Pharmacokinetics Flashcards
1
Q
What does pharmacodynamics describe
A
the interaction of drugs and their receptors (including affinity and efficacy) and the tissue distribution of the receptor
2
Q
What does pharmacokinetics describe
A
the factors that determine the concentration of the drug at the target receptor
3
Q
What does relationship between administered dose and concentration at the target site depend upon
A
absorption,
distribution,
metabolism
excretion
4
Q
How does plasma concentration of a drug vary over time for:
a) a single iv bolus dose
b) oral dose
A
a) initially high then decreases
b) initially increases to a peak as drug is absorbed, before decreasing as metabolism and excretion increase
5
Q
What is the range the plasma conc of a drug must be within
A
therapeutic window - higher than minimum effective conc. but lower than the minimum toxic conc
6
Q
Do you want the therapeutic window to be wide
A
yes this is ideal
7
Q
How is the therapeutic window reflected in dosing strategies
A
An effective dosing strategy will maintain the plasma concentration within
the therapeutic window for as long as necessary
8
Q
What kind of chemicals are local anaesthetics
Where do they act? What does this mean?
A
weak bases
intracellular side of the Nav channels
They must cross the plasma membrane to access the intracellular compartment.
9
Q
How do local anaesthetics cross into the intracellular compartment
A
in their un-ionised form (D)
10
Q
Why does the chemistry of inflammation affect the transport of local anaesthetics
A
Local inflammation decreases tissue pH (higher H+
concentration).
This shifts the equilibrium to favour DH+
Local anaesthesia is delayed or even prevented
11
Q
Which form of a weak base/acid is more likely to cross the PM
A
un-ionised form is usually more lipid soluble so diffuses readily, whereas
the ionised form cannot cross the membrane
12
Q
Name 2 subgroups in the SLC superfamily
A
organic anion transporters (OATs)
organic cation transporters (OCTs).
13
Q
Name a SRC that is a drug target itself
A
SERT (transports serotonin)
14
Q
Name members of the SRC superfamily that are a) highly selective and b) less selective
A
a) SERT
b) OCT, OAT - can transport a wide range of structurally diverse molecules
15
Q
Describe the ABC superfamily
Give an example
A
ATP-binding cassette superfamily use ATP to drive drug efflux from cells.
MDR1 (P-glycoprotein, P-gp) is a particular example. They may be important drug resistance.
16
Q
What are SLC and ABC superfamilies particularly important for in pharmacokinetics
A
absorption from the small intestine, excretion into the bile or urine, and transport across
the blood-brain barrier
17
Q
What is the only time a drug does not have to cross a barrier to reach the plasma
A
iv
18
Q
What is the fastest and most certain route of drug administration
When would this be useful
A
iv
if the drug has a small therapeutic window
19
Q
Why might you use a slow iv administration of a drug over a fast administration
A
A rapid bolus injection can produce a very high plasma
concentration, initially in the right side of the heart and pulmonary circulation. Slow i.v.
infusion avoids this high peak plasma concentration while still avoiding uncertainly inherent
in absorption from other sites
20
Q
Disadvantages of iv drug administration (3)
A
injection or infusion requires a
skilled practitioner, and inconvenience to the patient. There is also risk of infection
21
Q
What are disadvantages of subcut. or intramuscular injections
A
rate of absorption can be unpredictable and inconsistent. These
injections can also be painful.
22
Q
What is the rate of absorption dependant on for subcutaneous/ intramuscular injections
A
diffusion through the tissue and removal by local
blood flow, as long as the drug can cross the capillary endothelium
23
Q
How does absorption differ between intramuscular and subcit injections
A
Blood flow to
the muscle is higher than to the skin, so absorption from intramuscular is often more rapid
than for subcutaneous. Exercise increases muscle blood flow, increasing absorption.
24
Q
Why is oral administration the most common route for drug administration
A
cheap and easy to administer (self administering)
25
How are oral drugs absorbed
via gut epithelium
lipophilic molecules will diffuse passively
26
What does rate of diffusion of oral drug across gut epithelium depend upon (4)
rate of diffusion is highest for highly lipophilic drugs, whereas
charged or highly polar drugs diffuse poorly. The rate of diffusion also depends on the
concentration gradient and the surface area of membrane.
27
Where does most oral drug absorption occur in the gut
small intestine (large SA)
28
Are drugs absorbed in the stomach
e stomach has a relatively low surface area and a thick mucosa, so little drug absorption
occurs. An exception are the tetracyclines, which are soluble at acid pH but insoluble at
neutral pH.
29
Why are tetracyclines absorbed in the stomach
what if they are not absorbed in the stomach
soluble at acid pH but insoluble at
neutral pH.
