WGS 6 - Renal & Genitourinary Pharmacology PDF

Vander’s Renal Physiology, 9e Basic & Clinical Pharmacology, 15e Bertram G. Katzung, Todd W. Vanderah  Session Outline Renin inhibitors Aliskiren Angiotensin converting enzyme (ACE) inhibitors Ramipril Angiotensin receptor blocker...

Vander’s Renal Physiology, 9e Basic & Clinical Pharmacology, 15e Bertram G. Katzung, Todd W. Vanderah  Session Outline Renin inhibitors Aliskiren Angiotensin converting enzyme (ACE) inhibitors Ramipril Angiotensin receptor blockers Valsartan Loop diuretics Furosemide Thiazide diuretic Hydrochlorothiazide Potassium-sparing diuretic Spironolactone Amiloride Carbonic anhydrase inhibitors Acetazolamide Osmotic diuretics Mannitol PCT-proximal convoluted tubule TAL-thick ascending limb of the loop of Henle DCT-distal convoluted tubule CCT-cortical collecting tubule  Once it gets to proximal convoluted tubule, things start to get reclaimed. Reclaim water by driving nAcL BACK (WATER Filtration. Passive FOLLOWS NaCl) process determined by size of solute Aqua-Orin 4 here - need ot be phosphorylated by g protien coupled receptor - tightly regulated As it entered from cortex to medulla Concentrating loop The thin descending limb is the last permeable portion in hitch water can move in or out (its water permeable. From ascending loop to distal convoluted tubule its water impermeable. Water can be reabsorbed again in collecting tubule Clean out ur apartment by throwing everything on the streeet and pick up what u need  Reabsorption is not jsut water but many things – Significant amount: Bicarbonate, which is essential for maintaining acid-base balance of blood, Look at the cells that line the tubule. Tubular epithelial cells have apical side that face Thee cells reabsorption most of NaCl and water – slumen of nephron and basso lateral side phases interstitial fluid, interstitial fluid = blood. Basolateral side of nephron has – Anything that gets to interstitial Filtrate/urine/ fluid itll get to blood without sodium potassium ATPase - Most of this process is regulated by whatever problem classic transporter found in all driving back chloride thru channel. cells. Large % of total energy – prod is dedicate to kidney A loop - countercl ockwise - thi is process These cells by which r involved we ina Clive reclaim process of bicarbon reabsorption ate.. Bicarbon – ate reclamati on Exchanges sodium ions from lumen for hydrogen ions. – Chloride is being absorbed for exchange of bases – – Ur if acid which is waste prod is actively secreted. Pterygoid organic acids bases byproducts and toxins also secreted Protons r being pumped out in exchange for sodium and protons r recombined w bicarbonate to form carbonic acid. Carbonic acid has to be converted dry carbonic a hydrate to water and CO2. Once it finds its way inside, carbon dioxide recombines w water to form carbonic acid (can hydro Inhibits carbonic anhydride in the lumen and cytoplasm lyse proteins and bicarbonate).a dbicarbonate finds its way out of the transporter.  Is diuretic effect bc by preventing sodium from being absorbed, allows more sodium to stay in lumen so less drive to reabsorption water (water follows sodium). Bc bicarbonate is not beign reabsorbed, side effects is metab acidosis. Bc of high lvl of bicarbonate left in filtrate can result in inc formation of kidney stones. In order for this process to work long term, requires Hco3- ADMINSITRAITON to maintain acid base balance. 6  Mannitol works bc its a huge molecule and filters thru filtrate and finds its way in filtrate in lumen of kidney. Mannitol has such high osmolality (impossible to reabsorbed cuz its large compound) - traps water in the tubule and water remains there. This is the only diuretic that doesnt work by preventing sodium reuptake. If it u think of diabetes (diabetes means siphon - it means u pee too much). Mech by which diabetes Mellitus induces diuretics bc glucose behaves similarly to mannnitol. Once excess glucose in liu en of kidney, it acts as osmotic driver and retain water in kidney. This why diabetics historically known to pee a lot - common clinical symptom in type 1 diabetes sin kids. Mannitol not used particualrly for hypertension but some applications in other conditions Is water permeable via aquaporins. Part of countercurrent exchange mech. WATER IS DRAWN OUT EASILY into interstitial. Vessels surrounding nephron take up this water restoring