CSB536 QUT - Lecture - Week 3 - Pharmacology_2024_SW1 PDF

Week 3 – Pathology Testing and Prescribing (Lecture) CSB536 Clinical Therapeutics for Podiatrists – Lecture Bachelor of Podiatry, School of Clinical Sciences, Faculty of Health TEQSA Provider ID PRV12079 Australian U...

Week 3 – Pathology Testing and Prescribing (Lecture) CSB536 Clinical Therapeutics for Podiatrists – Lecture Bachelor of Podiatry, School of Clinical Sciences, Faculty of Health TEQSA Provider ID PRV12079 Australian University | CRICOS No.00213J CSBS536 Clinical Therapeutics for Podiatrists Bachelor of Podiatry, School of Podiatry  ACKNOWLEDGEMENT OF TRADITIONAL OWNERS QUT acknowledges the Turrbal and Yugara, as the First Nations owners of the lands where QUT now stands. We pay respect to their Elders, lores, customs and creation spirits. We recognise that these lands have always been places of teaching, research and learning. QUT acknowledges the important role Aboriginal and Torres Strait Islander people play within the QUT community. TEQSA Provider ID PRV12079 Australian University | CRICOS No.00213J CSBS536 Clinical Therapeutics for Podiatrists Bachelor of Podiatry, School of Podiatry  Learning Outcomes Addressed ULO3 – Interpret and evaluate patient’s medical, medication, podiatric and social history to manage podiatric conditions. TEQSA Provider ID PRV12079 Australian University | CRICOS No.00213J CSBS536 Clinical Therapeutics for Podiatrists Bachelor of Podiatry, School of Podiatry  Where are we looking on the NPS Framework? To understand the management options and later inform therapeutic monitoring, interpreting diagnostic testing can be TEQSA Provider ID PRV12079 Australian University | CRICOS No.00213J necessary CSBS536 Clinical Therapeutics for Podiatrists Bachelor of Podiatry, School of Podiatry  Pathology Testing Most pathology testing is organised by medical practitioners. It is important for podiatrists to work up to their scope of practice, but to understand their own limitations. Managing and interpreting the significance of pathology tests will often require training. Many pathology tests are non-specific and the findings can be misinterpreted. It is less burdensome for patients to schedule a blood test with other blood tests. Currently no Medicare rebate for patients if a podiatrist refers a patient to pathology TEQSA Provider ID PRV12079 Australian University | CRICOS No.00213J CSBS536 Clinical Therapeutics for Podiatrists Bachelor of Podiatry, School of Podiatry  Pathology testing Kidney function (e.g. Creatinine, eGFR) Hepatic function (LFTs) Important for indicating Microbiology (bacterial, fungal) pharmacotherapeutic approach. Aspirates Blood tests (FBC (or CBC), CRP, ESR) Monitoring therapeutic response to management? Histology TEQSA Provider ID PRV12079 Australian University | CRICOS No.00213J CSBS536 Clinical Therapeutics for Podiatrists Bachelor of Podiatry, School of Podiatry  Liver - Metabolism Ultimately the liver wants to make the drug more water soluble so it can be eliminated in the urine. It does this by Functionalisation reactions and Conjugation reactions. Functionalisation reactions involve the addition of a functional group to the drug. This is enhanced by the Cytochrome P450 enzymes. These enzymes are divided into groups. They are named CYP followed by a number that denotes the family, a letter that denotes the sub family and a second number that denotes the form eg CYP2D6. These enzymes are important in understanding drug interactions as several drugs may be metabolized by the same enzyme. Conjugation reactions involve the addition of a polar group from an endogenous substance (eg acetyl-coenzyme A) to the drug. TEQSA Provider ID PRV12079 Australian University | CRICOS No.00213J CSBS536 Clinical Therapeutics for Podiatrists Bachelor of Podiatry, School of Podiatry  Liver - Metabolism TEQSA Provider ID PRV12079 Australian University | CRICOS No.00213J CSBS536 Clinical Therapeutics for Podiatrists Bachelor of Podiatry, School of Podiatry  Liver Function Blood flow through the liver is approx. 