
what is important to remember about the route of administration of osmotic diuretics
require IV administration
what are the indications for osmotic diuretics
- forced diuresis (intoxication, impending kidney failure)
- emergency tx of acutely raised intracranial or intraocular pressure
what is the mechanism of action of carbonic anhydrase inhibitors
- block reaction of CO2 with H2O
- thus prevent Na/H exchange and HCO3 ion reabsorption in prximal convoluted tubule and Na reabsorption is also reduced
- increased HCO3 in filtrate opposes water reabsorption
- diuretic effects in the PCT can be compensated in more distant part of the tubules
- bicarbonate is eliminated in the urine leading to systemic acidosis
- consequently plasma HCO3 also depletes which makes its diuretic effects self limiting
- used for glaucoma, idiopathic benign intracranial hypertension and altitude sickness
what is the mechanism of action of loop diuretics
- Na, K and Cl enter blood by a co-transport system
- loop diuretics act on NKCC2 symporter in the thick ascending limb of the LoH
- inhibit Na, Cl and K reabsorption thus causing diuresis with loss of electrolytes
- principal cells in the collecting ducts will respond to increased Na in urine by increasing K secretion in return for Na reabsorption
- transcellular voltage also falls thus paracellular Ca and Mg reabsorption also reduced
what is the mechanism of action of thiazides
- bind to the Cl site of the distal tubule NCC co-transport system
- act to inhibit Na reabsorption
- thus more Na delivered to collecting duct and some Na will be reabsorbed in exchange for K excretion
- less powerful than loop diuretics thus can be combined with a loop diuretic or potassium sparing diuretic in treating refractory fluid retention
- stimulate Ca re-absorption
what is the mechanism of action of potassium sparing diuretics
triamteren and amiloride
- directly blocks the epithelia Na (ENaC) channel
- inhibiting Na reabsorption in the collecting ducts
- this is linked with the apical K exchange
- promotes the loss of Na and water from the body but without depleting K
what is the mechanism of action of aldosterone antagonists
spirolactone
- tubule cells are impermeable to Na in the absence of aldosterone
- aldosterone acts on mineralcorticoid receptor within the collecting duct
- increased ENaC channel and Na/K ATPase expression
- increase Na and Cl reabsorption
- increase K and Ca excretion from renal tubules
- spirolactone competes with aldosterone at its receptor site and causes mild diuresis and potassium retention
compare and constrast all the diuretics
