Principles of Pharmacology Flashcards
Approximately what percentage of hospital admissions can be directly attributed to adverse drug reactions?
~5%
What is pharmacology?
The study of drug action.
It’s about understanding how drugs interact with living organisms and how this interaction influences physiological function.
What are therapeutics?
Branch of medicine concerned with drug prescribing and the treatment of disease
What is the main difference between pharmacology and therapeutics?
Pharmacology is more focused on the drugs whereas therapeutics focuses more on the patient.
What is meant by pharmacodynamics?
What the drug does to the body
What is meant by pharmokinetics?
What the body does to the drug
It is defined as ‘the study of the time course of drug absorption, distribution, metabolism and excretion’.
What are the three most important questions to consider when exploring pharmacodynamics?
- Where is this effect produced?
- What is the target for the drug?
- What is the response that is produced after interaction with this target?
What are the two main effects of cocaine?
Euphoria
Local anaesthetic
Thinking about the pharmacodynamics of cocaine: how does cocaine produce a euphoric effect in the body?
- Where is the effect produced?
- What is the target?
- What is the response?
- Dopaminergic neurones in the nucleus accumbens in the brain
- Dopamine reuptake protein on pre-synaptic terminal
- Blocks dopamine reuptake protein –> dopamine not removed from synapse as quickly –> accumulates –> more dopamine available to bind to D1 receptor
Activation of this D1 receptor is what causes euphoria
Why must drugs bind to a specific target in the body?
To produce a measurable effect and response
What are the two main actions that can drugs can have on a target?
- Enhance activation of a target - stimulatory effect
2. Prevent activation of a target - inhibitory effect
What are the majority of drug targets?
Proteins
What are the 4 main classes of drug target proteins?
- Receptors
- Enzymes
- Ion channels
- Transport proteins
What is the target of aspirin? What class is the target?
Target class - Enzyme
Binds cyclooxygenase (COX) + blocks prostaglandins production
What is the target of local anaesthetic. What class is the target?
Target class - Ion channel
Block Na+ channels, preventing nerve conduction
What is the target of Prozac (anti-depressant)? What class is the target?
Target class - Transport protein
Blocks serotonin carrier proteins, preventing serotonin removal from synapse
What is the target of Nicotine? What class is the target?
Target class - Receptor
Binds and activates nicotine acetylcholine receptor
What must a drug show for a particular target to be an effective therapeutic agent?
The drug must show a high degree of selectivity for a particular drug target
Why is it difficult to design a drug that has complete selectivity?
Many drugs and chemicals are structurally similar
E.G. dopamine, noradrenaline and serotonin are structurally very similar
What problem do dopamine, noradrenaline and serotonin have when it comes to selectivity?
????EDIT QUESTION & ANSWER?????
Dopamine, noradrenaline and serotonin are all structurally similar.
They all have a high degree of specificity for their specific receptors.
Dopamine is the most specific for the dopamine receptor
However, serotonin and adrenergic receptors have some degree of specificity for dopamine
Therefore, a drug targeting dopamine receptors could interact with serotonin and adrenergic receptors, causing side/adverse effects
Dopamine is the most specific for the dopamine receptor.
How then might drugs targeting the dopamine receptor interact with other receptors?
Dopamine, noradrenaline and serotonin are all structurally similar.
Serotonin and adrenergic receptors have some degree of specificity for dopamine
Therefore, a drug targeting dopamine receptors could interact with serotonin and adrenergic receptors, causing side/adverse effects
Why might a drug targeting dopamine receptors interact with serotonin and adrenergic receptors?
Dopamine, noradrenaline and serotonin are all structurally similar.
Serotonin and adrenergic receptors have some degree of specificity for dopamine so a drug targeting dopamine receptors could interact with serotonin and adrenergic receptors.
Drug dose is related to selectivity.
If drug A is 50 times more selective for drug target A than B, how would you find the dosage needed to see effects at B?
Start with a low dose of the drug and increase it until an effect is observed at A (call this dosage x).
As you know the drug is 50x more selective for target A than B, we then know that the dosage “x” would need to be increased 50x before seeing effects at B.
Why is it difficult to accurately predict how much of a drug might arrive at a specific drug target?
It’s difficult to predict this because of how the body handles the drug (pharmokinetics)
What is the therapeutic effect of Pergolide?