90L/Hour - this designated QH ~100mL/min per 100g liver wet weight 25% cardiac output flows through the liver. Each time a drug passes through the liver some of it will be metabolised, CLH. The hepatic extraction ration EH is then given by EH = CLH /QH TEQSA Provider ID PRV12079 Australian University | CRICOS No.00213J CSBS536 Clinical Therapeutics for Podiatrists Bachelor of Podiatry, School of Podiatry  Liver Function Tests Non-invasive method of screening Patterns: Hepatocellular Cholestatic Tests do not always correlate with disease severity or prognosis Useful in acute disease to track liver disease on a day-today basis, and Response to treatment TEQSA Provider ID PRV12079 Australian University | CRICOS No.00213J CSBS536 Clinical Therapeutics for Podiatrists Bachelor of Podiatry, School of Podiatry  Liver Function Tests and Liver Function Technically the majority of the analytes that are routinely measured reflect liver damage not function. Normal LFTs do not always mean that the liver is normal. e.g. patients with cirrhosis can have normal LFTs. Abnormal liver function tests are a common finding. Deranged LFTs ≠ Deranged LF May reflect problems arising outside the liver, such as haemolysis or bone disease. TEQSA Provider ID PRV12079 Australian University | CRICOS No.00213J CSBS536 Clinical Therapeutics for Podiatrists Bachelor of Podiatry, School of Podiatry  Liver function tests A blood test is taken to determine concentrations of: Alanine aminotransferase (ALT) – Hepatocellular damage eg viral infection, drugs, Alcohol, toxins, Anoxia, biliary obstruction. Aspartate aminotransferase (AST) – Hepatocellular disease (Egs same as ALT) TEQSA Provider ID PRV12079 Australian University | CRICOS No.00213J CSBS536 Clinical Therapeutics for Podiatrists Bachelor of Podiatry, School of Podiatry  Liver function tests continued… Gamma glutaryl transferase (GGT) – Alcohol abuse Alkaline phosphatase (ALP) – Liver disease, bone disease (or metastases) Lactate Dehydrogenase (LD) – Non-specific indicator of disease (wide tissue distribution) AST = aspartate aminotransferase ALT = alanine aminotransferase TEQSA Provider ID PRV12079 Australian University | CRICOS No.00213J CSBS536 Clinical Therapeutics for Podiatrists Bachelor of Podiatry, School of Podiatry  ALT/AST Ratio Of more use than the absolute values of AST and ALT is the ratio between ALT and AST. In order of decreasing ratios of plasma concentrations of AST/ALT Toxic/ischemic injury > Acute viral hepatitis > Alcoholic hepatitis > Chronic hepatitis > Cirrhosis > Normal TEQSA Provider ID PRV12079 Australian University | CRICOS No.00213J CSBS536 Clinical Therapeutics for Podiatrists Bachelor of Podiatry, School of Podiatry  Gamma glutaryl transferase (GGT) Elevated levels may indicate: Cholestasis Enzyme induction Alcohol, phenytoin, barbiturates, rifampicin Congestive heart failure Cirrhosis Hepatic ischemia Hepatic necrosis Hepatic tumour Hepatitis Hepatotoxic drugs. TEQSA Provider ID PRV12079 Australian University | CRICOS No.00213J CSBS536 Clinical Therapeutics for Podiatrists Bachelor of Podiatry, School of Podiatry  Prescribing in liver impairment No easy guide or rules Prescribing in hepatic impairment is less well defined when compared to guidelines for prescribing in renal failure. Knowledge of the metabolism of drugs eliminated by the liver is useful along with close monitoring of the patient for unwanted adverse effects related to possible toxicity. When introducing long-term treatment with a drug with high hepatic clearance or a narrow therapeutic index, assess liver function with liver function tests. If doubt about impairment or low therapeutic index → reduce dose by 50% & titrate TEQSA Provider ID PRV12079 Australian University | CRICOS No.00213J CSBS536 Clinical Therapeutics for Podiatrists Bachelor of Podiatry, School of Podiatry  Renal Structure and Function Kidneys make up 1% of body mass, but receives about 25% of cardiac output. Kidney has four major functions: 