D11 - drug excretion Flashcards
Excretion
- process by which an unchanged drug is permanently removed by the body via the kidneys of hepatobiliary system - only removal of parent drug - not metabolism
- Different to drug elimination - a broader term including irreversible loss of unchanged parent drug from the blood stream due to excretion or biotransformation that may form metabolites
Excretion - Primary organ ○ Kidneys and liver ○ Main drug excreting organs - Excretion into sweat and tears can also occur - excretion into saliva (which is just swallowed gain - Excretion via breastmilk esp. nitrogen containing drug results in drug dosing to the infant eg. Crack babies - during the cocaine epidemic of the 1980s - Minor excretory routes ○ Hairs, nails, skin - minor overall ○ Can be used for forensic purposes
Excretion of some drugs
- Enterohepatic recycling
○ Drugs go into bile and then to the duodenum and small intestine and then back to the liver via enterohepatic recycling
Metabolism is the main clearance route for three quarters of clinically used drugs
main clearance route for three quarters of clinically used drugs
metabolism
The kidneys
- Receive a large amount of blood flow
- 1/4 of cardiac output goes to the kidneys
- The kidneys play the primary role in excretion for about 1/4 of al drugs
○ Remove parent unmetabolized drug from circulation
○ Get rid of metabolites formed in the liver
○ Lipid soluble molecules are poorly metabolised by the kidneys - required metabolism in the liver - Chemicals that are lipophilic last longer in the body
The main stages of renal drug excretion
- Glomerular filtration
○ Only free unbound drugs are filtered through the glomerular pores
○ All unbound drugs get filtered
○ Influenced by blood flow, whether the drug is protein bound- Passive reabsorption
○ Lipophilic drugs that tend to be reabsorbed
○ Small lipophilic neutral drugs
○ Influences by pH, pKa of drug (ionisation behaviour) - Active transport
○ Transports drug into the urine (including protein bound drugs)
○ Energy dependant transporters
○ ATP dependant processes - export drugs including protein bound drugs
- Passive reabsorption
- Glomerular filtration
○ Only free unbound drugs are filtered through the glomerular pores
○ All unbound drugs get filtered
○ Influenced by blood flow, whether the drug is protein bound
- Passive reabsorption
○ Lipophilic drugs that tend to be reabsorbed
○ Small lipophilic neutral drugs
○ Influences by pH, pKa of drug (ionisation behaviour)
- Active transport
○ Transports drug into the urine (including protein bound drugs)
○ Energy dependant transporters
○ ATP dependant processes - export drugs including protein bound drugs
Excretion
• Shaped by the summation of
○ Active transport and filtration - pushes drugs into the urine
○ Passive reabsorption - subtracts from the overall drug excretion
Glomerular filtration
○ Driven by blood pressure
○ Occurs in the Bowman’s capsule
§ Where the glomerular structures do filtration based on the molecular weight of the molecule
○ The amount of filtration that occurs is constant across individuals
§ Any unbound drug goes into tubular fluid
§ FU - fraction unbound in plasma - measure glomerular filtration by measuring fraction unbound in plasma and multiplying by the glomerular filtration rate
○ salvages large molecules eg. plasma proteins
○
○ 120ml/minute multiplied by the fraction unbound = GFR
Bowman’s capsule
§ Where the glomerular structures do filtration based on the molecular weight of the molecule
FU - fraction unbound in plasma
§ FU - fraction unbound in plasma - measure glomerular filtration by measuring fraction unbound in plasma and multiplying by the glomerular filtration rate
glomerular filtration rate =
120ml/minute multiplied by the fraction unbound
Active transport
○ Occurring at the proximal tubules - strong expression of range of organic anion (OAT1,3) transporters and organic cation transporters (OCT2)
○ Strongly expressed on basolateral membrane in the vasculature of the renal kidney
○ Uses SLC and ABC transporters
○ Proximal tubular epithelial cells - polarised with 2 membranes
§ Basolateral membrane - series of transporters bringing drugs out of the blood into the renal epithelial cells - uses SLC transporters - OAT1,3 and OCT2
§ Apical membrane - characteristic for brush like appearance - expression of different types of transporters - usually ATP dependant ABC type eg. P-gp
○ Amount of drug transported is constant
○ Only saturable at high drug doses - sometimes a factor in overdose patients
§ Eg. Alcohol - substrate for active transport
§ Factors contributing to drunkenness - saturation of renal transport
○ Most clinically used drugs do not induce saturation - only in overdose patients
