PHAR 2: Intro to Pharma - Pharmacokinetics Flashcards
1
Q
What is pharmacokinetics?
A
- pharmacokinetics deals with what the body does to the drug
2
Q
List some of the main pharmacokinetic factors
A
- absorption
- distribution
- metabolism
- excretion
3
Q
Observe the learning outcomes of this session
A
4
Q
Describe absorption with regard to pharmacokinetics
A
- With regard to pharmacokinetics, absorption can be defined as the passage of a drug from the site of administration into the plasma.
5
Q
What is bioavailability?
What is other concept is it linked with?
A
- Bioavailability is defined as the fraction of the initial dose that reaches the systemic circulation
- it is linked with absorption
6
Q
What does the site of administration influence?
A
- has a very big influence on the absorption and bioavailability of a drug
7
Q
Give some examples of forms of drug administration
A
- A drug administered by the intra-venous route (where the entire dose is injected straight into the circulation) will have a bioavailability of 100%, by definition.
- Oral
- Inhalational
- Dermal (Percutaneous)
- Sub-lingual
In each case, the bioavailability is likely to be less than 100%.
8
Q
What are the two ways drug molecules can move around the body from the initial site of administration?
A
- Bulk flow transfer
- i.e. in the bloodstream - Diffusional transfer
- i.e. molecule by molecule across short distances
9
Q
Which methods of administration use bulk flow transfer and which use diffusional?
A
- With regard to the intravenous route, the drug is injected straight into the bloodstream, and therefore bulk flow transfer will then deliver the drug to its intended site of action.
- With all other routes of administration, in order for the drug to reach the bloodstream, it is first going to need to be transferred across at least one lipid membrane.
10
Q
What are the four main mechanisms by which drugs can cross lipid membranes?
Describe them
A
- pinocytosis
- pinocytosis involves a small part of the cell membrane enveloping the drug molecule and forming a vesicle containing the drug
- the vesicle can then release the drug on the other side of the membrane
- whilst this is relevant for some molecules, it is not used in many instances
- e.g. insulin access to the brain
- diffusion through lipid
- diffusion through aqueous pores
- carrier proteins
11
Q
What are the major mechanisms for drug transfer across lipid membranes?
A
- most drugs move across membranes either by:
- diffusion across lipid membranes or
- by carrier-mediated transport, which involves a transmembrane protein that binds drug molecules on one side of the membrane and then transfers them across to the other side of the membrane.
- Diffusion across aqueous pores; i.e., the gaps between epithelial/endothelial cells that make up the membrane, is not a major route for movement of drugs across membranes.
- Most pores are less than 0.5 nm in diameter, and since there are very few drugs this small, there is little movement of drugs across this aqueous route.
12
Q
What is a huge determinant of drug action when drugs diffuse through lipid?
A
- lipid solubility
- For example, it can determine drug absorption from the gut or drug penetration into tissues or drug elimination in the kidneys
13
Q
Describe some lipid membranes that need to be crossed before a drug can exert its action through these routes of administration:
- oral
- inhalational
- intra-nasal
A
- Oral:
a) small intestine microvilli
b) blood vessel wall to enter blood
c) blood vessel wall to access relevant tissue for effect. - Inhalational:
a) alveoli/bronchi
b) blood vessel wall to enter blood
c) blood vessel wall to access relevant tissue for effect. - Intra-nasal:
a) mucous membranes of nasal sinus
b) blood vessel wall to enter blood
c) blood vessel wall to access relevant tissue for effect.
14
Q
Describe the lipid membranes passed during the oral route of drug adminstration
A
15
Q
What is a very important factor to consider when thinking about the lipid solubility of drugs?
A
- most drugs are either weak acids or weak bases
- these drugs will exist as a combination of both ionised and unionised forms.
16
Q
What are the pKa and acid/base properties of aspirin and morphine?
