L21: Pharmacokinetics II Flashcards
What is meant by elimination?
Metabolism and excretion
Why are drugs removed from the body?
Drugs tend to accumulate in the body and need removing
Body has homeostatic mechanisms to regulate many hundreds of endogenous molecules to ensure they exist within a given concentration range over time
Drugs are recognised and eliminated from the body
Mechanism evolved to deal with xenobiotics which were normally toxic
What is metabolism?
Changing of the molecular structure ready for excretion
Split into two phases
1. Phase 1: introduce or unmask more polar groups on the drug molecule (OH or NH2) by oxidation and reduction reactions or hydrolysis
2. Phase 2: addition of a number of molecules that conjugate with the drug molecule
Why is metabolism important?
Essential for lipophilic compounds that would otherwise just diffuse through renal cell plasma membranes into the plasma and back into the body
Can also activate an inactive pro-drug
What happens during phase 1 metabolism?
Cytochrome P450; CYP450, large family of molecules will optimally metabolise different drug molecules
What are CYP450s?
Enzymes
Generalist
Take a long time to metabolise compared to highly specific specialised enzymes
What factors can affect metabolism?
Age, gender, general health (heart, renal, hepatic), induction and inhibition by Rx and OTC drugs
How does induction affect metabolism?
Increase the transcription and translation or slow the degradation of CYP450s
Over 200 inducers
Increases the rate of metabolism
Typically occurs over 1-2 weeks
What impact does induction have?
Alters the rate of metabolism of drugs meaning the dosage of certain drugs may have to be increased
How does inhibition affect metabolism?
Elevation of drug plasma levels
Risk of toxic side effects
Occurs over 1-2 days
What type of inhibitors are there?
Competitive- Metabolised at the same site
Non competitive- Inhibitor binds to a separate site
What happens during phase II?
Carried out by hepatic enzymes
Further increases the ionic charge
Conjugated to other molecules
What other molecule are they conjugated to?
- Glucornonide
- Sulphate
- Gluathione
- N-acetyl
What is excretion?
Removal of the metabolised drug from the body
Where does excretion take place?
Mainly the kidneys but some via the intestines, lungs or skin
What are the three stages of renal elimination?
Glomerular filtration
Active Proximal tubular secretion
Passive Distal tubular reabsorption
What happens in the glomerulus?
20% of renal blood supply
Unbound free metabolites diffuses out into the Bowman’s capsule
Process is limited by the GFR 125ml/min
What happens in the proximal tubules?
Remaining 80% of renal blood flows through the peritubular capillaries
Charged molecules and their polar metabolites are transported through OATs and OCTs
Most effective as it receives 80% blood
What happens in the distal tubules?
Water is reabsorbed
Drug concentration increases
If in lipophilic form it is reabsorbed down it concentration gradient
Define clearance?
Rate of elimination
The volume of plasma that is completely cleared of drug per unit time
How is it calculated?
Total body clearance= Hepatic clearance + Renal clearance
What factor affect clearance?
Same as affect elimination
HRH
Heart - cardiovascular/ circulatory factors affecting flow to main organs of elimination
Renal - factors affecting renal elimination
Hepatic - factors affecting hepatic elimination
What is the drug half life?
The amount of time over which the concentration a drug in the plasma decreases to one half of that concentration value it had when it was first measured
What does the drug half life tell you?
How long the drug will stay in your body
Dosing regime
What is the drug half life calculation?
t1/2= 0.693 (or 0.7) x Vd / CL
What does linear or first order kinetics mean?
Rate of the process of interest is dependent on the concentration
e.g. relatively few molecules in the plasma (low concentration) rate of elimination is slow
Concentration is high the rate of elimination is high
What is zero order or non linear kinetics or saturated kinetics?
For a high concentration of drug the kinetics are no longer concentration dependent and are said to be saturated as they cannot work any faster
Is drug clearance linear or non linear kinetics?
Most drugs at therapeutic levels have linear kinetics
At high concentration non linear
Transporters are generalists- sometimes it takes a long time to clear a drug sometimes
What drugs display saturated kinetics?
High dose aspirin, phenytoin, verapamil, fluoxetine
Alcohol and MDMA (ecstasy)
Can only occur with polypharamacy