1. Filtration of blood: Removes metabolic wastes from the body, esp. those containing nitrogen 2. Regulation: Blood volume and composition Electrolytes Acid-Base Balance 3. Endocrine: Erythropoietin (EPO) Renin 1,25 dihydroxycholecalciferol (1,25 Vitamin D) 4. Formation of urine TEQSA Provider ID PRV12079 Australian University | CRICOS No.00213J CSBS536 Clinical Therapeutics for Podiatrists Bachelor of Podiatry, School of Podiatry  Kidney Functions TEQSA Provider ID PRV12079 Australian University | CRICOS No.00213J CSBS536 Clinical Therapeutics for Podiatrists Bachelor of Podiatry, School of Podiatry  Glomerular Filtration Rate(GFR) Volume of plasma filtered/unit time Approximately 180 L/Day Urine output is about 1-2 L/Day About 99% of filtrate is reabsorbed https://shorturl.at/eEXY8 TEQSA Provider ID PRV12079 Australian University | CRICOS No.00213J CSBS536 Clinical Therapeutics for Podiatrists Bachelor of Podiatry, School of Podiatry  GFR Influenced by Blood pressure and blood flow Obstruction to urine outflow Loss of protein-free fluid Hormonal regulation: Renin–Angiotensin Aldosterone ADH ANP https://shorturl.at/emwPS TEQSA Provider ID PRV12079 Australian University | CRICOS No.00213J CSBS536 Clinical Therapeutics for Podiatrists Bachelor of Podiatry, School of Podiatry  Renal Clearance The kidneys are the main site for the clearance of water soluble drugs from the blood Renal Clearance is the net effect of glomerular filtration, secretion and passive reabsorption. Egs of drugs principally excreted by the kidneys are; Penicillins and Cephalosporins (both on the List of medications available to endorsed podiatrists). When the renal function is decreased more than 50% and the drug is more than 50% cleared by the kidneys, dosage adjustments must be made! TEQSA Provider ID PRV12079 Australian University | CRICOS No.00213J CSBS536 Clinical Therapeutics for Podiatrists Bachelor of Podiatry, School of Podiatry  Why is Renal Clearance so Important? When a drug is administered over a period of time, the amount of drug administered eventually equals the amount of drug cleared, and plasma levels of the drug remain constant. However, in the case of impaired clearance, the amount of drug administered (if administered normally), will exceed the amount of drug cleared, and plasma levels will gradually rise! TEQSA Provider ID PRV12079 Australian University | CRICOS No.00213J CSBS536 Clinical Therapeutics for Podiatrists Bachelor of Podiatry, School of Podiatry  Renal Function Tests Creatinine clearance Creatinine Waste product of skeletal muscle breakdown Excreted by filtration only No tubular reabsorption ! Perfect marker! TEQSA Provider ID PRV12079 Australian University | CRICOS No.00213J CSBS536 Clinical Therapeutics for Podiatrists Bachelor of Podiatry, School of Podiatry  Creatinine Clearance (CrCl) The creatinine clearance is used to measure the GFR of the kidney. The traditional CC test requires 24 hour urine collection and a serum creatinine level. Creatinine clearance= UV/P UV = number of milligrams per decilitre of creatinine excreted in 24 hour period. V = volume of urine in millilitres per min P = serum creatinine in milligrams per DL Very expensive and time consuming. TEQSA Provider ID PRV12079 Australian University | CRICOS No.00213J CSBS536 Clinical Therapeutics for Podiatrists Bachelor of Podiatry, School of Podiatry  eGFR – Modification of diet in renal disease (MDRD) Study equation Uses the serum creatinine, age, and numbers that vary depending on sex and ethnicity to calculate GFR. A complex equation is involved in calculation! Female with Creatinine < 62 μmol/L eGFR = 144 x (SCr x 0.0113/0.7)-0.329 x (0.993)Age Female with Creatinine > 62 μmol/L eGFR = 144 x (SCr x 0.0113/0.7)-1.209 x (0.993)Age Male with Creatinine < 80 μmol/L eGFR = 141 x (SCr x 0.0113/0.9)-0.411 x (0.993)Age Beware of mathematical Male with Creatinine > 80 μmol/L abstractions – one size eGFR = 141 x (SCr x 0.0113/0.9)-1.209 x (0.993)Age does not fit all! Where SCr is serum creatinine in μmol/L