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YEAR 1 - Physiology and Pharmacology (Anton) > 4. Principles Of Drug (& Hormone) Action (TT) > Flashcards

4. Principles Of Drug (& Hormone) Action (TT) Flashcards

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.

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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
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3
Q

Describe the different stages of oxidation of a saturated hydrocarbon.

A

Each of these is more oxidised than the previous.

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4
Q

What is the oxidised form of this aromatic ring?

A
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5
Q

What are two important forms of conjugation reactions in metabolism?

A

Formation of:

  • Esters
  • Amides
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6
Q

What things react to make an ester? Give an example.

A

Acid + Alcohol

Example: Acetic acid + Choline -> Acetylcholine

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7
Q

What things react to make an amide? Give an example.

A

Acid + Amine

Example: Arachidonic acid + Ethanolamine -> Anandamide

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8
Q

What is the name for the reaction when you form or break an ester or amide bond?

A

Formation: Conjugation

Breaking: Hydrolysis

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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
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10
Q

What is physiological pH? [IMPORTANT]

A

7.4

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11
Q

What is the name for the ionised form of a carboxylic acid?

A

Carboxylate ion

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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
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13
Q

What is the ionised form of an amine?

A
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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
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15
Q

What happens when you place a base in water?

A

It becomes basic since it gains protons that it can then donate.

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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.

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17
Q

What is the size limit for glomerular filtration?

A

Around 20 kDa.

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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
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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.

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20
Q

Give an example of a drug that is secreted into the tubular fluid (not by glomerular filtration).

A

Penicillin

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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).
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22
Q

Summarise the goal of drug metabolism.

A

Conversion of toxic, lipophilic compounds to polar, more water-soluble derivatives for excretion.

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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.

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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
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25
Q

What reaction type do monoamine oxidases (MAO) carry out?

A

Oxidative deamination

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26
Q

What functional group changes do monoamine oxidases (MAO) catalyse?

A

From amine to aldehyde.

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27
Q

What type of reaction is catalysed by monoamine oxidases (MAO)?

A

Oxidation

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28
Q

Draw an example reaction catalysed by monoamine oxidases (MAO). What are the reactants and products?

A

Amine -> Aldehyde + NH3

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29
Q

What are the main reactions that cytochrome P450s catalyse?

A
  • Mostly hydroxylation (replacing C-H with C-O, as in the conversion from hydeocarbon to alcohol)
  • N-, O- & S- dealkylations
  • N-oxidation & deamination
  • Dehalogenation
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30
Q

Draw an example hydroxylation of aliphatic hydrocarbons by cytochrome P450s.

A
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31
Q

Draw an example hydroxylation of aromatic hydrocarbons by cytochrome P450s.

A
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32
Q

What are the different types of cytochrome P450 enzymes? What type of molecule does each metabolise?

A
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33
Q

What molecule is this?

A

Paracetamol

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34
Q

Describe the mechanism for the toxicity of paracetamol in overdose.

A
  • 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
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35
Q

What can be given to reverse paracetamol poisoning?

A

N-acetylcystein

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36
Q

Are cytochrome P450s constitutive or inducible?

A

Inducible

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37
Q

Draw a diagram to show how induction of cytochrome P450s happens.

A
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38
Q

Give an example of a drug interaction that can arise in the cytochrome P450 system.

A
  • 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
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39
Q

What are some of the different molecules that drugs can be conjugated with in phase II of drug metabolism?

A
  • Glucuronic acid
  • Glycine
  • Glutathione
  • Sulfate
  • Methyl group
  • Acetyl group
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40
Q

What is the main purpose of conjugation of drugs with methyl and acetyl groups in phase II metabolism?

A

Inactivation of function (rather than increase in polarity, as is usually the case)

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41
Q

What thing can stop (even small) drugs from being freely filtered via glomerular filtration?

A

If they are conjugated with albumin.

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42
Q

Draw a graph of the plasma concentration of a drug after a single oral dose is administered.

A
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43
Q

On this graph, show how the therapeutic window might be represented.

A
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44
Q

What is the therapeutic window?

A

The range of drug dosages which can treat disease effectively without having toxic effects.

45
Q

What can the therapeutic window be defined as, mathematically?

A

Therapeutic window = Lethal dose / Therapeutic dose

(Where the therapeutic dose is the lowest possible drug dose that is effective)

46
Q

What is LD50?

A

It is lethal dose of a drug for 50% of the population.

47
Q

What is ED50?

A

The minimum effective dose of a drug for 50% of the population.

(NOTE: This is different from the EC50!)

48
Q

What is the therapeutic index of a drug?

A
  • 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
Q

What is NOAEL and why is it used?

A
  • 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
Q

What are the units for ED50 and LD50?

A

mg/L usually.

51
Q

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?

A
  • 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
Q

What is the significance of a narrow therapeutic window?

A

You have to be very careful to carefully dose the drug you are administering.

53
Q

What are the three main factors that influence the rate at which a drug is absorbed?

A
  1. Chemical nature of compound
    • Charge
    • Lipophilicity
    • Size
  2. Route of administration
  3. Formulation
    • Fast vs Slow release (coating)
54
Q

What are the main chemical features of a drug that influence the rate at which it is absorbed?

A
  • Charge
  • Lipophilicity
  • Size
55
Q

Are charged or uncharged drugs absorbed more quickly and why?

A

Uncharged, because they can cross membranes more easily.

56
Q

Compare in which environments acidic and basic drugs are charged.

A
  • Acidic drugs (e.g. -COOH) are charged in a basic environment
  • Basic drugs (e.g. -NH3) are charged in an acidic environment
57
Q

Aspirin has a carboxylic acid group (-COOH). How can you prolong or reduce the duration of action?

