Lecture 21 - Pharmacokinetics 3 Flashcards
What are some examples of substances transported into the Proximal tubule by OATs?
Urate (Gout)
Penicillins
NSAIDs
Antivirals
What are some examples of substances transported into the Proximal tubule by OCTs?
Morphine
Histamine
Chlorpromazine
What is chlorpromazine?
Anti psychotic
How can taking multiple drugs affect metabolism?
The transport of the drugs is subject to competition
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?
Further down the tubule you go the higher the concentration of solutes
Will diffuse from the tubule back into the blood
What is pKA?
What is pKb?
pKA = the pH which a weak acid is ionised/dissociates its proton
pKb = the pH which a weak base is ionised
What happens if the Distal Convoluted Tubule is acidic in terms of weak acid reabsorption?
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
What happens if the Distal Convoluted Tubule is basic in terms of weak base reabsorption?
Weak bases become charge neutral so more are reabsorbed
What is the definition of Drug clearance?
What should it really be known as?
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
What 2 things contribute to the total body clearance of a drug?
Total body clearance = Hepatic Clearance + Renal Clearance
What is the significance of Clearance and Apparent Volume of Distribution (Vd)?
Helps predict how long drug will state in the body and if its doing any therapeutic good
What is the definition of Drug Half life (t1/2)?
T1/2 = the time which it takes for the concentration of a drug in the plasm to become half of its original value
How does T1/2 (half life) change as Clearance stays the same and Vd increases?
Half life increases
Takes longer to half in conc
How does half life (t1/2) change as Clearance increases but Vd stays the same?
Half life decreases (t1/2)
Drug gets cleared quicker
What is hypothetical when considering a drugs half life?
We are assuming that the drug injected via IV distributes immediately through the whole body (no distribution phase)
What is linear elimination kinetics?
When you convert a plasma drug conc / time graph to a log[plasma] Vs Time the graph is linear
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?
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)
For a drug that shows first order/linear elimination kinetics how catalytic rate over time change?
Decreases as the amount of drug decreases since more gets removed
What type of elimination kinetics is referred to when all the elimination processes become saturated? (No more available enzymes/carriers working flat out)
Zero order / saturated kinetics
What is zero order elimination kinetics?
The rate of drug elimination is independent of drug plasma concentration
How does the elimination kinetics change as higher doses of a drug are reached?
Why does this happen?
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
Why do drugs with first order elimination kinetics make for easy administration whereas zero order kinetics dont?
First order kinetics = can adjust dose for optimal therapeutic effect
Allows predictable dose response
What type of elimination kinetics does phenytoin have?
Zero order kinetics
Why are drugs with zero order elimination kinetics more likley to result in Adverse Drug Reactions/toxicity?
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
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?
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
Why does drugs with zero order kinetics need careful monitoring in people who are seriously ill?
Reduced hepatic/renal capacity functional reserve
Its easier for the elimination pathways to become saturated
What is bioavailability/availability?
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)
What is oral availability?
Amount of drug taken compared to the amount of drug made available to systemic circulation
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?
Reduced amount of drug reaching hepatic blood supply
So less drug reaches systemic supply
How does the bioavailability of an IV drug compare to an oral drug?
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)
What happens to a drugs Vd as it gets more and more lipophilic?
What does this mean in terms of drug penetration?
More lipophilic = higher Vd
More easily penetrates from the Plasma to Extracellular fluid to the Intracellular fluid of tissues like adipose tissues
What is the function of Warfarin?
How does it work?
Anti-coagulants = Blood thinner
Inhibits an enzyme that uses Vit K to produce clotting factors
As the Vd of a drug increases, how does this affect the amount of the drug that makes it into the tissues?
Increases
For Apparent Volume of Distribution Vd, what is the reference compartment that is measure out of the 3 compartments?
Plasma concentration of the drug
Since its easier to measure
What is the isozyme which St John’s Wort is an inducer of?
CYP3A4
How does St John’s Wort have therapeutic effects?
It increases/induces the levels CYP3A4 increasing the rate they are metabolised, this will help reduce side effects of the drugs
