Pharmacokinetics Flashcards
Pharmacokinetics definition
What the body does to the drug
Pharmacodynamics definition
What the drug does to the body
PK/PD
The relationship between pharmacokinetics and pharmacodynamics
What is ADME
Absorption
Distribution
Metabolism
Excretion
Measures of ADME
A - Permeability - ability to cross membranes
D - Volume of distribution - ability to distribute from the plasma into tissue
ME - Clearance - efficiency of irreversible elimination from the plasma
What are the 2 primary measures of ADME?
-Clearance
-Volume of distribution
What are the 2 secondary measures of ADME?
AME - Bioavailability - Fraction of unchanged drug reaching the systemic circulation
DME - Half life - Time taken for plasma drug levels to decline by 50%
What parameter determines the maintenance dose rate?
Clearance is the only parameter which determines maintenance dose rate required to achieve a target plasma concentration
What if 2 drugs have the same clearance, but different volumes of distribution?
-Volume of distribution is an essential determinant of drug half-life
-2 drugs with the same clearance, but different Vd
-Bigger volume will have longer half life because drug is more distributed in tissues
What is bioavailability for IV and oral route?
IV = 100%
Oral dosing: Bioavailability depends on absorption and clearance
Graph of IV drug administration
Graph of oral administration
Differences in parameters between oral and IV dosing
-Volume of distribution cannot be calculated from oral dosing
-Oral dosing increases Tmax - time taken to reach Cmax
Definition of absorption
The process by which a drug moves from the site of administration to the site of action
What is absorption quantified by?
-Absorption rate constant (first order process)
What properties must drugs have for oral absorption?
-Water soluble in gut
-Lipophilic for membrane permeation
-Water soluble in plasma
-Absorption can be solubility and pH dependent
-Solubility is also pH dependent
What is the Volume of distribution?
-“Ration between the amount of drug in the body and the amount in the plasma”
-Total amount of drug dosed/Plasma concentration at t0
-If Vd is greater than volume that you’ve got, the drug must have gone elsewhere out of the plasma
2 ways to calculate Vd
Vd = Total IV dose/Plasma concentration at t0
Vd = Clearance/elimination rate constant (k)
Metabolism definition
-Irreversible chemical alteration of a drug by a biological
Metabolism phase 1 reaction
Introduces a new chemical group via:
-Oxidation reactions
-Reduction reactions
-Hydrolysis reactions
Aim: To produce inactive metabolites
Metabolism phase 2 reaction (prodrug)
Conjugates the molecule with charged chemical species via:
-Glucouronidation
-Acylation
-Sulfation
Aim: To decrease lipophilicity and increase solubility for enhanced excretion
Excretion definition
-Irreversible elimination of a drug from the systemic circulation
-Clearance can be used to define excretion
2 major routes of drug excretion
Renal excretion - Into the urine
-Glomerular filtration of unbound drug
-Active secretion in the kidney
-Active and passive reabsorption in the kidney
Hepatic excretion - Into the bile (faeces)
-Trans-hepatocyte
-Hepatic drug transports
-Sum of influx and efflux pumps
Other excretion routes
-Sweat
-Milk
-Saliva
How do we visualise the half life more simply?
-Linearise the curve by converting plasma drug concentration to the natural log and plot against time
-Slope of the line = elimination rate constant (k)
2 ways of calculating slope of line on natural log vs time graph
Linear regression analysis
y=mx+c
Estimate gradient using concentration and time
Slope = C2-C1/T2-T1
What is the equation for half life or elimination rate constant (k)
Half life = Natural log of 2/ k
Natural log = 0.693
Why is clearance the most important primary measure of pharmacokinetics
2 ways of calculating clearance
What is the main organ for drug clearance?
Liver
Limited by:
-Enzymatic activity in liver
-Hepatic blood flow (rate limiting step)
How do you calculate whole body clearance?
Whole body clearance is the sum of all organ clearances
For oral dosing, what does bioavailability depend on?
-Absorption from the gut
-Clearance
A drug can be 100% absorbed but still have zero bioavailability. Why?
First pass effect
Key equations
Therapeutic window graph
