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brs (phase 1b) > (pharm) pharmacology of CKD > Flashcards

(pharm) pharmacology of CKD Flashcards

1
Q

what are four commonly prescribed drugs for CKD?

A

statins

aspirin

trimethoprim (usually in the form on co-trimoxazole)

gentamicin

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2
Q

what are statins?

A

selective, competitive HMG-CoA reductase inhibitors

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3
Q

name statins that are commonly prescribed to treat CKD

A

atorvastatin

simvastatin

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4
Q

explain the primary mechanism of action of statins

A

selective, competitive inhibitor of HMG-CoA reductase

usually converts HMG-CoA to mevalonate in the cholesterol synthesis pathway

so when HMG-CoA reductase is inhibited = reduced hepatic cholesterol synthesis

less cholesterol in the liver so upregulation of LDL receptors and therefore increase hepatic uptake of LDL cholesterol from circulation

= reducing serum LDL cholesterol levels and therefore also cardiovascular risk

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5
Q

what is the drug target for statins?

A

hydroxymethylglutaryl-CoA (HMG-CoA) reductase

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6
Q

what are the main side effects of statins?

A

muscle toxicity

constipation/diarrhoea

other gastrointestinal symptoms

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7
Q

what do statins inhibit and what is the impact of this?

A

statins inhibit HMG-CoA reductase and therefore the conversion of HMG-CoA to mevalonate

= so there will be reduced hepatic cholesterol synthesis

= an upregulation of LDL receptors and increased hepatic uptake of LDL cholesterol from circulation

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8
Q

what is HMG-CoA reductase and what does it normally do?

A

hydroxymethylglutaryl-CoA (HMG-CoA) reductase

enzymes that catalyses the conversion of HMG-CoA to mevalonate in the cholesterol synthesis pathway

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9
Q

how is cholesterol synthesis reduced as a result of statin administration?

A

statins inhibit HMG-CoA reductase so less HMG-CoA is converted into mevalonate, hindering the cholesterol synthesis pathway

= less hepatic cholesterol synthesis

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10
Q

what is the impact of reducing hepatic cholesterol synthesis?

A

by reducing hepatic cholesterol synthesis, LDL receptors are upregulated so there is increased LDL cholesterol uptake from the circulation into the liver

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11
Q

why is it important to reduce hepatic cholesterol synthesis?

A

to stimulate the upregulation of LDL receptors

= to then increase LDL cholesterol uptake from the circulation into the liver

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12
Q

why are higher doses of statins dangerous?

A

the likelihood of muscle toxicity occuring as a side effect increases at higher doses

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13
Q

when is there an increased risk of muscle toxicity with statins?

A

at higher doses of statins

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14
Q

why are statins prescribed for chronic kidney disease patients?

A

patients with CKD have an increased cardiovascular risk

= statins will reduce serum cholesterol, thereby reducing the risk of strokes and MIs

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15
Q

why are patients with CKD at a higher risk of cardiovascular events?

A

in renal dysfunction, the endocrine system works harder to regulate blood pressure + increased blood supply to the kidneys

= your heart has to pump harder, which can lead to heart disease

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16
Q

why do patients taking statins have to be followed up?

A

should be regularly followed up to monitor for hyperkalaemia and acute renal failure

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17
Q

what can increase statin serum concentrations and why?

A

coadministration with potent 3A4 inhibitors may result in increased statin serum concentrations

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18
Q

explain the mechanism of action of aspirin

A

irreversible inactivation of COX enzyme = prevents oxidation of arachidonic acid to produce prostaglandins

  • reduction of thromboxane A2 in platelets reduces platelet aggregation
  • reduction of PGE2 at sensory pain neurones reduces pain and sensation and in the brain decreases fever
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19
Q

what does aspirin prevent?

A

prevents the oxidation of arachidonic acid to produce prostaglandins
(as a result of COX-2 inhibition)

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20
Q

the production of which substances in downregulated due to aspirin administration?

A

prostaglandins including thromboxane A2 and PGE2

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21
Q

how does aspirin affect platelets?

A

platelets aggregate less as there is less thromboxane A2 prostaglandin

(due to inhibition of COX-2 enzyme by aspirin)

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22
Q

how does aspirin affect PGE2 and what are the implications of this?