It has an anti-Parkinsonian effect
What receptor is Pergolide most selective for?
Dopamine (D2) receptor
Besides the dopamine receptor, what receptors can Pergolide bind to?
Serotonin (SHT-2B) receptor
Adrenergic (A1) receptor
How does the specificity/selectivity of Pergolide change as the dosage increases?
At a low dose (~0.5mM) - therapeutic effect
At higher dose - binds serotonin (SHT-2B) receptor –> hallucinations
At even higher dose - binds adrenergic (A1) receptor –> hypotension
At low doses, its effect is more specific and the therapeutic effect is observed. As the dose increases, its effect becomes less specific because the drug starts to interact with other targets, causing side effects.
What side effect occurs when Pergolide interacts with the serotonin (SHT-2B) receptor?
Hallucinations
What side effect occurs when Pergolide interacts with the adrenergic (A1) receptor?
Hypotension
Drugs can interact with receptors through a variety of chemical interactions. Name at least 2 types of chemical interactions.
Electrostatic interactions
Hydrophobic interactions
Covalent bonds
Stereospecific interactions
What’s the most common mechanism by which drugs can interact with receptors?
HINT - think chemical ineractions
Electrostatic interactions
Inc. hydrogen bonds, London forces
Hydrogen bonds and Van der Waals (London) forces are types of what chemical interaction?
Electrostatic interactions
What type of chemical interactions are particularly important for lipid soluble drugs?
Hydrophobic interactions
Hydrophobic interactions are particularly important in the mechanisms of what type of drugs?
Lipid soluble drugs
What are the least common types of chemical interactions between drugs and receptor targets?
Why?
Covalent bonds
These interactions tend to be irreversible
Why can some drugs interact with receptors through stereospecific interactions?
Many drugs exist as stereoisomers and interact stereospecifically with receptors
For a specific concentration of a drug, a specific number of drug receptor complexes are formed.
If you were to increase the concentration of the drug, equilibrium would shift in which direction?
Why?
Right
This is because there is more drug available to bind to free receptors
For a specific concentration of a drug, a specific number of drug receptor complexes are formed.
If you were to increase the concentration of the drug, equilibrium would shift to the right.
Since this is a two-way reaction, in what direction would equilibrium shift if you were to dramatically reduce the amount of drug available?
Why?
Left
This is because more receptors would become available again due to the lower drug concentration
Drugs can be divided into 2 categories based on how they interact with receptors. What are these 2 categories?
Agonists & Antagonists
How do agonists affect receptors?
They bind and activate receptors
How do antagonists affect receptors?
They bind and inhibit receptors
What are 2 key properties of agonists?
Affinity & Efficacy
Each individual drug-receptor interaction is permanent. True or False?
False
Each individual drug-receptor interaction is transient
What does drug affinity determine?
How strongly a drug binds receptor
What factor determines the strength of each drug-receptor complex?
The affinity of the drug
What is drug affinity strongly linked to?
Receptor occupancy
If you have two drugs added to the same tissue and the same number of receptors available, which drug is likely to be found bound to more receptors?
(In terms of affinity)
The drug with the higher affinity will form stronger drug-receptor complexes. It is more likely that more of this drug will be bound to receptors.
What does drug efficacy refer to?
The ability of an individual drug molecule to produce an effect once bound to its receptor
What level of response may occur when a drug binds to a receptor and what level of efficacy is there at each level?
No response –> no efficacy
Partial response but not capable of inducing maximal response –> partial efficacy
Maximal response –> high efficacy
Based on efficacy, what 3 classes of drug interaction at the receptor level are there?
Antagonists
Partial agonists
Full agonists
A drug has affinity for the receptor but no efficacy:
is it an antagonist, partial agonist or full agonists?
Antagonist
A drug has affinity for the receptor but no efficacy:
Is it an antagonist, partial agonist or full agonists?
Antagonist
A drug has affinity for the receptor and sub-maximal efficacy:
Is it an antagonist, partial agonist or full agonists?
Partial agonist
How does a partial agonist act?
It binds to a receptor, producing a partial response but cannot induce the maximal response from that receptor.
A drug has affinity for the receptor and maximal efficacy:
Is it an antagonist, partial agonist or full agonists?
Full agonist
How does a full agonist act?
It binds to a receptor, producing the maximal response expected from that receptor.
