Pharmacokinetics (drug out) Flashcards
Which processes are involved in drug out?
Metabolism and elimination
What is drug elimination?
Metabolic and excretory process
These are integrated to optimise drug removal
What can elimination remove?
Exogenous and endogenous chemicals
Advantage of elimination
Evolutionary advantage of recognising xenobiotics (potential toxins)
It’s protective and homeostatic (eg remove hormones no longer needed to send signals)
Organs involved in drug elimination
Liver and kidneys
Drug metabolism (first part)
Hepatic drug metabolism - phase 1 and 2
Where does drug metabolism largely take place?
Liver - Phase 1 and 2 enzymes
Why is liver good place for this to occur?
Even though these enzymes are expressed throughout body, liver has large functional reserve
It is the first port of call after GI absorption
What do phase 1 and 2 enzymes do?
Metabolise drugs by increasing ionic charge - this enhances renal elimination
Why do drugs need to be ionically charged to be excreted?
Lipophilic (non charged/not ionised) drugs will just diffuse out of renal tubules and back into plasma - will not be excreted
What happens to drugs once ionised/metabolised?
Become inactive - but there are some exceptions known as ‘pro drugs’
Enzymes involved in phase 1 metabolism
Cytochrome P450 (CYP450’s)
Cytochrome P450 enzymes - location
Large group 50 isoenzymes located on external smooth endoplasmic reticulum (liver)
What do cytochrome p450 enzymes catalyse?
Redox (oxidation and reduction)
dealkylation
hydroxylation
(enhance ionic charge)
What are Cytochrome P450’s enzymes behaviour?
Versatile generalists - metabolise a wide range of molecules (not very specific)
What do cytochrome p450’s do?
Increase ionic charge on a drug
What happens after phase 1 (cytochrome p450)?
Eliminated directly or go to phase 2
What are drugs called that are activated by metabolism? (doesnt usually do this)
Pro drugs eg codeine
Pro drug example
0-15% Codeine is metabolised by CYP2D6 to morphine
Morphine has higher affinity (x200) for µ-opioid receptor
= enhances pain relief
What does CYP2D6 exhibit?
Genetic Polymorphism
What enzymes carry out phase 2?
Hepatic cytosolic enzymes
Behaviour of cytosolic hepatic phase 2 enzymes
Generalists but exhibit more rapid kinetics than CYP450
What do cytosolic hepatic enzymes do?
Enhance ionic charge even more - enhance hydrophilicity = enhance renal elimination
Reactions that cytosolic hepatic enzymes catalyse
Sulphation Glucorinadation Glutathione conjugation Methylation N-acetylation
(conjugation reactions)
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
Cytochrome superfamilies
CYP 1, 2 and 3
Isozyme members coded by suffix (eg cyp3 A4)
Prescription drug metabolism and cytochrome isozymes
Only 6 isozymes metabolise 90% of prescription drugs - STRONG generalists
What does each isoenzyme do?
Optimally metabolises specific drugs but there is some overlap between cytochrome isozymes
CYP that metabolises large amount of drugs
CYP3A4/5 - 36%
CYP2D6 - 19%
CYP2C8/9 - 16%
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
What can drugs do to cytochrome P450’s?
Can inhibit them or induce them
What else can effect CYP450’s?
Genetic variability
Polymorphism
Non-expression
Major categories affecting drug elimination
HRH - royal acronym
Heart (CVS)
Renal
Hepatic
= reduced functional reserve
How do drugs induce CYP450’s?
Transcription
Increase translation
Slower degradation
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
Consequences of induced CYP450
Therapeutic consequences - levels drop significantly, no therapeutic effects
Induction process time
1-2 weeks
Example of CYP450 induction
Carbamezepine (CBZ) - antiepileptic drug
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
How can CYP450’s be inhibited?
Competitive/non-competitive inhibition
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
Consequences of inhibited CYP450
Serious side effects - high drug levels in plasma
Inhibition time
1 to a few days (shorter than induction)
CYP450 inhibition example
Grapefruit juice inhibits CYP3A4
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
Genetic variation of CYP 2C9 + what does it metabolise
Not expressed in 1% Caucasians and 1% Africans
Metabolises NSAIDS, Tolbutamide (diabetes 2), Phenytoin (antiseizure)
Genetic variation in CYP 2C19 + what does it metabolise
Not expressed in 5% Caucasians and 30% Asians
Metabolises Omeprazole (PP inhibitor), Valium, Phenytoin
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
CYP2D6 (enzyme that catalyses codeine (prodrug) to morphine types
Highly polymorphic:
Classed based on metabolism speed
Poor
Normal
High
Ultra-rapid metabolisers
Poor CYP2D6 metaboliser means
Codeine to morphine is slow/not much morphine produced
Patient may not experience pain relief
Ultrarapid CYP450 metaboliser means
Codeine to morphine = rapid
Morphine intoxication or adverse drug reactions
CYP2D6 genetic variation/polymorphism
CYP2D6 not expressed in 7% caucasians, HYPERACTIVE in 30% east africans
What do you need to do if someone possesses ultrarapid metabolisers? (pro drug situation)
Reduce/titrate dosage
Main route of drug elimination
Kidney
others: sweat, tears, bile, lungs, genital secretions and breast milk
3 processes of renal excretion
Glomerular filtration
Active tubular secretion
Passive tubular reabsorption
(GAP)
What modification of capillaries allows kidney to filter effectively?
Fenestrations of capillary increase permeability and enable optimised exchange of ions/molecules
Glomerular filtration phase
Glomerulus = 20% renal blood flow
Unbound drug enters bowmans capsule
Proximal tubular secretion phase
Remaining 80% of blood via peritubular capillaries
High expression of OAT and OCT
OAT and OCT types in proximal tubule
Low affinity/high capacity
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)
How do drugs get reabsorped by distal tubule reabsorption?
Through OAT’s and OCT’s
But they are subject to competition between drugs
Drugs reabsorbed via OAT’s
Urate (gout)
Penicillins
NSAID’s
Antivirals
Drugs reabsorbed by OCT’s
Morphine
Histamine
Chlorpromazine
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
Urine normal pH
6.0 - 7.5
Typical = 4.5 - 8.0
What happens if distal collecting tubule is acidic?
pH is low
Weak acids protonate (become charge neutral)
They will be reabsorbed
What happens if distal collecting tubule is alkaline?
pH is higher
Weak bases become deprotonated (become charge neutral)
They will be reabsorbed
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)
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
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
Total body clearance equation
Hepatic clearance + renal clearance
How do we measure clearance?
Use Vd (apparent volume distrubution) measured in ml/min
Problem with clearance model
Real volume of plasma cannot be completely cleared of a drug via glomerular filtration/tubular secretion
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
What do Vd and clearance allow us to calculate?
Half life (t 1/2)
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
Half life equation
(0.693 x Vd) / CL
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)
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)
Drug injected by Iv hypothetically
Skips distribution phase and distributes throughout whole body straight away
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
Exponential –> linear graph when logged shows
Linear elimination kinetics
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
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
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
What happens as molecules are metabolised over time?
Plasma concentration decreases
Catalytic rate decreases
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
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
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
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
Examples of zero order kinetics
Alcohol
Phenytoin
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)
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
Example drugs of zero order kinetics
Phenytoin Prozac Alcohol MDMA Paracetamol at high doses
