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Pharmacology > Pharmacodynamics: Principles of Pharmacology > Flashcards

Pharmacodynamics: Principles of Pharmacology Flashcards

1
Q

What is the difference between pharmacology and therapeutics?

A

Pharmacology is more focused on the drugs but therapeutics is about drug prescribing and the treatment of disease (more focused on the patient)

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2
Q

What is the difference between pharmacodynamics and pharmacokinetics?

A

Pharmacodynamics deals with what the drug does to the body and pharmacokinetics deals with what the body does to the drug

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3
Q

What are the 3 main concepts to consider about drugs?

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?

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4
Q

Drugs have 1 effect each, true or false?

A

FALSE
Drugs can have more than 1 effect

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5
Q

Effects can be produced in different parts of the body, true or false?

A

TRUE

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6
Q

What are the classes of drug targets?

A
  1. Receptors
  2. Enzymes
  3. Ion channels
  4. Transport proteins
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7
Q

What is the ideal selectivity of a drug?

A

Drugs should ideally have a high selectivity

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8
Q

What is complete selectivity?

A

Where the drug only binds to 1 target
- ideal
- but difficult as drugs and chemicals are structurally similar

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9
Q

What is the link between selectivity and dose?

A
  • Where we have higher selectivity, we require lower doses of the drug (the effect seen is also more specific)
  • As the dose increases, the effect becomes less specific (drug starts to interact with other drug targets, and produces unwanted effects)
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10
Q

It is quite difficult to accurately predict how much drug might arrive at your specific drug target, true or false?

A

TRUE

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11
Q

What are the different chemical interactions that occur between drugs and their target receptors?

A
  1. Electrostatic interactions - this is the most common mechanism and includes hydrogen bonds and Van der Waals forces.
  2. Hydrophobic interactions - this is important for lipid soluble drugs.
  3. Covalent bonds - these are the least common as the interactions tend to be irreversible
  4. Stereospecific interactions - a great many drugs exist as stereoisomers and interact stereospecifically with receptors.
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12
Q

Describe the effect drug concentration has on the drug-receptor interactions

A

a. For a specific concentration of the drug, a specific number of drug receptor complexes are formed

drug + receptor <—> drug- receptor complex

b. If you were to increase the concentration of the drug, then the equilibrium is strongly shifted to the right- this is because there is more drug available to bind to free receptors

drug INCREASES, drug-receptor complex INCREASES

c. However, since this is a two-way reaction, if you were to dramatically reduce the amount of drug available, then more receptors would become available again due to the lower drug concentration. This shifts the equilibrium to the left

drug DECREASES, drug-receptor complex DECREASES

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13
Q

What are the 2 different ways a drug can interact with a receptor?

A
  1. As an agonist (“fits”/ binds to the receptor AND activates it)
    OR
  2. As an antagonist (binds but prevents activation)
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14
Q

Why can agonists bind and activate?

A

They can do this because of 2 properties:
- Affinity
- Efficacy

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15
Q

what does affinity tell use about a drug?

A

“Drugs with higher affinity, form stronger drug receptor complexes, and, so, you are more likely to find more of that drug bound to receptors”
WHY?
- The affinity of a drug determines strength of binding of the drug to the receptor
- Each individual drug receptor interaction is transient, with many interactions only lasting milliseconds
- at any given moment that particular drug molecule might be bound to a receptor, or it may have unbound and may currently be free with the potential to bind another receptor
- So if you have two drugs that could be added to the tissue (i.e. same number of receptors available), then the drug with the higher affinity will form stronger drug receptor complexes
- and thus at any given moment, it is more likely that more of this drug will be bound to receptors

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16
Q

What does efficacy tell us about a drug?

A

“The ability of an individual drug molecule to produce an effect once bound to a receptor”
It can produce
a. A complete response (would be considered a full agonist)
b. No response (would be considered a receptor antagonist)
c. A partial response (would be considered a partial agonist)

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17
Q

What is meant by potency?

