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2MBChB Renal > Pharmacology > Flashcards

Pharmacology Flashcards

1
Q

Which drug classes act on the kidney?

A

Diuretics.

Vasopressin (ADH) receptor agonists and antagonists.

Inhibitors of sodium-glucose cotransporter 2 (SGLT2).

Uricosuric drugs (promoting excretion of uric acid into the urine).

Renal failure drugs.

Drugs that alter urine pH.

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2
Q

What are the mechanisms by which diuretics work?

A

Increase urine flow, normally by inhibiting the reabsorption of electrolytes (mainly sodium salts) at various sites in the nephron.

Are used to enhance excretion of salt and water in conditions where an increase in the volume of extracellular fluid (i.e. oedema) causes tissue swelling.

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3
Q

Which disease states increase hydrostatic pressure in capillaries or decrease plasma oncotic pressure?

A

Nephrotic syndrome.

Congestive heart failure.

Hepatic cirrhosis with ascites.

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4
Q

How does oedema occur?

A

Results from an imbalance between the rate of formation and absorption of interstitial fluid.

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5
Q

How does congestive heart failure arise?

A

Arises from reduced cardiac output and subsequent renal hypoperfusion that activates the RAAS.

Expansion of blood volume contributes to increased venous and capillary pressures that combined with reduced plasma oncotic pressure, causes pulmonary and peripheral oedema.

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6
Q

How does hepatic cirrhosis with ascites occur?

A

Increased pressure in the hepatic portal vein, combined with decreased production of albumin, causes loss of fluid into the peritoneal cavity and oedema (ascites).

Activation of the RAAS occurs in response to decreased circulating volume.

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7
Q

What are the major sites of diuretic actions in the kidney?

A

Proximal convoluted tubule:

  1. Na+ (passive Cl- absorption).
  2. Na+/H+ exchange (blocked by carbonic anhydrase inhibitors).

Thick ascending limb of the loop of Henle:

  1. Na+/K+/2Cl- co-transport (blocked by loop diuretics) - 25% Na absorption.

Early distal convoluted tubule:

  1. Na+/H+ exchange (blocked by carbonic anhydrase inhibitors).
  2. Na+/Cl- co-transport (blocked by thiazide diuretics) - 5-10% modest diuresis.

Collecting tubule and duct:

  1. Na+/K+ exchange (blocked by potassium-sparing diuretics).
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8
Q

Where is the site of action of most diuretics?

A

Apical membrane of tubular cells.

Thiazides, loop agents, some potassium-sparing agents.

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9
Q

What are the pharmacodynamics of loop diuretics?

A

Inhibit the Na+/K+/2Cl- transporter by binding to the Cl- site and thus:

  • Decrease the tonicity of the interstitium of the medulla.
  • Prevent dilution of the filtrate in the thick ascending limb.
  • Increase the load of Na+ delivered to distal regions of the nephron (causing K+ loss).
  • Increase excretion of Ca2+ and Mg2+.
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10
Q

What are the pharmacokinetics of loop diuretics?

A

Absorbed from the G.I. tract, but subject to variation in CHF.

Strongly bind to plasma protein.

Enter nephron by the OAT mechanism.

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11
Q

What are the clinical indications for using loop diuretics?

A

To reduce salt and water overload associated with:

  • Acute pulmonary oedema (IV) – with oxygen and nitrates.
  • Chronic heart failure.
  • Chronic kidney failure.
  • Hepatic cirrhosis with ascites.
  • Nephrotic syndrome – however, proteinuria may reduce effectiveness.

To increase urine volume in acute kidney failure.

To treat hypertension [in patients resistant to other diuretics (thiazides are generally preferred) or anti-hypertensive drugs - usually in the presence of renal insufficiency].

To reduce acute hypercalcaemia.

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12
Q

What are the contraindications of loop diuretics?

A

Severe hypovolaemia.

Dehydration.

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13
Q

What are the cautions for using loop diuretics?

A

Severe hypokalaemia and/or hyponatraemia.

Hepatic encephalopathy.

Gout.

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14
Q

What are the main adverse effects of loop diuretics?

A

Causes low electrolyte states: hypokalaemia, metabolic alkalosis, hypocalcaemia, hypomagnesaemia.

