Pharmacokinetics: Absorption and Distribution Flashcards
What is pharmacokinetics?
- what the body does to a drug that is administered
What is pharmacoDynamics?
- what the Drug does to the body once administered
Pharmacokinetics is the branch of pharmacology that is concerned with the movement of drugs within the body. What are the 4 things that can affect the course of the drug once administered?
- use A.D.M.E
- A = absorption
- D = distribution
- M = metabolism
- E = excretion
In order for any drug to be effective, what are the 2 main aspects of the A.D.M.E mnemonic that the drug must overcome?
1 - absorption = overcome physiological barriers
2 - digestion = directed to target tissue in appropriate concentration and overcoming internal physiological barriers)
Even if a drug can be absorbed and distributed around the body, what are 2 limitations that are part of the mnemonic A.D.M.E that the body imposes on any drug?
1 - metabolism = all or very little of the drug may be metabolised
2 - excretion = may be excreted slowly or quickly affecting therapeutic window or toxicity
If the body cannot absorb a drug, what problem can this cause for its clinical use?
- difficult to get its concentration up to a therapeutic level
If the body absorbs a drug, but it cannot be distributed, what problem can this cause?
- drug cannot reach target tissue
- may have off target effects
If the body absorbs a drug, but cannot metabolise the drug, what problem can this cause?
- if drug is not metabolised well, too much of it may circulate in the body
If the body absorbs, distributes and metabolises a drug, but cannot excrete the drug, what problem can this cause?
- drug level may become toxic to the body
What is the most common route of drug administration and why?
- oral
- cheap, convenient, acceptable
- no special skills needed
Injection is one form of drug administration, and there are 3 main types, what are they?
1 - intravenous (quickest)
2 - intramuscular
3 - subcutaneous
Inhalation is one form of drug administration, what is a key example where this is useful?
- asthma
- less adverse effects
- direct effect on tissue
Sublingual is one form of drug administration, what is a key example where this is useful?
- glyceryl trinitrate (GTN) for angina
- absorbed quickly under the tongue
Rectal suppository is one form of drug administration, what is this?
- drugs are place in the anus
When we talk about pharmaceutical properties of a drug, what are we referring to?
- syrups, pills etc…
- what form they take
When we talk about Physicochemical properties of a drug, what are we referring to?
- solubility of drugs
- pH of drug (acidic drugs better absorbed in the stomach; alkaline drugs in the intestine)
- molecular weight (affects diffusion)
When we talk about Physiological properties of a drug, what are we referring to?
- surface area =GIT has a huge surface area
- contact time = digestion is a long process, increaisng absorption
- concentration of the drug on the absorption site
- absorption site (blood flow, increases with food pH)
- interactions with enzyes and bacteria
- transport systems
The oral route of drug administration is by far the most common. What is the main aspect of A.D.M.E that oral drug administration must overcome?
- absorption
The digestive tract is one of the biggest barriers to taking drugs orally. What are a few of the things in the digestive tract that may affect drug digestion?
- pH
- enzymes
- bacteria
- motility
- food
- drugs
What is first pass metabolism?
- a phenomenon of drug metabolism whereby the concentration of a drug, specifically when administered orally, is greatly reduced before it reaches the systemic circulation
Why are the physicochemical properties inside the GIT important to allow drugs to be administered orally, digested and then absorbed?
- crucial to ensure crossing of the GIT membrane
- drugs must be soluble to be absorbed
- drug must reach GIT where pH is optimally for absorption
- drugs molecular weight must be suitable for absorption
What does biotransformation systems relate to in drugs in the GIT?
- the ability of drugs to resist enzymatic action
- if enzymes break drug down in GIT, it may not be effective or absorbed
What is an example of where the physicochemical properties of a drug are dependent on pH?
- antacids are active once they reach a low pH
- they can raise the pH in the stomach reducing reflux
- patients must have a gap between taking them, otherwise pH will not be low enough for the next dose
What is an example of where the physicochemical properties of a drug are dependent on food being present in the GIT?