A

“the concentration or dose of a drug required to produce a defined effect”

STANDARD MEASURE OF POTENCY:
to determine the concentration or dose of a drug required to produce a 50% tissue response. The standard nomenclature for this measure is the EC50 (Half maximal effective concentration or the ED50 (Half maximal effective dose)

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18
Q

What is the difference between EC50 and ED50?

A

EC50= the specific concentration that produced a 50% response
ED50= the dose of drug that produced a 50% response

NOTE: sometimes you cannot measure a 50% response (e.g. in individuals, what is a 50% improvement in breathlessness?), so instead you look for the conc/ dose that produce the desired effect in 50% of the individuals tested.

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19
Q

How does potency affect dose?

A

The less drug required to produce an effect, the more potent the drug is

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20
Q

What do we use to compare potency between drugs?

A

ED50

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21
Q

Potency is related to efficacy, true or false?

A

FALSE: potency is related to dose, not efficacy
- A highly potent drug produces a large response at relatively low concentrations.
- A highly efficacious drug can produce a maximal response and this effect is not particularly related to drug concentration.

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22
Q

What is the clinical 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.
- The 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.

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23
Q

In order for a drug to produce an effect, it must reach the relevant tissue in sufficient concentrations, true or false?

A

TRUE

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24
Q

What factors determine the amount of drug that will reach their target tissue?

A
  1. Absorption
  2. Distribution
  3. Metabolism
  4. Excretion
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25
Q

What is absorption?

A

Absorption can be defined as the passage of a drug from the site of administration into the plasma (deals with the process for drug transfer into the systemic circulation)

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26
Q

Another pharmacokinetic concept linked with absorption is bioavailability, what is meant by bioavailability?

A

Bioavailability is the fraction of the initial dose that gains access to the systemic circulation (deals with the outcome of drug transfer into the systemic circulation, i.e. how much)

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27
Q

what is a huge determinant of absorption and bioavailability?

A

Site of administration

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28
Q

What are the different forms of drug administation?

A
  1. Intra-venous
  2. Oral
  3. Inhalational
  4. Dermal (Percutaneous)
  5. Intra-nasal

(there are many more- no need to learn all)

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29
Q

Which form of drug administration results in full dose administration?

A

Intra-venous:
The process for drug passage is injecting the full dose straight into the circulation. The outcome if the full dose is administered straight into the circulation is that the bioavailability must be 100%.

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30
Q

Why do other forms of drug administration (other than IV) have bioavailability less than 100%?

A

Consider how drug molecules move around the body from the initial site of administration. Drugs can move around the body in two ways;

  1. Bulk flow transfer (i.e. in the bloodstream)
    or
  2. Diffusional transfer (i.e. molecule by molecule across short distances)
  • With regard to the intravenous route, the drug is injected straight into the bloodstream, and therefore bulk flow transfer will then deliver the drug to its intended site of action.
  • With all other routes of administration, in order for the drug to reach the bloodstream it is first going to need to diffuse across at least one lipid membrane.
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31
Q

What are the different mechanisms by which chemicals can diffuse across plasma membranes?

A
  1. Simple diffusion
  2. Diffusion across aqueous pores
  3. Carrier mediated transport
  4. Electrochemical gradient
32
Q

What is “pinocytosis”?

A

Another diffusion mechanism
- Small part of the cell membrane envelopes the chemical molecule & forms a vesicle containing the drug
- The vesicle can then release the chemical on the other side of the membrane

33
Q

Which of the diffusion processes are not particularly relevant for drugs?

A
  • Pinocytosis
  • Diffusion across aqueous pores ( Most pores are less than 0.5nm in diameter, and since there are very few drugs this small, there is little movement of drugs across this aqueous route.)
34
Q

What is required for drugs to be able to diffuse across lipid membranes?

A

Drugs need to be lipid soluble

35
Q

How are non-lipid soluble drugs transported across the plasma membrane?

A

Via carrier mediated transport:
- 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.
- In most cases drugs will diffuse from an area of high concentration to an area of low concentration, although transport proteins can transport drugs against a concentration gradient in some instances (a process called active transport that requires ATP).

