Lecture 2- Social pharmacy

NOTE: nothing important took place during this lecture. This is a list of things the patient said: Dialysis patient Does it at home, takes several hours Hour to get set up 6 hours on it Hour to get off Has hundreds of capilary tubes and has a countercurrent flow with dialysis fluid to remove wastes 1.4m2 surface area per tube

They didn't diagnose her easily Headaches and tiredness and high blood pressure Tried to salvage kidneys by high dose prednisone (but was too late) Due to glomerulonephritis Couldn't pin it down to anything Blood pressure tablets + low protein diet Sister had a near-perfect match for a kidney But expected to fail, did so after 7 years Was on cyclosporine, swelling in hips and feet, so replaced with steroids After being taken off it, then rejection occurred Back on the machine again Hard mentally and physically But was feeling good for those 7 years EPO is important for these people for blood production (otherwise anaemic) Feels very tired otherwise And required regular blood transfusions Tumours found in kidneys, needed to remove it, given the all clear Once again ellegible to be on the transplant waiting list BP can get high with increased blood volume, need to monitor and remove as nessesary Offered another kidney Mixed emotions, thinking about the donor family and what they're going through The joy of being free again Don't have to restrict fluids Second transplant was a success Need to be on highish prednisone Tacrolimus being used Mycophenylate as well But parameters are stabilising (urea and creatinine) Thankful for the donor family for offering it up for someone else Acyclovir prophylaxis (epstein barr virus) Cotrimoxazole phophylaxis against lung infections Stent left in between kidney and urethra to keep things open (having problem with UTIs, needed to have treatment) Nitroferitoin prophylaxis while stent is in Metoprolol 23.5 (but BP is normal, for heart palpitation) Omeprazole 20mg Can try to run home dialysis overnight, but might not be able to get to sleep properly Might have to be on the machine post op for 1 month to help things to start off (33%) She had it running immediately post-op

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Lecture 3- Renal and hepatic tests

Intro Doctors will order tests to see what could be going on with a patient's organs We need to understand some of these tests

Hepatic
There are many hepatic biomarkers we need to consider, no one marker will tell us everything They can be divided into three main categories: Hepatocyte integrity (i.e. tells us if the cells of the liver are injured) Biliary function (check if the are any problems with the billiary tree) Liver function (after a significant amount of damage, the liver's normal functions could be compromised) Integrity The transaminases are measured to check for hepatocyte integrity Alanine transaminase (ALT) and Aspartate transaminase (AST) Both enzymes are involved in amino acid production Both are found around the body ALT is found in high concentrations in the liver, so it's a bit more specific for the liver AST is found in other organs as well in high concentrations, so it's not so specific Cardiac injury, skeletal muscle injury, haemolysis can also cause AST elevation as AST is found in those organs as well Mild to moderate elevations (2x -20x) are indicative of: Non-specific damage, could be due to a night of alcohol ingestion Chronic viral hepatitis Alcoholic hepatitis Obstructive jaundice While severe elevations are indicative of serious liver disease Ischemic damage Acute viral hepatitis Fulminant (sudden) necrosis Drug toxicities And there are two patterns we should be aware of: AST/ALT ratio which is greater than 2 indicates alcoholic hepatitis ALT requires Vitamin B6 to produce, a vitamin which is usually deficient in alcoholics So with liver damage, the AST is elevated, but the ALT remains the same Fluctuating AST and ALT Indicative of hepatitis C (check the HepC antigen results) Biliary function Alkaline phosphatase (ALP), bilirubin and Gamma glutamyltranspeptidase (GGT) can be used to check for biliary function ALP and GGT are found on the canalicular surface of hepatocytes i.e on the 'bile side' Since ALP deals with phosphate, it's not surprising to see it's also present in bone in small amounts (but it's mostly present in the liver, making it quite specific) Bone growth and pregnancy will cause a mild elevation of ALP A mild elevation could also signal liver damage as well A large elevation indicates cholestatic disease (bile can't get out) or bone disease or cancer GGT is less specific compared to ALP, but it's more sensitive (i.e. can pick up lower levels) Also found in the kidney, pancreas and gut GGT + ALP elevation is pretty much guaranteed cholestasis
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 GGT + ALP elevation is pretty much guaranteed cholestasis GGT only elevation suggests alcohol abuse Can also be elevated by drugs as well Bilirubin instead is not an enzyme, but it's a breakdown product from heme (mostly red blood cells) Can be elevated due to: Overproduction of bilirubin Impaired metabolism Under-excretion, most likely due to some kind of blockage Obstructed by an object, likely to be a gallstone Inflammation can also block the biliary tree Elevation can lead to jaundice, which gives people a nice yellow colour as it's deposited on the skin and eyes and mucosae Instead of total bilirubin, conjugated and unconjugated bilirubin can be measured Bilirubin will be glucuridated in the liver to form a conjugate A huge amount of unconjugated bilirubin, and a small amount of conjugated bilirubin suggests haemolytic anaemia, because the amount of bilirubin is so high, it can't all be conjugated While a huge amount of conjugated bilirubin and a small amount of unconjugated bilirubin suggests there is an obstruction, because the bilirubin production isn't high (because it's all conjugated) but it just can't leave the body properly, so it builds up See diagram below for a summary

