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BRS Year 2 > Principles Of Pharmacology > Flashcards

Principles Of Pharmacology Flashcards

1
Q

What is pharmacology?

A

The study of drug action

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2
Q

What is therapeutics?

A

Drug prescribing and treatment of disease

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3
Q

What is pharmacodynamics?

A

Understanding the effect of a drug on a patient

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4
Q

What questions do we need to consider in 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?

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5
Q

What are the classes of drug targets?

A

Receptors
Enzymes
Ion channels
Transport proteins

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6
Q

What is the target of aspirin?

A

Enzyme

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7
Q

What is the target for local anesthesia?

A

Ion channel

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8
Q

What is the target for prozac (anti-depressant)?

A

Transport protein

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9
Q

What is the target of nicotine?

A

Receptor

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10
Q

What is the importance of selectivity?

A

Many drugs and chemicals are similarly structured so we need to design a drug that is very selective

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11
Q

How are dopamine, serotonin and noradrenaline similar?

A

These three have high specificity for their specific receptors however they are specifically structured meaning they also have a degree of specificity for each others receptors which is a problem.

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12
Q

What is the importance of dose?

A

Different doses of a drug can affect its selectivity for its chosen target e.g. at a too low dose or too high dose it may bind to the wrong target

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13
Q

How does the effect of pergolide (parkinson’s disease treatment) change with does?

A

At a low dose, the drug is selective for a dopamine receptor which gives the wanted therapeutic effect.

As you increase the dose the drug becomes selective for the serotonin and adrenergic receptor which leads to hallucinations and hypotension respectively.

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14
Q

What are the 4 key drug-receptor interactions?

A

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

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15
Q

What’s the difference between antagonists and agonists?

A

Only agonists can bind and activate receptors

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16
Q

What is the affinity of a drug?

A

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

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17
Q

What is the efficacy of a drug?

A

This is the ability of an individual drug molecule to produce an effect once bound to a receptor.

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18
Q

What are three classes of drug interaction based on receptor efficacy?

A

Antagonists- doesn’t produce response so no efficacy
Partial agonists- partial efficacy
Agonists- full response so maximal efficacy

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19
Q

What is potency?

A

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

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20
Q

What is the standard measure of potency?

A

The standard measure of potency is to determine the concentration or dose of a drug required to produce a 50% tissue response

This is measured as EC50 (half maximal effective concentration) OR ED50 (half maximal effective dose)

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21
Q

How does potency link to dose?

A

The less drug you require to produce a desired effect, the more potent the drug is

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22
Q

How does efficacy link to potency?

A

Efficacy is more important- want to know if the drug can produce maximal response
Potency only determines the dose you will deliver the drug at to produce the response

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23
Q

What is pharmacokinetics?

A

Looks at what the body does to the drug?

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24
Q

What are the four important factors in pharmacokinetics?

A

Absorption
Distribution
Metabolism
Excretion

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25
Q

What is absorption?

A

The passage of drugs from the site of administration into the plasma

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26
Q

What is bioavailabilty?

A

The fraction of the initial dose that gains access to the systemic circulation

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27
Q

What drug passage ensures 100% bioavailability?

A

Intra-venous administration

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28
Q

What are the different forms of drug administration?

A 
Oral
Inhalation
Dermal (Percutaneous)
Intra-nasal
and many more!
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29
Q

How do drugs move around the body?

A
  1. Bulk flow transfer (e.g. bloodstream)

2. Diffusional transfer (molecule by molecule over short distance)

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30
Q

Why is bioavailability less than 100% for methods other than intravenous administration?

A

In order for drugs to reach the bloodstream they need to diffuse across at least one lipid membrane

31
Q

What is pinocytosis?

A

involves a small part of the cell membrane enveloping the chemical molecule and forming a vesicle containing the drug

32
Q

How do most drugs move across membrane?

A

Either by diffusing across lipid membranes ( need to be lipid soluble)
Or by carrier mediated transport- transmembrane proteins are involved

33
Q

What are the different ways of a drug crossing a membrane?

A

Pinocytosis
Diffusion across aqueous pores (uncommon since pores are too small)
Diffusion across lipid membrane
Carrier mediated transport

34
Q

Are most drugs water soluble or lipid soluble, and why?

A

Water soluble because most oral drugs need to be water soluble to dissolve into the aqueous environment of the gastrointestinal tract

35
Q

How can drugs be categorized based on acidity?

A

Most drugs are either weak acids or weak bases. This means that these drugs will exist in two forms - ionised or unionised.

36
Q

What is the ionisation of aspirin?

A

Aspirin is a weak acid. In ionised state it will donate protons

37
Q

What is the ionisation of morphine?

A

Morphine is a weak base. In it’s ionised state it will accept protons

38
Q

What is the relationship between ionisation and lipid solubility?

A

The unionised form of the drug retains more lipid solubility and is more likely to diffuse across plasma membranes

39
Q

What does drug ionisation depend on?

A

The dissociation constant (pKa) of the drug and its pH in that part of the body

40
Q

How can we determine of a drug will be ionised?

A

If pKa of the drug and pH of tissue are equal then the drug will be equally dissociated between the two forms (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.

41
Q

How is ‘ion trapping prevented’?

A

Weak acids and bases find it more difficult to cross from the stomach into the blood.
However once the drug reaches the small intestines there is an abundance of transporter proteins that will enable absorption from the GI tract

42
Q

How may a weak acid drug become ‘trapped’ in the blood?

A

A weak acid could potentially be absorbed from the stomach in its unionised state. However, it would then become more ionised at physiological pH and potentially become ‘trapped’ in the blood.

However it would have transport proteins which would move the ionised drug from blood to the tissue.