Any tetracycline that enters the intestines precipitates and is lost in the faeces
30
What happens to the equilibria of weak bases in the stomach
what does this mean for absorption
shifted to DH+
poor absorption, may become trapped
31
What happens to weak acids in the stomach
shifts equilibrium towards DH so absorption is favoured
32
Does the small intestine favour absorption of weak acids or bases
upper small intestine favours absorption of weak bases over weak acids. Despite these
effects, the extremely large surface area of the small intestine means that most oral drugs
are absorbed in the small intestine
33
Name a drug that is absorbed by a gut transporter
which transporter
what does it treat
levadopa
phenylalanine transporter
Parkinson's
34
Name 2 things that affects general drug absorption in the gut
splanchnic bloodflow
| gastric motility
35
How does gastric motility affect drug absorption
The rate of
absorption of drugs that are mainly absorbed in the intestines will be increased if gastric
emptying is accelerated and decreased if gastric emptying is slowed
36
How does vomiting or diarrhoea affect drug absorption
reduces absorption
37
How does splanchnic blood flow affect drug absorption
Increased splanchnic blood
flow after a meal may increase the rate of absorption, whereas decreased splanchnic blood
flow in heart failure may reduce the rate of drug absorption.
38
How can you stop stomach acid degrading oral drugs
enteric coating
39
describe enteric coating
usually stable at acidic pH but break down at higher pH.
| Digestion of peptides and proteins prevents their use as orally-active drugs (e.g. insulin)
40
What is the first pass effect
To reach the systemic plasma, the drug must be absorbed through gut epithelium and then
travel through via the portal circulation and the liver. Many drugs are metabolised by
enzymes in the small intestinal wall or the liver
41
What is bioavailability
The fraction of the delivered dose that reaches the systemic circulation
42
Name some factors that can cause low bioavailability (5)
inability to cross the gut epithelium,
transport back into the gut lumen,
metabolism of the drug in the intestinal
wall or liver (or by bacteria),
patient-specific factors such as interactions with other drugs
or food,
altered motility (e.g. vomiting).
43
Which drug administration routes can be taken to avoid stomach or the first pass effect (2)
rectal or sublingual
44
What is the series of the aqueous compartments in the body considered in pharmacokinetics
plasma |(endothelium) | interstitial fluid | (PM) | intracellular | (specialised barrier eg BBB) | transcellular
45
Describe the vascular endothelium
a single layer of cells that lines blood vessels and separates the
plasma compartment from the interstitial compartment. The nature of the endothelial
barrier varies between tissues.
46
What and how can some molecules pass through the vascular endothelium
endothelial cells of peripheral capillaries have small gaps between the cells that allow free passage to polar small molecules less than approximately 500-600 daltons. Small, lipophilic molecules can also diffuse through the endothelial cell plasma membrane
47
Give an example of a larger molecule that is restricted to the plasma unless specifically transported
Why is it restricted to the plasma
the anti-coagulant, heparin
Unfractionated
heparin is a carbohydrate polymer of variable chain length, with a molecular weight of 3-30
kDa. It cannot permeate the gaps between endothelial cells, and is not specifically
transported
48
Describe the capillary walls supplying the brain
have very tight junctions between endothelial cells and are further surrounded by astrocytes
49
which molecules can pass the BBB
if they are sufficiently lipophilic or if taken up by transporters/ via transcytosis
50
What can disrupt the BBB
Give an example
inflammation
In bacterial meningitis, for example, allowing increased access to hydrophilic
antibiotics such as aminoglycoside antibiotics and β-lactam antibiotics (e.g. penicillin).
51
Name an important BBB transporter
Pglycoprotein (P-gp; MDR1)
52
What is ivermectin toxicity associated with
a frameshift mutation and
| premature stop codon in the mdr1a gene in collie dogs
53
Why can human MDR1 polymorphisms be associated with drug toxicity
What is it also associated with
. P-gp reduces the
therapeutic effects of some drugs in the CNS, but also reduces the CNS toxicity of some
drugs
even clinical efficiency of antidepressants, but
this is less well established.
54
How does fetal pH relate to maternal pH
What can this lead to
Fetal pH is usually slightly lower
| than maternal pH, which can lead to ion trapping
55
Name an example which shows the placenta is not a perfect barrier to drugs
What is an ongoing scandal showing it is still a problem
thalidomide
The recent sodium valproate scandal
56
What is Vd and what does it describe
volume of distribution (Vd)
often used to describe the distribution of drugs in the body.
the volume that would contain the total amount of drug in the body at a
concentration equal to the plasma concentration.
57
What is the equation to Vd
𝑉𝑑 =
𝑡𝑜𝑡𝑎𝑙 𝑎𝑚𝑜𝑢𝑛𝑡 𝑜𝑓 𝑑𝑟𝑢𝑔 𝑖𝑛 𝑡ℎ𝑒 𝑏𝑜𝑑𝑦
-------------------------
𝑝𝑙𝑎𝑠𝑚𝑎 𝑐𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛 (𝐶)
where C=C(free) + C (bound)
58
What is the Vd of heparin similar to
plasma volume (restricted to this compartment)
59
What kind of drug is gentamicin
Why is it useful when considering Vd
aminoglycoside antibiotic
it is small enough to cross the endothelium between the cells. It
distributes in the plasma and interstitial compartments -
represent the total extracellular fluid
60
What is the Vd of ethanol
similar to total body water water (42-45 litres) as it has a broad distribution throughout the body compartments
61
How does tissue binding/ partitioning into fat affect Vd
Why
increases Vd
it is the free (unbound) drug that exchanges between
compartments. As more drug binds to tissues in the interstitial, intracellular or fat
compartments, the concentration of free drug there falls. More drug will leave
the plasma and the plasma concentration falls. Therefore, tissue binding or partitioning
means that a greater amount of drug is accommodated with a lower plasma concentration.
