Unit 3: Pharmacokinetics Flashcards
How do drugs work?
Drugs are distributed throughout the body by the blood and other fluids.
When they are at the site of action, they act by binding to receptors, usually located on the outer membrane of cells//enzymes within the cells.
Receptors ‘turn on’ when stimulated/blocked by a drug which binds to the receptor.
How do narcotic pain relievers like morphine work?
Bind to receptors in the brain that sense pain and decrease the intensity of that perception
How to non-narcotic pain relievers like aspirin or ibuprofen work?
Bind to an enzyme (cyclooxygenase) located in cells outside of the brain close to where pain is localised (not brain).
Decrease the formation of biologically-active substances known as prostaglandins, which cause pain/inflammation
What is onset, duration and intensity of action of a drug after administration controlled by?
The rate at which the drug reaches site of action
The concentration of the drug
The metabolism of the drug in the body
The rate of excretion of the drug
The sensitivity of the individual to the drug
ADME processes occur at the same time until…
- All of the drug is absorbed and there is no more absorption phase
- All the drug has been metabolised and there is no more parent drug and it is no longer detectable in the blood.
Absorption
The process by which a drug is made available to the fluids of distribution in the body (blood, plasma, lymph)
In the fasting state, how long does it take for most orally administered drugs to reach the peak blood conc?
1-2 hours
Most rapid route to least rapid route of administration
Intravenous administration (IV)
Intranasal
Inhalation
Sublingual (under tongue)
Intramuscular (IM)
Subcutaneous (under skin)
Percutaneous (through skin)
Distribution
Circulated by some degree to all areas of the body to which there is blood flow.
What organs are the first to accumulate drugs
Organs with high blood flow (e.g. heart, liver, kidneys) are first, while drugs accumulate more slowly into connective tissue
Metabolism
Altering the chemical structure of the drug to promote its excretion.
Transformation of the drug molecule into a chemically related substance that is more easily excreted from the body
What do urine drug screens usually determine in terms of drugs and use the example of cocaine.
Determine metabolites in urine not original ‘parent’ drug which was ingested/taken.
E.g. if cocaine is snorted/injected, a urine drug screen will most often detect the cocaine metabolite called benzoylecgonine in the urine, not cocaine.
Excretion
Process by which drug is eliminated from the body
How is a drug absorbed if administered orally?
There are layers of protective mucus in many parts of the gastrointestinal tract, which must be traversed before the drug reaches the cell membranes of the epithelial cells lining the tract.
Several membranes may have to be penetrated before the drug eventually reaches the bloodstream.
Two mechanisms that drugs are absorbed by
Passive diffusion of unionised drug
Active transport
peristalsis
the involuntary muscle movement that moves food through your gastrointestinal tract.
Major site of absorption
Small intestine
Why is the small intestine the major site of drug absorption?
high peristalsis,
a high surface area,
high blood flow
optimal pH (pH 5–7) for the absorption of most drugs all of which result in a high absorption rate.
absorption tends to be much less rapid from other parts of the gastrointestinal tract.
Which type of drugs are absorbed in the stomach and give examples
Largely acidic drugs that are un-ionised in the low pH (pH 1–3) environment in this organ.
Drugs include aspirin, nonsteroidal anti-inflammatory drugs and some angiotensin-converting enzyme inhibitors.
What happens to drugs following absorption by the GI tract and what are the exceptions?
drug molecules are taken up by hepatic portal system
exceptions are lipids, which normally enter the lymphatic system and are eventually deposited in the blood via that thoracic duct into the superior vena cava.
high hepatic first pass effect
when metabolism may be very rapid so that the drug never ‘makes it’ past the liver
an example of high hepatic first pass effect and why is it administered the way that it is
glyceryl trinitrate, used to treat angina pectoris; almost 96% is destroyed by the liver on its first journey through.
