Lecture 20 - Pharmacokinetics I + II Flashcards
What are the 3 body fluid compartments?
What are their typical model volumes?
Plasma water = 3L
Extracellular water = 14L
Total body water = 42L
What makes up extracellular water?
Plasma water + interstitial water
What makes up total body water?
Plasma water _ interstital water + intracellular water
What fluid compartment is heparin targeted for?
What is the function of heparin?
Plasma fluid compartment
Anticoagulant
What is Vd?
The apparent volume of distribution
Models the grouping of the main fluid compartments as all one compartment
Vd is referenced to plasma concentration
How does increasing drug penetration into interstitial and intracellular fluid compartment affect Vd and plasma drug concentration?
Increasing Vd
Decreasing plasma drug concentration
Do lipophilic/lipid soluble drugs need carriers like OATs and OCTs to get through membrane barriers into the different fluid compartments?
No can diffuse through membrane barriers themselves
Do lipophilic/lipid soluble drugs need carriers like OATs and OCTs to get through membrane barriers into the different fluid compartments?
No can diffuse through membrane barriers themselves
What does a large Vd value mean in terms of penetration of drug into the interstitial/Intracellular fluid compartment?
What does a small Vd value mean in terms of penetration of drug into the interstitial/Intracellular fluid compartment?
Large Vd = greater penetration
Small Vd = less penetration
Why is Vd more a pretend value?
You have to pretend the drug is fully distributed throughout the whole body evenly at time zero which just isn’t true
It takes time to fully distribute
What is the main organ which metabolises drugs in drug elimination?
Liver
What is the main organ which Excretes drugs in drug elimination?
Kidneys
What is the importance of drug/chemical elimination from the body?
Homeostasis
Protective function
What are the enzymes responsible for Hepatic Drug Metabolism?
Phase I and Phase II enzymes
What is the general function of Phase I and II enzymes in drug metabolism/elimination?
They make the drugs less lipophilic by increasing their ionic charge
This enhances their renal elimination (kidney) since the drugs with added charge struggle to be reabsorbed back into the plasma
If a drug has been metabolised does this normally mean its active or inactive?
What are the 2 exceptions?
Metabolised normally = inactive
Exceptions who get activated by metabolism:
-Codeine
-Fluoxetine
In the liver, what are the Phase I enzymes collectively referred to as?
CYP450s (Cytochrome P450s)
What are the different enzymes that are in the family of Cytochrome P450s in the liver called?
Isozymes
What type of reactions do the Phase I CYP450 enzymes catalyse?
Redox
Dealkylation
Hydroxylation
What is the relative rate of metabolism of Phase I CYP450?
Why is the speed like this?
Relatively slow due to the CYP450 family being versatile generalists, they can metabolism many molecules but not very quick
Between Codeine and Fluoxetine, which one is a Pro-drug?
What is meant by a pro drug?
Codeine is a pro-drug
This means they go from being inactive to an active state as a result of being metabolised by Phase I enzymes
What does the pro-drug codeine become when it gets activated by metabolism of Phase I enzymes?
How does this active drugs Kd compare to codeine?
What does this Kd value mean?
Codeine metabolised to the active Morphine
Codeine = high Kd
Morphine = much lower Kd
Morphine has a much higher affinity for the Opioid mu-receptor than codeine
Fluoxetine is an active drug that gets metabolised by Phase I enzymes (CYP450s) to another active drug:
What is this active drug?
Fluoxetine metabolised to Norfluoxetine
What is the Phase I isozyme (CYP450) which metabolises codeine to morphine?
CYP2D6
What is the function of Phase II metabolism by hepatic enzymes?
Further enhances the hydrophilicity by adding MORE IONIC charge
Adds large charged groups by Conjugation further enhancing renal elimination
What metabolises drugs faster, Phase I enzymes or phase II enzymes?
Phase II enzymes
What are the 3 amino acids that make up Glutathione (GSH)?
Glutamate
Cysteine
Glycine
What is the main CYP450 isozyme which contributes the most to drug metabolism?
CYP3A4
How are isozymes named?
CYP for Cytochrome
Number then 1-3 due to 3 superfamilies
Then letter and number
E.g:
CYP3A4
What factors can affect drug metabolism?
Age
Sex
General health/dietary/disease can lead to decreased functional reserve
Drugs which induce or inhibit CYP450s
Genetic variability / polymorphism / non expression
What is the acronym which is used to remember the major organs which if affected can lead to decreased functional reserve of drug metabolism?
What does it stand for?
HRH
Heart (CVS)
Renal
Hepatic
What are the mechanisms by which a drug can induce CYP450 enzymes?
Transcription
Translation
Slower degradation
What is Carbamezepine used to treat?
Epilepsy
Carbamezepine = anti-epileptic
What Phase I (CYP450) isozyme metabolises Carbamezepine?
What affect does Carbamezepine have on this Isozyme?
CYP3A4
Induces CYP3A4
What are the type of inhibition mechanisms by which certain drugs can have inhibitory affects on CYP450s?
Competitive inhibition
Non-competitive inhibition
What happens to the rate of elimination if a drug inhibits phase I enzymes/CYP450s?
How will the plasma levels of the drug change?
Decreased rate of elimination
Increased plasma levels
What is Verapamil used to treat?
What isozyme metabolises Verapamil?
Hypertension/high blood pressure
CYP3A4
How does Grapefruit Juice affect CYP3A4?
What affect does this have on the therapeutic efficacy of Verapamil and its risk of side effects?
What effects would these effects be?
Grapefruit juice inhibits CYP3A4
Increased therapeutic efficacy. Less of verapamil needed since it is harder for it to be removed. Increased risk of side effects
Can have a much reduced BP and fainting
What is Tolbutamide used to treat?
Diabetes
What is Valium/what is it used treat?
Anxiolytic (treats anxiety)
What is Omeprazole?
What is it used to treat?
Proton pump inhibitor
Treats acid reflux
What is phenytoin used to treat?
Epilepsy
Why does ethnicity need to be carefully considered when administering drugs?
Genetic variation in the expression of certain phase I isozymes
What 3 drugs do many Asians have reduced ability to metabolise due to reduced expression of CYP2C19?
Omeprazole
Valium
Phenytoin
What are the 4 categories of metabolisers?
Poor
Intermediate
Extensive
Ultra rapid
What is an example of genetic polymorphism of an isozyme?
What drug is metabolised here?
CYP2D6 not expressed in 7% of Caucasians
CYP2D6 ultra rapid in 30% East Africans
Codeine
What happens if the CYP2D6 isozyme is a poor metaboliser of Codeine compared to if its an ultra rapid metaboliser?
Not much codeine turned to Morphine so low therapeutic efficacy
Ultra rapid metaboliser = fast metaboliser to morphine so enhanced therapeutic effect and risk of Adverse Drug Reactions
What does ADR stand for?
Adverse Drug Reactions
What type of blood vessels are drugs excreted/eliminated through in the kidneys?
Fenestrated renal capillaries
What are the 3 steps to renal excretion?
Glomerular filtration
Active tubular secretion
Passive tubular reabsorption
What happens in the Glomerular filtration stage of Renal Excretion?
Unbound drug enters into bowman’s capsule from the glomerulus
What happens in the Proximal Tubular Secretion stage of Renal Excretion?
High expression of OATs and OCTs
Carry ionised molecules out of the body
