pharmacokinetics Flashcards
Define absorption..
the movement of drug from site of administration into plasma
what determines the absorption of a drug?
route - blood flow to that region, 1st pass metabolism, local affects only?
drug - its chemistry (acid, base, Pka, lipid solubility, size, partition coefficients)
method of absorption - ions channels, active transport, simple diffusion, pinocytosis.
factors affecting diffusion - ficks and grahams law
- size, lipid solubiltiy including proportion of ionisation (PKA), conc gradient, thickness of membrane, S.A.
how does subcut or IM absorption compare to oral?
faster
however rate is variable depending on blood flow to that site
also more painful
which routes of administration are subject to 1st pas metabolism?
oral
rectal
(nasal, sublingual, dermal, sub cut, IM and IV all bypass)
what factors determine transdermal absorption?
patient factors
* age - poor blood supply in elderly
* gender - men have thicker skin
* ethnicity
* type of skin e.g. thick callus , different blood supply via region.
* diseased skin - inflammed
device factors
* the type of drug - small, lipid soluble e.g. fentanyl patch.
* more potent, the less needed so quicker absorption to effect
* good contact or cream rubbed in well
what are the pros and cons of giving a drug IM?
pros
* bypass 1st pass
* quicker acting
* can be used for patients that are non-compliant without capacity
cons
* painful
* can result in swelling / haematoma/ abscess
* less predictable as different blood supply to different regions/ individuals
* risk of accidental IV
define bioavailabilty?
Refers to the fraction of drug that enters the systemic circulation after non-IV administration compared to that in IV administration.
calculated by AUC in oral / AUC IV when drug conc vs time is plotted
what factors influence bioavailability?
- drug chemisty - acid/base, pKA etc
- type of preparation - enteric coated tablets prevent stomach acid breaking down
- the route of administration - where its affected by 1st pass metabolism, its blood supply etc
- 1st pass metabolism - degree the drug is affected, liver blood flow, efficiency of enzyme systems.
- metabolism - e.g. broken down by esters before fully reaching systemic circulation
- co-administered drugs - may inhibit 1st pass metabolism, may change GI absorption e.g. prokinetics
can you think of examples where 0 bioavailability is useful?
vancomycin in c.diff
antacids in stomach
anytime you want local actions only
what is the difference between absolute and relative Bioavailability?
absolute bioavailability = AUC oral/IV
Relative is for those that cant be given IV . Relative bioavailability compares the bioavailability of a drug from a particular formulation or route of administration to that of a reference formulation or route. It does not require an intravenous reference dose.
what factors impact amount of drug absorbed by the inhalation route?
Drug
* blood:gas partition coefficient
* size - MW
* conc gradient
carrier gas:
* e.g. for inhalers like salbutamol - can influence where the drug reaches.
* 1-3um will reach alveolus.
* may not need to reach this far e.g. bronchodilators and can be bigger
Patient
* minute ventilation
* surface area, thickness
* deadspace
which drugs can be given by epidural route?
analgesic .. local anaesthetic, opioids, ketamine, clondine
steroids
adrenaline and bicarb as adjuncts - bicarb improves onset of local anaesthetics, adrenaline causes vasoconstiction to prevent systemic uptake of drugs.
what factors affect absorption via oral route?
drug
- Pka, acid / base
- formula (enteric coating, modified release)
- size
patient
* GI motility
* vomitting
* villous atrophy in elderly/ underdeveloped in kids
* microbiome
* other drugs - acidity, motility
* first pass metabolism
what determines where in GIT a drug is absorbed?
S.A of small intestine means most drugs absorbed here.
some drugs are more unionised at stomach pH e.g. weak acids - aspirin however still mostly by duodenum due to S.A
weak bases more unionised in duodenum
stomach emptying time
can you give examples of drugs that undergo high first pass metabolism and low?
high first pass
- morphine , nitrites
variable - propanolol
low - paracetamol, aspirin
define volume of distribution…
the theoretical volume a drug distrubutes into in the body to produce the concentration of drug found in the plasma
calculated by based on formula
conc = amount of drug / volume
determined by drug properties - molecular size, lipid solubility, tissue binding, plasma binding, ionisation.
define distribution..
the transfer of a drug into different body compartments
depends on drug properties and barriers present between compartments and protein binding.
what factors affect distribution of drugs..
drug properites
* ability to cross membranes - size, unionisation, pka.
