4. Principles Of Drug (& Hormone) Action (TT) Flashcards
(109 cards)
1
Q
When learning specific examples of drug metabolism, what is it important to do?
A
Note the chemical groups, etc. because this helps us generalise so that we can predict what will happen to an unknown drug if we are presented with it.
2
Q
What do the acronyms PD, PK and ADME stand for?
A
- PD -> Pharmacodynamics: what a drug does to the body
- PK -> Pharmacokinetics: what the body does to a drug
- ADME -> Absorption, distribution, metabolism & elimination
3
Q
Describe the different stages of oxidation of a saturated hydrocarbon.
A
Each of these is more oxidised than the previous.
4
Q
What is the oxidised form of this aromatic ring?
A
5
Q
What are two important forms of conjugation reactions in metabolism?
A
Formation of:
- Esters
- Amides
6
Q
What things react to make an ester? Give an example.
A
Acid + Alcohol
Example: Acetic acid + Choline -> Acetylcholine
7
Q
What things react to make an amide? Give an example.
A
Acid + Amine
Example: Arachidonic acid + Ethanolamine -> Anandamide
8
Q
What is the name for the reaction when you form or break an ester or amide bond?
A
Formation: Conjugation
Breaking: Hydrolysis
9
Q
What structure is this and what is interesting about it? [EXTRA]
A
- Arachidonic
- If unconjugated, it can go down a pathway that forms prostagladins and leads to inflammation, but if it is conjugated with ethanolamine to produce an amide it can bind to cannabinoid receptors producing bliss
10
Q
What is physiological pH? [IMPORTANT]
A
7.4
11
Q
What is the name for the ionised form of a carboxylic acid?
A
Carboxylate ion
12
Q
At physiological pH, which parts of an amino acid act as the base and which act as the acid?
A
It is sort of counter-intuitive:
- The amino part is the acid, because it can act as a proton donor
- The carboxylate group is the base, because it can act as a proton acceptor
13
Q
What is the ionised form of an amine?
A
14
Q
How does the R group of an amine affect the strength of the base?
A
- Aliphatic R chains can push electrons towards the nitrogen, making it more able to pick up a hydrogen, so it is a stronger base
- Aromatic R groups can do the opposite
15
Q
What happens when you place a base in water?
A
It becomes basic since it gains protons that it can then donate.
16
Q
What is the importance of drug polarity in drug metabolism?
A
Non-polar hydrophobic molecules diffuse across membranes much more easily than polar hydrophilic molecules.
17
Q
What is the size limit for glomerular filtration?
A
Around 20 kDa.
18
Q
Once a drug is filtered into the tubular fluid, what factors affect how well it is retained there?
A
Filtered drugs may be passively reabsorbed or trapped in urine according to:
- Lipid solubility
- Tendency to ionize
19
Q
Are most drugs passed into the tubular fluid by glomerular filtration?
A
No, most of them are actively secreted into the tubualr fluid via transporters.
20
Q
Give an example of a drug that is secreted into the tubular fluid (not by glomerular filtration).
A
Penicillin
21
Q
What are the two main types of carriers involved in secretion of drugs into the renal tubule?
A
- Basic carriers -> Transport basic drugs (amiloride, dopamine, histamine)
- Acidic carriers -> Transport acidic drugs (frusemide, penicillin, indomethacin).
22
Q
Summarise the goal of drug metabolism.
A
Conversion of toxic, lipophilic compounds to polar, more water-soluble derivatives for excretion.
23
Q
What are the two parts of drug metabolism and what happens in each?
A
Phase I:
Increases polarity of the drug by transforming or removing the functional groups.
Phase II:
Addition of endogenous compounds to the drug, further increasing polarity and preparing them for excretion.
24
Q
What are the main categories of enzymes that carry out oxidation in phase I of metabolism? When is each used?
A
- Specific monooxygenases -> Used to oxidise specific molecules
- Monoamine oxidase (MAO)
- Alcohol dehydrogenase
- General, mixed-function monooxygenases -> Used to metabolise everything else
- Cytochrome P450s
25
What reaction type do monoamine oxidases (MAO) carry out?
Oxidative deamination
26
What functional group changes do monoamine oxidases (MAO) catalyse?
From amine to aldehyde.
27
What type of reaction is catalysed by monoamine oxidases (MAO)?
Oxidation
28
Draw an example reaction catalysed by monoamine oxidases (MAO). What are the reactants and products?
Amine -\> Aldehyde + NH3
29
What are the main reactions that cytochrome P450s catalyse?
