Drugs and the kidney Flashcards
What are most drugs converted to in the kidney in order to be excreted?
An inactive compound
Does the kidney excrete more polar drugs more readily than non-polar drugs?
Yes
Can non-polar drugs be reabsorbed by the kidney?
Non-polar (uncharged drugs) can be reabsorbed by kidney
What drugs can pass through the GF?
What is the clinical importance
Glomerular capillaries allow drugs of MW < 20kDa to be filtered freely, but not when bound on albumin (albumin MW ~ 68kDa
Clinical importance
Anti-coagulant drug warfarin
98% bound to albumin : 2% into filtrate
This results in a long half-life – stays in the body a long time
Issues of toxicity with continued dosing – e.g. excess bleeding
Which part of the kidney does the secretion of drugs occur?
Occurs mainly in proximal tubule
What transports charged drugs?
Give some examples
What does ionisation depend on?
Non-specific cation and anion transporters for charged drugs or metabolites, e.g.
Morphine (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 environment
What are diuretics?
What other effects can diuretics cause?
Diuretics cause an increase in urine output (diuresis)
Many diuretics also produce increased
Na (natriuresis) / and K excretion (hypokalaemia)
What are the side effects of diuretics?
Very important drugs – hypertension, acute pulmonary oedema, heart failure
What are the 2 major groups of diuretics and what do they cause?
Mainly affect H2O excretion:
Water
Ethanol (Decreases ADH release)
Osmotic diuretics
Increase in electrolyte excretion: Carbonic anhydrase inhibitors Loop diuretics Thiazides K- sparing diuretics
Describe the mechanism of action of diuretics
Site 1:
Re-absorption of Na with passive movement of organic molecules (glucose, amino acids) and H2O
Site 2:
Re-absorption of Na in exchange for H - Role of carbonic anhydrase
Site 3:
Transport of NaCl by a co- transporter for Na, K, 2Cl
Thick ascending Loop of Henle is NOT permeable to H2O
Interstitial fluid in this region becomes hypertonic
Re-absorption of H2O from the collecting duct (controlled by ADH)
Distal Convoluted Tubule (DCT)
Site 4: Re-absorption of Na/Cl (co-transporter), followed by H2O
Site 5: Na is reabsorbed (through ENaC channels) in exchange for K efflux (through K channels) - stimulated by aldosterone
Site 6: Another Na-H exchanger - also stimulated by aldosterone
Mannitol - an agent that mainly affects water excretion
Is it filtered and reabsorbed?
What does it cause at high concentrations?
Where does it act?
Inert substances, freely filtered but not reabsorbed
High concentrations -> Osmolarity in tubules -> Reabsorption of H2O
Acts at PCT, DCT, and collecting duct
Little effect on electrolyte excretion
What are the uses of agents that mainly affect water excretion (mannitol)?
Uses
Reduce intracranial and intraocular pressure
Mannitol does not enter the CNS -> creates an osmotic gradient
-> H2O leaves the CNS (into plasma)
Prevent acute renal failure
Mannitol can prevent ANURIA
Distal nephron can dry up when filtration is very low
Excretion of some types of poisoning
How do drugs that excrete Na cause water to follow?
Drugs increase urine flow by increasing excretion of Na (natriuresis) – where Na goes -> H2O follows (osmosis)
How can an increase in NaCl excretion decrease oedema?
Inc NaCl excretion ECF vol Blood vol Cardiac output Oedema
How do Carbonic anhydrase inhibitors work?
Mild diuretics
Inhibit the activity of CA - decrease formation of protons in the luminal cells of PCT (Site 2)
Loss of NaHCO3 into lumen - loss of H2O
Also used in non-renal effects - in glaucoma, aqueous humor formation is dependent on CA activity
What are loop diuretics and how do they work?
What do they prevent?
Loop diuretics e.g. Frusemide
Powerful diuretics with rapid effect (i.v.)
Inhibit Na/K/Cl co-transporter at thick ascending loop of Henle (Site 3)
Decreases 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) - H2O loss
What are the uses of loop diuretics?
How do they cause vasodilation?
How do they treat acute renal failure?
How do they treat acute pulmonary oedema?
Chronic heart failure - Decreases ECFV, CVP and CO
Vasodilatation – by increase PGs in blood vessels
Acute renal failure - Increases renal blood flow
Acute pulmonary oedema - Decreases Capillary pressure
What are the side effects of LD?
Significant loss of K -> hypokalaemia Metabolic alkalosis (compensatory, see thiazide)
What are Thiazide drugs e.g. Bendrofluazide and how do they work?
What do they inhibit?
Compensation mechanisms
What does them decreasing blood volume leads to?
Moderately powerful diuretics
Inhibit Na/Cl uptake via co-transporter at distal convoluted tubule (Site 4)
Compensation mechanisms:
Site 5: Na uptake via ENaC - K excretion – K loss
Site 6: Na uptake via Na/H exchanger – H loss
Decreases BV, increases RAAS, increases aldosterone increases Na re-absorption (sites 5/6) - increases K/H loss
What are the uses of Thiazide drugs?
How do they treat hypotension?
How do they treat mild heart failure?
What are the side effects?
Treatment of hypertension
Diuresis causes decreases BV and CO
Major effect is causing vasodilatation DECREASES TPR
Mild heart failure - DECREASES ECFV
Oedema
Side effects Hypokalaemia (loss of K) Metabolic alkalosis (loss of H) Hypercalcemia (Increased Ca/Na exchanger) Hypotension (too much vasodilatation
What are K- sparing diuretics?
Where do they act?
Weak diuretic action
Important as they cause K retention- counter the powerful electrolyte secretions of diuretics such as frusemide
Act at end of DCT and collecting duct (Sites 5 + 6)
How do these drugs work?
Spironolactone
Amiloride
Captopril
Spironolactone Competitive antagonist of aldosterone at sites 5 and 6 CVS diseases linked to overproduction of aldosterone -> volume overload, e.g. Heart failure tion - Decreases aldosterone
