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Phase 1b - Pharmacology & Therapeutics > Principles of Pharmacology > Flashcards

Principles of Pharmacology Flashcards

1
Q

What are the 4 different drug target types?

A
  • Receptors
  • Enzymes
  • Ion channels
  • Transport protein
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2
Q

Define selectivity.

A

If we want to see a selective effect, then it is important that the drug (the key in this analogy) only binds to one target (the lock in this analogy).

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3
Q

Why is drug dose important?

A

Different effects at different dosages, depending on how selective a drug is.

Using Pergolide (drug used in the treatment of Parkinson’s disease) as an example.
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4
Q

What are the 4 different drug receptor chemical interactions?

A
  • Electrostatic interaction (i.e. Hydrogen bonds & Van der Waalss forces)
  • Hydrophobic interactions (importabt for lipid soluble drugs)
  • Covalent bonds (usually irreversible interactions)
  • Stereospecific interactions
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5
Q

What are the 4 classes of drug interactions?

A
  • Antagonists
  • Partial agonists
  • Full agonists
  • Reverse agonists
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6
Q

What are antagonists?

A
  • It has affinity for the receptor but no efficacy. When bound to the receptor, it is effectively blocking the receptor and preventing an agonist from binding to the receptor and inducing activation.
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7
Q

What are partial agonists?

A
  • It has the affinity for the receptor and sub-maximal efficacy. When bound to the receptor, it can produce a partial response, but cannot induce the maximal response from the receptor.
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8
Q

What are full agonists?

A
  • It has affinity for the receptor and maximal efficacy. When bound to the receptor, it can produce the maximal response expected from the receptor.
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9
Q

Define potency.

A

The concentration or dose of a drug required to produce a defined effect.

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10
Q

What is EC50?

A

Half maximal effective concentration

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11
Q

What is ED50?

A

Half maximal effective dose

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12
Q

What are the 4 major forms of drug absorption?

A
  • Oral
  • Inhalational
  • Dermal (Percutaneous)
  • Intra-nasal
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13
Q

How can drugs move around the body?

A
  • Bulk flow transfer (i.e. in the bloodstream)
  • Diffusional transfer (i.e. molecule by molecule across short distances)
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14
Q

What does drug distribution depend on?

A
  • Regional blood flow
  • Plasma protein binding
  • Capillary permeability
  • Tissue localisation
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15
Q

How does regional blood flow affect drug distribution?

A

Different tissues receive differing amounts of the cardiac output.

Liver – 27%
Heart– 4%
Brain – 14%
Kidneys – 22%
Muscles – 20%

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16
Q

What does the amount of drug that is protein bound depend on?

A
  • The free drug concentration
  • The affinity for the protein binding sites
  • The plasma protein concentration

D (Free Drug) + P (Protein binding site) ↔ DP (Drug-protein binding site

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17
Q

How does capillary permeability affect drug distribution?

A

‘Discontinous’ – 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 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.

‘Fenestrated’ – 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 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 excretion of these drugs.

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18
Q

How does tissue localisation affect drug distribution?

A
  • Very lipid soluble substances will diffuse from an area of high concentration to an area of low concentration
  • Water soluble drug will diffuse from an area of high concentration to an area of low concentration
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19
Q

Why is drug metabolism important?

A

In order to eliminate drugs from the body, there must be pathways for excretion (we’ll deal with this in the last section). Without a process for excretion, drugs would circulate in the body eternally continuing to have an effect. In order for drugs to be effectively excreted, it would be ideal if drugs were not particularly lipid soluble. If this were the case, the drug 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. However, in terms of therapeutic effectiveness, we want drugs to be at least partially lipid soluble, so that they can easily access tissues to produce their effects.
As a result, the process of metabolism involves the conversion of drugs to metabolites that are as water soluble as possible and easier to excrete.

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20
Q

What are the 3 major routes for drug excretion via the kidney?

A
  • Glomerular filtration
  • Active tubular secretion (or reabsorption)
  • Passive diffusion across tubular epithelium
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21
Q

What is the non-kidney drug excretion method?

A

Biliary excretion

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22
Q

What are the 4 ways of diffusion?

