Pharmacology- Drug administration and elimination Flashcards
Define bioavailability (F)
fraction (F) of the administered dose that reaches the systemic circulation
intravenous route: F= 1 (ie 100%)
rest of the route: F < 1
What is first pass metabolism
phenomenon of drug metabolism whereby the concentration of a drug is greatly reduced before it reaches the systemic circulation
Route of drugs that goes through first pass metabolism
oral > GI > portal vein > liver (liver enzyme metabolises it) > hepatic vein > systemic circulation > hepatic artery > liver
What are prodrugs and why are they used
prodrugs: biological inactive parent drug that requires chemical/enzymatic rxn to activate it
What is phase 1 and 2 reactions
Drug — (phase 1) —> derivative – (phase 2) —> conjugate
Drug metabolism is divided into three phases.
In phase I, enzymes such as cytochrome P450 oxidases introduce reactive or polar groups into xenobiotics.
These modified compounds are then conjugated to polar compounds in phase II reactions. These reactions are catalysed by transferase enzymes such as glutathione S-transferases.
In phase III, the conjugated xenobiotics may be further processed, before being recognised by efflux transporters and pumped out of cells.
Drug metabolism often converts lipophilic compounds into hydrophilic products that are more readily excreted.
Phase 1 oxidation hydroxylation dealkylation deamination hydrolysis
Phase 2
conjugation (+ molecule)
What enzyme is usually responsible for phase 1 drug metabolism? And what does it do to the drug
cytochrome p450
introduce reactive or polar groups into the drug
What enzyme is usually responsible for phase 2 drug metabolism? And what does it do to the phase1- modified compound
transferase enzyme (eg. glutathione S- transferase)
modified compounds are conjugated to polar compounds
therefore cannot diffuse across membranes
What is the enzyme that is shared by humans, which may produce resistance in drug metabolism in microorganisms?
glutathione S-transferases
What is the cofactor used by CYP (human cytochrome P450s) terminal oxidase enzymes?
heme
What are 4 common ways which CYP450s metabolises drug?
oxidation
reduction
hydrolysis
hydration
H OR H
What is the DNA adduct form of benzo(a)pyrene from tobacco smoke, coal and tar?
BPDE
after metabolism via CYP1A1/1B1
T/F: Rifampicin and barbiturates is an inhibitor of CYP450 3A4
False
Rifampicin is one of the most potent inducer of hepatic CYP450
It increases its metabolic activity, thereby can make drugs less effective/ineffective
eg. reduce effect of warfarin, birth control pills…
Why is knowing the inducer/inhibitor of CYP450s important?
If a drug is metabolised by liver:
Inducer of P450: more breakdown of drug, less bioavailabiltiy (.’. requires dose boost)
Inhibitor of P450: doesn’t /reduce breakdown of drug, person may OD
Where does phase 2 reactions usually occur?
mainly liver (but can be in kidney/lungs)
What causes paracetamol toxicity?
Normally: converted to non-toxic metabolites via Phase 2 metabolism
- sulfate conjugation-bypassed phase 1
- 2) Glucuronide conjugation
Small amount converted to NAPQI (highly reactive & toxic intermediate) by CYP450
- but its quickly detoxified by glutathione conjugation
Overdose: sulfate and glucuronide pathways are saturated > more paracetamol is metabolised via CYP450>
too much NAPQI produced, irreversibly binds to liver protein -> necrosis
What is the non-toxic form of NAPQI (N-acetyl-p-benzoquinone imine) after glucuronide conjugation?
mercapturic acid
What comes out of phase 1 reactions
smaller, polar/non-polar form of drugs
can be active/inactivated
what comes out of phase 2 reactions
larger, polar, water soluble and INACTIVE
How to calculate clearance of drug?
Clearance = (Drug conc. in urine x rate of urine production) / drug concentration in plasma
Hydrophillic molecule > Kidney > urine
Or
Conjugate from liver > Bile > intestine > Feces/ de-conjugation and reuptake via entero-hepatic cycling
What is a half life of a drug?
Time taken for plasma concentration to reduce to half its original concentration
What is zero order elimination, give 2 examples
Is half life constant?
Linear relationship
NOT CONSTANT half life
(elimination rate is not proportional to drug concentration)
Rare
Phenytoin (anti-seizure)
Aspirin
Drug is eliminated constantly per time unit, what order elimination is this?
(Elimination is proportional to drug concentration)
1st order
In a first order eliminated drug, is the amount removed at time point T and T+ 1 the same?
No.
Less amount of drug is excreted at T+1 BUT it’s ALWAYS 50% of the drug concentration remaining
.’. proportion is constant
Within how many half lives do accumulation of drug occurs?
4 half lives
by 5 half lives, most drugs will be removed from the system