What does potency refer to?
The concentration/dose of a drug required to produce a defined effect
What does potency refer to?
The concentration/dose of a drug required to produce a defined effect
Potency is referred to as ‘the concentration/dose of a drug required to produce a defined effect’
However, this definition is vague. What else can be used to define potency?
The standard measure of potency
What is the standard measure of potency?
To determine the concentration or dose required to produce a 50% tissue response
What is the standard nomenclature for potency?
EC50 - half maximal effective concentration
ED50 - half maximal effective dose
What is EC50?
The half maximal effective concentration
What is ED50?
The half maximal effective dose
What is the difference between EC50 and ED50?
EC50 considers concentration (the 1/2 maximal effective conc.) whereas ED50 considers dosage (the 1/2 maximal effective dose)
In order to test drug effectiveness in an in vitro experiment, what standard measure of potency would be used?
What are we looking for?
EC50
We’re looking for the concentration that produces a 50% response
In order to test drug effectiveness in a clinical trial, what standard measure of potency would be used?
What are we looking for?
ED50
We’re looking for the dose that produces the desired effect in 50% of the individuals tested
How is potency related to dose?
For a more potent drug, a smaller dose is required to produce a particular effect
What standard nomenclature is often used to compare potencies of drugs?
ED50
When comparing potencies of different drugs, how would we find the most potent drug?
By looking at the drug that produces a 50% response (half maximal response) at the lowest conc./dose
Efficacy is related to dose.
True or False?
False
Potency is related to dose. Efficacy is not.
Compare how potency and efficacy relate to dosage
Potency is related to dose while efficacy is not
- A highly potent drug produces a large response at relatively low concentration
- A highly efficacious drug can produce a maximal response, and this effect is not particularly related to drug concentration
Compare potency and efficacy
- Potency is related to dose while efficacy is not
- Clinically, efficacy is more important than potency
Clinically, efficacy is more important than potency.
Explain why.
?????EDIT ANSWER - MAKE LESS WAFFLEY???
We want to know whether the drug that’s being given can induce the maximal response.
Potency determines the dose you need to administer to produce a response, not the actual efficacy of the response.
If 2 drugs have the same efficacy, it doesn’t matter which drug is more potent. You can still reach the maximal response with the less potent drug - you’d just need to administer a slightly higher concentration.
Name the 4 main principles/concepts of pharmacokinetics.
Drug…
- Absorption
- Distribution
- Metabolism
- Excretion
What is the concentration of a drug that reaches the tissues dependant on?
A number of different pharmacokinetic factors, inc. absorption, distribution, metabolism & excretion
What is clinical pharmacokinetics?
Using pharmacokinetic concepts to safely and effectively manage and use drugs to treat an individual patient
What is absorption?
The passage of a drug from site of administration into plasma (in terms of pharmacokinetics)
It deals with the process for drug transfer into the systemic circulation
What is bioavailability?
The fraction of the initial drug dose that gains access to the systemic circulation
It deals with the outcome of drug transfer into the systemic circulation (i.e. how much)
Thinking of pharmacokinetics principles, what does the site of administration of a drug largely impact?
Absorption & Bioavailability
What is intra-venous administration?
A process for drug passage - injecting the full drug dose into the systemic circulation
What is the outcome of intra-venous administration?
If the full dose is administered straight into the circulation, bioavailability will be 100%
Name (at least) 2 common examples of different types of drug administration
Oral Inhalational Dermal (percutaneous) Intra-nasal (+ more)
Drugs can move around the body in 2 main ways.
What are these ways?
- Bulk flow transfer (i.e. in bloodstream)
2. Diffusional transfer (i.e. molecule by molecule across short distances)
Below are some common examples of different methods of drug administration:
Oral
Inhalational
Dermal (percutaneous)
Intra-nasal
For each of these methods, bioavailability is likely to be <100%.
Explain why.
For drugs to reach the bloodstream via these routes, they’ll need to undergo diffusional transfer. They’ll need to diffuse across at least 1 lipid membrane.
By what route of travel do drugs administered by IV move around the body?
Bulk flow transfer - drug will be delivered to intended site of action in the blood stream
What are the 4 main mechanisms by which chemicals can diffuse across plasma membranes?
And, of these 4, which 2 are the most relevant for drugs (most common methods)?
