Lecture 4: Clearance Flashcards
What does drug deposition refer to?
Refers to all the processes involved in the absorption, distribution, metabolism, and excretion of a drugs in a living organism.
These processes influence the free drug concentration that is achieved in the plasma. Hence why free drug in plasma has a much stronger relationship with pharmacological effect.
What factors influence the free drug concentration in the plasma?
- Binding to plasma proteins (albumin)
- Binding and storage in tissues (Protein and fat)
- Metabolism (liver or extrahepatic)
- Metabolites (active or inactive)
- Biliary excretion (enterohepatic recirculation)
- Renal excretion (secretion vs excretion)
Describe the flow of drug dosage to pharmacological effect
Drug dosage -> Free drug concentration in plasma -> Drug. conc. in plasma -> Drug concentration at site of action = Pharmacological effect
What is the strongest dose and effect relationship?
The relationship between drug plasma concentration and pharmacological effect
Where do most medicines go?
Most medicines enter the tissues not the blood
What is pharmacokinetics?
Pharmacokinetics is the study of the concentration-time profile of a drug in the body.
- Blood (plasma)
- Tissues
- Saliva, milk, urine, feaces
Drug conc. typically sampled from plasma.
What are some important pharmacokinetic parameters?
- Clearance
- Volume of distribution
- Half life
Why is pharmacokinetics important?
Knowledge of pK allows more rational dosing
- Can identify therapetuic window
- Gives drugs its best chance of achieving efficacy and minimising side effects
- Identifies optimal routes of administration and schedules of dosing
What can knowing the drug concentrations in the body be used for?
Drug concentrations in the body can be used to predict effect and allow more rational dosing.
Matching drug concentrations to therapeutic and adverse effects allows for the identification of a therapeutic window, which is a range of concentrations where the drug is effective and causes minimal toxicity.
What is clearance?
Describes the relationship between concentration and elimination of the drug from the body
- Clearance (L/h) = Elimination rate (mg/h) / Concentration (mg/L)
Clearance is constant for a particular drug in a particular patient, therefore the elimination rate is proportional to the drug concentration.
What is plasma clearance equal to?
Plasma clearance = sum of clearances from individual organs
Describe the bathtub model in relation to clearance:
Clearance can be compared to the plughole in a bath. In a bath, the flow of water out of a bath is equal to the size of the plughole multiplied by the height in the bath. Plughole size is constant therefore the flow out of the plug is proportional to the height.
Clearance provides a measure of how efficient the body is at eliminating a medicine.
What are some methods of drug elimination?
- Metabolism (predom liver)
- Biliary excretion in liver
- Excretion by glomerular filtration or tubular secretion in the kidney (renal excretion)
Write some notes on hepatic elimination:
Drugs can be eliminated in the liver by:
- Hepatic metabolism
- Biliary excretion
Any orally administered drugs enter the hepatic portal vein and onto liver thus; thus can be metabolised, deactivated or enter into systemic circulation (metabolised drugs can enter the biliary tract and onto intestines; enterohepatic circulation, can repeat many times)
Describe renal excretion:
Glomerular capillaries very porous: Most drugs will be filtered (Except those large in size or bound to plasma proteins)
Active transport of drugs/metabolites by drug transporters
Small, non-ionised, lipophilic drugs reabsorbed by passive diffusion (lipophilic drugs must be made polar to be excreted)
Drugs excreted in urine
What drugs are typically eliminated in the kidney?
- Hydrophilic drugs
- Polar metabolites of lipophilic drugs
- Unfiltered medicines can be actively transported from the peritubular capillaries to the PCT or DCT by transporter proteins by the process of tubular secretion. (however, any drug here can also be reabsorbed)
Describe the organs contributions to clearance:
Liver blood flow:
- ~90L/h , cleared by metabolism and biliary excretion
Kidney blood flow:
- ~70L/h
- Cleared in urine
- Glomerular filtration rate = 6 L/h
- Tubular secretion (variable rate)
- Tubular reabsorption
What are some common high and low clearance drugs from the liver?
Hepatic CL drugs:
High (40-90L/h) : Propranolol, verapamil, morphine
Low (<20L/h) : Theophylline (3L/h), warfarin (3 L/day)
What are some common renal CL drugs:
High: Benzyl penicillin (Tubular secretion)
Low: Gentamicin (Solely glomerular filtration)
What are some drugs cleared by multiple routes?
Digoxin : Liver (2.5L/h) and Kidney (6.5L/h)
Whats the implication for drugs that rapidly cleared by the liver?
Would not be suitable for oral dosing.
What is maintenance dose?
Dose rate to achieve and maintain a target conc.
- Steady state conc. (of plasma, preferable within therapeutic window)
- Dose rate = rate of elimination
What is the equation for maintenance dose?
Maintenance dose (mg/h) = CL (L/h) x target concentration (mg/L)
What are the different types of clearance?
- Constant
- Concentration-dependent
- Flow-dependant
Describe constant clearance:
Constant
- Independent of concentration and organ blood flow
- AKA “First order or linear elimination”
- i.e glomerular filtration, most metabolism
Describe concentration dependent clearance and two examples of drugs that do this:
Concentration dependent
- CL changes with concentration
- “Mixed order or non-linear elimination” , for when elimination mechanisms become saturated..
- i.e tubular secretion of benzyl penicillin, metabolism of phenytoin
Describe flow dependent clearance:
Flow dependent
- CL approximates organ blood flow
- i.e Morphine Cl = 60L/h
- Some drugs are rapidly cleared and therefore are proportional to the blood flow to the organ
Is it strictly one type of clearance?
A drug can be eliminated by a combination of these processes
What is Vmax and Km?
Applicable to enzymatic reactions:
Vmax = Maximum rate of elimination Km = concentration producing 50% Vmax
Describe enzymatic clearance based on concentration and Km:
Enzymatic drug metabolism is largely drive by concentration
- If concentration is small relative to Km then elimination will appear first order
- If concentration is large relative to Km then elimination rate will appear zero order (elimination rate is independent of concentration as clearance changes)
Medicines that are neither small nor high will usually follow mixed order elimination. True zero order doesnt occur except at very high concentrations
How is phenytoin an example of mixed order elimination?
Phenytoin = Anticonvulsant
Low concentrations: Phenytoin metabolism is a first order process (clearance is conc. independent)
Higher concentrations: Metabolism is saturated and clearance becomes concentration dependant and elimination is a zero order process.
Whats the implication of phenytoin elimination?
Small increases in dose, cause large increases in plasma drug level (exponentially once elimination is saturated)
