4. Drug Excretion Flashcards
What is the role of the nephron
-Filtration, reabsorption, secretion and excretion
-Maintains fluid balance, electrolyte homeostasis and waste elimination
Give the key structures of the nephron
-Glomerulus and Bowman’s capsule
-Proximal Convoluted Tubule
-Loop of Henle
-Distal Convoluted Tubule
-Collecting duct
Describe the glomerulus and bowman’s capsule
-Filters blood plasma to form glomerular filtrate
-Filtration barrier consists of fenestrated endothelium, basement membrane and podocytes, of which blood pressure forces compounds through
-Water, ions, glucose, AA and urea pass through
Describe the Proximal Convoluted Tubule
-Major site of reabsorption
-Reabsorbs glucose, AA, bicarbonate, Na+
-Secretes H+, drugs and toxins
-Key transporters include Na+/K+ ATPase, and SGLT2
Describe the Loop of Henle
-Creates a concentration gradient for eater reabsorption
-Descending limb is permeable to water but not solutes, meaning water leaves via osmosis
-Ascending limb is impermeable to water, but actively transports ions out
-Creates a hypertonic medullary gradient, enabling water conservation in collecting duct
Describe the Distal Convoluted Tubule
-Regulates reabsorption and secretion
-Reabsorbs sodium (via aldosterone), chloride and Ca2+, and water (if ADH is present)
-Secretes potassium, protons (acid base balance)
-Regulated by key hormones aldosterone and parathyroid hormone
Describe the Collecting Duct
-Adjusts urine concentration based on hydration status
-ADH presence causes water reabsorption, concentration urine
-Urea recycling helps maintain medullary osmotic gradient
-Key transporters include aquaporins
What is the aim of the filtration barrier?
-Specialised structure in the glomerulus
-Allow passage of water, ions and small molecules
-Prevent large proteins and blood cells from entering the filtrate
Give the three layers of the filtration barrier
-Fenestrated endothelium of glomerular capillaries
-Glomerular basement membrane
-Podocyte foot processes and slit diaphragm
Describe the fenestrated endothelium of glomerular capillaries layer of the filtration barrier in the nephron
-Allows passage of plasma (water, electrolytes, glucose, AA, small proteins, urea) whilst blocking blood cells (RBCs, WBCs, platelets)
-Endothelial cells have 70-100nm fenestrated pores allowing small solutes and plasma to pass
-Negatively charged glycocalyx repels large negatively charged molecules (eg albumin)
Describe the glomerular basement membrane layer of the filtration barrier in the nephron
-Acts as a charge and size selective barrier, blocking large plasma proteins and providing structural support to the filtration barrier
-Thick negatively charged matrix prevents large and negative charged proteins passing
Describe the podocyte foot processes and slit diaphragm layer of the filtration barrier in the nephron
-Acts as the final size selective filtration barrier
-Foot processes of the podocytes interlock, creating filtration slits ~10nm wide
-The mesh-like slit diaphragm prevents medium sized proteins from crossing
-These allow ultra filtrate to pass into Bowman’s capsule
Describe the relationship dictating the amount excreted from the nephron through tubular handling
Excretion = Filtration − Reabsorption + Secretion
Describe where filtration, reabsorption, secretion and excretion occur in the nephron
-Filtration = Amount of substance filtered at the glomerulus
-Reabsorption = Movement of substances from tubules back into blood
-Secretion = Movementt of substances from blood into tubules
-Excretion = Final amount in urine
Describe what is indicated when the amount filtered in the nephron is equal to the amount excreted? (excreted = filtered)
-Substance moves freely through the nephron without being significantly modified
-No significant reabsorption or secretion
-Example is inulin and creatine, which can be used to measure glomerular filtration rate
Describe what is indicated when the amount filtered in the nephron is greater than the amount excreted? (excreted < filtered)
-Substance is partially or completely reabsorbed in the tubules
-Most is retained in the body
-Example is glucose, amino acids, which are ideally 100% reabsorbed (unless diabetes)
Describe what is indicated when the amount filtered in the nephron is less than the amount excreted? (excreted > filtered)
-Tubules secrete additional amounts from blood into filtrate
-Meaning substance is active secreted into the tubule
-Example is penicillin, which is actively secreted, increasing excretion rate
Describe how you find total renal clearance
TRC = Clearance by filtration + Clearance by secretion - Retention by reabsorption
When may renal function affect elimination of an active compound?
-When the active drug/metabolites are excreted in the kidneys
-If it is metabolised to inactive metabolites then it does not affect elimination
What is the size of molecules that can pass through the glomerular capillaries to the filtrate
Molecular Weight < 20,000
Describe how protein binding affects renal excretion
-Only the free (unbound) fraction of a drug is filtered at the glomerulus.
-Highly protein-bound drugs have reduced renal clearance because they cannot pass freely through the filtration barrier.
-Changes in plasma protein levels (e.g., albumin) can affect drug excretion and dosing requirements.
What dictates the rate of clearance by filtration?
Rate of clearance by filtration = GFR x Fraction of unbound drug in plasma (fu)
Give the physicochemical properties that affect a substance’s renal excretion
-Molecular weight
-Protein binding
-Lipophilicity (low) vs hydrophilicity (high)
-Ionisation and urine pH
Describe how urinary pH can be altered to influence the excretion of weak acidic and basic drugs
-Utilises ion trapping to alter excretion
-Can be done utilising NaHCO3, NH4Cl, Vitamin C
-Can be used to enhance drug elimination in overdose
-Can be used to prevent drug reabsorption in renal tubules