* e.g. small lipid soluble generally have high Vd, lo
* tissue vs plasma protein binding - plasma protein binding reduces Vd, tissue binding increases it.
patient factors
* regional blood flow - i.e. initially distributes to areas of high blood flow, then medium, then low.
* fat content
* body pH
* hepatic / renal disease
what assumptions can be made based on Vd of a drug?
high Vd - absorbed into all compartments e.g. lipid compartments too and thus very lipid soluble - can go into all 3 compartments - intracellular, interstial and plasma
small Vd - absorbed only into water soluble compartments e.g. plasma.
is 14L a small or large Volume of distribution?
small
per Kg this would be 0.2L/kg
e.g. NMBA
which drugs require a loading dose?
those with a large Vd
this will help them reach their effective plasma concentration quicker
e.g. digoxin , amiodarone
equation for loading dose..
Vd x plasma target conc
how do hepatic and renal disease effect volume of distribution?
hepatic
* affects protein binding- less proteins, more free drug to distribute to lipid rich areas
* ascites - increased Vd of water soluble drugs due to extra fluid areas
renal disease
* fluid retension
* acidosis can also protein binding, ionised/unionised
explain the effects of plasma protein binding…
WHAT IS PPB…
drugs can bind plasma proteins through ionic bonds, hydrogen bonds or weak van deer waals.
the 2 main plasma proteins that bind drugs are albumin and alpha 2 acid glycoprotein. albumin binds acidic drugs e.g. aspirin and ACG bind basic drugs e.g. lidocaine.
Due to the weak interactions, the process is usually reversible and exists in equilibrium
plasma protein + free drug <=> plasma protein-D
thus the drug will exist as partly free form and partly bound form in the blood. it is the free form that is able to cross barrier to other compartments and exert effects and be excreted.
hence PPB effects
* drug distribution
* onset of action
* duration - metabolism & excretion effected
* Drugs can also displace one another resulting in DDIs.
* risk of drugs with narrow therapeutic index - PPB is acting as a reservoir, if plasma protiens reduced or displacement can result in quick increase in free drug portion and toxicity. usually only significant if PPB is 90% or more
what effect does tissue protein binding have on drugs?
increases Vd
increases terminal elimination half life
increases duration of action
can cause toxic build up e.g. amiodarone
Can you explain why propofols effects wear off after 10mins …
Drug given IV and instantly will have a high conc in blood.
this conc reaches the brain, anaesthesia
it is assumed the effector site brain is in equilbrium with plasma with a slight delay - due to highly perfused organ
then redistributes as very lipid soluble to fatty compartments etc
plasma conc drops , brain conc drops
less effect on brain
how are drugs removed from the body?
3 routes - spontaneous breakdown e.g. hoffmans degradation, metabolism by enzymes and excreted as their metabolites OR excreted unchanged (vancomycin)
define metabolism…
Process by which a drug or molecule is chemically changed by the body usually to aid the process of excretion by making the drug more water soluble.
however may also include activation of pro drugs.
mostly takes place in the liver by phase 1 and phase 2 metabolism.
however some drugs rely on alternative routes - ester hydrolysis, by kidneys (dopamine) and lungs (steroids, local anaesthetics) and by the gut wall or gut bacteria.
can you list some prodrugs
enalopril and ramipril
diamorphine
codeine
what is the difference between phase 1 and 2 metabolism ..
phase 1 and 2 metabolism both take part in liver and both aim to increase water solubility of drugs for excretion.
phase 1 = hydrolysis, reduction, oxidation - CYP450
phase 2 = glucuronidation, sulphation, acetylation, methylation. e.g. conjugation with various groups to increase water solubility.
some drugs undergo both consequentively. some only undergo phase 1. sometimes phase 1 reactions activate prodrugs.
what factors affect the metabolism of a drug?
drug
* type of drug e.g. does it have an ester link that can be hydrolysed by esterases
* is it a prodrug, whic enzymes can break it down all depends on chemistry
patient
* age - reduced enzyme systems in neonates/elderly, reduced hepatic blood flow in elderly
* gender - higher enzyme activity in men
* genetic polymorphism - CYP450
* disease - liver disease, reduced CO
* pregnancy - reduced plasma cholinesterase activity
* obesity - increased phase 2 in obese and hence reduced effect of lorazepam.
external
* other drugs - competing, inducers/ inhibitors of CYP450, smoking and drinking can induce CYP450, and certain foods.
define first pass metabolism
Refers to the process where an orally administered drug is significantly metabolized in the liver (and sometimes the intestines) before it reaches the systemic circulation.
