Drugs and the kidney Flashcards
Excretion of drugs by the kidney
Takes place in
- Glomerular filtration
- Tubular reabsorption
- Tubular secretion
Glomerular filtration of drugs
Some drugs may/may not bind to albumin. Only 20% of renal plasma flow is filtered in the glomerular. Glomerulus capillaries allow the drug of MW <20kDa to be filtered freely, but not when bound albumin.
What is the clinical importance of glomerular filtration for drugs?
Anti-coagulant drug warfarin
98% bound to albumin: 2% into the filtrate
Results in a long half -stay in the body along
Issues of toxicity with continued dosing - e.g. excess bleeding
Tubular secretion of drugs
Occurs mainly in the proximal tubule
Non-specific cation and anion transporters for charged drugs or metabolites
- Morphine (a weak base) - cation transporter
- Penicillin (weak acid) - anion transporter
Most drugs are weak acids or bases - degree of ionization depends on drug pKa and pH of the environment
Diuretics
An increase in urine output also produces Na (natriuresis)/ and K excretion (hypokalaemia).
Very important drugs - hypertension, acute pulmonary oedema, heart failure.
Increase in electrolyte excretion
Carbonic anhydrase inhibitors
Loop diuretics
Thiazides
K- sparing diuretics
Site 1 PCT
Reabsorption of Na with passive movement of organic molecules (glucose, amino acids) and water
Site 2 of PCT
Reabsorption of Na in exchange for H - the role of carbonic anhydrase
SIte 3 Loop of Henle
- Transport of NaCl by a co-transport for Na, K, 2Cl
- Thick ascending Loop of Henle is not permeable to water
- Interstitial fluid in this region becomes hypertonic
- Re-absorption of water from the collecting duct (controlled by ADH)
Site 4 DCT
Re-absorption of NA/Cl (co-transport), followed by water
Site 5 DCT
Na is reabsorbed (through ENaC channels) in exchange for K efflux (through K channels) - stimulated by aldosterone
Site 6 DCT
Another Na- H exchanger - also stimulated by aldosterone
Agents that mainly affect H2O excretion
Osmotic agents
Mannitol - usually administered i.v.
Inert substances, freely filtered but not reabsorbed
High concentrations - increases osmolarity in tubules - decreases reabsorption of water
Act at PCT, DCT, and collecting duct
Little effect on electrolyte excretion
Use of osmotic agents
Reduces intracranial and intraocular pressure
Prevent acute renal failure
Agents that affect electrolyte excretion
Carbonic anhydrase inhibitors
How does intracranial and intraocular pressure decrease?
Mannitol doesn’t enter the CNS- creates an osmotic gradient - water leaves the CNS (into plasma)
How do drugs reduce renal failure
Mannitol can prevent Anuria
Distal nephron can dry up when filtration is very low
How do osmotic agent affect electrolyte excretion
- Drugs increase urine flow by increasing excretion of Na (natriuresis)
- NaCl is the major determinant of extracellular fluid (ECF) volume
- Increase NaCl excretion - decrease ECF vol- decrease blood vol, decrease Cardiac output- decrease in oedema
Carbonic anhydrase inhibitors
Acetazolamide
Mild diuretics
Inhibits the activity of CA- decrease formation of protons in the luminal cells of PCT (site 2)
Loss of NaHCO3 into lumen - loss of water
Also used in non-renal effects - in glaucoma, aqueous humor formation is dependent on CA activity
Loop diuretics
Frusemide
Powerful diuretics with rapid effect
Inhibit Na/K/Cl co-transport at the thick ascending loop of Henle (site 3)
Decrease reabsorption of Na, K, and 2Cl - marked loss of these electrolytes
Prevents concentration of cortico-medullary interstitial fluid and therefore reduces effect of ADH on the collecting duct (less osmotic drive) - increase water loss
Uses of loop diuretics
Chronic heart failure - decrease ECFV, decrease CVP, decrease CO
Vasodilatation - by increase PGs in blood vessels
Acute renal failure- increase renal blood flow
Acute pulmonary oedema- decrease capillary pressure
Side effects of loop diuretics
Significant loss of K - hypokalemia Metabolic alkalosis (compensatory)
Thiazide drugs
Moderately powerful diuretics
Inhibit Na/Cl uptake via co-transporter at distal convoluted tubule
Compensation mechanisms
Site 5: Na uptake via ENaC- K excretion - K loss
Site 6: Na uptake via Na/H exchanger - H loss
Decrease BV - increase RAAS, increase aldosterone - increase Na reabsorption (site5/6) - increase K/H loss
Uses of thiazide
Treatment of hypertension diuresis causes decrease BV- decrease CO The major effect is causing vasodilation - decrease TPR Mild heart failure - decrease ECFV Oedema
Side effects of thiazide drugs
Hypokalaemia (loss of K)
Metabolic alkalosis (loss of H)
Hypercalcemia (increased Ca/Na exchanger)
Hypotension (too much vasodilation)
K- sparing diuretics
Weak diuretic action
Important as they cause K retention - counter the powerful electrolyte secretions of diuretics such as frusemide
Spironolactone
The competitive antagonist of aldosterone at sites 5 and 6. CVS diseases linked to overproduction of aldosterone - volume overload, e.g. heart failure
Amiloride
Blocks ENaC at site 5, Reduces Na reabsorption and K loss
Captopril
Inhibition of angiotensin-converting enzyme - decrease Ang 2 formation - Decrease aldosterone
NSAIDs
Prevent formation of prostaglandins (PGs) by inhibiting COX
PG are important for vasodilation in the afferent renal arterioles
Hence, COX and PGs formation is important for renal blood flow and GFR
Importantly: NSAIDs are contraindicated in renal failure
Exacerbate issues of poo GFR
Drugs that induce kidney damage
NSAIDs Radiocontrast agents Aminoglycosides (gentamicin) Lithium (bipolar disorders) Cyclosporine (anti - rejection) Chemotherapy drugs