Liver function There are two which we need to learn: Albumin Prothrombin time and INR The reason is, the liver is important in producing proteins, which includes albumin and clotting factors Therefore, if the liver is sufficiently damaged, then it can't produce these proteins The liver enzymes don't measure the function of the liver, the liver needs to be about 70-80% damaged before there is a decline in function Albumin is a prevalent plasma protein Has a half-life of 20 days, so it's good to check for chronic illnesses (an acute event won't cause a change in albumin until a few weeks after the event) It is important to pharmacokinetics, as drugs bind to it (more in later lectures) It is also important to maintaining osmotic pressure, a reduction in albumin will cause water to leave the blood and enter tissues, causing ascites and oedema A reduction in albumin can be caused by: Liver disease (obviously) Inflammation (think about chronic inflammatory diseases) Malnutrition (may occur with frail elderly patients Protein loss (e.g. nephrotic syndrome, which causes the albumin and other proteins to leak out into the urine) Prothrombin time and INR Measure of the clotting cascade Note: INR is just the international normalised ratio of the prothrombin time, so they go hand in hand
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hand in hand Factors II, VII, IX and X are produced by the liver (uses vitamin K) INR will be elevated in people with liver failure, as they are unable to synthesise the clotting factors as much It could also be elevated due to: Anticoagulant therapy (VCORC1 antagonists like warfarin or direct thrombin inhibitors like dabigatran) Genetics Renal Background renal physiology: Kidney is made up of nephrons The glomerulus of the neprhon is where filtration occurs The proximal tubule is important for Secretion Active reabsorption Passive reabsorption While the distal tubule is important for passive reabsorption What goes into the urine is determined by: How much of it is filtered into the urine Plus how much of it is actively secreted into the urine Minus how much of it is absorbed back into the body Renal function is simple to determine function, because we can use biomarkers The most commonly used marker is creatinine clearance Creatinine is a normal molecule which is secreted by muscle So patients with reduced muscle (elderly and cystic fibrosis patients) will have inaccurate results as their production isn't the same as everyone else Serum creatinine needs to be measured, and checked against a formula (See below) Because creatitine levels depends on age and weight, the number by itself is useless Urine creatinine can also be measured over 24 hours to determine clearance, but it's more intensive due to requiring 24 hours of collection (compared to just one blood test) The reason is that creatinine is filtered, but not reabsorbed (and a little bit of secretion), which is good, because a substance which is filtered only will allow us to estimate the GFR (glomerular flow rate) i.e. since we know it is almost purely filtered, it's directly proportional to how much blood flows into the nephron. If it were reabsorbed or secreted, the correlation isn't as good because active processes are involved With serum creatinine, we can use two formulae: Cockcraft & Gault (CG) equation MDRD (Modification of Diet in Renal Disease) formula The CG equation is based on simple pharmacokinetics At steady state (rearranged formula):

And if you look at the formula, it's just substituted with creatinine:

