Week 7 - Diuretics and Renal Flashcards
What are the functions of the kidneys?
- Act as a filter (filters blood, leading to production of urine)
- Most of filtrate (components filtered out of blood) is reabsorbed + some components are secreted into filtrate
Homeostasis:
- Regulate blood vol. + pressure
- Regulate osmolarity (ion levels)
Excretion:
- Excrete metabolites, chemicals, drugs
Endocrine:
- Hormones, vitamin D3 production
How is the kidney structure related to its function?
- 1.4 million nephrons per kidney
- Nephron: 2 halves
1. Cortex: glomerulus, Bowmans capsule, proximal and distal tubules
2. Medulla: loop of hence, collecting ducts (tubule) - Blood flows into glomerulus (through afferent arteriole) + is filtered (producing filtrate)
- blood leaves through efferent arteriole - Filtrate flows down loop of henle into collecting duct
- Urine out in bladder
Explain how the kidney tubules work
Proximal Tubule
- Filtrate flows through after leaving glomerulus
- Is leaky = allows substances to move between filtrate + epithelial cells
- Na+ diffuses down electrical / concentration gradient into epithelial cells
- 65-70% of Na+ reabsorption (sodium / proton exchanger)
- Secretes organic acids + bases
Distal Tubule
- Impermeable to water
- 7% Na+ reabsorbed (down conc. gradient)
Collecting Tubule
- Water reabsorbed via aquaporin (AQP) channels
- AQP is inserted into apical membrane when vesicles move to surface + exocytosis
- 1% Na+ is reabsorbed (aldosterone bind to nucleus = ↑ Na/K pump expressed = ↑ Na+ absorbed and K+ is secreted)
Explain how the loop of henle (LoH) works
(Thick) Descending LoH
- Permeable to water (diffuses out) and salt (diffuses in)
- water out due to high conc. Na+ in interstitial fluid
- conc. of interstitial fluid increases as LoH depends
(Thick) Ascending LoH
(absorbs Na+, K+, Cl- from lumen into LoH)
- 25% Na+ is reabsorbed from lumen into LoH (sodium / potassium pump)
- Na+ / H+ exchanger = Na+ in and H+ out into lumen = acidic urine
- Low permeability to water
- Na+ is AT out of filtrate into interstitial fluid (of medulla)
apical membrane - faces lumen
basolateral membrane - faces blood
lumen = inside nephron
blood = outside nephron
What are diuretics
Drugs which work on the nephrons of the kidneys
- They ↑ excretion off Na (sodium) and water (into filtrate)
- ↓ in plasma volume = ↓ in blood pressure (BP)
- useful in cardiac failure ~ reduced workload on heart = easier to pump blood
- ↑ production of urine = oedema treated (build up of interstitial fluid is excreted)
- Prevent hyperaldosteronism (retention of H2O + Na+)
- Prevent liver failure (fluid leak into cavity = aldosterone secreted = H2O retained)
- Prevents hypertension (↓ plasma / blood vol.)
- Prevents acute renal failure (caused by small production of dilute urine)
KEY TIP: water tend to follow sodium
- if reabsorb sodium = will reabsorb water = ↑ BP
- diuretics prevent this reabsorption
- Na+ reabsorbed = K+ and H+ are lost / exchanged
List the 4 types of diuretics?
- Loop
- Osmotic
- Thiazide
- Potassium sparing
How does “Loop Diuretics” e.g. Bumetanide work?
