Lecture 3- Pharmacokinetics and pharmacodynamics Flashcards
some things to consider when thinking about pharmakinetics (patient factors)

after a drug has entered systemic circulation (absorbed)
- it can stay free
- it can bind and unbind to its target receptor
- it can enter tissue reservoirs (where is can bind to proteins or adipose)
- it can bind to protein in the blood (albumin)
- it can be metabolised (to become active or inactive)
- it can be excreted
Clinical consideration of PK influences MHRA (medicines and healthcare products regulatory agency) and FDA approval and standard dosing. Key factors
- Bioavailability
- Half-life
- Drug elimination
- Inter-subject variability
- Drug-drug interactions

Absorption
Used to describe the journey of a drug travelling from the site of administration to site of action.
Bioavailability (F)
- Measure of drug absorption where is can be used
- Drugs administered via intravenous bolus is said to have 100% bioavailability
- Oral dose will not be 100%
- Therefore : other routes references a fraction of IV

bioavailability is affected by
absorption and first pass metabolism
absorption and bioavailability
- Formulation i.e. oral or IV
- Age
- Food (chelation, gastric emptying)
- Vomiting/malabsorption
- Previous surgery (bariatric)
First pass metabolism
- Metabolism before reaching systemic circulation
- E.g. drugs absorbed in GI, goes straight to the liver via the hepatic portal vein and is metabolised before reaching systemic circulation
- E.g. metabolised in the lungs
Rate of absorption
- Plasma conc-time graphs show distinct phases
- Rate of absorption dictates the visibility of distribution and elimination phases
- Look at the initial gradient of [plasma/ time curve]

if absorption is very quick

(steep gradient)
distinct phase between the absorption and distribution (circled part on graph)
- Rise in plasma conc very quickly
- Then distribution as the drug distributes through the tissue (pronounced drop on the graph- coving)
- Run off phase with elimination
If absorption is slow
then the absorption and distribution phase will be occurring at the same time – no coving on the graph seen- slightly less steep accumulation of drug in the plasma.

Manipulating absorption of drugs using modified release preparation
we want to keep drug concentration within the therapeutic range as long as possible
- If elimination is rapid large fluctuations in [plasma] will be seen
- Large periods of time below minimum effective concentration
- Periods of time above the maximum safe conc- side effects
how do modified preparations work
- Plasma conc becomes more dependent on the rate of absorption vs rate of elimination
-
Can help with adherence
- E.g. if fast onset release medication is causing bad side effect
Some factors affecting therapeutic agent distribution- Volume of distribution (Vd)= function of these factors
-
Blood flow
- Better distribution in highly vascularised tissue
- Capillary structure
-
Lipophilicity
- Drugs can pass through plasma membrane
-
Hydrophilicity
- Drugs pass through aqueous channels
-
Protein binding (sequesters drug, changing PK in terms of distribution)
- Albumin- acidic drugs (most common)
- Globulins- hormones
- Lipoproteins- basic drugs
- Glycoproteins- basic drugs
distribution and multiple compartments
Rate of distribution and equilibration from IV admin typically follows a multiple compartment model

Drug protein binding and distribution
- *
- Typically only free drugs will afford response at target receptor site and/ or be eliminated
- Displacement of a drug from binding site can result in protein binding drug interaction
- If highly protein bound
- Narrow therapeutic index
- Low Vd

Increased free drug will be able to afford increased response or be eliminated
- E.g. if a second drug is given that displaces first drug from binding protein
- More free drug to elicit a response
- Potentially causing harm e.g. pregnancy (fluid balance), renal failure, hypoalbuminemia (amount of protein in diet will change the amount of albumin in plasma- effect amount of free drug)

(apparent) Volume of distribution
- It is a proportionality factor
- Dose/[drug]plasma
- We can’t easily measure whole body drug concentration- only blood plasma
- Concentration = the amount of solute in given volume

calculate this Vd (1)

100mg/ 20 mg/L= 5l (Vd)
calculate this Vd (2)

- High proportion of adipose in compartment increases amount dissolved, limiting amount dissolved in the plasma
- Vd = 100/5 ug/mL = 20L
- 5ug/mL = 5 mg/L
calculate Vd of (3)

always remmeber units
- High protein binding. Plasma conc slightly higher than in high adipose example. Vd= 100/10= 10L
- 10 ug/mL= 10mg/L

calculate presuming dose is 100mg/L

- Lipophilic drug.
- Plasma conc 500 ng/mL = 0.5 mg/L.
- Vd= 100/0.5= 200L
what does a Vd of 200L mean
200L of fluid would be required to have a drug conc of 0.5mg/L in the plasma–> very high Vd (not much found in the plasma)