This is because drugs absorbed by the gut are taken to the liver via the portal system pre entering systemic circulation.
what factors influence hepatic metabolism of a drug?
drug factors - lipid solubility, ionisation, protein bidning.
patient factors- age, liver disease, hepatic blood flow, nutritional deficiencies (albumin and also enzymes), pharmacogenetics
what is meant by the hepatic extraction ratio?
The fraction of drug removed from the blood by the liver in one pass through the circulation
factors affecting this are blood flow, hepatocyte function, enzyme kinetics (inducers / inhibitors)
defined by
HER = difference in drug conc of blood entering and leaving the liver / conc in blood entering
define hepatic clearance…
volume of blood removed of a drug by the liver per unit time
HER x hepatic blood flow
what is the significance of a low and high HER?
High HER (more than 0.7) - rapidly and extensively metabolised by the liver. These will have a high first pass metabolism. These are more likely to be affected by liver blood flow rather than changes to enzyme activity.
Low HER (less than 0.3)- capacity limited, more dependant on liver function and protein binding than blood flow. inducers and inhibitors of liver enzymes are more likely to have an effect here. more likely to have a higher oral bio-availability.
high ER is less effected by plasma protein binding - this is because the liver efficiently extracts the free portion of the drug from the plasma. low ER is affected by plasma protein binding.
give 2 examples of low HER and high HER
high HER = morphine, ketamine, propofol
low ER = paracetamol, warfarin
Can you tell me about the CYP450 system…
mono-oxygenase enzyme family consisting of 57 isoenzymes.
Named based on their relatedness in DNA sequence e.g. 2E1 and 2C9 are part of same family but different subfamily
mainly found in SER of hepatocytes and responsible for phase 1 metabolism.
but also present in gut, kidneys, adrenals and lung
have this name because they absorb light in the wavelength of 450.
What affects the functioning of CYP450…
genetic polymorphism
* variation in CYP450 alleles within populations hence variation to functioning and drug metabolism. e.g. CYP2D6 and codeine.
DDI
* various drugs and dietary substance inhibit and induce CYP450
patient factors - nutritional status, age, liver disease
what is meant by genetic polymorphism
term describing differences in peoples genotype and subsequent variation in phenotypes.
this can affect drug pharmacokinetics and dynamics.
e.g. refers to the occurrence of two or more different alleles (variants) of a gene within a population.
enzymes affecting metabolism may show genetic polymorphisms e.g. seen in CYP450 family
for example various alleles of CYP2D6 which metabolises codeine to morphine.
ultrarapid metabolisers of codeine convert prodrug to active form quicker and can result in opioid side effects. some caucasions have inactive enzyme and cant metabolise for analgesia
NAT2 enzyme can lead to slow or fast acetylation of drugs such as isoniazid and hydralazine
suxamethonium apnoea
can you give examples of extra-hepatic CYP450…
11 B hydroxylase found in adrenals
3A4 found in gut wall
also others found in lungs, PCT of kindey
state 2 CYP450 enzymes you know and common drugs they metabolise
CYP 2D6 = codeine, opioids, B blockers
CYP2E1 anaesthetic inhalation agents, ethanol, benzos
CYP3C9 = warfarin, NSAIDs, propofol
state the CYP450 inducers and inhibitors…
inducers: PSCRAP
Phenytoin
St johns
Carbemazepine
Rifampicin
Alcohol (chronic)
Phenobartibital
** inhibitors: FEGAC**
fluoextine
erythromycin
grapefruit
Amiodarone / alcohol acute
cimetidine / ketonazole
give some specific examples of CYP450 inhibition…
Warfarin:
metabolised by CYP2C9
inhibited by amiodarone, induced by St Johns, phenytoin and rifampicin
CYP2E1 induced by chronic alcohol, affects anaesthetic agents.
fluoextine inhibits CYP2D6 - codeine is less analgesic
how is propofol metabolised?