- Simple Diffusion
- Diffusion across aqueous pores
- Carrier-mediated transport
- Pinocytosis
[1] and [3] are the most common forms of transport across plasma membranes
What does pinocytosis involve?
Pinocytosis involves a small part of the cell membrane enveloping the chemical molecule and forming a vesicle containing the drug.
The vesicle can then release the chemical on the other side of the membrane.
Pinocytosis is rarely used to transport drugs.
With this said, name 1 example of when it’s useful.
Insulin access to the brain
Where might you find aqueous pores in the cell membrane?
Gaps between epithelial/endothelial cells comprising the membrane
Why is diffusion across aqueous pores not a common mode of transport for drugs in the body?
Most pores are <0.5nm in diameter.
There are very few drugs this small.
What property must drugs have if they are to diffuse across a lipid membrane?
They must be lipid-soluble
What does carrier-mediated transport involve?
It involves a transmembrane protein, which can bind drug molecules on one side of the membrane and then transfer them across to the other side of the membrane
What is the most common direction of diffusion?
From an area of high concentration to an area of low concentration (down concentration gradient)
In what direction do molecules move across the membrane in active transport?
From an area of low concentration to an area of high concentration (against concentration gradient)
What organic compound does active transport require?
ATP
Many drugs are more water soluble than lipid soluble.
Why can this be useful?
Many drugs are given orally and need to be hydrophilic to be able to dissolve in the aqueous environment of the GI tract for absorption
The lipid-solubility of a drug can change depending on its environment. How is this possible?
Most drugs are weak acids or bases so they can exist in 2 forms:
- Ionised
- Unionised
What equation can we look at to determine whether a drug is going to be ionised or unionised in a given tissue?
Henderson Hasselbach equation
Aspirin is a weak acid.
How will it interact with its protons in an ionised state?
It will donate protons, i.e. H+
Morphine is a weak a base.
How will it interact with protons in an ionised state?
It will accept protons, i.e. B(Morphine)H+
Unionised forms of aspirin and morphine are more likely to diffuse across plasma membranes. Why?
Their unionised forms retain more lipid solubility and so are more likely to diffuse across plasma membranes
Whether a drug is ionised or unionised in a given tissue depends on 2 factors.
What are these factors?
- Dissociation constant (pKa) for that drug
2. pH in that particular part of the body
Describe the dissociation of a drug if the pKa of the drug and the pH of the tissue are equal.
The drug will be equally dissociated between the 2 forms i.e. 50% ionised + 50% unionised
Most weak acids have a pKa between what range?
pKa between 3-5
Describe the dissociation of a drug if the pKa of the drug and the pH of the tissue are equal.
The drug will be equally dissociated between the 2 forms i.e. 50% ionised + 50% unionised
E.G. Aspirin is a weak acid and has a pKa of 3.5. When both the pKa and the pH = 3.5, aspirin will be equally dissociated between its two forms.
Describe the dissociation of a drug if the pKa of the drug and the pH of the tissue are equal.
The drug will be equally dissociated between the 2 forms i.e. 50% ionised + 50% unionised
E.G. Aspirin is a weak acid and has a pKa of 3.5. When both the pKa and the pH = 3.5, aspirin will be equally dissociated between its two forms.
E.G. Morphine is a weak base and has a pKa of 8. When pH = 8, it’ll be equally dissociated between its 2 forms.
Most weak bases have a pKa between what range?
pKa between 8-10
In terms of dissociation, what happens to weak acids as the pH decreases?
The unionised form starts to dominate
In terms of dissociation, what happens to weak acids as the pH increases?
The ionised form starts to dominate
In terms of dissociation, what happens to weak bases as the pH decreases?
Ionised form starts to dominate
In terms of dissociation, what happens to weak bases as the pH increases?
The unionised form starts to dominate
In areas of low pH (e.g. the stomach), will a weak acid be more ionised or unionised?
Unionised
In areas of higher pH (e.g. the blood, urine), will a weak base be more ionised or unionised?
Unionised
What is the concept of ‘ion trapping’?
“Ion trapping is the build up of a higher concentration of a chemical across a cell membrane due to the pKa value of the chemical and difference of pH across the cell membrane”
E.G. Weak acids are more unionised in areas of low pH. In their unionised, they retain lipid-solubility and are more likely to diffuse across a plasma membrane.
