03-09-22 – Drug Distribution Flashcards
Learning outcomes
- To describe the factors which affect drug distribution once they are absorbed into the blood stream.
- To define what is meant by the volume of distribution (Vd) of a drug and perform basic interpretation of what a Vd indicates.
- To relate Vd to clinical parameters (e.g. how changes in Vd influence the elimination half-life of a drug, or how patient-specific factors may influence Vd).
What is drug distribution?
What does it help us understand?
What are 6 factors that affect distribution?
- Drug distribution is the Movement of a drug to/from blood and tissues of the body
- It helps understand the relative proportions of drug in the tissues, and to predict dose/response/risk
- Factors that affect distribution:
1) Cardiac output and blood flow
2) Plasma protein binding
3) Lipid solubility – how likely they are to diffuse across membrane or if they need a transport mechanism
4) Degree of drug ionisation
5) pH of compartments
6) Capillary permeability
What does initial rate of distribution of drugs depends heavily on?
How does cardiac output % and blood flow differ in the kidneys and skeletal muscle?
Why is this?
How does this affect kidney/skeletal muscle exposure to flow and concentration of drug in the blood?
- Initial rate of distribution of drugs depends heavily on blood flow
- 20% of cardiac output goes to both the kidneys and skeletal muscles
- Kidneys have 450ml/min/100g of tissue
- Skeletal muscle has 3ml/min/100g
- This is because kidneys are a lot smaller than total skeletal muscle
- This will result in the kidneys being exposed to high flow and high concentration of any drugs in the plasma
- This means there is a high probability of drugs being distributed to the kidneys, while there is a low probability of blood being distributed to things like skeletal muscle and fat, where the blood flow is low
What is albumin?
How do lipid soluble drugs bind to albumin?
How do weak acids bind to albumin?
How does this alter free drug levels?
How does it bring competition between drugs?
What kind of binding is this?
What are 3 factors that can affect binding?
What is 1 cause of hyperalbuminemia?
How does it affect free drug levels?
What are 4 causes of hypalbuminaemia?
How does it affect free drug levels?
- Albumin is the predominant plasma binding protein (40g/L)
- Lipid-soluble drugs bind non-specifically to albumin (they coat the protein more than bind)
- Weak acids bind to a specific, saturable site on albumin
- Since these specific binding sites are limited, this can lead to a greater free level of drug that doesn’t have an active site to bind
- If there are multiple weak acid drugs competing for limited binding sites, this will lead to a drug being displaced, which can be excreted from the body, or raise drug free drug concentration, leading to side effects
- This binding is reversible, and can be influenced by:
1) pH
2) Temperature
3) Drug interactions - Hyperalbuminemia decreases free drug levels, and can be caused by dehydration
- Hypoalbuminemia increases free drug levels, and can be caused by:
1) Burns
2) Renal disease
3) Hepatic disease
4) Malnutrition
What are hydrophilic drugs soluble in?
What is their rate of distribution dependent on?
What do they need to get across the membrane?
What are lipophilic drugs soluble in?
What is their rate of distribution dependent on?
What do they need to get across the membrane?
What do they need to get around the body?
- Hydrophilic drugs are highly soluble in aqueous, polar media
- Their rate of distribution dependent on diffusion characteristics of the drug
- They can’t get across membranes without carrier proteins and mechanisms
- Lipophilic drugs are soluble in fats and non-polar solutions.
- Rate of distribution dependent on the rate of delivery to tissues e.g blood flow
- Lipophilic drugs can diffuse across the membrane without the need of carrier proteins
- Lipophilic drugs likely will need to be bound to proteins to get circulated around the body e.g albumin
What are many drugs?
What do ionised: unionised ratios depend on?
How lipid soluble are ionised drugs?
How does this affect their diffusion?
What does degree of distribution and ability to cross cell membranes depend on?
- Many drugs are weak acids or strong bases
- ionised: unionised ratio depends on pH
- Ionised drugs have low lipid solubility, meaning ionised drugs will not be able to diffuse across cell membranes
- Degree of distribution and ability to cross membranes depends on how ionised/unionised a particular drug is in the plasma/different compartments with differing pH levels
How does surface area of capillary, time in capillary, and type of capillary affect diffusion of Hydrophilic and lipophilic drugs across capillaries?
