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Francesca's ESA2 > M&R 9.1/9.2 Pharmacokinetics > Flashcards

M&R 9.1/9.2 Pharmacokinetics Flashcards

1
Q

Describe the difference between the pharmaceutical process, the pharmacokinetic process, the pharmacodynamic process, and the therapeutic process

A

Pharmaceutical process = is the drug getting into the patient
Pharmacokinetic process = is the drug getting to the site of action (what the body does to the drug)
Pharmacodynamic process = is the drug producing the desired effect (what the drug does to the body)
Therapeutic process = is this translated to a therapeutic effect

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2
Q

Which process describes whether the drug is getting into the patient?

A

The pharmaceutical process

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3
Q

Which process describes whether the drug is getting to the site of action?

A

The pharmacokinetic process (what the body does to the drug)

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4
Q

Which process describes whether the drug is producing the desired effect?

A

The pharmacodynamic process (what the drug does to the body)

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5
Q

Which process described whether the desired effect is translated to a therapeutic effect?

A

Therapeutic process

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6
Q

Describe how properties regarding how patients take drugs can affect the pharmaceutical process (whether the drug gets into the patient)?

A

Formulation (solid vs liquid, if solid - acid stability, solubility)

Compliance (fewer doses/day - more patient compliance)

Site of administration (focal/systemic, if systemic - enteral/parenteral)

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7
Q

What are some sites of focal drug administration?

A

Eyes
Skin
Ears
Inhalation

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8
Q

What are 2 advantages of focal drug administration?

A

Concentrates drug at site of action

Less systemic absorption –> less off target effects/side effects

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9
Q

What are 3 routes of enteral drug administration?

A

Oral
Sublingual
Rectal

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10
Q

What are 4 routes of parenteral drug administration?

A

Subcutaneous
Intramuscular
Intravenous
Transdermal

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11
Q

Define ‘oral bioavailability’ of a drug

A

The proportion of a drug given orally (or by any route other than IV) which reaches the systemic circulation in an unchanged form

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12
Q

In what 2 ways can you measure oral bioavailability of a drug?

A
  1. By amount (depends of GI absorption & first pass metabolism) - measure area under curve of a plasma drug level vs time plot (then (AUC oral/ AUC injected) x 100)
  2. By rate of availability (depends on GI absorption and pharmaceutical factors) - measured by peak height and rate of rise of drug level in blood
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13
Q

Does everyone have the same bioavailability for the same drug?

A

No!

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14
Q

How do you calculate therapeutic ratio?

A

LD50/ED50

=maximum tolerated dose/minimum effective dose

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15
Q

What does it mean if there is a large therapeutic window/index?

A

There is a wider gap between the effective conc of the drug and the toxic conc of the drug

Therefore a mistake in dose is less likely to have a negative effect on the patient

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16
Q

Name a drug with a large therapeutic window

A

Penicillin

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17
Q

What does it mean if a drug has a small therapeutic window/index?

A

There is a narrow gap between the effective conc of the drug and the toxic conc

Therefore any mistake in dose can have severe effects

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18
Q

Name a drug with a small therapeutic window

A

Warfarin

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19
Q

What could we alter to stop a drug entering the toxic window?

A

The formulation
E.g. if a fast-release formulation causes plasma concentration to rapidly rise and enter the toxic window, then could formulate a slow-release preparation that causes plasma levels to rise slower so the toxic window is not reached

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20
Q

What is first pass metabolism? Why does it happen?

A

Because blood from the gut goes straight to the liver via the portal system, drugs that are absorbed through the gut can get metabolised by the liver before ever reaching the systemic circulation

(e.g. opiates)

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21
Q

Name 3 routes of administration which would avoid first-pass metabolism

A

Parenteral routes (e.g. IV, IM, SC)

Sublingual (e.g. use of GTN in angina)

Rectal (rectum has drainage to both portal and systemic systems - so only some of the drug would undergo first-pass metabolism by liver

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22
Q

What is the volume distribution of a drug?

