Drug Elimination I Flashcards
Other than plasma, what compartments can drugs distribute to
Interstitial fluid
Fat store
Intracellular fluid
Trans cellular fluid
Why isn’t drug distribution equal
Blood perfusion to organs /tissues
Ability to cross membranes (lipid solubility,ionisation)
Plasma protein binding (if bound can’t pass)
What is another barrier apart from the GI tract
Blood brain barrier
Drugs can’t enter the brain from blood unless psychotic
What does albumin bind to
Acidic drugs
Which protein can bind to neutral drugs
a1 acid glycoprotein
What happens if drugs are bound to eg A1 acid glycoproteins
They can’t pass membranes into other fluid compartments
How do you work out volume of distribution of drug (Vd)
Total amount of drug administered (Q)
/
Plasma concentration of drug (Cp)
Why does chloroquine drug have high volume of distribution
Because it’s lipiphillic
Why do drugs like heparin and warfarin have a low Vd
Because they are bound to proteins so more in the plasma
Which types of drugs need to be metabolised first before elimination and why
Lipophillic drugs
Need to be converted to water soluble products before elimination eg via kidney
What are the major sites of metabolism
Liver , enterocytes , kidney, lungs
What kind of reactions are phase 1
Catabolic
What are drugs introduced to in phase 1 to become reactive/ soluble
OH, amino NH2, COOH(carboxylic)
What are the 3 oxidation reactions which occur in phase 1 (loss of e/h)
1- hydroxylation : H —-> OH
2- deamination: NH2 —-> C=O
3- dehydrogenation: OH ——> C=O
Where do oxidation reactions occur and name some enzymes
Liver
(Monooxygenases)
Cytochrome p450
Alcohol dehydrogenase
Which kind of reaction occurs in reduction (gain of H/e)
Hydrogenation
C=O —-> OH
Which enzymes are involved in reduction in phase 1 (hydrogenation)
Reductases
What is the 3rd reaction type in phase 1 and where does it occur
Hydrolysis (addition of HOH)
Usually in plasma (not often in liver)
What are the enzymes involved in hydrolysis usually in plasma
Esterases eg cholinesterase, peptidase
What do cytochrome p450s require in oxidation
Oxygen, NADPH, NADPH reductase
Why do P450 vary
Species differences
Environmental factors which can induce them
Genetic polymorphism
Other drug interference
What does aspirin esterase do
Hydrolyses aspirin into salicylate
WhAt does butrylcholine esterase do
Hydrolyses SUXAMETHONIUM drug which usually binds to cholinergic receptors and causes muscle paralysis
Where do phase 2 reactions occur
Usually in liver but can happen in kidney or lung too
What happens in phase 2
Donors add a group to the drugs to make them less reactive than in phase 1 = form a conjugate
Give an example of a donor in phase 2
Acetyl coA which forms an acetyl conjugate out of the drug
What are prodrugs
Drugs which become active only within metabolism
Give 3 examples of drugs which become active after metabolism (prodrugs)
Diacetylmorphine—-> morphine
L dopa —-> dopamine
Valaciclovir —-> acyclovir
Where are most drugs which aren’t absorbed excreted
In the gut as faeces
Which kind of drugs are excreted through the kidney as tribe
Water soluble via metabolism
Give 3 other excretion sites other than gut and kidney
Liver in bile which is emptied to small intestine
Gases —> exhaled
Secretion in glands —> breast milk or sweat
When can saturation of elimination route happen and what happens in result
If organ is failed eg kidney failure
Causes build up in plasma which is toxic
What is CLtot
Total clearance
Volume of plasma which has been cleared of the drug per unit of time
How do you work out total clearance cltot
Dose / total exposure (AUC)
How do you work out clTOT for administration with little bioavailability
Dose x bioavailability/ AUC (exposure)
What is first order kinetics in elimination
Rate of elimination is related to Cp (plasma conc)
How much of the drug given affects Kel
What is Kel
Elimination constant rate
How do you work out Kel
CLtot/ volume of distribution
How do you work out Kel from a slope on a graph
Plot conc and time and then take 2 readings under curve
Do log concA/conc B
/ time difference between A and B
What is elimination half life
Time taken for plasma drug conc Cp to decrease by 1/2
How do you work out half life elimination off the same slope a and b
Log2
/
Kel
How many half life’s do drugs have
6
When can someone’s half life increase
If they have lower conc of enzymes in metabolism eg via age,genetics or taken inhibitors for eg CYP enzymes
Means they have lower rates of metabolism and elimination
What is zero order kinetics
Dosage of the drug given isn’t related to plasma conc and Kel
Elimination is limited due to other factors such as number of enzymes rather than dosage/conc of drug