The top bit on the fraction is an estimate as to how much creatinine a person produces (the dose rate). Since only muscle produces creatinine, it's a good idea to use lean body weight (LBW) instead of actual weight. The CLcr (creatinine clerance) is a good measure of renal function, where 100 ml/min is considered to be normal function
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considered to be normal function Adjustment depends on the gender The CG equation however, has some drawbacks: Cimetidine and other drugs which cause an increase in serum creatinine (i.e. prevents secretion) will cause an underestimation in CLcr Doctors will be aware of this, they know not to assume a person has declining renal function if someone's CLcr changes due to these drugs The CG formula is 'behind a week' in showing renal function, because the half-life of creatinine is 6 hours, and it takes some time to reach steady state again See below Creatinine production also varies as well The elderly and cystic fibrosis patients (i.e. the malnorished) will not produce enough creatinine, leads to overestimation of renal function Creatinine concentrations drop in pregnancy due to dilution Protein rich foods can increase creatinine The renal function is overestimated in severe renal impairment, because the glomerulus becomes leaky, letting through more creatinine The MDRD equation gives us the eGFR Only an estimate, as it doesn't take the weight into consideration (fixes the body surface area to 1.73m2) Don't rely on it at all. Not validated for dose adjustments Only use if you can't calculate the CLcr Also inaccurate if renal function is quickly changing, as it also relies on creatinine as well. MDRD and CG equations should NOT be used in children Other markers include Gentamycin Especially good at detecting changes in renal function before changes in creatinine are seen, because creatinine has a half-life of 6 hours, so it can't be used to determine an accurate GFR if the renal function is rapidly changing Cystatin C Apparently just as good as measuring creatinine clearance, but more expensive Inulin EDTA There are three possible causes of renal failure Pre-renal Reduced blood flow to the kidneys, can be seen in dehydration or NSAID use Remember: filtration at the glomerulus depends on how much blood flows past Renal A problem with the nephron itself Example, immune complexes getting stuck in the glomerulus and setting up inflammation Post-renal Blockage in the urinary tract Example, urinary tract infections can form stones which obstruct urine flow What about urea? Measured in the US, not here Also filtered, but it is resorbed Problem is it increases with non-renal conditions, reducing specificity e.g. heart failure and protein rich foods will raise it Uremia will not be examined in our exams (i.e. ignore it)

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Lecture 4- Common urinary tract infections

Introduction Normally, urine should be sterile And due to the pressure of the urine leaving, it will wash away anything in the tract Our immune system will mop up anything else But, infections of the urinary tract are common They tend not to be associated with mortality, but they are generally associated with morbidity i.e. won't likely to kill anyone But instead, it accounts for a lot of sick leave days (or kidney damage if unlucky) 95% of urinary tract infections are ascending, i.e. start at the urethra and make their way up to the bladder and the kidney and then into the blood So it's very unlikely that a person's urinary tract infection is from blood borne bacteria The organisms responsible are usually normal microflora: E. coli from the GI tract is the most common organism responsible Skin bacteria (e.g. Staph species) might be present Candida can also be responsible STIs might also be responsible as well Risk factors The major risk factor is gender Women have a massively high risk compared to males (30 times more likely) There are two anatomical reasons: Women have a shorter urethra, so the bacteria can reach the bladder easily The opening of the urethra in women is located near the anus, so the gut microflora (especially E. coli) can enter easily And pregnancy will also increase the likelihood of infection Hormonal changes makes the urine less effective against bacteria Age is another factor The elderly have a weaker immune system, so infections are more likely Infants will wear diapers, which easily allows gut microflora to enter the urinary tract Not surprisingly, the infection rates are similar between the sexes in this age bracket Obstruction of the urinary tract Provides a surface for bacteria to adhere to Prevents urine from flushing out the bacteria Kidney stones and catheters Catheters also open a hole from the skin into the bladder, providing easy access to bacteria Diabetes Normally the urine is a poor growth medium, one reason being the lack of glucose in urine But diabetics will have glucose in large amounts in the urine, making it a better growth medium for bacteria Immune compromisation Urine composition Some people might have urine which is better for bacterial growth Microflora composition Some people can have bacteria which is more likely to cause infections (see below) Complicated vs uncomplicated Uncomplicated infections are the 'normal' infections They occur in people with normal immune function and urinary tract structure These patients will respond well to antibiotics Reoccurring cases are due to new infections (i.e. original bacteria are gone, a new lot moved in)
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 Reoccurring cases are due to new infections (i.e. original bacteria are gone, a new lot moved in) Complicated infections are seen with people with abnormalities Occur in people with either reduced immunity or an abnormal urinary tract (see bladder below) They tend not to respond to antibiotics, the bacteria will remain Therefore, reoccurring cases are due to the remaining bacteria flourishing again It is a cause for concern, recurrent infections are associated with higher risk of kidney damage Urethritis Infection of the urethra (i.e. the lowest part of the urinary tract) Common organisms are: Chlamydia trachomatis Neisseria gonococcus Candida E. coli It's more common in adults than children And, it could be non-infectious urethritis Inflammation without infection Can be caused by trauma or detergents Common symptoms are: Pain on urination (dysuria) A discharge could be present Tend to go often (frequency) and urgently But gonococcal (from Neisseria gonococcus) will cause leukorrhea, a white/yellow vaginal discharge Diagnosis is generally via symptoms. But there are other diagnostic things doctors can do: Checking for protein in mid-stream urine(MSU) with OTC urine testing kits Checking MSU is a better idea than checking the first bit of urine that comes through. The reason for this is the first bit of urine will wash out anything first, so it's got a high amount of protein, which can give a false positive. Urinanalysis on MSU to check for proteins, enzymes, blood, cells, bacteria etc. Culturing can be carried out as well, which is important for recurrent or complicated cases where doctors may want to see what's going wrong Treatment is simple Antibiotics, trimethoprim for 3 days (for women) is the most common treatment Extra: sell them a urinary alkaliser to reduce the stinging pain Extra: sell them cranberry supplements to reduce recurrence Prevention As stated above, cranberries will actually prevent infections Drink plenty of water to produce plenty of urine to wash out bacteria Wipe from front to back to prevent spread of microorganisms Showers instead of baths Clean the genital area before intercourse Avoid hygiene sprays around the area, it can irritate the urethra, causing inflammation Cystitis Infection of the bladder (even higher up) Common organisms are: Uropathogenic E. coli (UPEC) By far the most common organism Normally found in the GI tract They are specialised to grow in urine: Adhesion factors to prevent from being washed out Toxins to cause local inflammation and effects Capsules to evade the immune system Possesses enzymes to synthesise substances required for growth not present in urine
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urine Urease produced by these bacteria will increase the pH to cause ions to precipitate out and form obstructions (which then encourages further infection) Staphylococcus saphrophyticus Enterobacter Klebsiella Candida Adenovirus Symptoms Dysuria (again) Incontinence (can't hold it) Abdominal pain Frequency Urgency Low fever Foul smelling urine (after all, it is E. coli) Blood or pus in the urine Treatment Again, antibiotics for 2-3 days But due to resistance, ciprofloxacin (quinolone) should be used Again, also think about the extra OTCs as well Recurrent cystitis is generally a bad sign There may be underlying reasons for it, the doctor should find and correct them if possible Prophylactic treatment is recommended (3 months to a year) Urinanalysis should be carried out regularly to test to see if bacterial counts are kept low (or completely eliminated if possible) Very important to treat, because recurrent infections can lead to kidney infection and damage Asymptomatic bacteriuria 2 MSU samples have E. coli in them But there are no associated symptoms More common in the elderly Treatment or screening is not required in the majority of the population, because it has no ill effects EXCEPT in pregnant mothers Can lead to pyelonephritis, premature delivery or low birth weights Should be treated and screened for in this group only