This is why glyceryl trinitrate is administered by placing the tablet under the tongue (sublingual) or by an oral spray so that it is absorbed through the mucous membranes of the mouth directly into the blood stream
an example of comparing the effects of a drug given orally with those resulting from parenteral administration
Pethidine, for example, when given parenterally, may require an injection of only 25 mg to produce an analgesic effect equivalent to 100 mg taken orally.
sites of absorption
lungs
mucous membranes
skin
sublingual
buccal
vaginal
ocular
How can the extent of ionisation be calculated?
by the Henderson-Hasselbach equation and whether the molecule is acidic or basic in nature
How is the extent of the equillibrium between the ionised and unioned form of a molecule determined?
Diffferent between pH of the solution and pKa of the solution
What does the pH partition hypothesis say?
that only the unionised form can cross a membrane and that the concentration of the unionised form on each side of the membrane will be equal.
partition coefficient
coefficient (P or logP) which is a measure of how a drug molecule partitions (divides) itself between an organic layer (normally octanol) and an aqueous (water) layer.
what is the value of partition coefficient dependent on?
the pH of the aqueous layer, indicating that the absorption potential of a drug will vary with pH.
where in the body is the pH highly acidic
fasted stomach
where in the body is the pH basic
intestine
what does the extent of ionisation of a drug molecule depend on
pH
when can gastric emptying be delayed?
following severe trauma and in any condition producing nausea or vomiting
Which drugs are more readily absorbed from upper regions of the GI tract and why
Acidic drugs- Non ionised (more lipid soluble) form of a drug is more readily absorbed than the ionised form. Acidic drugs usually in a non-ionised form in the upper regions
Characeristics of a drug needed so that it can cross a membrane barrier.
Must normally be lipid soluble to the membrane to get into the membrane
Soluble in the aqueous phase to get out of the membrane
For drugs that are weak acids/bases, what will control the solubility of the drug and therefore the rate of absorption through membranes lining GI tract?
pKa of drug
pH of GI tract fluid
pH of bloodstream
Why is distribution usually uneven?
Due to differences in blood perfusion (local fluid flow), tissue binding (due to lipid content), regional pH, and permeability of cell membranes.
what does entry rate of a drug into tissue depend on
rate of blood flow to tissue
tissue mass
partition characterisitics between blood and tissue
where is distribution equillibrium reached more quickly?
in richly vascularised areas, unless diffusion across cell membrane is the rate determining step.
after equilbrium, drug concentrations in tissues and extracellular fluid are reflected by…
plasma concentration
xenobiotics
non essential foreign compounds
what is an integral part of xenobiotic elimination?
metabolism
what does metabolism do to a drug?
facilitates excretion
may also affect pharmacological response by altering potency/duration of action
charactersistics of metabolites of drugs
with few exceptions, they are more polar and water soluble than parent drug- more likely to be excreted from body.
in general what does metabolism do?
converts active compounds into less active and less toxic compounds
where does drug metabolism take place
primary site= liver
but may be metabolised in blood, brain, kidneys, lungs, skin, gastrointestinal tract
biotransformation reactions
individual chemical reactions of drug or foreign compound metabolism
main organs responsible for drug excretion
kidneys - renal excretion
liver- biliary excretion
other organs can be involved- lungs for volatile/gaseous agents
what compounds can slightly concentrate in milk and why, why is this important?
basic compounds- milk is more acidic than plasma
this is important to estimate the amount of drug administered to the breastfed baby
what drugs cannit be excreted before metabolism into more polar compounds?
lipophillic drugs
what is the excretory system made up of?
2 kidneys
ureter
bladder
urethra
branches of two renal arteries and veins
glomerular filtration
small drug and metabolite molecules and those not bound to plasma proteins are filtered from the blood.
large molecules or those bound to plasma proteins are poorly excreted by glomerular filtration.
tubular secretion
most drugs enter the kidney tubule by tubule secretion rather than glomerular filtration
the process involves active transport against a concentration gradient and therefore requires energy and carriers for acidic drugs such as furosemide and penicillin
tubule reabsorption
some drugs and metabolites are absorbed back into the bloodstream.
this doesnt require energy- it is passive transport
initial phase
the delivery of the drug to the body in a dosage form from which the drug molecule has to be released (dissolution). The drug then absorbs, is distributed around the body before elimination.