43
Q

In pharmacokinetics what are the most important carrier systems relating to drug actions in the body?

A

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

44
Q

What is distribution?

A

Once the drug has been absorbed, it will then be distributed to various tissues where it will produce it’s eventual effects.

45
Q

What factors will influence tissue distribution?

A

Regional blood flow
Plasma protein binding
Capillary permeability
Tissue localisation

46
Q

How does regional blood flow affect tissue distribution?

A 
Different tissues receive different amounts of cardiac output:
Liver – 27%
Heart– 4%
Brain – 14%
Kidneys – 22%
Muscles – 20%\

Therefore more drug will be distributed to those tissues which receive more blood

In addition: remember distribution of blood can decrease and increase e.g. in exercise

47
Q

How does plasma protein binding affect tissue distribution?

A

Drugs commonly bind to plasma proteins once they reach systemic circulation.

Most important protein is albumin- good at binding drugs

48
Q

What does he amount of drug that is being bound depend on?

A
  1. The free drug concentration
  2. The affinity for the protein binding sites
  3. The plasma protein concentration
49
Q

What is the concentration of albumin in the blood and what is its binding capacity?

A

the concentration of albumin in the blood is approximately 0.6mmol/l. Each albumin protein has two binding sites. So binding capacity of albumin is 1.2mmol/l.

50
Q

What is the plasma concentration required for clinical effect?

A

The plasma concentration needed clinical effect for most drugs is much less than 1.2mmol/l.
This means plasma proteins are NEVER saturated with drugs.

51
Q

Can drugs bound to plasma proteins diffuse through tissues?

A

No.

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.

52
Q

What are the different types of capillaries?

A

Continuous
Blood Brain Barrier
Fenestrated
Discontinuous

53
Q

How does capillary permeability affect tissue distribution?

A

Blood brain barrier- is continuous and makes the brain the hardest tissue to get drugs to

Continuous- Made up of endothelial cells. If drugs are lipid soluble they can diffuse across the endothelial cell and access the tissue

Fenestrated- Has circular windows within endothelial cells that allow passage of small substances e.g. glomerulus of kidney

Discontinuous- Had big gaps between endothelial cells allowing drugs to easily diffuse e.g. liver

54
Q

How does tissue localisation affect tissue distribution?

A

Different tissues will have different compositions e.g. blood has more water, brain has more fat.

This means drugs with different solubilities will be weighted towards retention in one tissue over another

E.g. for delta9-TCH its equilibrium will be more heavily weighted towards retention in the brain instead of the blood as it has a higher fat content (diffuses from high to low conc.)

55
Q

What is metabolism?

A

The process of metabolism involves the conversion of drugs to metabolites that are as water soluble as possible and easier to excrete.

56
Q

What is the major metabolic tissue and what enzymes are responsible for drug metabolism?

A

The liver. Mainly cytochrome P450 enzymes that are responsible for drug metabolism.

57
Q

What are the two kinds of reactions that drug metabolism involves?

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 act to decrease lipid solubility so it can be excreted

58
Q

What occurs in phase 1 metabolism?

A

Reactive polar groups are introduced into the substance. These reactions can occur by oxidation, reduction and hydrolysis.

59
Q

What is the most common form of phase 1a metabolism?

A

Oxidation. However all oxidation reactions start with a hydrolysis step using cytochrome p450 system.
This incorporates oxygen into non-activated hydrocarbons

60
Q

What functional chains are likely incorporated in a phase 1 reaction?

A

-OH, -COOH, -SH, NH2.

61
Q

What will phase 1 often produce?

A

Pharmacologically active drug metabolites, In some cases the parent drug has no activity of its own, and will only produce an effect once it has been metabolized. These are known as pro-drugs

62
Q

What happens in phase 2 metabolism?

A

A substituent group is added 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

63
Q

How do enzymes differ between phase 1 and 2?

A

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.

64
Q

What is first pass (presystemic) metabolism?

A

Oral drugs are often absorbed and enter the hepatic portal blood supply where they will pass through the liver- this means the drug can be heavily metabolised and leave little active drug behind

65
Q

How do we overcome first pass metabolism?

A

Administer a larger dose of drug to ensure enough drug reaches the systemic circulation.

66
Q

What is the problem with first pass metabolism?

A

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.

67
Q

How can drugs be excreted?

A

Via lungs
Via Breast milk
Via kidney

68
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
69
Q

Why does drug excretion vary so much?

A

The extent to which drugs use the three processes in the kidney differs enormously

70
Q

What is the role of glomerular filtration in excretion?

A

Allows drug molecules of less than 20.000 diffuse into filtrate.

71
Q

What is the role of active tubular secretion in excretion?

A

Most important method for drug excretion in kidney
80% of renal plasma passes into the proximal tubule’s blood supply so more drug is delivered to it.
In the proximal tubule capillary endothelial cells there are two active transport carrier systems- one transports basic drug and other transports acidic drugs

72
Q

What is the role of passive diffusion in excretion?

A

Generally leads to reabsorption. If drugs are particularly lipid soluble, then they will also be reabsorbed. Factors which affect extent of reabsorption:

  1. Drug metabolism – phase 2 metabolism tend to be 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, acidic drugs will be better reabsorbed at lower pH and basic drugs will be better reabsorbed at higher pH.
73
Q

What is the role of biliary excretion?

A

Liver cells transport some drugs from plasma to bile – primarily via transporters.

This is effective at removing phase 2 glucuronide metabolites.

Drugs transported to bile are then excreted in intestines then faeces.

74
Q

What is enterohepatic recycling?

A

Can significantly prolong a drug effect

E.G.

  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.



BRS Year 2 (110 decks)

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