Drug Absorption and Elimination Flashcards
What 2 factors does drug distribution depend on?
how lipid soluble the drug is (to pass through membranes)
how well drug binds to proteins (eg albumin)
What is steady state and how many half-lives does this take?
Steady-state is where the Plasma conc of a drug is at a level which has the desired therapeutic effect and is at equilibrium with the amount of drug being eliminated
this takes 4-5 half-lives to reach
What is definition of drug absorption?
passage of drug from site of administration to blood
What is definition of drug distribution?
delivery of drug from blood to tissue (to exerts its effect)
Which factors affect drug absorption?
blood flow
pH
non-ionised (non-polar) drugs are lipid soluble - can diffuse across CSM
ionised (polar) drugs are lipid insoluble - cannot diffuse across CSM
p-glycoprotein binding
Total surface area and contact time
What is dissociation constant a measure of?
The dissociation constant of a weak acid is a measure of its tendency to lose a proton and become ionised in aqueous solution.
What does high Ka value mean?
Stronger acids have higher dissociation constants, meaning that they dissociate more readily and completely than weaker acids
A high value of Ka for an acid means that it is a strong acid, and will readily dissociate into hydrogen ions and its conjugate base in solution.
What does low Ka value mean?
A low value of Ka for an acid means that it is a weak acid, and will only partially dissociate into hydrogen ions and its conjugate base in solution.
Why is important to consider the pH environment which the drug is in and how does this relate to ionisation?
If the pH is inappropriate, the drug cannot
become unionised (lipid soluble) and will be ineffective as the pH wil determine the amount of unionised (lipid-soluble) drug which can pass through CSM
What effect does changing pH have on ionisation?
if pH is changed then ratio of U:I is changed
what does the degree of ionisation depend on?
- pKa of the drug
- pH of the environment
What is pKa of the drug?
The pKa of a drug is the pH value of the solution in which 50% of
the drug is dissociated, therefore half the drug is ionised (I) and
half unionised (U)
why are most drugs absorbed via SI instead of stomach?
larger SA and longer transit time
why does SL and buccal administration bypass the liver and FPE?
Because venous drainage from mouth and esophagus flows into SVC and not portal system
What factors affect rate of distribution?
lipid permeability
plasma protein binding
blood perfusion - the amount of blood that gets to a body compartment as this will regulate how much drug can get in there
tissue perfusion
tissue binding
What is the general order of drug distribution?
well perfused organs (eg kidneys, brain, liver)
less perfused organs (viscera, skin, muscle)
What 2 factors can limit rate of distribution?
perfusion
permeability
What factors affect drug distribution?
non-ionised drugs are lipid soluble - and can diffuse across CSM
ionised drugs are lipid insoluble - cannot diffuse across CSM
blood flow to tissue
drug lipophilicity
molecular weight of the drug
protein binding
How do drugs obey the law of mass action?
Once plasma conc is greater than tissue conc, drug will move from plasma to tissue.
when does eqm occur?
when plasma drug conc = tissue drug conc
what does one-compartment model refer to?
drug administered IV over short time period
body is single tank where a drug is added over a period of time - drug distributes rapidly and homogenously
what does two-compartment model refer to?
drug is distributed to central compartments (well-perfused organs and blood)
then more slowly to rest of body (poorly perfused tissue)
drug moves back and forth from these 2 compartments and leaves the central compartment
Explain what a 1-compartment model plasma-conc graph would look like?
the drug would be rapidly distributed throughout the body
conc would decline steadily in exponential manner over entire sampling period
Explain what a 2-compartment model plasma-conc graph would look like?
drug distributes to tissues in the central compartment - initially more rapid decline
then followed by a slower decline after the drug has been distributed around the body and plasma conc is lower
what is vol of distribution (Vd) equation?
amount of drug in body/concentration
what does Vd tell us?
small Vd = drug is not widely distributed, high plasma conc in blood
high Vd = drug is better distributed amongst tissues, low plasma conc in blood
What does it mean if Vd > total body volume?
it means the drug is concentrated in the tissues, v low plasma conc in blood
What is first-order (linear) kinetics?
exponential decay = first order = linear graph
rate of elimination is proportional to the drug concentration
AS DRUG CONC INCREASES IN THE BODY, THE RATE OF ELIMINATION INCREASES
elimination processes not saturated
What is zero order (non-linear) kinetics?
straight line rate-conc graph as the system becomes saturated
rate of elimination remains constant despite ↑ drug conc
overall drug clearance decreases with increasing drug concentration
elimination processes are saturated
above a certain drug concentration at the absorption site, there is no further increase in the absorption rate.
what factors affect first pass metabolism?
plasma protein binding
GI motility
aging: enzyme activity, hepatocytes decrease as you get older
disease: HF reduces hepatic blood flow
genetic deficiency
environmental
alcohol and drugs
what effect does grapefruit juice have on cyp450 activity?
certain compounds in grapefruit juice which inhibit CYP3A4 enzymes
this leads to higher bioavailability of drug conc in plasma with high first-pass metabolism
What effect does St Johns wort have on drug interaction?
herbal remedy used for anxiety, depression
induces CYP450 enzyme activity
this leads to lower bioavailability of drug conc in plasma with high first pass metabolism
what are the 3 processes of drug excretion?
- glomerular filtration
- tubular secretion
- tubular reabsorption
which environments are weak acids (eg aspirin) best absorbed in?
acidic
best absorbed in duodenum due to high H+ concentration
which environments are weak bases best absorbed in?
alkaline
eg distal ileum is more alkaline
how does SA and contact time affect absorption?
↑ SA ∝ ↑ absorption
↓ SA → ↓ absorption
↓ contact time → ↓ absorption (eg diarrhoea)
↑ contact time → ↑ absorption (eg constipation)
how does blood flow affect absorption?
↓ blood flow (eg shock) → ↓ absorption into bloodstream → no drug reaching system
bypass this via IV administration
What effect does P-glcyoprotein on drug absorption?
when drug is bound to PBP is inactive
however, sometimes P-glycoprotein spits drug back out into GI tract for excretion
therefore ↓ absorption
what is loading dose?
initial higher dose given to achieve therapeutic effect quicker
Loading doses are larger than maintenance doses and are usually administered as a single bolus, although some drugs (eg, amiodarone or digoxin) may require multiple loading doses administered over several hours to days
what is maintenance dose