Pyelonephritis Upper urinary tract infection, infection of the kidneys and ureters Uncommon in the community, because they tend to be treated before the bacteria can reach the kidneys Common in hospitals, especially with catheterisation of the bladder Risk factors: Recurrent infections lower down the tract Obstructions Immune compromised Abnormalities, especially ureteral reflux, which is where urine is able to flow back into the kidneys from the bladder:

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kidneys from the bladder:

Again, most of the time it's E. coli causing these problems Candida as well Acute symptoms (tends to be caused by toxin release): Flank or back pain (i.e. in the region of the kidneys) Fever Nausea and vomiting Fatigue Dysuria Urgency Frequency Foul smelling urine Blood or pus in the urine Chronic symptoms: Low, chronic pain Fever Urinary symptoms may or may not be present Weight loss Malaise Fatigue Note: this is what the patient in lecture 2 was experiencing Diagnosis is with: Urinanalysis CT scan to check for abdomen (also to rule out other things as well) Treatment should be urgent (can cause mortality in elderly, or renal failure) Antibiotics oral or IV for 2-3 weeks Note: NZF lists oral ciprofloxacin should be used for 7 days for acute pyelonephritis Chronic treatment requires prophylatic treatment, a longer treatment duration and examination to correct any underlying causes Prostatitis

Infection of the prostate (males only) Tends to be rare, three forms Acute infection- sudden and severe Chronic- not as severe and more common Non-infectious- theorised to be from unculturable bacteria Risk factors are exactly the same as pyelonephritis E coli is again a causative agent, so is Klebsialla Acute infection is actually life threatening Lower abdominal pain Fever Frequency Urgency
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 Urgency Dysuria Foul smelling urine DRE will reveal the prostate is large and very tender Treat with antibiotics (cipro again) and monitor Chronic isn't as bad Recurring cystitis Can have urinary symptoms Can have painful ejaculation Antibiotic treatment isn't as successful, because it's hard to get drugs into the prostate Low dose prophylaxis Surgery to remove it Can prevent it by condom use Kidney stones They can form in the kidney and ureters Very common Can be made up from a range of ions: Calcium is by far the most common type High calcium excretion is a risk factor (due to calcium salt intake or loop diuretics) Uric acid (considering it's present in the urine, it's hardly a surprise) Cystine Struvite, second most common, caused by infection, tends to be made of ammonia The risk factor for struvite stone formation is recurrent cystitis, and women will have a higher chance as well Struvite stones can hurt a lot, because they form jagged structures (think about it, they can poke through and pierce tissues). The ones shown below are only microscopic, but they can grow up to 8mm

