Pharmacokinetics (drug out) Flashcards
(94 cards)
1
Q
Which processes are involved in drug out?
A
Metabolism and elimination
2
Q
What is drug elimination?
A
Metabolic and excretory process
These are integrated to optimise drug removal
3
Q
What can elimination remove?
A
Exogenous and endogenous chemicals
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)
5
Q
Organs involved in drug elimination
A
Liver and kidneys
6
Q
Drug metabolism (first part)
A
Hepatic drug metabolism - phase 1 and 2
7
Q
Where does drug metabolism largely take place?
A
Liver - Phase 1 and 2 enzymes
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
9
Q
What do phase 1 and 2 enzymes do?
A
Metabolise drugs by increasing ionic charge - this enhances renal elimination
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
11
Q
What happens to drugs once ionised/metabolised?
A
Become inactive - but there are some exceptions known as ‘pro drugs’
12
Q
Enzymes involved in phase 1 metabolism
A
Cytochrome P450 (CYP450’s)
13
Q
Cytochrome P450 enzymes - location
A
Large group 50 isoenzymes located on external smooth endoplasmic reticulum (liver)
14
Q
What do cytochrome p450 enzymes catalyse?
A
Redox (oxidation and reduction)
dealkylation
hydroxylation
(enhance ionic charge)
15
Q
What are Cytochrome P450’s enzymes behaviour?
A
Versatile generalists - metabolise a wide range of molecules (not very specific)
16
Q
What do cytochrome p450’s do?
A
Increase ionic charge on a drug
17
Q
What happens after phase 1 (cytochrome p450)?
A
Eliminated directly or go to phase 2
18
Q
What are drugs called that are activated by metabolism? (doesnt usually do this)
A
Pro drugs eg codeine
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
20
Q
What does CYP2D6 exhibit?
A
Genetic Polymorphism
21
Q
What enzymes carry out phase 2?
A
Hepatic cytosolic enzymes
22
Q
Behaviour of cytosolic hepatic phase 2 enzymes
A
Generalists but exhibit more rapid kinetics than CYP450
23
Q
What do cytosolic hepatic enzymes do?
A
Enhance ionic charge even more - enhance hydrophilicity = enhance renal elimination
24
Q
Reactions that cytosolic hepatic enzymes catalyse
A
Sulphation Glucorinadation Glutathione conjugation Methylation N-acetylation
(conjugation reactions)
25
Molecular weights and what route this molecule will take
If MW
>300 goes to gall bladder and is excreted in bile
If <300 goes to kidney to be excreted in urine
26
Cytochrome superfamilies
CYP 1, 2 and 3
| Isozyme members coded by suffix (eg cyp3 **A4**)
27
Prescription drug metabolism and cytochrome isozymes
Only 6 isozymes metabolise 90% of prescription drugs - STRONG generalists
28
What does each isoenzyme do?
Optimally metabolises specific drugs but there is some overlap between cytochrome isozymes
29
CYP that metabolises large amount of drugs
CYP3A4/5 - 36%
CYP2D6 - 19%
CYP2C8/9 - 16%
30
Factors affecting drug metabolism
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
31
What can drugs do to cytochrome P450's?
Can inhibit them or induce them
32
What else can effect CYP450's?
Genetic variability
Polymorphism
Non-expression
33
Major categories affecting drug elimination
HRH - royal acronym
Heart (CVS)
Renal
Hepatic
= reduced functional reserve
34
How do drugs induce CYP450's?
Transcription
Increase translation
Slower degradation
35
What happens to drugs (metabolised by P450) in body if cytochrome p450 has been induced?
It will be eliminated at a faster rate (cytochrome P450 is more active at removing drug)
= plasma levels will fall
36
Consequences of induced CYP450
Therapeutic consequences - levels drop significantly, no therapeutic effects
37
Induction process time
1-2 weeks
38
Example of CYP450 induction
Carbamezepine (CBZ) - antiepileptic drug
39
What does Carbamezepine do?
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
How can CYP450's be inhibited?
Competitive/non-competitive inhibition
41
Rate of elimination of drug (that is metabolised by CYP450) if CYP450 has been inhibited
Rate of elimination of drug will be slowed down
| Plasma levels will increase
42
Consequences of inhibited CYP450
Serious side effects - high drug levels in plasma
43
Inhibition time
1 to a few days (shorter than induction)
44
CYP450 inhibition example
Grapefruit juice inhibits CYP3A4
45
What does CYP3A4 metabolise? What happens if CYP450 is inhibited?
