S2: Drugs on the Kidney Flashcards
Explain the central role of the kidney in eliminating drugs
- Eliminating drugs from body in urine
- Some drugs are excreted unchanged e.g. aspirin
- Most drugs are metabolised by liver to an inactive compound which can be excreted by the kidney
- Kidney excretes polar (charged) drugs more readily that non-polar (uncharged) drugs
- Non polar drugs can be reabsorbed by kidney
- Kidney function affects the action of drugs so it needs to be taken into account when prescribing
Describe glomerular filtration of drugs
- Drug may or may not bind to albumin
- Drugs bound to albumin are held in the circulation because they have high molecular weight when bound and cannot be filtered
What MW does gomerular capillaries allows drugs to be filtered freely?
<20kDa
Albumin is 68kDa
Explain the clinical important of the anti-coagulant drug warfarin at glomerulus
98% bound to albumin and 2% is filtered into filtrate
This results in a long half life so warfarin stays in the body for a long time. This means that there are issues of toxicity with continued dosing – e.g. excess bleeding
Describe tubular secretion of drugs
- This occurs in the PCT
- Transporters are non specific and they bind to any cation and anion drug
- These transporters can become saturated e.g. when taking too many drugs
Give an example of anion/cation transporter
· Cation transporter e.g. Morphine (weak base)
Anion transporter e.g. Penicillin (weak acid)
Explain clinical importance of penicillin and probenecid being administered together (tubular secretion of drugs)
Penicillin (antibiotic) and Probenecid (removes uric acid, treat gout)
Competition can occur between drugs at these transporters (as they are non-specific, no selective binding sites)
· This causes side effects because the individual is overdosing on drugs and they are not being secreted
· Half-life of penicillin is increased – both act at anion transporters
Describe passive tubular re absorption of drugs
- Reabsorption of H2O increases concentration of drug in tubular filtrate
- This increases drug concentration gradient for reabsorption bacl into the blood plasma from filtrate
- Occurs mainly in proximal and distal convoluted tubule
What is an important determinant of passive reabsorption?
Urinary pH is an important determinant of passive re-absorption (whether drug is excreted or reabsorbed). pH determines ionisation whether it is a weak acid or base and can be used to ‘trap’ drugs.
· Uncharged or unionised drugs are (lipophilic) and they cross lipid membrane
· Charged or ionised drugs are (lipophobic) and they need transporter to cross lipid membrane
· Most drugs are weak acids or bases
What does degree of ionisation of drug depend on?
- pKa of drug
- pH of enviroment
Describe diuretics
- Diuretics cause an increase in urine output (diuresis)
- Many diuretics also produce increased Na+ (natriuresis) / and K+ excretion (hypokalaemia)
- Very important drugs – hypertension, acute pulmonary oedema, heart failure
Mechanism of action of diuretics
- Diuretic agents act a specific sites (1-6) of nephron and collecting ducts
Diuretics block Na+ transporters so less Na+is reabsorbed and more remains in tubule. Water therefore follows so volume of filtrate and eventually urine increases.
Where is site 1 and 2?
PCT
Describe Na+ transport at site 1 and 2
Site 1: Reabsorption of Na+ with passive movement of organic molecules (glucose, AA) and H2O
e.g. Na+ and glucose symporter
Site 2: Reabsorption of Na in exchange for H+ (Na/H antiport) - role of carbonic anhydrase providing H+
- Higher concentration of Na+ inside tubular cell and this is transported into intersititial fluid with HCO3- (sodium bicarbonate symporter)
- In lumen, protons are pumped out and combine with bicarbonate to make carbonic acid and carbonic anhydrase eventually forms bicarbonate inside tubular cell
Where is site 3?
Loop of Henle
Describe Na+ transport at 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)
Where is site 4, 5 and 6?
DCT
Describe Na+ transport at site 4,5 and 6
Site 4: Reabsorption of Na+/Cl- cotransporter followed by H2O
Site 5: Na+ is reabsorbed through ENaC channels in exchange for K+ efflux through K+ channels - this is all stimulated by aldosterone
Site 6: Another Na+ and H+ exchanger stimulated by aldosterone
Describe osmotic agents
Give an example
Agents that mainly affect H2O excretion
- Usually administered i.v.
