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Section 1: Renal

Lectures 2-6 and workshops 1 and 2 deal with renal conditions

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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


Summary (since it's not being directly assessed): The kidney has mechanisms which regulate its own activity: Renal autoregulation If systemic blood pressure is reduced (e.g. sleeping at night), then the pressure at the glomerulus is reduced and we'd expect a reduction in GFR However, the kidney is able to constrict other vessels to maintain GFR even over a wide range of blood pressure Reminder: the afferent arterioles supply the glomerulus and the efferent arterioles drain it. The kidney can cause contraction or dilation in either to regulate itself Problem is, people with renal damage, the autoregulation system is less robust due to damage. It won't be able to compensate as well (blue arrows below) Hypertension is a huge problem as well, because in hypertension, the central pressure is high, keeping their GFR high. However, if we bring their pressure down back to normal, their GFR deteriorates as their physiological set point has shifted (red arrows below)

COX-2 and PGI2 Unlike the inflammatory response, COX-2 is constitutively expressed in the kidneys (i.e. always switched on) The PGI2 produced from COX-2 is important, because it allows enough blood flow to reach the kidneys during periods of sympathetic activation (i.e. PGI2 is a vasodilator, allowing enough blood to flow to the kidneys during times of vasoconstriction) If this protection is lost (via COX inhibitors), then patients may be at risk of acute renal failure due to ischemia. This is why we never sell NSAIDs to sportspeople, prolonged sympathetic activation during physical activity can cause renal damage
We also have to think about damage: Pre-renal- before the kidneys, e.g. low or high BP, Renal- direct damage to the kidneys/nephrons, e.g. gentamicin Post-renal- after the kidneys, e.g. UTI or blockage Renal damage (at the glomerulus): Nephrotic syndrome- the podocytes of the glomerulus have gaps between them due to damage allowing large proteins like albumin to be filtered, causing proteinuria. Nephritic syndrome- even worse, the gaps are large enough to let blood cells through,
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Nephritic syndrome- even worse, the gaps are large enough to let blood cells through, causing haematuria (blood in urine) Dipsticks can be used quickly to pick up on these two syndromes, which would warrant further investigations. Lastly, we need to consider the role of ACE inhibitors in renal failure ACE reduces blood pressure, which leads to a reduction of glomerular pressure and GFR That sounds like a bad thing, but they are renoprotective, keeping the arterioles dilated So even after this initial reduction in GFR, it is maintained for a long time BUT if the ACE inhibitor is stopped, the GFR rebounds back up a few ml/min. But it won't be maintained, and their GFR will deteriorate over time (not good)

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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 Fecal incontinence 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
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There are two forms 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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Section 2: Hepatic
These lectures and workshops deal with hepatic conditions

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Lecture 7- ADRs and the liver


Intro (and refresher) Adverse drug reactions (ADRs) are unwanted effects caused by a drug They come in two general flavours: Type A 'Augmented' ADRs occur due to a pharmacological action of the drug For example, warfarin is expected to cause bleeding events Because it's pharmacological, ADRs tend to be dose dependent AND predictable Type B 'Bizarre' ADRs occur due to an immune reaction to the drug So even very small doses can cause full blown effect (so doesn't depend on the dose) Hard to predict, we don't know who will have an immune reaction against the drug The most common example is penicillin sensitivity They all cause similar symptoms Fever Rash Eosinophillia Lymphadenopathy And finally, we really need to remember the fact that drug molecules are too small to cause an immune reaction just on their own. They will be bound to other molecules, or expressed along with something else to cause the immune reaction See dermatology lecture 4 to get a full idea about these ADRs The liver may be affected by ADRs, they are called drug-induced liver diseases (DILD) Quite common, 10% of ADRs involve the liver, 15% of acute liver failures are attributable to a drug Quite worrying, because liver ADRs are quite severe conditions (think liver failure), need to avoid them if possible Not normally detected during drug development Cases can be very rare, which is hard to pick up in smaller trials Cases may require certain co-morbidities, which might not occur or be screened for in trials An example is Ximelagatran, a direct thrombin inhibitor (similar to dabigatran) Caused permanent liver damage (and elevated enzymes) during phase III trials (the large one) Had to be canned for that reason Mechanisms of ADRs Again, we need to think about Type A and B reactions Direct toxicity of substances against hepatocytes (type A) Immune reaction against it or any of its products (type B) Reactive metabolites can play a role in both types of ADRs The reactive metabolites can covalently bind to macromolecules (such as proteins, which are rather important for the normal functions of cells) The loss of proteins, lipids etc. leads to cellular damage and death (type A) Or these conjugated molecules can be immunogenic (type B) Our body has mechanisms to deal with these reactive metabolites Scavenger molecules, like glutathione (GSH) will bind to these reactive metabolites instead Note: the thiol group (SH) is attractive for these reactive species Enzymes can metabolise a few Catalase breaks down peroxide But sometimes, it might not work, and these reactive species can cause toxicity
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But sometimes, it might not work, and these reactive species can cause toxicity Scavenger molecules can become depleted, which allows the reactive species to go ahead and cause damage The metabolism of substances may be reduced due to genetics Isoniazid can cause hepatotoxicity in people with reduce acetylation capabilities The immune system can also play a role People who express the HLA-B*5701 allele (i.e. express slightly different MHC) are susceptible to having immune reactions against flucloxacillin and ritonavir Two important examples: Paracetamol is an example of a type A ADR Excessive paracetamol intake (12g compared to 1g per dose) Normally, paracetamol is mostly sulfated But the sulfation pathway becomes saturated during overdose, forcing more to be metabolised by CYP2E1 The product of CYP2E1 is NAPQI, a reactive species Normally, the body has enough GSH to bind the NAPQI to prevent it from doing much damage, but in overdose, GSH is depleted, so NAPQI accumulates and damages the liver N-acetyl cysteine can be administered as an antidote, as it can help to replenish GSH to prevent damage But it needs to be given within 8 hours for maximal effect. Patients tend to be asymptomatic during the first 24 hours Also, we need to be careful in giving paracetamol to people, paracetamol is in many different products, and patients seem to believe paracetamol is a very safe drug (too complacent) Aromatic anticonvulsants, like phenytoin and carbamazepine can cause type B reacitons They produce reactive species as well, and they are normally cleared by epoxide hydrolase But they can accumulate and bind to proteins, which are antigenic People with HLA-B*1502 are susceptible to immune reactions against them What are the effects of toxicity? (i.e. what are the mechanisms of liver damage?) Necrosis Cellular disintegration which occurs due to damage or injury to cells and their components It can be located in certain parts of the kidney Remember: the kidney is separated into several zones, depending on how far away it's from the portal triad (the blood supply) Paracetamol will cause damage to the cells closest to the triad as they get the most toxins Ischemia will cause damage to the cells furthest away as they get the lest oxygen Or it can be diffuse, where it occurs all over the liver, regardless of zone. This is usually due to an immune reaction Steatosis Accumulation of fat droplets in the liver (i.e. fatty liver) Can be small droplets of fat due to mitochondrial toxicity (microvesicular) Valproate is metabolised by beta oxidation in mitochondria, can cause toxicity Larger droplets are usually due to triglyceride accumulation (macrovesicular) Methotrexate and amiodarone can cause this Appears to be similar to fatty liver seen in alcoholism Cholestasis Blockage of the bile duct, causing bile to build up and accumulate Can lead to jaundice due to accumulation Could be due to a physical blockage of substances or inflammation causing the ducts to narrow Can occur independently from hepatitis Steroids (cleared hepatically and secreted into bile) and antibiotics (especially flucloxacillin) are known to cause cholestasis And others we don't have to know about: Fibrosis and cirrhosis Vascular lesions
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Vascular lesions Neoplasms and cancers Overall management Consider risk factors for ADRs of the liver (these are the major factors): Age- older people are less tolerant, they are more susceptible to ADRs Pre-existing liver disease- the liver is already damaged, easier to damage it some more Alcoholism falls under this category Polypharmacy- high chance of interactions Need to diagnose it Identify anything significant in their history Medication history to see if any hepatotoxic drugs were used Social history to see how much they are drinking Clinical history to check risk factors Timing of any drugs or symptoms, might be able to see a drug causing a particular symptom Rule out anything by using the information gathered Then carry out tests to make a diagnosis Liver enzymes and function Imaging via scans Biopsy (take a tissue sample) The symptoms They tend to be non-specific, making it hard to diagnose Anorexia, nausea and vomiting in hepatitis Abdominal discomfort and pain Chance in urine or stools or jaundiced (usually due to bilirubin buildup caused by cholestasis) Systemic symptoms only present in hypersensitivity reactions (body wide rash, fever etc.) Signs