the volume. Easy to draw water out of the nephron here. The Renton the interstitial is hypertonic bc the loop is powerful mech of reclaiming sodium in ascending limb - creating hypertonic env in interstitium - 5-6x normal levels of salt. Mechanism Prevents reabsorption of water in PCT and thin descending limb Acts as an impermeant solute to retain water in the tubular fluid Increase extracellular volume of water Applications: Poorly absorbed Parenteral Reduce intracranial or occular pressure Adverse effects Edema Remember everywhere this mannitol finds its way, itll result in water retention, if mannitol found in vascular bed or vascular space it’ll retain water there. Once its exerted then it’ll retain water int he kidneys Severe dehydration and hyponatremia Not v easy to titrate so if someone has hypertension u want consistent level fo diuretics over long temp period of time thats easy to predict. Dont want sudden flood of gettign rid of excess water. So not useful for high BP. Useful to reduce intracranial or ocular pressure 8  Numbers ar eocncentration fo salt Salt building up in Water interstiti imperm um eable so draws puts out Water moves out of here water sodium out of descen ding loop. Creates v hypertonic env at bottom of loop of henle We end up having all this pressure e- very dilute nephoron at distal tubule. COLLECTIGN tubule will cause water beign As u move up to distal tubule it starts reabsorbed in a v regulated fashion. to dilute again. The ascending limb and distal tubule are diluting mech. Theres also Theres a little movie in the original ppt file to watch - watch it to help movement understand of urea here in loop of henle Theres one concept in physiology that always oce sup called countercurrent multiplication effect or countercurrent exchange mechanism. He wont ask this question but this countercurrent x effect come sup in future exams. Incredible feat of engineering, this concep used in desalination plants. Vasa recta are permeable to water and solutes  Critical role in concentrating urine by absorbing key ions while preventing water absorption into the lumen As u ascend AIDS in concentrating urine. But it also sets up to allow water to be reabsorbed into urine later on in nephron Sets up excess of K+. Some moves out by passive diffusion thru a cayenne, create env – where u take in 2 + and 2- and + gets out, causing lumen of thick ascending limb to become electro positive. This +ve env drives reabsorption of magnesium and calcium thru intercellular tight junction space. – – This effect is so imp for creating the counter current exchange mech that if u block the NKCC2 transporter u also prevent countercurrent e haha eg effect from happening. Loop diuretics is most potent diuretic we have.  Mechanism Not limited by available HCO3- Potent - high-ceiling diuretics Target NKCC2 in the TAL When it blocks, it presvetns reabsorption of these ions. No electorppostive gradient - retain more Increase Ca2+ , Cl- , Mg2+ loss sodium in filtrate and also cause it to retain more mg and more ca. loss of mg, ca, and k is once of the adverse effects of furosemide. K loss leads to Applications: When u need rlly potent diuresis hypokalemia - systemic hypokalemia is problem bc k is imp for setting up gradient so more protons being pumped in to makeup for loss of k so Pulmonary and peripheral edema end up w hypokalemia metabolic alkalosis - extracellular env becomes alkaline. CHF Acute renal failure- induce diuresis Adverse effects Loss of Mg2+,Ca2+ and K+ Hypokalemic metabolic alkalosis Decreased GFR Bc it doesnt allow kidney to work properly Due to effect on glomerular filtration rate - mech affects glomerular filtration pressure Ototoxic Transporter in ear that lows balancing fluid in ear, some o these drugs partially inhibit that causing ototoxicity Contraindications: Anuria, diabetes, dyslipidemia, hyperuricemia, gout 11 Impermeable to water still  Absorption of ca is controlled by pth which also controls another transporter for calcium shown in diagram here. – – – Calcium driven ATPase a transporter – Pth is imp in reabsorbing calcium nd this is its main site of action.  