Therefore (in theory) weak acids will be less likely to diffuse across plasma membranes in areas of higher pH, such as the blood or the urine as they would be in their ionised states in these places.
Describe the absorption of a weak base (drug) from the stomach and then from the small intestine.
A weak base will be poorly absorbed from the stomach.
However, once the drug eventually reaches the small intestine, it’ll be able to access a large number of transport proteins that will enable absorption from the GI tract.
Why would a weak base be poorly absorbed from the stomach?
The low pH in the stomach will lead to a high drug ionisation.
Why would a weak base be poorly absorbed from the stomach?
The low pH in the stomach will lead to a high drug ionisation. Ionised drugs are less likely to diffuse across plasma membrane.
Why could a weak acid (drug) potentially become ‘trapped’ in the blood?
How might a weak acid be absorbed into tissues from the blood regardless?
The lower pH of the blood would lead to a high drug ionisation. Ionised drugs are less likely to diffuse across the membrane.
However, most tissues possess transport proteins that could potentially move ionised drug from the blood into the tissue.
In terms of pharmacokinetics, what are the 4 locations of the most important carrier systems in the body relating to drug action?
- Renal tube
- Biliary tract
- Blood brain barrier
- GI tract
The locations listed below are of the most important carrier systems in the body relating to drug action:
Renal tube
Biliary tract
Blood brain barrier
GI tract
What are the 3 main things that these carrier systems are responsible for?
- Drug access to the bloodstream (absorption from GI tract)
- Drug access to certain tissues (absorption across BBB)
- Excretion of drugs from body (from kidney or GI tract)
What pharmacokinetic principle occurs following absorption of a drug?
Distribution - the distribution of the drug to various tissues where it will produce its eventual effects
Different tissues will be exposed to different amounts of a drug depending on certain factors.
What 4 main factors influence tissue distribution of a drug?
- Regional blood flow
- Plasma protein binding
- Capillary permeability
- Tissue localisation
What do we mean by regional blood flow?
The proportion (%) of the cardiac output received by different tissues.
At rest, what is the regional blood flow to the liver?
27%
At rest, what is the regional blood flow to the heart?
4%
At rest, what is the regional blood flow to the brain?
14%
At rest, what is the regional blood flow to the kidneys?
22%
At rest, what is the regional blood flow to the muscles?
20%
How does regional blood flow affect drug distribution?
Different tissues receive different % of cardiac output.
More drug will be distributed to tissues receiving the most blood flow.
However, distribution of blood can increase/decrease depending on circumstance.
E.G. during exercise, more blood to muscles
E.G. after large meal, more blood to stomach + intestines
Give an example of a situation in which more blood will be distributed to the muscles
During exercise
Give an example of a situation in which more blood will be distributed to the stomach and intestines
After a large meal
What do many drugs commonly bind to upon reaching the systemic circulation?
Plasma proteins
Many drugs bind plasma proteins upon reaching the systemic circulation.
What is the most important plasma protein in this regard?
Albumin
Many drugs bind plasma proteins upon reaching the systemic circulation.
What 3 factors does the amount of drug bound depend on?
- The free drug concentration
- The affinity for the protein binding sites
- The plasma protein concentration
Give a general equation for the binding reaction that can occur between drugs and plasma proteins.
D(free drug) + P(protein binding site) DP(drug-protein binding site)
Similar to drug + receptor reaction
What is the approximate concentration of albumin in the blood?
~0.6mmol/L
How many binding sites does albumin have?
2
The approx. concentration of albumin in the blood ~0.6mmol/L and albumin has 2 binding sites.
Therefore, what is the binding capacity of albumin alone?
Why is this important?
1.2mmol/L
This is important because the plasma concentration required for a clinical effect for nearly all drugs is considerably less than 1.2mmol/L.
Therefore, plasma proteins are NEVER fully saturated with drugs.
This means that the differences in the extent of plasma protein binding for individual drugs is largely due to its particular affinity for protein binding sites
Many drugs bind plasma proteins upon reaching the systemic circulation, and an important plasma protein in this regard is albumin.
Albumin has a total binding capacity of 1.2mmol/L however, the plasma concentration required for a clinical effect for nearly all drugs is considerably <1.2mmol/L.
What is the significance of this? (in terms of the amount of drug bound to proteins)
Plasma proteins are NEVER fully saturated with drugs.