active transport occurs at
Occurring at the proximal tubules
○ Proximal tubular epithelial cells - polarised with 2 membranes
§ Basolateral membrane - series of transporters bringing drugs out of the blood into the renal epithelial cells - uses SLC transporters - OAT1,3 and OCT2
§ Apical membrane - characteristic for brush like appearance - expression of different types of transporters - usually ATP dependant ABC type eg. P-gp
Passive reabsorption
○ Counteracts excretion / active transport
○ Large degree of concentration and reabsorption of fluid - essential compounds in fluid are reabsorbed back into the blood stream
○ Undergoes process of concentration
○ 120ml/minute
○ 99% of fluid recovered by process of volume reduction
○ Any lipophilic drug that is freely permeable - not ionised - diffuses back into the blood stream - only if the drug in neutral
§ If it has a positive or negative charge it will be trapped and undergo secretion
○ Proportional to drug concentration in the blood - determines whether it is energetically favourable for it to diffuse
Summary of renal excretion
- Filtration at the glomerulus
- Active transport at proximal tubules
○ Two processes accounting for drugs being excreted into urine - Reabsorption of uncharged neutral molecules back into the blood stream
- Overall renal clearance = the sum of renal filtration plus active secretion, minus renal absorption
- Active transport at proximal tubules
- Protein binding
○ Filtration: Doesn’t have much influence on filtration - only free unbound drug undergoes this process - bound drug is not filtered
○ Diffusion: Can influence process of diffusion - string binding to plasma proteins can decrease passive diffusion by reducing the concentration gradient in the microvasculature - less energetically favourable for the drug to diffuse
§ Not a major factor
○ Active transport: is not affected by protein binding - even highly bound protein drugs can be subject to active transport renal excretion
Filtration
Doesn’t have much influence on filtration - only free unbound drug undergoes this process - bound drug is not filtered
Diffusion
Can influence process of diffusion - string binding to plasma proteins can decrease passive diffusion by reducing the concentration gradient in the microvasculature - less energetically favourable for the drug to diffuse
§ Not a major factor
Active transport:
is not affected by protein binding - even highly bound protein drugs can be subject to active transport renal excretion
- Urinary pH
○ Esp. in people with acidic urine - eg. caused by high protein diet (because of amino acids)
§ High amino acid concentration in urine - sulphur containing amino acids release protons and decrease prevailing pH
○ Influences excretion of ionisable drugs
§ Used in managing overdose patients
§ Eg. Aspirin (acidic) - alkalinise the urine of the aspirin poisoned patient - drug shifts into negative ionised state - cant undergo passive reabsorption - increases excretion from the body
§ Eg. Amphetamine (basic) - If a patient has overdose on amphetamine - basic and carries positive charge in acidic environment - acidify the urine to increase removal from the body and reduce passive reabsorption
Eg. Aspirin (acidic)
alkalinise the urine of the aspirin poisoned patient - drug shifts into negative ionised state - cant undergo passive reabsorption - increases excretion from the body
Eg. Amphetamine (basic)
If a patient has overdose on amphetamine - basic and carries positive charge in acidic environment - acidify the urine to increase removal from the body and reduce passive reabsorption
Dominant process in renal excretion
○ Measure amount of drug in the urine FU x GFR
§ If there is more drug than expected based on FU x GFR
□ Drug must be undergoing active secretion - must be undergoing active transport
§ If less than expected
□ Drug is undergoing reabsorption
○ Co-administer inhibitors of renal transporter to see what impact there is on renal excretion
§ Eg. Probenecid - supresses active secretions of organic anions
§ Eg. Cimetidine - suppresses active secretion of organic cations
amount of drug in urine =
FU x GFR
Liver and drug secretion
- Some drugs undergo direct hepato-biliary excretion (3-4% of all clinically used medicine)
○ Absorbed from the GI, go through portal vein to liver and parent drug excreted into bile- Bile forms in hepatocytes then secreted into caniculi
- Having been absorbed into the liver and the excreted via the bile
○ Drugs excreted this way appear in faeces
§ Find out how much is recoverable from faeces to find out if a drug is being lost through biliary secretion - Entero-biliary recirculation
○ When a drug has a functional group that undergoes conjugation eg. Glucuronides
○ Excreted by bile into GI tract
