Pharmacokinetics Flashcards
how does the dosing or oral and IV GTN differ?
oral much higher because high first pass metabolism
how does protein binding affect Vd?
depends if plasma or tissue proteins
plasma proteins - low Vd
tissue proteins - high Vd
can the Vd be larger than total body volume?
yes
what is the formula for Vd?
Concentration = mass of dose/Vd.
what are the 2 main plasma binding proteins?
albumin and alpha1-acid-glycoprotein
is desflurane a good induction inhalation agents?
no because smells and irritant to airways
(however it is fast)
how much is desflurane metbaolised?
0.2%
all inhalation agents except one are metabolised to trifluoroacetic acid. which one?
sevoflurane
what is more soluble in blood N20 or N2?
Nitrous oxide is more soluble than nitrogen in blood
what is MAC a measure of and what does it correlate to in terms of physical properties?
MAC is a measure of potency and correlates with lipid solubility (and therefore oil:gas partition coefficient).
what determines speed of onset of inhalation agents?
blood:gas coeffiecient - lower blood solubility the quickest
which is the most potent inhaled agent?
halothane
what does pregnancy do to speed on onset of inhalation anaesthetic?
increases
There are several physiological changes in pregnancy: hyperventilation and reduced FRC will favour a faster onset, but an increased cardiac output would tend to oppose this. Overall the respiratory effects predominantly increase the speed of onset
how does emphysema affect speed of onset of inhalation anaesthesia?
Emphysema increases the FRC volume and dilutes the agent in the alveoli.
how is thiopentone handled in phase 1 metabolism?
oxidation
what is the most common form of phase 1 reaction? what are the other types of reaction for phase 1
oxidation
reduction and hydrolysis are the others
list some enzymes involved in phase 1 reactions?
cyp450
monoamine oxidases
monooxygenases
esterases
high extraction ratio is dependant on what
low extraction ratio is dependant on what?
high - blood flow
low - protein binding
do the following have high or low extraction ratio? Propofol, ketamine, etomidate and morphine
all high
how does fat change in elderly?
increase in fat
how is half life related to time constant?
half life = 0.693 x time constant
how does urine pH change excretion of drugs
weak acids are excreted faster in alkaline urine as alkalinity promotes the dissociation of acid into ion and conjugate base
what is the equation for the graph showing concentration of a drug with time in first order kinetics?
C = C0e-k.t
negative exponential - decreases exponentially with time.
what is the equation relating clearance to elimination rate constant?
Clearance = Vol of distribution (Vd) x elimination rate constant (Ke).
what reactions make up phase 2 metabolism?
sulphation, glucuronidation, acetylation, methylation.
list some meds that are prodrugs?
codeine, diamorphine, enalapril
which of the following have active metabolites… morphine, diazepam, pethidine, atracurium and pancurium?
all of them
which metabolite of morphine is clinically active?
morphine - 6 -glucuronide
how is vancomycin elimated?
excreted by kidneys unchanged
where are cyp450 enzymes found?
hey are primarily found in the liver, bound to the lipid bilayer of the S endoplasmic reticulum of hepatocytes.
also found in the kidneys, and adrenals.
what are roles of CYP450
make drugs more hydrophilic for excretion - phase 1
synthesis of physiologically active substances
which CYP metabolises fentanyl and midazolam
CYP3A4 is involved in the metabolism of fentanyl
how does t1/2 relate to T (half life and time constant)
t1/2=0.693T
how does clearance relate to Vd?
clearance = Vd x k
(k = rate constant of elimination)
how does Time constant relate to rate constant of elimination?
T= 1/k
can kidney failure effect bioavailability?
yes as renal failure can have an effect on liver and GIT function
what is the intercompartment clearance and elimination clearance equations?
Inter-compartmental clearance is given by V1.k12 or V2.k21.
elimination clearance is given by V1.k10
what is the following equal too… ln2/k
half life
ONLY for first order kinetics, 1 C model
how many exponential processes in a 1C , 2C and 3 C model?
1C = 1
2 C = 2
3C =3
for propofol how does the intercompartment clearance compare to elimination clearance?
elimination clearance > inter compartment
what is the different between a mamillary model and catenary model?
mamillary - V2 and V3 each connected to central compartment
caternary V1–> V2–>V3
how does the intercompartment clearance of second compartment compare to third ?
how do these compare to elimination clearance?