Site of Action:
- LoH (esp. ascending LoH)
- 25% Na+ excreted here (Na+/K+ pump)
- Reaches site via excretion from proximal tubule
Aim:
- ↑ urine flow (due to prevented reabsorption)
- ↑ Na+, Cl-, K+, H2O, Ca2+, Mg2+ excretion
- Can also be vasodilators
Mechanism:
- Most powerful diuretic
- INHIBITS Na+/2Cl-/K+ transporter
= prevents reabsorption of Na+ into blood = no H2O reabsorption = ↓ BP
- Also prevent reabsorption of Ca2+ / Mg2+ = ↑ excretion of them
Uses:
- Pulmonary oedema (↓ heart pressure + fluid excreted = ↓ oedema)
- Chronic heart failure (↓ blood vol. = ↓ workload)
- Liver cirrhosis (↓ Na+ retention, more Na+ excreted)
- Hypertension
- Renal failure (prevented reabsorption = more conc. urine produced)
Side effects:
- Hypotension (low BP)
- Hypokalaemia (low K+ in blood) ~ can ↑ effects of other drugs
- more Na+ in cell cause more K+ to be secreted
- Gout ( due to ↑ of uric acid)
- Metabolic Alkalosis (↑ bicarbonate conc. in blood_
Administration + elimination:
- 60-90% absorbed when given orally (through GI tract)
- Can be given orally or IV
- Short duration of action (Oral = <1hr | IV = 30min)
- Excreted in urine
Example:
- Furosemide
- Bumetanide (more potent + higher bioavailability)
How does “Osmotic Diuretics” e.g. Mannitol work?
Site of Action / Act on:
- Proximal Tubules + LoH + Collecting ducts
Aim:
- ↑ solute conc. within tubules (osmolarity) = ↑ conc. of solution = H2O is retained in tubule
- ↑ excretion of Na+ + H20 (urine)
Mechanism:
- Prevents reabsorption of H2O from tubule into blood = ↓ plasma (blood) vol. = ↓ BP
- diuretics enter blood, filtered in glomerulus (not reabsorbed = remain in filtrate)
Uses:
- Treat acute renal failure
- Treats raised lens pressure
- Treat oedema in brain (excess interstitial fluid in brain = fuid drawn back into blood)
Side effects:
- headaches, nausea, vomiting
- hyponatraemia (low Na+ levels in blood)
Administration + elimination:
- IV
- Have short duration of activity + quickly metabolised
- Excreted in urine
- Given with loop / thiazide to maintain K+ balance
Example:
- Mannitol (IV)
How does “Thiazide Diuretics” e.g. Chlortalidone work?
Site of Action:
- Distal tubule (DCT)
Aim:
- ↑ excretion of Na+, K+, Cl-, Ca2+, H2O (lost in urine)
- ↑ secretion of Mg2+
- ↓ uric acid secretion
reabsorption of urea in proximal tubules
- Can have vasodilator effects
Mechanism:
- INHIBITS Cl-/Na+ transporter
= prevent reabsorption of Na+ and Cl- (into blood)
- Inhibits secretion of Ca2+ (from blood to lumen)
- Promotes secretion of Mg2+ (from blood to lumen)
Uses:
- Hypertension
- Oedema
- Heart failure
- Large volume of dilute urine
Side effects:
- Hypokalaemia
- Increased urinary frequency (= take in morning NOT night)
- Erectile Dysfunction
- Impaired glucose tolerance (insulin secretion is inhibited)
Administration + elimination:
- Given orally ONLY
- Excreted in urine
- Have smaller effects than loop, as less Na+ is reabsorbed in DCT
- Better tolerated than loop (↓ risk of stroke / MI)
Example:
- Chlortalidone
~ 25mg daily for hypertension, longer acting drug
- Indapimide
How does “potassium sparing diuretics” work?
2 types of K+ sparing diuretics (Aldosterone inhibitors + Triamterene and Amiloride)
Site of Action:
- DCT
- Collecting duct
Aim:
- ↓ reabsorption of Na+
- Prevent excretion (loss) of K+
- ↑ excretion of Na+, H2O and Cl- = ↓ BP
Mechanism:
1. Triamterene and Amiloride (T&A)
- INHIBIT lumen epithelial Na+ channels
- inhibit Na+ reabsorption (from lumen into tubule) = K+ excretion is inhibited
- Aldosterone Inhibitors (AI)
- Prevent aldosterone binding to nucleus to produce Na+/K+ pump and Na+ epithelial channels
= ↓ excretion of K+ (out of blood into tubule)
= ↓ Na+ reabsorption (from tubule into blood / lumen into tubule)
Uses:
AI:
- Primary hyperaldosteronsim
- Ascites, Oedema, Severe heart failure
T&A
- Hypertension, Heart failure, Ascites, Cirrhosis
Side effects:
- Hyperkalemia (too much K+ in blood)
- GI upset
- Menstrual disorder / testicular atrophy
- Breast development in males
Administration + elimination:
- Spironolactone is metabolised by liver
- well absorbed, slow onset of action
- given with ACE Inhibitor = further ↓BP
Tiameterene is partially metabolised in liver
- well absorbed
Amiloride slower onset of action
- poorer absorption
- Excreted in urine
- Used alongside other diuretics to prevent loss of K+
Example:
- Spironolactone (aldosterone inhibitor)
- Tiameterene
- Amiloride
Combined Talets
Can treat hypertension, oedema, heart failure
Examples:
1. Co-amilofruse – amiloride and furosemide combined
2. Co-amilozide – amiloride and hydrochlorothiazide
How to reduce loss of K+
- Increase intake of:
- fruit juice
- bananas
- instant coffee - Take potassium supplements
- Use K+ sparing diuretics
Loss occurs with loop, thiazide and osmotic diuretic use
Explain briefly how renal function works?