Once of the safest diuretics we have causes gentle diuresis By blocking abs of na here, which increases sodium conc in lumen of urine which causes diuretic effect of loss of water. Calcium is moving down gradient They’re v gentle, easy to predict effects This process doesn’t interfere w ca absorption. Na is being pumped in here and when u block abs of sodium here I set up intracellular env in Prevent skidney stones cell is hypotonic which allows for alicium absorption to be more efficient Calcium with bicarbonate can precipitate to form stones V good for stim calcium reabsorption Cond where’s have too much diuresis. It affects the macula dense and the glmerular filtration rate ina way that allows someone w unmitigated diuresis to retain water Like loop diuretics Leading to hypokalemia and metabolic alkalosis In ppl predisposed to diabetes, blocking this pathway can induce hyperglycaemia Anuria, diabetes, dyslipidemia, hyperuricemia, gout, hypercalcemia 14  Blood Decreased sodium in the serum - bc we wanna lose water by preventing reabsorption of sodium - sodium stays in lumen of tubule - end up w hyponatremia (an adverse effect of this med). Potassium - decreases  In fact they inc the calcium reabsorption  Principal cells reabsorption sodium via DnaC channel – When ur dehydrated aldosterone causes ind’s absorption of sodium w inc reabsorption of water For every an reclaimed, more k is being put out – – Sodium then pumped out via na/k atpase – – – 2. CCT-Intercalated cells: Control the acid base balance mediate bicarbonate absorption and secretion in response to aldosterone Int he water impermeable [patrts, sodium accumulatemulates wihtout being followed by water. So the drugs that inc sodium excretion into lumen/filtrate, then we need channels to be in collecting tubule. type A intercalated cells reabsorb potassium and secrete hydrogen ions  Water is reabsorbed only when specific aquaporin channels r inserted. Binding of ADH to a receptor (protein coupled receptor - causes G proteins o disassociate, phosphodiester are, camp, then cap works on inserting the channels). ADH reg’s abs of water here In absence of channels, little water moved.  Also imp in RAAS  These channels pump sodium from nephron into interstitial space - cause more sodium to be found in nephron and this sodium is in filtrate and when it gets to collecting tubule that excess sodium is reabsorbed in DnaC channel. For every sodium reabsorbed at DnaC, 1 molec of k is being excreted. Excess salt causes body to put out poteassium. Thus these called potassium wasting diuretics Thiazides and Loop Diuretics increase Na+ delivery to the collecting duct Increased Na+ delivery leads to an increased demand to reabsorb Na+ by the CCT with concomitant increased secretion and excretion of K+ Hypokalemia causes shift of H+ to intracellular space resulting in metabolic alkalosis If we block aldosterone or block DnaC, these diuretic effects dont cause wast eof k. The last 2 diuretics we discuss conserve potassium. Thiazides often used in combination with ACEI or ARBs Mechanism Amiloride is direct inhibitor of ENaC in the CCT By blocking sodium import here it prevents Applications: Preserve cardiac function in coronary ischemia Prevent HF Adverse effects Hyperkalemia 22 Mechanism Spironolactone is a synthetic steroid that binds to mineralocorticoid receptor and interferes (antagonist) with Aldosterone actions in the CCT Reduce Na+ reabsorption by reducing Na+/K+-ATPase expression Applications: Preserve cardiac function in coronary ischemia Prevent heart failure Adverse effects Hyperkalemia Gynecomastia Both prevent DnaC from working causing more k to be retained These drugs rlly imp bc if u pare potassium sparring w ppotassiu sparring diuretics - strong diuretic effect 23 and effect on k cancels out so u still have diuresis without going into hypo or hyperkalemia. This summary table captures everything Segment Functions Water Transporters and Diuretic with Major Permeability Drug Targets (in Action bold) at Apical Membrane Glomerulus Formation of glomerular filtrate Extremely None None No direct ar gets at ths is point. One for diabetes thats not high covered in this lec Proximal Reabsorption of 65% of filtered Na+ Very high 1 Na/H (NHE3), Carbonic anhydrase convoluted and K+; 85% of NaHCO3, and nearly carbonic anhydrase inhibitors tubule (PCT) 100% of glucose and amino acids. Isosmotic reabsorption of 60% water. Secretion and reabsorption of organic acids and bases, including uric acid and most diuretics Thin descending Passive reabsorption of water High Aquaporins None limb of Henle's loop Thick ascending Active reabsorption of 15–25% of filtered