- Inert substances, freely filtered but not reabsorbed
- Acts at PCT, DCT and collecting ducts
- Little effect on electrolyte excretion
High concentrations of osmotic agents increases osmolarity in tubules and decreases reabsorption of water
Example: Mannitol
Uses of Osmotic Agents
- Reduce intracranial and intraocular pressure
- Give 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 increase urine flow?
Drugs increase urine flow by increasing excretion of Na (natriuresis) where Na goes, H2O follows (osmosis).
NaCl is the major determinant of ECFV
Increase in NaCl excretion –> decrease ECFV –> decrease blood volume –> decrease CO –> decrease oedema
Describe carbonic anhydrase inhibitors
Give example
e.g. Acetazolamide
- Mild diuretics due to potency and amount of Na+ uptake
- Inhibit the activity of CA decreases formation of protons in the luminal cells of PCT (site 2)
- Loss of NaHCO3 into lumen leads to loss of H2O
e.g. Acetazolamide
Describe loop diuretics
Give example
- Powerful diuretics with rapid effect (i.v.)
- Inhibit Na/K/Cl cotransporter at thick ascending LoH (site 3)
Dec Reabsorption of Na, K, and 2Cl – marked loss of these electrolytes
Prevents concentration (reduce osmolarity) of cortico-medullary interstitial fluid and therefore reduces effect of ADH on the collecting duct (less osmotic drive) - inc H2O loss
e.g. Frusemide
Uses of loop diuretics
· Chronic heart failure - dec ECFV, dec ECFV, dec congestion
· Vasodilatation – by increase PCl2 in blood vessels
· Acute renal failure - inc renal blood flow
Acute pulmonary oedema - dec Capillary pressure
Side effects of loop diuretics
· Significant loss of K-> hypokalaemia Metabolic alkalosis (due to compensatory increase in Na/H exchanger, too much excretion of protons, see thiazides)
Describe thiazide drugs
Give an example
- Moderately powerful diuretics
- Inhibit Na+/Cl- uptake via co-transporter at DCT (site 4)
e.g. bendrofluazide
Compensatory mechanisms when using thiazide drugs
Compensation mechanisms:
Site 5: Na uptake via ENaC - K excretion – K loss
Site 6: Na uptake via Na/H exchanger – H loss
Dec BV , inc RAAS, inc aldosterone, inc Na re-absorption (sites 5/6) - inc K/H loss
Uses of thiazide drugs
Treatment of hypertension Diuresis causes dec BV, dec CO Major effect is causing vasodilatation , dec TPR Mild heart failure , dec ECFV Oedema
Side effects of thiazide drugs
Some are due to compensatory mechanisms
Hypokalaemia (loss of K)
Metabolic alkalosis (loss of H)
Hypercalcemia (Increased Ca/Na exchanger as more Na+ in tubular fluid due to Na/Cl channel blocked )
Hypotension (too much vasodilatation)
Describe K+ sparing diuretics
- Weak diuretic action
- Important as they cause K+ retention which counter the powerful electrolyte secretions of diuretics such as frusemide
- Act at the end of DCT and collecting duct (sites 5+6)
Describe spironolactone
- Competitive antagonist of aldosterone at sites 5 and 6
- CVS diseases linked to overproduction of aldosterone –> volume overload eg. Heart failure
Describe Amiloride
- Blocks ENaC at site 5
- Reduces Na+ reabsorption and K+ loss
Describe captopril
Inhibition of angiotensin- converting enzyme - ¯ Ang II formation - ¯ aldosterone
List drugs that induce kidney damage (nephrotoxic)
· NSAIDs · Radiocontrast agents · Aminoglycosides (gentamicin) · Lithium (bipolar disorder) · Cyclosporine (anti-rejection) Chemotherapy drugs
Describe NSAIDs
· NSAIDs prevent formation of prostaglandins (PGs) by inhibiting COX
· PGs are important for vasodilatation 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 poor GFR