See lecture 3 for more details Otherwise, just remember ALT and AST are mainly hepatocyte DAMAGE GGT and ALP indicate biliary damage Jaundice and change in liver function (hypoalbinemia and increased INR) indicate liver failure

Options/plans: Withdraw all drugs which are non-essential (especially if it's started around the time the ADRs were starting to appear) Re-introduce drugs cautiously (and take them off if you discovered what was causing it) If there's an antidote, use it Paracetamol is the classic example If not, just give supportive treatment Fluids if required Anything for symptomatic relief like nausea and vomiting and coagulation Hope they make it (steroids won't help here)

Paracetmol overdose Most common cause of liver disease in NZ Supposed to be 1-4g daily in adults, 60mg/kg/day in children BUT it takes about 12g to cause a serious toxicity reaction Smaller doses will be serious for people who have risk factors (e.g. alcholics and the elderly) The pathophysiology is quite straightforward: Normally paracetamol is mostly metabolised by sulfation, while only a small amount is oxidised by CYP2E1 The small amount which is metabolised by CYP2E1 is converted to NAPQI, a toxic compound NAPQI is conjugated with gluthathione (GSH) to neutralise it and make it safe
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NAPQI is conjugated with gluthathione (GSH) to neutralise it and make it safe In overdose, the sulfation pathway becomes saturated because there's too much paracetamol. So most NAPQI gets metabolised by CYP2E1 This means there's more NAPQI being produced The huge amounts of NAPQI depletes the GSH, so the NAPQI remains unconjugated and it causes damage by oxidising cell components causing cell death To counter damage, N-acetylcysteine (NAC) needs to be given within 8 hours of taking the paracetmol as it will replenish GSH and keep GSH levels high to limit the amount of damage NAPQI can do Problem is, patients tend to be asymptomatic in the first 24 hours, so they won't call for help or feel anything so the NAC won't be administered in time After that, they feel really sick with anorexia, nausea and vomiting LFT elevation can be seen 18 hours after ingestion The maximum damage occurs 3-4 days after overdose, and liver failure will occur 3-5 days If they make it past these dates, then they'll be fine Pharmacists have a huge role to play here. We should be able to easily see and prevent any potential overdoses, as lots of different products contain paracetamol