Observe their structures
A
- aspirin:
- a weak acid
- pKa 3.5)
- morphine:
- a weak base
- pKa 8.0
17
Q
What would happen if aspirin and morphine were at physiological pH (7.4)?
A
- Aspirin would act as a weak acid and dissociated / donate protons (H+) into solution
- morphine would act as a weak base and accept protons (H+) from solution
18
Q
What are some important points in terms of absorption when it comes to pKa of aspirin and morphine?
A
- The unionised (uncharged) forms of aspirin and morphine are going to be more lipid soluble than the ionised (charged) forms of the drugs;
- charged molecules are more polar and thus less lipid-soluble, and will find it difficult to cross membranes. - The pH of the cellular/tissue/fluid environment will be a huge determinant of absorption of drugs across lipid membranes.
- Weak acids will be mainly unionised in acidic environments (pH lower than their pKa) and weak bases will be more unionised in alkaline environments (pH higher that their pKa).
19
Q
How would you represent weak bases in an equation?
A
20
Q
How would you represent weak acids in an equation?
A
21
Q
What does dissociation of the protonated form of the weak acid/base drug involve?
A
- dissociation of the protonated form of the drug involves the loss of the proton (H+).
22
Q
What equation describes the relationship between the pKa, the pH, and the relative concentrations of the acidic and basic forms of the drug?
A
- the Henderson-Hasselbalch equation
23
Q
Observe the maths recap on logs
A
24
Q
Does the pKa of a drug change?
How does the body affect the drug?
A
- The pKa of a drug WILL NOT change.
- However, as the drug passes through the body, the pH of the different body compartments WILL change.
- Therefore the pH of the body compartment will have a significant impact on the realtive proporations of the ionised and unionised forms of a weakly acidic or weakly basic drug in that particular compartment.
- If the pH and pKa are the same, then the ionised:unionised ratio will equal 1.
- or 50% of the drug is ionised and 50% of the drug is unionised when the pH = pKa.
25
The table below shows three separate aqueous body compartments separated by lipid membranes.
Using the Henderson-Hasselbalch equation, calculate the ratio of the ionised and unionised forms of aspirin and morphine across the different body compartments
- 0.0001 means: for every 10,000 molecules of ionised drug (A-), there is 1 molecule of unionised drug (AH)
- 0.0003 means: for every 100,000 molecules of ionised drug (A-), there are 3 molecules of unionised drug (AH)
- 100,000 means: for every 100,000 molecules of ionised drug (NH+) there is 1 molecule of unionised drug (B)
26
Looking at this data, what can we observe about the ionisation of aspirin?
- Aspirin is largely unionised in the stomach:
- As a result, a significant proportion of the drug (the unionised form) should easily cross the lipid membranes of the stomach and thus gain access to other body compartments.
- Aspirin is largely ionised in the blood and urine:
- As a result, a very significant proportion of aspirin will struggle to diffuse across the lipid membranes of the blood vessels and kidney tubules and this will remain ‘trapped’ in these compartments.
27
What is the pH partition hypothesis?
- the proportion of drug in any body compartment is dependent on pH and results in the phenomenon of ‘ion trapping’.
- Acidic drugs tend to become ‘trapped’ in compartments with high pH and basic drugs tend to become ‘trapped’ in body compartments with low pH.
28
What are carrier transport systems?
What do carrier proteins bind to?
- Carrier transport systems are present to regulate the entrance and exit of physiologically important molecules across lipid membranes.
- The carrier protein binds to one of more molecule(s) and transports the molecule to the other side of the membrane.
- Drugs that resemble endogenous molecules may also interact with these carrier systems.
- As a result, it is possible for less lipid-soluble drugs to gain access to tissues via this route.
29
In terms of pharmacokinetics, the most important carrier systems relating to drug action are found in the?
What are they responsible for?
1. Renal tubule
2. Biliary tract
3. Blood brain barrier
4. Gastrointestinal tract
These particular carrier systems are therefore responsible for drug access to the bloodstream (absorption from the gastrointestinal tract), for drug access to certain tissues (absorption across the blood-brain barrier) and excretion of drugs from the body (excretion from the kidney of the gastro-intestinal tract).
