20. Pharmacokinetics 2 Flashcards
What is drug elimination?
Metabolic and excretory processes
Both processes closely integrated to optimise drug removal
Removes both exogenous and endogenous molecular species
What is the role of phase I and II enzymes?
Metabolism drugs - increase ionic charge, enhance renal elimination
Lipophilic drugs diffuse out renal tubules back into plasma
Once metabolised drugs usually inactivated
Which enzymes are used in phase I metabolism?
Cytochrome P450 enzymes (CYP450s)
What are CYP450s?
Large group of isoenzymes located on external face of ER
Catalyse redox, dealkylation and hydroxylation reactions
Versatile generalists
What happens to metabolised drugs after phase I?
Metabolised drugs are eliminated directly or go onto phase II
What are pro-drugs?
Activated by phase I metabolism to active species
E.g. codeine to morphine
What is phase II metabolism?
Carried out by hepatic enzymes - phase II enzymes (mainly cytosolic)
Still generalists but exhibit more rapid kinetics than CYP450s
Enhances renal elimination
What do phase II enzymes do?
Enhance hydrophilicity by further increasing ionic charge
Catalyse sulphation, glucorinadation, glutathione conjugation, methylation and N-acetylation
What factors affect drug metabolism?
Age - variable patterns in paediatric groups, reduced in elderly
Sex
General health/dietary/disease - especially hepatic, renal, CVS (HRH)
Gives decreases functional reserve
What happens in CYP450 induction?
Concurrent administration of certain drugs can induce specific CYP450 isoenzymes
Induction mechanism via:
- increased transcription
- increased translation
- slower degradation
If another drug in body metabolised by induced CYP450 isoenzymes then it’s rare of elimination be increased
Plasma levels of drug will then fall
How long does induction process occur for?
1-2 weeks
Describe how carbamezepine (CBZ) work (CYP450 induction)
CBZ is an anti-epileptic metabolised by CYP3A4
It induces expression of CYP3A4 - lowering its own levels affecting control of epilepsy
How does CYP450 inhibition work?
Concurrent administration of certain drugs can inhibit specific CYP450 isoenzymes
Inhibition mechanism is via:
- competitive or non-competitive inhibition
If another drug in body metabolised by inhibited CYP450 isoenzymes then it’s rate of elimination will be slowed down
Plasma levels of drug will then decrease
How long does inhibition process occur for?
1 to a few days
What are the routes of drug elimination?
Main: kidney
Minor: bile, lungs, sweat, tears, genital secretions, saliva, breast milk
Why are the 3 processes in renal excretion?
Glomerular filtration
Active tubular secretion
Passive tubular reabsorption
Where are the OAT and OCT in the kidneys?
In capillaries and proximal tubule
Describe the features of proximal tubular secretion
Low affinity/high capacity OATs and OCTs Competitive transport Carry ionised molecules out Reverse of process in small intestine Facilitated diffusion/secondary active transport
What are examples of OATs and OCTs in distal tubular reabsorption?
OATs: urate, penicillins, NSAIDs, antivirals
OCTs: morphine, histamine, chlorpromazine
In a weak acid, what is the effect of acid urine and alkaline urine?
Acid grind increases absorption
Alkaline urine decreases absorption
Look at diagram
In a weak base, what is the defect of acid urine and alkaline urine?
Acid urine decreases absorption
Alkaline urine increases absorption
See diagram
What is clearance?
The apparent rate of elimination of a drug from he body
Total drug clearance consists of that from all routes
Total body clearance = hepatic clearance + renal clearance
What is the formal definition of clearance?
The volume of plasma that is completely cleared of the drug per unit time
What do Vd and CL provide?
Predicts how long drug will stay in body
Provide estimate of drug half life
What is drug half life?
Amount of time over which the concentration a drug in plasma decreases to one half of that concentration value it has when it was first measured
If CL stays sane and Vd increases, t1/2 increases
If CL increases and Vd stays same, t1/2 decreases absorption
Why is the graph log [plasma] vs time linear?
Rate of metabolism or excretion is proportional to plasma concentration of drug
If there is a large functional reserve
Lots of phase I/II enzyme sites
Plenty of OAT/OCT transporters
What happens when elimination processes become saturated?
When processes are saturated they become rate limited
They cannot go any faster - all enzymes or carriers are working
Referred to as saturated or zero order
Describe drug elimination kinetics graph
If y axis rate of elimination
If x axis dose of drug
At low doses drug metabolism is first order, proportional to drug dose
At high doses, drug metabolism is zero order, constant and independent of drug dose
1st order kinetics vs zero order kinetics
1st- predictable, therapeutic resonate from dose increases (most drugs)
Zero- therapeutic response can suddenly escalate elimination mechanisms saturate (alcohol)
What is the clinical importance of zero order kinetics?
Drugs at or near therapeutic dose with saturation kinetics
More likely to result in ADRs or toxicity
Fixed rate of elimination per unit time
Relatively small doses can produce large increments in plasma [drug], lead to serious toxicity
Greater risk of drug- drug interactions due to taking up sites