Cmax
maximum/peak concentration of drug after administration
Tmax
time after administration when max concentration is reach
rate of absorption= rate of elimination
area under curve
total drug exposure over time
Cmax is affected by
first pass metabolism (can inactivate drug)
losses due to route (does not dissolve)
excretion/elimination
what does t max depend on
absorption rate
how can the time taken for the drug to show an effect/duraction of action of the drug be assessed?
if the minimum effective conc (MEC) where the drug is effective at any level is above threshold
and the maximum tolerated concentration (MTC) are known
bioavailability
is the fraction (%) of an administered drug that reaches the systemic circulation.
when is a drugs bioavailability 100%, when is it lower and why?
when a medication is administered intravenously (IV), its bioavailability is 100%
Routes other than IV due to incomplete release from the dosage form, incomplete absorption and first-pass metabolism.
how is bioavailability calculated?
by comparing the AUC for the particular dosage form in question to that obtained when the drug is administered intravenously, taking any differences in the amount administered into account
what does it mean if two products are said to be bioequivalent
means that they would be expected to behave in the body, for all intents and purposes, the same.
volume of distribution
expresses how the administered drug has distributed itself throughout the body.
the theoretical volume that would be necessary to contain the total amount of an administered drug at the same concentration that it is observed in the blood plasma.
what does a larger vD suggest
indicates a greater extent of drug distribution in the tissues
have a tendency to leave plasma and enter extravascular compartments of the body- so higher dose of a drug is required to achieve a given plasma conc.
what does a drug with a lower vD suggest
indicates a lower extent of drug distribution in the tissues
have a tendency to remain in plasma- so lower dose of a drug is required to achieve a given plasma conc.
what concentration is required from the concentration time graph for volume of distribution
extrapolate backwards to concentration at time zero
plasma protein binding classified into…
restrictive and non restrictive binding
restrictive binding
important drug-plasma binding and thus limits the extensive distribution of the drug to tissues
non-restrictive binding
does not limit the drug distribution to tissues due to a greater binding capacity to tissues than that to the plasma proteins
vD and description for Warfarin
vD= 0.14 L/kg
Very strongly bound to plasma protein (approximately 99% bound). Shows limited distribution into body tissues.
vD and description for Paracetamol
vD= 0.9 L/kg
Distributes rapidly and evenly throughout most tissues and fluids
vD and description for Digoxin
vD= 7.3 L/kg
Widely distributed and extensively bound in varying degrees to tissues throughout the body (skeletal and cardiac muscles intestines and kidney)
What will influence the effect of a highly bound drug?
Changes in the concentration of plasma proteins
when may low plasma protein levels occur and what occurs?
may occur in old age or in malnutrition.
a sharp increase in the free drug concentration in the plasma may occur. greater amount of free drug may produce a greater therapeutic effect or side effect and reduced drug dosages may be indicated in these cases.
what happens when a highly protein bound is given to a patient who is already recieving another highly bound protein drug
the second drug may displace the first drug from the plasma proteins leading to increased free drug concentration that may cause an increased therapeutic effect and/or adverse effects – this is an important mechanism of drug – interactions.
clearance
is the efficiency of the irreversible elimination of drug from the systemic circulation
if the clearance is high
the drug is removed quickly
if the clearance is low
the drug remains in the body for a longer period of time
what does the clearance value indicate
indicates the theoretical volume of plasma from which a substance would be completely removed per unit time. Usually, clearance is measured in L/h or mL/min.
total body clearance equation
dose// area under the curve (mg x hours/L)
half life
the time taken for the concentration of the drug in the plasma to have dropped by half
first order reaction
concentration vs time graph is an exponential decay, where the gradient of the line is equal to the rate of drug loss.