A

aspirin reduces PGE2 prostaglandin synthesis due to COX-2 inhibition

= less PGE2 at sensory pain neurones results in reduced pain and sensation

= less PGE2 in the brain decreases fever

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23
Q

what does PGE2 reduction at sensory pain neurones cause?

A

reduced pain and sensation

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24
Q

what does PGE2 reduction in the brain cause?

A

decreases fever

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25
Q

what is the drug target for aspirin?

A

COX enzyme

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26
Q

what are the side effects of aspirin?

A

dyspepsia
haemorrhage
(increased risk of peptic ulcers)

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27
Q

what must you ensure when prescribing aspirin to the elderly?

A

avoid doses greater than 160mg daily (any higher = increased risk in bleeding)

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28
Q

what is the maximum dose of aspirin that can be prescribed for the elderly and why?

A

maximum 160mg daily

= any higher is associated with an increased risk in bleeding

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29
Q

what must you ensure when prescribing aspirin to patients with a history of peptic ulcers and WHY?

A

ensure you co-administer PPIs

= as aspirin increases the risk of peptic ulcer fomration

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30
Q

what is low-dose aspirin particularly good at preventing?

A

most cost-effective medicine for the prevention of secondary events of thrombosis

31
Q

explain how aspirin overuse can lead to peptic ulcers

A

blockade of COX1 in gastric mucosal cells reduces mucus/bicarbonate production + reduced prostaglandin production (due to COX-2 inhibition)

= can expose the stomach lining to acid

32
Q

explain the mechanism of action of trimethoprim

A

direct competitor of the enzyme dihydrofolate reductase

= inhibits the reduction of dihydrofolic acid to tetrahydrofolic acid (active form)

= so less tetrahydrofolate available for synthesising purines required for DNA and protein production

33
Q

what is the drug target for trimethoprim?

A

dihydrofolate reductase enzyme

34
Q

what are the side effects of trimethoprim?

A

diarrhoea

skin reactions

35
Q

what is trimethoprim often administered with?

A

often administered with sulfamethoxazole – known as co-trimoxazole

36
Q

what is co-trimoxazole?

A

trimethoprim + sulfamethoxazole = co-trimoxazole

= block two steps in bacterial biosynthesis of essential nucleic acids and proteins

37
Q

explain the mechanism of action of co-trimoxazole

A

in combination, trimethoprim AND sulfamethoxazole block two steps in bacterial biosynthesis of essential nucleic acids and proteins

38
Q

what does co-trimoxazole block?

A

two steps in bacterial biosynthesis of essential nucleic acids and proteins

39
Q

when and how must trimethoprim use be monitored?

A

long term use = monitor blood count

folate-deficient patients = monitor blood count

patients at risk of hyperkalemia = measure serum electrolytes

40
Q

what does trimethoprim inhibit?

A

inhibits the reduction of dihydrofolate to tetrahydrofolate (active form)

= latter is required to synthesis purines for DNA and protein synthesis

41
Q

how does dihydrofolate compare to tetrahydrofolate?

A

tetrahydrofolate is the active form, made form the reduction of dihydrofolate by dihydrofolate reductase

42
Q

what is tetrahydrofolic acid important?

A

a necessary component for synthesising purines required for DNA and protein production

43
Q

how does dihydrofolate compare to tetrahydrofolate?

A

tetrahydrofolate is the active form, made from the reduction of dihydrofolate by dihydrofolate reductase

44
Q

what is the mechanism of action of gentamicin?

A

binds to the bacterial 30s ribosomal subunit disturbing the translation of mRNA leading to the formation of dysfunctional proteins

45
Q

what is the drug target for gentamicin?

A

bacterial 30s ribosomal subunit

46
Q

what are the side effects of gentamicin?

A

ototoxicity and nephrotoxicity

47
Q

what does gentamicin bind to?

A

bacterial 30s ribosomal subunit

48
Q

what does gentamicin prevent?

A

prevents the translation of mRNA leading to the formation of dysfunctional proteins

49
Q

define ototoxicity

A

ear poisoning which results from exposure to drugs or chemicals that damage the inner ear, often impairing hearing and balance

50
Q

define nephrotoxicity

A

rapid deterioration in the kidney function due to toxic effect of medications and chemicals

51
Q

what kind of antibiotic is gentamicin?

