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Medicinal Chemistry (3rd Year) > Drug Metabolism - Prof. Coleman > Flashcards

Drug Metabolism - Prof. Coleman Flashcards

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1
Q

What factors have the greatest impact on drug therapy?

A

Other drugs, some supplements, patients activities.

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2
Q

Define pharmacodynamic changes.

A

Changes at the tissue/receptor level.

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3
Q

What can hepatic metabolic changes lead to?

A

Drug accumulation or drug disappearance.

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4
Q

What can drug drug accumulation lead to?

A

Drug toxicity.

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5
Q

What can drug ‘disappearance’ lead to?

A

Drug failure.

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6
Q

Within what time frame can drug toxicity begin to show effects?

A

Within hours.

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7
Q

Within what time frame can drug failure begin to show effects?

A

Within days.

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8
Q

Define pharmacokinetic changes.

A

Changes in the ADME profile of the drug (see Dr. Badhan notes).

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9
Q

How is therapeutic index (TI) calculated?

A

Toxic concentrations divided by normal therapeutic range.

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10
Q

Give an example of a drug class with a wide therapeutic index.

A

SSRI’s.

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11
Q

Give examples of drug classes with narrow therapeutic indices.

A

TCA’s and lithium.

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12
Q

Define drug clearance.

A

Clearance is the removal of drug by all processes from the biological system.

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13
Q

If drug clearance increases, what happens to the drug?

A

The drug disappears, reduced efficacy.

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14
Q

If the drug clearance decreases, what happens to the drug?

A

The drug accumulates, leading to increased efficacy including toxicity.

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15
Q

If drug clearance us < drug entry, what occurs?

A

Drug toxicity.

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16
Q

If drug clearance = drug entry, what occurs?

A

Drug success.

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17
Q

If drug clearance > drug entry, what occurs?

A

Drug failure.

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18
Q

What is the reason for the development of clearance within the human body?

A

Drugs, toxins, food-borne chemicals, environmental chemicals threaten homeostasis. Even our own chemicals, that we made for ourselves,
such as hormones, can threaten homeostasis. Clearance was developed/evolved to protect homeostasis against these chemicals.

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19
Q

What are some issues that clearance faces?

A

Living systems struggle to clear highly oil-soluble chemicals.
In the kidney, the filtered oily agent will simply be reabsorbed at the collecting tubule stage.
The patient can only really ‘clear’ water
soluble chemicals through urine and faeces.

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20
Q

What are endobiotics?

A

Substances from within the body such as hormones that influence the activity of internal organs or systems.

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21
Q

What are xenobiotics?

A

Substances from outside the body such as toxins and drugs.

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22
Q

Describe the threat posed by endobiotics.

A
  • Hormones must be stable, this stability means they are ‘out of control’.
  • Some processes must be fine-tuned.
  • Hormones must be inactivated quickly.
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23
Q

Describe the threat posed by xenobiotics.

A
  • Membrane disruption.

- They resemble hormones.

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24
Q

Give examples of some substances with high lipophilicity.

A

Cholesterol, polycyclic aromatics, steroid hormones, benzene, many drugs.

25
Q

Give examples of some substances with high hydrophilicity.

A

Phase one and two metabolites, ethanol/methanol, metal ions, phenols, sugars.

26
Q

How does the clearance of poorly clearable drugs occur?

A

They must be made more soluble so the kidneys can remove them.
They must be made heavier so there can be more routes of excretion.

27
Q

Which organs are the biotransforming organs, where metabolism occurs?

A

Liver, gut, kidney.

28
Q

What are the main biotransforming human cytochrome classes?

A

CYP2D6, CYP3A4/5, CYP2C.

29
Q

What metal ion is at the core of CYP450 enzymes?

A

Iron.

30
Q

What ability of metal ions is exploited by enzymes?

A

Their ability to gain and lose electrons.

31
Q

Where in cells does CYP450 enzymes reside?

A

The lipophilic SER, lipophilic compounds are drawn to this area.

32
Q

Give some examples of high extraction drugs.

A

Pethidine, metoprolol, propranolol, lignocaine, verapamil.

33
Q

What affect on plasma levels of high extraction drugs does extraction have?

A

Changes in extraction has some impact on plasma levels.

34
Q

Give some examples of low extraction drugs.

A

Phenytoin, paracetamol, diazepam, naproxen, metronidazole.

35
Q

What affect on plasma levels of low extraction drugs does extraction have?

A

Change in extraction has a large impact on plasma levels.

36
Q

Define bioavailability.

A

How much drug reaches the plasma after an oral dose.

37
Q

What characteristic of a drug does bioavailability depend on?

A

Whether the drug is high or low extraction.

38
Q

How is bioavailability calculated?

A

Blood concentration after IV dose minus blood concentration after oral dose, divided by blood concentration after IV dose.

39
Q

What symbol is used to describe bioavailability?

A

F.

40
Q

What are cytochrome inducers?

A

Substances that increase the metabolic activity of cytochrome enzymes.

41
Q

What effect does induction of cytochrome enzymes have?

A

Reduced plasma levels of the drugs metabolised by the affected cytochrome enzymes.

42
Q

What is enzyme induction?

A

An adaptive increase in enzyme capacity in response to increased drug load.

43
Q

How long does enzyme induction take for it to have its full effect?

A

1-3 weeks.

44
Q

Is enzyme induction fully reversible?

A

Yes.

45
Q

What is the most important receptor in enzyme induction?

A

PXR.

46
Q

What substances induce the enzymes CYP2D6 and CYP2C?

A

Rifampicin, anticonvulsants.

47
Q

What substances induce the enzymes CYP2A4/5?

A

Steroids, rifampicin, anticonvulsants, SJW.

48
Q

Are the toxic effects of enzyme inhibition reversible?

A

Toxic effects will usually be rapidly reversible once the inhibiting
drug is withdrawn (not always).

49
Q

What types of CYP450 inhibitors are the most potent/persistent? Give examples.

A

Mechanism based. Such as SSRI’s, grapefruit juice, MDMA.

50
Q

What types of CYP450 inhibitors are less potent/non-persistent? Give examples.

A

Azoles, gemfibrozil.

51
Q

In terms of CYP450 inhibition, what does the term persistent mean?

A

The enzyme doesn’t survive the interaction.

52
Q

What is torsades des pointes?

A

A specific type of abnormal heart rhythm that can lead to sudden cardiac death. Drug-induced TdP is concentration dependent.

53
Q

How can drugs lead to TdP?

A

Inhibition of CYP450 enzymes metabolising specific drugs leads to a toxic build up of said drugs, these drugs block the HerG channels in the heart muscle, leading to TdP.

54
Q

Give examples of some drugs which are known to cause TdP at toxic levels.

A

Amiodarone, pimozide, astemizole, terfinidine.

55
Q

At toxic levels, what drugs cause sedation?

A

Anticonvulsants.

56
Q

At toxic levels, what drugs cause rhabdomyolysis?

A

Statins (apart from fluvastatin/pravastatin).

57
Q

What is rhabdomyolysis?

A

The death of muscle fibres and release of their contents into the bloodstream. This can lead to serious complications such as renal (kidney) failure.

58
Q

In terms of drug metabolism, define enzyme polymorphisms.

A

Genetic variation in a biotransforming
isoform which is prevalent in more
than 1% of the population.

Medicinal Chemistry (3rd Year) (15 decks)

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