30
What are the two major advantages of administering drugs for local effects rather than systemic?
1. You can deliver the drug directly to the intended site of action
2. You can administer a high local concentration without worrying about systemic effects
31
Which drugs are administered systemically or locally?
32
Can a drug effect be completely localised?
- It is very rare that a drug effect can be completely localised.
- Most tissues receive a good blood supply – as a result, if the drug is lipid soluble at all, some of it will diffuse into the tissue blood supply from where it may exert a systemic effect.
33
Once the drug has been absorbed, what are some factors that will influence tissue distribution?
What factors affect how different tissues will be exposed to different amounts of drug?
- Regional blood flow
- Plasma protein binding
- Capillary permeability
- Tissue localisation
34
Describe how regional blood flow means for drug distribution?
- With regard to regional blood flow, different tissues receive differing amounts of the cardiac output.
- At rest the following tissues would receive the following percentage of the cardiac output as seen in image
- As a result, more drug will be distributed to those tissues that receive most blood flow.
- It is important to remember that the distribution of blood to tissues can increase or decrease depending on the circumstances;
- e.g., during exercise more blood will be diverted to the muscles, whereas after a large meal more blood will be diverted to the stomach and intestines.
35
Once drugs reach the systemic circulation, what will most of them bind to?
- most will bind to plasma proteins
- some drugs can be up to 99% bound to proteins
36
What is the most important plasma protein?
What type of drug does it bind to?
The most important plasma protein in this regard is albumin, which is particularly good at binding acidic drugs.
37
What three factors determine the amount of drug that is bound to plasma proteins?
1. The free drug concentration
2. The affinity for the protein binding sites
3. The plasma protein concentration
38
Describe the binding reaction of drugs with plasma protein binding sites
39
Using albumin as an example, describe its binding capacity
If we only consider albumin (although there are other plasma proteins that bind drugs), the concentration of albumin in the blood is approximately 0.6 mM. Each albumin protein has two binding sites.
- As a result, the binding capacity of albumin alone is 1.2 mM.
- This is important because the plasma concentration required for a clinical effect for nearly all drugs is considerably less than 1.2 mM.
- The consequence of this is that the plasma proteins are NEVER saturated with drugs.
- Therefore, differences in the extent of plasma protein binding for individual drugs is largely due to the particular affinity for the protein binding sites for that particular drug.
- As mentioned above, acidic drugs bind particularly well to albumin and therefore tend to be more heavily plasma protein bound.
40
Can drugs bound to plasma proteins leave the blood?
- Only free drug is available to diffuse out of the blood and access tissues.
- Any drug that is bound to plasma proteins CANNOT leave the blood until it dissociates from the protein.
41
What is capillary permeability an important contributor to?
- it is an important contributor to drug distribution
42
What are the different types of capillary structures found in the cardiovascular system?
43
Describe continuous capillary structures
- what drugs cross through?
- In the section on absorption, we mentioned that the major routes for drug absorption were diffusion across lipids or via carrier proteins.
- Most of the capillaries in the body have the ‘continuous’ structure illustrated here – endothelial cells aligned in single file with small gap junctions between the cells.
- If drugs are very lipid soluble then they can diffuse across the endothelial cell and access the tissue.
44
Describe the capillary structure in the brain
Is it easy for drugs to access?
- If drugs are less lipid soluble, then (unless they are very small and can pass through gap junctions), they will need to be transported into the tissue via carrier proteins.
- The blood brain barrier (BBB) refers to the capillary structure in the brain, where there is a ‘continuous’ structure, but with the addition of tight junctions between endothelial cells.
- This makes the brain the most difficult tissue in the body for drugs to gain access to – which makes sense, when you consider the critical physiological role of the brain.
45
Describe discontinuous capillary structures
- example tissue
- drug access
- an example of a tissue with this capillary structure is the liver.