- Glomeluar filtration
- Secretion
- Reabsoprtion
Explain glomerular filtration process
- Blood is filtered in glomerulus
- glomerular capillaries = leaky = allow movement of molecules - Components cross Bowmans capsule into Bowmans space (filtrate)
- i.e. salts, ions NOT proteins - Filtrate flows along nephron
- Remaining blood leaves glomerulus through efferent into vasa recta
Afferent arteriole = wider (than efferent) = ↑ pressure in glomerulus (helps filtration)
If find many proteins in urine = renal issues
Explain secretion process
- Molecules secreted from blood into tubules
-e.g. K+ (in Na+/K+ pump) - Then are excreted through urine
Explain reabsorption process
- Molecules move from tubules back into blood
- molecules move into vasa recta capillaries - renal veins - systemic circulation - Used to reabsorb glucose
What is Renal Clearance?
Is how drugs are excreted from body (via kidneys)
- Drugs that are cleared via kidneys may need dose adjustments
- Some drugs are excreted via urine (move from tubule cell into tubule fluid)
What is Glomerular Filtration Rate (GFR)?
The rate that plasma is filtered by the kidneys
- GFR can be estimated = eGFR
- by measuring blood creatine levels - Creatine is converted into creatinine (which is removed from body by kidneys)
How do transporter proteins aid renal drug clearance?
- Transporters on apical + basolateral membrane which transport specific drugs
- e.g. OAT (organic anion transporter)
Types of Renal Dysfunction
- Acute Kindey Injury (AKI)
- sudden kidney failure
- occurs within hours / days
- common cause = medicines (nephrotoxic) - Chronic Kidney Disease (CKD)
- long term condition (progressive + ongoing)
- gradual decline in kidney function
- common cause = hypertension
Age: causes changes in structure (e.g. ↓ nephrons), function of kidneys, ↓ GFR,
Medicine use in dysfunction can cause:
- ↓ renal excretion of drug = accumulates = side effects = toxic
- increase sensitivity if other drugs
- reduce effectiveness of drug
List renal function tests + what they are used for
- Serum creatinine
- eGFR
- eCrCl
- Urinalysis
- Blood tests
eGFR and eCrCl are NOT interchangeable
- eGFR of 50 ≠ eCrCl of 50
Why it is assessed?
- Identify risk of kidney disease
- Show sign /symptoms of kidney disease
- Identify cause of kidney disease
- Monitor progression of diagnosed kidney disease
- Routine screening
Serum Creatinine
Usual range: 59 - 104 micromol/L
- Serum test measures serum creatinine levels
- Creatinine is produced at constant rate + is cleared by kidneys
(its a product of muscle breakdown) - Used to diagnose AKI (grade 1-3)
- Use value to calculate eGFR (by inputting into formula)
- Use value to calculate estimated creatinine clearance (eCrCl ~ use formula)
AKI Criteria:
- serum creatinine >26 micromol/L within 48 hr
- 50% rise in past 7 days
- Fall in urine
eGFR
- Used to diagnose CKD
- Can be used to determine drug dose / make adjustments
- BNF dosage is expressed in terms of eGFR
Formulas Used to Calculate eGFR:
1. Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI)
- 1st line method
- uses serum creatine, age, sex, race and BSA
- Normal GFR > 90ml/min/1.73m2
- Modification of Diet in Renal Disease Study equation (MDRD)
- uses serum creatine, age, sex and race
- not as accurate (overestimates GFR in elderly)
eCrCl
- Used to diagnose CKD
- Majority of drug dosing is based on this value
- Used in elderly (> 75), those w/ extreme muscle mass
- Used in medicine with narrow therapeutic index, have bleeding risks
Formula Used:
Cockcroft and Gault equation
- uses age, weight, sex, serum creatinine
- doesn’t take into account race, muscle mass etc.