A

The theoretical volume into which the drug is distributed, assuming that this occurred instantaneously

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23
Q

How would you calculate volume distribution of a drug?

A

On a time vs serum concentration graph, you would extrapolate back to time zero to find C0 (the hypothetical drug concentration predicted if the distribution had occurred instantly)

Then do: amount given/C0

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24
Q

Do drugs which are bound to plasma proteins exert effects?

A

No - it is the FREE level of drug that exerts the effect, not the total level

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25
Q

Drugs which have a very high volume distribution tend to be concentrated where?

A

They tend to concentrate into fatty tissue, which leads to a very high volume distribution

26
Q

In protein-binding interactions, what are Object (class I) drugs?

A

Drugs which are used at a dose much lower than the number of albumin binding sites

Most of the drug molecules are bound to albumin, so the concentration of free drug is low

27
Q

In protein-binding interactions, what are Precipitant (class II) drugs?

A

Drugs which are used at a dose much higher than the number of albumin binding sites

Most albumin molecules contain a bound drug
the concentration of free drug is significant

28
Q

What happens when an Object drug and a Precipitant drug are taken together?

A

The precipitant drug will displace the object drug from its albumin binding sites
This temporarily increases free levels of the object drug, leading to a higher risk of toxicity

29
Q

When are protein binding drug interactions most important?

A
  1. For drugs that are highly bound to albumin (because there is a low amount of free drug - so any displacement leads to a big rise)
  2. For drugs with a small volume of distribution (so if displaced the conc rise will be much greater)
  3. For drugs with a small therapeutic window (therefore a rise in levels is more likely to lead to side effects)
30
Q

Name an object drug that is particularly susceptible to protein binding interactions. Why is it susceptible?

A

Warfarin
Highly bound to albumin
Has a low volume of distribution
Has a small therapeutic window

31
Q

Which precipitant drugs can displace warfarin?

A

Sulphonamides
Aspirin
Phenytoin

32
Q

Name the two main types of drug pharmacokinetics

A

First order kinetics

Zero order kinetics

33
Q

When does first order kinetics occur? What does it mean?

A

When a drug is used at a concentration [C] lower than Km

The rate of elimination is proportional to drug level

  • > so the higher the drug level, the faster the rate of destruction
  • > a constant FRACTION is eliminated per unit time - so can determine HALF LIFE
34
Q

When does first order kinetics appear linear on a graph?

A

When log(plasma concentration) is plotted against time

35
Q

If linear plasma concentration is plotted against time on a graph, which type of kinetics appears curved and which appears linear?

A

First order kinetics appears curved (only linear if log(conc) used)

Zero order kinetics appears linear

36
Q

When does zero order kinetics occur? What does it mean?

A

When a drug is used at a concentration [C] much higher than Km
The enzyme is saturated, so the rate of elimination is CONSTANT
Regardless of drug concentration, it will be eliminated at the same rate (e.g. 9g/hour)

37
Q

What is the significance of first order kinetics?

A

There is a predictable therapeutic response from dose increases
(Most drugs behave like this)

38
Q

What is the significance of zero order kinetics?

A

The therapeutic response can suddenly escalate as elimination mechanisms saturate

(different in different people, so need to monitor concentrations of the drug and only increase doses incrementally)

39
Q

Name 2 examples of drugs subject to zero order kinetics

A

Phenytoin

Alcohol

40
Q

During repeated drug administration, how long does it take to reach a steady state of the drug?

A

5 half-lives of that drug

therefore is a property of a drug itself

41
Q

If an immediate effect is required from a drug which has a long half life (so you can’t wait 5 half-lives), what do you do?

A

Give a loading does of the drug
This puts the drug concentration into the therapeutic range very quickly
Loading dose often determined by volume of distribution

42
Q

During drug elimination, drugs tend to be metabolised by…

A

…the liver

43
Q

During drug elimination, drugs tend to be excreted by…

A

… the kidneys

44
Q

What is the significance of the high volume of distribution of lipid-soluble drugs?

A

They concentrate in lipid, so when adipose tissue is high, their plasma concentration is lower.

