S10 + 11 - Pharmacokinetics Flashcards
Why do phase 1 and 2 enzymes increase of drug elimination?
Metabolism of drugs increases their ionic charge and so enhances renal elimination
What are phase 1 enzymes?
Cytochrome P450s (CY450s)
What reactions do phase 1 enzymes do?
- redox
- dealkylation
- hydroxylation
Why are CYP450s versatile generalists?
They metabolise a very wide range of molecules
Do metabolised drugs have increased of decreased ionic charge?
Increased
What are the two outcomes from phase 1?
- Eliminated directly
2. Go onto phase 2
Can some drugs be activated by Phase1 metabolism?
Yes (pro-drugs can be activated to the active species)
What are examples of pro-drugs?
Codeine to morphine
What kind of enzymes carry out phase 2 metabolism?
Conjugate enzymes - hepatic enzymes -cytosolic
What is the difference between phase 1 and phase 2 metabolism?
Phase 2 exhibits more rapid kinetics than CYP450s
Still generalists
What do phase 2 enzymes do?
Enhances the hydrophilicity further by increasing the ionic charge
What reactions do phase 2 enzymes do?
- sulphation
- glucorinadation
- glutathione conjugation
- methylation
- N-acetylation
What does phase 2 metabolism lead to?
Leads to enhanced renal elimination
What factors affect drug metabolism?
- Age
- Sex
- General health/dietary/disease (esp. hepatic, renal, CVS diseases)
- Other drugs (induce/inhibit CYP450s)
- Genetic variability/polymorphism/non-expression affects CYP450s
What does the HRH acronym stand for?
Heart (CVS)
Renal
Hepatic
How do some drugs induce CYP450?
- increased transcription
- increased translation
- slower degradation of the enzyme
This increases the metabolism of the specific drugs that the CYP450 metabolises and so increases elimination of that drug - can lead to serious therapeutic consequences
How do some drugs inhibit CYP450s?
- competitive/non-competitive inhibition
If a drug is usually metabolised by CYP450s then it’s rate of elimination will be slowed down - can have serious side effects
What is the main route of drug elimination?
The kidney
What are other routes of drug elimination?
- bile
- lung
- sweat
- tears
- genital secretions
- saliva
- breast milk
What are the three processes of renal excretion?
- Glomerular filtration
- Active tubular secretion
- Passive tubular reabsorption
What is genetic polymorphism?
What is genetic variation?
A gene can make different versions of the same protein.
How much a gene is expressed.
What type of capillaries are in the kidneys?
Fenestrated - increases the permeability, increases exchange of ions/molecules
How much of the renal blood flow goes to the glomerulus (glomerular filtration) or to the peritubular capillaries (proximal tubular secretion)?
Glomerulus - 20%
Peritublar capillaries - 80%
How does does the drug pass through the membrane in glomerular filtration?
Unbound drug enters via bowman’s capsule
How does the drug pass through the membrane in proximal tubular secretion?
There is high expression of OATs and OCTs
What happens in distal tubular reabsorption?
- along the whole tubule length water is reabsorbed
- along the whole tubule length the solute conc increases
If the drug/metabolite is still lipophilic, it passes back into the blood.
If the drug/metabolite is ionic, use of OATs and OCTs
What is clearance? What is total drug clearance?
The rate of elimination of the drug from the body (the volume reached of plasma that is completely cleared of drug per unit time)
Total drug clearance is clearance from all routes
How do you calculate total body clearance?
Total body clearance = hepatic clearance + renal clearance
What is a drug half life?
The amount of time over which the concentration of a drug in plasma decreases to one half that of the concentration value it had when it was first measured
What is the drug half-life dependent on?
Vd and CL
What is Vd?
The apparent volume of distribution (a model)
What are linear elimination kinetics? Why are they linear?
The rate of metabolism/excretion is proportional to the plasma conc of the drug (if there is a large functional reserve - lots of phase 1 and 2 enzymes and lots of OATs and OCTs).
So the rate of metabolism/transport will be proportional to the number of molecules occupying a catalytic/carrier site per unit time
What happens when elimination processes become saturated? What is this called?
They become rate limited - can’t go any faster - all enzymes and carriers are working
Saturated or zero order kinetics
What does the shape of zero order kinetics curve look like in comparison to a 1st order kinetics curve?
1st order - straight line
Zero order - curved
What is the likely result of a small drug dose change with saturation/zero order kinetics?
A relatively small dose can lead to:
- large increments in the plasma drug concentration
- toxicity
Can you calculate the half life of a zero order drug?
No
Which patients are most at risk of drugs with zero order kinetics?
- elderly and infants due to decrease/immature capacity
* the seriously ill (cancer, liver disease, alcoholics) due to reduced hepatic and renal capacity