- accuracy issues in pregnant women, malnourished
Urinalysis
- Urine dipstick
- tests for: blood, protein, leucocytes, nitrates, glucose - Albumin Creatinine Ratio (ACR)
- checks amount of albumin to creatine in urine - Protein Creatinine Ratio (PCR)
- checks amount of protein to creatinine in urine
- less sensitive as ACR - Urine output
- Useful in AKI
- testsed to calculate urine creatinine clearance
Blood Tests
Give indicators of renal function + dysfunctions
- can measure creatinine
- Urea
- kidney damage = ↑ urea in blood
- urea = waste product produced by liver
- usually excreted in urine BUT reabsorbed into blood if kidney damage - Potassium
- kidney damage = ↑ K+ in blood
- K+ is excreted from blood into kidneys - Phosphate
- ↑ phosphate (accumulates) - Sodium
- kidney damage = ↑ Na+ in blood
What is nephrotoxic medicines?
Medicines that can cause kidney damage
- BNF states if drug nephrotoxic or not
Risk factors for drug-induced nephrotoxicity
- Age ( >60)
- Diabetes
- Renal impairment
- Sepsis
- Heart failure
Prevent:
- Use non-nephrotoxic medicine
- Monitor renal function during treatment
- Avoid combining nephrotoxic drugs
- Assess renal function before begin treatment + adjust dose
Examples:
- NSAIDs
- Narrow therapeutic medicines that are really excreted
- ACE Inhibitors
ADME Considerations of drug use in renal impairment
- Absorption
- ↓ for some oral medicine
- due to GI effects, high urea levels - Distribution
- altered by fluid status, protein binding, tissue binding
- dehydrated = ↓ distribution
- excess fluid = ↑ distribution - Metabolism
- altered in some patients with CKD as many drugs are metabolised ion kidneys - Elimination
- altered due to build up of medicines
- filtration + reabsorption is reduced = ↑ conc. of drug in medicine
Changes in ADME can cause ↑ conc. of drug in body or urine
= drug dose alteration needed
What is Chronic Kidney Disease (CKD)
Long term condition with gradual decline in kidney function over time
(abnormal kidney function / structure which last >3 months)
- Can cause ↑ mortality, cardiovascular disease and end-stage kidney failure
List symptoms of CKD
- tiredness
- poor appetite
- urinating more frequently
- swollen feet + ankle
- dry, itchy skin
- muscle cramping
Causes and risk factors of CKD
Cause:
- Kidney infections
- Hypertension
- Diabetes
- Nephrotoxic medicines
- Kidney stones
- Hereditary kidney diseases
Prevalence increases with:
- Age (older)
- Ethnic minority group (African, Asian)
Risk Factors:
- Smoking
- Chronic NSAIDs use
- AKI
- Cardiovascular disease
- Hypertension, Diabetes, Age
- Family history
Classification and Management of CKD
Criteria for CKD:
- eGFR < 60 mL/min/1.73m2 (↓ eGFR = greater risk)
- ACR > 3 mg/mmol (↑ albumin in urine = greater risk)
- Blood in urine / other abnormalities in urine
- Kidney structural abnormalities
Management:
- NO CURE
- Prevent / delay progression
- Prevent complications
- Manage symptoms
- Reduce risk of CVD
Achieved through BP control + controlling protein in urine
Medicine:
- Start low dose then gradually increase
- Use drugs which aren’t really excreted
- Review medication regularly
- Avoid NSAIDs + drugs which worsen symptoms