- formation of complexes / chelation
- tetracyclines taken with milk is bad
- Ca2+ binds and inactivates tetracyclines
What does bioavailability mean?
- the fraction of a drug that reaches the systemic circulation and the target tissue as an intact drug
What is the formula for calculating bioavailability?
- calculate how much drug reaches target via oral administration
- calculate how much drug reaches target via intravenous (IV) administration
- oral area under the curve (AUC) / IV AUC
- accounts for digestion and metabolism
Why is caclualting bioavailability important?
- if a drug has an oral bioavailability of 20% compared to 100% when given intravenously then to ensure therapeutic effectiveness the oral dose will need to be multiplied by 5
Bioavailability is important as it takes into account absorption in the GIT, but it also accounts for something else once it has been absorbed, what is this?
- metabolic degradation by enzymes in the gut wall and liver
- first pass metabolism for example
Do oral and intravenous administration both undergo first pass metabolism?
- no
- just oral administration
When comparing oral, intravenous, subcutaneous and intramuscular injections, which one has the fastest effect on the body and which will stay in the blood the longest?
- intravenous = fastest
- oral = longest
How can liver disease affect first pass metabolism?
- drugs may not be metabolised as effectively
- means larger concentrations of drug enter circulation
- increased risk of toxicity
If glyceryl trinitrate (GTN) is taken orally and instead of being dissolved sub lingually, what would happen to the effectiveness of GTN?
- if swallowed it would be useless
- GTN is metabolised 100% by first pass metabolism
Once a drug has been digested and absorbed it needs to be distributed around the body and into tissues. Are free drugs and bound drugs able to move freely?
- no
- just free drugs
- bound drugs bind to proteins (albumin etc.), making it more difficult to move around tissues
What is the four compartment model?
- model that explains how drugs are distrubuted around the body
What are the four compartments of the body that are taken into account in the four compartments model?
1 - plasma
2 - intracellular fluid (inside cells)
3 - interstitial water (surrounding cells)
4 - fat
Once a drug enters a different compartment in the four compartmental model approach does the drug remain free or does it bind to proteins within that cell?
- both
- some of the drug remains free
- some of the drug becomes bound in that space
When looking at drug distribution in the four compartmental model, what determines the distribution of a drug?
- solubility of the drug
- soluble in water and lipids
Generally how do drugs enter cells, and do they follow any rules like ions and osmosis?
- drugs passively diffuse
- always move down concentration gradient
Drugs are able to passivley diffuse into cells down concentration gradients. However, they are also able to use 2 other methods to enter cells, what are these?
1 - facilitated transport
2 - active transport
What does Vd refer to in drug delivery?
- volume of distribution
What does the volume of distribution (Vd) in reference to drug delivery mean?
- a measure of how widely a drug is distributed between various body fluids and tissues
How is the volume of distribution (Vd) in reference to drug delivery measured?
- to calculate Vd we need to know:
1 - amount of drug in the body (dose)
2 - concentration of drug in plasma (Cp)
- Vd = dose / Cp
What protein do drugs generally bind to in the plasma?
- albumin
If a drug is able to accumulate outside plasma compartments such as in fat or when bound to tissues, what can happen to the volume of distribution (Vd)?
- Vd may be much greater than the volume of total body water
When we are talking about the volume of distribution, what are the 2 key physicochemical properties that we need to be aware of?
1 - solubility (MAIN factor)
2 - ability to bind to proteins
Once a drug has been absorbed and pass through the first pass metabolism, what problems can occur in diffusion if the drug is too large?
- cannot pass the membrane
If a drug is highly soluble in water, where will it be confined to and will it have a high volume distribution (Vd)?
- compartments of the body that have a high water content
- plasma, intra and extra cellular compartments
- lower Vd
What would the Vd be if a drug has been administered at a dose 25mg and the concentrartion in the plasma (Cp) of the drug is 10mg/L?
