Drug Administration and Elimination Flashcards
what are the different routes of admin for drugs? (8)
- oral
- IV
- IM (intramuscular)
- subcutaneously: fat depot
- rectum
- inhalation: lung then blood
- transdermal: skin to systemic blood supply
- topical: skin (but at local site)
- sublingual (under tongue): enters systemic blood directly
what is difference in bioavailability of oral v IV drug admin?
which is quicker?
oral: 10 to 50 %
IV: 100% quicker
which route of admin is slow release?
- IM
- Subcut
which route of admin bypasses 1st pass metabolism?
sublingual
what are some more specialist route of admin?
- intranasal
- intrathecal (into CSF )
- epidural (outside of spinal dura)
- intra-articular (joint space)
which route of admin bypassese the BBB to allow drug to work on brain?
intrathecal: into CSF
which quckest to slowest route of admin?
what is 1st pass metabolism?
= all drugs absorbed by the GI tract enter portal blood supply and directly to the liver: main organ for metabolising drugs before entering systemic blood supply
drugs are metabolised and destroyed by liver before goes to heart (and being pumped out)
how can we use the fact that oral administation of drug undergoes liver metabolism to a beneficial way?
prodrug mechanism:
- biological inactive parent drug, when passing through liver require chemical / enzymatic transformation to release active drug
why is prodrug mehcanism useful?
- some drugs cannot pass through physiological barriers (e.g. BBB): pro-drug can instead
- after passing through - gets cleaved into drug
- some prodrugs are active parent drug and then when metabolised, are also active: longer effect
how can prodrug use its environment to stop growth of a tumour cell? (e.g. using EGFR)
due to different environments:
- Epidermal Growth Factor Receptor (EGFR) is an oncogene
- drug is attached to cobolt: in normal o2 conditions = inactive
- drug moves into hypoxic tissue (the tumour): activated:
- hypoxic env means cobolt3+ –> cobolt 2+
- this releases the inhibitor of EGFR to bind to EGFR = switched off / inhbited
what are the two types of metabolism?
phase 1- biotransformation: drug becomes smaller and more water soluble so the kidney can remove it
- a polar group is introduced or unmasked (this is the biotransformation) to the drug
- biotransformation occurs by: oxidation (majority), hydrolysis or reduction
- some metabolites after this: water soluble enough to be excreted straight away (via kidneys) = metabolite A
- other drugs may need additional step to make more water soluble / polar -> go to phase 2
phase 2: synthesis (stick a group onto drug to make it more soluble)
- *-** conjugation
- e.g. liverr takes big chem (e.g. glucose) adds it onto drug
- is able to be excreted
what method of biotransformation in phase 1 drug metabolism occurs the majority of the time? by which family of enzymes?
what are the other ways?
majority of time = oxdidation. undergone by cytochrome P450 family enzymes
also: hydrolysis or reduction
do all drugs do both phase 1 / phase 2 metabolism? / describe route of phases
some will do:
- phase 1 & excreted
- phase 1 –> phase 2 & excreted
- phase 2 & excreted
which of phase 1 or phase 2 reactions are:
- a) synthetic?
b) degradative reaction? - form smaller or larger molecules?
- a) phase 2 metabolism uses synthetic reactions
b) phase 1 metabolism uses degradation reactions (unmask polar group) - phase 2 makes larger molecules, phase 1 makes smaller molecules
which is main family that undergoes oxidative degradative reaction in Phase 1?
cyctochrome P450 (monoxygenases)
prodrugs are usually metabolised in which phase? why?
prodrugs metabolised in phase 1 - so can be turned into active metabolites
what can be added to metabolite / drug in phase 2 metabolism?
add:
sugars, sulphates, acetyl and methyl units
where does phase 1 / phase 2 metabolism occur?
are phase 1 / 2 products active or inactive?
in the liver !!
(phase 1 = active (prodrug) or inactive. phase 2 = inactive)
what are elimination methods?
which type do drugs do
- majority of drug goes out via urine: cuz water soluble
- some goes out via bile: to go through urine or then defecate
what happens to drugs if reabsorbed back into bile?
if phase 1 drug? phase 2 drug?
if goes back via bile:
- goes back into GI system:
i) phase 1 drug: reabsorbed from GI system and goes back to liver 4 further met.
ii) phase 2 drug: exits via defecation
what is clearance?
how calculate?
clearance: rate of elimination in relation to the drug concentration
clearance = rate of elimination (through urine) / concentration remaining (in blood plasma)
what is half life of drug?
what happens to drug with low half life?
time taken for plasma concentration to reduce to half its original concentration
low half life: quickly eliminated from the body
how do u work out half life of drug?
most drugs, with first order kinetics, have how many half lifes?
5
what is 1st order vs zero order kinetics ?
first order elimination: elimination is proportional to drug concentration. 95% drugs
- e.g. 100g - 50g - 25g - 12.5g
zero order kinetics: elimination is a constant quantity per time unit of the drug - e.g. per hour, lose 2.5 units / lose same amount each hour. linear elimination. rare !
which type of drug elimination is this?
first order elimination
what type of drug elimination is this?
zero order elimination
how many half lifes are gained by doubling dose for first order kinetic drugs?
doubling dose = 1 half life gained (not that much - could make it tox too)
whats therapeutic window / range ?
what is the safe range of drug betweeen?
- the drug concentration that has therapeutic effects
- safe range: between minimum therapeutic conc and minimum toxic range
why do u need to understand drug half life for dosing?
what happens if dosing interval is more than 5 half lives?
what happens if dosing interval is shorter than 4 half lives?
need to understand drug and redose before it leaves therapeutic window so can maintain therapeutic range
- if dosing interval is more than five half lifes: single dose will go back to 0 (picture 1)
- *- if dosing interval is shorter than 4 half lifes accumulation will occur**
- second dose means that will go back into therapeutic range, but third could make it go into toxic range. need to be careful with dosing to keep in therapeutic window.
what are two different types of dosing?
- *loading dose:**
- larger than normal dose
- gets to therapeutic range quicker (emergencies)
- mainly for drugs with large vol. of distribution
- *maintenance dose:**
- small fixed dose
- maintains drug in therapeutic range
what is this type of dose?
maintenance doses - small fixed dosees
what type of dosing is this?
loading dose AND maintence dose
what are factors that afect drug metabolism?
- ethinicity
- age
- gender
cytochrome P450 effectiveness differ in these ^^
- diet
- alcholism
- disease e.g, liver and kidney disease
- smoking
- DDI