- The liver is one of the key metabolic tissues in the body and deals with metabolism of a huge variety of (bio)chemicals including the majority of drugs.
- A discontinuous capillary structure (big gaps between capillary endothelial cells) allows for drugs to easily diffuse out of the bloodstream and access the liver tissue.
46
Describe fenestrated capillary structures
- example tissue
- drug access
- an example of a tissue with this capillary structure is the glomerulus of the kidney.
- The kidney is a key tissue involved in excretion of chemicals including a large number of drugs.
- Fenestrations are circular 'windows' within endothelial cells that allow for the passage of small molecular weight substances including some drugs.
- This allows for some small drugs to pass from blood to kidney tubules which will enhance the excretion of these drugs.
47
How is localisation to tissues an important factor that influences distribution?
Use body fat as an example
- The most important tissue with regard to this factor is body fat.
- Fat is essentially a large non-polar compartment, and thus has the capacity to absorb and retain lipid-soluble drugs.
- We have already established that most drugs are heavily ionized in the blood, and thus not particularly lipid-soluble.
48
What factors will determine whether the non-ionised drug will accumulate in the body fat?
1. Blood flow to the body fat is very low – approximately 2% of the cardiac output.
- As a result, at any given moment in time, only small amounts of the non-ionised drug is being delivered to the body fat.
2. The lipid solubility of the drug.
- We mentioned morphine above.
- Morphine can access the brain, which suggests it is fairly lipid soluble.
- However, its oil/water partition coefficient (i.e how well it dissolves in fat versus how well it dissolves in water) is 1.
49
What is the oil/water partition coefficient?
- The oil/water partition coefficient is more formally referred to as the octanol/water partition coefficient.
- These terms are used interchangeably.
- The octanol/water partition coefficient has the symbol P, and is typically discussed/displayed as a logarithm of this value: logP.
50
If 98% of the drug is being distributed to body water (i.e. other tissues) and only 2% of it to body fat, then how much is distributed to body fat?
- If 98% of the drug is being distributed to body water (i.e. other tissues) and only 2% of it to body fat, then very little will distribute to body fat.
51
What happens when some drugs have high oil/water partition coefficients?
- For example, some general anaesthetics can have an oil/water partition coefficient of 5000.
- As a result, the 2% that reaches the body fat will accumulate in this tissue very effectively.
- The drug that resides in the body fat will then slowly leak back into the bloodstream (due to the poor blood flow to this tissue and the preference of the drug for the body fat versus the aqueous blood)
52
Looking at this diagram, describe how morphine will accumulate in the adipose tissue at equilibrium?
- At equilibrium, morphine will partition equally between the blood and adipose tissue.
- At equilibrium, the anaesthetic will partition to a greater extent in the adipose tissue.
- As a result, more anaesthetic will accumulate in the adipose tissue
53
What is the issue with lipid-soluble drugs in terms of excretion?
- In order to eliminate drugs from the body, there must be pathways for their excretion.
- Without a process for excretion, drugs would simply circulate/accumulate in the body forever.
- In order for drugs to be effectively excreted, it would be ideal if they were not particularly lipid-soluble as this would mean they would be more effectively retained in the blood (drugs would not diffuse out of the blood into tissues) and more of the drug would be delivered to the various excretion sites (e.g., kidney).
- However, in terms of therapeutic effectiveness, we WANT drugs to be lipid-soluble, so that they can easily access tissues to produce their effects.
- Therefore, we tend to design relatively lipid-soluble drugs. It is then up to the body to alter the drug to make it less lipid-soluble if it is to be readily excreted.
54
What does the process of drug metabolism involve?
- The process of drug metabolism involves the biotransformation of the parent drug (usually quite lipid-soluble) into one or more metabolites (usually but not always less lipid-soluble and easier to excrete).
55
What is the major site of drug metabolism?
- The major metabolic tissue and site of drug metabolism is the liver.
- Cells in the liver exhibit high expression of enzymes that perform drug metabolism reactions.