Therefore for the same dose, in a very thin person there would be loads in the plasma, whereas for a very fat person there would be loads in the adipose tissue and hardly any left in the plasma to act

45
Q

Briefly describe the 2 phases of liver metabolism of drugs

A

Phase 1 - oxidation, reduction and/or hydrolysis
(drug may get activated, unchanged, or (most often) inactivated

Phase 2 - Conjugation to conjugation products (usually inactive)
(NB - some drugs directly enter phase 2 metabolism)

46
Q

What kinds of enzymes carry out phase 1 metabolism of drugs in the liver?

What are some main features of them?

A

Mixed function oxidases (e.g. cytochrome P450)

Low substrate specificity
Affinity for lipid-soluble drugs
Inducible and inhibitable

47
Q

Regarding phase 1 liver metabolism, what is an enzyme inducer?

A

A drug which induces liver enzymes and therefore can cause other drugs to be metabolised more quickly

48
Q

What is an example of an enzyme inducing drug and what drugs does it affect?

A

Phenobarbitone (Causes warfarin & phenytoin to be metabolised more quickly)

Rifampicin (causes the OCP to be metabolised more quickly)

49
Q

Regarding phase 1 liver metabolism, what is an enzyme inhibitor?

A

A drug which can inhibit liver metabolism enzymes, causing other drugs to be metabolised more slowly

50
Q

Give an example of a drug which acts as a liver enzyme inhibitor, and which drugs it slows the metabolism of

A

Cimetidine

Causes warfarin and diazepam to be metabolised more slowly

51
Q

When are metabolism-related drug interactions most clinically important?

A

When drugs have a low therapeutic ratio (e.g. warfarin)
When a drug is being used at the minimum effective concentration (e.g. the OCP)
When the drug metabolism follows zero order kinetics

52
Q

Which drugs can potentiate warfarin’s actions and how?

A

Alcohol - inhibits warfarin metabolism
Aspirin, sulphonamides, phenytoin - displace warfarin from plasma proteins
Broad spectrum antibiotics - reduce vitamin K synthesis by gut bacteria (warfarin normally works against vitamin K to prevent clotting)

53
Q

Which drugs can inhibit warfarin’s actions and how?

A

Barbiturates and rifampicin - induce liver metabolising enzymes

54
Q

Which proportion of a drug is filtered by the glomerulus?

A

Only the free, unbound fraction

55
Q

Name a drug that can be actively secreted by kidney tubules

A

Penicillin

56
Q

What is the pK of a drug?

A

The pH at which half of it is ionized and half is non-ionized

57
Q

What is the key difference between the ionised and un-ionised part of a drug?

A

Only the un-ionised part is lipid soluble and can cross membranes easily
Therefore whether or not the drug is ionized affects how well it can be reabsorbed (and therefore how much is excreted)

58
Q

If a drug is a weak acid (e.g. aspirin) describe how the urine pH will affect its excretion

A

Alkaline urine will ionise the drug

Therefore alkaline urine = decreased reabsorption and increased excretion (more stays in the tubule lumen)
Acidic urine = increased reabsorption and decreased excretion (more leaves tubule lumen and gets reabsorbed)

59
Q

If a drug is a weak base (e.g. amphetamine) how will the pH of the urine affect its excretion?

A

Making the urine acidic ionises more of the drug

Therefore acid urine = decreased reabsorption so more excreted

Alkaline urine = increased reabsorption so less is excreted

60
Q

Explain one way in which the urine pH affecting drug excretion can be exploited clinically

A

Aspirin poisoning

Aspirin is a weak acid. Give forced alkaline diuresis
The alkalinity causes more of the aspirin to get ionized and therefore remain in tubule lumen to be excreted (rather than reabsorbed)

61
Q

How can renal disease affect drugs in the body?

A

Lower rate of excretion = longer half-life

  • > = lower maintenance dose required
  • > = longer time to reach steady state (5 half lives)

Protein binding of drugs is altered

Francesca's ESA2 (16 decks)

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