This means that the differences in the extent of plasma protein binding for individual drugs is largely due to its particular affinity for protein binding sites
What is significant about plasma protein bound drugs in terms of movement out of the blood?
Only free are available to diffuse out of the blood and access tissues.
Therefore, any drug that’s bound to plasma proteins cannot leave the blood until it dissociates from protein
How do most drugs travel across capillary membranes unless very small and lipid soluble?
Carrier protein-mediated transport
What are the 4 main types of capillary structure?
- Continuous
- Blood brain barrier (BBB)
- Fenestrated
- Discontinuous
What type of structure do most capillaries in the body have?
Continuous
Describe the continuous structure of capillaries.
Endothelial cells aligned in single file with small gap junctions between them
What kind of drugs can diffuse across endothelial cells of a continuous-structured capillary to access the tissue?
Very lipid soluble drugs
How do most drugs travel across capillary membranes unless lipid soluble and/or small enough to pass through gap junctions?
Carrier protein-mediated transport
What does the blood brain barrier refer to?
The capillary structure in the brain where there is a ‘continuous’ structure, but with the addition of tight junctions between endothelial cells.
Why is the brain the most difficult tissue in the body for drugs to gain access to?
Why is this important?
The brain has the blood brain barrier.
This barrier comprises capillaries with a continuous structure and additional tight junctions between endothelial cells.
This is important as the brain has a vital physiological role.
Describe the discontinuous structure of capillaries.
Big gaps between capillary endothelial cells
Give an example of a tissue with a discontinuous capillary structure.
Liver
The liver has a discontinuous capillary structure. What does this allow?
The liver is highly metabolically active.
The discontinuous structure allows for drugs to easily diffuse out of the bloodstream and access the liver tissue.
Describe the fenestrated structure of capillaries.
What do fenestrations allow?
Fenestrations are circular windows within endothelial cells.
They allow passage of small molecular weight substances, inc. some drugs
Give an example of a tissue with a fenestrated capillary structure.
Kidney - glomerulus
The kidney glomeruli have a fenestrated capillary structure. What does this allow?
Kidney - key tissue involved in drug excretion
Fenestrations allow some small drugs to pass from blood to kidney tubules, enhancing the excretion of these drugs
How might a very lipid soluble drug diffuse into the brain from the blood?
A very lipid soluble drug will diffuse out of the blood and into the brain down its concentration gradient to produce its effects. Eventually an equilibrium is established between the blood and the brain
A very lipid soluble drug will diffuse out of the blood and into the brain down its concentration gradient to produce its effects. Eventually an equilibrium is established
A water-soluble drug could diffuse down its conc. gradient and into the brain also. An equilibrium will be established.
What will be the main difference between these two drugs (in terms of equilibrium and retention)?
The difference is the relative position of that equilibrium.
The brain has the higher fat content whereas the blood has the higher water content.
Therefore, the lipid-soluble drug is going to be more heavily weighted towards retention in the brain and the water-soluble drug is going to be more heavily weighted towards retention in the plasma.
–> A larger proportion of the lipid-soluble drug is going to be ‘localised’ in the brain compared with the water-soluble drug
The brain has a higher fat content whereas the blood has a higher water content.
With this knowledge, how will the tissue localisation of a lipid-soluble drug (in the brain) differ to that of a water-soluble drug?
A larger proportion of the lipid-soluble drug is going to be ‘localised’ in the brain compared with the water-soluble drug
What does metabolism involve and why?
The conversion of drugs to metabolites that are as water-soluble as possible and easier to excrete.
This is because drugs need to be at least partially lipid soluble for them to be absorbed and therapeutically effective.
However, their lipid solubility hinders their excretion. Metabolism helps deals with this issue.
What does the excretion of drugs prevent?
It prevents the innapropriate accumulation of drugs in the system to stop them from producing their effects.
For drugs to be properly excreted, what should their solubility ideally be like?
Low lipid-solublility
For drugs to be properly excreted, ideally they shouldn’t be particularly lipid soluble.
Why is this?
If this is the case:
- Would be more effectively retained in the blood so wouldn’t diffuse out of the blood and into tissues
- More drugs would be delivered to various excretion sites
What is the major metabolic tissue?
Liver
What is mainly responsible for drug metabolism within the liver?
Cytochrome P450 enzymes
What is mainly responsible for drug metabolism within the liver?
