pK Flashcards
what affects the rate and extent of absorption?
1.anatomical site
2.disease state
3.drug properties
4.formulation
how are drugs absorbed ?
transcellular - thru the cell using carriers
paracellular - AQ environment between cells
what does the rate of passive diffusion depend on?
-drug lipophilicity
-surface area available
-increase drug concentration
-thickness of epithelial layer
-potential mucus layer
-absorption area
what does the rate of carrier mediated depend on?
why are efflux transporters not good for absorption?
bring the drug back into the lumen, instead of being absorbed
what order of kinetics is used if the carrier transporter is saturated?
zero order
how are drugs effluxed in the gut?
active transport
needs ATP to go against the drug conc. gradient
what drugs influence the effect of efflux receptors?
Substrates- can be taken out of the cell
Inhibitors- inhibit efflux transport, affcting bioavailability
Inducer- increase number of efflux transporters, increasing activity
how are nanomedicines removed?
phagocytosis
what happens in endocytosis?
The binding of a substrate to a receptor on cell wall, triggers formation of vesicles (endosome)
how are drugs absorbed into the cell?
phagocytosis
pinocytosis
endocytosis
What is Pinocytosis
A process by which the cell takes in the fluids along with dissolved small molecules
characteristics of subcutaneous injection
characteristics of intradermal injection
characteristics of intramuscular injection
what are the drug properties that affect absorption?
what is biopharmaceutical drug disposition system classification (BDDSC)?
class I - high solubility, high metabolism
class II - low solubility, high metabolism
class III - high solubility, poor metabolism
class IV - low solubility, poor metabolism
what are the formulation considerations of non-enteral routes? (Oro-mucosal, rectal, intranasal, pulmonary, transdermal)
what are some non-enteral routes?
Oro-mucosal, rectal, intranasal, pulmonary, transdermal
what does zero order absorption mean?
constant rate of absorption
independent of the dose
- carrier-mediated transport
- must have a high drug concentration
- modified release formulation
- must be a constant release rate
what does first order absorption mean?
dependent on concentration
applies to MOST drugs
- rate is initially high
- rate decreases over time
when may absorption be delayed?
using oral dosage forms
what factors can affect absorption?
- physiological factions
e.g. delayed gastric emptying for oral dosage forms - formulation factors
- site specific delivery (e.g. colon)
- dosage form
- modified release
how does bioavailability affect absorption?
Bioavailability is the fraction of the administered drug that reaches the systemic circulation in the unchanged form
what are some examples at each stage of first pass effect/pre-systemic circulation?
what type of receptor do we ideally want on the apical or basal lateral side?
influx - apical side
efflux - basal lateral
what are ATP-binding cassette (ABC’s)?
generally efflux transporters
which requires energy due to going against the concentration gradient
what are ATP-binding cassette examples?
P-glycoprotein (ABC1, Pgp)
multi-drug resistant associated protein (MRP, ABCC)
Breast cancer resistant protein (BCRP, ABCG2)
what are solute carrier transporter (SLC)?
generally influx transporters
what are solute carrier transporter examples
what are the efflux/influx transporters name in the GIT?
efflux - ATP-binding cassette (ABC)
influx - solute carrier transporter (SLC)
which transporter (influx/efflux) in the GIT requires energy? and why?
efflux - ATP-binding cassette (ABC)
as they go against the concentration gradient
when are proton dependent oligopeptide transporters used?
for the use of prodrug
where are p-glycoprotein (ABC1, Pgp) expressed?
gut wall, BBB, kidney, liver, lung, colon
Pgp also found in the small intestine on the APICAL side of enterocytes
what are some examples of Pgp inhibitors?
what are some examples of Pgp inducers?
what are some examples of Pgp substrates?
what some enzymes that metabolise drugs in the small intestine?
CYP3A4
CYP2C9
UDP-glucuronosyltransferase
sulfotransferases
which enzymes in the small intestine detoxicify the drug and how?
UDP-glucuronosyltransferase and sulfotransferases
by decreasing the lipophilicity and increasing the hydrophilicity
where is mainly CYP3A4 located?
gut, small percentage in the liver
what enzyme is responsible for most drug metabolism?
CYP3A4
what are characteristics of CYP3A4?
what are some examples of CYP2C9 drug metabolisers?
warfarin
phenytoin
losartan
diclofenac
how does UDP-glucuronosyltransferase drug metabolise?
conjugation of lipophilic drugs with glucuronic acid
how does sulfotransferases drug metabolise?
sulfation of hydrophobic drug molecules
what are the factors that affect rate of distribution?
tissue perfusion
membrane permeability
drug properties (plasma binding/tissue binding)
anatomical factors
tissue composition
physiological factors/barriers
what are some examples of well/poor perfused tissue?
well perfused tissue -liver, kidney, lung
poorly perfused tissue -fatty tissue
what are the extent of distribution?
