Medicines and the Kidney Flashcards
Describe how drugs are excreted in the kidney.
2 ways
- Freely filtered through the glomerulus. The glomerular capillaries allow a drug molecular weight of <20kDa to pass through the filtrate. Drugs bound to albumin cannot be filtered out as they have a high molecular weight.
- The glomerulus gets 20% of blood circulation, so 80% is delivered to the peri-tubular capillaries, where drugs are secreted though the PCT via non-specific transported.
How does impaired renal function alter drug handeling?
- Reduced clearance: Can lead to toxic build up of metabolites and a change in the drug distribution.
- Certain drugs that are excreted unchanged can give high plasma concentraions. E.g. Gentamicin (antimicrobial for GI infection and urinary sepsis), digoxin, ferusemide, metmorfin, methotrexate. Can be highly nephrotoxic.
- Increased sensitivity: E.g. CNs depressants and antihypertensives. Also opiates (morphine) are accumulation can lead to respiratory depression as it alters control centres in the brain.
- Decreased sensitivity: Diuretics and urinary antibiotics.
Describe issues of reduced clearance as a result of CKD?
Accumulation of drugs and metabolites and change in distribution leads to;
- Impaired drug absorption: fluid retention in the kidney/oedema in bowel wall can lead to reduced absortion of oral drugs.
- Decreased protein binding: Proteinuria/albuminuria causes decreased proteins available for binding to drugs in the plasma, hence increased plasm concentrations of that drug.
- Impaired kidney metabolism: Impaired function can lead to increased half lives of drugs, raising the plasma concentration.
Describe drug adjustment options in CKD?
Must calculate eGFR to estimate renal function.
1. Can decrease the dose and keep the interval constant (lower peak concentrations).
2. Can keep the dose constant and increase the dose interval (lower trough concentrations).
Must monitor drug levels closely as toxicity can be serious.
Nephrotoxic drugs must be avoided.
What factors would be considered to select appropriate drugs in CKD?
Drugs predominately eliminated by hepatic/biliary.
Less than 25% excreted unchanged in kidneys.
No active metabolites.
Wide therapeutic margin.
Disposition unaffected by protein binding changes or fluid balance changes.
Response unaffected by tissue sensitivity changes.
Drugs that are not nephrotoxic.
Why are the kidneys vunerable to the toxic effect of drugs?
As they receive a large blood flow.
Drugs and metabolites can become very concentrated in the renal medulla as they go through the loop of henle.
There can be further concentration in tubular cells.
What is Acute Tubular Necrosis? Give example of drugs that cause it.
Death of tubular epithelial cells and one of the common causes of acute kidney injury.
Aminoglycosides (Gentamicin)
NSAIDs
What is Glomerulonephritis? Give examples of drugs that cause it.
Nephrotic syndrome - inflammation of the glomerulus.
Gold salts
Penicillamine
What is Interstitial Nephritis? Give examples of drugs that cause it?
Inflammation of the interstitium surrounding the tubules (acute/chronic).
Ferosemide
NSAIDs
Penicillins
Thiazides
What is Nephrogenic Diabetes Insipidus? Give examples of drugs that cause it.
Excessive thirst and excretion of large amounts of dilute urine.
Lithium
Demeclocycline
How do loop diuretics act? Give an example.
What are they used to treat?
Cause excretion of upto 20% of filtered sodium.
Act of the TALH inhibiting action if N/K/2CL carrier in the lumen membrane.
e.g. Furosemide.
Used to treat pulmonary oedema, hypercalcaemia, renal failure.
How do Thiazide diuretics work? Give an example.
What are they used to treat?
Less poewrful that loop diuretics but better tolerated.
Act on the DCT inhibiting the Na/Cl cotransported, causing sodium excretion, so sodium and chloride are lost in urine.
The resulting contraction of blood volume stimulates renin secretion leading to AT2 secretion and aldosterone secretion. Hence the hypotensive effect is limited by the RAAS - making it the most suitable for uncomplicated hypertension.
e.g. Bendoflumethiazide.
Used to treat hypertension, hypercalcuria (renal stones), nephrogenic diabetes insipidus.
How do K+ sparing diuretics work? Give an example.
What are they used to treat?
Work by competing with aldosterone for its intracellular receptor, and inhibiting sodium retention and inhibiting K+ excretion.
Has limited diuretic action as the distal Na+/K+ exchanger only accounts for 2% of filtered Na. Mainly used to treat hyperkalamea, although does have some hypertensive effect.
E.g. Spironolactone (mineralcorticoid receptor antagonist).
Amiloride (blocks ENaC in collecting duct)
Used to treat hyperkalamia, hypertension, hyperaldosteronism.