This file is licensed under the Creative Commons Attribution-Share Alike 3.0 Unported license. Author : Doruk Salanc Obviously, pain is a common symptom Low pain for smaller stones which can pass through on their own Larger ones will get lodged and cause pain As well as: Nausea and vomiting Fever Tenderness in the abdomen Blood Dysuria It is diagnosed using urinanalysis (as seen above) or imaging like ultrasound if it's lodged Treatment depends on size: For smaller ones, they should drink lots of water to dislodge it, and consider antibiotics to get rid of infections and treat the underlying causes of recurrent cystitis For larger ones, surgery may be needed, especially: If it stays there causing continuous pain for a while It's caught (not surprising, due to the oblique angle of the ureter) Blocks urine flow
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 Blocks urine flow Causes infections Causes damage and bleeding Is growing larger Can remove the stone by: Open surgery Uteroscopic (move up the urethra and into the bladder and then pull it out Ultrasound and shockwaves can be used to shatter the stones

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Lecture 5- Prescribing practice in renal and hepatic impairment

Clearance Clearance is a very important PK parameter:

Notice how it inversely affects plasma levels of a drug Increased clearance = reduced plasma levels (and vice versa) And importantly, increased clearance results in decreased half-life Drug gets removed quickly = so half-life is short What does this mean? Too much clearance = drug levels too low = therapeutic failure Not enough clearance = drug levels too high = overdose toxicity The main clearance organs of the body are the liver and kidneys Most drugs are mostly hepatically cleared Drugs tend to be lipophilic, they get modified (metabolised) in the liver to make the drugs more hydrophilic to help remove them from the body But they are trying to switch to renal, because it's easy to make dose adjustments We can characterise renal function by measuring CLcr, so we can make dose adjustments based off that The liver doesn't have a easy biomarker to look at, so it's harder to make adjustments Clearance doesn't stay constant throughout life: Kidneys become operational shortly after birth Liver takes longer to mature But once it matures, clearance is slightly increased in childhood (not by much, doesn't require dose adjustment) Once we get old, renal and hepatic function declines with time Renal drug elimination Refresher: The amount eliminated by the kidneys depends on the amount filtered and secreted and reabsorbed into the body. Filtration Filtration is reduced by protein binding i.e. if bound to plasma protein, then it can't be filtered So if 50% bound, filtration is reduced by 50% Secretion Substances can be actively secreted, and there are several transporters responsible Acidic drugs can be secreted via OAT transporters Methrotrexate (makes dosing difficult) NSAIDS Oxypurinol (active metabolite from allopurinol) Penicillins P glycoprotein will secrete basic drugs Digoxin (especially important, because digoxin is mostly renally cleared) Fexogenadine A problem is drugs can compete with each other (or endogenous molecules). This will lead to reduced clearance, which is a problem (can lead to overdose) Reabsorption Can be active or passive OAT4 and URAT are transporters which will resorb drugs (the other OATs are efflux transporters though)
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though) Oxypurinol will be resorbed by these transporters Renal dose adjustment Dose adjustments are more easily made with renally cleared drugs than hepatically cleared drugs Again, CLcr is the main method of estimating renal function I will not repeat myself. See lecture 3 for details for the CG equation The renal clearance will slowly decline with age The dosing rate needs to be changed for renal insufficiencies, a rate is composed of: The amount The frequency Either parameter can be changed to adjust the dose The amount of drug can be reduced The frequency can be increased Generally, we can check the Medsafe datasheet or other references to see if there are any dosing protocols e.g. a full dose of enoxaparin should be given to people with a CLcr above 30ml/min But a half dose should be given to people under 29ml/min But a problem with this is what do we do for people at the borders? If someone had 30ml/min, would it be reasonable to be safe than sorry by going with the half dose? We could also calculate the dose ourselves if we knew the: Fraction excreted (fe) Normal dose CLcr If a drug is mostly renally cleared (fe is greater than 0.9, or if a drug is 90% renally cleared):

Notice how this adjustment is just simply using the proportion (very simple) But if a drug was only partially cleared (50-90%)