Hypovolaemia and hypotension (particularly in the elderly).

Hyperuricemia.

Dose-related loss of hearing.

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15
Q

What are the pharmacodynamics of thiazide diuretics and thiazide-like drugs?

A

Inhibit the Na+/Cl- carrier by binding to the Cl- site and thus:

  • Prevent the dilution of filtrate in the early distal tubule.
  • Increase the load of Na+ delivered to the collecting tubule (causing K+ loss).
  • Increase reabsorption of Ca2+ (mechanism debatable – actions at the PCT and DCT have been proposed).
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16
Q

What are the pharmacokinetics of thiazide diuretics and thiazide-like drugs?

A

Well absorbed from the G.I. tract.

Enter nephron by organic anion transporters.

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17
Q

What are the clinical indications for thiazide diuretics?

A

Used widely in:

  • Mild heart failure (loop agents are an alternative).
  • Hypertension.

Additionally in:

  • Severe resistant oedema.
  • Renal stone disease.
  • Nephrogenic diabetes insipidus.
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18
Q

What are the contraindications for using thiazide diuretics?

A

Hypokalaemia.

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19
Q

What are the cautions for using thiazide diuretics?

A

Hyponatraemia.

Gout.

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20
Q

What are the adverse effects of thiazide diuretics?

A

Hypokalaemia.

Metabolic alkalosis - they promote proton loss.

Hypovolaemia and hypotension (particularly in the elderly).

Hypomagnesemia.

Hyperuricaemia – mechanism as for loop agents – may precipitate gout.

Erectile dysfunction at higher doses.

Impaired glucose tolerance in diabetics possibility due to impaired insulin release.

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21
Q

How do amiloride and triamterene work?

A

Block the apical sodium channel and decrease Na+ reabsorption.

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22
Q

How do spironolactone and eplerenone work?

A

Compete with aldosterone for binding to intracellular receptors preventing the actions of the steroid.

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23
Q

What are the clinical indications for potassium-sparing diuretics?

A

Used in conjunction with other agents that cause potassium loss; if given alone, they cause hyperkalaemia.

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24
Q

What are the contraindications of potassium-sparing diuretics?

A

Severe renal impairment.

Hyperkalaemia.

Addison’s disease.

[Aldosterone receptor blockers.]

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25
Q

What are osmotic diuretics?

A

Are membrane impermeant polyhydric alcohols (hence IV administration).

Enter nephron by glomerular filtration, but are not reabsorbed.

Increase the osmolality of the filtrate, opposing the absorption of water in parts of the nephron that are freely permeable to water.

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26
Q

Where is the major site of action for osmotic diuretics?

A

The proximal tubule -> where most iso-osmotic reabsorption of water occurs.

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27
Q

When are osmotic diuretics used?

A

In the prevention of acute hypovolaemic renal failure to maintain urine flow.

In urgent treatment of acutely raised intracranial and intraocular pressure. The solute does not enter the eye or brain, but increased plasma osmolality extracts water from these compartments.

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28
Q

What are the osmotic effects of osmotic diuresis?

A

Transient expansion of blood volume and hyponatraemia.

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29
Q

When may osmotic diuresis occur?

A

In hyperglycaemia - the reabsorptive capacity of the proximal tubule for glucose (by SGLT1 and SGLT2) is exceeded. Glucose remaining in the filtrate retains fluid.

As a consequence of the use of iodine-based radiocontrast dyes in imaging - dye is filtered at the glomerulus but is not reabsorbed constituting an osmotic load. Patients with borderline cardiovascular status may experience hypotension due to a reduction in intravascular volume.

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30
Q

What is the action of carbonic anhydrase inhibitors?

A

Increase excretion of HCO3- with Na+, K+ and H2O – alkaline diuresis and metabolic acidosis result.

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31
Q

When is alkalinising the urine useful?

A

Relief in dysuria.

Prevention of the crystallisation of weak acids with limited aqueous solubility – favours ionised form. Can decrease the formation of uric acid stones.

Enhancing the excretion of weak acids (e.g. salicylates, some barbiturates) – favours ionised form that is not reabsorbed.

32
Q

What are carbonic anhydrase inhibitors useful in?

A

Glaucoma and following eye surgery (to reduce intraocular pressure by suppressing formation of aqueous humour).

