Lecture 4: Clearance

Question 1

What does drug deposition refer to?

Answer 1

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.

Question 2

What factors influence the free drug concentration in the plasma?

Answer 2

• 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)

Question 3

Describe the flow of drug dosage to pharmacological effect

Answer 3

Drug dosage
-> Free drug concentration in plasma
-> Drug. conc. in plasma
-> Drug concentration at site of action
= Pharmacological effect

Question 4

What is the strongest dose and effect relationship?

Answer 4

The relationship between drug plasma concentration and pharmacological effect

Question 5

Where do most medicines go?

Answer 5

Most medicines enter the tissues not the blood

Question 6

What is pharmacokinetics?

Answer 6

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.

Question 7

What are some important pharmacokinetic parameters?

Answer 7

• Clearance
• Volume of distribution
• Half life

Question 8

Why is pharmacokinetics important?

Answer 8

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

Question 9

What can knowing the drug concentrations in the body be used for?

Answer 9

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.

Question 10

What is clearance?

Answer 10

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.

Question 11

What is plasma clearance equal to?

Answer 11

Plasma clearance = sum of clearances from individual organs

Question 12

Describe the bathtub model in relation to clearance:

Answer 12

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.

Question 13

What are some methods of drug elimination?

Answer 13

• Metabolism (predom liver)
• Biliary excretion in liver
• Excretion by glomerular filtration or tubular secretion in the kidney (renal excretion)

Question 14

Write some notes on hepatic elimination:

Answer 14

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)

Question 15

Describe renal excretion:

Answer 15

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

Question 16

What drugs are typically eliminated in the kidney?

Answer 16

• 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)

Question 17

Describe the organs contributions to clearance:

Answer 17

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

Question 18

What are some common high and low clearance drugs from the liver?

Answer 18

Hepatic CL drugs:
High (40-90L/h) : Propranolol, verapamil, morphine
Low (<20L/h) : Theophylline (3L/h), warfarin (3 L/day)

Question 19

What are some common renal CL drugs:

Answer 19

High: Benzyl penicillin (Tubular secretion)
Low: Gentamicin (Solely glomerular filtration)

Question 20

What are some drugs cleared by multiple routes?

Answer 20

Digoxin : Liver (2.5L/h) and Kidney (6.5L/h)

Question 21

Whats the implication for drugs that rapidly cleared by the liver?

Answer 21

Would not be suitable for oral dosing.

Question 22

What is maintenance dose?

Answer 22

Dose rate to achieve and maintain a target conc.

• Steady state conc. (of plasma, preferable within therapeutic window)
• Dose rate = rate of elimination

Question 23

What is the equation for maintenance dose?

Answer 23

Maintenance dose (mg/h) = CL (L/h) x target concentration (mg/L)

Question 24

What are the different types of clearance?

Answer 24

• Constant
• Concentration-dependent
• Flow-dependant

Question 25

Describe constant clearance:

Answer 25

Constant - Independent of concentration and organ blood flow - AKA "First order or linear elimination" - i.e glomerular filtration, most metabolism

Question 26

Describe concentration dependent clearance and two examples of drugs that do this:

Answer 26

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

Question 27

Describe flow dependent clearance:

Answer 27

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

Question 28

Is it strictly one type of clearance?

Answer 28

A drug can be eliminated by a combination of these processes

Question 29

What is Vmax and Km?

Answer 29

Applicable to enzymatic reactions: ``` Vmax = Maximum rate of elimination Km = concentration producing 50% Vmax ```

Question 30

Describe enzymatic clearance based on concentration and Km:

Answer 30

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

Question 31

How is phenytoin an example of mixed order elimination?

Answer 31

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.

Question 32

Whats the implication of phenytoin elimination?

Answer 32

Small increases in dose, cause large increases in plasma drug level (exponentially once elimination is saturated)