Cytochrome P450 enzymes
Drug metabolism involves 2 kinds of biochemical reaction.
What are the 2 main phases (aims) of drug metabolism?
Phase 1 - main aim is to introduce a reactive group to the drug
Phase 2 - main aim is to add a conjugate to the reactive group
What do the two phases of drug metabolism act together to do?
Decrease lipid solubility which then aids drug excretion and elimination
What is the aim of Phase 1 Metabolism?
To introduce reactive polar groups into their substrates
What are the 3 mechanisms by which Phase 1 metabolism reactions can occur?
Oxidation
Reduction
Hydrolysis
What is the most common form of Phase 1 metabolism reaction?
Oxidation
What step do all oxidation reactions start with in Phase 1 metabolism?
What is the aim?
Hydroxylation step using cytochrome P450 system
Aim - to incorporate oxygen into non-activated hydrocarbons
Phase 1 metabolism reactions will likely lead to the incorporation of one of 4 functional groups into the parent drug.
What are these 4 potential functional groups?
- OH
- COOD
- SH
- NH2
What may Phase 1 metabolism reactions unmask?
Existing functional groups
What is the general end result of Phase 1 metabolism?
The production of metabolites with functional groups
These functional groups serve as a point of attack for the conjugating systems of Phase 2
What family are Phase 1 metabolism enzymes predominantly apart of?
Cytochrome P450
Phase 1 metabolism often produces pharmacologically active drug metabolites.
Why is this significant?
Sometimes the parent drug has no activity of its own and only produces an effect once metabolised. In this case, the metabolite is the drug which will bring about an effect.
In other cases, active metabolites can have negative unintended effects
What are pro-drugs?
Drugs that need to be metabolised in order for them to have their pharmacological effect. The parent drug has no activity of its own.
Phase 1 metabolism often produces pharmacologically active drug metabolites.
Why is this significant in terms of paracetamol metabolism and the liver?
Sometimes, active metabolites can have negative side effects. Metabolism of paracetamol produces a metabolite that can cause liver damage in cases of paracetamol overdose.
Describe the properties of the resulting metabolite of Phase 2 metabolism.
- Almost always inactive
- Much less lipid-soluble than the phase 1 metabolite
The resulting metabolite of Phase 2 metabolism is always inactive and far less lipid-soluble than the phase 1 metabolite.
What does this facilitate?
This facilitates excretion in urine or bile
What type of enzymes are found in Phase 2 metabolism predominantly?
Why?
Phase 2 enzymes are predominantly transferases
These transfer substituent group onto phase 1 molecule
Below are some common reactions that can occur in Phase 2 metabolism to change the phase 1 metabolites to phase 2 metabolites.
What type of reactions have occurred in 1, 2 and 3?
- R-OH —-> R-GI
- R-SH —-> R-Ac
- R-NH2 —-> R-SO2H
- Glucuronidation
- Acetylation
- Sulfation
What is the aim of Phase 2 metabolism?
To attach a substituent group to the phase 1 metabolite
What is another name for First Pass Metabolism?
Pre-systemic Metabolism
What is another name for First Pass Metabolism?
Pre-systemic Metabolism
First pass hepatic metabolism
First pass metabolism is particularly a problem for drugs administered via what route?
Orally administered drugs
What route do orally administered drugs travel in order to reach the systemic circulation?
Predominantly absorbed from small intestine
Enter hepatic portal blood supply where they first pass through liver before reaching systemic circulation
At this point can be heavily metabolised
Orally administered drugs pass through the liver before reaching the systemic circulation.
How can this negatively affect their therapeutic effect?
Upon passing through the liver, OADs can be heavily metabolised. This then means that little active drug will reach the systemic circulation.
However, first pass metabolism is a pre-requisite for the activity of pro-drugs
First pass metabolism is a pre-requisite for which class of drugs?
Pro-drugs
How do we overcome the problem presented to orally administered drugs by first pass metabolism?
Administer larger dose of drug to ensure enough reaches systemic circulation
How do we overcome the problem presented to orally administered drugs by first pass metabolism in order to ensure enough drug reaches the systemic circulation?
Administer larger dose of drug to ensure enough reaches systemic circulation
In order to overcome the problem presented to orally administered drugs by first pass metabolism, we administer larger doses of drugs to ensure enough reaches systemic circulation.