36
Q

What is our aim for drugs in terms of lipid solubility?

A
  • We need drugs to be lipid soluble when we’re trying to absorb them- in order for the drug to get out of our blood, past the lipid bilayer (plasma membrane) and into the target tissue.
37
Q

What is the issue we face with most drugs in terms of lipid solubility?

A

Large majority of drugs tend to be more water soluble:
- Most drugs are given orally
- Need to be water soluble to dissolve in the aqueous environment of the gastrointestinal tract
- To be available for adsorption in the first place

38
Q

Drugs are either lipid soluble or are not lipid soluble, true or false?

A

FALSE:
lipid solubility is not an ‘all or nothing’ deal. Most drugs are either weak acids or weak bases. This means that these drugs will exist in two forms - ionised (charged) or unionised
- The unionised form of the drug retains more lipid solubility and is more likely to diffuse across plasma membranes.
- ionised is more polar

39
Q

What determines whether a drug is ionised or unionised?

A
  1. The dissociation constant (pKa)
  2. the pH in that particular part of the body

If the pH of solution is greater than the pKa, the group is in the conjugate base form (ionised). If the pH of solution is less than the pKa, the group is in the conjugate acid form (unionised).

40
Q

What is the relationship between pKa & pH, with ionisation of a drug?

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.

41
Q

If you have a weak acid, with a pKa of 3.5, what form will it be in a pH of 3.5?

A

when the pH is 3.5, it will be equally dissociated between the two forms.

42
Q

If you have a weak acid, with a pKa of 3.5, what form will it be in a pH of 2?

A

Unionised

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

43
Q

If you have a weak acid, with a pKa of 3.5, what form will it be in a pH of 6?

A

Ionised

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

44
Q

If you have a weak base, with a pKa of 8, what form will it be in a pH of 8?

A

it will be equally dissociated between the two forms

45
Q

If you have a weak base, with a pKa of 8, what form will it be in a pH of 2?

A

Ionised

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

46
Q

If you have a weak base, with a pKa of 8, what form will it be in a pH of 10?

A

Unionised

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

47
Q

a weak acid is going to be more unionised in areas of low pH like the stomach, true or false?

A

TRUE

48
Q

a weak base is going to be more unionised in areas of higher pH like the blood and urine, true or false?

A

TRUE

49
Q

weak bases would be trapped in the stomach and weak acids would be trapped in the blood, true or false?

A

FALSE: The concept of ‘ion trapping’ is very real, but as always there are ways around this
- A weak base will indeed be poorly absorbed from the stomach due to the low pH leading to a high drug ionisation. However, once the drug eventually reaches the small intestine, it will be able to access a huge number of transport proteins that will enable absorption from the gastrointestinal tract.
- Once again, however, most tissues possess transport proteins that could potentially move the ionised drug from the blood into the tissue.

50
Q

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

51
Q

Different tissues will be exposed to different amounts of the drug depending on, what?

A

Regional blood flow
Plasma protein binding
Capillary permeability
Tissue localisation

52
Q

What affect does regional blood flow have on drug distribution?

A
  • Different tissues receive differing amounts of the cardiac output
  • At rest the following tissues would receive the following percentage 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
  • The distribution of blood to tissues can increase or decrease depending on circumstance e.g during exercise more blood will be diverted to the muscles, whereas after a large meal more blood will be diverted to the stomach and intestines.
53
Q

What affect does plasma protein binding have on drug distribution?

A

Once drugs reach the systemic circulation, it is very common for them to bind to plasma proteins, the most important plasma protein in this regard is albumin, which is particularly good at binding acidic drugs.
- 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.

54
Q

What factors determine the amount of drug that is bound to plasma proteins?

A
  • The free drug concentration
  • The affinity for the protein binding sites
  • The plasma protein concentration
55
Q

There are times where the albumin in our body become fully saturated with drugs, true or false?