The third compartment has a smaller inter-compartmental clearance than the second compartment
Inter-compartmental clearance between the central and second compartment may be greater than elimination clearance e.g. fentanyl and alfentanil (but usually elimination clearance is larger)
which of the opioids has smallest Vd?
remifentanil
the volume of the 3rd compartment directly reflects lipid solubility true or false
false related but not directly reflected by
Why is fentanyl shorter acting than morphine
Very lipophilic.
Distributes via intercompartments
how does concentration of a drug change with time in first order kinetics
negative expontential decay - the rate of decay changes with time
There is a constant proportionality between concentration and rate at which concentration falls: dC/dt = -kC.
what has a greater intercompartmental clearance - fentanyl or propofol?
fentanyl
for fent intercompart> elimiantion clearance
for prop elimination clearance > intercompartment
what is the equation for loading dose?
loading dose = Css x Vd
Css = plasma conc at steady state i.e. your target
A drug behaves according to a single-compartment model. Experimentally you find that it has a half-life of 70 min and a clearance of 100 ml/min. Which one of the following is its approximate volume of distribution?
equations:
T1/2 = 0.693 x T
T= 1/k
Clearance = Vd x k
therefore answer is 10L
The clearance of a drug is 1.4 L/min. The initial half-life is 10 min. What loading dose is required to give a plasma concentration of 10 mcg/ml?
equations:
T1/2 = 0.693 x T
T= 1/k
Clearance = Vd x k
PLUS
loading dose = Css x Vd
answer = 200mg
what info is needed when measuring clearance after an oral dose,
bioavailabilty fraction
list factors that can alter pharmacokinetics of a drug ?
age, BMI, other drugs, hepatic or renal failure.
how long before the context sensitive half life of propofol is constant
around 70 hours
how long does it take a steady state fentanyl infusion to be reached?
60 hours
when an infusion is stopped what does the duration of its hypnotic effect depends on?
how much was in the plasma at steady state
CSHT
what reaches steady state quicker - propofol or remifentanil?
remi as it has a smaller Vd
what is the elimination of clearance for propofol and fentanyl?
propofol - 1.9L/min
fentanyl 600ml/min
how does absorption of drugs in neonates compare to adults?
slower due to longer gastric emptying time
when can adult metabolism of drugs in a neonate be similar to adults?
some drugs after 2-4 weeks e.g. barbiturates
what is GFR in neonates compared to adults?
20-40%
how does aging change the GI absorption of drugs?
Ageing is associated with changes in gastric pH, slowing of gastric emptying, and reduced small bowel surface area
how does body water change with age?
decreases with age
how is bio-availability affected in elderly?
may be higher due to reduced hepatic flow and thus reduced extraction fraction
what factors in pregnancy effect pharmacokinetics?
Hepatic blood flow
Hormone levels
Placental enzymes - some can metabolise drugs
Cardiac output
Protein binding
how do opioids affect absorption of other drugs?
Opioid analgesics may lead to impaired absorption of enterally administered drugs - changes gastric motility
how is the free fraction of drug altered in pregnancy?
increased
less PB
how does body water compare in neonates?
higher percentage
how does obesity affect lorazepam metabolism?
increased metabolism - decreased sedation effect
how is pharmacokinetics affected in septic shock ?
decreased plasma proteins - increase in free fraction
reduced hepatic activity as making acute phase proteins
delayed feeding causes gut atrophy - reduced absorption
hepatic blood flow increases when hyperdynamic circulation and then reduces in shock
what can the minto model be used for?
remi
also propofol
2 separate models by same company - allows use concurrently
how does the central compartment vary in schnider?
it doesnt
central compartment is fixed
which mathematical/ pharm model for propofol uses lean and actual body weight?
schnider - lean
marsh - actual
what are the mathematical compartment models for TCI for fentanyl and alfentanil and ketamine?
fentanyl - shafer
alfentanil - maitre
ketamine - domino
which 2 CYP 450 enzymes show most pharamacokinetic variation?
CYP2D6 & 2C9
which CYP450 enzyme metabolises carvidilol and what can inhibit this?
CYP 2C9 -
amiodarone inhibits this
what drugs are metabolised by CYP 2C9?
losartan
glipizide
warfarin
carvidilol
NSAIDS and selective COX 2 inhibitors
fluoxetine, phenytoin
polycyclic hydrocarbons in cigarrete smoke induce CYP - which enzyme and which drugs does this effect?
1A2
2E1
caffeine, theophylline and propanolol
What is the feature of a sprotte needle that reduces post Dural headache
Sprotte needle = spinal needle
Has a bevel to reduce trauma
