Pharmacokinetics Flashcards
what does area under the curve (AUC) mean?
total exposure of the body to a drug over a period of time
what is pharmacodnamocs?
what the drug does to the body
what is pharmacokinetics?
what the body does to the drug
what is partitioning?
process of molecules distributing themselves between two domains
what are the two ways of a drug reaching a target site?
direct
indirect (blood)
what are the quantitative significance of pharmacokinetics?
dosing regimen
empirical measures
track and trace
what is passive diffusion?
– Major mechanism of drug delivery
– Depends on the ability of drug
(physiochemical characteristics)
crossing lipid bilayer membrane
what is the rate of diffusion of passive diffuion determined by?
-surface area
-thickness of membrane
-molecular size & lipid solubility
(diffusion constant)
what is the [D] amount transfer relient on in passive diffusion?
trasfer rate
residence time at membrane
what is active diffusion?
Require transporter/carrier for the
uptake of drug across cell membrane
what is the pH of the mouth?
7.4
what is the pH of the stomach?
1.5-3
what is the pH of the small intestine?
5.3
what is the ionisation state of acidic and basic drugs in the mouth?
acid drug: 0.5% unionsed
basic drug: 99.5% unionised
what is the ionisation state of acidic and basic drugs in the stomach?
acid drug: 100% unionised
basic drug: 0% unionised
what is the ionisation state of acidic and basic drugs in the small intestine?
acid drug: 40% unionised
basic drug: 60% unionised
what are the factors influencing G.i absorption?
gi mobility
gi secretions and enzymes
drug-food/ supplemennts interactions
what are the advantages of G.I absorption?
– Large surface area for passive diffusion
– Range of pH environments promote uptake of weak acids/bases
– Richly vascularised (high blood supply)
– Long tract and long dwell time
– Some active transport (e.g. Levodopa taken up by phenylalanine
transporter)
– Small intestine is a major site for drug absorption
what is bioavailabilty?
measure of proportion of dose absorbed, compared to i.V (same) dose
what is the formula for bioavailability (F)?
F=AUC of oral/AUC of IV (for oral drug)
what is time to peak (tmax)?
time required to reach maximum drug concentration in plasma (is a measure of rate of absorption
what is partitioning?
the distriution of a substance between two immiscible phases
what is a partition coefficient (P)?
measure of relative affinity of the solute for an aqueous and a lipid phase at equilibrium
what is log P?
gives an indication of the lipophilicity of a drug
what is apparent partition coefficent (formula) ?
Papp= [HA]0/ [HA]w+ [A-]w
what is fraction unionised?
in the aqueous phase determines the ifference between Papp and P
Papp=P x Funionised
Funionised= HA/HA+A-
what drugs can readily partition into rubber or plastic substances?
drugs with high log P
this can be a major problem for storage of lipophilic drugs
what is MAC?
minimum alveolar concentration
why is the small intestine better desinged for absortion than the stomach?
− Surface area of the small intestines is up to 200 m2 as a result of microvilli
− Drugs have a longer residence time in the small intestines than the stomach
− Small intestines have an excellent blood supply
what are the partition theory limitations?
pH of the bulk gastr-intestinal fluid may differ from that at the surface or within the epithelium
degree of ionisation is not the only determinant of absorption from the GI tract
− Molecular weight
− Lipid solubility (log P often used as a proxy)
− Water solubility
− Binding to Ca2+, Mg2+, Al3+ present in milk, antacids etc.
− Ion-pairing
− Presence of active transport mechanisms
what plasma proteins do acidic and neutral drugs bind to?
albumin
what plasma proteins do basic drugs bind to?
beta-globulins
what are the characteristics of plasma protein binding with drugs?
- [Free] or [bound] drug is in dynamic equilibrium
- High binding to plasma proteins- less available for target action
- One drug can displace other drug binding of other drug
- (Thermodynamic motion, collision; thermal energy dominate the electrostatic forces)
what are the barriers of distribution of drugs?
cell arrangements
active transporters
size and lipid solubility
what are the influencing factors of the distibution of drugs?
barriers
blood flow
tissue accumulation
what does a Vd of more than 40 litres mean?
drug accumulation in tissues
what does a Vd of less than 10 litres mean?
drug restricted to plasma and interstitial fluid
how is absolute bioavailability calculated?
by comparing the amount absorbed by one route to the IV route
what is the salt factor?
the fraction of the dose that is the active drug
what is included in phase 1 of drug metabolism?
oxidation, reduction, hydrolysis
Catalysed by Cytochrome P450 (haem-containing mono-oxygenase enzymes)
requires oxygen and NADPH
RH(drug)+ O2+NADPH–>(CYP)–>ROH+NADP++H2O
what is included in phase 2 of drug metabolism?
conjugation
addition of polar groups (OH, NH2, COOH)
Catalysed by UDP (Uridine-diphospho)-glucuronyl transferas (UGTs)
where is the major site of drug elimination of water soluble molecules?
urinary system (kidney)
where is the major site of drug elimination of large molecules?
biliary system (entero-hepatic recirculation)
bile
gut
liver
can be blocked by activated charcoal
what is CLp?
the volume of plasma (ml) that is cleared of drug in unit of time (min)
CLp= CLliver+ CLrenal
what are the characteristics of drug excretion?
