Lecture 19 - Pharmacokinetics I Flashcards
What type of signalling molecule is a drug?
Exogenous or endogenous?
Exogenous signalling molecule
What are the 4 basics steps to a drugs lifecycle in the body?
Absorption
Distribution (around body)
Metabolism (producing its effect)
Excretion
What are the 2 stages which involve the drug going in?
Absorption
Distribution
What are the 2 stages which involve the drug going out?
Metabolism
Excretion
What mneumonic can be used to remember the 4 stages of the lifecycle of a drug?
ADME
What are the 2 classes of drug administration?
Enteral
Paraenteral
What is enteral drug administration?
When the drug is directly administered into the GI tract
What are the 3 methods of enteral drug administration?
Oral
Sublingual
Rectal
What is paraenteral drug administration?
Delivery via all other routes that are not the GI tract
What are some examples of paraenteral drug administration?
Intravenous
Subcutaneous
Intramuscular
Transdermal
Inhalation
Intranasal
What is the pneumonic to remember some drug administration routes?
Oi It is Sir
What does the mneumonic for remembering drug administration routes stand for?
Oi It Is Sir
Oral
Intravenous
Intramuscular
Transdermal
Intra -nasal
Subcutaneous
Sublingual
Inhalation
Rectal
What is the main site of drug absorption in the body?
Small intestine
Why is the stomach not an ideal target for drugs?
Has a thick mucus which acts as a barrier to drug absorption
How does the pH of the small intestine compare to the stomach?
Small intestine is much more weakly acidic (pH 6-7)
How is surface are of the small intestine for absorption maximised?
Villi
Microvilli on villi
Plica circularis (numerous folds of mucous membrane)
What are the 3 methods by which drugs can be absorbed into the body?
Passive diffusion
Facilitated diffusion
Secondary active transport
What type of drugs are absorbed by passive diffusion?
Lipophilic drugs like steroids
Weak acids and weak bases
What type of dissocation does a weak acid or base do?
Partial dissociation (not full)
What is an example of an anti-epileptic drug (weak acid)?
Valproate
What is the typical transit time of drug absorption in the small intestine?
Between 3-5 hrs
Will a drug be able to pass through a membrane if it’s charged or uncharged?
Pass through more readily when uncharged
Will a weakly acid drug pass through a membrane more easily if a higher proportion of it is Protonated or un-Protonated?
More Protonated = more easily absorbed due to it not being charged
What process must molecules with a net charge undergo in order too be absorbed across GI epithelia?
Facilitied diffusion (Solute Carrier (SLC) transport)
Where are SLC 22 family like OATs and OCTss highly expressed?
GI epithelia
Hepatic epithelia
Renal epithelia
What is the general process of secondary active SCL transport across on OAT or OCT?
Transport driven by pre-existing electrochemical gradient drives against electrochemical gradient across GI epithelial membrane
What are some examples of negatively charged drugs that cross the GI epithelia via SLC transport?
Prozac/Fluoxetine
Penicillins
What is Fluoxetine/Prozac co-transported with?
What type of drug is it?
Co-transported with Na+ (drug is -Ve)
Is an SSRI antidepressant
What does a SSRI antidepressant stand for?
Selective serotonin re up take inhibitor
What are penicillins co-transported with via secondary active SLC transport?
H+
What Physicochemical factors affect drug absorption?
GI length or surface
Drug lipophilicty
Density of SLC 22 OAT/OCT expression in GI
What GI Physiological factors affect drug absorption?
Blood flow (higher post meal)
GI motility (slow post meal)
Food/pH
What is first pass metabolism?
When the drugs begin to get metabolised/denatured before it gets absorbed
Which parts of the body does first metabolism occur?
GI (gut lumen and gut wall)
Liver
What are the different types of Phase Enzymes?
Phase I Enzymes
Phase II Enzymes
What is an example of Phase I Enzymes?
Cytochrome P450s
What is an example of Phase II enzymes?
Conjugating enzymes
Where are the majority of Phase I and II enzymes?
Liver
How does first pass metabolism affect therapeutic potential of a drug?
The more that a drug gets metabolise, the less of the drug that will actually get absorbed
What is Bioavailability?
The fraction of a defined dosewhich reaches its way into a specific body compartment
What is the most common reference body compartment for bioavailability?
CVS circulation
What is meant by the IV bolus = 100% for CVS compartment bioavailability?
No physical/metabolic barriers to overcome
What is intravenous bioavailability commonly compared with?
Oral bioavailability
(O)/(IV)
What is the first stage of how drugs journey through the body?
Bulk flow
Diffusion
What is bulk flow of a drug?
Large distance travelled by the drug via the arteries to the capillaries
What are some potential barriers to diffusion?
Certain interactions of substances with the drug may prevent diffusion
Area may not be permeable
What are the 3 different types of capillaries with varying permeability?
Continous
Fenestrated
Sinusoid
What endogenous transporters do capillary membranes express?
OATs
OCTs
Where are continuous capillaries typically found?
CNS (Blood Brain Barrier))
PNS
Cochlea
Muscle
Skin
Fat
Where are fenestrated capillaries typically found?
Intestine
Endocrine/exocrine
Kidney Glomeruli
Where are sinusoid capillaries typically found?
Liver
Bone marrow
Spleen
Lymph
Compare lipophilic and hydrophiliic drugs ability to cross membrane barriers:
Lipophilic = freely move across membrane barriers
Hydrophilic = can journey across membrane barriers dependant on factors for Absorption:
Capillary permeability
Drug pKa + local pH
Presents of OATs/OCTs
What is an example a plasma protein which a drug may bind to?
Albumin
Can a drug bind to its target site when bound to a tissue protein?
No
Drug must be dissociated from the plasma/tissue protein
How may multiple drugs affect there binding to tissue proteins?
2 drugs might bind to the same site on albumin so there may be competition for binding site affecting free plasma concentration of the drug
What are the 3 main body fluid compartments in the body?
Plasma
Extracellular water
Total body water
How much total body water in the average 70kg male?
42 litres
How does a drug move from between the 3 body fluid compartments?
Plasma —> Interstitial fluid —> Intracellular
When increasing penetration by a drug into interstitial and intracellular fluid compartments, how does this affect:
Plasma drug concentration?
Vd?
Decreasing Plasma Drug Concentration
Increasing Vd
What is Vd?
Apparent Volume of Distribution
It summarises the movement of drug from plasma —> interstitial —> intracellular compartment
It is referenced to plasma concentration
What does a small Vd value for a drug indicate?
Less penetration of Interstitial/Intracellular fluid compartment
What does a Larger Vd value indicate?
Greater penetration of interstitial/intracellular fluid compartment
What are the units for Apparent Volume of Distribution (Vd)?
Litres (assuming the standard 70kg male)
What can affect Vd?
Changes in regional blood flow
Hypoalbunimea - affecting protein binding
Drug interactions
Pregnancy
Cancer patients
Anaesthetics