in liver by glucuronidation and sulphation
to be excreted by the kidneys
may also have some extra hepatic due to such high clearance rate.
how are opioids metabolised?
in the liver but also some in the gut wall
glucuronidation
morphine 6 glucuronide (10%) - more potent than morphine.
morphine 3 glucuronise (70%)
excreted in urine and bile
how is paracetamol metabolised?
phase 1 and phase 2 metabolism in the liver - mostly by phase 2
phase 2 - sulphation and glucuronidation
phase 1 - NAPQI toxic metabolite –> conjugation with glutathione (phase 2)
if gluthione is deplete - NAPQI is toxic and causes hepatic necrosis
describe the metabolism of ethanol..
ethanol –> acetaldehyde
(alcohol dehydrogenase) - 0 order kinetics
acetaldehyde –> acetic acid
by the liver.
define excretion…
The removal of waste from the body, this includes drug metabolites or unmetabolised drugs.
usually involves kidneys but can also be via exhalation, bile, sweat, breast milk.
give examples of drugs cleared unchanged by kidneys?
Gentamicin, furosemide, digoxin
can you give examples of drugs excreted in bile…
rocuronium, erythomycin
steroids and COCP
can you give examples of drug excreted by lungs
inhalation agents
alcohol
what factors affect the clearance of a drug…
drug factors
* its chemistry - lipid solubility, water solubility, size, chemical bonds
* e.g. larger molecules cant cross glomerular filter and need breaking down
* lipid soluble molecules may be reabsorbed by kidneys and need to be made more hydrophillic.
* amount of protein binding - reduces the free portion for excretion
other drugs
* inducers/ inhibitors
* competition for plasma proteins
* probenecid inhibits the renal clearance of penicillin by blocking its active secretion
patient factors
* liver function - enzyme deficiencies, glutathione deficiency etc, poor liver blood flow
* renal function - low GFR , number of glomeruli decreases with age.
define rate of elimination…
The rate of removal of a drug from the plasma
Rate of elimination (mg/min) = C x Cl
conc at a particular time x clearance of the drug
define clearance..
Clearance (Cl) is the volume of plasma (mls) that is cleared of drug per unit time (min).
Can be calculated by Clearance = Vd x K
K = rate constant of elimination
clearance can also be found from the area under the curve of a conc time curve. where clearance = dose at time 0 / AUC.
define rate of excretion…
rate of removal of a drug from the body
how does the kidney handle drugs…
Renal handing of drugs is divided into 3 stages - glomerular filtration, reabsorption, secretion
glomerular filtration
- most will be filtered
- rate / degree depends on size, charge, free portion (PB)
Reabsorption:
* passive diffusion if lipid soluble hence depends on PKA and ionisation e.g. aspirin in alkaline acidic urine will become unionised and reabsorbed.
* some may have transport processes
active tubular secretion
* e.g. penicillin and aspirin
give examples of drugs heavily affected by renal function..
opioids = morphine (morphine 6 glucuronide will accumulate)
digoxin - excreted unchanged
Abx - gentamicin (excreted unchanged)
explain the difference between 1st and 0 order kinetics..
1st order = the rate of drug removal depends on the concentration of the drug at that time. this is because enzyme systems are not saturated, so more drug available, increases the rate of metabolism/clearance. Thus the conc time curve is a negative exponential . clearance is constant and half life is constant. constant proportion removed per unit time.
0 order = rate of removal is constant regardless of the concentration. there is a linear relationship between concentration in plasma and time. e.g. alcohol, phenytoin. enzyme systems are saturated so rate remains at maximal. clearance is variable, half life is variable.
draw a graph for rate vs time for 1st, 0 order and 2nd order kinetics
write the equation for a 1st order kinetics conc - time graph..
rearrange this to produce a straight graph
Ct= Co . e ^-kt
by taking logarithms can produce a semi log curve which is y=mx+c
Ln Ct = LnCo + Lne-kt
LnCt = LnCo - Kt
LnCt = -Kt + LnCO
y=mx + C
now can interpret from the curve
* conc at time 0 through extrapolation
* k via the gradient of the curve.
using a graph show how the half life varies in 0 order kinetics..