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Lecture 8- Viral hepatitis


Revision: viruses Viruses are arguably not 'alive' They are just bits of genetic material and proteins (lipids sometimes) Genetic material (DNA or RNA) Can be single stranded (ss) or double stranded (ds) or even circular Since the genome is tiny, they only carry a handful of genes (3-30 genes) DNA viruses can use cellular machinery directly to replicate their genome and use host transcriptase enzymes to produce RNA to make proteins They can also borrow the host's error checking mechanisms to make their genomes stable and error free RNA viruses come in two forms: (+)RNA can be directly translated to produce proteins, no modifications needed (-) RNA which needs to be converted into DNA (via reverse transcriptase) and then to (+) RNA to be translated by the host Proteins and enzymes required for certain viral processes, like reverse transcription of RNA A caspid (outer protein coat) Protects DNA from physical, chemical and enzymatic damage Has attachments to allow them to gain access into cells Requires lysis of the host cell to release viruses if they don't have an envelope, see below These are called the naked viruses May have a membrane (envelope) Lipid bilayer stolen from the host membrane via budding (so the host cell can't be lysed) Has proteins studded in the membrane to allow the virus to gain access into cells Because they are so simple, the offer very few drug targets They are obligate parasites, they must hijack cellular machinery to replicate There are a few targets we can consider for viruses: Attachment- how they gain access to the host cell They attach to a receptor on the cell to trigger entry We can make antibodies which can outcompete the virus for these binding sites to prevent entry Or we can make antibodies which binds directly to the virus itself, because it appears to be similar to the receptor Release- the virus needs to eject its DNA out into the host cell once it's gained entry Amantadine can be used against influenza viruses, but it's not well understood Replication- they need to replicate their proteins, enzymes and genetic material Most of our drugs target here Reverse transcriptase is needed by some viruses for replication So it's targeted frequently, as human cells have no need for reverse transcription NRTIs and NNRTIs used in HIV are good examples Sometimes, viruses carry their own polymerase enzymes instead of using the host's, so we can target these enzymes Acyclovir is an example Assembly- they need to glue the pieces together HIV and hep C virus have a massive block protein which needs to be cleaved into useful proteins like capsid proteins and other useful enzymes So protease inhibitors will stop this Release- the virus has to be released from the host, can be either lysis for naked viruses, or budding for enveloped viruses Oseltamivir and zanamivir are neuraminidase inhibitors The flu virus needs to be released from the host cell during budding, neuraminidase will cleave the link between the virus and host cell But if it's inhibited, the virus is stuck and can't infect other cells Resistance is possible
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Resistance is possible Loss of drug target Change in the drug target so our drug can't bind to it Lastly, we can consider interferon treatments They cause cells to have a general anti-viral response Prevents entry Prevent uncoating Prevents translation of viral code

Viral hepatitis
Hepatitis A (HAV), Hepatitis B (HBV) and Hepatitis C (HCV) are viruses which can infect the liver and cause problems
HAV Severity HBV HCV Acute and chronic Asymptomatic primary infection Some get chronic infection, leading to liver failure Also high chance of carcinoma

Acute and self limiting Acute and chronic Limited damage caused due Disease can be cleared But can progress to chronic to immune response Very low mortality in immunocompromised or older patients Liver damage May also be an asymptomatic carrier Increased risk of hepatic carcinoma

Genetics

(+)ssRNA Naked
2-7 week incubation Acid resistant Massive protein needs to be cleaved (-)RNA made to be used as a template (+)RNA made is translated or packed into viruses Lysis to release

Unusual, semicircular DNA Long (-) strand Short (+) strand


The short (+) strand is completed by the host The looped DNA then is transcribed and translated RNA is packed into a capsid Then a reverse transcriptase will synthesise the original looped DNA The virus is budded using the golgi body

(+)ssRNA Enveloped
Similar to HAV, will talk about body markers instead HCV RNA seen in blood at ~1 month May have symptoms over 1-3 months Detectable anti-HCV antibodies produced at ~3 months Major spike in ALT, will remain elevated for life

Life cycle

Transmission Mainly: faeco-oral route Common in third world countries as a result Blood transmission uncommon Not passed from mother
Treatment None required

Blood-borne Sexual contacts Insects Can be passed from the mother


Interferons NRTIs IgG available Subunit vaccine available

Blood-borne (same as HBV)

Immediately give anti-HCV IgG Pegylated-INF (subcut) Ribavirin (Protease inhibitor) IgG available No vaccine available!

Prevention

IgG available Vaccine available (heat killed)

Note: IgG available means we can passively immunise people by administering IgG. Normally our bodies produce IgG against invaders, but we don't have time to give our immune system to set one up, so we just cut out the middle man and inject IgG IV.

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Lectures on alcohol
Pharmacies won't sell alcohol, but can sell homebrew kits, because we have historically provided chemicals to people More about distribution: less first pass (ADH in gastric wall, like Jap) and higher body fat in females (Vd lower, higher effective conc) [UNDER CONSTRUCTION]

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Workshop 4- Pharmacokinetics

Unedited notes from the presentations from the different groups: See below for other notes Case 2 (hepatic and paroxitene): start at lower end of range, and adjust as required Monitor for liver enzymes more frequently, monitor for signs of toxicity Case 3 citalopram in cirrhotic patient: citalopram is hepatically cleared, half life is doubled Low extraction drug, bioavailability not affected Doses (starting and maintanence) to be halved, but max of 40mg/day (as per normal) if not responding

Case 4 buspirone: non-benzo anxiolytic, partial agonist of 5-HT1A instead of GABA Normally low bioavailability CYP3A4 interactions possible Mainly excreted in urine Changes in serum protein binding reduced hepatic blood flow and reduction in activity of metabolising enzyme, F increases enormously, and reduction in clearance (so drug levels very high), high extraction drug! Variation too great, can't predict, just approach with caution and monitor liver enzymes, and avoid in complete failure
Case 5 metoclopramide on alcoholic cirrosis: Low extraction, clearance is halved, half-life is 2 fold, F unchanged Accumulation is a problem again, reduce dose by half, monitor for overdose symptoms (dystonia)