A

FALSE:
- If we only consider albumin (although there are other plasma proteins that bind drugs), the concentration of albumin in the blood is approximately 0.6mmol/l. Each albumin protein has two binding sites. As a result the binding capacity of albumin alone is 1.2mmol/l.
- The plasma concentration required for a clinical effect for nearly all drugs is considerably less than 1.2mmol/l
- Therefore, the plasma proteins are NEVER saturated with drugs.
- Therefore, differences in the extent of plasma protein binding for individual drugs is largely due to the particular affinity for the protein binding sites for that particular drug
- Acidic drugs bind particularly well to albumin and therefore tend to be more heavily plasma protein bound.

56
Q

What types of capillary structures can be found in the cardiovascular system?

A
  1. Continuous (with H20- filled gap junction)
  2. Blood brain barrier (tight junctions)
  3. Fenestrated
  4. Discontinuous
57
Q

Give an example of where different capillary structures are seen throughout the cardiovascular system

A
  1. Continuous:
    Most of the capillaries in the body have the ‘continuous’ structure illustrated here – endothelial cells aligned in single file with small gap junctions between the cells. If drugs are very lipid soluble then they can diffuse across the endothelial cell and access the tissue.
  2. Blood brain barrier:
    The ‘blood brain barrier’ refers to the capillary structure in the brain, where there is a ‘continuous’ structure, but with the addition of tight junctions between endothelial cells. This makes the brain the most difficult tissue in the body for drugs to gain access to – which makes sense, when you consider the critical physiological role of the brain.
  3. Discontinuous:
    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.
  4. Fenestrated:
    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.
58
Q

What affect does tissue localisation have on drug distribution?

A

Let’s consider a very lipid soluble substance like detla9-tetrahyrdrocannabinol (delta9-THC):
-delta9-THC will diffuse out of the blood down it’s concentration gradient and into the brain
-Eventually an equilibrium is established between the blood and the brain
-The brain has the higher fat content whereas the blood has the higher water content
- For delta9-THC the equilibrium is going to be more heavily weighted towards retention in the brain
- Similar concept for water soluble drugs- the equilibrium is going to be more heavily weighted towards retention in the plasma
- As a result, you can state that a larger proportion of delta9-THC is going to be ‘localised’ in the brain compared with the water soluble drug.

59
Q

What is the importance of drug metabolism?

A
  • In order to eliminate drugs from the body, there must be pathways for excretion
  • 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.
60
Q

What is the major metabolic tissue?

A

The liver:
Within the liver, it is mainly cytochrome P450 enzymes that are responsible for drug metabolism

61
Q

What 2 biochemical reactions are involved in drug metabolism?

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.

62
Q

Explain what happens during phase 1 of drug metabolism

A
  • Reactive polar groups are added into the substrates
  • Can occur by oxidation, reduction and hydrolysis
  • The end result of phase 1 metabolism is to produce metabolites with functional groups that serve as a point of attack for the conjugating systems of phase 2
  • In some instances, the parent drug has no activity of its own, and will only produce an effect once it has been metabolized to the respective metabolite – these drugs are known as pro-drugs.
  • In this case, metabolism is required for the pharmacological effect
  • But active metabolites can also have negative unintended effects
  • Liver damage as a result of paracetamol overdose, is due to a certain metabolite and NOT paracetamol itself.
63
Q

Explain what happens during phase 2 of drug metabolism

A
  • The result of phase 2 metabolism is the attachment of a substituent group, and the resulting metabolite is nearly always inactive and far less lipid soluble than the phase 1 metabolite- This facilitates excretion in the urine or bile.
64
Q

What is meant by first pass hepatic metabolism?

A
  • This is a particular problem for orally administered drugs.
  • Orally administered drugs are predominantly absorbed from the small intestine and enter the hepatic portal blood supply where they will first pass through the liver before they reach the systemic circulation.
  • At this point, the drug can be heavily metabolized and as a result, little active drug will reach the systemic circulation (although first pass metabolism is a prerequisite for activity of pro-drugs).
65
Q

How is the problem of First pass (presystemic) metabolism tackled?