* Mostly hydroxylation (replacing C-H with C-O, as in the conversion from hydeocarbon to alcohol)
* N-, O- & S- dealkylations
* N-oxidation & deamination
* Dehalogenation
30
Draw an example hydroxylation of aliphatic hydrocarbons by cytochrome P450s.
31
Draw an example hydroxylation of aromatic hydrocarbons by cytochrome P450s.
32
What are the different types of cytochrome P450 enzymes? What type of molecule does each metabolise?
33
What molecule is this?
Paracetamol
34
Describe the mechanism for the toxicity of paracetamol in overdose.
* Paracetamol does not need to pass through phase I metabolism since it is already quite polar
* Therefore, 60% is conjugated to glucuronate (phase II)
* 30% is conjugated to sulfate (phase II)
* The remaining 10% pass through phase I metabolism by cytochromes CYP2E1:
* The resulting product can form N-acetyl-p-benzoquinoneimine
* This is a very reactive product that can react with sulfhydryl groups (-SH) that may be on proteins
* If this conjugation occurs on functional proteins in the liver, they can lose their function and toxicity can result
35
What can be given to reverse paracetamol poisoning?
N-acetylcystein
36
Are cytochrome P450s constitutive or inducible?
Inducible
37
Draw a diagram to show how induction of cytochrome P450s happens.
38
Give an example of a drug interaction that can arise in the cytochrome P450 system.
* Cytochrome CYP3A can be induced by carbamazapine, phenytoin and St John's Wort
* A side effect of this is that the metabolism of ethinylestradiol is also sped up
* This can result in a positive pregnancy test result
39
What are some of the different molecules that drugs can be conjugated with in phase II of drug metabolism?
* Glucuronic acid
* Glycine
* Glutathione
* Sulfate
* Methyl group
* Acetyl group
40
What is the main purpose of conjugation of drugs with methyl and acetyl groups in phase II metabolism?
Inactivation of function (rather than increase in polarity, as is usually the case)
41
What thing can stop (even small) drugs from being freely filtered via glomerular filtration?
If they are conjugated with albumin.
42
Draw a graph of the plasma concentration of a drug after a single oral dose is administered.
43
On this graph, show how the therapeutic window might be represented.
44
What is the therapeutic window?
The range of drug dosages which can treat disease effectively without having toxic effects.
45
What can the therapeutic window be defined as, mathematically?
Therapeutic window = Lethal dose / Therapeutic dose
(Where the therapeutic dose is the lowest possible drug dose that is effective)
46
What is LD50?
It is lethal dose of a drug for 50% of the population.
47
What is ED50?
The minimum effective dose of a drug for 50% of the population.
(NOTE: This is different from the EC50!)
48
What is the therapeutic index of a drug?
* Therapeutic index = LD50 / ED50
* It is therefore the ratio between the lethal dose for 50% of the population and the minimum effective dose for 50% of the population
49
What is NOAEL and why is it used?
* No-observed-adverse-effect level (NOAEL)
* It is the highest concentration of drug at which there are no extra adverse symptoms for the tested subjects
* It is used as an alternative to therapeutic window calculations since we cannot calculate
50
What are the units for ED50 and LD50?
mg/L usually.
51
Assuming that a single espresso containing 100mg of caffeine is the minimum required to produce a response in a man with 80L of water and that the toxic dose is around 28g for the same man, what is the therapeutic index?
* ED50 = 100 mg/80 L = 1.25 mg/L
* LD50 = 28000 mg/80 L = 350 mg/L
* Therapeutic index = 350/1.25 = 280
This means that a person needs to drink 280 espressos at once to die.
52
What is the significance of a narrow therapeutic window?
You have to be very careful to carefully dose the drug you are administering.
53
What are the three main factors that influence the rate at which a drug is absorbed?
1. Chemical nature of compound
* Charge
* Lipophilicity
* Size
2. Route of administration
3. Formulation
* Fast vs Slow release (coating)
54
What are the main chemical features of a drug that influence the rate at which it is absorbed?
* Charge
* Lipophilicity
* Size
55
Are charged or uncharged drugs absorbed more quickly and why?
Uncharged, because they can cross membranes more easily.
56
Compare in which environments acidic and basic drugs are charged.
* Acidic drugs (e.g. -COOH) are charged in a basic environment
* Basic drugs (e.g. -NH3) are charged in an acidic environment
57
Aspirin has a carboxylic acid group (-COOH). How can you prolong or reduce the duration of action?
