RENAL - Renal Drug Excretion Flashcards
RECAP: Describe the basic steps of renal drug excretion
- To be excreted, should be polar/hydrophilic
- Hydrophilicity increased by metabolism and drugs can be conjugated to terminate action
- Drugs filtered at glomerulus if bioavailable to terminate action
- If too big, charged or strongly PPB - drugs secreted into nephron
- Reabsorbed from PCT if neutral
Describe the types of drugs cleared via glomerular filtration. PART 1
Parent drugs and metabolites can be filtered at the glomerulus when arterial pressure forces ultrafiltrate from the glomerular capillaries into the Bowman’s capsule
- Small drug molecules (<5000 Mr) in both a charged and uncharged state cross the glomerular membrane
Describe the types of drugs cleared via glomerular filtration. PART 2
- Concentration in the ultrafiltrate are identical to those in the free state (bioavailable not PPB) in the blood
- Negatively charged proteins in the capillary wall can impede the filtration of large, negatively charged molecules (drugs and metabolites)
- Drugs or metabolite that are PPB are not filtered
Describe molecular size determines drug glomerular filtration.
- Low molecular weight (<5500Da) and small effective molecular radius gives equal concentration in the plasma and filtrate (no sieving)
- High molecular weight and large effective molecular radius higher concentration in the blood plasma than the filtrate (sieving)
Describe how charge and PPB influence drug glomerular filtration.
- Neutral up to <2nm pass readily (4.2nm limit of passage)
- Anionic (-ve) restricted filtration
- Cationic (+ve) increased filtration
Only drugs that are not bound to plasma protein can be excreted via glomerular filtration
Describe the influence of nephritis on drug filtration.
- Removes the negative charge from the barrier of the glycocalyx - increases the the filtration of anions
- Albumin size of 3.5nm if neutral would have a clearance ratio of 0.1 but heavily negatively charged so 0 in nephritis the negative charge of glycocalyx diminished
- So filtered into the bowman’s filtrate
RECAP: How are inulin and creatinine used in GFR measurement?
- INULIN filtered but not reabsorbed or secreted
- Creatinine - waste product of muscle metabolism - processed in a similar way
RECAP: How is PAH clearance used to demonstrate tubular secretion?
- Very little filtered at glomerulus - majority secreted into nephron and not reabsorbed
- So most that enters the peritubular capillary bed (found immediately after the efferent arteriole) is excreted
What are the major principles regarding renal drug clearance via active tubular secretion? PART 1
- Parent drugs and metabolites can be secreted into the nephron so long as they can transverse the cells and move from the blood into the nephron lumen
- Larger drug molecules (>5000 Mr) in an uncharged state cross can cross the membranes by passive diffusion if they are in the neutral form and lipid soluble (unlikely after metabolism)
- Concentration in the ultrafiltrate are identical to those in the free state (bioavailable not PPB) in the blood
What are the major principles regarding renal drug clearance via active tubular secretion? PART 2
- Negatively charged proteins in the capillary wall can impede the passive diffusion of large, charged molecules (drugs and metabolites) so transporters are necessary to facilitate the drugs movement across the membranes
- Drugs or metabolite maybe PPB so long as the affinity is higher for the transporter than the plasma protein, they will transport leaving the plasma protein behind in the blood
At the late proximal tubule, if the drug is negatively charged then it uses anionic transporters. Describe these transporters.
- OAT1/3 substrates are typically smaller, negatively charged molecules that include: antibiotics, antivirals, H2 antagonists, diuretics, NSAIDs, statins, methotrexate
- Many anionic drugs (e.g. probenecid, penicillin, furosemide) compete for basolateral PA-anion exchanger or the apical PAH-anion exchanger
- Apical transport to the ultrafiltrate is via facilitated diffusion
- Anionic drugs secretion similar to renal handling of PAH in late proximal tubule. Transporters move endogenous substances and drugs from the plasma to the tubular fluid
- Transporters have low specificity
If the drug is negatively charged it will use an anionic transporter
Positively charged drugs also have their own basolateral cationic transporters. Describe them.
- OCT Transporters are non-specific - drugs can be substrates for more than one transporter
- OCT transporters at basolateral membrane - Driven by internal negative membrane potential
- MATE transporters at apical membrane - transport to nephron lumen - driven by electrochemical proton gradient across apical membrane
If the drugs are not transported by OCTs and OATs what are they transported by? Give some examples of substrates that would use these extra transporters.
MDR1
- Cardiac drugs e.g digoxin
- Antibiotics e.g erythromycin
- CCBs e.g verapamil
- H2 antagonists e.g ranitidine
- Steroids e.g aldosterone, dexamethasone and hydrocortisone
- Lipid lowering agents e.g atorvastatin
Inhibitors amiodarone and verapamil (often co-administered with OTHER cardiac drugs) so can affect excretion and elimination of pharmacologically active drug
What happens to drugs filtered by the glomerulus and by active tubular secretion?
- Reabsorbed by passive tubular reabsorption/passive diffusion across membrane if needed
Describe how pH influences excretion and how this can be mainpulated to influence reabsorption.
- Influences rate of excretion of both acidic and basic drugs by ion trapping and reduced passive resorption
- Altering urine pH to enhance drug excretion or increase reabsorption to raise drug persistence
What would happen if a weakly acidic drug is excreted into alkaline urine?
- Drug is highly ionised and therefore not lipid soluble
- Not reabsorbed across renal epithelial membrane and excretion enhanced
Describe pKa and what happens when it is equal to pH of solution it is dissolved in
- Dissociation constant - used to describe acid strength
- 50% of the drug exists ionized and 50% exists nonionized.