Notice how the adjustment is similar to the one above, but with an extra bit for account for nonrenal clearance NOTE: NOT EXAMINABLE Overall: it's very important to keep in mind the fact that we're only doing these adjustments to try and scale it down to fit within the therapeutic window. Change dosing as fit to fir the therapeutic window i.e. don't religiously follow the protocols Three important renal examples: Digoxin Important because it's got a narrow therapeutic range TDM is important, do it regularly Remember: carry out rough dose adjustments and then fine tune to get levels within therapeutic levels Also important because it's mostly renally cleared as well (about 80%) Don't forget, it will compete for P-gp at the tubule Allopurinol Although hepatically cleared, its active metabolite, oxypurinol, is renally cleared i.e. active metabolites with a high fe Again, don't forget about the clinical endpoint, adjust the dose until serum urate is lower than 0.36mmol/L (i.e. it's the point of taking allopurinol)
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0.36mmol/L (i.e. it's the point of taking allopurinol) Also remember: competes for OAT4 and URAT at the tubule Gentamycin Very high fe (0.9) Also requires TDM And remember, it's better than CLcr to determine renal function Hepatic clearance As stated before, it's hard to make dose adjustments for hepatic insufficiencies Refresher: Liver is responsible for phase I and II reactions Phase I is where it attaches polar groups or makes it more polar (e.g. adding OH) Phase II is where it attaches large polar molecules (e.g. adding glucuronide) Refresher II: There is a difference between high extraction and low extraction drugs High extraction drugs will be cleared easily by the liver First pass effect is huge Since the liver will easily metabolise it, clearance depends on how quickly it can reach the liver (i.e. blood flow) So higher blood flow to the liver = more clearance for these drugs Low extraction drugs can't be easily cleared by the liver Small first pass effect Blood flow doesn't have an effect What does it mean? The clearance in the liver depends on: Enzyme metabolising capacity (the intrinsic clearance) The blood flow Hepatic shunting can occur, which is where liver damage causes the blood to be shunted to paths of lesser resistance (i.e. other arteries and veins) to bypass the liver (and avoid metabolism) Strangely, the phase II metabolism is preserved longer than phase I metabolism So recommend drugs which use phase II metabolism in patients with hepatic failure e.g. lorazepam over diazepam Again, since there aren't any clear biomarkers we can use to measure liver function, it's hard to make dose adjustments We can use serum albumin and INR to get an idea about how the liver is functioning Measuring liver enzymes will be useless, they measure hepatic/billiary damage, not function 50% dose reduction for high clearance drugs 25% dose reduction for low clearance drugs Monitor closely if the drug has a low therapeutic index It's better to decrease the dose as low as possible, and then having to adjust the dose back up i.e. better safe than sorry

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Lecture 6- Consultant 1, renal cases

[UNDER CONSTRUCTION] Urinanalysis Protein and blood are important to pick up Dipsticks are good for fast checks Proteinuria shows glomerui are under increased stress- shows endothelial damage, require ACE inhibitors Good cardiovacsular marker as well (30% of patients with hypertension, ACE important) Proteuria means worse prognosis as well!

Two common syndromes, not nessesarily exclusive Nephrotic syndrome Hypodlbuminia and associated odema Odema is a positive feedback loop as well Often normal renal Nephritic syndrome Blood Hypertension, retains water in the CVS instead
Case One 84 year old woman, MIDDM, metformin Hypertension 20 years IHD Signs of heart failure eGFR of 25-40ml/min Intervention dropped blood pressure to normal but... Lactic acidosis, especially with metformin Plus acute kidney injury and poor perfusion due to sudden drop in pressure Poor perfusion = anerobic = more acidosis as well Kidney injury probably required for acidosis with metformin What's worse is contrast (a dye, used for coronary aniography) can induce nephrotoxicity as well Renal impairment will predispose to damage, along with everything else like Diabeets Volume depletion (hypotension) CHF High doses It will cause renal vasoconstriction and icshemic damage, and maybe direct toxicity Renal autoregulation Bloodlfow will be redistributed away from the kidneys if required, yet kidney function (glomerular pressure) doesn't change Allows for a wide range of pressures of normal function (remains protected) BUT protection lost (e.g. hypertension), then they will see the kidney change quickly So renal function will be dramatically affected by changes in pressure In 30% Not fully recoverable, kidneys will reset somewhat, but additional insults will increase chances of kidney failure 5x increase in 12 month mortality Prevention?
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 Prevention? To contrast, need to maintain adequate perfusion to the kidneys (plenty of water) So normal saline is for it, nothing else What about N-acetyl cystine to increase GSH, but no evidence for use unless high rish Metformin and contrast Only cautioned with reduced renal function But it's usually unsubstantiated Only if accutely unwell, then stop until they are well Reduces risk of metformin Therefore, metformin itself isn't a problem Too many people stop it too quickly and too often, it's a great drug (doen't cause hypoglycemia and doen't increase weight gain) Metformin to be discontinued for a bit with contrast Case two- radical prostatectomy (open surgery)

