Pharmacokinetics Flashcards
what type of drug is flucloxacillin
beta-lactam antibiotic
chemistry of flucloxacillin
has a fluoride and a chloride
has a core penicillin part
is a beta-lactam antibiotic so has a beta-lactam part in the structure
pharmacology of flucloxacillin
targets bacterial transpeptidase enzymes
=penicillin-binding protein (PBP)
activity: irreversible inhibitor
=suicide substrate
physiology of flucloxacillin
-D-ala-D-ala is integral part of cell wall peptidoglycan, PG: structure/synthesis
transpeptiases normally crosslink :the D ala to other amino acids in PG
beta lactase inhibition of the cell wall synthesis
dividing bacteria lose rigid cell wall integrity
osmosis and cells then pop
they’re bactericidal
clinical side of flucloxacillin
antibiotic
narrow spectrum, gram positive
infections caused by sensitive organisms e.g. staphylococcus and streptococcus
what is pharmacokinetics
what the body does to the drug
absorption, distribution, metabolism, excretion/elimination
what is pharmacodynamics
what the drug does to the body
absorption
from outside to inside
-routes of administration
-bioavailability
-drug properties
-biological properties
distribution
form one place to another in the body
-volume of distribution
-blood flow
-drug properties
-biological properties
metabolism
from one thing to another
-biotransformation
-transforming enzymes
-drug properties
-biological properties
excretion/elimination
from inside to outside
-clearance
-removal mechanisms
-drug properties
-biological properties
routes of administration
parenteral
enteral
parenteral definition
avoiding the gastro-intestinal tract
methods of parenteral administration
intravenous
intramuscular
sub-cutaneous
epidural
trans-dermal
sublingual
inhalation
intravenous
directly into the blood
intramuscular
directly into a muscle
highly vascular tissue
sub-cutaneous
under the skin
poorly vascular space q
epidural
into the epidural space
systemic
drug will be administered everywhere
topical
treatment is localised
e.g. local anaesthetic
trans-dermal
across the skin
sublingual
under the tongue
inhalation
through breathing via the lungs
enteral
via the gastro-intestinal tract
examples of enteral
oral
rectum
oral
into the mouth
then stomach
then intestines
rectum
e.g. suppositories
oral bioavailability
is the same as fractional availability
fraction of a drug that gets into the systemic circulation
100%= all the drug in the tablet gets into the plasma
higher the bioavailability the more useful the drug will be as an oral, systemic medicine
what factors affect oral bioavailability
drug stability within the gut
drug absorption across the gut wall into the blood
drug metabolism in the liver (first pass effect)
drug stability in the gut
chemical stability: acidic in the stomach, pH varies in small intestine
biological stability: enzyme action in the gut, intestinal bacteria
drug properties: chemical (the drug), pharmaceutical (the formulation), biological (the patient)
drug absorption across the gut wall
gut is adapted
pathway: gut lumen, gut epithelium, extracellular matrix, capillary endothelium, blood vessel lumen
what does absorption in the gut depend on
drug properties: solubility size, pKa
pharmaceutical
gut properties: anatomy, physiology, pathology
which drugs cross membranes most easily
unionised
weak acid and absorption
H+ + A- reverse HA
un-ionised form HA predominates
better absorption
when does equilibrium shift
at low pH
weak base and absorption
H+ + B reverse HB+
ionised form HB+ predominates
poor absorption
drug metabolism in the liver
drugs with substantial hepatic metabolism may have poor oral bioavailability
which is the principle organ of drug metabolism
the liver
first pass effect
drugs absorbed in most of the gut pass entirely to the liver
hepatic portal vein runs from the gut to the liver
how to calculate volume in ml
amount in mg/ concentration in mg.ml-1
volume of distribution equation
total amount of drug in the body/ concentration in the plasma
defines the relationship between two real important values
why concentration in the plasma
something measurable
directly related to clinical effects
why is it an “apparent” volume of distribution
drug may not leave the blood, erythropoietin= very high Cp
drug freely enters/leaves the cells, cimetidine= low Cp
drug doesn’t enter the cells (evenly in the extracellular fluid)gentamicin= high Cp
drug accumulates in fat (lipophilic), midazolam=very low Cp
effect of high blood flow
high blood flow to the brain
propofol= IV general anaesthetic
intravenous= rapid delivery to brain
effect of low blood flow
low blood flow to the bones/cartilage/joints
antibiotics
difficult to achieve adequate concentrations of drug= infections difficult to treat
what does the volume of distribution tell us
the distribution of the drug in the body compared to the plasma
how much drug is required in the body to achieve a specific concentration in the plasma
what does metabolism do to drugs
alters the chemical structure
biochemical (enzymes)
where are drugs metabolised
liver
gut wall
kidney
lung
plasma
any tissue with metabolic activity
what are the two phases of drug metabolism q
synthetic
conjugation
synthetic
oxidation: hydroxylation, dealkylation,deamination
reduction
hydrolysis
makes the drug more polar and soluble
conjugation
glucuronidation
methylation
sulphation
acetylation
glutathione
makes drug larger
makes the drug more polar
what do drugs change into in the synthetic phase
can convert to active, inactive, toxic metabolites
what do drugs change into in the conjugation phase
converts drug to inactive form
except morphine
phase one of phenacetin metabolism
it is a prodrug
and is inactive
changes to paracetamol
which is active
phase one paracetamol metabolism
NAPQI
toxic and in phase two of this drug metabolism forms glutathione-conjugated paracetamol which is inactive
phase two of paracetamol metabolism
forms glucuronide-conjugated paracetamol
inactive
elimination
disappearance of the drug from the plasma
excretion: parent drug is physically gone
metabolism: parent drug changed into something else
excretion
physical removal of the drug from the body
kidney-urine
lungs-breath
skin-sweat
what is renal elimination promoted by
increased polarity
increased aqueous solubility
increased size
metabolites by phase one and two are normally faster eliminated
rate of elimination
drug mg is eliminated from the plasma over time in mins
units: mg.min-1
clearance
plasma ml is cleared of drug over time min
units: ml.min-1
rate of constant elimination ke
proportion of drug (unitless) eliminated in one unit of time min
units: min-1
half-life (t1/2)
time in min taken for the plasma concentration to fall by half
units: min
what is the rate of elimination proportional to
the concentration
what is the proportionality constant
clearance
how to achieve a desired plasma concentration
dose= Vd x Cp
mg= ml x mg.ml-1
how to maintain a desired plasma concentration
dose rate = Cl x Cp
mg.min-1 = ml.min-1 x mg.ml-1
cl= flow rate of leak
how to calculate the half life
t1/2 =ln2 / ke
ke= rate constant of elimination
if you increase the clearance what happens to the half-life
shortens
for an oral drug what is ideal dosing q
once per da
short half life q
second/minutes
onset/offset rapid
uses a lot of drug
long half life
hours/days
onset/offset slow
uses less drug
1st order elimination
constant clearance
rate of elimination is proportional to the concentration in the plasma
linear kinetics
practical, predictable and analytically simple