Very low Na/K/2Cl (NKCC2) Loop diuretics Na+/K+/Cl–; secondary reabsorption of Block reabsorption of sodium. Loop diueretic limb of Henle's effect may be realized upstream in thin descending limb bc it interferes w loop (TAL) Ca2+ and Mg2+ countercurrent exchange mech Distal convoluted Active reabsorption of 4–8% of filtered Very low Na/Cl (NCC) Thiazides Na+ and Cl–; Ca2+reabsorption under Block reabsorption of sodium tubule (DCT) parathyroid hormone control Cortical (CCT) Na+ reabsorption (2–5%) coupled to Variable Na channels K+-sparing diuretics: and medullary K+ and H+ secretion and is under controlled by (ENaC), Amiloride collecting tubule aldosterone control ADH K channels, Spironolactone Water reabsorption is H+transporters, ADH(vasopressin) under ADH control Aquaporins receptor antagonists: Conivaptan  – – – when someone dehydrated, mech relates to sensory sys called JG. Ant ii - short half-life  Angiotensin II has several effects that all lead to increase intravascular volume: Inc adrenal cortex secretio n of aldoster one. Aldoster one induces DnaC Posterior channel s and Pituitary to an/k atpase release ADH => retain ADH increases more salt/ collecting tubule water permeability and water retention All lead to inc in BP. Interfering w this pathway imp way to manage hypertension  – – – –  Actions of aliskiren, angiotensin- converting enzyme inhibitors, and AT1 receptor blockers. 1. Renin converts angiotensinogen Pharmacologically can target any part of this pathway to Angiotensin-I aliskiren blocks the sequence at its start. 2. ACE is responsible for activating Angiotensin-I to Angiotensin-II and for inactivating bradykinin ACE inhibitors decrease the concentration Prevent degradation of vasodilator, prevent creation of of vasoconstrictor and vasoconstrictor antidiuretic - Angiotensin-II ACE inhibitors also increase the concentration of a vasodilator - Bradykinin 3. Type I Angiotensin-II Receptor (AT1 Receptor) targeted by AT1 Receptor Blockers (ARB) Mechanism Reduce levels of Angiotensin-II by inhibiting ACE Also inhibit breakdown of other vasoactive peptides such as bradykinin resulting in vasodilation Prodrug – requires hepatic activation Applications: vasodilator Hypertension CHF Post-MI Mitigate CV risk Adverse effects Hypotension Sot likely bc they work on bradykinin Hyperkalemia Angioedema AKI Cough Increased creatinine and BUN Contraindications Not to be used during pregnancy 30  Type 1 Angiotensin II receptor blockers (ARB) Valsartan and Losartan Mechanism Antagonist of Angiotensin-II Receptor Type 1 (AT1) Promote vasodilation and increase water and salt By blocking AT1 excretion Applications: Effect is similar to ace inhibitors. But they dont work on bradykinin (degraded without problem bc ace is sitll working) bu they work on reeptor for angiotensin II Same as ACE inhibitors Adverse effects Not to be used during pregnancy Hyperkalemia CNS dizziness Hypotension *Recalls due to impurities 31  Similar contraindications, used in similar comorbid i ties – – – – ARB avail as generic drug. 2y agora roudn covid impossible to get arb cuz of this but now this is sorted out  Session Outline Xanthine Oxidase Inhibitor Allopurinol Chelating Agent Penicillamine Muscarinic Receptor Antagonists Tolterodine Darifenacin Beta 3 Adrenergic Agonist Mirabegron Alpha-1 Adrenergic Receptor Antagonists Tamsulosin 5-alpha Reductase Inhibitor Dutasteride Immunotherapy Bacillus Calmette-Guerin (BCG) Kidney stones 80% calcium oxalate stones 10% urate stones 10 % struvite and other salts Mechanism Inhibits xanthine oxidase Prevents formation of kidney stones Reduces uric acid formation Reduction of uric acid allows for higher solubility of oxalate Applications: Gout Nephrolithiasis, prevention of recurrent calcium stones Calcium oxidate stones - easy to prevent when u prevent Uric acid formation Adverse effects But its overall pre well tolerated Acute gout attacks at onset of treatment Eosinophilia and systemic symptoms Delayed hypersensitivity To be avoided during breastfeeding 36 Mechanism of Action: Penicillamine is a chelating agent that binds to metals such as copper, forming stable, water-soluble complexes that are excreted in the urine. It also has immunomodulatory effects, making it useful in certain autoimmune conditions. Applications: Wilson's Disease: Used to reduce copper accumulation by promoting urinary excretion of copper. Rheumatoid