MW
lipophilicity
ionisation - pH/pKa
protein binding
intracellular binding
patient factors
what factors means there’s an increase volume of distribution?
small MW
lipophilic
poorly perfused
unionised at a pH
when does the equilibrium of drug distribution reach quickly? and how can this occur?
for tissues with high blood flow
occur by increasing the blood flow via exercise
what is the apparent volume of distribution?
each body of compartment has a different volume
so we can use specific test compounds to estimate the volume of a given body compartment
how can we estimate there total body water?
using ethanol
how can we estimate the plasma?
using dextrans (large polysaccharides, polar molecules)
whats the estimated values of apparent volume of distribution in each region? and their drug properties
what type of drugs bind to albumin, alpha-1 acid glycoprotein, lipoproteins?
albumin=acidic drugs
alpha-1 acid glycoprotein= basic drugs
lipoproteins= neutral drugs
true or false: protein-binding drugs can diffuse into tissue
false! must be unbound to cross as they are too large
name some drugs that are affected by protein binding, lowering the volume distributed?
how can molecular and physico-chemical properties affect protein binding?
due to the ability to interact with negatively charged membranes
how can protein-related factors affect protein binding?
-change in protein concentration
e.g. liver disease, pregnancy, cystic fibrosis, aging, burns, malnutrition
-change in affinity for drugs
how do drug interactions affect protein binding?
displacement of protein-bound drug by endogenous/exogenous compounds due to competition
what happens if a drug prescribed bind to the same protein?
protein displacement risk
risk of interaction of protein displacement occurs if…
- highly bound to proteins (>90%)
- small volume of distribution
- interaction in initial stage of co-treatment
what is the interaction between valproic acid and phenytoin?
valproic acid displaces phenytoin from protein binding sites, inhibiting metabolism of phenytoin
what happens if the drug conc. is above the Css Max?
toxic
what happens if the drug conc. is below the Css Min?
no drug effect due to below the MEC of the drug
what does multiple administrations of a drug allow?
the conc. of the drug in the systemic circulation to be established - reach Css
drug administered= drug cleared
also known as INPUT = OUTPUT
what factors depend on INPUT of multiple administrations?
DOSE
BIOAVAILABILITY
DOSING
what factors depend on OUTPUT of multiple administrations?
Css
CLEARANCE
what is the bioavailability of parenterals E.G. IV?
1
how do you calculated INPUT of multiple administrations?
how do you calculated OUTPUT of multiple administrations?
if INPUT=OUTPUT, how can we calculate Css in multiple administration?
drugs with a shorter half life will reach Css … in multiple IV bolus inj
Css FASTER
how is maximum conc. at steady state calculated multiple IV bolus inj.?
how is minimum conc. at steady state calculated in multiple IV bolus inj.?
how is maximum conc. at steady state calculated in multiple administration?
how is minimum conc. at steady state calculated in multiple administration?
how is conc. at steady state at any time calculated in multiple administration?
why do we monitor drug conc?
Can help identify common issues with dosing regimens:
- Wrong drug
- Plasma/blood concentration within therapeutic window/higher end
* Different drug? Combination? - Wrong dose
- Plasma/blood concentration at lower end of therapeutic window/below MEC - Adherence issues
- Drug toxicity vs. disease progression
what drugs are do we monitor? BROAD
- NTW drugs = high risk
- variable PK profiles for pts
- use in high risk patients e.g. polypharmacy affecting drug PK
what drugs are do we monitor? SPECIFIC
- antibiotics - aminoglycosides, vancomycin
- anti-epileptics - phenytoin, carbamazepine, valproic acid
- CV drugs - digoxin
- immunosuppressants
- cytotoxic drugs - MTX
- Bronchodilators- theophylline
- lithium, tricyclic antidepressants
when would you sample your pt for drug monitoring?
ALLOW Css to be established except if aminoglycoside/vancomycin treatments
If monitoring for efficacy- Css determined right before dosing
If monitoring for toxicity - sampling when highest concentration expected
If long elimination half-life or multiple-compartment PK - sample 6-8h after dosing
what is measured when monitoring for drug conc.?
bound drug - to proteins/plasma
free drug is not routinely measures
when is free drug used to monitor drug conc.?
when plasma/protein binding is affected due to …
1. Medical conditions (e.g. renal or hepatic disease, malnourishment, cystic fibrosis, etc.)
2. Drug interactions (e.g. displacement)
how do you separate free and bound drug for drug monitoring?