- Drugs are metabolised to more water soluble
- Phase I process is catalysed by CytochromeP450 and Phase II process is by UDP glucuronyl transferases
- The water soluble drug metabolites are excreted via kidneys and large molecules are processed through biliary (entero-hepatic recirculation process).
- Renal excretion depends on filtration and active transport
- Lipid solubility modulate the kinetics of drug reabsorption
- Drug elimination (most) follow first order kinetics.
- Half-life and plasma clearance rate are commonly used to determine drug elimination kinetics
- Volume of distribution, plasma clearance and half-life are interrelated.
what is the equation for apparent partitioning coefficient?
log( (P/Papp)-1)= pH- pKa (weak acids)(flipped if weak bases)
what needs to change for a person with liver problems?
lower the dose
when is it not true that drug is delivered into plasma, and reach steady-state conc.?
the drug effect is mediated through a metabolite
the drug effect is irreversible
follow different kinetics in the target compartment
what are the factors affecting ionisation?
pH
pKa of drug(pH at which 50% of molecules are in each state)
what are the steps to practical partitioning?
- Immiscible liquids added to separating funnel
- Drug under investigation added to the mixture
- Separating funnel shaken (open tap regularly to release pressure build-up)
- Immiscible phases separated and concentration of drug in each liquid determined
- Partition coefficient is determined from these values
what does the pH-partition theory state?
the greater the proportion ionised then the lower the overall absorption will be
what is ion-pairing?
ion pairing is when opposite charged ions are held together without the formation of a covalent bond
the ion paur behave as a neutral species and may be better able to permeate the gastric mucosa
how does active transport mechanisms change pH-partition theory?
require energy
therefore molecules may be absorbed even if they are ionised or highly hydrophilic
what are the parameters for the degree of drug distribuion into breastmilk?
pKa of drug (milk has a pH of 7.2)
degree of plasma protein binding
log P of drug (milk fat content varies from 4-9%)
drug excretion in the kidney?
- In the kidney unionised drug may partition from the blood (pH 7.4) → lipid membrane → urine
- If urine pH favours the ionised (water-soluble) form of the drug → excreted in the urine
- If unionised form is favoured, the molecule may be reabsorbed back into the circulation by passing back through the lipid membrane in Loop of Henle
- Drug re-enters the circulatory system, free to exert its therapeutic action again
renal excretion can be controlled by altering the pH of the urine with salt solutions
what are the characteristics of acidic urine?
weak basic drugs are more likely to be ionised
decrease in re-absorption and increase in excretion
what are the characteristics of alkaline urine?
weak basic drugs are more likely to be unionised
therefore increase in re-aborption and decrease in excretion
where in the body is there high blood flow?
heart, brain, lungs, kidney, glands
where in the body is there low blood flow?
skin, muscle
what happens in the areas with tissue accumulation (fat depots)?
highly lipid soluble drugs accumulate
what are the characteristics of distribution in the blood brain barrier?
diffusion only possible for lipid soluble drugs
the integrity compromised during meningitis
active transport possible
what are the characteristics of the blood placental barrier?
lipid solubility and size of the drug determines the distrobution to foetus
drug use in pregnancy has a risk of adverse/ toxic teratogenic effects and neonatal toxicity during labour
what is Vd?
volume of distribution
theoretical volume of plasma that would accommodate total drug amount at the measured plasma concentration
what is the equation for Vd?
Vd= total amount of drug (Q)/ plasma concentration (Cp)
what does IV administration mean?
the entire dose reaches the systemic circulation
100% bioavailability
what is F?
fraction of administered dose of drug which reaches system circulation (intact)
what is first pass metabolism?
drugs absorbed from the stomach, small intestine and upper colon pass into the hepatic portal system–> liver
what is naloxone, and what is it used for?
used to combat opiate overdose, rapid onset required, undergoes first pass metabolism
what can reduced bioavailability be from?
due to incomplete absorption and/or first-pass clearance
what is relative bioavailability?
comparing the amount absobed from a test formulation to a standard formulation such as a tablet
Frel= AUCtest/ AUC standard
relative bioavailability is?
used to evaluate bioequivalance of two products containing the same drug
(considered bioequivalent if the ration is between 0.8 to 1.25)
what are the 3 major sites of drug elimination in the kidneys?
glomerular filtration (passive removal of [free] drugs
tubular secretion (active transport)
reabsorption (depomds on lipid solubilty and pH)
what is half-life?
time taken to reduce the plamsa drug concentration by half from the administered [drug] or a time at which 50% of drug eliminated from plasma