Define an exponential process…
defined by a process whereby the rate of change alters overtime and is proportional to the value at any given time
in its simplest form
y=e^x
a negative exponential is where the rate of change is decreasing with time. the proporiton of removal remains the same. e.g. half each time.
draw graph for simiple positive and negative exp.
how do you calculate renal and hepatic clearance?
renal = (urine conc x urine flow) / plasma conc
hepatic = hepatic blood flow x HER
draw different exponential functions and give an example
exponential decay - drug wash in and wash out
e.g. drug wash in 1-e^-x
exponential growth e.g. bacterial growth
define half life and time constant…
half life = the time taken for drug concentration to fall by half. this is constant for 1st order kinetics, but decreases for 0 order
time constant the time taken in 1st order kinetics for the drug concentration to fall to 37% of its original (OR the time taken to fall to 0 if the initial rate of decline were to continue.
DRAW THESE
how many half lifes and time constants does it take for the reaction to fall to almost complete…
5 half lives for elimation to be 97% complete
4 half lives = 94%
3 time constants - 95% complete
how does half life compare to Clearance and Vd..
can derive this from the other equations…
t1/2 = 0.693 x Vd/Cl
after how many half lives is steady state said to be achieved?
5 or 3 time constants
how does time constant and half life relate
how does time constant and rate constant of elimination relate?
T1/2 = 0.693 x T
T=1/k
what is e?
e is eulers number
it is the base of the natural logarithm
e = 2.718
many biological / natural processes have exponentials with this base.
what is meant by pharmacokinetic modelling?
mathematical model to predict metabolism, clearance and distribution of drugs
models can be used to preduct plasma concentrations with time.
there are 1 , 2 and 3 compartment models depending on how many compartments a drug distributes into
1 being the simplest but probably an over simplification for most drugs
likely that most drugs probably distribute into 3 if not more compartments.
Can you describe a 1 compartment model..
drug is given and distributes evenly into 1 compartment.
the concentration after this is given depends on the Vd of the compartment
it is then eliminated from this compartment
if via first order kinetics = negative exp. = Ct= Co.e-kt
unfortunately very few drugs can truely be described like this as the body is not homogenous and there are areas which are rich in vessles and those less so. e.g. propofol is far from a 1C model.
can you describe a 2 compartment model…
2 compartment model describes proces whereby drug is given and distributes in main compartment e.g. plasma but then there is a second process by which it is distributed into a second compartment (the tissues) at another specific rate (depends on drug, blood supply to the compartment)
during elimination, there is initial redristibution so plasma conc falls quicker and then elimination from main compartment and gradient of graph levels out.
C= Ae-at + Be-bt (i.e. 2 expoential functions)
rate of distribution = K12
at steady state K12=K21 and clearance is only dependant on that from central compartment.
clearance = K10x V1
(product of Volume of compartment 1 and elimination from compartment 1)
can you describe a 2 compartment model…
most accurate of compartment models especially for lipid soluble drugs and is the basis of most TCI models.
plasma –> highly vascularised tissue e.g. muscle –> poorly vascularised (fat)
graph shows oringal curve = 3 phases, fast distribution, slow distribution, elimination. And the log of each of these on same graph.
what is the difference between caternary and mamilary models?
caternary = V1 –> V2 –>V3 (linear model)
mamilary = V2<–V1–>V3 (most commonly used)
in each case main elimination from V1 = K10
describe the changes to plasma concentration during an infusion of a drug..
wash in curve
steady state
wash out
wash in - drug aded to C1 and distributes to C2, C3. it is being eliminated too. C1 slowly fills up as infusion continues.
steady state - rate of elimination of drug = infusion rate
wash out
- 2 exponential decays for 3 C model.
what is the plasma conc at steady state if clearance is 100ml/min and infusion rate is at 200mg/min
in = out
200mg/min = conc x clearance
200/100 = 2
2mg/ml = conc
when a drug is not given via infusion but instead as bolus, how does the concentration change with time. how long until steady state is reached?
if dose is repeated everytime it drops by half it would take 5 half lives/ 3 time constants to reach steady state
what is the purpose of a loading dose?
can help reach steady state quicker
esp useful if Vd is large
Loading dose = Vd x plasma conc
What is meant by TCI?
target controlled infusion
this describes the use of pharmacokinetic models by infusion devices to achieve a target plasma concentration or effect site concentration.
these models use parameters such as height, weight, gender, age and algorithms to predict the pharmacokinetics of drugs to estimate infusion rate to reach a target plasma conc .
consists of…
* a pump with an interferace for user to enter data, select target plasma conc
* computer/ procesor with stored algorithms, control
system to control output, alarms
* infusion device
what are the ideal properties of a drug that is used in TCI?
short and constant CSHT after long infusion e.g. remi
no active metabolites
rapid clearance and small Vd
predictable pharmacokinetics that can be modelled e.g. not affected by renal function, genetic polymorphisms.
can you name 2 TCI models for propofol can give some differences in these..