Case 6 Zidovudine in a patient with hepatic dysfunction: Half-life doubled, accumulation risk again No predictable dose modification, but not required, clinical records show any danger. But do monitor everything (adverse effects, liver enzymes and function)
General: Ask about social history (alcohol intake, liver surgery), other drugs, other conditions, what stage of cirrhosis Intro The liver and kidneys are important organs in clearing drugs Therefore, liver or kidney malfunctions will cause differences in pharmacokinetics Liver There are three types of drug metabolism we need to think about: Capacity limited Binding sensitive Binding insensitive Flow limited For all three types, we need to think about blood flow, protein binding and the intrinsic clearance Flow limited drugs are subject to a high intrinsic clearance, in other words, if it reaches the liver, it will be metabolised very quickly Therefore, the rate of metabolism (i.e. the rate limiting step) is determined by the hepatic blood flow, the more blood which reaches the liver = faster the drug will be removed It doesn't matter if the drugs are protein bound, they will be metabolised anyway
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It doesn't matter if the drugs are protein bound, they will be metabolised anyway It's hard to predict what happens to people with cirrhosis because: A reduction in metabolism occurs due to changes in blood flow (reduced blood flow, referred to as hepatic shunting) , occurs in cirrhosis and in other conditions like hepatosplenic schistosomiasis, where shunting occurs, but not liver cell damage Changes in the sinusoids (holes in capillaries) to prevent the protein bound drugs from accessing the hepatocytes Capacity limited drugs have a low intrinsic clearance, so it doesn't matter how much blood reaches the liver, the rate depends on the metabolism pathway itself. In liver disease, the number of cells will be reduced, so less metabolism can occur, leading to a decrease in the metabolic rate. And there are two types: Binding sensitive drugs (high fraction bound) may have a high intrinsic clearance, but the protein bound form can't be metabolised, so it appears to have a low clearance Because the fraction bound is so high, causing a change in the binding will cause a change in metabolism Binding insensitive drugs (low fraction bound) have a low intrinsic clearance, changes in protein binding won't affect metabolism much Makes it simple to guess what will happen, because the metabolism doesn't change with blood flow or protein binding Why is this all important? Because there are people out there with cirrhosis and other liver diseases, and we need to carry out dose adjustments to prevent overdosing them Hepatically cleared drugs will see a decrease in clearance, which increases AUC, so you need to adjust down to prevent accumulation and overdose toxicity Even worse, some drugs will have a high first pass effect (i.e. it gets metabolised a lot before entering the systemic circulation), and the bioavailability of these drugs will increase because it won't be metabolised as much before entering the circulation, adding to the problem above. i.e. more drug gets through because the liver doesn't break it down. It's like taking a larger dose, so overdose is possible if the dose isn't adjusted Another thing to consider are the hepatically activated prodrugs, such as ACE inhibitors, which need to be activated in the liver. We'd expect to have less effects of the ACE inhibitors, but in reality, the reduced production of the active forms is offset by the reduced metabolism i.e. although less active form is being made, the active form is being broken down slower, keeping the amount of actives similar to normal people Lastly, the metabolism can be entantiomer specific, such is the case for carvediol, a beta and alpha adrenoreceptor blocker. The (S) form blocks beta receptors, while the (R) form blocks the alpha receptors. In HEALTHY people, the bioavailability of the (S) form is about half that of the (R) form, but for people with cirrhosis, the first pass metabolism doesn't work as well and the bioavailability of both are drastically increased. The effect of this is to decrease the ratio of R:S, so relatively speaking, there is more S present compared to healthy people. Therefore, the beta blockade will be stronger in people with cirrhosis. i.e. be careful of enantiomers, they might not be handled identically by the liver Generally speaking, for patients with cirrhosis, we should: Ask about social factors, like how much and how often they drink (drinking contributes to liver disease) Look up references to see how much it should be rounded down But remember: carry out dose adjustments based on clinical outcome Check the severity of the liver disease, it's important. For example, drugs which are eliminated by conjugation will continue to be metabolised as normal until late stages of liver failure Ask about any other medicines and conditions. These people are susceptible to ADRs and interactions Renal
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Renal Refer to lectures to see how we can gauge renal function Refer to answers posted on blackboard (they are good) Be aware of altered pharmacokinetics: Odema due to fluid retention can increase the Vd of water soluble drugs Odema can also impair absorption of drugs When carrying out dose adjustments, you can change either the frequency (decrease frequency) or decrease the dose. Gentamycin has a dose-dependent kill, having a large concentration is desired, so a change in frequency is more desirable to get a large Cmax for the good bacterial kill action Look up oxypurinol and allopurinol (active metabolite which is renally cleared)

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Lecture 15 Prescribing practice and errors


Issues: the main one is overdose in both children and elderly (remember: they are frail and they tend to use narrow therapeutic range drugs. Pharmacy defence association releases cases to help test everyone

Near miss: up to the point where it's handed over, if self-checked and picked up = okay, but if someone else checks it, = near miss. Important for auditors, so as interns, we can make near misses a lot. Self check a lot. Dispensing error is after the point it's handed over
Types of errors Counting is off Wrong person They tend not to read the labels, they also don't tend to listen to names Double check via address Wrong calculation of dose Didn't call the doctor in time Due to self or others, communication was poor A lot are due to a mix of a lot

50 million scripts, 155 notifications for dispensing errors


Why take so long to pick up on these errors? 3 month stat Patients used to generics, changes are common, so they don't ask They might not read the labels They trust us, they don't expect to do the checking Wrong item and wrong strength account for most mistakes Similar names, especially if close to each other Very bad around insulins, don't know what the new mixes do Similar strengths Similar spelling Wrong dose form CR can't be seen easily sometimes. Be careful Similar packaging and colours What do to when an error occurs When notified- acknowledge and apologise and express immediate concern Inform you will investigate Question if they have taken it, or if any side effects Might be able to tell them Talk to the PDA (Pharmacy Defence Association) as soon as possible

Stock bottle there to check Check with prescriber if unsure. Important.