What are the 3 types of capillaries from least permeable to most permeable?
- How different factors affect the diffusion of hydrophilic and lipophilic drugs across capillaries:
1) Surface area of capillary
* A greater surface area of capillary will lead to greater concentrations of drug diffusion across the capillaries into the tissues
* Both hydrophilic and lipophilic
2) Time
* Greater time spent in capillaries will lead to greater concentrations of drug diffusion across the capillaries into the tissues
* Both hydrophilic and lipophilic
3) Type of capillaries
* Types of capillaries from least permeable to most permeable:
* Continuous capillary, fenestrated capillary, and sinusoid/discontinuous capillary
* Lipophilic drugs can rapidly get across any capillaries
* Large hydrophilic (aka lipophobic) drugs can get across all capillaries, but their size impacts the rate at which they can diffuse
* In continuous capillaries, small hydrophilic drugs diffuse slowly, while large hydrophilic drugs diffuse very slowly
What is the Blood brain barrier (BBB)?
Why is it difficult for things to get across the BBB?
How can substances get across the BBB?
What does meningitis inflame?
How does it affect the permeability of the BBB?
How does this aid treatment?
- The blood brain barrier (BBB) is a physical and functional barrier between the brain’s capillaries and the cells and other components that make up the brain tissue
- It is difficult for substances to get across the BBB as there is a lack of expression of transport proteins
- Substances that get across the BBB need to have very specific pharmacokinetic properties, and need to be very lipophilic, or transported via specific transport mechanisms
- Meningitis causes inflammation of the meninges in the brain
- Meningitis results in the decrease in the integrity of the BBB
- This aids treatment, as it can allow medication, such as antibiotics, to cross the BBB
What are 3 other examples of specialised barriers/compartments?
- 3 other examples of specialised barriers/compartments:
1) Placenta
* There are tight endothelial cell junctions in maternal and foetal capillaries which protect foetal circulation
* These barriers are partially protective, except with: lipid soluble drugs and unionised forms of weak acids and bases
* Foetal circulation/tissues can be at different pHs, meaning drugs can move in, become ionised, then get trapped and accumulate
* This means treatment can change with pregnant patients
2) Chronic abscesses
* These structures can be very avascular and have different pHs
* This will make it difficult to find a drug to get to this area through the blood and remain in an active form due to the pH
3) Lung infection
* Local low PO2 and high PCO2 cause vasoconstriction in the lungs (no point supplying area that isn’t perfusing)
* This is opposite from what typically happens in other tissues
* This is likely to happen more in lung infections, which can make it difficult to get blood flow to these areas
What are the 5 different body fluid volumes of a 70kg male?
What molecules will be found in each body of fluid?
- 5 different body fluid volumes:
1) Extracellular fluid – 15L (consists of both the plasma and interstitial fluids)
* Large, water-soluble molecules e.g mannitol
2) Plasma – 3L
* Highly plasma-bound molecules
* Highly charged molecules
3) Interstitial fluids (12L)
4) Intracellular fluid (27L)
5) Total body water (42L – for a 70kg adults)
* Small, water-soluble molecules e.g ethanol
What is the plasma steady state concentration?
What is the formula for plasma steady state concentration?
What is clearance?
What does the time taken to reach Css depend on?
What is elimination half-life?
What does elimination half-life directly depend upon?
What is Vd?
What is the formula for Vd?
What is the formulae that link together all of these concepts? How do these concepts work into the analogy?
- The ‘steady state’ or Plasma steady state concentration (Css) is where the rate of drug infusion matches the rate of elimination (metabolism)
- Css = infusion (X) / Clearance (CL)
- Clearance (CL) is defined as the volume of blood or plasma cleared of drug in a unit time e.g 10ml/min and is a constant
- The time taken to reach Css depends on the elimination half-life (t1/2) of a drug
- The half-life of a drug is the time it takes for the amount of a drug’s active substance in your body to reduce by half (how fast drugs are metabolised)
- Elimination half-life directly depends on upon the apparent volume of distribution (Vd)
- Vd is the theoretical volume required to account for the amount of drug in the body (Units are in litres (L) or sometimes L/kg of body weight)
- Analogy (based on the formula)
- In this analogy, Vd is the size of our bath tub and clearance is the bucket we use to filter this bath tub
- Clearance is a constant, and doesn’t change, so the larger our bath tub is, the longer it will take to filter
- A larger bath tub will allow our drug to stay active for a longer period of time, as it will take longer to filter, increasing the half like of the drug
What can Vd (apparent volume of distribution) be used for?
