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ICPP 2023 > Pharmacokinetics (drug out) > Flashcards

Pharmacokinetics (drug out) Flashcards

1
Q

Which processes are involved in drug out?

A

Metabolism and elimination

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2
Q

What is drug elimination?

A

Metabolic and excretory process

These are integrated to optimise drug removal

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3
Q

What can elimination remove?

A

Exogenous and endogenous chemicals

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4
Q

Advantage of elimination

A

Evolutionary advantage of recognising xenobiotics (potential toxins)

It’s protective and homeostatic (eg remove hormones no longer needed to send signals)

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5
Q

Organs involved in drug elimination

A

Liver and kidneys

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6
Q

Drug metabolism (first part)

A

Hepatic drug metabolism - phase 1 and 2

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7
Q

Where does drug metabolism largely take place?

A

Liver - Phase 1 and 2 enzymes

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8
Q

Why is liver good place for this to occur?

A

Even though these enzymes are expressed throughout body, liver has large functional reserve

It is the first port of call after GI absorption

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9
Q

What do phase 1 and 2 enzymes do?

A

Metabolise drugs by increasing ionic charge - this enhances renal elimination

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10
Q

Why do drugs need to be ionically charged to be excreted?

A

Lipophilic (non charged/not ionised) drugs will just diffuse out of renal tubules and back into plasma - will not be excreted

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11
Q

What happens to drugs once ionised/metabolised?

A

Become inactive - but there are some exceptions known as ‘pro drugs’

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12
Q

Enzymes involved in phase 1 metabolism

A

Cytochrome P450 (CYP450’s)

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13
Q

Cytochrome P450 enzymes - location

A

Large group 50 isoenzymes located on external smooth endoplasmic reticulum (liver)

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14
Q

What do cytochrome p450 enzymes catalyse?

A

Redox (oxidation and reduction)
dealkylation
hydroxylation

(enhance ionic charge)

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15
Q

What are Cytochrome P450’s enzymes behaviour?

A

Versatile generalists - metabolise a wide range of molecules (not very specific)

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16
Q

What do cytochrome p450’s do?

A

Increase ionic charge on a drug

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17
Q

What happens after phase 1 (cytochrome p450)?

A

Eliminated directly or go to phase 2

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18
Q

What are drugs called that are activated by metabolism? (doesnt usually do this)

A

Pro drugs eg codeine

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19
Q

Pro drug example

A

0-15% Codeine is metabolised by CYP2D6 to morphine
Morphine has higher affinity (x200) for µ-opioid receptor
= enhances pain relief

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20
Q

What does CYP2D6 exhibit?

A

Genetic Polymorphism

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21
Q

What enzymes carry out phase 2?

A

Hepatic cytosolic enzymes

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22
Q

Behaviour of cytosolic hepatic phase 2 enzymes

A

Generalists but exhibit more rapid kinetics than CYP450

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23
Q

What do cytosolic hepatic enzymes do?

A

Enhance ionic charge even more - enhance hydrophilicity = enhance renal elimination

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24
Q

Reactions that cytosolic hepatic enzymes catalyse

A 
Sulphation 
Glucorinadation 
Glutathione conjugation 
Methylation
N-acetylation

(conjugation reactions)

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25
Q

Molecular weights and what route this molecule will take

A

If MW
>300 goes to gall bladder and is excreted in bile
If <300 goes to kidney to be excreted in urine

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26
Q

Cytochrome superfamilies

A

CYP 1, 2 and 3

Isozyme members coded by suffix (eg cyp3 A4)

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27
Q

Prescription drug metabolism and cytochrome isozymes

A

Only 6 isozymes metabolise 90% of prescription drugs - STRONG generalists

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28
Q

What does each isoenzyme do?

A

Optimally metabolises specific drugs but there is some overlap between cytochrome isozymes

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29
Q

CYP that metabolises large amount of drugs

A

CYP3A4/5 - 36%
CYP2D6 - 19%
CYP2C8/9 - 16%

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30
Q

Factors affecting drug metabolism

A

Age (paediatric and elderly)
Sex (gender differences - eg alcohol metabolism slower in females)
General health/dietary/disease - Hepatic, renal, CVS

THESE ALL DECREASE FUNCTIONAL HEPATIC RESERVE

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31
Q

What can drugs do to cytochrome P450’s?

A

Can inhibit them or induce them

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32
Q

What else can effect CYP450’s?

A

Genetic variability
Polymorphism
Non-expression

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33
Q

Major categories affecting drug elimination

A

HRH - royal acronym

Heart (CVS)
Renal
Hepatic
= reduced functional reserve

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34
Q

How do drugs induce CYP450’s?

A

Transcription
Increase translation
Slower degradation

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35
Q

What happens to drugs (metabolised by P450) in body if cytochrome p450 has been induced?