A
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23
Q

How does pKa affect lipid solubility?

A
  • If the pKa of the drug and the pH of the tissue are equal, then the drug will be equally dissociated between the two forms i.e. 50% ionised and 50% unionised.
  • A weak acid is going to be more unionised in areas of low pH like the stomach and a weak base is going to be more unionised in areas of higher pH like the blood and urine.
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24
Q

Describe how drugs are excreted via active tubular secretion from the kidney.

A
  • 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
  • Two active transport carrier systems in proximal tubule capillary endothelial cells
    • One effective at transporting acidic drugs
    • One effective at transporting basic drugs
      • Both are quite capable of transporting drugs against a concentration gradient
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25
Q

Describe how drugs are excreted via glomerular filtration from the kidney.

A
  • Allows drug molecules of molecular weight less than 20,000 Daltons to diffuse into the glomerular filtrate
    -> quicker rate of excretion
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26
Q

Describe how drugs are excreted via passive diffusion from the kidney.

A
  • Generally leads to reabsorption from the kidney tubule
  • Dependent on:
    • Drug metabolism (drugs more water soluble less well reasborbed)
    • Urine pH (acidic drugs better reabsorbed at lower pH, basic at higher pH)

pH partition hypothesis

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27
Q

How are drugs excreted through the biliary system?

A
  • Transported to the bile then excreted into the intestines and eliminated in the faeces
Particularly effective at removing phase 2 glucuronide metabolites
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28
Q

How does capillary permeability influence drug distribution?

A
  • Most of the capillaries in the body have the ‘continuous’ structure
    • 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
    • Less lipid soluble need carrier proteins
29
Q

How does plasma protein binding influence drug distribution?

A
  • Common for drugs to bind to plasma proteins
  • Amount of drug that is bound depends on three factors:
    • The free drug concentration
    • The affinity for the protein binding sites
    • The plasma protein concentration

The most important plasma protein in this regard is albumin, which is particularly good at binding acidic drugs. The binding capacity of albumin alone is 1.2mmol/l. The plasma concentration for nearly all drugs is considerably less than 1.2mmol/l

D (Free Drug) + P (Protein binding site) ↔ DP (Drug-protein binding site)

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.

30
Q

How does regional blood flow influence drug distribution?

A
  • Different tissues receive differing amounts of the cardiac output:
    • Liver 27%
    • Heart 4%
    • Brain 14%
    • Kidneys 22%
    • Muscles 20%

More drug will be distributed to those tissues that receive most blood flow

31
Q

How does tissue localisation influence drug distribution?

A
  • Eventually an equilibrium is established between the blood and the brain with both lipid and water soluble drugs
  • However the brain has a higher fat content, and the blood has a higher water content
    • Eq is more heavily towards retention in brain for lipid soluble
    • Eq is more heavily towards retention in plasma for water soluble
32
Q

In terms of pharmacokinetics, where are the most important carrier systems relating to drug action found?

A
  1. Renal tubule
  2. Biliary tract
  3. Blood brain barrier
  4. Gastrointestinal tract

These particular carrier systems are responsible for drug access to the bloodstream (absorption from the GI tract), for drug access to certain tissues (absorption across the blood brain barrier) and excretion of drugs from the body (from the kidney)

33
Q

What are pro-drugs?

A
  • Parent drug has no activity of its own, and will only produce an effect once it has been metabolized to the respective metabolite

Metabolism is required for the pharmacological effect

34
Q

What are some major pharmacokinetic factors? (4)

A
  • Absorption
  • Distribution
  • Metabolism
  • Excretion

Pharmacokinetics: what the body does to the drug

35
Q

What are the pharmacodynamics of cocaine?

A
  1. Affects the dopaminergic neurons in the nucleus accumbens
  2. Dopamine reuptake protein on the pre-synaptic terminal
  3. Cocaine blocks the dopamine reuptake protein
    * This means that dopamine is not removed from the synapse as quickly, and is thus more available to bind to the dopamine (D1) receptor. Activation of this receptor is what causes euphoria
36
Q

What are two key properties of agonists?