Age is in years TEQSA Provider ID PRV12079 Australian University | CRICOS No.00213J CSBS536 Clinical Therapeutics for Podiatrists Bachelor of Podiatry, School of Podiatry CrCl: Cockcroft-Gault formula Widely used for estimating creatinine clearance (CrCl) from serum creatinine and other patient factors. Used to assess renal function, particularly for adjusting doses of medications that are renally excreted (work out individual’s kidney function). CrCl= (140−Age)×Weight (kg)×K​/Serum Creatinine (mg/dL) Where: Age = yrs Weight = kg A proxy for Serum creatinine = mg/dl eGFR K is constant: K =1.23 for men, K = 1.04 for women  Normal values for eGFR Age (Years) Mean eGFR 20-29 116 mL/min/1.73 m2 30-39 107 mL/min/1.73 m2 40-49 99 mL/min/1.73 m2 50-59 93 mL/min/1.73 m2 60-69 85 mL/min/1.73 m2 70+ 75 mL/min/1.73 m2 TEQSA Provider ID PRV12079 Australian University | CRICOS No.00213J CSBS536 Clinical Therapeutics for Podiatrists Bachelor of Podiatry, School of Podiatry  Dose Adjustments in Renal Impairment? Once renal impairment has been detected and creatinine clearance estimated, the need for dose alteration of renally cleared drugs must be determined. Generally dose adjustment is needed when the creatinine clearance is below 60 mL/min. People who have been taking a drug for many years may need a dose adjustment as they age. Adjustments can be achieved by a reduction in dose, or an extension of the dosing interval, or both. Knowledge of appropriate dosage adjustment is important to ensure the drug is effective and that accumulation and further kidney damage is avoided. There are various references to consult in Australia including the approved product information and the Australian Medicines Handbook. International references include the Renal Drug Handbook and Drug prescribing in Renal Failure. TEQSA Provider ID PRV12079 Australian University | CRICOS No.00213J CSBS536 Clinical Therapeutics for Podiatrists Bachelor of Podiatry, School of Podiatry  Relevant Drugs that May Require Dose Adjustment in Renal Impairment? 1. Antibiotics – including Amoxicillin, Amoxicillin plus Clavulanic acid, Cefalexin, Ciprofloxacin, Dicloxacillin, Flucloxacillin, Roxithromycin 2. Antifungals including – Terbinafine 3. Opiates – including Codeine 4. Gout – including Colchicine AMH has dosage adjustment recommendations TEQSA Provider ID PRV12079 Australian University | CRICOS No.00213J CSBS536 Clinical Therapeutics for Podiatrists Bachelor of Podiatry, School of Podiatry  Microbiology Swab Podiatrists may often Biopsy/aspirate organise these in a hospital setting Blood culture TEQSA Provider ID PRV12079 Australian University | CRICOS No.00213J CSBS536 Clinical Therapeutics for Podiatrists Bachelor of Podiatry, School of Podiatry  Bacteria analysis Care should be taken to sample wounds that look infected – all wounds will culture bacteria Coloniser vs infective organism(s) Charcoal swab To take an appropriate swab, necrotic and non-viable tissue should be debrided, area cleaned and swab taken from the wound base. Tissue biopsy is another option – particularly for wounds that have not responded to As growth of bacteria is treatment. rapid, cultures can be Punch biopsy grown quickly TEQSA Provider ID PRV12079 Australian University | CRICOS No.00213J CSBS536 Clinical Therapeutics for Podiatrists Bachelor of Podiatry, School of Podiatry  Lab Investigation of Infection TEQSA Provider ID PRV12079 Australian University | CRICOS No.00213J CSBS536 Clinical Therapeutics for Podiatrists Bachelor of Podiatry, School of Podiatry  Diagnostic tests – Bacterial Infection Culture-based tests are mainly used to diagnose and direct treatment with anti- microbials for bacterial infections. Broth dilution Agar dilution Disk diffusion TEQSA Provider ID PRV12079 Australian University | CRICOS No.00213J CSBS536 Clinical Therapeutics for Podiatrists Bachelor of Podiatry, School of Podiatry  Antibiotic Susceptibility Report MIC = lowest conc needed to inhibit growth of microorganism. Does not always mean the best