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Medicine Year 1 - Semester 2 - Part 2 > Pharmacokinetics 2 > Flashcards

Pharmacokinetics 2 Flashcards

1
Q

Describe drug metabolism

A

Mainly occurs in the liver in 2 phases:

  • Phase 1 metabolism
  • Phase 2 metabolism

This is not always linear, not all drugs need to pass Phase 1 to be subject to Phase 2 metabolism.

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2
Q

Liver

A

Contains the highest concentration of enzymes that are capable of metabolising drugs in the body.

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3
Q

What does Phase 1 metabolism tend to be involved with ?

A

Functionalisation reactions

Introducing or revealing reactive chemical moieties / groups onto a drug compound.

Produces more reactive products.

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4
Q

Phase 1 metabolism

A

Generally oxidation, reduction or hydrolysis

  • Introduce/reveal a reactive chemical group
  • “Functionalisation”

Products are often more reactive

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5
Q

Why are reactive products produced in Phase 1 metabolism ?

A

These reactive products can bind on and introduce a conjugate.

This adds on large clunky groups to the chemical compound to make it more soluble in water.

If it is more soluble in water, it is more likely to be excreted out by the kidneys, eliminated by the body.

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6
Q

Phase 2 metabolism

A

Synthetic, conjugative reactions

Hydrophilic, inactive compounds generated (usually)

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7
Q

What are cytochrome P450 enzymes ?

A

Mixed function mono-oxygenases

Throughout the body, extensively in the liver.

57 human genes coding for CYP P450 enzymes.

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8
Q

Function of cytochrome p450 enzymes

A

Biosynthesis of steroids, fatty acids and bile acids.

Metabolism of endogenous and exogenous substrates.

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9
Q

Main function of metabolism

A

To make reactive metabolites that can be eliminated out from the body as easily as possible.

They need to water soluble or so bulky that the body just rejects them out in the faeces and they get eliminated.

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10
Q

What is involved in Phase 1 metabolism ?

A

The Cytochrome P450 enzymes which are found in high concentrations in the liver.

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11
Q

Metabolism of Paracetamol - conjugation step

A

Paracetamol is conjugated either with

  • sulphate conjugate
  • glucoronide conjugate

without the need for Phase 1 metabolism

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12
Q

Metabolism of paracetamol

A

A small amount of paracetamol undergoes metabolism by cytochrome P450 enzymes.

This produces reactive compounds which need to be detoxified.

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13
Q

Describe the degradation and elimination of the toxic metabolite produce from metabolism of paracetamol

A

2 pathways:

1:
- Normal glutathione levels
- Combination with glutathione
- Conjugation and excretion

2:
- Too much toxic metabolite
- Depleted glutathione levels
- Combination with hepatic proteins
- Toxicity + irreversible liver damage

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14
Q

How to solve toxicity caused by metabolism of paracetamol ?

A

Replenish glutathione levels
- give acetylcysteine which is the precursor to glutathione

More glutathione to detoxify the toxic metabolite.

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15
Q

Key examples of metabolism

A

Metabolism of paracetamol
Warfarin and phenobarbital
Grapefruit juice and statins

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16
Q

Warfarin and Phenobarbital

A

Phenobarbital upregulates the expression of cytochrome p450 enzymes quite substantially.

Warfarin is metabolised by Cytochrome P450s.

So if they are co-prescribed you would see a decrease in effectiveness of warfarin.

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17
Q

Grapefruit juice and statins

A

NOT to take statins with grapefruit juice.

Simvastatin metabolised by CYP3A4 in gut wall and liver.

High 1st pass metabolism - around 5% reaches circulation.

Grapefruit juice blocks CYP3A4.

So increased amount of statins reaches the bloodstream, could be toxic.

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18
Q

What is the function of different routes of metabolism ?

A

Different routes of metabolism allow for patient specific choices to be made.

e.g. genetic variability, disease state and other treatments

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19
Q

Vecuronium - metabolism/elimination

A

Liver - eliminated via urine and bile

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20
Q

Atacurium - metabolism/elimination

A

Spontaneous degradation in plasma

21
Q

Mivacurium - metabolism/elimination

A

Plasma cholinesterase

22
Q

Feature of metabolites

A

Metabolites can be active or toxic

23
Q

Feature of metabolism - summary

A

Genetic variability in metabolic enzymes occurs and expression of metabolic enzymes can be induced and/or inhibited.