MARSH
* takes into accound weight and target conc
* gives a larger bolus at the beginning
SCHNIDER
* takes into account weight, height, geder and age
* estimates lean body mass
* so more sensitive
* better for obesity and elderly
* gentler in delivery so better for CVS instability
do you know any paediatric TCI models?
Paedfusor
Kataria
what plasma conc of propofol is usually given for sedation & anaesthesia
sedation 1-2 ug/ml
anaeasthesia 3-10ug/ml
what is meant by context sensitive half time?
the half life of a drug is the time taken for it to fall by 50%
this can depend on how long the infusion has been running for an how much it has accumulated.
some drug can accumulate and their half life rapidly increases with infusion time e.g. fentanyl.
others do not accumulate and rapidly metabolised and thus CSHT remains relatively constant e.g. remifentanil is constant after 10 mins of infusion.
what is the CSHT at 8 hours for remi, propofol, alfentanil and fentanyl
remi = 5mins
propofol = 40mins
alfentanil = 50 mins
fentanyl = 250mins
why is remifentanil context insensitive after 10 mins?
has rapid method of metabolism by tissue and plasam esterases
thus has a small Vd and v high clearance
doesnt accumulate
what is the TCI model for remifentanil? what is the usualy plasma target conc?
Minto model
plasma concs are in nanomolar/l
(propfol is in umol/l)
usually around 4-8nmol/l target conc
what are the limitiations of pharamcokinetic models?
making many assumptions - all people have same proportion of different compartments, all people metabolise and eliminate drugs at the same rate, the rate of distribution/elimination in different compartments is same amoungst everyone.
no actual measurement of plasma conc or effect site conc
hence should use BIS
what is TIVA?
total intravenous anaesthesia (TIVA)
maintaining anaesthesia with IV agents only without the use of inhaled anaestheitc agents
uses TCI models and BIS to determine adequate level of infusion for anaesthesia.
usually uses a combination of remifentanil (minto model) and propofol (schnider/marsh).
at around plasma conc of propofol 4-6ug/mol and remifentanil 2-8ng/ml
these have a synergistic effect
can you describe the ideal TIVA agent…
physical
* cheap and easy to manufacture
* no reconstitution needed
* long shelf life
* inert with giving sets and other drugs
* environmentally friendly
pharmacokinetic
* context INsensitive half time or very short
* this will inturn be determined by rapid clearance, small Vd
* non active metabolites
* lipid soluble to have effect at brain but doesnt accumulate.
pharmacodynamic
* painless on injection
* minimal CVS side effects
* depresses laryngeal reflexes
* antiemetic , analgesic
why are propofol and remi used commonly in TCI?
propofol
-familirity
- antiemetic, supresses laryngeal reflexes
- okay CSHT e.g. 8 hrs, 40mins
- no active metabolites
remi
- almost context insensitive
- works synergistically with propofol
- no active metabolites
- potent analgesic
- depression of respiration, can be useful if NMBA cant be used.
pros and cons of TIVA
pros
- environmentally friendly
- reduced transmission of cancer
- reduced PONV
- good for those with MH
- good for bronchoscopy cases
cons:
* increased risk of awareness
* more complicated to set up
* no real measurement of plasma conc of agent like MAC.
how do you end a TIVA case?
turn off propofol first - when you turn this off will depend on how long the operation has been running
dont need to turn off remi until the end.
what are the issues with remifentanil?
needs reconstituting
hyperalgesia
chest wall rigidity risk
bradycardia
IS there a method for manually administering TIVA rather than a TCI?
yes the bristol model
1mg/kg bolus at the start
10mg/kg/h for next 10mins
8mg/kg/h next 10
then 6mg/kg/hr from then on
achieves conc of 3ug/ml
innacuratre - probably gives more
what are your options if your TIVA pump switches off half way through?
