ADME Flashcards
What is elimination of a drug, what does it depend on?
Rate at which plasma concentration of drug falls over time
Depends on:
1) Metabolism of drug
2) excretion
What factors are considered when governing choice of drug administration ensuring correct concentration reaches relevant tissues?
Rate of absorption from site of administration
Rate of transport to site of action
Desire to administer close to desired site of action to minimise side effects
Susceptibility to metabolism or digestion
Desired time course of action
How can you give drug topically, what’s the benefit?
By skin, eye or sniffing - delivered directly to target area
What is the therapeutic window?
The range of drug plasma concentrations between it being toxic and ineffective
Define therapeutic window (equation)
Toxic or lethal dose/therapeutic dose
What is the therapeutic index?
LD50/EC50
LD50: the lethal dose of a drug for 50% of the population (e.g mg per litre of body fluids)
EC50: the minimum effective dose for 50% of the population (e.g. mg per litre of body fluids)
What are different routes of drug administration? From quickest to slowest
IV, inhalation, sublingual (under the tongue), oral/rectally, intramuscular/subcutaneous, transcutaneous
What are the four ways drugs can be injected?
Intravenous
Subcutaneous
Intramusuclar
Intraspinal
What does delivery of drug from subcutaneous and intramuscular injections depend on?
Drug diffusion at site of injection and local blood flow
What is intrathecal delivery used for?
Deliver straight into CSF. lumbar puncture (used for CNS drugs that can’t cross BBB)
Different types of types of drug delivery to GI tract
Oral - but some drugs inactivated by gastric acid in stomach
Rectal - used when you can’t swallow
When is it inappropriate to deliver drugs to the GI tract, how can this be combated?
Unsuitable for peptides (drugs broken down) and drugs metabolised by liver
Either use alternative delivery or a protective capsule
What factors determine drug absorption?
Gut motility (i.e. just after meal drug has slowed progression through intestine)
Size
Coating - tablet to slow absorption and decrease local peak concentration
Lipid solubility pass through epithelia
Rate at which drug enters blood stream e.g. blood flow
How is lipid solubility determined by degree of ionisation and pH of environment?
Charged species repelled by uncharged lipid molecules
Weaker acids/base more soluble (less readily ionised) at neutral pH
Weak acidic drug ionises more rapidly in alkaline conditions and vice versa
Why can ion trapping occur?
Substance can only move across membrane in non-ionised form
If there is a pH difference across the membrane, may ionise inside.
Cannot get out
How is dissociation constant derived, what is it used for?
Used for quantifying what % of drug will be ionised and water soluble or non-ionized and lipid soluble
Lower pKa (acidic) = greater tendency to ionise at physiological pH Higher pKa (basic) = lower tendency to ionise at physiological pH (more lipid soluble)
Derived using Henderson Hassel bach:
For weak acid: pKa = ph + log10 x ([AH]/[A-])
What does the Henderson-Hasselbalch equation describe?
Estimate percentage of drug ionised at given pH (dissociation constant)
If mostly unionised then drug can cross cell membrane
Why does increasing lipid solubility infinitely not increase drug absorption?
Lipophilicity increases so much drug stays at site of injection
What is the volume distribution of a drug , why is this important, what does it tell us?
Theoretical volume that would be needed to contain a total amount of administered drug at same concentration as observed in plasma
If greater than total volume of aqueous compartment of body then drug must have accumulated in non aqueous compartments (e.g. subcutaneous fat)
If drug distributes equally throughout aqueous body compartments, plasma conc of drug =
dose/volume of drug
What is equation for volume of distribution?
Dose/conc in plasma - lets you know how much of drug has accumulated elsewhere
What if estimated plasma conc of drug is greater than actual conc?
Drug has accumulated elsewhere
How is conc of drug at site of action affected by size of compartments?
Drug concs is equal in both compartments at equilibrium but more drug in larger compartment
List the factors that affect volume of distribution of a drug (4)
1) Blood flow to/from target tissue
2) Lipid solubility
3) Binding to plasma protein
4) Carrier mediated transport
Where do liposoluble drugs accumulate?
Fat
How does lipid solubility effect drug distribution?