- equilibrium dialysis
- ultracentrifuge
- ultrafiltration
when is metabolite drug conc monitored?
when the metabolite is pharmacologically active
contributes to adverse effects and toxicity
how do you monitor metabolite drug conc.?
immunoassays
liquid chromatography
how can drug-drug interactions impact absorption?
Impact on rate and/or extent of absorption
* Gastric emptying - e.g. Metoclopramide increase
* Dissolution rate / change in pH - e.g. Change in pH after PPI or antacids
* GIT motility - e.g. Opioids, Anti-cholinergic drugs
* Complexation - e.g. Cholestagel, calcium supplements
* Change in first-pass metabolism
how can drug-drug interactions impact distribution?
Change in plasma/tissue protein binding
* Competition for the same binding site
* Drug with higher affinity/binding constant displaces the other
* Often both drugs are highly bound to proteins - Change to therapeutic response and/or toxicity
how can drug-drug interactions impact metabolism?
- Inhibition of metabolising enzymes
* Competitive inhibition
* Non-competitive inhibition
* Onset immediate…
* Reversible
* Irreversible - induction of metabolising enzymes
* Synthesis of new enzymes by the liver- Increased hepatic clearance
- Reduce steady-state concentrations
* Onset gradual
* Recovery gradual
how can drug-drug interactions impact absorption + excretion?
Impact on transporters (influx or efflux) - induction/inhibition
Intestine, brain, BBB, renal tubules, hepatocytes, placenta, etc.
- Pgp =
- Decreased intestinal absorption
- Increase tubular/bile excretion
- Decreased uptake in brain
how can drug-drug interactions impact excretion?
- Renal excretion
* Changes in pH of urine- Acidic drugs excreted faster at higher pH
- Basic drugs excreted faster at acidic pH
* Competition for active tubular secretion sites - Probenecid – inhibition of renal excretion
- Aspirin and methotrexate
- Bile excretion
* Hydrolysis by gut bacteria -> enterohepatic recycling ->longer drug effect
when is herceptin used?
for the treatment of qHER2 expressed breast cancer
what does polymorphism of CYP2D6 cause?
- complete deficiency - no expression of enzyme
- intermediate deficiency - some expression
- extensive deficiency - normal activity
- ultrarapid deficiency
who is at risk of ultrarapid deficiency of CYP2D6?
middle eastern and north African people
When are CYP2D6 used?
metabolism for elimination
metabolism for activation
when does CYP2D6 activates a drug via metabolism?
codeine to morphine = faster drug onset
when does CYP2D6 eliminate a drug via metabolism?
tricyclic antidepressants, antipsychotics = faster excretion
how is codeine activated?
metabolised into morphine by CYP2D6 enzyme
what is CYP2C9 responsible for?
metabolism of warfarin, phenytoin, losartan, glipizide, NSAIDs
how is warfarin metabolised?
by CYP2C9 enzymes
what is CYP2C19 responsible for?
Responsible for the metabolism of
* S-enantioners of diazepam, citalopram, propranolol, omeprazole
* Fluoxetine, sertraline, tricyclic antidepressants
who is at risk of CYP2C19?
asia and south pacific are poor metabolisers
what is Thiopurine methyltransferase (TPMT)?
Catalyses the S-methylation of thiopurine pro-drugs
what is low activity of Thiopurine methyltransferase (TPMT) linked to?
higher risk of haematological ADRs
what drugs are metabolised with Thiopurine methyltransferase (TPMT)?
azathioprine
mercaptopurine
what is N-acetyltransferase (NAT)?
Catalyses the acetylation of different drugs to allow elimination
what drugs are metabolised with N-acetyltransferase (NAT)?
isoniazid, hydralazine, phenelzine (MAOI)
how does acetylation depend for isoniazid and hydralazine?
- For isoniazid (tuberculosis)
* Slow acetylators = lower doses to avoid neurological ADRs
* Fast acetylators = increased risk of hepatotoxicity (linked to metabolite concentration) - For hydralazine (hypertension)
* Slow acetylators = increased risk of SLE-like syndrome
what is UDP-glucuronosyltransferase?
glucuronidation of different drugs
when is UDP-glucuronosyltransferase used ?
irinotecan
what makes patients poor metabolisers of irinotecan?
reduced UGT1A1 activity
what is intra-patient variability?
variations of a drugs pharmacokinetic parameters, resulting in fairly different plasma concentration-time profiles after administration of the same dose to the same patient
what is inter-patient variability?
variations of a drugs pharmacokinetic parameters, resulting in fairly different plasma concentration-time profiles after administration of the same dose to different patients
what factors influence variability?
- Genetic
- Disease
- Age and body size
- Concomitant drugs - drug-drug interactions
- Environmental factors (e.g. foods, pollutants)
- Other factors include :
- Adherence - correct dose and time
- Pregnancy
- Alcohol intake
- Chronopharmacy - timing of drug administration
how can circulatory system impact pK?
heart failure = diminished perfusion
how can liver disease be effect pK?