However, the extent of first pass metabolism varies amongst individuals.
Why is this a problem?
As the extent of FPM varies between individuals, the amount of drug reaching the systemic circulation also varies. As a result, drug effects and side effects are difficult to predict.
There are a number of routes for drug excretion and elimination.
Give 2.
- Excretion via lungs - e.g. basis of alcohol breath test
- Excretion via breast milk
- Excretion via kidney - in urine
- Excretion via liver - in bile
What is the basis of the alcohol breath test?
To measure alcohol excreted via lungs
Why must lactating women be careful about what they drugs they’re taking if breastfeeding?
Drugs can be excreted in the breast milk - must take care that this does not negatively affect the baby
What are the 3 major routes for drug excretion via the kidney?
- Glomerular filtration
- Active tubular secretion (or reabsorption)
- Passive diffusion across tubular epithelium
Why does the excretion of different drugs vary greatly?
- The extent to which drugs use the three main processes involved in excretion via kidney (glomerular filtration, active tubular secretion, passive diffusion) differs hugely
- The rate of metabolism - phase 1 + 2 metabolism produce more water soluble metabolites that are easier to excrete
What does glomerular filtration allow?
Diffusion of drug molecules of molecular weight <20,000 into glomerular filtrate
This means that drugs with a molecular weight <20,000 have an additional route for excretion (glomerular filtration) vs larger drugs.
This should result in a quicker rate of excretion
What is the most important method for drug excretion in the kidney?
Why?
Active tubular secretion
Only 20% of renal plasma filtered at glomerulus
Remaining 80% passes to proximal tubule
Therefore, more drug delivered to PT than G
What proportion of renal plasma is filtered at the glomerulus?
20%
What proportion of renal plasma passes onto the blood supply to the proximal tubule?
80%
How many active transport carrier systems can be found within the proximal tubule capillary endothelial cells?
2
There are 2 active transport carrier systems can be found within the proximal tubule capillary endothelial cells.
What do these systems transport?
- Very effective at transporting acidic drugs
- Very effective at transporting basic drugs
Both capable of transporting drugs against a concentration gradient
What transport mechanism generally leads to reabsorption from the kidney tubule?
Passive diffusion
What proportion of filtered water is reabsorbed as the glomerular filtrate moves through the kidney?
99%
99% of filtered water is reabsorbed as the glomerular filtrate moves through the kidney.
What property of drugs will allow some of them to be reabsorbed also?
If drugs are particularly lipid-soluble they will also be reabsorbed, passively diffusing across the tubule and back into the blood
What 2 factors affect the extent of reabsorption?
Why?
- Drug metabolism
Phase 2 metabolites tend to be considerably more water-soluble than parent drug –> less well reabsorbed
- Urine pH - can vary from 4.5 - 8
Based on pH partition hypothesis:
- Acidic drugs better reabsorbed at lower pH
- Basic drugs better reabsorbed at higher pH
Drug A - an analgesic - 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?
Unionised drugs tend to retain more lipids and are more easily absorbed.
As drug A is acidic, it will become more ionised in an alkaline environment, reducing its solubility.
As a result, less of the drug will be reabsorbed in the kidney tubule and more will be excreted.
Therefore, the drug effect will be reduced due to this more effective secretion
Drug A - an analgesic - 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?
Unionised drugs tend to retain more lipids and are more easily absorbed.
As drug A is acidic, it will become more ionised in an alkaline environment, reducing its lipid-solubility.
As a result, less of the drug will be reabsorbed in the kidney tubule and more will be excreted.
Therefore, the drug effect will be reduced due to this more effective secretion
What are drugs transported to the bile excreted into before being eliminated in the faeces?
Intestines
What can enterohepatic recycling prolong?
Drug effect
Describe how a glucuronide metabolite that is transported into the bile can undergo enterohepatic recycling.
- A glucuronide metabolite is transported into bile.
- Metabolite = excreted into small intestine, where it’s hydrolysed by gut bacteria. The glucuronide conjugate is released.
- Loss of glucuronide conjugate —-> increases lipid solubility of molecule
- Increased lipid solubility —-> greater reabsorption from small intestine back into the hepatic portal blood system for return to the liver
- Molecule returns to the liver where a proportion will be re-metabolised, but some may escape into the systemic circulation to continue to have effects on the body