A
  • Affinity
  • Efficacy
37
Q

What determines whether a drug is unionised or not?

A
  • The dissociation constant (pKa) for that drug
  • The pH in that particular part of the body

If the pKa of the drug and the pH of the tissue are equal, then the drug will be equally dissociated between the two forms i.e. 50% ionised and 50% unionised

For weak acids, as the pH decreases, the unionised form starts to dominate. As the pH increases, the ionised form starts to dominate.

For weak bases, as the pH decreases, the ionised form starts to dominate. As the pH increases, the unionised form starts to dominate.

As a result, a weak acid is going to be more unionised in areas of low pH like the stomach and a weak base is going to be more unionised in areas of higher pH like the blood and urine.

38
Q

What does drug metabolism involve?

A
  • The conversion of drugs to metabolites that are as water soluble as possible and easier to excrete
39
Q

What factors are important to consider when thinking of pharmacodynamics?

A
  • Where is this effect produced?
  • What is the target for the drug?
  • What is the response that is produced after interaction with this target?
40
Q

What is a discontinuous capillary structure?

A
  • 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
41
Q

What is a fenestrated capillary structure?

A

Glomerulus of the kidney
* Fenestrations allow for passage of small molecular weight substances including some drugs. This allows some small drugs to pass from blood to kidney tubules which will enhance excretion of these drugs.

42
Q

What is a huge determinant of absorption and bioavailability?

A

Site of administration

Intra-venous: injecting the full dose straight into the circulation, bioavailability must be 100%

Some other examples: Oral, Inhalational, Dermal (Percutaneous), Intra-nasal

43
Q

What is absorption with regard to pharmacokinetics?

A
  • The passage of a drug from the site of administration into the plasma
44
Q

What is bioavailability?

A
  • The fraction of the initial dose that gains access to the systemic circulation
45
Q

What is enterohepatic recycling? (5)

Use Drug-Glucuronide metabolite as an example

A
  1. Glucuronide metabolite transported into bile
  2. Metabolite 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
  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
46
Q

What is first pass hepatic metabolism?

A
  • Orally administered drugs predominantly absorbed from the small intestine
    • Enter hepatic portal blood supply
    • Pass through liver before they reach the systemic circulation
  • Drug can be heavily metabolized
    • Little active drug will reach the systemic circulation

Although first pass metabolism is a prerequisite for activity of prodrugs

47
Q

What is maximal efficacy?

A
  • Full agonist
    • When bound to the receptor, it can produce the maximal response expected from that receptor
48
Q

What is one major issue concerning first pass metabolism?

A
  • Varies amongst individuals
    • Amount of drug reaching the systemic circulation varies
    • Drug effects and side effects difficult to predict

CYP450 enzyme activity is heavily genetically determined

49
Q

What is pharmacodynamics?

A

What the drug does to the body

50
Q

What is pharmacokinetics?

A

What the body does to the drug

51
Q

What is pharmacology?

A
  • The study of how a drug interacts with living organisms and how this influences physiological functions
52
Q

What is pinocytosis?

A
  • A small part of the cell membrane enveloping the chemical molecule and forming a vesicle containing the drug
  • Vesicle can then release the chemical on the other side of the membrane
Whilst this is relevant for some molecules e.g. insulin access to the brain, it is rarely used to transport drugs
53
Q

What is sub-maximal efficacy?

A
  • Acts as a partial agonist
    • When bound to the receptor, it can produce a partial response, but cannot induce the maximal response from that receptor
54
Q

What is the affinity of a drug?

A
  • Determines strength of binding of the drug to the receptor

  • The strength of each drug-receptor complex is determined by the affinity of the drug. As a result, affinity is strongly linked to receptor occupancy
55
Q

What is the clinical relevance of the difference between potency and efficacy?

A

Efficacy is more important
* You want to know if the drug you are giving can induce a maximal response
* Potency simply determines the dose that you will need to administer to produce a response

  • If you have two drugs that have equal efficacy, then it doesn’t really matter if one is more potent than the other, since you can still produce the maximal response with the less potent drug – you just need to administer a slightly higher concentration
56
Q

What is the difference between absorption and bioavailability?