67 year male 72 hours oliguria (reduced urine, 10ml) Can be pre-renal (volume loss?), post-renal (inflammation?) or renal (neprotoxin? Ischemia?) Fluid is okay, pressure is also okay GFR dropped, but kidneys show no obstruction So it's renal, what is it? Anaestetic causes ADH release, but the effects shouldn't last longer than 42 hours Possible drug: COX-2 inhibitor, celecoxib When stressed, the prostaglandins will be protective PGI2 will counter the vasoconstriction during stress So, if removed, then protected effect is lost, so vasoconstriction is worse Strong reason not to sell to sell to sports people, during extended events, the sympathetic system kicks in and causes too much constriction, because the PGI2 protection is lost Prostaglandins (PGE2)also modulate tubules More reabsorption + more ADH sensitivity Again, do not sell to sports people who excessively drink water, because losing the PGE2 prevents sodium retention, so they get hyponatremia Note: kidneys constituitively express COX-2 as well! Care! Take off the COX inhibitor, should return in function
Case 3 Hypotensive on admission Has a UTI with E. coli Thought normal renal function (but actually had half-normal) Given normal gent dose Also given contract Also given NSAID for pain Still hypotensive after hip replacement Given frusemide for oliguria Gent dose not adjusted, eventually drops GFR to 15 Hypotension : pre-renal NSAID- prerenal Gent- renal First dose of gent doesn't cause nephrotoxicity, so use it to save a person from sepsis Changes in GFr 48 hours after damage, too late For aminoglycosides, NEED to know GFR to know how to dose Remember: aminoglycosides have a long post-dose effect, conc dependent kill Here, we keep same dose, but different frequencies depending on
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 Here, we keep same dose, but different frequencies depending on For TDM Take blood samples 2hr and 6hr dose to calculate AUC and when trough concentration is 0 People don't tend to check levels at 1am or some absurd time Since they'll be on another antibiotic anyway, recommend next dose at a normal time to make sure the levels are checked Give dose when conc is about 0 (to prevent accumulation) Only problem is, only valid for stable normal renal function Someone has declining renal function (65 yr male) ACE inhibitor started half-way Should we stop it? No, do not take it off It's actually working. Because the glomerular pressure has been reduced due to vasodilation, which is protective Protective, because the contsction AT THE LOCAL LEVEL causes the damage If pressure is reduced at the SYSTEMIC level, then it can increase glomerular pressure It looks like it increases GFR, but over time, it causes rapid decline due to damage Reduce the pressure = vasodialtion = prevent damage Small amount of change in pressure will reduce GFR

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Workshop 1- Managing renal conditions in the pharmacy

Intro Most of the workshop mainly deals with urinary incontinence. We need to be aware about treatment options, red flags etc.