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Consultant pediatric -Paediatric platitudes


Thursday, 20 September 2012 12:03 p.m.

Don't need to know everything, need to know what to do next (working structure) Remember: Children are growing and learning. Need to teach them, but hard to captivate them to teach So use play to galvanise their attention Always remember: primum non nocere (do no net harm) 3 big (90%) acute in paediatrics: Infection- usually affects: Respiratory GI Problem is not so much the child They have different presentations, and are undifferentiated (i.e. general symptoms only), hard to diagnose Parents can freak out We need to determine if it's serious or not

Physiologically, they are not small adults (esp. with PK) They present different symptoms (as above), severity also depends on age as well (think neonate)
Babies 200g a week for the first few months 1 year, 10kg 5 or 6, 20kg (doubled during preschool) so 2kg a year on average So slowing down of growth during these years, if parents ask if they aren't growing enough, then just tell them the growth slowing down Ball park figures are good, especially as a safety measure (e.g. that doesn't sound right) Shape of child suggests metabolism Infants are round and growing (immautre shape)- immature hepatic and renal metabolism, physiology is immature in general Since so small, getting a cold can be hospitalised because they can't eat properly, but for us (large), we'll be fine So predisposed to things due to size or anatomy Children Starting to thinning out, some musclular growth and their BMIs will be abnormal compared to adullts (do not use adult measures) Tend to be healthy Adolescent Size and anatomy and physiology same as adult Know your limits: If self-limiting, don't touch (plus if normal, don't try to fix it like spilling out of the mouth which is normal) Fess up to the limitations of therapies (might not be working, or very effective), a lot of our role is education instead, realign expectation to reality So understand what's normal and tell them it's normal and try not to rip people off by selling useless stuff If I don't know, then ask someone else, can work with people (ethical as well) Viral upper resperitory tract infections are the most common (all the following, remember they
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Viral upper resperitory tract infections are the most common (all the following, remember they don't know anatomy) Antibiotics really don't work much here, small role only (parents will ask for them) Viruses don't know anatomy, they will only infect contiguous areas of epithelium they are desinged to invade (e.g. laryngitis and pharyngitis)

Acute Otitis Media Eair pain, fever and discharge Inflammatory process, pus behind the drum Usually occurs with a cold, tubes become blocked, fluid build up will cause secondary bacterial infection NNT is 7 to reduce pain by 3-4 days But the side effects to everyone else is pretty bad (e.g. GI upset), so harm>benefit for most people Glue ear is not acute, but chronic serous otitis media Persistent and troublesome, hearing loss is possible Can lead to developmental deficiencies Croup Big-airway-itis (in the voicebox, they can't breathe properly) Have cold for a few days, and suddenly having trouble breathing (sounds gasping) because breathing through narrow space Seal or dog bark like coughing Laryngitic cough Normally mild, self-limiting illness, so don't have to treat everyone Less than 1% it's a true breathing problem (intubation or steroid use is rare) Steroids and adrenaline can be given, refer to doctor instead
Bronchiolitis Asthma like, won't respond to asthma treatments as it's viral Can't breathe properly Don't have smooth muscles much and no inflammation, so asthma treatments don't work Treatment is supportive If can't feed or oxygenate self, then they need hospitalisation (shouldn't need it too much Common in winter or spring Tonsillitis, pharyngitis Mostly viral in children Just a headcold symptom with throat Group A strep can also cause it (e.g. pyogenes) can cause rheumatic fever (bad for heart valves) Genetics dependent, HLA types determine suspeptibility, Northland is very bad Pussy looking and older children in throat will be bacteria Teething One symptom most consistently- teeth Local symptoms common Local pain common Minor distant symptoms, but nothing major A bit grumpy and maybe a bit of a fever at most (perhaps) But if fever with GI and stuff, then it's something else Cough Even when healthy, 30% still have a chronic cough (6-8 weeks in one year) and so it's common Doesn't have to be unwell to have this common cough Usually minor illnesses, like post viral cough can be a few weeks
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Usually minor illnesses, like post viral cough can be a few weeks Can be imporant Cough suppressants don't work well So just use demulcents Wheezing Expiratory noise, usually asthma or bronchiolitis Cough + wheeze can be asthma Children and neonates can wheeze eaily because of their small airways Especially when exacerbated by infection So why and how hard they wheeze is the issue Persistent or frequently episodic or cause difficulty in breathing needs assessment By early school age, they can: Such on a turbuhaler properly Can swallow tablets And blow on turbuhaler So it all depends on the child's ability to determine things like route and type of therapy The more things you ask someone to do more, then they'll be less complient Paracetamol- panacea For distress due to pain or fever, but it's not a wonderdrug which fixes everything Gasteroenteritis Feed and give fluids as normal Brestfeeding should be continued 5-10ml every 5-10 minutes (not much so can't vomit a lot)= small amonts regularly ORS will only work for more dehydrated people (mildly dehydrated people won't like the salt, more dehydrated people tend to be salt craving due to depletion), so normal fluids are better if midly dehydrated

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Childhood complaints
Thursday, 20 September 2012 2:04 p.m.