1) Simple diffusion across epithelia
2) Effect of pH across epithelia on distribution of ionisable drugs. Non ionised drugs can diffuse but equilibrate. If theres a
pH difference: ion trapping
3) liposoluble drugs partition into body fat
What are the effects of drug accumulation in non aqueous compartment (i.e. fat)?
Decrease initial free conc
Slow distribution to target tissue
Slow clearance
Prolong duration of action
How does binding to plasma proteins affect drug distribution?
Reduces free drug able to diffuse into tissue fluid
Reduces renal clearance of drugs
Drug drug interactions occur through competitive displacement from plasma proteins.
How does carrier mediated transport affect drug distribution?
Specific transporters (accumulation in cells)
Uptake of some drugs from gut
Excretion into bile/urine
What are examples of natural barriers?
Blood brain barrier
Blood placenta barrier
What are depot drugs?
Slow releasing, slow acting form of medication, the active drug is the same but they are administered with another substance that slows the release.
Why are depot drugs used?
For people who are unwilling/forget to take tablets (i.e. psychosis medication) then they can receive an injection (e.g. intramuscular) that slows release
What 3 methods of transport can occur across the BBB?
Transcellular diffusion (greasy lipid soluble) Carrier mediated transport
Efflux transport.
What does the multi-drug resistance transporter do?
Pumps out anything hydrophobic or big to prevent it being in brain interstitium
Why are is parkinsons disease treated with L-dopa instead of dopamine?
Oral dopamine is broken down by gut peptidases
L-dopa enters blood then can cross BBB by amino acid co-transporter
How is L-dopa useful in the brain in treating parkinsons?
In brain converted to dopamine by dopa decarboxylase.
What is the use of carbidopa?
Prevents action of dopa decarboxylase before the brain, so L-dopa is not converted to dopamine before the brain, dopamine cant cross the BBB
What is the pharmacological definition of clearance (units)?
Clearance is the volume of plasma from which a substance is completely removed per unit time (L/hr or ml/min).
This reflects the rate of drug elimination divided by plasma concentration.
How is clearance different to excretion?
Clearance - drug removed from plasma (may be reabsorbed)
Excretion - drug removed from body
What is the elimination half life of a drug?
Time it takes for concentration of a drug in plasma to be halved or total amount of drug in the body to be reduced by 50%.
Where are drugs mainly metabolised?
Liver, then GI, kidney and lungs
Why are non-polar/lipophilic drugs hard to excrete?
It can escape the urine by travelling back into cells / blood stream by diffusing though renal epithelium and membrane.
What is a xenobiotic?
A foreign chemical
What is meant by saying the two phases of metabolism are independent of eachother?
Drugs not necessarily metabolised sequentially by both mechanisms
What are the two key phases of drug metabolism?
Inactivate the xenobiotic → through introduction of a functional group, oxidation or hydroxylation
To conjugate the to a polar molecule
Why conjugate inactive xenobiotic to a polar molecule?
Makes it more soluble such that it will remain in the urine
What happens in phase 1 of metabolism?
Introduce/reveal functional group for phase 2, can abolish activity or generate toxic metabolites
What two ways are xenobiotics transformed in phase one?
Hydrolysis
Oxidation (hydroxylation)
What are the two key ways xenobiotics can be oxidised?
Hydroxylation - cytochrome P450 oxidase introduction of C-O in replacement of C-H
Deamination of monoamines via addition of oxygen - Monoamine oxidase MAO
Where are P450 oxidases present?
Membranes of SER in liver and small intestine
What do P450 oxidases require to hydroxylate?
NADPH
What molecules are target by P450 oxidases?
Aliphatic and aromatic
Why can phase 1 be dangerous?
Can generate toxic metabolites e.g. severe hepatotoxicity in paracetamal overdose
What happens in phase 2 normally, what is the exception?
Conjugation of functional group from phase 1 to large polar molecule for excretion (e.g. sulfate, glycine, gluthathione)
Exception: small, non polar methyl groups via transferases
What is the most common conjugation?
Glucuronic acid
What happens in paracetamol overdose?
Toxic metabolite generated from P450 oxidation exceeds supply of glutathione conjugate
Toxic substance accumulates
What is involved in renal excretion of drugs?
