Clinical Pharmacology of Renal Disease

Question 1

with regards to functions of the kidney, what is the most important in relation to clinical pharmacology

Answer 1

the excerpt of active drugs or their metabolites

also important are regulations extracellular volume and regulation of ionic concentration

Question 2

what happens to levels of drugs if renal function is impaired

Answer 2

rapid build up of active drug, or toxic or active metabolites

Question 3

what type of drugs are less likely to cause renal impairment

Answer 3

drugs that have a high therapeutic index or low toxicity e.g. benzylpenicillin

Question 4

what type of drugs are more likely to cause renal impairment

Answer 4

drugs that have a narrow therapeutic index or high toxicity

Question 5

give examples of 4 drugs that can cause toxicity and name the resulting complications

Answer 5

gentamicin - may cause renal or ototoxicity

digoxin -may cause arrhythmia, nausea or death

lithium - renal toxicity and death

tacrolimus - renal and CNS toxicity

Question 6

name some factors that can interact to generate de novo renal impairment or worsen pre existing renal impairment/toxicity

Answer 6

sickness level (i.e. the more unwell a patient is the more likely they are to have complications)

volume depletion

hypotension

polypharmacy of potentially reno-toxic agents

Question 7

what mechanism of renal excretion is most affected in renal impairment and what is the result

Answer 7

GLOMERULAR FILTRATION

• passive tubular reabsorption
• active tubular secretion

**changes in parameters due to disease, age or drug therapy will automatically change pharmacokinetics and pharmacodynamics

Question 8

define pharmacokinetics

Answer 8

the bodies affect on the drug

Question 9

define pharmacodynamics

Answer 9

the drugs affect on the body

Question 10

how does renal impairment affect the half life of drugs

Answer 10

prolongs the half life of all drugs or their metabolites cleared by the glomerulus

**need to be extra careful when using drugs with a low therapeutic index

Question 11

give some examples of normal drug half lives vs impaired half lives

Answer 11

benzylpen - 0.5hr - 8hr

gentamicin - 2.5 - 50

atenolol - 6 - 100

digoxin - 36 - 120

glibenclamide - 10 - 100

chlopropramide - 36 - 200

Question 12

name two pharmacokinetic effects of renal impairment

Answer 12

1. reduced GFR - leads to reduced clearance of drugs from the kidneys = ACCUMULATION
2. reduced protein bindign - more active drug present in blood

Question 13

what can be done to reduce the pharmacokinetic effects of renal impairment

Answer 13

• REDUCE DOSE
• increase dose interval
• therapeutic drug monitoring (TDM) of blood levels for toxic drugs like gentamicin, lithium, digoxin, vancomycin

Question 14

name three pharmacodynamic effects of renal impairment

Answer 14

1. the blood brain barrier (and barrier to the testis and ovaries) becomes more permeable - e.g. brain becomes more sensitive to tranquillisers, sedatives and opiates
2. circulatory volume may be reduced - patient more sensitive to antihypertensives, ACEIs or a-blockers
3. increased tendency to bleed - beware warfarin or NSAIDs (ibuprofen, paracetamol, etc)

Question 15

what can be said about the direct nephrotoxic actions drugs

Answer 15

SYNERGISTIC

• gentamicin toxicity may be unmasked when used in conjunction with furosemide or lithium
  i. e. leads to increased sensitivity to the toxic effects of combined therapy

Question 16

what are important things to know when prescribing drugs to a patient with renal impairment

Answer 16

• which drugs can be used safely when eGFR decreased
• which drugs have a low therapeutic index
• risk/benefit ratio
• severity of possible side effects
• severity of toxicity
• availability of TDM

Question 17

what are important things that can reduce the possibility of renal impairment

Answer 17

• reduce loading dose
• reduce maintenance dose
• increase down interval
• importance of monitoring throughout course of treatment (TDM, renal function, blood pressure)

Question 18

Ideally if a patient suffers from renal impairment what types of drug should be used

Answer 18

• drugs with a high therapeutic index

- drugs that are metabolised by the liver to produce non-toxic metabolites

Question 19

what is a common medical problem that can arise from renal damage

Answer 19

hypertension (HBP causes renal damage and vice versa)

Question 20

normally what drugs would be used for a patient with hypertension

Answer 20

thiazide-type diuretics, CCBs, ACEIs

Question 21

why can’t hypertensive patients with renal damage have the usual HBP treatments

Answer 21

they have a low GFR - can lead to hyperuricaemia

they are also more sensitive to the hypotensive actions of antihypertensives

eg ACEIs commonly recommend but can produce severe acute renal dysfunction

eg direct vasodilators can produce profound hypotension and salt and water retention

eg thiazide diuretics may precipitate gout

Question 22

how can hypertensive really impaired patients be managed

Answer 22

use drugs which are totally metabolised by the liver or elsewhere in the body
- ACEIs (BUT monitor!)

reduce dose of the drug with longer dosing periods - i.e. atenolol 25mg/day or on alternate days

Question 23

how does drug induced renal disease come about

Answer 23

any drug in the blood will eventually reach the kidney

if the drug is primarily cleared by the kidney, will be increasingly concentrated as it moves from glomerulus along tubules

concentrated drug exposes kidney tissue to far greater drug concentration per surface area