Headlice products not good for eggs, don't have to do the whole family Headlice stay close to the scalp, 6 legs (can't see them) and two are gripping type. Break either one of the grippers (or legs), they can't grip and they can't mate (no longer attractive) Colour described as eigher light or dark colour, they are actually translucent (so depends on hair colour and feeding, because feeding = darker) so colour isn't important Nits = eggs stage or egg casings, hard to see unless they are in a population. Firmly attached to the scalp, if able to flick off, then it's dermatitis instead. Oval- yellow to white colour. Takes a week to hatch. Look behind the ears and the nape of the neck, they are common there. They target that area because it's WARMER. It's temperature (31 degrees), plus close to the skin, easy to feed Hatches into nymphs- baby lice. Look like small adults, matures in 7 days and begins to feed on blood Adult stage- females are larger and are in a higher ratio compared to males (4:1), also feeds on blood If they fall off, they die in 1-2 days, and pretty much they won't let go, so the only ones which fall off tend to be the weak and sick, so they aren't reviable again. (cf. scabies which can live easily for a few days and come back on, so washing is required for them, not for lice) Females lay 7-8 eggs per day and live 30-40 days (lots of eggs) 45 minutes per feed (very long, they use anticoagulants in saliva to keep it open), several feeds per day Itching caused by saliva The only worst thing that could possibly happen is a secondary bacterial infection Fine tooth comb recommended ALL the time. Comb out and examine what's caught on it Use conditioner, because it stuns the lice and makes the comb easier to run through the hair They move around for about 20 minutes after application, they don't like it, so they won't be able to hold on as tight What they see on tissue is confirmation Then treat the children only if they have adult headlice, not if they don't have any But monitor for headlice formation for a week The diagnosis with conditioner and the comb can actually be a treatment, just takes a bit of time Failure rates of chemicals is due to not repeating. Because it kills adults and lymphs, so no new eggs, but the eggs survive and they come through. So hit them again 7 days after initial treatment If it's a genuine failure, try another chemical

Note: tea tree and eucalyptus oils actually have the same LD50s as the chemicals, so there's no point to using them and they are not to be used as preventer (toxicity). Tiny amounts as additives (i.e. dilluted), then it's fine. Use during treatment phase is alright, not alright for continuous use prophylaxis
Prevention: Washing the headwear and combs is recommended, everything else isn't required Females get it more, length doesn't matter. Instead, it's because the activity of the girls (playing with each other's hair) Note: they prefer clean hair Hair tied back Check for lice every week Treatments:
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Treatments: Malathion 1% Shampoo affected area Leave in for 10 minutes Repeat 1 week later Avoid: Broken skin Under 2 years Pregnant or expected mothers Avoid eyes and face Not to be used as a preventer Permethrin also available, same instructions Nappy rash Uncomplicated rash- just direct damage, looks angry and the margins are really clear, no maceration or white skin, so no antifungals are required If there is spotting around past the margins and whiteness, especially around the folds of the skin, that's fungal and requires an antifungal IF using HC+antifungal, can't use the cream every nappy change (tid vs a few changes per day), so would have to also include a normal cream + antifungal between the HC applications Should resolve in 3-4 days

Reflux: Try cow dairy free diet for 2 weeks Food thickener before feeds, feed from a spoon to the child before feeds Reduce volume rate entering stomach to reduce it If that don't work, move onto gaviscon infant sachets Alginates are a raft antacid 1 dose below 4kg, 2 doses above 4kg Mix into hot water to form paste, and mix into 10ml and feed via spoon (breastfeeding) Add sachets to feed (120ml) if bottle 6 doses max daily Do not use with thickener Raise baby when awake to reduce reflux Avoid pressure on stomach Crying over spilt milk for reflux Colic Cried for more than 3 days a week for 3 hours for 3 weeks Source of anxiety Screaming after feeds or wakes while sleeping Not colic Crying is normal crying Drawing legs up to tummy not all the time Cannot settle after feeds for a long time Grumbling is not colic If not calm if setting to sleep If happy for 15 minutes between crying Checking crying over spilk milk website as well Infantcol

Q5- mother comes in with 9mo kid who is going through teething, wants paracetamol AND ibuprofen

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Paracetamol: 15 mg/kg x 8 kg = 120 mg, that's 5ml because it's 120mg/5ml 4 doses in 24 hours (q6h) Ibuprofen: 20 mg/kg daily, 8kg = 160mg, 3 doses = ~50mg a dose, 2.5ml of a 100mg/5ml Can also use bonjela gel (salicylate) every 3 hours Minimum Tid for micoconazole cream, barrier ointment all times, HC only tid max Nappy rash Overhydration of skin causes weakening of SC 'breathable' sheets allows moisture to leave the nappy to reduce overhydration Now nappies can apply petrolium (vaseline) to skin continuously as well (barrier) Diarrhoea can also make it worse Can occur after or during a course of antibiotics as a side effect Diarrhoea can also increase fungal growth Should settle down after the antibiotics Increase in pH on skin increases enzyme activity, more damage to SC See above for barrier Caused by ammonia production from urea by bacterial urease Proteases from GI tract will also cause direct damage Avoid wipes of higher pH? Not really Frictional damage wears away SC Mild More pink spots rather than patches No spread Crying after passing bowel motions Moderate is in between Severe: Cracking of skin Patches Spread away from nappy Brighter red with fungal Small white spots around the edges with fungal as well Spread along skin folds Seborrheic appears crusty and greasy Mostly the overhydration was the problem, has been reduced in the new designs HealthE fatty is best ointment (hold moisture and provides barrier) and feels alright. Zinc oxide and castor oil is even better though so try it first HealhtE fatty cream is good because it's also a moisturiser Second line, retains moisture well Can mix easily with antifunals Note: antigunal then base if using two creams/ointments ZnO can be used every nappy change Barrier and astringent First line, superior barrier and healing is best Stiff, hard to mix with antifungals If not working, check to see if they are using it often or if changing nappies often enough Miconazole can be used every nappy change (directions say bd, but can be used all the time) Use for at least 7 days after symptoms resolved The Miconazole + HC can only be used 3 times a day Prefer normal miconazole only cream Or just HC cream indidually Note: vaseilne is white soft parafin
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Note: vaseilne is white soft parafin

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Poly pharmacy lecture


Monday, 24 September 2012 2:01 p.m.

