Drugs And The Kidney Part One, Two And Three WARWICK

Drugs and the Kidney Phase 1 Block 1 Part One - Basic Principles Dr Dan Mitchell, WMS ([email protected])  Learning Outcomes (all three parts) Describe how altered physiology, pharmacokinetic handling and pharmacodynamic responses occur in patients with impaired rena...

Drugs and the Kidney Phase 1 Block 1 Part One - Basic Principles Dr Dan Mitchell, WMS ([email protected])  Learning Outcomes (all three parts) Describe how altered physiology, pharmacokinetic handling and pharmacodynamic responses occur in patients with impaired renal function Appreciate the precautions that should be taken when prescribing in kidney disease List the classes of diuretics Describe the molecular and cellular mechanisms of action of diuretic drugs Relate molecular and cellular mechanisms of action of diuretic drugs to responses at the tissue and organ level in the treatment of common and important disorders Explain the principles of diuretic therapy Describe how normal physiology can be manipulated to cause a therapeutic action Outline the ways in which renin-angiotensin-aldosterone system (RAAS) blockade can be achieved  Further reading/Resources (all three parts) Medical Pharmacology & Therapeutics, 5th Edition (Waller & Sampson) – Available in print at Library and also via ClinicalKey Student https://www.clinicalkey.com/student/login Chapter 14 covers Diuretics (plus there is a useful quiz at the end) See also: Guyton and Hall Textbook of Medical Physiology, 13th Edition also available via ClinicalKey Student - https://www.clinicalkey.com/student/login Chapter 32 features Diuretics Healthtalk – a terrific online resource for understanding patient perspectives in healthcare This section of the online resource focuses on the experiences of patients taking medication for heart failure, including diuretics Free online flashcards – Click here for the useful Michael J Neal pharmacology flashcards From the Phase 1, Block 1 Drugs List Diuretic drugs Drug class/ group Generic drug name(s) Principal Mechanism of Action for indication Loop diuretics Furosemide Inhibits Na+/K+/2Cl- transporter in loop of Henle Thiazides class (and thiazide- Bendroflumethiazide, Inhibits Na+/Cl- co-transporter in early like drugs) Hydrochlorothiazide, distal tubule Chlortalidone, Indapamide Potassium sparing diuretics Spironolactone, Eplerenone Mineralocorticoid receptor blockade (mineralocorticoid receptor (Spironolactone, Eplerenone) (aldosterone) antagonists), Amiloride (epithelial sodium Blockade of sodium reabsorption via ENaC channel (ENaC) antagonist) channel (Amiloride) Drugs that affect the renin-angiotensin-aldosterone system (RAAS) Angiotensin-converting Ramipril, Lisinopril Inhibits conversion of angiotensin I to enzyme (ACE) inhibitors angiotensin II. Reduces vasoconstriction Angiotensin-II receptor Losartan Blockade of cell signalling induced by antagonists angiotensin II Aldosterone antagonist Spironolactone Blockade of mineralocorticoid activation  General Principles: The special role of the kidneys in Pharmacology (See also the “Principles of Pharmacology – Part Two” PPT presentation from Welcome Week ) Drugs and the kidney A large proportion of acute kidney injury (AKI) is drug induced Kidneys are susceptible to damage due to:  High vascularity  Large surface area for binding & transport of molecules, including drugs  Reabsorption of water from kidneys concentrates some drugs in the nephron  Main route of excretion for most of the common and important drugs in medicine  Drugs & kidney function When treating patients with renal disease consider: How does the degree of renal impairment affect the handling and effectiveness of the drug?  Drugs may accumulate to toxic levels if they are excreted through the kidneys and renal function is impaired Does the drug have the potential to worsen the degree of renal impairment?  Nephrotoxic drugs should be avoided in renal impairment or disease  Drugs & kidney function (continued) Reasons for problems with medications in patients with impaired renal function include:  Reduced renal excretion of a drug or its metabolites  Many side-effects are poorly tolerated by patients in renal failure (e.g. increased potassium in blood)  Increased sensitivity to some drugs  Some drugs are less therapeutically effective when renal function is reduced (e.g. diuretics)  Renal function declines with age and therefore understanding drug handling is especially important when treating the elderly Diuretics – Part Two Classes of diuretics Diuretic: a substance that promotes the excretion of urine  Loop diuretics  Thiazide (and thiazide-like) Most of the commonly used diuretics do this by promoting renal excretion of diuretics sodium (natriuresis)  Potassium sparing diuretics Most