Arthritis: Acts as a disease-modifying antirheumatic drug (DMARD) by modulating immune responses. Cystinuria: Reduces cystine stone formation by increasing the solubility of cystine in the urine. Adverse Effects: Renal Toxicity: Risk of proteinuria and nephrotic syndrome; regular monitoring of renal function is required. Blood Dyscrasias: Can cause leukopenia, thrombocytopenia, and aplastic anemia, necessitating frequent blood count monitoring. Dermatologic Reactions: Skin rash and potential worsening of skin elasticity. Other: Risk of autoimmune conditions such as myasthenia gravis and lupus-like syndrome. Special Considerations: Monitoring: Regular monitoring of blood counts, liver and kidney function is essential due to potential toxicities. Allergic Reactions: Cross-reactivity may occur in patients allergic to penicillin, although the risk is low. 37  Parasympathetic = starts with p. Is dominant in bladder control. Every time u activate ACh which act on muscarinic m3 receptors - causes bladder to contract facilitating bladder emptying. Internal urethral sphincter also responds to this Sympathetic control - dominant in bladder filling. NA act on alpha 1 adrenergic receptor causing relaxation of detruser muscle allowing bladder to stay full/fill. Also affects urethra where it causes urethra to contract - prevents urine leakage Efferent pathways and neurotransmitter mechanisms that regulate the lower urinary tract. ACh, acetylcholine; NA, noradrenaline. Nature Reviews Neuroscience  Used to treat overactive bladder, detrusor muscle overactivity Detrusor muscle is activated by parasympathetic mech and inh by sympathetic mech. If antagonist m3 receptor (muscarinic receptor), causing this muscle to relax and inc urine volume Mechanism Competitive antagonist of muscarinic receptors (darifenacin is M3 subtype selective) Increases residual urine volume, decreased urinary bladder contraction and decreases detrusor muscle pressure Applications: Reduce urgency in mild cystitis Inc ashes of overacting bladder cystitis, bladder surgery Reduce bladder spasms after urologic surgery Treat stress incontinence (not typically) Adverse effects Angioedema, QT prolongation (more so for Tolterodine) GI constipation (more so for Darifenacin), dry mouth (more so for Tolterodine), CNS headache Contraindicated for patients with uncontrolled angle-closure glaucoma. 40 Mechanism of Action: Mirabegron is a selective beta-3 adrenergic agonist that stimulates beta-3 receptors in the bladder's detrusor muscle, leading to relaxation of the muscle. This reduces bladder contractions and increases bladder capacity, helping manage symptoms of overactive bladder (OAB). Applications: Overactive Bladder (OAB): Used to reduce symptoms such as urinary urgency, frequency, and urge incontinence. Alternative to Antimuscarinics: Suitable for patients who experience adverse effects with antimuscarinic agents or have contraindications to them. Adverse Effects: Hypertension: Can cause a mild increase in blood pressure, so it is used cautiously in patients with uncontrolled hypertension. Urinary Tract Infections (UTIs): Slightly increased risk of UTIs in some patients. Tachycardia: Possible increase in heart rate, especially in higher doses. Advantages Over Antimuscarinics: Lower risk of dry mouth and constipation, which are common side effects of antimuscarinic agents. Generally well-tolerated and provides an alternative mechanism of action for OAB management. 41  Benign Prostate Disorders Benign prostate hyperplasia (BPH) is a histologic condition BPH. Cells r growing and getting enlarged proliferating characterized by benign proliferation of stromal and/or epithelial prostate tissue. Subset of hyperplasia can have visible enlargement, subset of enlarged pt can have obstruction Benign prostate enlargement (BPE) occurs in about half of men with BPH, and is quantified by milliliters increase in prostate tissue. Bladder outlet obstruction (BOO) occurs in only a subset of men with BPE. Lower urinary tract symptoms (LUTS): urgency, frequency, nocturia, slow stream, hesitancy, incomplete emptying, postvoiding dribbling, and incontinence. Mechanism of Action: Selective antagonist of alpha-1A adrenergic receptors in the prostate, bladder neck, and urethra. Since 75% of alpha-1 receptors in the prostate are of the alpha- 1A subtype, this selective blockade leads to relaxation of smooth muscle in