Glomerular filtration, most drugs freely filtered into interstitium
Drugs enter kidney tubule by tubule secretion, through active carriers
Filtered drugs passively reabsorbed or trapped in urine according to tendency to ionise and lipid solubility
Why do drugs bound to serum proteins have a longer half life?
Not filtered out at the glomeruli
Why might you inhibit active carrier that moves drug from interstitium into tubule?
To increase a drugs half life (i.e penicillin)
How else can drugs be excreted except via kidneys?
Sweat, milk and breath
What is aspirin hydrolysed into?
Salicylic aid and acetic acid
At blood pH 7.4 how much salicylate is in ionised salicylic acid form?
99.99%
What does the effect of acidic urine have on the % of salicylic acid?
Decreases it to about 99%
Why is having 1% salicylate in urine bad?
Reduces excretion of aspirin as non-ionised form can be reabsorbed
How can you increase excretion of aspirin (such as after an overdose)?
Give NaHCO3 to alkalinize urine, more salicylic acid to salicylate ratio thus more excreted.
How can P450 oxidases be induced?
By other drug compounds and substrates.
By transcription
Although they are constitutive (always there and on), they are inducible in presence of toxins or xenobiotics. Such as alcohol.
Where is ethanol metabolised?
In the liver
What are the two main steps of alcohol metabolism?
Ethanol + Alcohol dehydrogenase (ADH) = Acetaldehyde
Acetylaldehyde (oxidised) + aldehyde dehydrogenase = acetic acid.
What is a metabolic use of acetic acid produced?
Acetate produced can be conjugated into Acetyl CoA
Why is methanol toxic?
Formaldehyde produced by alcohol dehydrogenase cannot be digested by aldehyde dehydrogenase - accumulates
Why do some people have alcohol intolerance?
Deficiency of aldehyde dehydrogenase - toxic acetylaldehyde builds up
What can excessive alcohol deplete the liver of?
NAD+, NAD+/NADH ratio decreases
What are the consequences of depleted NAD+?
Pushes the equilibrium of lactate dehydrogenase to lactate, reducing the amount of pyruvate available for gluconeogenesis.
This can lead to lactic acidosis and hypoglycaemia. Hyperuricemia due to increased uric acid production
What are the two equations for clearance calculations?
Clearance = (Dose/Interval) / Average steady state concentration
OR
Clearance = Elimination constant x Volume of distribution
What gives volume of distribution?
Dose/Concentration
What is the equation for drug 1/2 life?
t1/2 = Vd x ln2 (0.693)/ Clearance
What is the value for ln2?
0.693
What can we conclude if Vd > actual blood volume?
Drug accumulated elsewhere
How does 1st order elimination look vs 0th order on a graph?
1st order curves (straight on log graph)
0th order straight
An enzyme which is commonly used as a marker for liver cell damage is
Aspartate aminotransferase
What method of administration can bypass the first pass of drug metabolism?
Sublingual route
What do flavin containing monooxygenases do?
Oxidation
What do Monoamine oxidases do MAO?
Catalyzes the deamination of monoamines via addition of oxygen
What are the negative effects of cytochrome P450?
Promote the metabolic activation of carcinogens
Produce mediators that result in oxidative stress
What can induce P450?
Smoking
Can cytochrome P450 function as a monooxygenase?
Yes
Why cant insulin be administered orally?
Degraded by digestive proteases
What does cytochrome P450 contain?
Iron containing haem
Where is cytochrome P450 found?
The ER
Does cytochrome P450 reduce drugs?
No, oxidises by hydroxylation
What is most likely to affect the drugs Vd?
Physicochemical properties
What may lead to toxic drug concentrations if it is normally renally cleared?
Renal damage
Which route of administration has the highest bioavailability?
IV
Why may a drug peak then fall over the 1st two hours?
Distribution
If 1/2 life increases/decreases how does this effect the resting plasma conc?
Directly proportionally
What is approx blood plasma volume?
~4L
Approx body fluid?
~42L
Extracellular fluid volume?
~15L
How to calculate blood volume with plasma volume and haematocrit?
Plasma volume = blood volume - (%haematocrit x blood volume)