Use of 2 or more medicines for 480 days in 2 years (i.e. regularly on more than 2 drugs) Use of a drug not indicated for that person Why important? Increased risk of all types of reactions (drug-food, drug-drug and ADRs) Who's most at risk? Multiple co-morpidities, chronic diseases, oldler people and people with several doctors ADR (reaction) Undineded, noxious and occurs at standard dose Think about A and B types ADE (event) ADRs plus harm from errors (e.g. dispensing error) DRP (drug related problem) Above + interferes with optimal outcome A huge number of people were on medications which had no indication or were less than optimal Oldest people tend to have polypharmacy, high risk (plus increases with age, diseases and care visits, which all come with age as well) Most common: CVS drugs by far most common

Multiple drugs can be needed for multiple conditions, or is more effective, but at higher risk of ADRs
Poly pharmacy can increase hospital admissions, interactions and non-adherence Can cause geriatric syndrone Some drugs like benzos become enhanced binding (pharmacodynamic) Gastro protetion reduced, more likely to have an ulcer Reduction Continuing medical education, so doctors prescribe better or less Consensus crieria developed, say which meds are best avoided in older people (.e.g STOPP for stop, START for start and Beers to see what to be avoided) Clinical pharmacists to reduce MUR- med use review- patients are educated about the drugs, compliance etc. (adherence) MTA- med therapeutic assessment- more advanced, check patient notes and check doctor's prescription and see if appropriate (called medication review) Make sure patients undertsand about drugs, more likely to adhere, see what they think about their meds Impairments can affect adherence (e.g. poor eyesight)

See repeat patterns, see if they're taking meds and resupplying regularly Encourage family support so they can help them with meds Written instructions Simpify medicine regimens where possible Medico packs Maintain comprehensive med profiles, including OTCs

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Temazepam- best out of the three, but really, can't we just do this without drugs? Suggest zopiclone short t1/2 Digoxin a cause of concern, renally cleared, same with quinapril, because it might be too high dose Digoxin a huge cause of concern, 70% renal cleared, increases and it's also a low TI as well. Check signs of overdose, like vision problems, can lead to death. Reduce the dose and carry out TDM Not A or B (amitriptiline) because strong anticholinergic, C (nortriptyline not as bad. D (gabapentin) is best Amiodarone and warfarin interaction, 2C9 = amiodarone is a substrate, 2C9 important for warfarin metabolism (affects the S active form), reduce dose by 33%. Monitor INR closely Pneumonia, allergic to penicillin, Azithromycin is no interaction with CYP, the other mycins will affect CYP Potassium supplement and on quinapril and spironolactone (those two would be risk of hyperkalemia) but wants to buy K on top of that bad idea See recipie 6 or more drugs 12 or more daily doses 2 or more chronic conditions 2 or more prescribers 1 or more of the following: High risk drugs High risk drug combos (e.g. tripple whammy) High risk drug-condition combos Various herbal or alternative therapies

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Hepatic guest
Monday, 24 September 2012 2:58 p.m.

[UNDER CONSTRUCTION] Hepatic artery DOES NOT brings most of the oxygen (comes through venous system) Major immunological organ All orally taken drugs will pass through the liver (first pass) All blood from the gut will enter the portal vein system, so will enter the liver Drugs leave through the hepatic triad into sinusoids to touch all the cells and then into central vein, Central veins drain into the hepatic vein and into vena cava

VLDL (fat metabolism), glyucogen and protein production (albumin and clotting) as well as metabolism of mostly lipophiilic drugs to make them hydrophillic for excretion Tends to be in two steps (phase I and II metabolism)
Direct bilirubin=conjugated then is excreted into the bile. Direct is normal, indirect is up, ALP is normal (no damage to ducts) while ALT is high (hepatocyte damage) GGT is also high (bile duct enzyme) This person has Gilbert's syndrome (or if hemolysis is taking place), faulty UGT transferase Hepatocellular damage = high ALT, other enzymes can be mildly raised (viral hepatitis) Cholestatic is the oposite (PBC/PSC and billiary obstruction Mixed is raisure for everything Statins rarely cause severe drug induced liver damage, so don't need to worry about giving statins for these people, risk tends to be over stated Drug induced liver injury Intrinsic- like type A Idiosyncratic- like type B Mechanism unknown about drug induced damage, appears to be a multistep process leading to damage and cell death NAFLD (non-alcoholic fatty liver disease) 2/3 of people had it with elevated enzymes Insulin resistance leads to steatosis (diabets and obesity as well) As long as it's just fat, it's alright. But if inflammation starts, then we start to worry, can cause cirrhosis Causes NASH Pioglitazone is good for treatment: reduces inflammation while increasing sensitivity and reducing lipid accumulation But will lead to weight gain (increase adipose)

HBV: lamivudine, adefovir, entecavir, tenofovir, PEG-IF, HCV: PEG-IF/Ribavirine or Telaprevir


These cause increased risk of hepatocarcinomas Hep C no cure and no vaccine IV drug use is the major cause
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IV drug use is the major cause Small proportion will clear the infection Most will progress to cirrhosis and then liver cancer Hep C is the most common indication for hepatic transplant Treatment for HCV can be: Non responder (no effect) Parital, just never clear the infection, slight drop Relapse is where it drops down to assymptomatic, but comes back Sustained vironogical response, keeps HCV RNA -ve at 6 weeks after treatment RVR- rapid clearance at wk 4 EVR is 12 weeks, slower, but still good because it's undetectable as well (so is good) Genotype 1 doesn't doesn't respond as well as 2 or 3 Geno 3 = 6 months, geno 1 is 12 months Depression is the major side effect, very danagerous if personality issues, plus they will be battling with drug use as well Warning: successful treatment doesn't mean immunity, can become reinfected causing relapse (regardless of genotype) So vaccination not successful HBV infection Can be asymptomatic for life, don't develop cirrhosis Not everyone should be treated Treatment goal is to reduce the level of viremia to low levels HBV baby 90% chance if mother is infected First phase: immune tolerance, the body doesn't regognise Treat only during immune clearance, Tenofivir a good choice, because they don't cause resistance Slides on Bb

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Workshop 8- PK in elderly
Tuesday, 25 September 2012 10:57 a.m.

