Pharmacokinetics - Metabolism and Excretion Flashcards
What is Excretion ?
The process by which a drug (unchanged) or its metabolite is removed from the body
Where does excretion primarily occur ?
In the kidneys (urine), but can take place in the biliary system (faeces), lungs (expired air), skin (sweat) , hair and breast milk
Excretion of drugs by the kidney is dependent on 3 main mechanisms:
- Glomerular filtration of unbound drug
- Active tubular secretion of drug transporters
- Tubular reabsorption by passive diffusion down the concentration gradient
The rate of drug elimination depends on ?
The balance between filtration, secretion and reabsorption
Excretion =
Filtration + Secretion - Reabsorption
Capillaries in the glomerulus allow drugs with a ?
Molecular weight (MW) <20kD to pass into the filtrate
Large molecules like heparin and drugs that bound to?
Protein (albumin ~68kDa) - like warfarin (98% bound) - cannot be filtered
What does the amount of filtered drug depend on ?
Renal blood flow, glomerular filtration rate and degree of drug binding to plasma proteins
What does the glomerular filtration rate vary on ?
It varies between individuals, the normal range is 110-130 ml/min
What happens to ~20% of the blood which enters the glomerulus is ? and what happens to the remaining ~80% ?
~20% of the blood which enters the glomerulus is filtered. The remaining 80% will pass on to the peritubular capillaries and possibly undergo tubular secretion in the proximal tubules
What is Tubular secretion ?
Transfers of molecules from peritubular capillaries to renal tubular lumen
Secretory mechanisms in the tubules are not ? but depend on ?
They are not drug specific. But depend on non-selective carrier systems (transporters):
- Organic cation transporters (OCTs)
- Organic anion transporters (OATs)
- P-glycoprotein (an ABC transporter)
The carriers can be ?
Saturated, usually only occurs in drug interactions, where one drug competitively inhibits the secretion of another
E.g. probenecid competes with penicillin for OATs, reduces extraction ratio and prolongs action of penicillin
Explain Organic cation transporter (OCT) ?
- Can only transport molecules DOWN an electrochemical gradient (passive transport)
- Uniporters (only one substrate)
- Substrates include histamine, morphine, pethidine
Explain Organic anion transporters ?
- Can transport molecules against their gradient (active transport)
- Use energy of Na+ gradient
- Can therefore extract virtually all of a drug from the plasma
- E.g. penicillin and p-aminohippuric acid (PAH) are almost completely extracted
OCT and OAT transporters ?
Transporters in the kidney
Explain Tubular reabsorption?
Only ~1% of the glomerular filtrate actually leaves the body, in the rest (~99%) is reabsorbed into the blood
Tubular reabsorption is the process by which ?
Solutes, drugs, metabolites and water are removed from the tubular fluid
These transport processes are mostly driven by ?
Passive diffusion in the distal tube
Lipid-soluble (hydrophobic) drugs are passively reabsorbed into ?
Plasma down the concentration gradient in the distal tube. They are extensively reabsorbed and poorly excreted
Polar/charged drugs are unable to ?
Be reabsorbed and are voided in urine
Hence metabolism of drugs to make them more ?
Polar increases renal excretion
Many drugs are either weak bases or acids and thus the pH of the filtrate can ?
Greatly influence the extent of tubular re-absorption for many drugs
When urine is alkaline, weak acid drugs will ?
Not be reabsorbed
Due to pH partitioning, acidic drugs are ?
Better excreted if urine is alkaline, and vice versa
These changes can be quite significant as urine pH ?
Can vary from 4.5 to 8.0 depending on the diet (e.g. meat can cause a more acidic urine) or drugs (which can increase or decrease urine pH)
How can urine pH be increased or decreased ?
It can be increased by oral dose of sodium bicarbonate and decreased by dose of ammonium chloride
What can this be useful to increase ?
Increase excretion in cases of overdose or poisoning with acidic or basic drugs
Where are some drugs secreted from ?
Plasma to bile in liver (biliary system)
exceptions e.g. temoporfin (anticancer) - 99.9% excreted in faeces
What are the mechanisms for drug excretion in bile ?
Mechanisms include OCTs, OATs and P-glycoprotein transport
How does bile enter the duodenum ?
Via the hepatic duct
Drugs can therefore be eliminated, how ?
In faeces (if they are not reabsorbed in gut)
Glucuronide conjugates from?
Phase 2 metabolism are often secreted into bile
Drugs entering the liver via ? may be what ?
Via the portal vein (from the intestine) or via the hepatic artery (from the general circulation) may be glucuronidated in the liver
The glucuronide metabolite re-enters the intestine via?
The bile duct, destined to be excreted in faeces
However, the glucuronic acid can be cleaved off by ?
β- glucuronidase produced by the bacteria in gastro-intestinal tract, re-forming the original drug can be reabsorbed
This recycling traps ?
The drug in the body, and prolong drug action,
-E.g. steroid hormones, contraceptives, morphine, chloramphenicol
Glomerular Filtration Rate (GFR) is used ?
To indicate renal function
What is Glomerular Filtration rate ?
This is the volume of plasma filtered from the glomerular capillaries into the Bowman’s capsule per unit time
Inulin is filtered but not ?
Secreted and reabsorbed
Inulin clearance = GFR
Why is Inulin not used to measure GFR?
It is a plant polysaccharide and must be administered intravenously (IV) to achieve constant plasma levels
What is Creatinine ?
An endogenous substance with inulin-like properties used instead
What is the clinical application of Bioavailability (F) ?
Determines the amount of drug reaching the systemic circulation and therefore the amount at the site of action
What is the clinical application of Volume of distribution (Vd)?
Determines the size of a loading dose
What is the clinical application of Clearance (CL)?
Determines the maintenance dose
What is the clinical application of Half-life (t½)?
Determines the amount of time needed to reach steady state plasma concentrations or eliminate the drug (4-5 t½)
In order to have the desired therapeutic effect, a drug has to be ?
At a concentration within a certain therapeutic window/range
What happens if the concentration are too high or too low ?
Too high concentration- toxic
Too low concentration- sub-therapeutic (not effective)
What does single compartment model assume ?
The drug is in a single well-stirred compartment of volume Vd
How is the dose Q administered ?
IV bolus injection
Cp decreases exponentially over time, as the drug ?
Is metabolised and excreted
Many drugs show this behaviour - ?
First-order kinetics
Rate of elimination is directly proportional to ?
To the drug concentration
Elimination half life defined as ?
The time taken for half of the drug to be eliminated
Drugs with short half-lives reach steady state quickly but may require?
Frequent administration or continuous infusion to maintain a constant concentration in the body
Drugs with a long half-life may require ?
A large ‘loading dose’ followed by smaller maintenance doses as they take longer to reach steady state
If a drug is administered by intravenous (IV) infusion. Cp increases exponentially until it reaches a ? and at the end of drug administration ?
Steady state concentration, Css, where the rate of infusion is equal to the rate of elimination of the drug. At the end of drug administration, Cp decrease exponentially
Drugs with long t½ may need a ? and what is this called ?
Larger initial dose in order to reach Css more quickly. This is called loading dose
Loading dose given initially to ?
Reach Css
A maintenance dose is then given to ?
Keep the plasma concentration at Css
If a drug is give by means other than IV injection, what must be considered?
The absorption
What does rate of absorption, Kabs , depend on ?
The drug and method of administration
Faster Kabs causes ?
Causes faster increaser in Cp - drug reaches the effective concentration sooner