commonly used for conditions (Carbonic anhydrase inhibitors, associated with oedema, and some Osmotic agents – rarely used as for hypertension diuretics nowadays, but are important for treating conditions such as glaucoma – more in Phase 2) Drugs acting on the RAAS – Part Three The Renin-Angiotensin Aldosterone System (RAAS) is Classes of RAAS acting highly active in the kidney and is crucial in control blood pressure drugs: and flow  Angiotensin Converting Enzyme Common and important drugs (ACE) inhibitors used to treat cardiovascular  Angiotensin Receptor Blockers disorders block key functions of  Aldosterone Antagonists the RAAS at specific checkpoints in the kidney and other tissues (overlap with Potassium sparing diuretics) Also – more on these drugs and the RAAS System in Block 2 Drugs and the Kidney Part Two - Diuretics  Diureti cs Classes of diuretics Diuretic: a substance that promotes the excretion of urine  Loop diuretics  Thiazide (and thiazide-like) Most of the commonly used diuretics do this by promoting renal excretion of diuretics sodium (natriuresis)  Potassium sparing diuretics Most commonly used for conditions (Carbonic anhydrase inhibitors, associated with oedema, and some Osmotic agents – rarely used as for hypertension diuretics nowadays, but are important for treating conditions such as glaucoma – more in Phase 2)  Diuretics - overview From “Molecular Pharmacology and Therapeutics 5th Ed. By Waller & Sampson Also, useful free flashcard: http://www.ataglanceseries.com/pharmacology8e/  Proximal tubule (PT) Scheme of Sodium Na+ reabsorbed (~65%) and Water Movement in the Nephron Distal tubule Reabsorbed and Collecting (~65%) Duct (CD) Na+ reabsorbed Na+ filtered (~8%) 100% Descending Cortical collecting Loop of Henle duct & medullary (~20%) collecting duct Key: Ascending Sodium (Na+) Loop of Henle Urine to be excreted Water Na+ reabsorbed (~25%)  WHERE DO THE DIFFERENT DIURETIC DRUG CLASSES WORK? Proximal tubule Early distal tubule (Carbonic anhydrase inhibitors) Thiazide (and thiazide- like) diuretics Late distal / cortical collecting tubule Potassium sparing diuretics Proximal tubule & descending limb Loop of Henle (Osmotic diuretics) Thick ascending limb Loop of Henle Loop diuretics  Loop diuretics – mechanism of action Example: Furosemide Act on thick ascending limb of Renal Loop of Henle interstitial fluid Inhibit the Na+K+2Cl- co- transporter (compete with Cl- binding in transporter molecule) Tubular cell Tubular lumen As a result of loop diuretic action, Na+ (and also K+) remain in tubule Loop diuretics - mechanism & effects These are powerful diuretics (potentially can drive excretion of ~25%of the filtered load of Na+) Reduced NaCl reabsorption in thick ALH causes reduced osmotic concentration in the renal medulla – this also reduces Antidiuretic Hormone (ADH) mediated H2O absorption Other effects – potentially adverse: Increased delivery of NaCl to the distal tubule causes increased Na+ reuptake there by principal cells, with a corresponding loss of K+ and H+ into the urine via sodium exchange pumps (Also reduced Ca2+ and Mg2+ reabsorption can occur)  Loop diuretics – uses and side effects Main uses: Peripheral oedema in cases of chronic heart failure Acute pulmonary oedema Can be used in resistant hypertension (More about these in Block 2…!) Selected side-effects: Hypovolaemia & hypotension Hyponatraemia and hypokalaemia Low potassium in blood can cause muscle paralysis Image: Guyton & Hall Textbook of Medical Physiology (12e) - Hall and abnormal heart rhythm Thiazide diuretics - mechanism Renal Examples: Bendroflumethiazide, interstitial hydrochlorothiazide, fluid indapamide, chlortalidone Act on early distal tubule Inhibit the Na+Cl- co-transporter (compete with Cl- binding to Tubular cell transporter molecule) Tubular lumen Image: Guyton & Hall Textbook of Medical Physiology (12e) - Hall  Thiazide diuretics – uses & side effects Weak/moderate diuresis (these drugs are usually well tolerated) Slower acting, but longer lasting than loop diuretics Selected side-effects Hyponatraemia / hypokalaemia Main uses: Increase plasma uric acid (gout) Peripheral oedema in chronic heart failure Hypertension Image: Kumar & Clark’s Clinical Medicine (8e) – Kumar Potassium sparing diuretics Renal interstitial Act on principal cells in late fluid distal & cortical collecting tubule Either inhibit epithelial sodium channels (ENaC) or inhibit the mineralocorticoid receptor (MR) Principal cell Reduce K secretion into the + tubular lumen Tubular lumen Image: Guyton & Hall Textbook of Medical Physiology (12e) - Hall  ENaC antagonists – mechanism of action Example: Amiloride Blocks the Epithelial Na+ Channels (ENaC) and decreases luminal permeability to sodium Weak diuretic alone Used in combination with thiazide