Week 7 - Diuretics and Renal Flashcards

1
Q

What are the functions of the kidneys?

A
  • 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

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2
Q

How is the kidney structure related to its function?

A
  • 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
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3
Q

Explain how the kidney tubules work

A

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)

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4
Q

Explain how the loop of henle (LoH) works

A

(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

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5
Q

What are diuretics

A

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

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6
Q

List the 4 types of diuretics?

A
  1. Loop
  2. Osmotic
  3. Thiazide
  4. Potassium sparing
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7
Q

How does “Loop Diuretics” e.g. Bumetanide work?

A

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)

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8
Q

How does “Osmotic Diuretics” e.g. Mannitol work?

A

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)

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9
Q

How does “Thiazide Diuretics” e.g. Chlortalidone work?

A

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

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10
Q

How does “potassium sparing diuretics” work?

A

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

  1. 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

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11
Q

Combined Talets

A

Can treat hypertension, oedema, heart failure

Examples:
1. Co-amilofruse – amiloride and furosemide combined
2. Co-amilozide – amiloride and hydrochlorothiazide

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12
Q

How to reduce loss of K+

A
  1. Increase intake of:
    - fruit juice
    - bananas
    - instant coffee
  2. Take potassium supplements
  3. Use K+ sparing diuretics

Loss occurs with loop, thiazide and osmotic diuretic use

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13
Q

Explain briefly how renal function works?

A
  1. Glomeluar filtration
  2. Secretion
  3. Reabsoprtion
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14
Q

Explain glomerular filtration process

A
  • 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

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15
Q

Explain secretion process

A
  • Molecules secreted from blood into tubules
    -e.g. K+ (in Na+/K+ pump)
  • Then are excreted through urine
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16
Q

Explain reabsorption process

A
  • Molecules move from tubules back into blood
    - molecules move into vasa recta capillaries - renal veins - systemic circulation
  • Used to reabsorb glucose
17
Q

What is Renal Clearance?

A

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)
18
Q

What is Glomerular Filtration Rate (GFR)?

A

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)
19
Q

How do transporter proteins aid renal drug clearance?

A
  • Transporters on apical + basolateral membrane which transport specific drugs
  • e.g. OAT (organic anion transporter)
20
Q

Types of Renal Dysfunction

A
  1. Acute Kindey Injury (AKI)
    - sudden kidney failure
    - occurs within hours / days
    - common cause = medicines (nephrotoxic)
  2. 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

21
Q

List renal function tests + what they are used for

A
  1. Serum creatinine
  2. eGFR
  3. eCrCl
  4. Urinalysis
  5. 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

22
Q

Serum Creatinine

A

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

23
Q

eGFR

A
  • 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

  1. Modification of Diet in Renal Disease Study equation (MDRD)
    - uses serum creatine, age, sex and race
    - not as accurate (overestimates GFR in elderly)
24
Q

eCrCl

A
  • 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

25
Q

Urinalysis

A
  1. Urine dipstick
    - tests for: blood, protein, leucocytes, nitrates, glucose
  2. Albumin Creatinine Ratio (ACR)
    - checks amount of albumin to creatine in urine
  3. Protein Creatinine Ratio (PCR)
    - checks amount of protein to creatinine in urine
    - less sensitive as ACR
  4. Urine output
    - Useful in AKI
    - testsed to calculate urine creatinine clearance
26
Q

Blood Tests

A

Give indicators of renal function + dysfunctions
- can measure creatinine

  1. Urea
    - kidney damage = ↑ urea in blood
    - urea = waste product produced by liver
    - usually excreted in urine BUT reabsorbed into blood if kidney damage
  2. Potassium
    - kidney damage = ↑ K+ in blood
    - K+ is excreted from blood into kidneys
  3. Phosphate
    - ↑ phosphate (accumulates)
  4. Sodium
    - kidney damage = ↑ Na+ in blood
27
Q

What is nephrotoxic medicines?

A

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

28
Q

ADME Considerations of drug use in renal impairment

A
  1. Absorption
    - ↓ for some oral medicine
    - due to GI effects, high urea levels
  2. Distribution
    - altered by fluid status, protein binding, tissue binding
    - dehydrated = ↓ distribution
    - excess fluid = ↑ distribution
  3. Metabolism
    - altered in some patients with CKD as many drugs are metabolised ion kidneys
  4. 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

29
Q

What is Chronic Kidney Disease (CKD)

A

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
30
Q

List symptoms of CKD

A
  • tiredness
  • poor appetite
  • urinating more frequently
  • swollen feet + ankle
  • dry, itchy skin
  • muscle cramping
31
Q

Causes and risk factors of CKD

A

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

32
Q

Classification and Management of CKD

A

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