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KBF- Kidney and Body Fluids > S2: Drugs on the Kidney > Flashcards

S2: Drugs on the Kidney Flashcards

1
Q

Explain the central role of the kidney in eliminating drugs

A
  • 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
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2
Q

Describe glomerular filtration of drugs

A
  • 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
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3
Q

What MW does gomerular capillaries allows drugs to be filtered freely?

A

<20kDa

Albumin is 68kDa

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4
Q

Explain the clinical important of the anti-coagulant drug warfarin at glomerulus

A

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

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5
Q

Describe tubular secretion of drugs

A
  • 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
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6
Q

Give an example of anion/cation transporter

A

· Cation transporter e.g. Morphine (weak base)

Anion transporter e.g. Penicillin (weak acid)

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7
Q

Explain clinical importance of penicillin and probenecid being administered together (tubular secretion of drugs)

A

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

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8
Q

Describe passive tubular re absorption of drugs

A
  • 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
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9
Q

What is an important determinant of passive reabsorption?

A

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

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10
Q

What does degree of ionisation of drug depend on?

A
  • pKa of drug

- pH of enviroment

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11
Q

Describe diuretics

A
  • 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
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12
Q

Mechanism of action of diuretics

A
  • 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.

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13
Q

Where is site 1 and 2?

A

PCT

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14
Q

Describe Na+ transport at site 1 and 2

A

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
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15
Q

Where is site 3?

A

Loop of Henle

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16
Q

Describe Na+ transport at site 3

A
  • 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)
17
Q

Where is site 4, 5 and 6?

A

DCT

18
Q

Describe Na+ transport at site 4,5 and 6

A

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

19
Q

Describe osmotic agents

Give an example

A

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

20
Q

Uses of Osmotic Agents

A
  • 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
21
Q

How do drugs increase urine flow?

A

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

22
Q

Describe carbonic anhydrase inhibitors

Give example
e.g. Acetazolamide

A
  • 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

23
Q

Describe loop diuretics

Give example

A
  • 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

24
Q

Uses of loop diuretics

A

· 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

25
Q

Side effects of loop diuretics

A 
· Significant loss of K-> hypokalaemia
Metabolic alkalosis (due to compensatory increase in Na/H exchanger, too much excretion of protons, see thiazides)
26
Q

Describe thiazide drugs

Give an example

A
  • Moderately powerful diuretics
  • Inhibit Na+/Cl- uptake via co-transporter at DCT (site 4)

e.g. bendrofluazide

27
Q

Compensatory mechanisms when using thiazide drugs

A

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

28
Q

Uses of thiazide drugs

A 
Treatment of hypertension 
Diuresis causes dec BV, dec CO
Major effect is causing vasodilatation , dec TPR
Mild heart failure , dec ECFV
Oedema
29
Q

Side effects of thiazide drugs

A

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)

30
Q

Describe K+ sparing diuretics

A
  • 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)
31
Q

Describe spironolactone

A
  • Competitive antagonist of aldosterone at sites 5 and 6

- CVS diseases linked to overproduction of aldosterone –> volume overload eg. Heart failure

32
Q

Describe Amiloride

A
  • Blocks ENaC at site 5

- Reduces Na+ reabsorption and K+ loss

33
Q

Describe captopril

A

Inhibition of angiotensin- converting enzyme - ¯ Ang II formation - ¯ aldosterone

34
Q

List drugs that induce kidney damage (nephrotoxic)

A 
· NSAIDs
· Radiocontrast  agents
·  Aminoglycosides (gentamicin)
· Lithium (bipolar disorder)
· Cyclosporine (anti-rejection)
Chemotherapy drugs
35
Q

Describe NSAIDs

A

· 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

KBF- Kidney and Body Fluids (14 decks)

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