If the natural log (ln) of the concentration is plotted against time a straight line is obtained with a gradient of –k, which is the rate constant
the rate of drug elimination proportional to the concentration (C) in the systemic circulation, i.e. the higher the concentration of drug in the systemic the faster the rate of elimination
general equation for first order reaction
ln [A]t = ln [A]0 − kt
[A]t is the concentration after time, t
[A]0 is the initial concentration (at time=0)
k is the rate constant
t is the elapsed time
0.693/k
is the half life dependent or independent of concentration for first order
independent
half life equation, vD, and clearance
0.693 x vd/clearance
what happens if a drug is being infused into a patient?
initially the rate that the drug is being added is higher than the rate it is being eliminated, so the plasma concentration rises.
If the rate of drug elimination is 1st order, then the rate of elimination is dependant on the concentration (rate=clearance x concentration) so as more drug is added to the body, the elimination rate rises.
At some point the rate drug is being added= rate that it is being eliminated, so the concentration reaches steady state (constant concentration). When the infusion is stopped, then the concentration will fall.
how many half life does it take for a drug to be eliminated/reach steady state
5-6
time taken to achieve steady state is..
still independent of dose (half life dependent).
what must we assume to calculate the steady state conc
you assume that at steady state, rate of the drug entering the body is equal to the rate of the drug leaving the body
what does a loading dose do?
rapidly increase the plasma concentration up to the level that is required in steady state and give immediate efficacy.
how do we calculate the initial plasma concentration reached by the loading dose
Concentration = dose/volume of distribution
Typically loading doses and twice that of the subsequent maintenance dose.
what may cause non linear pharmokinetics and what order reaction does it tend to follow?
due to the saturation of one of the ADME steps for that drug.
tends to follow zero order kinetics.
zero order reaction
kinetics the rate is a constant value
a plot of concentration against time is linear
the half life depends on the concentration
zero order reaction- half life independent/dependent on concentration
dependent
example of non-linear behaviour
phenytoin
epileptic patient who has not responded to phenytoin after 2 weeks on 300 mg/day is observed to have a plasma concentration of 4 mg/ml.
Twenty days after the daily dose is subsequently increased to 500 mg/day, the patient develops severe toxicities. The plasma concentrations of phenotoin is now 36 mg/L
caused by the saturation enzymes that are responsible for metabolism in the liver, so after a certain amount of drug is in the blood stream, the liver is now working at its maximum rate and cannot process it any faster, so a constant amount of drug is eliminated per unit time no matter how much drug is in the body. This means that an increased dose cannot be metabolised any faster and so there is a higher concentration of free drug in the body.
what happens if the absorption process is saturated so the drug is absorbed at a fixed rate and what is an example of this?
If the absorption process is saturated, so that the drug is only absorbed at a fixed rate, independent of the drug concentration on the GI tract, the bioavailability (F) is affected
example of this is amoxicillin where the transport across the gut wall is saturated with a decrease in bioavailability
what happens if the distribution step is saturated and give an example
normally protein binding that restricts the drug to the blood stream), then more free drug is available & the volume of distribution are affected.
example is naproxen causing an increase in the fraction unbound & increase in the volume of distribution.
what can happen to the metabolic process in the liver and give an example?
either be restricted (inhibited) or enhanced (induced) and the clearance by the liver (CLH) is affected
example of phenytoin has already been given, but high doses of propanolol decreases the blood flow to the liver and so reduces the clearance.
High doses of carbamazepine can increase the metabolism rate (induced) and so increase the clearance.
what does penicillin G do in the kidney
penicillin G an saturate the active secretion, reducing the clearance, whilst ascorbic acid (vitamin C) saturates the active reabsorption, where the drug passes back from the nephrons back into the blood, causing an increase in the clearance.
Therapeutic Drug Monitoring
When drugs exhibiting non-linear pharmacokinetics show disproportionate increases (or decreases) in steady state concentration with increased dose and for drugs with a narrow therapeutic index, a small change in daily dose can easily cause side effects (are become non therapeutic), so for these, regular monitoring of the patients plasma concentration is vital