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
Genetic variation of CYP 2C9 + what does it metabolise
Not expressed in 1% Caucasians and 1% Africans
Metabolises NSAIDS, Tolbutamide (diabetes 2), Phenytoin (antiseizure)
47
Genetic variation in CYP 2C19 + what does it metabolise
Not expressed in 5% Caucasians and 30% Asians
Metabolises Omeprazole (PP inhibitor), Valium, Phenytoin
48
What is needed due to genetic variation of CYP450's
Prescriptive practice review
| - consider safety/efficacy of treatment if drug is not metabolised/rapidly metabolised
49
CYP2D6 (enzyme that catalyses codeine (prodrug) to morphine types
Highly polymorphic:
Classed based on metabolism speed
Poor
Normal
High
Ultra-rapid metabolisers
50
Poor CYP2D6 metaboliser means
Codeine to morphine is slow/not much morphine produced
| Patient may not experience pain relief
51
Ultrarapid CYP450 metaboliser means
Codeine to morphine = rapid
| Morphine intoxication or adverse drug reactions
52
CYP2D6 genetic variation/polymorphism
CYP2D6 not expressed in 7% caucasians, HYPERACTIVE in 30% east africans
53
What do you need to do if someone possesses ultrarapid metabolisers? (pro drug situation)
Reduce/titrate dosage
54
Main route of drug elimination
Kidney
| others: sweat, tears, bile, lungs, genital secretions and breast milk
55
3 processes of renal excretion
Glomerular filtration
Active tubular secretion
Passive tubular reabsorption
(GAP)
56
What modification of capillaries allows kidney to filter effectively?
Fenestrations of capillary increase permeability and enable optimised exchange of ions/molecules
57
Glomerular filtration phase
Glomerulus = 20% renal blood flow
| Unbound drug enters bowmans capsule
58
Proximal tubular secretion phase
Remaining 80% of blood via peritubular capillaries
| High expression of OAT and OCT
59
OAT and OCT types in proximal tubule
Low affinity/high capacity
60
How does drug get processed in proximal tubule?
Competitive transport
Carry ionised molecules out
Reverse process of small intestine
(facilitated diffusion and secondary active transport)
61
How do drugs get reabsorped by distal tubule reabsorption?
Through OAT's and OCT's
| But they are subject to competition between drugs
62
Drugs reabsorbed via OAT's
Urate (gout)
Penicillins
NSAID's
Antivirals
63
Drugs reabsorbed by OCT's
Morphine
Histamine
Chlorpromazine
64
Discuss distal tubular reabsorption
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
Urine normal pH
6.0 - 7.5
| Typical = 4.5 - 8.0
66
What happens if distal collecting tubule is acidic?
pH is low
Weak acids protonate (become charge neutral)
They will be reabsorbed
67
What happens if distal collecting tubule is alkaline?
pH is higher
Weak bases become deprotonated (become charge neutral)
They will be reabsorbed
68
If I am a weak acid drug I am reabsorbed when...
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
If I am a weak base drug I am absorbed when...
Alkaline urine increases absorption as I am becoming deprotonated (no charge)
Acidic urine decreases absorption as I am now becoming positively charged
70
What is clearance?
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
Total body clearance equation
Hepatic clearance + renal clearance
72
How do we measure clearance?
```
Use Vd (apparent volume distrubution)
measured in ml/min
```
73
Problem with clearance model
Real volume of plasma cannot be completely cleared of a drug via glomerular filtration/tubular secretion
74
What is Clearance and volume distribution used for clinically?
Designing dosing schedules
Therapeutic regimes
Minimising adverse drug reactions
it answers how long is drug in body and is it working
75
What do Vd and clearance allow us to calculate?
Half life (t 1/2)
76
What is half life?
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
Half life equation
(0.693 x Vd) / CL
78
Relationship of Vd and clearance with half life
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
Drug half life and concentrations
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
Drug injected by Iv hypothetically
Skips distribution phase and distributes throughout whole body straight away
81
What happens when you log the y axis of a graph that had previous exponential relationship?
Your graph becomes linear - y axis is exponentially compressed
82
Exponential --> linear graph when logged shows
Linear elimination kinetics
83
Linear elimination kinetics
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
What does large functional reserve mean?
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
Example of linear elimination kinetics (FIRST ORDER KINETICS)
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
What happens as molecules are metabolised over time?
Plasma concentration decreases
| Catalytic rate decreases
87
What happens when elimination processes become saturated?
They become rate limited - cannot go any faster, all enzymes/carriers are working flat out
= ZERO ORDER or SATURATED
88
Zero order kinetics graph
```
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
Dose X axis and Rate Y axis graph explained
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
Clinical importance of first order and zero order kinetics
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
Examples of zero order kinetics
Alcohol
| Phenytoin
92
Zero order kinetics problems
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
People higher risk of zero order kinetics
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
Example drugs of zero order kinetics
```
Phenytoin
Prozac
Alcohol
MDMA
Paracetamol at high doses
```
