Lecture 9: Pharmacokinetics Flashcards
List the 4 domains that govern pharmacokinetics?
- Absorption: how a drug enters the body
- Distribution: how the drug moes from systemic circulation to the target site(s)
- Metabolism: how the drug is chemically altered by the body
- Excretion: how the deug is removed from the body
What are the two types of routes for drug delivery?
- Local administration: drug is delivered directly onto the target site
- Systemic administration: drug is given not on the target site but once enters the body via the systemic circulation, it moves to its target site.
Give an example of a drug that is given by local administration?
- Common examples include drugs acting on the skin (e.g. creams or ointment), eyes (e.g. eye drops) or lungs (e.g. inhaled therapy)
- E.g. topical steroids used for eczema
Describe the pros and cons for local administration route for drug delivery?
Pro:
- Administer the drug directly on its drug target to minimise adverse effects
Cons:
- Only suitable for situations in which the site of action of the drug is readily accessible
Describe the pros and cons for systemic administration for drug delivery?
Pros:
- Preferred in most cases as
- Tissue inaccessible and/or
- Widespread distribution of drug necessary e.g. direct application of the drug to multiple tissues is impractical
Cons:
- Adverse effects
What are the two types of systemic administration for drug delivery?
Enteral:
therapy within the GI tract which is systemically absorbed
Paraentral:
drug is given by a mechanism that does not involved in the GI tract for systemic absorption
Give examples of some common local drug delivery routes?
- Cutaneous e.g. on the skin
- Ocular e.g. eyes
- Respiratory e.g. inhaled
- Luminal to the GI tract, this is when the drug is administered orally or in suspension but without the intension of the drug being systemically absorbed e.g. laxative, will have its action locally within the bowel
- Implanted
Give examples of some systemical enteral drug delivery routes?
Means therapy within the GI tract which is systemically absorbed
- Oral
- Rectal
- Naso-gastric
- Sub-lingual
- PEG tube, tube going directly into the abdominal wall into the stomach to allow drugs and food to be administered
Give examples of some systemical paraenteral drug delivery routes?
Means therapy that is given by a mechanism that does not involved GI systemic absorption
- Intra-venous
- Intra-muscular
- Sub-cutaneous
- Inhaled e.g. general anaesthetic where the goal is to no keep the drug in the lungs but can also use the lungs for the systemic absorption of the drug
- Intra-osseus (more invasive route)
What are the 4 principles when selecting the appropriate drug route?
- Must provide adequate delivery of the drug that is suitable for its purpose.
- Acceptable for the patient
- Minimise adverse drug effects
- Some routes of administration are much more burdensome than others
- E.g. specialist training and equipment or administration by a health professional may be required e.g. Intravenous administration.
Describe the intravenous administration for drug delivery?
- Drug is administered into a vein
- Delivered through a vascular access device
- Absorption is instant
- Can be effectively ignored
- Direct access to the circulation, there is very rapid systemic delivery of the drug
- No or short delay of the onset of treatment
- Frequently needs to be slowed down
- Slow injection or infusion
- This is because patients often have significant side effects if given too fast e.g. nausea
Describe the intramusclar administration for drug delivery?
- Means drug administered into a muscle
- In general, broad process is similar to IV but slower onset of action
- Absorption from skin/muscle may be unpredictable at times
- E.g. patients who regularly inject insulin may find variable onset of the effects of their insulin if they don’t change their injection site regularly
- Only a small volume can be given
- May be painful/unpleasant for patients, particularly the intramuscular if frequent dosing is required
- Requires training and equipment. Tends to be limited to healthcare professionals.
Describe the oral route of drug delivery?
- Simplest and most convenient method of drug administration in most circumstances
- Should be the default method of drug administration in most circumstances
- There are a number of exceptions:
- Drug is digested or poorly absorbed- limiting its usefulness
- Very rapid onset of action is required e.g. patient is critically ill
- Drug is irritant to the stomach
Describe the inhalation route of drug delivery?
- Local administration route
- Often employed for topical delivery of drugs to the respiratory tract
- Metered dose inhalers most common method
- Delivers fixed dose of fine powder into the upper respiratory tract is the most common route
- Drug particles must be sufficiently small to penetrate deep into the respiratory tract (can be a limiting factor as some drugs cannot be made easily into an appropriate powder size)
- Some patients poorly tolerate and often technique is ineffective
Give an example of a condition in which local administration of the drug is the gold standard treatment?
Impetigo
Topical antibiotics e.g. fusidic acid
Give a reason why UTIs are treated with oral antibiotics and not local therapy?
Because for local administration antibiotics would have to give administrated through a urinary catheter.
Very invasive for a patient
What is the gold standard drug route for the condition meningococcal sepsis?
Give 3 reasons why this route is chosen?
Antibiotics via IV route.
- A rapid onset of action is required
- Patients with severe infection may have compromised blood flow to the gut, which may impair drug absorption
- Antibiotics pass poorly through the blood brain barrier into the central nervous system. Patients with meningococcal disease often have central nervous system infection.
Describe the two compartment model of drug distribution?
- One compartment called the circulation, and the other the tissues (i.e. the rest of the body)
- Almost always when measuring a drug level in the body, what we are actually measuring is a blood sample i.e the levels of drugs in the circulation.
- Drugs distribute differently in the body (some evenly while others may be more distributed in the tissues than the circulation)
- The vast majority of drugs, the passage through the systemic circulation is simply a vehicle to reach the target site. Therefore, we use the blood level of the drug as a surrogate for what the level might be at the drug target site.
If a drug had a high level of lipid soluble molecules, what would be the most likely drug distribution?