antibiotic! Letter Meaning R – Resistant Bacteria not inhibited by achievable conc of antibiotic, resistance likely and unlikely to work. S- Bacteria is inhibited by antibiotic at dosage usually Susceptible/se used to tx the infection. nsitive I- Bacteria may respond at achievable conc, but Intermediate response less likely than S. TEQSA Provider ID PRV12079 Australian University | CRICOS No.00213J CSBS536 Clinical Therapeutics for Podiatrists Bachelor of Podiatry, School of Podiatry  Fungal analysis Skin shavings or nail debris can be collected and sent to the lab for analysis. Wipe area with alcohol before sampling. Sample tissue (in case of nail, as proximal as possible) Place sample in envelope of urine container Do not refrigerate Microscopy is quick and will detect presence of fungal hyphae. Culture is slow – will take appx. 4 weeks. TEQSA Provider ID PRV12079 Australian University | CRICOS No.00213J CSBS536 Clinical Therapeutics for Podiatrists Bachelor of Podiatry, School of Podiatry  OM Diagnostic Techniques TEQSA Provider ID PRV12079 Australian University | CRICOS No.00213J CSBS536 Clinical Therapeutics for Podiatrists Bachelor of Podiatry, School of Podiatry  Aspirates For suspected septic arthritis Synovial fluid analysis (microscopy +/- culture) For suspected septicaemia Blood culture Suspected gouty arthritis Synovial fluid analysis (microscopy) TEQSA Provider ID PRV12079 Australian University | CRICOS No.00213J CSBS536 Clinical Therapeutics for Podiatrists Bachelor of Podiatry, School of Podiatry  Haematological Analyses When a test is ordered, a ‘normal’ reference range is given which advises the patient result in the context of population norms. Certain conditions or medications can cause elevation or reduction in some enzymes and biomarkers. Understanding ‘if’ something is abnormal is straightforward, understanding ‘why’ can be difficult. TEQSA Provider ID PRV12079 Australian University | CRICOS No.00213J CSBS536 Clinical Therapeutics for Podiatrists Bachelor of Podiatry, School of Podiatry  CRP – C-reactive protein Globulin released by the liver during an inflammatory reaction Helpful for differentiating infection from non-infection Is elevated in some disease states – e.g. diabetes, obesity An acute phase marker – not good for chronic inflammation Normal = < 5mg/L TEQSA Provider ID PRV12079 Australian University | CRICOS No.00213J CSBS536 Clinical Therapeutics for Podiatrists Bachelor of Podiatry, School of Podiatry  CRP Example Reference range TEQSA Provider ID PRV12079 Australian University | CRICOS No.00213J CSBS536 Clinical Therapeutics for Podiatrists Bachelor of Podiatry, School of Podiatry  ESR – Erythrocyte Sedimentation Rate Measures rate of fall of rbs when suspended in plasmsa Aggregation of rbcs known to increase ESR Useful measure of chronic phase inflammation Normal ESR Males Females 0-50 years 0-15 mm/hr 0-20 mm/hr >50 years 0-20 mm/hr 0-30 mm/hr TEQSA Provider ID PRV12079 Australian University | CRICOS No.00213J CSBS536 Clinical Therapeutics for Podiatrists Bachelor of Podiatry, School of Podiatry  Complete (Full) Blood Count (CBC) A powerful and inexpensive diagnostic tool in a variety of haematological and non-haematological conditions. Provides extremely valuable information about blood and (to an extent) bone marrow. Provides direct and indirect evidences of health and disease states. CBC values vary by age, sex, race and demography. Normal values (reference ranges) may be determined by the lab performing test in a particular population. TEQSA Provider ID PRV12079 Australian University | CRICOS No.00213J CSBS536 Clinical Therapeutics for Podiatrists Bachelor of Podiatry, School of Podiatry  Complete (Full) Blood Count (CBC) Mean corpuscular volume Haematocrit TEQSA Provider ID PRV12079 Australian University | CRICOS No.00213J CSBS536 Clinical Therapeutics for Podiatrists Bachelor of Podiatry, School of Podiatry  What can the results of a CBC tell us? May be used to as a diagnostic aid: - Anaemia - Thrombocytopaenia - Viral fevers, autoimmune