Competition for metabolic enzymes occurs and metabolic pathways can be saturated.

24
Q

What can metabolism affect ?

A

Metabolism can affect the bioavailability of drugs.

25
Q

How are drugs eliminated ?

A

Drugs are eliminated either unchanged or as metabolites:

  • Hydrophilic drugs eliminated more readily than lipophilic drugs (except the lungs)
26
Q

State some possible source of excretion

A

Urine
Faeces
Milk
Sweat
Expired Air
Hair

27
Q

What is the most important organ involved in elimination ?

A

The kidneys are the most important organs involved in the elimination of drugs and their metabolites.

28
Q

Minimum effective dose

A

The minimum plasma concentration that needs to be achieved before evidence of a therapeutic effect could be observed.

29
Q

Minimum toxic dose

A

The minimum plasma concentration required to observe unwanted or toxic effects of the drug.

30
Q

Therapeutic window

A

The gap between the minimum effective concentration and the minimum concentration that has unwanted side effects (toxicity).

31
Q

Onset of action

A

How long it takes your drug plasma concentrations to reach the minimum effective concentration following administration.

32
Q

Describe onset of action for oral vs IV drugs.

A

Most IV drugs will have a quicker onset of action than orally administered drugs, because you do not have to undergo the same processes of dissolution and absorption before the drug can get into the bloodstream.

33
Q

Duration of action

A

How long evidence of a drug’s pharmacological action remains evident.

34
Q

Cmax

A

The peak plasma concentration achieved after administration of a drug.

35
Q

Tmax

A

The time taken to reach Cmax

36
Q

Absorption half life

A

Can be used to predict T max if known.

If absorption half life increases, you would expect the Tmax to take longer to reach.

If absorption half life shortens, you would expect Tmax to be reached quicker.

37
Q

What influences absorption half-life ?

A

The preparation of the drug

Soluble, disperaible forms vs prolonged release formulations

38
Q

Plasma clearance half-life (elimination half-life)

A

Elimination half-life is independent of preparation of drug and formulation.

It describes how quickly the drug is removed from the body and is a function of rate of elimination, plus how well distributed a drug is around your body.

39
Q

Plasma drug concentration during IV infusion

A

Plasma concentration increases during infusion until rate of input = rate of output.

  • STEADY STATE
40
Q

Factors that can affect pharmacokinetic parameters

A

Age
Sex
Pregnancy
Body weight
Diet
Disease
Ethnicity
Genetic variability
Other medications

41
Q

How to calculate:
- minimum effective concentration
- minimum toxic concentration

A

Experimentally

By carrying out dose escalation trials and relating the plasma concentration to observed effect.

42
Q

How to calculate: Therapeutic window

A

On a drug plasma concentration graph, draw a horizontal line along the minimum effective concentration and another along the minimum toxic concentration.

43
Q

How to calculate: Onset of action

A

Draw a horizontal line along the minimum effective concentration.

The onset of action will be at the time which the drug plasma concentration curve breaches this line.

44
Q

How to calculate: Duration of action

A

Draw a horizontal line along the minimum effective concentration.

Mark the time at which the drug plasma concentration curve breaches that line.

Mark when the drug plasma concentration curve descends back below that line.

The time between these 2 marks is duration of action.

45
Q

How to calculate: Cmax

A

Extrapolate horizontally from the highest point on your drug plasma concentration graph.

That is Cmax.

46
Q

How to calculate: Tmax

A

Extrapolate vertically down from the highest point on the drug plasma concentration graph.

47
Q

How to calculate: Absorption half life

A

How long it takes for 50% of Cmax to be reached.

Start at Tmax and work towards the left.

48
Q

How to calculate: Plasma clearance half-life

A

1st identify Cmax and Tmax.

Start at Tmax and work towards the right and work out how long it takes for 50% of Cmax to be reached.

The duration of time between those 2 points is the half life.

Medicine Year 1 - Semester 2 - Part 2 (53 decks)

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