or loop diuretics (e.g. with hydrochlorothiazide in co- amilozide®) Reduced K+ secretion into tubular lumen Therefore K+ is retained in the blood. Image: Guyton & Hall Textbook of Medical Physiology (12e) - Hall  Aldosterone antagonists Examples: Spironolactone, Eplerenone These drugs are aldosterone antagonists, as they bind to the mineralocorticoid receptor (MR) and block the receptor activation by aldosterone Weak diuretic if used alone – often co-prescribed with loop or thiazide diuretic Prevents synthesis of ENaC and also Na+/K+ ATPase activation and thus reduced potassium secretion into tubular lumen. Thus potassium is retained. Image: Guyton & Hall Textbook of Medical Physiology (12e) - Hall  Potassium sparing diuretics – uses &Main side effects uses (especially aldosterone antagonists) Chronic heart failure Peripheral oedema, also ascites caused by cirrhosis Resistant hypertension Can be used in combination to prevent K+ loss from use of loop or thiazide diuretics – a major use for ENaC antagonists Selected side effects Hyperkalaemia (can interact negatively with RAAS drugs such as ACE-inhibitors) Dangerously high K+ levels in blood can cause life- threatening arrhythmia Image: Kumar & Clark’s Clinical Medicine (8e) – Kumar Mechanisms of Clinical Signs - Dennis  Diuretic combinations Loop diuretics with thiazides – rarely used together As loop diuretics increase the amount of NaCl delivered to distal nephron, this increases efficiency of thiazides Can cause very large water and K+ losses, which carry hypovolaemia and hypokalaemia risks Loop, or thiazide, with K+-sparing diuretics Examples: Co-amilofruse; co-amilozide Achieves good diuretic function without loss of K+ **Beware of K+ retention** – hyperkalaemia risk Careful management required – more in Phase  Drugs and the Kidney Part Three – Drugs acting on the RAAS System Drugs acting on the RAAS – Part Three The Renin-Angiotensin Aldosterone System (RAAS) is Classes of RAAS acting highly active in the kidney and is crucial in control blood pressure drugs: and flow  Angiotensin Converting Enzyme Common and important drugs (ACE) inhibitors used to treat cardiovascular  Angiotensin Receptor Blockers disorders block key functions of  Aldosterone Antagonists the RAAS at specific checkpoints in the kidney and other tissues (overlap with Potassium sparing diuretics) Also – more on these drugs and the RAAS System in Block 2 Renin-Angiotensin-Aldosterone System ↓ arterial Covered further in pressure Block 2…! Angiotensin converting Renin enzyme (ACE) (kidneys) (lungs) Angiotensinogen Angiotensin I Angiotensin II (liver) Vasoconstriction ↑Aldosterone (adrenal ↑Sodium & gland) water ↑ arterial reabsorption pressure (kidneys) Images: Gray’s Anatomy for Students (3e) - Drake  Where are the RAAS drugs working? Kidney Angiotensinogen Response to low Renin BP/low fluid volume Angiotensin I Endothelium ACE (lungs) Angiotensin Angiotensin II II receptors Adrenal gland Aldosterone Principal cells (Collecting Duct) secrete (i.e. you lose) K+ in exchange for Mineralocorticoid Na+ receptor (MR)  Kidney Angiotensinogen Response to low Renin e.g. Losartan BP/low fluid volume Angiotensin I e.g. Ramipril ARB Endothelium ACE ACE-inhibitor (lungs) Angiotensin Angiotensin II Key: II receptors ACE = Angiotensin converting enzyme Adrenal gland Aldosterone ARB = Angiotensin II receptor blocker Aldoste ro ne anta gonist e.g. Spironolactone Mineralocorticoid receptor (MR) Image: Dr Rose Bland  Regulation of GFR via vascular control Balance of afferent (AA) and efferent arteriole (EA) resistances determine GFR General rule: AA dilation &/or EA constriction increases GFR AA constriction &/or EA dilation reduces GFR  Briefly – Drug Interactions Non steroidal anti- and GFR inflammatory drugs (NSAIDs) such as ibuprofen can inhibit production of prostaglandins. These prostaglandins normally promote dilation of the afferent arteriole and increase GFR. Therefore the NSAIDs can reduce GFR ACEi / ARB prevent the action of angiotensin II which drives efferent arteriolar constriction; therefore these drugs can also reduce GFR Image: Guyton & Hall Textbook of Medical Physiology (13e) - Hall Summary – Drugs and the Kidney (Parts 1-3) The kidney is pharmacologically very important – as a major organ involved in the excretion of most drugs, and also as a target organ for specific, therapeutic drug action. The kidney can be especially vulnerable to drug toxicity in higher risk patients Diuretics are important drugs that act directly on specific molecules in the nephron to alter the transport of electrolytes and increase urine volume Drugs that block the RAAS can also act directly on cells in the kidney to alter local blood pressure and promote diuresis Don’t forget the live Block 1 PPT Quiz on Tuesday of Week 5…!