○ Glucuronidase enzymes in the microbiome cleave glucuronide releasing parent drug which is taken up by portal circulation and sent back to the liver
○ Undergo continual circulation - increase half life
○ Sometimes causes a bump in the plasma concentration time curve
Entero-biliary recirculation
○ When a drug has a functional group that undergoes conjugation eg. Glucuronides
○ Excreted by bile into GI tract
○ Glucuronidase enzymes in the microbiome cleave glucuronide releasing parent drug which is taken up by portal circulation and sent back to the liver
○ Undergo continual circulation - increase half life
○ Sometimes causes a bump in the plasma concentration time curve
drugs excreted by direct hepato-biliary excretion appear in
faeces
Transporters and Hepatobiliary drug excretion
○ Hepatocytes strongly express many transporters for organic acids, bases, and neutral compounds
○ Removing drugs and putting into bile
§ Mostly SLC type transporters in basolateral membranes (blood interface)
□ Uptake drugs from circulation
§ Mostly ABC type transporters in canicular membrane inc. P-gp
□ Export drug/metabolites into bile
○ Canicular transporters prefer large molecules containing polar and lipophilic groups
§ conjugation - especially with glucuronic acid - facilitates hepato-biliary excretion
transporters in basolateral membranes
§ Mostly SLC type transporters in basolateral membranes (blood interface)
□ Uptake drugs from circulation
transporters in canicular membranes
§ Mostly ABC type transporters in canicular membrane inc. P-gp
□ Export drug/metabolites into bile
canicular transporters prefer
○ Canicular transporters prefer large molecules containing polar and lipophilic groups
§ conjugation - especially with glucuronic acid - facilitates hepato-biliary excretion
Clearance
- The volume of blood cleared of drug per unit time
- Hepatic clearance
a. Liver is the primary route of removal
b. Drug undergoes metabolism
c. FE close to 0 - very little parent molecules in the urine
d. Metabolites forming in liver
e. Paracetamol - most recovered at metabolises in urine - Renally cleared
a. Probably hydrophilic - not a substrate for P450
b. Directly excreted in the urine
c. Ampicillin - penicillin derivative - not metabolised FE close to 1 - all administered dose is recovered unchanged in the urine
- Hepatic clearance
Hepatic clearance
a. Liver is the primary route of removal
b. Drug undergoes metabolism
c. FE close to 0 - very little parent molecules in the urine
d. Metabolites forming in liver
e. Paracetamol - most recovered at metabolises in urine
- Renally cleared
a. Probably hydrophilic - not a substrate for P450
b. Directly excreted in the urine
c. Ampicillin - penicillin derivative - not metabolised FE close to 1 - all administered dose is recovered unchanged in the urine
Fraction excreted unchanged Fe
- In urine
- Renal clearance in Fe tends to 1
○ Eg. Ampicilin - Hepatic clearance if Fe tends to 0
○ Eg. Paracetamol
- Renal clearance in Fe tends to 1
Liver vs. kidney
• Important for people with disease
• Eg. Alcohol - shot liver not normally secretary capacity
• Renal insufficiency - cautious about giving a patient a drug with FE close to one - person may be poisoned
• Drugs with FE’s above 0.5 should be used cautiously in patients with renal disease
• Vancomycin
○ Used to treat patients that are drug resistant bacterial infections and don’t respond to antibiotics
○ Narrow therapeutic window
○ Drug doesn’t et metabolised - relies on the kidney
○ A person with renal insufficiency - a single dose will last a week - kidneys cannot remove it from the blood stream - continual doses will kill them
Vancomycin
○ Used to treat patients that are drug resistant bacterial infections and don’t respond to antibiotics
○ Narrow therapeutic window
○ Drug doesn’t et metabolised - relies on the kidney
A person with renal insufficiency - a single dose will last a week - kidneys cannot remove it from the blood stream - continual doses will kill them
Determining total body CL for a drug
• Use plasma concentration time curve • Calculate area under the curve AUC ○ Divide dose by area under the curve ○ = litres per hour cleared of drug ○ If oral - correct for bioavailability
Organ clearance is controlled by blood flow
• Q = blood flow to a specific organ
• E = extraction ration for particular organs (ranges from 0 to 1)
• Proportion of clearance is QxE
Cin and Cout are steady state drug concentrations in blood (usually arterial and venous respectively)
Clearance
Clearance
• Tells how much blood can be cleared of the drug per unit time
• Use to determine dosing - steady state
○ Often needs repeated dosing to reach steady state
CL and F are key determinant factors in steady state drug levels with oral dosing