- Highly lipid soluble molecules usually diffuse easily across cell membranes
- More effective distribution
- Ability to accumulate easily within cells
- This usually results in the drug moving readily out of the circulation into the tissues
If a drug had a high level of protein binding molecules, what would be the most likely drug distribution?
- Association with proteins allows drugs to be sequestered within tissues
- Drugs which bind strongly to serum proteins (proteins found within the blood e.g. albumin) can be found at high concentrations in blood
- For some drugs it is the free (unbound) drug that matters
If a drug had a high level of water soluble molecules, what would be the most likely drug distribution?
- Tend to distribute within the circulation and within the other fluid components of the body relatively evenly
For a drug that distributes evenly throughout the body.
Compare the blood sample to the drug concentration in the circulatory system and in the rest of the tissues?
The drug level in the blood is a representation of the drug level in the circulatory system.
Would be very similar to the drug level in the rest of the tissues
For a drug that distributes strongly the circulatory system.
Compare the blood sample to the drug concentration in the circulatory system and in the rest of the tissues?
The drug concentration in the blood sample will be the same as the circulatory system
The drug concentration in the blood sample will be higher than it would be within the tissues
For a drug that distributes strongly to the other tissues in the body.
Compare the blood sample to the drug concentration in the circulatory system and in the rest of the tissues?
When we measure blood level, there will be a low concentration of the drug but this does not reflect the concentration of the drug within the tissues
Define apparent volume of distribution?
When you measure the blood level, what volume of fluid would the drug have been dissolved in in order to produce that level.
Mathematical way of describing the way the drug has been distributed.
If a drug had a high lipid solubility: what would be its associated apparent volume of distribution?
associated with high volume of distribution (type of drug C)
If a drug had a high protein solubility: what would be its associated apparent volume of distribution?
associated with low volume of distribution (Type of drug A)
What is the apparent volume of distribution for the following drugs (see image)
Drug A:
Apparent volume of distribution = 100 / 1 = 100L
Drug B:
Apparent volume of distribution = 100 / 10 = 10L
Drug C:
Apparent volume of distribution = 100 / 0.1 = 1,000L
Why is the apparent volume of distribution a mathematical concept?
Because the equation sometimes gives you a volume of distribution that is higher than the total volume in the body
What is the equation for apparent volume of distribution?
Apparent volume of distribution = Dose / concentration
Define the loading dose?
It is the dose required to brings the concentration of drug to the target range with a single dose
What is the equation for the loading dose for drugs given intra-venously?
Volume of distribution (first to apparent volume) is calculated as a function of body weight
Volume of distribution= V/kg x body weight
Calculate the loading dose for the following case:
- Patient is 70kg
- Drug: theophylline
- Approx volume of distribution= 0.5L/kg
- Target concentration = 10mg/L
Define the term top up doses?
This is doses given to the patient who has already received the drug but the concentration was too low
What is the equation to calculate a top up dose?
Question 1: Calculate the patient’s volume of distribution
Question 2: Calculate the appropriate loading dose
- The patient is 74kg and has no other significant past medical history.
- The volume of distribution of phenytoin is approx. 0.7L/kg.
- The target phenytoin concentration is 20mg/L.
- Since phenytoin comes in 50mg/ml vials, doses should be given in multiples of 50mg.
Questions 1: What was the initial loading dose you would suggest on day 1?
Question 2: What topup dose would you give on day 3?
On day 1, patient is given a loading dose of vancomycin. The patient weighs 74kg. Unforunately, a dose of vancomycin is missed on the ward and when a level is checked on day 3, the concentration of vancomycin is only 7mg/L. A topup dose is planned to return the level to the therapeutic range.
The volume of distribution of vancomycin is approx. 0.75L/kg.
The target vancomycin concentration is 25mg/L. Since vancomycin is made up to 100mg/ml solution before dilution, doses should be given in multiples of 100mg.
What are the 3 organs an orally passed drug must pass through that is critical to drug absorption?
- Stomach
- Intestine
- Via. portal circulation to the liver
Define bioavailability
- Bioavailability is a statement of the fraction of administered drug which reaches the systemic circulation and accounts for both absorption and 1st pass metabolism.
what is the equation to calculate the bioavailability of a drug?
What is the equation for the loading dose for oral drugs?
- Need to takes into account the loss of drug
Describe modified release system of drug delivery?
- Drug delivery systems designed to slow the absorption of a drug
- Designed to provide a smoother profile of drug concentration and avoid high peaks and low troughs
- Various delivery methods of generating modified release preparations are available.
- E.g. analgesia
Describe pro-drugs?
- Absorption or distribution of some drugs can be improved by the use of pro-drugs.
- Pro-drug is administered but subsequently converted in the body into the active drug.
- Use of pro-drugs may allow a drug that would not otherwise be suitable for oral administration to be given by this route.
- E.g. acyclovir, has poor oral bioavailability. However, if you attach a valine residue to create acyclovir. Greatly increases its absorption in the GI tract.
What are the two significant barrieres to drug absoprtion into the systemic circulation faced when drugs are orally administrated?
- Absorption into the portal circulation from the bowel
- Passage through the liver to enter the systemic circulation (1st pass metabolism)
What two ways can be used to alter the characteristics of oral drug delivery?
- Modified release preparations
- Pro-drugs
What is the name of the guidelines used to determine when to change from oral to intravenous drug delivery?
IVOST guidelines
The nasogastric tube will delivery drug who will be subject to ___ pass metabolism?
First pass metabolism
Remember to reduce the __ when changing a patient from oral to IV because of ___?
- Dose
- Bioavailability: the fraction of the drug that reaches the systemic circulation