Prophylaxis of altitude sickness.

Some forms of infantile epilepsy.

33
Q

What is the effect of aldosterone on the kidney?

A

Enhanced tubular Na reabsorption and salt retention.

Increases the activity of Na channels in the collecting tubule.

34
Q

What is the effect of ADH on the kidney?

A

Enhanced water reabsorption.

Increases the number of aquaporins present in the collecting tubule.

35
Q

What are the symptoms of diabetes insipidus?

A

Thirst.

Polydipsia.

Polyuria.

Urine is copious and dilute.

36
Q

What is the treatment for neurogenic diabetes insipidus?

A

Desmopressin (a synthetic analogue of vasopressin with V2 receptor selectivity - avoids the increase in BP associated with V1 receptor activation).

37
Q

What inhibits and enhances the secretion of vasopressin?

A

Inhibits secretion - ethanol.

Enhances secretion - nicotine.

38
Q

What is the treatment for nephrogenic diabetes insipidus?

A

No current pharmacological treatment.

39
Q

What is neurogenic diabetes insipidus?

A

Lack of vasopressin secretion from the posterior pituitary.

40
Q

What is nephrogenic diabetes insipidus?

A

Inability of the nephron to respond to vasopressin - rare and usually caused by recessive and X-linked mutations in the V2 receptor gene ( AVPR2).

41
Q

What inhibits vasopressin action on the kidney?

A

Lithium (used in bipolar disorder).

Demeclocycline – antibiotic but has been used to block effects of the excessive release of vasopressin (e.g. tumours).

Vaptans.

42
Q

What are vaptans?

A

Act as competitive antagonists of vasopressin receptors.

43
Q

What doe V1a receptors mediate?

A

Vasoconstriction.

44
Q

What doe V2 receptors mediate?

A

Water reabsorption in the collecting tubule by directing aquaporin 2-containing vesicles to the apical membrane.

45
Q

What does blockade of V2 receptors cause?

A

Excretion of water without accompanying Na -> raises plasma Na concentration.

46
Q

What condition is tolvaptan used in?

A

Syndrome of inappropriate anti-diuretic hormone secretion (SIADH).

Tolvaptan correct hyponatraemia.

47
Q

Where does the reabsorption of glucose occur in the kidney?

A

In the proximal tubule mediated by sodium-glucose cotransporter 1 (SGLT1) and 2 (SGLT2).

48
Q

Where is SGLT1 expressed?

A

In both the intestine (enterocytes) and the kidney (S2/3 segment).

49
Q

Where is SGLT2 expressed?

A

Almost exclusively in the proximal tubule of the kidney (S1 segment).

50
Q

Where does reabsorption of glucose by secondary active transport occur?

A

Apical membrane.

51
Q

Where does reabsorption of glucose by facilitated diffusion occur?

A

Basolateral membrane.

52
Q

What does inhibition of SGLT2 result in?

A

Glucosuria.

53
Q

What do SGLT2 inhibitors cause?

A

Excretion of glucose.

Decreases HbA1c.

Weight loss (calorific loss and mild osmotic diuresis).

54
Q

What are prostaglandins?

A

Prostaglandins are part of a family of molecules (prostanoids) formed from the fatty acid arachidonic acid by the cyclo-oxygenase enzymes (COX1 and 2).

55
Q

What are the major prostaglandins synthesised by the kidney?

A

PGE2 - medulla.

PGI2 (prostacyclin) - glomeruli.

56
Q

What are the actions of PGE2 and PGI2 ?

A

Both act as vasodilators, are natriuretic and are synthesised in response to ischaemia, mechanical trauma, angiotensin II, ADH and bradykinin.

Under normal conditions, prostaglandins have little effect upon on renal blood flow (RBF), or glomerular filtration rate (GFR).

Prostaglandins gain importance under conditions of vasoconstriction, or decreased effective arterial blood volume, where they cause compensatory vasodilation.

57
Q

How do prostaglandins affect GFR?

A

A direct vasodilator effect upon the afferent arteriole.

Releasing renin leading to increased levels of angiotensin II that vasoconstricts the efferent arteriole – filtration pressure increases.

58
Q

How do NSAIDs cause renal impairment?