Case One a. Take ideal body weight into consideration instead (compared to the first one which uses actual weight), this might be required because patients with renal failure can be heavy, but it's due to extra fluid a. The other part of the equation takes renal function into consideration, as higher GFR = higher Vd, allows different stages of renal disese to be taken into consideration b. Note: binds strongly to lean weight (binding sites), will be displaced from sites if stuff from renal clearance builds up b. Renal clearance blunted by 10%, non-renal blunted by 50%, probably blunted due to reduced blood flow to the organs a. Range of models available, all take both non-renal and renal into consideration c. Give the loading dose is 750 micrograms, just 3 250microgram tablets NOT to be given at once, 250 micrograms (1 tablet) every 6-8 hours. The reason is it takes very long to distribute, so space them out to allow distribution. Otherwise massive overdose before distribution. a. Also, if in doubt, round down in terms of dosage forms d. Take TDM dose at least 6 hours after taking dose, takes a long time to distribute into tissues a. But the trough is the best one, it's the most dependable, we know when it's trough because we dose before it b. Plus take first dose after steady state (about a week), but check a level earlier if they have side effects e. Toxicity: a. See NZF f. Half-life is (assuming 352L, 132L/day), 1.85 days g. Assume first order a. D=Do.e-kt b. At 7 hr, 89.6% left c. At 1 day 68.7% left h. Factors a. Hyperkalaemia, toicity can occur at normal digoxin levels if high potassium b. Thyroid status, either hyper or hypo causes different responses to digoxin, hypo -0.3, hyper +0.3 in CL factor c. Interactions like quinidine, changes CL and V d. Adsorption of dose can occur with high fibre flood and other adsorbent products, so bioavailability drops

Case two
a. A linear relationship, higher GFR= more filtration of ions a. Influenced by sodium b. 0.25xCLcr, because it's freely filtered, but in the proximal tubule, it's reabsorbed like sodium, so expect it to be less compared to GFR b. 39.1ml/min is CLcr, so 9.78ml/min c. Vd= 49L, k is 0.01198 so t1/2 is 57.8h d. Yes, 39 ml/min is low function, need to be careful a. MW of lithium carbonate is 73.9g/mol, so each 500mg tablet containes 6.77mmol, and since there are 2 lithium ions per lithium carbonate, there's 13.6mmol (and since it's a monovalent cation, it's 13.6mEq) b. Dose rate is 1.13mEq/h as it's 13.6mEq every 12 hours c. Average plasma level is 2.1mEq/L (dose rate per hour/clearance per hour), so 2.1 is high d. This level is higher compared to the actual, could be due to: i. Sterum cretitione stable? ii. Compliance? iii. Sodium intake? Changes how it's reabsorbed, so high sodium decreases amount absorbed, so increased clearance e. Yes, needs to be reduced because he's got , work out later a. Dose rate = Cp x CL f. Hemodyalysis? Since it's a small polar molecule, it will be dialysed. BUT Not really going to work much, because the volume of distribution is high, rebound can occur if hemodyalosis is stopped too soon because lithium will enter into central from peripherial areas Case three

Try to avoid use in elderly (Beers' list med)- confusion and falls risk, plus lots of CYP interactions possible, additive effects with CNS depressants (they can be using a few already), and longer half-life with longer risk of accumulation But use short t1/2 with no active metabolites for geriatric patients as a hypnotic - temazepam or zopiclone Ambulatory (can move around), need to use a medium to long- lorazepam But for bed-ridden, use med-long as well Not for long term use, if they are, see the reason for it, and try to discuss with the patient and doctor to see if it can be withdrawn
Changes: t1/2 can be longer, so accumulation is higher

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Integrator
Thursday, 27 September 2012 9:06 a.m.

Therapeutic 75 year old with a list of meds

Felodimine 10mg daily ISMN 10mg bd Cilazapril 2.5mg daily Frusemide 80mg bd Amitriptyline 25mg n -- change to nortryptyline Laxol 2 n Digoxin 250mcg daily Warfarin per INR COX-2 inhibitor (selective NSAID)
FALL= they go down hill from there. So one primary objective of geriatric meds is to prevent falls. Associated with huge morbilidty and mortality Problems Review blood pressure control and monitor blood pressure, postural hypotension may be an issue Digoxin and warfarin, interactions? TDM ? Triple whammy- NSAID, cilazapril and frusemide Triple whammy = renal damage with 10% mortality NSAID normally can cause renal failure in heart failure patients, the other two parts of the whammy just make it more common Digoxin and hypokalemia with frusemide, potassium competes with digoxin at the target pump, causes toxicity- burred vision and diziness so falls risk Warfarin + NSAID = bleeding possible Amitrptyline- anticholinergic effect (constipation, confusion, dry mouth, urinary retention), also arrythmia (very important) Laxol started similar time along with antiarrythmics, stop amitriptyline Laxol could probably be removed at the same time Arrythmias should be reviewed If not arrythmias, can change warfarin to aspirin because risk of stroke is reduced A good nights sleep is important for mood Consider changing ISMN to GTN spray for angina, 10mg is a low dose

Falls:
Non-pharmacological Bed pot/chamber Adequate lighting at night Move room closer if possible Check frusemide, make sure not taking it at night, because he's getting up at night 160mg od at morning SOB Anaemia? Heart failure uncontrolled Renal failure starting? Odematous lungs can cause SOB NSAID as well

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