Absorption
* Increase in bioavailability possible in cases of cirrhosis
* Reduced first-pass metabolism
* Physiological changes can also lead to drug bypassing portal circulation
* Potentially more problematic for drugs heavily metabolised by the liver
- Distribution
* Decrease in protein levels (albumin, alpha-acid glycoprotein) for albumin-bound drugs
* Displacement/competition- changes in Vd for albumin-bound drugs
- Changes in Cl
- Metabolism and Excretion (bile)
* Depending on importance of hepatic metabolism and clearance
* CYP450 enzymes tend to be affected more and some enzymes affected more than others
how can kidney disease be effect pK?
reduced clearance = increase half life
reduce protein binding
uremic toxins = reduce hepatic enzyme activity
what are pK properties of anaesthetics?
highly lipid soluble = accumulate in fatty tissue
what is the pharmacological considerations of administering anaesthetics?
obesity = higher proportion of adipose + lower water vol = affecting Vd of hydrophilic drugs
what are the pK considerations of paediatric patients?
Absorption
* Infants after the newborn period have
* low stomach acid levels,
* delayed gastric emptying
* irregular intestinal peristalsis causing slower absorption of some drugs in infants and young children.
- Distribution
- Total body water as a fraction of body weight decreases throughout the first
year of life. - However binding to plasma proteins is also reduced
Metabolism
* The various pathways of drug metabolism mature at different rates, and therefore the ability of the newborn to metabolise drugs differs both quantitatively and qualitatively from that of older subjects.
* After the enzyme system has mature (6 months), metabolism will depend on growth of the liver (perfusion, volume, bile function)
Excretion
* Glomerular filtration and renal tubule function in premature infants and newborns
is somewhat immature.
* GFR, normalized for body surface area, increases gradually reaching adult values at about 6 months
what are the pK considerations of elderly patients?
Absorption
* There are a number of physiologic changes that potentially will alter drug absorption, GI motility, pH changes, etc. There has been little evidence, however, to suggest that this is of major consequence.
Distribution
* Great changes in body composition occur with age. Body fat increases from 15% to 30% and lean body weight decreases in proportion to total body weight. Thus the distribution of drugs that are sequestered into fatty tissues will be altered
* Changes to perfusion and cardia output can also impact distribution rates. Possible reduction in protein binding due to decreased albumin concentration
* Vd of lipophilic may be more affected
Metabolism
* The liver is the major organ involved in metabolism and liver blood
flow and liver mass tend to decrease with age.
Elimination
* With increasing age the glomerular filtration process is reduced by a reduction in kidney size (20%), reduction in the number of nephrons (35%), reduction in the number of functioning glomeruli (30%), and a decrease in renal blood flow (40- 50%). Adjustments should be made for drugs that are renally excreted.
what are the pK considerations of pregnant patients?
Absorption
* Delayed gastric emptying, prolonged GI transit, reduced motility have been observed in pregnant patients and can cause reduced absorption rates. Elevated gastric pH can affect the absorption of some drugs. Nausea and vomiting can have an impact for orally administered drugs
Distribution
* Pregnancy is associated with increase blood flow, decreased levels of albumin and alpha-acid glycoprotein will affect protein binding. Increased levels of unbound drug can affect response and increase risk of ADRs. Increase in body weight linked to increase extracellular and intravascular volumes, which can affect distribution of hydrophilic drugs, while increase in body fat can change Vd of lipophilic drugs.
Metabolism
*Both oestrogen and progesterone and induce and inhibit CYP metabolising enzymes. Increase in blood flow can lead to lower plasma concentration of drugs with high extraction ratio which will be metabolised more extensively
Elimination
*Renal blood flow increases in pregnancy which increased renal excretion of hydrophilic drugs. For drugs that are eliminated by the kidney after metabolism, adjustment needs to consider impact of pregnancy on both metabolic and renal clearance
what are the pK considerations of lactating patients?
Small vs. plasma concentration for nursing patients but can represent a high dose for infants
* Drug properties: pH slightly more acidic in breast tissue (7.1) so some basic drugs may become ionised and unable to transfer back to plasma. Drugs transported by passive diffusion, so lipophilic drug may accumulate more. Macromolecules less likely to be excreted in milk. Protein binding will have an impact.
* Pharmacology: concentration gradient plasma:milk, dose, route, frequency and time of feeding will all affect how much of the drugs is excreted in milk.
* Infant: dose will depends of volume of milk and drug concentration in nursing patient. Low accumulation, but immaturity of metabolism and excretion could be problematic.