- Vd = dose / Cp
- Vd = 25/10 = 2.5L
- 2.5L is a low volume of distribution
If a drug is highly soluble in fat will it be widely distrubuted around the body and will it have a high or low volume distribution (Vd)?
- widely distributed
- able to cross plasma membranes well
- high volume of distribution (Vd)
What would the Vd be if a drug has been administered at a dose 25mg and the concentrartion in the plasma (Cp) of the drug is 0.5mg/L?
- Vd = dose / Cp
- Vd = 25/0.5 = 50L
- 50L is a high volume of distribution
In addition to transporting into cells across cell membranes within drug distribution, what is a another key factor that contributes to if the drug reamins free to move within different compartments of the body?
- its ability to bind proteins
- specifically albumin
Once a drug is bound to a protein, is this permanent or reversible?
- this is reversible and saturable
- if proteins are saturated and none left to bound, this can be bad and you may have too much drug moving around in the body
- drug bound to proteins in plasma acts as a resevoir if more drug is needed, so if the resevoir is full drug cannot bind and spills into tissue
Drugs can be free and move within different compartments of the body, or it can be bound to proteins, such as albumin and not freely move. Are the drugs that are bound to proteins or free drugs responsible for the clinical effects of drugs?
- free drugs
Does free or bound drug stay in the plasma for the longest period of time?
- bound drug remains longer and lasts longer acting as a resevoir
- unbound drug can be distributed, metabolised or excreted
If a drug is bound the proteins such as albumin it does not have any clinical affect, like we see in the unbound drug. The unbound drug is distributed and has clinical therapeutic effects, but can also be metabolised and excreted quicker, meaning the affects dont last as long. How does the drug that is bound to albumin then have clinical effects?
- an equilibrium between bound and unbound drug is maintained
- unbound drugs are distributed, metabolised and/or excreted
- unbound drug levels reduce and then the bound drug becomes unbound and is distributed into other tissues as a free drug
Are the majority of the drugs in the body bound or free?
- bound to proteins
Why is the concentration of the free drug important in binding to proteins?
- larger concentrations = greater binding
- however, if saturated more free drug will be present
Why is the affinity of a drug important in binding to proteins?
- stronger affinity to drug = greater binding
Why is the concentraiton of proteins that drugs can bind with important for drug delivery?
- low concentration of binding proteins = more free drug
- more free drug affects how long the drug remains in the blood and could alter the therapeutic window
- chronic liver disease can cause hypoalbuminaemia and can affect drug delivery
Why is it important that clinicians are aware of what drugs a patient is taking in relation to competitive drug binding?
- albumin can bind to many different drugs
- competitive binding can occur
Why is it important that clinicians are aware of what drugs a patient is taking in relation to the strenght of some drug binding?
- some drugs bind very strongly with proteins
- means other drugs cannot bind
- leave other drugs unbound and potentially have a larger effect
What are the 3 clinically relevant criteria that need to be met to ensure a drug is clinically relevant?
1 - drug must have a high protein binding (> 90%)
2 - drug must have a change in binding
3 - drug must be water soluble and have a low Vd
How can saturability affect how much of a drug is unbound?
- if proteins that bind to drugs are saturated with other drug then they are unable to bind to new drugs, thus increasing unbound drugs
- can increase toxicity or alter therapeutic window
How can displacement by other drugs/toxins affect how much of a drug is unbound?
- if a drug is displaced from being bound, it has to become unbound
- greater displacement by drugs/toxins = greater unbound drug
How can late pregnancy affect how much of a drug is unbound?
- late pregnancy reduces albumin levels
- less albumin = more unbound drug
How can renal impairment affect the level of unbound drugs?
- glomerula is damaged proteinuria occurs (reduced albumin)
- hypoalbuminaemia can occur and increase unbound drug
How can low albumin levels affect the level of unbound drugs?
- no albumin for drug to bind with
- drug is therefore unbound