Describe what happens to alkaline drug molecules in acidic urine.
- Removed - readily give up hydrogen molecules to become polar
- Reabsorption through non-polar cell membranes becomes more difficult
- Easily removed by ionic active processes
- Weak acids remain in neutral form and reabsorbed
Describe what happens to acidic drug molecules in alkaline urine.
Same first three bullet points as previous flashcard
Define osmotic diuresis.
Osmolality of urine is greater than osmolality of plasma
- Caused by disease, drugs influencing medullary function, excessive excretion of organic solutes (glucose, urea or mannitol) or a very high rate of excretion of electrolytes
How does osmotic diuresis affect GFR, active tubular secretion and tubular reabsorption?
- Glomerular filtration will decrease due to increased oncotic pressure in the Bowman’s capsule
- Active tubular secretion may decrease depending on pH of filtrate and pKa of the drug
- Tubular reabsorption may increase due to increased ultrafiltrate solute concentration (Monitor)
Describe what happens during osmotic diuresis on a physiological level using mannitol as the example of the cause of diuresis. PART 1
- Na+ is being actively pumped from the ICF across the membrane to the ECF
- Creates a decreased Na+ concentration inside the cell activating the Na+ pumps on the apical membrane
- Na+/ H+ transporter and Na+/ glucose co-transporter on the apical membrane move Na+ from the nephron lumen to the ICF.
Describe what happens during osmotic diuresis on a physiological level using mannitol as the example of the cause of diuresis. PART 2
- Osmotic diuretics such as mannitol increase the concentration of solute in the nephron lumen pulling water back into the lumen to dilute the concentration of solute.
- More water remains in the nephron lumen and is excreted.
Describe the clinical indications, side effects and pharmacokinetics of mannitol.
- Manage cerebral oedema, in acute traumatic brain injuries, reduced ischaemic cerebral damage following surgery
- Expansion of plasma volume leading to heart failure and urinary potassium loss leading to hypokalaemia
- Administered IV, filtered at glomerulus, half-life increased by huge factor in renal impairment, NOT USED IN HEART FAILURE
Describe what happens to drug clearance via glomerular filtration with increased blood flow.
- Increased blood flow increases GFR
- Increased filtration = increased drug in Bowman’s capsule
- Drug should be small and not negatively charged
OPPOSITE FOR REDUCED BLOOD FLOW
Describe drug clearance via tubular secretion with reduced blood flow.
RELEVANT DURING GLOMERULOPATHY
- Decreased blood flow and decreased eGFR can cause increased reliance on excretion via active tubular secretion
Describe drug clearance via tubular secretion with increased blood flow.
- Reduced tubular secretion by diffusion
- Active tubular secretion determined by transport maximum of carriers and solutes transported don’t usually diffuse at glomerulus
- Increased blood flow - more ligand interaction with carriers
Describe the ratio that determines the extent to which renal clearance is influenced.
EXTRACTION RATIO - ranges from 0 to 1
- 0 indicates that most of the drug escapes elimination
- 1 indicates that most of the drug is eliminated in a single pass of the kidney
Describe how extraction ratios determine what drug renal clearance can be influenced by.
- Drugs with a high extraction ratios are influenced by renal blood flow
- Drugs with high extraction ratios are influenced by plasma protein binding
- Drugs with both low and high extraction ratios are influenced by the kidneys intrinsic ability to eliminate the drug
Describe the effects of having a drug with low extraction ratio.
- Venous drug concentration identical to arterial concentration - clearance influenced by blood flow variations
- Changes in kidney’s intrinsic ability to eliminate drug will affect organ clearance
- Only unbound drug penetrates membrane and available for elimination - an increase in this will proportionally increase clearance - unbound drug concentration remains constant
Describe the effects of having a drug with high extraction ratio.
- Changes in blood flow produce corresponding changes in clearance e.g an increase in blood flow increases amount of drug eliminated
- Organ capable of removing all of drug regardless of plasma binding - clearannce remains constant so increasing unbound fraction may have toxic effects
- Raised kidney ability to eliminat drug - clearance remains constant but unbound drug fraction increases leading to toxicity
What are the mechanisms of nephrotoxicity?
- Lysosomal induced injury/ lack of lysosomal enzymes or rupture of membrane
- Dysfunctional MDR transporters - build up of drug leading to mitochondrial toxicity
- MATE1 transporter dysfunctional - build up producing ROS - mitochondrial toxicity
When may a doctor simply prescribe the dose recommended by the manufacturer?
- Drug has a wide therapeutic index
- Duration of therapy is short
- Dose is low (e.g., prophylaxis dosing)
- Ability to titrate the dose on the basis of clinical
Give an example of a time when additional adjustments to dosing regimen may be required in patients.
- Change in clearance
- Coprescribed drug - inducing or inhibiting elimination pathways of index drug
When should drug dosages be adjusted?
Unlikely if <30% of dose excreted by kidneys
- Dose adjustments for primarily hepatically metabolized drugs may be required, because their pharmacologically active and/or toxic metabolites are primarily excreted by the kidney, which may increase the pharmacologic effect and/or risk of adverse events.
- Example morphine - metabolised to a more potent form that can cause renal failure
What pharmacokinetic parameters can influence the dosing regimen?
Clearance and volume of distribution
When are dose adjustments particularly required?
- Drugs with a long treatment duration and high intrinsic toxicity - particularly if they have a long t 1/2
- Examples are metformin, digoxin and lithium
RECAP - Describe glomerular filtration.
Most common route of renal elimination
- Free drug cleared whilst PPB remains in circulation
RECAP - Describe PCT-related active tubular secretion.
- Occurs to both weak acids and weak bases
- Occurs for penicillin and procainamide