A

It will be eliminated at a faster rate (cytochrome P450 is more active at removing drug)
= plasma levels will fall

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36
Q

Consequences of induced CYP450

A

Therapeutic consequences - levels drop significantly, no therapeutic effects

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37
Q

Induction process time

A

1-2 weeks

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38
Q

Example of CYP450 induction

A

Carbamezepine (CBZ) - antiepileptic drug

39
Q

What does Carbamezepine do?

A

Metabolised by CYP3A4
Induces CYP3A4
Lowers it’s own levels in the plasma affecting its control

Needs careful monitoring in first few months of prescription - could be sudden induction and no therapeutic effects

40
Q

How can CYP450’s be inhibited?

A

Competitive/non-competitive inhibition

41
Q

Rate of elimination of drug (that is metabolised by CYP450) if CYP450 has been inhibited

A

Rate of elimination of drug will be slowed down

Plasma levels will increase

42
Q

Consequences of inhibited CYP450

A

Serious side effects - high drug levels in plasma

43
Q

Inhibition time

A

1 to a few days (shorter than induction)

44
Q

CYP450 inhibition example

A

Grapefruit juice inhibits CYP3A4

45
Q

What does CYP3A4 metabolise? What happens if CYP450 is inhibited?

A

Verapimil which is used to treat high blood pressure

So if CYP450 is inhibited, plasma levels of drug will rise and = LARGE reduction of BP and fainting

46
Q

Genetic variation of CYP 2C9 + what does it metabolise

A

Not expressed in 1% Caucasians and 1% Africans

Metabolises NSAIDS, Tolbutamide (diabetes 2), Phenytoin (antiseizure)

47
Q

Genetic variation in CYP 2C19 + what does it metabolise

A

Not expressed in 5% Caucasians and 30% Asians

Metabolises Omeprazole (PP inhibitor), Valium, Phenytoin

48
Q

What is needed due to genetic variation of CYP450’s

A

Prescriptive practice review

- consider safety/efficacy of treatment if drug is not metabolised/rapidly metabolised

49
Q

CYP2D6 (enzyme that catalyses codeine (prodrug) to morphine types

A

Highly polymorphic:
Classed based on metabolism speed

Poor
Normal
High
Ultra-rapid metabolisers

50
Q

Poor CYP2D6 metaboliser means

A

Codeine to morphine is slow/not much morphine produced

Patient may not experience pain relief

51
Q

Ultrarapid CYP450 metaboliser means

A

Codeine to morphine = rapid

Morphine intoxication or adverse drug reactions

52
Q

CYP2D6 genetic variation/polymorphism

A

CYP2D6 not expressed in 7% caucasians, HYPERACTIVE in 30% east africans

53
Q

What do you need to do if someone possesses ultrarapid metabolisers? (pro drug situation)

A

Reduce/titrate dosage

54
Q

Main route of drug elimination

A

Kidney

others: sweat, tears, bile, lungs, genital secretions and breast milk

55
Q

3 processes of renal excretion

A

Glomerular filtration
Active tubular secretion
Passive tubular reabsorption

(GAP)

56
Q

What modification of capillaries allows kidney to filter effectively?

A

Fenestrations of capillary increase permeability and enable optimised exchange of ions/molecules

57
Q

Glomerular filtration phase

A

Glomerulus = 20% renal blood flow

Unbound drug enters bowmans capsule

58
Q

Proximal tubular secretion phase

A

Remaining 80% of blood via peritubular capillaries

High expression of OAT and OCT

59
Q

OAT and OCT types in proximal tubule

A

Low affinity/high capacity

60
Q

How does drug get processed in proximal tubule?

A

Competitive transport
Carry ionised molecules out
Reverse process of small intestine

(facilitated diffusion and secondary active transport)

61
Q

How do drugs get reabsorped by distal tubule reabsorption?

A

Through OAT’s and OCT’s

But they are subject to competition between drugs

62
Q

Drugs reabsorbed via OAT’s

A

Urate (gout)
Penicillins
NSAID’s
Antivirals

63
Q

Drugs reabsorbed by OCT’s

A

Morphine
Histamine
Chlorpromazine

64
Q

Discuss distal tubular reabsorption

A

Alone tubule length water is reabsorbed
So solutes concentration along tubule increases (as water is sucked out)
If a drug is still lipophilic it can pass back into blood

65
Q

Urine normal pH

A

6.0 - 7.5

Typical = 4.5 - 8.0

66
Q

What happens if distal collecting tubule is acidic?

A

pH is low
Weak acids protonate (become charge neutral)
They will be reabsorbed

67
Q

What happens if distal collecting tubule is alkaline?