A
  • Absorption deals with the process for drug transfer into the systemic circulation, whereas bioavailability deals with the outcome of drug transfer into the systemic circulation
57
Q

What is the difference between agonists and antagonists?

A
  • Both agonists and antagonists possess the ability to bind to receptors, but only agonists can bind and activate receptors

  • An agonist can fit into the lock (receptor) and open (activate) the receptor, whereas antagonists can fit in the lock (receptor) but would jam the mechanism and prevent the lock from being opened (activated)
58
Q

What is the difference between EC50 and ED50?

A
  • The concentration that produced a 50% response would be the EC50 in an in vitro lung tissue is EC50
  • The dose of drug that produced the desired effect in 50% of the individuals tested is ED50

  • You would give individuals a specific ‘dose’ of the drug to test effectiveness. It is very difficult to determine a 50% response in one individual (what is a 50% improvement in breathlessness?)
59
Q

What is the efficacy of a drug?

A
  • Refers to the ability of an individual drug molecule to produce an effect once bound to a receptor

  • When a drug occupies a receptor, it does not necessarily produce one standard unit of response
  • It may produce a complete response, or no response, or some partial response
  • A highly efficacious drug can produce a maximal response and this effect is not particularly related to drug concentration
60
Q

What is the importance of lipid solubility for drugs?

A

A large majority of drugs tend to be more water soluble than lipid soluble
* Need to be water soluble to dissolve in the aqueous environment of the GI tract
* Most drugs are either weak acids or weak bases. This means that these drugs will exist in two forms - ionised or unionised.

61
Q

What is the lock and key hypothesis?

A
  • It is important that the drug (the key in this analogy) only binds to one target (the lock in this analogy)

  • A lot of drugs and chemicals are structurally quite similar, and therefore it is very difficult to design a drug that has complete selectivity
  • The dopamine receptor is the most specific receptor for dopamine, but serotonin receptors and adrenergic receptors have some degree of specificity for dopamine
62
Q

What is the major metabolic tissue in the body?

A

Liver

Mainly cytochrome P450 enzymes responsible for drug metabolism

63
Q

What is the most difficult tissue in the body for drugs to gain access to?

A
  • The ‘blood brain barrier’ has a ‘continuous’ structure, but with the addition of tight junctions between endothelial cells
64
Q

What is the potency of a drug?

A
  • The concentration or dose of a drug required to produce a defined effect

  • The standard measure of potency is to determine the concentration or dose of a drug required to produce a 50% tissue response
  • EC50 (Half maximal effective concentration) or the ED50 (Half maximal effective dose)
  • A highly potent drug produces a large response at relatively low concentrations
65
Q

What is the solution to the first pass hepatic metabolism?

A
  • Administer a larger dose of drug to ensure enough drug reaches the systemic circulation
66
Q

What kinds of biochemical reactions does drug metabolism involve?

A
  • 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
Both stages together act to decrease lipid solubility which then aids excretion and elimination
67
Q

What occurs in phase 1 drug metabolism?

A

Introduce reactive polar groups into their substrates
* Oxidation (most common)
* Reduction
* Hydrolysis

Both stages together act to decrease lipid solubility which then aids excretion and elimination
68
Q

What occurs in phase 2 drug metabolism?

A

Attachment of a substituent group
* Resulting metabolite is nearly always inactive and far less lipid soluble than the phase 1 metabolite

Facilitates excretion in the urine or bile

Whereas the phase 1 enzymes are predominantly part of the cytochrome p450 family, the phase 2 enzymes are predominantly transferases to transfer the substituent group onto the phase 1 metabolite
Gluthiaone conjugation onto oxidised electrophiles
glucoronidation, acetylation or sulfation onto nucleophiles (reduced or hydrolysed)

68
Q

Why is the bioavailability likely to be less than 100%?

A
  1. Bulk flow transfer (ie in bloodstream)
  2. Diffusional transfer

  • Bulk flow transfer delivers the drug to its intended site of action
  • In order for the drug to reach the bloodstream it is first going to need to diffuse across at least one lipid membrane (not in intra-venous)

Phase 1b - Pharmacology & Therapeutics (12 decks)

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