Can it exceed these physiological compartments?
What has happened if we get a non-physiological value for Vd from calculations?
What can Vd differ depending on? What are examples of drugs that do this?
- Vd (apparent volume of distribution) is a theoretical volume which can be used to suggest physiological compartments e.g roughly match up in volume to a certain body fluid volume, which can potentially indicate where the drug has gone
- Vd can also exceed these physiological values
- If we get a non-physiological value to represent Vd from a calculation, this means the drug has moved out of the body fluid volume sampled, through the capillaries, and into a tissue, where it has started to accumulate, leaving very little in the sample taken
- This makes it appear that it is distributed over a massive volume, when in reality, its in a tissue that wasn’t taken account for in the sample
- Vd can differ depending on the body fluid volume sampled and where the drug moves to
- Examples of drugs that do this are cannabinoids (accumulate in fat tissue) and bisphosphonates for osteoporosis (accumulate on bones)
How does sample volume allow us to calculate apparent volume of distribution (Vd)?
- How sample volume allow us to calculate apparent volume of distribution (Vd)
- Use plasma as an example of body fluid sampled
- From the diagram:
1) Drug A
* 100mg of drug has been injected
* A sample taken tells us a concentration of 10mg/L
* This means the Vd is 10L
2) Drug B
* 100mg of drug has been injected
* A sample taken has a concentration of 100mg/L
* This means the Vd is 1L
* Potentially, the drug has bound to a plasma bound protein, such as albumin, with a high affinity
* This will lead to an accumulation of drug in the plasma
3) Drug C
* 100mg of drug has been injected
* A sample taken has a concentration of 1mg/L
* This makes the Vd 100L
* Potentially, the drug has bound to something with a high affinity that has moved out of the plasma, leading to a high Vd
* An example of this may be bisphosphonates, which stick to bone
What is the single compartment model of distribution?
What does this model assume?
What would occur if drug gets into another compartment with equal equilibrium?
What does drug need to do to be excreted or metabolised?
What is an example of this?
- The single compartment model of distribution:
- Drug has been injected into a single compartment, distributed evenly and rapidly, forming a single well stirred compartment
- This model assumes drug in plasma is in rapid equilibrium with drug in extravascular tissues
- If the drug can get into the interstitial space from the plasma but is in an equal equilibrium, then this would be a well-stirred compartment that makes up the extracellular fluid
- To be excreted or metabolised, drugs have to move back to the main compartment (in order to go to kidneys/liver)
- E.g ethanol can get into all of the body water, and can exist in constant equilibrium with all of those compartments, creating a well stirred, evenly distributed alcohol concentration over 42L
How are two-compartment models of distribution formed?
How does this affect Vd and half-life of the drug?
What is an example of this?
- The two-compartment model of distribution:
- Sometimes, drug is distributed form the central compartment into poorly perfused peripheral tissues, where they will accumulate (equilibrium is not equal and favours moving into the peripheral tissues)
- By drugs moving to another compartment, this increases the apparent volume of distribution massively, which will increase the half-life, which will increase the length of time the drug will stay active for
- Drugs will stay active for longer in poorly perfused peripheral tissues, as it will take them a long time to move back to the central compartment to be removed by the kidneys/liver
- An example of this are bisphosphonates, which will accumulate on bones
What 5 things does Vd vary with?
What does this mean for half-life and the effects of drugs?
What is the formula for Vd?
What can we do if we know the Vd value and rearrange the formula for Vd?
- Vd varies with:
1) Height
2) Weight
3) Age
4) Fluid accumulation e.g ascites, oedema, pleural effusion (build-up of pleura between layers of pleura)
5) Accumulation of fat - If all of these factors affect Vd, they will affect half-life, which will affect how long drugs will last in the body
- By knowing Vd, and rearranging the formula for Vd, we can work out the dose of drug we need to give in a one-off bolus dose in order to achieve a certain plasma concentration