A
  • 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
Q

Write the equation for the equilibrium between an ionised and unionised acidic drug.

A

HA + H2O ↔ H3O+ + A

59
Q

Write the Henderson-Hasselbalch equation for acids. [IMPORTANT]

A

pH = pKa + log([A-]/[HA])

60
Q

Write the Henderson-Hasselbalch equation for basic drugs.

A

pH = pKb + log([B]/[BH+])

61
Q

Derive the Henderson-Hasselbalch equation for acidic drugs.

62
Q

Why is the Henderson-Hasselbalch clinically relevant?

A

It helps you to calculate the percentage of ionised and unionised drug in the stomach, which is relevant to absorption.

63
Q

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?

A
  • 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
Q

What is bioavailability?

A

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
Q

How does size of a drug affect bioavailability?

A

Smaller drugs have a higher bioavailability.

66
Q

How does lipophilicity affect bioavailability and why?

A
  • 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
Q

What is a measure of the lipophilicity of a drug and how can this be calculated?

A
  • 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
Q

Draw a graph of permeability of a drug in a membrane against logP.

69
Q

What are some routes of drug administration from fastest to slowest?

A
  • 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
Q

Give an example of a physical barrier that might be important in drug administration.

A

Blood-brain barrier

71
Q

Give some examples of how the formulation of a drug can affect its action.

A
  • 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
Q

What is drug distribution?

A

How drugs equilibrate within the body after entering the systemic circulation.

73
Q

Describe how the distribution of a drug changes after administration.

A
  • 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
Q

Why is it important to consider the distribution of a drug?

A
  • 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
Q

Why might samples of hair be taken in a drug test?

A

In the long-term, the drug may be distributed in fat stores at the base of the hair.

76
Q

How can drug-drug interactions occur with relevance to binding proteins in the plasma?

A
  • 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
Q

Name some situations in which a drug may not be distributed.

A
  • 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
Q

What are some of the implications of a drug being distributed to fat?

A
  • Decreases the initial free concentration
  • Slows distribution to other sites
  • Slows clearance
  • Prolongs duration of action
79
Q

What is volume of distribution of a drug? [IMPORTANT]

A

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
Q

What is the equation for volume of distribution?

A

Vd = Dose / Concentration of drug in blood

81
Q

For a drug dose of 60mg that produces a blood drug concentration of 12mg/L, what is the volume of distribution?

A

60 / 12 = 5L

82
Q

For a drug dose of 60mg that produces a blood drug concentration of 0.3mg/L, what is the volume of distribution?

A

60 / 0.3 = 180L

83
Q

How can you explain a very high volume of distribution (e.g. 180L cannot be present within a person)?

A

It suggests that the drug is being compartmentalised so that the blood concentration is very low.

84
Q

What are the typical values for the percentage volume and absolute volume of water in a 70kg man?

A
  • 60% (50-80%)
  • 42L
85
Q

What are the typical values for the percentage volumes and absolute intracellular and extracellular volumes of water in a 70kg man?

A

Intracellular:

  • 40%
  • 28L

Extracellular:

  • 20%
  • 14L

Note: These add up to the 42L total water volume in a 70kg man.

86
Q

What are the typical values for the percentages volume and absolute blood and plasma volumes of water in a 70kg man?

A

Blood:

  • 8%
  • 5.5L

Plasma:

  • 4%
  • 3L
87
Q

The volume of distribution of a drug is 10L, what dose must be administered in order to achieve a plasma concentration of 100mg/L.

A
  • D = Vd x C
  • D = 10 x 100 = 1000mg/L
88
Q

What are the two arteries supplying the liver?

A
  • Common hepatic artery
  • Portal vein
89
Q

Write a general equation for the rate of elimination of a drug from the body.

A

dC/dt = -kCn

Where:

  • C = Concentration of drug
  • k = Constant
  • n = Order of reaction
90
Q

Write an equation for the rate of elimination of a drug from the body, for a zero order reaction.

A

dC/dt = -k

91
Q

Write an equation for the rate of elimination of a drug from the body, for a first order reaction.

A

dC/dt = -kC

92
Q

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.

A

C = -kt + A

Where:

  • C = Concentration of drug
  • k = Constant
  • t = Time
  • A = Concentration of drug at t=0
93
Q

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.

A

C = Ae-kt

Where:

  • C = Concentration of drug
  • k = Constant
  • t = Time
  • A = Concentration of drug at t=0
94
Q

What is the half-life of a drug?

A

The time taken for half of the drug to be eliminated from the body,

95
Q

What is the symbol of half-life?

96
Q

Derive an equation for the half-life of a drug (for a first order reaction).

A
  • 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
Q

In roughly how many half-lives is a drug eliminated?

98
Q

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?

A
  • 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
Q

What are some factors governing the choice of route of administration of a drug?

A
  • 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
Q

Draw the graph for the plasma concentration of a drug which is administered at regular intervals.

101
Q

Draw the graph for the plasma concentration of a drug administered by continuous intravenous infusion.

102
Q

Give some examples of drugs that cannot be taken orally due to susceptibility to digestion. How can they be taken instead?

A
  • 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
Q

Describe how penicillin is lost in the urine and how this can be stopped.

A
  • 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
Q

What are the 5 methods of transport at the blood-brain barrier?

105
Q

Draw how L-DOPA reaches the brain. [EXTRA]

106
Q

Draw the structure of aspirin.

107
Q

Draw the metabolism of aspirin.

108
Q

Give some approximate normal concentration ranges for different molecules (e.g. antibodies, drugs, etc.) that can be found in the body.

YEAR 1 - Physiology and Pharmacology (Anton) (13 decks)

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