Lecture 21 - Pharmacokinetics 3

Question 1

What are some examples of substances transported into the Proximal tubule by OATs?

Answer 1

Urate (Gout)
Penicillins
NSAIDs
Antivirals

Question 2

What are some examples of substances transported into the Proximal tubule by OCTs?

Answer 2

Morphine
Histamine
Chlorpromazine

Question 3

What is chlorpromazine?

Answer 3

Anti psychotic

Question 4

How can taking multiple drugs affect metabolism?

Answer 4

The transport of the drugs is subject to competition

Question 5

How does concentration of solutes change as you go across the tubule?

How does this affect the movement of a drug/metabolite if its still lipophilic?

Answer 5

Further down the tubule you go the higher the concentration of solutes

Will diffuse from the tubule back into the blood

Question 6

What is pKA?

What is pKb?

Answer 6

pKA = the pH which a weak acid is ionised/dissociates its proton

pKb = the pH which a weak base is ionised

Question 7

What happens if the Distal Convoluted Tubule is acidic in terms of weak acid reabsorption?

Answer 7

The weak aid will Protonate
Making the weak acid charge neutral making it more lipophilic so its reabsorbed back into the plasma

So if the urine is more acidic more weak acid will be reabsorbed back into the blood

Question 8

What happens if the Distal Convoluted Tubule is basic in terms of weak base reabsorption?

Answer 8

Weak bases become charge neutral so more are reabsorbed

Question 9

What is the definition of Drug clearance?

What should it really be known as?

Answer 9

The rate of elimination of a drug from the body

Volume of plasma that’s completely cleared of the drug per unit time

Volume is actually the Vd

Clearance better though of as apparent rate of elimination

Question 10

What 2 things contribute to the total body clearance of a drug?

Answer 10

Total body clearance = Hepatic Clearance + Renal Clearance

Question 11

What is the significance of Clearance and Apparent Volume of Distribution (Vd)?

Answer 11

Helps predict how long drug will state in the body and if its doing any therapeutic good

Question 12

What is the definition of Drug Half life (t1/2)?

Answer 12

T1/2 = the time which it takes for the concentration of a drug in the plasm to become half of its original value

Question 13

How does T1/2 (half life) change as Clearance stays the same and Vd increases?

Answer 13

Half life increases
Takes longer to half in conc

Question 14

How does half life (t1/2) change as Clearance increases but Vd stays the same?

Answer 14

Half life decreases (t1/2)

Drug gets cleared quicker

Question 15

What is hypothetical when considering a drugs half life?

Answer 15

We are assuming that the drug injected via IV distributes immediately through the whole body (no distribution phase)

Question 16

What is linear elimination kinetics?

Answer 16

When you convert a plasma drug conc / time graph to a log[plasma] Vs Time the graph is linear

Question 17

How is the rate of metabolism/excretion of a drug related to the plasma concentration of the drug if the drug shows linear/first order elimination Kinetics?

What does this depend on?

Answer 17

Rate of metabolism proportional to plasma conc of drug

As long as there is a large functional reserve of elimination apparatus i.e enzymes (Phase I/II enzymes, OATs and OCTs)

Question 18

For a drug that shows first order/linear elimination kinetics how catalytic rate over time change?

Answer 18

Decreases as the amount of drug decreases since more gets removed

Question 19

What type of elimination kinetics is referred to when all the elimination processes become saturated? (No more available enzymes/carriers working flat out)

Answer 19

Zero order / saturated kinetics

Question 20

What is zero order elimination kinetics?

Answer 20

The rate of drug elimination is independent of drug plasma concentration

Question 21

How does the elimination kinetics change as higher doses of a drug are reached?

Why does this happen?

Answer 21

Becomes zero order elimination kinetics

Since elimination pathways become fully saturated, rate of elimination cant increase further

The rate of drug metabolism become independent of the concentration

Question 22

Why do drugs with first order elimination kinetics make for easy administration whereas zero order kinetics dont?

Answer 22

First order kinetics = can adjust dose for optimal therapeutic effect
Allows predictable dose response

Question 23

What type of elimination kinetics does phenytoin have?

Answer 23

Zero order kinetics

Question 24

Why are drugs with zero order elimination kinetics more likley to result in Adverse Drug Reactions/toxicity?

Answer 24

They have a fixed rate of elimination per unit time so a relatively small dose change can lead to large increases in plasma conc of a drug

Question 25

Why do drugs with zero order kinetics need careful monitoring in infants and the elderly?

Why do drugs with zero order kinetics need careful monitoring in people with poly pharmacy?

Answer 25

Infants have immature functional reserve (liver enzymes not fully developed till 5yrs)

Elderly have decreased functional reserve/capacity

Poly pharmacy - multiple drugs competing for same hepatic/renal elimination processes

Question 26

Why does drugs with zero order kinetics need careful monitoring in people who are seriously ill?

Answer 26

Reduced hepatic/renal capacity functional reserve

Its easier for the elimination pathways to become saturated

Question 27

What is bioavailability/availability?

Answer 27

The proportion of the original dose of drug available to systemic circulation
(Has already gone past the first pass metabolism - gut wall metabolism an hepatic metabolism)

Question 28

What is oral availability?

Answer 28

Amount of drug taken compared to the amount of drug made available to systemic circulation

Question 29

As amount of gut wall metabolism is increased, how is the amount of drug reaching hepatic blood supply affected?
How is the amount of drug therefore reaching systemic circulation affected?

Answer 29

Reduced amount of drug reaching hepatic blood supply
So less drug reaches systemic supply

Question 30

How does the bioavailability of an IV drug compare to an oral drug?

Answer 30

IV drug = 100% bioavailability since it goes straight into systemic circulation bypassing first pass metabolism

Oral will always be less than 100% due to first pass metabolism (gut wall and hepatic metabolism)

Question 31

What happens to a drugs Vd as it gets more and more lipophilic?

What does this mean in terms of drug penetration?

Answer 31

More lipophilic = higher Vd

More easily penetrates from the Plasma to Extracellular fluid to the Intracellular fluid of tissues like adipose tissues

Question 32

What is the function of Warfarin?

How does it work?

Answer 32

Anti-coagulants = Blood thinner

Inhibits an enzyme that uses Vit K to produce clotting factors

Question 33

As the Vd of a drug increases, how does this affect the amount of the drug that makes it into the tissues?

Answer 33

Increases

Question 34

For Apparent Volume of Distribution Vd, what is the reference compartment that is measure out of the 3 compartments?

Answer 34

Plasma concentration of the drug

Since its easier to measure

Question 35

What is the isozyme which St John’s Wort is an inducer of?

Answer 35

CYP3A4

Question 36

How does St John’s Wort have therapeutic effects?

Answer 36

It increases/induces the levels CYP3A4 increasing the rate they are metabolised, this will help reduce side effects of the drugs