- switch to inhalational
- switch to manual propofol infusion - use rate the machine was giving before it turn off
you cant start the TCI again as it has forgotten what has already accumulated.
make sure you are using BIS to reduce risk of awareness
what are the risks and safety features when using TIVA…
TIVA has been associated with an increased risk of awareness this comes from a few risks associated with it…
- cant measure the actual plasma conc
- therefore relying on accuracy of BIS, TCI and good cannula access
- risk of cannula tissuing
safety features available
- using BIS
- being vigillant of clinical signs
- have the cannula site on show
- ensuring you have a good cannula
- anti syphoning and anti reflux valves
- low and high pressure alarms
can you use TIVA in morbidly obese?
yes
although TCI models level validated
probably under/over estimate
must use BIS
indications for TIVA..
cant use inhalation
* MH
* bronchoscopy
* not available ITU, transfer
less side effects
* PONV
* reduced cancer reoccurance
environmental
what is meant by pharmacogenetics?
the influence of individual genes on pharmacodynamic/kinetics
what factors cause a variable biological response to drugs amougst patients…
pharmacokinetics
* absorption - age, other drugs,
* distribution - protein binding in liver disease, age, fluid accumulation in liver/kidney disease, amount of body fat varies and water content
* metabolism - CYP450 - genetic polymorphisms, deficiency with disease/ age, inducers and inhibitors, hepatic blood flow with age/ gender etc. men have higher levels of enzymes.
* elimination - kidney function with age/disease
pharamodynamics
* genetic polymorphisms in receptors and downstream signalling pathways
* e.g. ryanodine receptor associated with MH
* allergies in some people
what is the enzyme problem and genetic problem in sux apnoea?
plasma cholinesterase deficiency
hence reduction in sux metabolism
chrom 3 can have 4 alleles = usual, atypical, flouride resistant, silent.
depending on combination of abnormal alleles paralysis can last up to minutes to severeal hours..
e..g Es/Es or Ef/Ef = >3hrs
Eu/Eu = normal - break down after around 6 mons
Ea/Eu - most common abnormality = 30 mins
how are pharmacokinetics altered in neonates…
Absorption - reduced GI motility, emptying, villous atrophy. slower absorption but potentially increased due to slower transit.
Distribution - high body water than adult hence can result in reduced conc if scaled down using adult dose, lower plasma proteins , less fat content so increased conc of lipid soluble drugs
metabolism - immature enzyme systems
Excretion - under developed renal function.
how is pharmacokinetics in older people effected?
Absorption - reduced GI motility, emptying, villous atrophy. slower absorption but potentially increased due to slower transit. changes to gastric pH
Distribution - low body water and higher fat content. lower plasma proteins.
metabolism - reduced hepatic flow, polypharmacy affecting enzyme systems
Excretion - reduced renal function.
what are the effects of changing cardiac output on pharmacokinetics?
reduced absorption
takes longer to distribute
less metabolism
less GFR /excretion
what are the effects of being critically ill on pharmacokinetics
absorption - reduced gastric motility e.g. ileus, villous strophy from illness, perfusion abnormality in low CO.
distribution - protein binding decreased (low albumin), pH changes change ionisation
metabolism - poor hepatic blood flow (low CO), liver may be making acute phase proteins etc and thus reduced function for drug metabolism
excretion - lower GFR
define the rate constant of elimination…
fraction of drug eliminated per unit time e.g. 0.1min-1 = 10% eliminated every min
inverse of time constant
show how t1/2 = 0.693 x t
using equation lnCt = LnCo - kt
at half life the conc will have fallen by 1/2 so LnCt = LnCo/2
sub in LnCo/2 = LnCo - Kt1/2
lnCo - Ln2 = lnCo - Kt1/2
ln 2 = kt1/2
t1/2 = ln2 / k
t1/2 = Tln2
t1/2 = 0.693 T
what are the properties of an exponential decay curve…
plasma conc approaches 0 and get infinitely closer but never reaches = asymptomates
proportion of drug eliminated is constant and the clearance is constant but the amount removed varies with time.
rate of change is proportional to the conc at a particular time.
what is a lipid emulsion made of e.g. intralipid, propofol?
egg phosphatide
soya bean
glycerol