* If you want a remove aspirin
* Take it with an agent that will alkalinize the urine (e.g. sodium bicarbonate)
* This will ionise the drug so that it cannot cross membranes and be reabsorbed from the urine
* If you want to extend its duration
* Acidify the urine (e.g. yoghurt)
* This will keep the drug unionised, so that it can be reabsorbed from the urine
58
Write the equation for the equilibrium between an ionised and unionised acidic drug.
HA + H2O ↔ H3O+ + A
59
Write the Henderson-Hasselbalch equation for acids. [IMPORTANT]
pH = pKa + log([A-]/[HA])
60
Write the Henderson-Hasselbalch equation for basic drugs.
pH = pKb + log([B]/[BH+])
61
Derive the Henderson-Hasselbalch equation for acidic drugs.
62
Why is the Henderson-Hasselbalch clinically relevant?
It helps you to calculate the percentage of ionised and unionised drug in the stomach, which is relevant to absorption.
63
Aspirin has a pKa of 3.5.
(i) Calculate the ratio of ionized/unionized of the drug in the stomach where pH is 1.
(ii) Based on these calculations, can aspirin absorbed from stomach?
* pH = pKa + log([A-]/[HA])
* 1 = 3.5 + log(ionised/unionised)
* ionised/unionised = 0.00316
* Therefore, for every 3 ionised there is around 1000 unionised
* So it is easily absorbed
64
What is bioavailability?
The proportion of a drug or other substance which enters the circulation when introduced into the body and so is able to have an active effect.
65
How does size of a drug affect bioavailability?
Smaller drugs have a higher bioavailability.
66
How does lipophilicity affect bioavailability and why?
* It increases as lipophilicity increases because the drug is more able to cross membrane bilayers
* However, this is only up to a point because after this the drug just stays at the site of administration
67
What is a measure of the lipophilicity of a drug and how can this be calculated?
* logP
* This can be calculated by shaking a drug in a mix of octane and water and seeing how the drug distributes between the layers
* P = Concentration of drug dissolved in octane / Concentration of drug dissolved in water
68
Draw a graph of permeability of a drug in a membrane against logP.
69
What are some routes of drug administration from fastest to slowest?
* Intravenous (e.g. vancomycin)
* Inhalation (salbutamol)
* Sublingual (under the tongue e.g. nitroglycerin)
* Orally (po) / Rectally (pr)
* Intramuscular (IM) / Subcutaneous (sc)
* Transcutaneous (across the skin)
70
Give an example of a physical barrier that might be important in drug administration.
Blood-brain barrier
71
Give some examples of how the formulation of a drug can affect its action.
* Liquids absorb faster than capsules
* Control release via adjusting particle size (i.e. grinding down crystals into a powder)
* Coating tables slows absorption and decreases local peak concentrations
* Differently soluble coatings allows controlled release
* Intramuscular injection of an oily depot (decanoate) of lipophilic drugs (eg. haloperidol) allows very slow release (eg. anti-psychotic drugs in noncompliant patients) -\> Can last weeks to months even
72
What is drug distribution?
How drugs equilibrate within the body after entering the systemic circulation.
73
Describe how the distribution of a drug changes after administration.
* The blood concentration rapidly falls
* First the drug passes into the brain and high-perfusion tissues
* Then the drug passes into low-perfusion tissues and finally fat
74
Why is it important to consider the distribution of a drug?
* In the long-term, the drug may remain in the fat and similar tissues, even if it has been cleared from the blood.
* Therefore, repeat administration can lead to accumulation in the fat, which can be toxic.
75
Why might samples of hair be taken in a drug test?
In the long-term, the drug may be distributed in fat stores at the base of the hair.
76
How can drug-drug interactions occur with relevance to binding proteins in the plasma?
* Drugs bind to plasma proteins preferrentially
* When these are saturated, they can bind to their receptors and elicit an effect
* If a second drug is started, it can outcompete the first drug for binding to the plasma proteins, so there is more of the first drug to bind to receptors -\> This can lead to toxicity
* If two drugs are being used simultaneously, stopping one drug can free up more spaces on the plasma proteins, meaning that the other drug binds to these more than its receptors -\> This can lead to reduced effect of the secon drug.
77
Name some situations in which a drug may not be distributed.
* Drugs binding to plasma proteins (e.g. heparin) -\> Don't leave circulation
* Drugs that are blocked by natural barriers such as the blood brain barrier and placenta -\> Remain in the blood
* Drugs that accumulate in cells
78
What are some of the implications of a drug being distributed to fat?
* Decreases the initial free concentration
* Slows distribution to other sites
* Slows clearance
* Prolongs duration of action
79
What is volume of distribution of a drug? [IMPORTANT]
The volume of fluid required to contain the total amount of drug in the body at the same concentration as that present in the plasma.