The other topic was about bedwetting (enuresis), which is common in children, and can be thought of as a subset of urge incontinence.
Note: all therapies in this workshop are non-pharmacological. We used to be able to give oxybutynin (anticholinergic, relaxes the bladder muscles), but it's been reclassified to prescription only. Urinary incontinence There are three main types of urinary incontinence Urge Bladder contractions are abnormally strong, the bladder is unable to store the normal amount of urine For some people, it can occur at night, leading to nocturia Diuretic use (especially thiazides and loop diuretics) can irritate the bladder as well, causing urge Prostate enlargement (common in men) will also cause similar symptoms (refer?) Urine loss can be from a few drops to a complete emptying of the bladder So people can suddenly and urgently need to go but might not make it in time Stress Caused by a weakness in the bladder, which causes leakage when the pressure in the abdomen increases (e.g. coughing or sneezing) Urine comes out as small spurts The weakness is usually due to weakened pelvic floor muscles, as they are a part of the external (and voluntary) sphincters keeping the urine in. They are frequently weakened after pregnancy due to birth causing damage Post-menopausal women may also a problems due to oestrogen deficiencies The causes could also be due to neurological damage (reduced innervation = can't contract muscles to close the sphincter) So if a woman who hasn't had children and isn't of menopausal age, she needs to be referred, because it's probably a congenital problem or neurological damage Overflow Caused by the partial emptying of the bladder Loss of full contraction to expel the urine (usually due to chronic urinary retention) Blockage in the urethra to prevent release Blockage may be due to tumours Can be caused by neuopathy (e.g. diabetes) And medications: TCAs and other anticholinergic drugs Alpha adrenoreceptor agonists Both prevent the sphincters from relaxing properly And a person can have a mix between urge and stress incontinence Need to manage on a case-by-case basis to see what symptoms can be reduced There are several ways to manage incontinence: Urge Bladder retraining to try and hold more urine in before having to go again Normally, a bladder should hold about 300ml, and it should take 3-4 hours to fill Bladder retraining is trying to increase the time it takes before they really need to go But they need to go if it becomes painful or really uncomfortable
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 But they need to go if it becomes painful or really uncomfortable Increase the time held slowly over time Tightening and relaxing the pelvic floor muscles helps to relieve the urge to go Keep a bladder diary to see improvements over time After some time, the bladder should be able to hold 300ml, and they should only need to go 8 times a day See a doctor to get oxybutynin Stress Pelvic floor exercises to strengthen that sphincter to keep the urine in Locate the muscles first by starting to urinate, and stopping half-way through Tighten these muscles up (they should feel like something is pulling up) Hold for 10 seconds (you're free to breathe by the way) Relax quickly, and repeat 3 to 10 times Quality, not quantity is important, these exercises are hard to do Oxybutynin won't help here (muscle tone is normal) Overflow Self-catheterisation to provide another route for the urine to leave See a doctor For obvious reasons, oxybutynin is contraindicated, because it will relax the muscles, which is what we DON'T want for a person who's struggling to push as-is. All Pads to absorb moisture if leaks occur Mainstay of treatment, these pads are specifically designed to pick up large amounts of moisture, and feel relatively dry against someone's skin There are different sizes and thicknesses, some can hold 25ml for light leaks, while others can hold 300ml+ for heavy leaks. Female hygiene pads are not suitable, they can only hold small amounts of fluid, and they will feel wet. For males: a pouch to collect urine They are also helpful for nurses, as they can easy measure the urine output of a patient Fluid intake Drink to thirst, do not overdrink (i.e. if you're not thirsty, there's no point to drinking water) Caffeine and alcohol will negatively affect you (they can increase urine production, and are bladder irritants), limit consumption, especially at night Diet and constipation Constipation will lead to straining, which can weaken the pelvic muscles. Therefore, have an adequate intake of fibre and water Laxatives should not be overused either, can lead to weakening of the pelvic muscles as well Weight Being overweight increases the pressure exerted on the pelvic floor muscles, makes them weaker Possible red flags: Emptying of the whole bladder in one go Symptoms of UTI (fever, pain, tenderness) Old males (could be prostate cancer) Youngish females without prior childbirths Bedwetting (Enuresis) Common in children Twice a month when 5 or younger is normal Once a month for 6 years old or above is worrying It is stressful for both the parents and the child There are two forms Primary- hasn't had the problem before, it's occurring now
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 Primary- hasn't had the problem before, it's occurring now Secondary- has occurred before, the problem has come back A possible trigger is stress, so if a child begins school, they might have secondary nocturnal enuresis A new sibling can also induce it as the child tries to get attention by imitating the younger sibling There are many possible causes: Caffeinated drinks at night Note: there's no point witholding fluids in the evening, let them drink water if they are thirsty Overactive bladder (similar to urge incontinence) Deep sleep, unable to feel the bladder is full Stress Neuropathic disorder (especially diabetes in secondary cases) Treatment: Diapers for trips away from home Water resistant covers for mattresses and duvets for easy clean up Sheets can be easy washed and returned Moisture alarms Very good for the deep sleepers who can't wake up These alarms detect moisture very quickly, so the child will wake up and realise their bladder is full A few weeks of treatment is very effective However, NOT to be used for already stressed children who are aware their bladder is full. Parents will buy these alarms to try and save themselves the hassle. Wake up the child at a certain time at night Physically wake up the child at the same time each night, then take them to the bathroom, they will learn that their bladder is full Do not lift the child to take them to the bathroom, they need to be fully conscious to learn their bladder is full Positive reinforcement (i.e. a reward for doing good) is much better than negative reinforcement (punishiments) Not only is it proven that positive reinforcement is better than negative reinforcement, negative reinforcement causes the child to get even more stresses Make the toilet accessible e.g. If they are afraid of the dark, make it light for them

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Workshop 2- Renal cases

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