56
What two kinds of biotransformation does drug metabolism involve?
- Functionalisation (a.k.a. Phase I reactions)
- These introduce/reveal/interconvert a functional group in/on the drug.
- Conjugation (a.k.a. Phase II reactions).
- These result in the conjugation of the drug with an endogenous biochemical molecule.
Together, these reactions typically decrease lipid solubility, which then aids excretion and elimination.
57
What are functionalisation reactions?
- Functionalisation reactions can be oxidations, reductions, or hydrolyses
- that lead to the introduction, interconversion, or unmasking, of functional groups.
58
Look at these examples and identified which is oxidised, reduced and hydrolysed?
59
Describe some of the main functionalisation reactions and their target functional groups
Note that in most cases, the metabolites of functionalisation reactions will have a very similar structure to the parent drug, and often produce pharmacologically active drug metabolites.
60
What are prodrugs?
- In some instances, the parent drug has no activity of its own, and will only produce an effect once it has been metabolized to the respective metabolite – these drugs are known as prodrugs.
- In this case, metabolism is required for the pharmacological effect.
61
Describe conjugation reactions
- Functionalisation reactions usually produce metabolites with (additional) functional groups that can undergo subsequent conjugation.
- Note that a drug may already contain a functional group suitable for conjugation without any functionalisation occurring.
- The result of conjugative metabolism is the covalent attachment of an endogenous molecule, with the resulting metabolite typically less pharmacologically active (or completely inactive) and less lipid-soluble.
- This facilitates excretion in the urine or bile.
62
Describe the main types of conjugation reaction and their target functional groups
As you will see, most of these are named in a fairly memorable/sensible way. You will also note that most target nucleophilic functional groups (-OH, -NH2, etc.) but glutathione conjugation targets electrophiles.
63
Observe the main route of aspirin metabolism
64
What is first-pass hepatic metabolism?
- first-pass hepatic metabolism (the first-pass effect, or presystemic metabolism) is how the route of administeration may alter the rate and routes of drug metabolism
- This is a particularly important consideration for orally administered drugs.
- Orally administered drugs are predominantly absorbed from the small intestine and enter the hepatic portal blood supply where they will first pass through the liver before they reach the systemic circulation.
- At this point, the drug can be heavily metabolised and as a result, little active drug may reach the systemic circulation (although first-pass metabolism is a prerequisite for the activity of prodrugs).
65
Describe the initial problem, solution and secondary problem of first-pass metabolism
- Initial Problem: Presystemic metabolism reduces the bioavailability of a drug below 100%, and therefore insufficient drug reaches the target at the required concentration.
- Solution: Administer a larger dose of drug to ensure enough drug reaches the systemic circulation.
- Secondary Problem: The extent of presystemic metabolism varies amongst individuals, and therefore the amount of drug reaching the systemic circulation also varies.
- As a result, drug effects / side effects (including overdose) are more difficult to predict.
66
Describe some routes for drug excretion and elimination
- drugs can be excreted via the lungs (the basis of the alcohol breath test is to measure alcohol excreted via the lungs)
- drugs can be excreted in breast milk (and therefore care needs to be taken that drugs excreted in milk do not affect a baby).
- By far the most (quantitatively) important routes of excretion are via the kidney (in urine) or via the liver (in bile).
67
What are the three major mechanisms for drug excretion via the kidney?
What affects the extent of which mechanism is chosen?
1. glomerular filtration
2. active tubular secretion or reabsorption
3. passive diffusion across tubular epithelium
The extent that drugs are excreted by these three mechanisms differs enormously, and explains why excretion of different drugs can vary so much.
- This is also influenced by the rate and route(s) of metabolism
68
Describe the kidney excretion method: glomerular filtration
- Glomerular filtration allows drug molecules of molecular weight less than 20000 Da to diffuse into the glomerular filtrate.