80
What is the equation for volume of distribution?
Vd = Dose / Concentration of drug in blood
81
For a drug dose of 60mg that produces a blood drug concentration of 12mg/L, what is the volume of distribution?
60 / 12 = 5L
82
For a drug dose of 60mg that produces a blood drug concentration of 0.3mg/L, what is the volume of distribution?
60 / 0.3 = 180L
83
How can you explain a very high volume of distribution (e.g. 180L cannot be present within a person)?
It suggests that the drug is being compartmentalised so that the blood concentration is very low.
84
What are the typical values for the percentage volume and absolute volume of water in a 70kg man?
* 60% (50-80%)
* 42L
85
What are the typical values for the percentage volumes and absolute intracellular and extracellular volumes of water in a 70kg man?
Intracellular:
* 40%
* 28L
Extracellular:
* 20%
* 14L
Note: These add up to the 42L total water volume in a 70kg man.
86
What are the typical values for the percentages volume and absolute blood and plasma volumes of water in a 70kg man?
Blood:
* 8%
* 5.5L
Plasma:
* 4%
* 3L
87
The volume of distribution of a drug is 10L, what dose must be administered in order to achieve a plasma concentration of 100mg/L.
* D = Vd x C
* D = 10 x 100 = 1000mg/L
88
What are the two arteries supplying the liver?
* Common hepatic artery
* Portal vein
89
Write a general equation for the rate of elimination of a drug from the body.
dC/dt = -kCn
Where:
* C = Concentration of drug
* k = Constant
* n = Order of reaction
90
Write an equation for the rate of elimination of a drug from the body, for a zero order reaction.
dC/dt = -k
91
Write an equation for the rate of elimination of a drug from the body, for a first order reaction.
dC/dt = -kC
92
For a zero order reaction of elimination of a drug from the body, write an equation for the concentration of the drug in the body at time t.
Draw a graph to show this clearance.
C = -kt + A
Where:
* C = Concentration of drug
* k = Constant
* t = Time
* A = Concentration of drug at t=0
93
For a first order reaction of elimination of a drug from the body, write an equation for the concentration of the drug in the body at time t.
Draw a graph to show this clearance.
C = Ae-kt
Where:
* C = Concentration of drug
* k = Constant
* t = Time
* A = Concentration of drug at t=0
94
What is the half-life of a drug?
The time taken for half of the drug to be eliminated from the body,
95
What is the symbol of half-life?
t1/2
96
Derive an equation for the half-life of a drug (for a first order reaction).
* C = Ae-kt
* After the first half-life, C = ½A
* ½ A = Ae-kt½
* ½ = e-kt½
* ln(½) = -kt½
* t½ = Ln(2)/k = .693/k
97
In roughly how many half-lives is a drug eliminated?
Around 6
98
What useful information can be found from a sloped straight line graph of ln(concentration of a drug) against time, showing elimination of the drug?
* Since the line is a sloped straight line, the not-logged reaction is first order curve
* This means that the equation C = Ae-kt has been converted to ln(C) = ln(A) - kt.
* Therefore, the gradient of the graph is equal to -k.
99
What are some factors governing the choice of route of administration of a drug?
* Rate of absorption of drug from the site of administration and transport to the site of action
* Desire to administer drug close to site of action
* Susceptibility of drug to degradation by digestion or metabolism
* Desired time-course of action
100
Draw the graph for the plasma concentration of a drug which is administered at regular intervals.
101
Draw the graph for the plasma concentration of a drug administered by continuous intravenous infusion.
102
Give some examples of drugs that cannot be taken orally due to susceptibility to digestion. How can they be taken instead?
* Drugs containing amide bonds (protein-like hormones)
* Insulin
* Oxytocin
* Antibodies (Herceptin)
* Growth hormone
* Drugs containing phosphodiester bonds
* siRNA
* Nucleotides
* Some types of penicillin (since they are susceptibility to stomach acid)
* Phenethylamine (the base of amphetamines)
They can be taken intravenously instead.
103
Describe how penicillin is lost in the urine and how this can be stopped.
* The majority of penicillin does not end up in the urine by glomerular filtration, but by tubular secretion
* This is an active process, which can be blocked by probenecid
* There is also passive reasborption from the tubule
104
What are the 5 methods of transport at the blood-brain barrier?
105
Draw how L-DOPA reaches the brain. [EXTRA]
106
Draw the structure of aspirin.
107
Draw the metabolism of aspirin.
108
Give some approximate normal concentration ranges for different molecules (e.g. antibodies, drugs, etc.) that can be found in the body.
109