these areas, easing urinary flow. Applications: Benign Prostatic Hyperplasia (BPH): Most effective in reducing lower urinary tract symptoms (LUTS) associated with BPH, including urinary hesitancy and retention. Safety Advantage: More selective than nonselective alpha blockers, which also act on alpha-1B and alpha-1D receptors, leading to fewer systemic side effects (such as orthostatic hypotension). Adverse Effects: Orthostatic Hypotension, Syncope, and Dizziness: Due to mild systemic vasodilation, especially with initial doses. Intraoperative Floppy Iris Syndrome: Increased risk during cataract surgery; When u relax smooth m. advisable to avoid or discontinue before surgery. That hold lens in place, can cause it to move and be hard to handle Contraindication with Angina: Should be used cautiously or avoided in patients with angina, as it can lower blood pressure and potentially worsen symptoms. Low bp can worsen angina pt’s symptoms 43 Mechanism of Action: Competitive, selective inhibitor of 5α-reductase in both reproductive tissues (type 2) and skin/hepatic tissues (type 1). Reduces prostate size by blocking the conversion of testosterone to dihydrotestosterone (DHT), which has a greater affinity for androgen receptors and is not converted to estradiol. Applications: DHT is more potent form of testosterone. Preventing DHT formation can lower progression fo prostate ehyperplasia to enlarge t to obstruction. Pt put on it to prevent progressionn. Benign Prostatic Enlargement (BPE): Reduces lower urinary tract symptoms (LUTS) by decreasing prostate size. Prevention of BPE Progression: Requires long-term treatment to prevent recurrence due to delayed onset of action. Prostate Cancer: Lowers overall risk of prostate cancer, although there is an increased risk for higher-grade tumors in cases that do develop. Adverse Effects: Sexual dysfunction, including decreased libido and impotence Anything that affects testosterone/sex hormones Potential for increased incidence of high-grade prostate cancers, despite Some prostate cancers can become hormone independent. Fewer tumours overall but the ones who do an overall reduction in prostate cancer rates take this can be higher grade. Mood changes, depression 44  Used for 40y for treating prostate/bladder cancer Mechanism of Action: BCG is an attenuated live vaccine derived from Mycobacterium bovis. It is proposed to traditionally used as vaccine for TB stimulate the immune system by activating macrophages, dendritic cells, and other immune cells, enhancing the body’s response against mycobacterial and cancerous cells. Applications: Tuberculosis (TB) Vaccination: Primarily used in countries with high TB prevalence as a vaccine for TB prevention, especially in children. Bladder Cancer (Non-Muscle Invasive Bladder Cancer - NMIBC): Used as intravesical immunotherapy to prevent recurrence and progression of bladder cancer. BCG stimulates an immune response in the bladder, targeting cancer cells. Adverse Effects: Local Reactions: Pain, inflammation, and cystitis (bladder irritation) with intravesical administration. Systemic Reactions: Fever, malaise, and flu-like symptoms are common with intravesical BCG. Rarely, severe systemic infections like BCGitis or BCG sepsis may occur. Granulomatous Infections: Rarely, BCG can cause granulomatous infections, especially in immunocompromised individuals, where the infection may disseminate. Special Considerations: Has good result sand continues Contraindications: Not recommended for immunocompromised patients (e.g., HIV- to be used positive individuals, patients on immunosuppressive therapy) due to the risk of disseminated BCG infection. Monitoring: Patients receiving intravesical BCG for bladder cancer should be monitored for signs of infection and systemic adverse effects. Precautions: BCG should not be administered during active urinary tract infections or 45 immediately after traumatic catheterization due to the risk of systemic spread.  