A

Solution – administer a larger dose of drug to ensure enough drug reaches the systemic circulation.
Problem – the extent of first pass metabolism varies amongst individuals, and therefore the amount of drug reaching the systemic circulation also varies. As a result, drug effects and side effects are difficult to predict.

66
Q

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

A
  1. Glomerular filtration
  2. Active tubular secretion (or reabsorption)
  3. Passive diffusion across tubular epithelium
    - The extent to which drugs use these three processes differs enormously
    - Also impacted by the rate of metabolism – phase 1 and 2 metabolism produce more water soluble metabolites that are easier to excrete.
67
Q

How are drugs excreted via glomerular filtration?

A
  • Excretion via the glomerulus is dependent on size
  • Glomerular filtration allows drug molecules of molecular weight less than 20,000 to diffuse into the glomerular filtrate
  • Drugs with a molecular weight less than 20,000 have an additional route for excretion (glomerular filtration) compared with larger drugs
  • Results in a quicker rate of excretion.
68
Q

How are drugs excreted via active tubular secretion?

A
  • Dependent on available transporters
  • Active tubular secretion is the most important method for drug excretion in the kidney
  • 80% of the renal plasma passes onto the blood supply to the proximal tubule, therefore, more drug is delivered to the proximal tubule than the glomerulus
  • Within the proximal tubule capillary endothelial cells are two active transport carrier systems.
  • One is very effective at transporting acidic drugs and one is very effective at transporting basic drugs.
  • Both are quite capable of transporting drugs against a concentration gradient.
69
Q

How are drugs excreted via passive diffusion/ passive reabsorption?

A
  • Dependent on urine pH and extent of drug metabolism
  • Leads to reabsorption from the kidney tubule
  • If drugs are particularly lipid soluble, then they will also be reabsorbed, passively diffusing across the tubule back into the blood.
  • The factors that will influence the extend of reabsorption:
    1. Drug metabolism – phase 2 metabolites tend to be considerably more water soluble than the parent drug and are therefore less well reabsorbed.
    2. Urine pH – this can vary from 4.5-8. Based on the pH partition hypothesis mentioned previously, acidic drugs will be better reabsorbed at lower pH and basic drugs will be better reabsorbed at higher pH.
70
Q

How are drugs excreted via biliary excretion?

A
  • Another major (less than the kidney) route of excretion is via the bile. Liver cells transport some drugs from plasma to bile – primarily via transporters
  • This system is particularly effective at removing phase 2 glucuronide metabolites.
  • Drugs transported to the bile are then excreted into the intestines and will be eliminated in the faeces.
  • However, a process called enterohepatic recycling can take place which can significantly prolong drug effect
71
Q

Describe enterohepatic recycling

A
  1. A glucuronide metabolite is transported into the bile.
  2. The metabolite is excreted into the small intestine, where it is hydrolysed by gut bacteria releasing the glucuronide conjugate.
  3. Loss of the glucuronide conjugate increases the lipid solubility of the molecule.
  4. Increased lipid solubility allows for greater reabsorption from small intestine back into the hepatic portal blood system for return to the liver.
  5. The molecule returns to the liver where a proportion will be re-metabolised, but a proportion may escape into the systemic circulation to continue to have effects on the body.
72
Q

What is meant by the term “clearance”?

A

Clearance is the measure of the ability of the body to eliminate a drug
- Clearance by means of various organs of elimination is addictive
- Elimination of drug may occur as a result of processes that occur in the liver, kidney and other organs

73
Q

What is meant by the term “Elimination half-life”?

A

Elimination half- life is the length of time required for the concentration of a particular drug to decrease to half of its starting dose in the body

74
Q

What is meant by “time to peak plasma levels”

A

Time to peak concentration is the time required for a drug to reach peak concentration in plasma.
- The faster the absorption rate, the lower is the time to peak plasma concentration

75
Q

What is a “pro drug”?

A
  • Drug that is inactive before metabolism
76
Q

What is an “active drug”?

A
  • Drug that takes effect directly

Pharmacology (7 decks)

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