conditions - Infections, leucocytosis, leucopoenia, eosinophilia - Haemopoietic malignancies - Nutritional deficiencies - Monitor the effects of drugs - Diagnose the effects of stresses – traumatic, metabolic, neoplastic, surgical. TEQSA Provider ID PRV12079 Australian University | CRICOS No.00213J CSBS536 Clinical Therapeutics for Podiatrists Bachelor of Podiatry, School of Podiatry  White Blood Cells Parameters Normal (x109) Classical reaction Total white cells 4-11 with stress Neutrophils 2-7 in bacterial infection Lymphocytes 1-3 in viral infection Monocytes 0.2-1 with chronic inflammation Eosinophils 0.02-0.5 in parasitic infection Basophils 0-0.1 in active allergic response TEQSA Provider ID PRV12079 Australian University | CRICOS No.00213J CSBS536 Clinical Therapeutics for Podiatrists Bachelor of Podiatry, School of Podiatry  Septicaemia Reference range TEQSA Provider ID PRV12079 Australian University | CRICOS No.00213J CSBS536 Clinical Therapeutics for Podiatrists Bachelor of Podiatry, School of Podiatry  Histopathology Used to accurately determine what tissue is present (or removed). Not used to determine the type of bacteria or fungus present. Used in podiatry following excision of skin lesions, surgeons will use this to characterise other tissues, including bone. Tissue is generally placed in formalin to ‘fix’. Examined using microscope evaluation by a pathologist. TEQSA Provider ID PRV12079 Australian University | CRICOS No.00213J CSBS536 Clinical Therapeutics for Podiatrists Bachelor of Podiatry, School of Podiatry  A presentation TEQSA Provider ID PRV12079 Australian University | CRICOS No.00213J CSBS536 Clinical Therapeutics for Podiatrists Bachelor of Podiatry, School of Podiatry  Report TEQSA Provider ID PRV12079 Australian University | CRICOS No.00213J CSBS536 Clinical Therapeutics for Podiatrists Bachelor of Podiatry, School of Podiatry  Use your clinical suspicion to inform testing… TEQSA Provider ID PRV12079 Australian University | CRICOS No.00213J CSBS536 Clinical Therapeutics for Podiatrists Bachelor of Podiatry, School of Podiatry  !? TEQSA Provider ID PRV12079 Australian University | CRICOS No.00213J Gao W et al. Medicine (Baltimore). 2017;96:e7541 CSBS536 Clinical Therapeutics for Podiatrists Bachelor of Podiatry, School of Podiatry Gao W et al. Medicine (Baltimore). 2017;96:e7541  Coronial Inquest TEQSA Provider ID PRV12079 Australian University | CRICOS No.00213J CSBS536 Clinical Therapeutics for Podiatrists Bachelor of Podiatry, School of Podiatry  Coronial inquest In March 2007 Mr Semmler presented to his general practitioner with what appeared to be an ulcerated lesion on the bottom of the heel of his left foot. The lesion was believed by the health professionals who were to treat him to be another diabetic foot ulcer. This lesion would never fully resolve until it was subject to debridement and biopsy in July 2008. TEQSA Provider ID PRV12079 Australian University | CRICOS No.00213J CSBS536 Clinical Therapeutics for Podiatrists Bachelor of Podiatry, School of Podiatry  Coronial inquest It was on this occasion that for the first time the lesion was diagnosed as a malignant melanoma. The malignant melanoma would metastasise with malignant deposits in other areas of Mr Semmler’s body. The disseminated cancer would claim his life in November 2008 TEQSA Provider ID PRV12079 Australian University | CRICOS No.00213J CSBS536 Clinical Therapeutics for Podiatrists Bachelor of Podiatry, School of Podiatry  Pathology Testing Clinical suspicion should drive the decision for pathology testing Pathology testing can be important in both the diagnosis and monitoring of a condition, but some can be non-specific so this needs to be considered Use clinical judgement when determining the need for a test, and if lesions are not healing as you might expect, consider testing to confirm your diagnosis TEQSA Provider ID PRV12079 Australian University | CRICOS No.00213J CSBS536 Clinical Therapeutics for Podiatrists Bachelor of Podiatry, School of Podiatry