Session Outline Aminoglycosides Gentamycin Tobramycin Penicillins Amoxicillin Amoxicillin/Clavulanic acid Fluoroquinolones Ciprofloxacin Miscellaneous Nitrofurantoin Trimethoprim Sulfonamides Sulfamethoxazole (trimethoprim + sulfamethoxazole = Septra) Cephalosporins Cephalexin (PO) Ceftriaxone (IV)  – Like penicillins – – – Dont have good handle on how they work  Drugs that work on bacterial wall Source: Waller DG. Medical Pharmacology and Therapeutics, 5th Edition, 2018. Chapter 51, figure 51.1  The bacterial cell wall consists of glycopeptide polymers (a NAM-NAG amino-hexose backbone) linked via bridges between amino acid side chains. In S. aureus, the bridge is (Gly)5-D-Ala between lysines found on neighboring chains. The cross-linking is catalyzed by a These bridges give bac wall strength, critical for transpeptidase, the enzyme that β- wall formation lactams inhibit and which is also referred to as a penicillin-binding protein (PBP) NAM, N-acetyl-muramic acid; NAG, N- acetyl-glucosamine  Drug Class and Mechanism of Action Metabolism/ Adverse Effects Contraindications Example Elimination Penicillins: Inhibit bacterial cell wall *depends Hypersensitivity, rash, Hypersensitivity to Amoxicillin synthesis by binding to on drug nausea, diarrhea, CNS with penicillins PBPs high doses, interstitial nephritis (rare) *depends on drug* Cephalosporins: Inhibit bacterial cell wall *depends Hypersensitivity, rash, Ceftriaxone synthesis by binding to on drug nausea, diarrhea PBPs *depends on drug* Ɓ lactamase Inhibits Ɓ lactamases *depends Diarrhea (clavulanic acid) inhibitors: that inactivate Ɓ lactams on drug clavulanic acid Antibiotics: Cell wall disruption  Most of the bac resistant ot penicilllins =- make bet alacatamase , which e grade the bpenicillin based drugs  Hell focus on the renal kidney type applications for this. Not the other applications Jsut know what’s ont he slide fro Pisa  This slide not on test - just know the slide before this Generation Example Gram(+) Coverage Gram(-) Coverage Anaerobic Coverage Incrementally, better and better g- coverage Primarily Gram(+) coverage limited Gram(-) coverage (PEcK: First Cephalexin (Staphylococcus aureus, Proteus mirabilis, E. coli, Poor anaerobic coverage Generation Streptococcus spp.) Klebsiella pneumoniae) Maintains Gram(+) Enhanced Gram(-) coverage, Some anaerobic coverage Second Cefuroxime coverage but less potent includes H. influenzae, (cephamycins like cefoxitin, Generation than first generation Neisseria cefotetan) Varying and reduced Gram(+) coverage, often Third Broad Gram(-) coverage, Ceftriaxone less than first gen; Limited anaerobic coverage Generation including Enterobacteriaceae *ceftriaxone has good anti- Strep coverage Similar to third generation; More stable against beta- but also active against Fourth lactamases than 2nd and 3rd Cefepime Streptococcus and Limited anaerobic coverage Generation gen; extensive Gram(-) Staphylococcus (excluding coverage incl Pseudomonas MRSA) Broad Gram(+) coverage, Fifth including MRSA (the only Moderate Gram(-) coverage, Ceftaroline Limited anaerobic coverage Generation cephalosporin with MRSA excluding Pseudomonas activity) Source: Waller DG. Medical Pharmacology and Therapeutics, 5 h Edition, 2018. Chapter 51.   STREPTOMYCIN some antibiotics r time dependent Source: Waller DG. Medical Pharmacology and Therapeutics, 5th Edition, 2018. Chapter 51, figure 51.1  All the floxacins r all derivatives of nalidixic acid. They inh dna synthesis. The mOA on slide is copied wrong. They work primarily on Gyrase activity of dna synthesis. Hell post correct slide after this. This entire slide has wrong info Source: Waller DG. Medical Pharmacology and Therapeutics, 5th Edition, 2018. Chapter 51, figure 51.1    Not entirely how this works. With impaired GFR, dont put on this cuz will lead to v high concentrations and increased risk of toxicity Good (> 60%): aminoglycosides, Amoxicillin, Amoxicillin/clavulanate, Fosfomycin, Cefadroxil, Cefazolin, Cefepime, Cefuroxime, Cephlalexin, Ciprofloxacin, Colistin, Ertapenem, Trimethoprim/sulfamethoxazole, Vancomycin, Amphotericin B, Fluconazole, Flucytosine Variable (30–60%): Linezolid (30%), Doxycycline (29 - 55%), Ceftriaxone, Tetracycline (~60%) Poor (< 30%): Azithromycin, Clindamycin, Cefdinir, Moxifloxacin, Oxacillin, Tigecycline, Micafungin, Posaconazole, Voriconazole Spec guidelines for uti associated w individual hospitals. Soem durgs we discussed today have v good renal excretion making it suitable for treating infections of urinary tract Bacterial Urinary Tract Infection (UTI) | Guidelines for Antibiotic Use Renal Excretion/Concentration of Selected Antibiotics Source: University Health Network Antimicrobial Stewardship Program, www.antimicrobialstewardship.com, clinical resources https://www.antimicrobialstewardship.com/uti – – – –