A

aminoglycoside antibiotic

52
Q

how does gentamicin interact with gram-negative bacteria?

A

can pass through gram-negative cell membrane in an oxygen-dependent manner

53
Q

why is gentamicin ineffective against anaerobic bacteria?

A

gentamicin can only pass through the (gram-negative) cell membranes in an oxygen dependent manner

= ineffective w bacteria that do not rely on oxygen (anaerobic bacteria)

54
Q

how is gentamicin likely to be administered?

A

more likely to be administered intravenously (in hospital)

55
Q

what is gentamicin likely to be administered for in a hospital setting?

A

or endocarditis, septicaemia, meningitis, pneumonia or surgical prophylaxis

56
Q

what other medications can be given for CKD?

A

calcium channel blokcers (amlodipine, felodipine)

ACE inhibitors (ramipril, lisinopril, perindopril)

angiotensin receptor blockers (losartan, irbesartan, candesartan)

daptaglifozin

NSAIDs (ibuprofen, naproxen, diclofenac)

57
Q

how is eGFR calculated?

A

calculated in ml/min using an online calculator

58
Q

what are the therapeutic objectives for a patient with:

1) stage 2 hypertension?
2) chronic kidney disease?

A

1) reduce the hypertension to reduce cardiovascular risk

2) tighter control of hypertension to slow progression of CKD

59
Q

why is it the aim to reduce hypertension in patients who have it?

A

to reduce cardiovascular risk

60
Q

how is the progression of CKD slowed?

A

tighter control of blood pressure

61
Q

what are the two most common causes of CKD?

A

diabetes and hypertension

62
Q

explain how CKD is linked to hypertension

A

persistent hypertension narrows, damages and hardens the arteries
= impairs the ability of renal arteries and vessels to filter the blood efficiently

63
Q

what treatment is best recommended for a patient with stage 2 hypertension?

A

initiate drug treatment depending on age & ethnicity

64
Q

what treatment is best recommended for a patient with chronic kidney disease?

A

tighter blood pressure control

to slow progression of CKD

65
Q

how is cardiovascular risk managed in patients w CKD?

A

1) conservative measures (e.g. lifestyle changes to do w diet, smoking, weight loss)
2) atorvastatin if CVR is high enough (to reduce cholesterol levels)

66
Q

in patients that have significant proteinuria, what treatments can be initiated?

A

1) ACEi or ARBs
2) SGLT2 inhibitors (e.g. daptaglifozin)
3) salt restriction (to normal recommended levels)

= drugs/interventions that improve proteinuria

67
Q

what is proteinuria a mark of?

A

glomerular dysfunction

68
Q

in hypertensive patients, when can the antihypertensive drug of choice sometimes be stopped?

A

if the drug reduces the BP too low and causes hypotension

69
Q

would you consider treating a patient w CKD with aspirin?

A
  • considered only in patients at a high risk of MI or stroke

but overall = in general, aspirin is avoided for primary prevention

70
Q

the use of trimethoprim invalidates GFR calculators

why is this?

A

trimethoprim inhibits tubular creatinine secretion

= rapid yet reversible increase in serum creatinine (independent of any changes in GFR - i.e. increase caused by something other than low GFR)

= translates into a falsely low estimated GFR when creatinine-based equations are used

71
Q

what is the link between GFR and creatinine?

A

as the GFR decreases, the creatinine concentration increases

72
Q

how does ibuprofen affect GFR levels?

A

causes GFR to worsen/reduce

= due to
1) inhibition of (vasodilatory) prostaglandin synthesis
= reduced renal blood flow
2) reduced creatinine clearance (more remains within the plasma)

73
Q

how do ACE inhibitors affect GFR?

A

as ACE inhibitors reduce glomerular perfusion pressure
= GFR falls

(exacerbated by sepsis)

74
Q

when prescribing for a patient with reduced renal function, what two things MUST you consider?

A

1) might the drug damage the kidney? = and possibly worsen the AKI (e.g. ibuprofen)
2) is the drug eliminated by the kidney? = and will it accumulate in the blood and cause side effects (e.g. metformin, morphine)

(damage, eliminate)

brs (phase 1b) (71 decks)

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