A

pH is higher
Weak bases become deprotonated (become charge neutral)
They will be reabsorbed

68
Q

If I am a weak acid drug I am reabsorbed when…

A

Acidic urine increases absorption (drug can be protonated and therefore uncharged, acid is usually -ve)

If alkaline urine, decreases absorption as I am now charged (negatively)

69
Q

If I am a weak base drug I am absorbed when…

A

Alkaline urine increases absorption as I am becoming deprotonated (no charge)

Acidic urine decreases absorption as I am now becoming positively charged

70
Q

What is clearance?

A

APPARENT Rate of elimination of a drug from the body
Total drug clearance is from all routes

Volume of plasma that is completely cleared of drug per unit of time

71
Q

Total body clearance equation

A

Hepatic clearance + renal clearance

72
Q

How do we measure clearance?

A 
Use Vd (apparent volume distrubution)
measured in ml/min
73
Q

Problem with clearance model

A

Real volume of plasma cannot be completely cleared of a drug via glomerular filtration/tubular secretion

74
Q

What is Clearance and volume distribution used for clinically?

A

Designing dosing schedules
Therapeutic regimes
Minimising adverse drug reactions

it answers how long is drug in body and is it working

75
Q

What do Vd and clearance allow us to calculate?

A

Half life (t 1/2)

76
Q

What is half life?

A

The amount of time it takes for the concentration of drug in the plasma to decrease to one half of the concentration it was when first administered

77
Q

Half life equation

A

(0.693 x Vd) / CL

78
Q

Relationship of Vd and clearance with half life

A

If CL stays the same and Vd increases, half life also increases (multiplying by a constant)

If CL increases and Vd stays the same, half life will decrease (dividing by a larger number)

79
Q

Drug half life and concentrations

A

T1 - 50% concentration (one half life)
T2 - 25% concentration (2 half lives)
T3 - 12.5% concentration (3 half lives)

(at each time interval equal to half life, concentration decreases by 50% each time)

80
Q

Drug injected by Iv hypothetically

A

Skips distribution phase and distributes throughout whole body straight away

81
Q

What happens when you log the y axis of a graph that had previous exponential relationship?

A

Your graph becomes linear - y axis is exponentially compressed

82
Q

Exponential –> linear graph when logged shows

A

Linear elimination kinetics

83
Q

Linear elimination kinetics

A

Rate of drug metabolism/excretion is proportional to plasma concentration of drug* (if there is large functional reserve)

*so if you have high concentration you have high rate of elimination

84
Q

What does large functional reserve mean?

A

Plenty of Phase 1 and 2 enzymes
Plenty of OAT and OCT transporters

If you have this, rate of metabolism will be proportional to the number of molecules occupying the carrier per unit of time

85
Q

Example of linear elimination kinetics (FIRST ORDER KINETICS)

A

If your drug concentration is 5mmol, rate is 10 million molecules per second

If your drug is 10 mmol, rate is 20 million molecules per second

86
Q

What happens as molecules are metabolised over time?

A

Plasma concentration decreases

Catalytic rate decreases

87
Q

What happens when elimination processes become saturated?

A

They become rate limited - cannot go any faster, all enzymes/carriers are working flat out

= ZERO ORDER or SATURATED

88
Q

Zero order kinetics graph

A 
Straight line (linear) when axis are both on linear scale
Elimination processes are saturated

Or curve and then plateau if on dose and rate graph

89
Q

Dose X axis and Rate Y axis graph explained

A

As dose first increases so does rate

At increasing doses, you approach a finite limit of functional reserve - there are only so many enzymes/carriers

These become saturated = rate reaches maximum

90
Q

Clinical importance of first order and zero order kinetics

A

First order: predictable linear relationship between dose and effects (if dose increases there are increased effects steadily)

Zero order: Therapeutic response can suddenly escalate as elimination mechanisms become saturated
- need to carefully monitor doses

91
Q

Examples of zero order kinetics

A

Alcohol

Phenytoin

92
Q

Zero order kinetics problems

A

More likely to result in toxicity or adverse effects

FIXED rate of elimination per unit of time

Small dosage changes can produce large changes in plasma and lead to toxicity

Half life not calculable - cannot predict dosage regime

Narrowing therapeutic window - and drugs at or near therapeutic dose with saturation

Greater risk of interactions with other drugs (occupies sites for longer)

93
Q

People higher risk of zero order kinetics

A

Elderly
Infants
(decreased/immature capacity)

Polypharmacy - competing at same elimination processes, cannot be metabolised

Seriously ill - cancer, liver disease, alcoholics

Reduced hepatic/renal capacity - easier to saturate

94
Q

Example drugs of zero order kinetics

A 
Phenytoin
Prozac
Alcohol
MDMA
Paracetamol at high doses

ICPP 2023 (31 decks)

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