Question 24

give an example how drug induced renal failure can go undetected

Answer 24

cardiac arrest

• from acute hyperkalaemia
• from acute renal dysfucntion
• from drug toxicity

Question 25

why can bloods show "normal" renal function even though a patient may be really impaired

Answer 25

if looking at urea and creatinine levels - only show up as increased in blood when GFR <60% of normal therefore patient have have some degree of renal impairment and reduced GFR but it not show up if not looking at correct things

Question 26

what are 4 types of disease that can occur from renal damage

Answer 26

1. acute kidney injury 2. acute tubular necrosis 3. chronic kidney disease 4. inflammatory disorders* *eg cystitis - can be a drug induced inflammatory disorder o the bladder

Question 27

how can renal involvement in disease be identified

Answer 27

salt and water abnormalities - dehydration, oedema acute renal failure - from e.g. acute tubular necrosis, acute interstitial nephritis chronic renal failure

Question 28

why is monitoring important when treating a patient with diuretics

Answer 28

to ensure renal function does not e impaired

Question 29

what are the four major syndromes associated with drug induced renal disease e

Answer 29

1. acute renal failure 2. nephrotic syndrome 3. renal tubular dysfucntion with potassium wasting 4. chronic renal failure

Question 30

define acute renal failure

Answer 30

A sudden deterioration in renal function which results in a rapid rise in creatinine Urine volume falls to < 400ml/day in 40% of patients. **Often elderly patients who are sick, have a poor fluid intake*, who are on multiple medications and who are not being monitored aggressively. *also don't have a thirst drive so don't drink fluids

Question 31

what are the three types of acute renal failure

Answer 31

pre-renal renal (intrinsic) post-renal (obstructive)

Question 32

give examples of drugs that can induce pre-renal AKI (and how)

Answer 32

Water and electrolyte abnormalities: diuretics, laxatives, lithium, NSAIDs Increased catabolism: Steroids, tertracyclines Vascular occlusion: Oestrogens/ OCP

Question 33

what are the three types of intrinsic acute renal failure

Answer 33

1. Acute tubular necrosis (ATN) 2. Acute interstitial nephritis 3. Thrombotic microangiopathy.

Question 34

what drugs can cause acute tubular necrosis

Answer 34

1. aminoglycoside, antibiotics 2. amphotericin B 3. cisplatin**, radiocontrast agents 4. statins + immunosuppressives (eg cyclosporin **always over hydrate patients before giving cisplatin

Question 35

when does acute interstitial nephritis present

Answer 35

Onset after drug exposure is 3-5 days with a second exposure, to as long as several weeks with a first exposure. Latency period may be as short as 1 day with rifampicin, or as long as 18 months with an NSAID

Question 36

give some examples of drugs that can lead to acute interstitial nephritis

Answer 36

penicillins, cephalospirins, cocaine, NSAIDS*, omeprazole chinese herbs *could even be from e.g. ibuprofen used on a daily basis

Question 37

what is thrombotic microangiopathy

Answer 37

thrombi in the microvasculature of many organs - can use acute renal failure include afferent arteriolar and glomerular thrombosis

Question 38

give some examples of drugs that can cause thrombotic microangipathy

Answer 38

cyclosporin, tacrolimus, OCP, cocain, quinine, clopidogrel

Question 39

how can drugs cause post renal/obstructive uropathy

Answer 39

drug associated obstruction of urine outflow: - within tubules or ureters (CRYSTAL FORMATION) - outside ureters due to retroperitoneal fibrosis (caused by e.g. methysergide)

Question 40

give some examples go drugs that can cause post renal damage

Answer 40

acyclovir, sulfonamides, methotrexate, vit C in alrge doses

Question 41

what drugs can lead to nephrotic syndrome

Answer 41

gold, NSAIDs, penicillamine, interferon due to glomerular dysfunction and marked by heavy proteinuria

Question 42

give examples of some NSAID-induced renal syndromes

Answer 42

acute renal fiercer, hypertension, hyperkalemia, papillary necrosis* *esp in women **can be caused from even paracetamol

Question 43

what is the most common type of NSAID-induced acute renal failure

Answer 43

deceased synthesis of renal vasodilators prostaglandins - leads to reduced renal blood flow and reduced glomerular filtration

Question 44

which NSAIDs are related to NSAID-induced acute allergic interstitial nephritis

Answer 44

propionic acid derivatives - ibuprofen, naproxen, and fenoprofen idiosyncratic reaction associated with nephritic syndrome in 90% of cases

Question 45

what is amino glycoside-induced renal injury

Answer 45

proximal tubular injury leading to cell necrosis from nephrotoxicity of amino glycoside antibiotics used to treat severe gram eve sepsis

Question 46

SUMMARY: what should you be on the look out for in patients with renal damage

Answer 46

asymptomatic increase in urea and creatinine fluid and electrolyte abnormalities acute tubular necrosis acute and chronic interstitial nephritis

Question 47

SUMMARY: what is the most common cause of acute renal failure

Answer 47

acute tubular necrosis due to aminoglycosides

Question 48

SUMMARY: what patients should you avoid nephrotoxic drugs in

Answer 48

volume deplete patients or hypotensive patients with pre-existing renal disease patents receives other nephrotoxic agents **be aware of elderly, sick, polypharmacy patients too