A

NSAIDs cause a decrease in prostaglandins, which regulate vasodilation at the glomerular level, disrupting the compensatory vasodilation response of renal prostaglandins to vasoconstrictor hormones released by the body -> acute deterioration of renal function after ingestion of NSAIDs.

NSAIDs can cause acute interstitial nephritis (AIN), which is characterised by the presence of an inflammatory cell infiltrate in the interstitium of the kidney. AIN is caused by an immunological reaction after NSAID exposure of about a week.

59
Q

What is an adverse drug reaction?

A

Any undesirable reaction, whether expected, predictable or not that results in a detriment to the wellbeing of the patient in any way, whether symptomatic, detectable or not, in the absence of another biologically plausible explanation.

60
Q

Which populations are adverse drug reactions most common in?

A

Elderly and frail.

Multimorbid (renal/hepatic clearance, etc. impaired).

Polypharmacy.

61
Q

What is the therapeutic index of a drug?

A

Therapeutic index = 50% of the toxic dose of drug/50% of the effective dose of drug.

62
Q

What common drugs have a narrow therapeutic index?

A

Theophylline.

Warfarin.

Lithium.

Digoxin.

Gentamicin.

Vancomycin.

Phenytoin.

Cyclosporin.

Carbamazepine.

Levothyroxine.

63
Q

What are the traditional stages of adverse drug reactions?

A

Drug development phase (pre-clinical).

Clinical trials (phases I-III).

Post-marketing surveillance (phase IV and beyond).

64
Q

What are the phases of drug metabolism?

A

Phase 1: usually through cytochrome P450 involving oxidation, reduction and hydrolysis.

Phase 2: conjugation (water-soluble) which enables excretion in the urine.

65
Q

What are the classifications of adverse drug reactions?

A

Type A - augmented pharmacological effects, dose-dependent and predictable.

Type B - bizarre effects (or idiosyncratic) - dose-independent and unpredictable.

Type C - chronic effects.

Type D - delayed effects.

Type E - end-of-treatment effects.

Type F - failure of therapy.

66
Q

How may NSAIDs precipitate acute renal failure?

A

NSAIDs inhibit COX and may precipitate acute renal failure (greatly decreased GFR) in conditions where renal blood flow is dependent upon vasodilator prostaglandins (e.g. liver cirrhosis, heart failure, nephrotic syndrome).

Combination of ACEI (or ARB), diuretic and NSAID may be particularly detrimental.

67
Q

What does the catabolism of purines produce?

A

Uric acid.

68
Q

How are probenecid and sulfinpyrazone useful in the treatment of gout?

A

They block reabsorption of urate in the proximal tubule (although largely superceded by allopurinol which inhibits urate synthesis).

69
Q

What does the little black triangle in the BNF mean?

A

A black triangle appearing after the trade name of a British medicine (or vaccine) indicates that the medication is new to the market, or that an existing medicine (or vaccine) is being used for a new reason or by a new route of administration.

Black triangle is only removed when safety is established.

70
Q

What are the mechanisms of type A adverse drug reactions?

A

Pre-renal (hypotension, hypovolaemia).

Renal (acute interstitial nephritis, acute tubular necrosis).

Post-renal (retroperitoneal fibrosis, crystaluria, urinary calculi).

Drug interactions: drug-drug, drug-disease or drug-food interactions.

71
Q

What is pharmacokinetics?

A

Behaviour of a drug with regard to absorption, distribution, metabolism and elimination.

72
Q

What is pharmacodynamics?

A

How the body reacts to the drug.

73
Q

Where are the majority of drugs metabolised and excreted?

A

Metabolised by the liver.

Excreted by the kidney.

74
Q

What are the 2 types of calcium channel blocker? Give examples.

A

Dihydropyridine e.g. amlodipine, felodipine, nifedipine.

Non-dihydropyridine e.g. verapamil, diltiazam.

75
Q

What is the action of non-dihydropyridine calcium channel blockers?

A

Negative chronotropic effect.
Work similar to beta-blockers to slow the heart rate down.

76
Q

What is the action of NSAIDs?

A

Sodium reabsorption which causes fluid retention.

Hence NSAIDs can precipitate cardiac failure in susceptible patients.

77
Q
A

2MBChB Renal (20 decks)

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