- This obviously means that drugs with a molecular weight less than 20000 Da have an additional route for excretion (glomerular filtration) compared with larger drugs – as a result, this should result in a higher rate of excretion.
69
Describe the kidney excretion method: active tubular secretion
- Active tubular secretion is the most important mechanism for drug excretion in the kidney.
- Firstly, whereas only 20% of the renal plasma is filtered at the glomerulus, the remaining 80% of the renal plasma passes onto the blood supply to the proximal tubule.
- Therefore, more drug is delivered to the proximal tubule than the glomerulus.
- Secondly, within the proximal tubule capillary endothelial cells are two active transport carrier systems.
- One is very effective at transporting acidic drugs and one is very effective at transporting basic drugs.
- Both are capable of transporting drugs against a concentration gradient.
70
Describe the kidney excretion method: passive diffusion
- Passive diffusion generally leads to reabsorption from the kidney tubule.
- As glomerular filtrate moves through the kidney, most of the water filtered (99%) is reabsorbed.
- If drugs are particularly lipid soluble, then they will also be reabsorbed, passively diffusing across the tubule back into the blood.
- The factors that will influence the extend of reabsorption;
1. Drug metabolism:
- Drug metabolites resulting from conjugation (Phase II) reactions tend to be considerably more water-soluble than the parent drug, and are therefore less well reabsorbed.
2. Urine pH:
- This can vary from 4.5 - 8.0.
- Based on the pH partition hypothesis mentioned above, acidic drugs will be better reabsorbed at lower pH and basic drugs will be better reabsorbed at higher pH.
71
Consider the following example. You are taking Drug A as an analgesic – it is a weak acid. The urine pH suddenly increases from 6.5 to 8. Will the drug effect be prolonged or reduced over the next few hours?
Prolonged or reduced?
- reduced
- Drug A is a weak acid.
- If the urine pH increases to 8, then Drug A will become more ionised in the alkaline environment.
- This will decrease the lipid solubility of Drug A. As a result, less of the drug will be reabsorbed in the kidney tubule, and more will be excreted.
- The drug effect will be reduced due to this more effective excretion.
72
Describe biliary excretion
- Another quantitatively important route of excretion is via the bile.
- Liver cells transport some drugs from plasma to bile – primarily via transporters similar to those in the kidney.
- This system is particularly effective at removing glucuronide, glutathione, and other larger/higher molecular weight metabolites.
- Drugs transported to the bile are then excreted into the intestines and will be eliminated in the faeces.
73
What is enterohepatic recycling?
- a process occurring via the bile that can significantly prolong drug effect
74
Describe the steps of enterohepatic recycling
1. A glucuronide metabolite is transported into the bile.
2. The metabolite is excreted into the small intestine, where it is hydrolysed by gut bacteria releasing the glucuronide conjugate.
3. Loss of the glucuronide conjugate increases the lipid solubility of the molecule.
4. Increased lipid solubility allows for greater reabsorption from small intestine back into the hepatic portal blood system for return to the liver.
5. The molecule returns to the liver where a proportion will be re-metabolised, but a proportion may escape into the systemic circulation to continue to have effects on the body.
75
How do we predict the time course of drug action?
Use the oral route as an example
- Consider the four concepts discussed above – absorption, distribution, metabolism, and excretion (collectively ADME).
- If we understand how each of these relates to a specific drug administered via a specific route, then we can attempt to predict the time course of drug action.
- If a drug is administered via the oral route;
1. We need to know bioavailability of this drug via the oral route to estimate how much will reach the systemic circulation.
- For arguments sake, lets say it is 50%.
2. We now know that 50% will distribute throughout the body based on various characteristics (e.g., lipid solubility) – this will give us the volume of distribution.
3. The drug will then be eliminated from the body at a certain rate.
- This is often termed clearance, and total clearance is the sum of the clearance by metabolism and by renal excretion.
76
What is half-life?
- In order to standardise across drugs, we utilise something called the half-life.
- The half-life is the time taken for 50% of the drug to be eliminated from the body.