62
Where can tissue binding occur
Where does it mostly happen for lipophilic drugs
to membranes, extracellular proteins or receptors
more likely to partition into fat
63
Which tissues can heavy metals adsorb to
bone
64
Why is the Vd very high for highly lipophilic drugs or heavy metals
Heavy metals
| can become adsorbed to bone, lipophilic drugs are more likely to partition into fat so more tissue binding has occurred
65
What is the Vd of morphine
250 litres!!
66
What must be remembered when considering the Vd of thiopental
it is a very lipophilic GA so partitioning in fat is particularly important
67
What can decrease Vd
binding to plasma proteins
68
Why will Vd increase as more drug binds to plasma proteins
total concentration in plasma will be higher so
total drug in body/ plasma conc
will be smaller as denominator is bigger
69
What does binding to plasma proteins allow in PK
allows the plasma to carry more drug
70
Is it free or bound drug that exchanges with other body compartments
free
It is the free (unbound) drug that exchanges with other body compartments, and it is the free drug that is cleared by metabolism or renal excretion.
71
What is the major binding protein in plasma
What is the plasma [albumin]
How does this concentration compare with therapeutic concentration of most drugs
albumin
0.6mM
much higher than therapeutic conc
72
True or false
| Albumin has many binding sites
true
including two sites for acidic drugs (e.g. warfarin,
salicylic acid, phenytoin) and other sites for neutral and basic drugs
73
Can warfarin bind to albumin
yes warfarin is acidc and albumin has two sites for acidic drugs (e.g. warfarin,
salicylic acid, phenytoin).
74
Give 4 instances when albumin levels can fall
liver disease,
old age,
nephrotic disease
major burns
75
What must you consider when using data about oral administration from one species to another (4)
What does this lead to
Taste and feeding behaviours (e.g. neophilia vs. neophobia) can affect how best to administer a drug to different species.
Differences in digestive tract physiology (e.g. in ruminants) can affect the rate and extent of drug absorption.
Grooming behaviour can lead to (often unintended) oral administration of topically-applied drugs.
Species-specific differences in drug metabolism are also extensive.
This can lead to poor correlations of bioavailability in humans other animals.
76
Which drugs can bind to α1-glycoprotein
Where is it expressed
basic (partitcularly beta blockers and antidepressants)
Although normally expressed at a low level in plasma,
it is an acute phase reactant that is increased during inflammation or stress.
77
True or false
plasma protein binding is saturable
What does this mean for C(free) and C(bound)
Which drugs is tshi knowledge important for
true
When a low percentage of binding sites are occupied,
an increase in dose gives a proportional increase in Cfree and Cbound. As the binding sites become saturated, an increase in dose will disproportionately increase in Cfree
drugs that almost saturate albumin in their therapeutic range (e.g.
phenytoin).
78
Give an example of competition for albumin binding
bilirubin which is normally eliminated by conjugation by neonates but competes against sulphonamides for binding
79
Why can it be dangerous to give sulphonamides to neonates
bilirubin normally
eliminated by conjugation, which is slow in neonates. If it is displaced from plasma proteins
by e.g. sulphonamides, Cfree will increase. This can lead to increased bilirubin in the brain and neurological damage.
80
Is a drug evenly distributed once it reaches the plasma
Once a drug has been absorbed into the plasma it will be rapidly and evenly distributed
through the blood. However, blood supply to different tissues is not evenly distributed
81
Which organs are not well perfused
skin, skeletal muscle and
| fat
82
What is a consequence of some drugs being rapidly distributed through well perfused tissues but distribute through poorly-perfused tissues more slowly
that the apparent volume of distribution immediately after an i.v. bolus injection may be
much lower than the apparent volume of distribution much later, or when a steady state is
reached during infusions.
83
What are drugs metabolised by
the same enzyme systems that defend us from xenobiotics
84
What are phytoalexins
toxins against predation
85
What are important sources of xenobiotics
plants
environmental pollution, cosmetic products, food additives, agrochemicals, foods processing, as well as pharmaceutical drugs.
86
Why do hydrophilic xenobiotics not have to be metabolised
Membranes are a barrier to absorption of hydrophilic
| xenobiotics, so can be readily excluded. Hydrophilic xenobiotics that are absorbed can also be readily excreted.
87
What would happen to lipophilic xenobiotics if they were not metabolised
not readily excreted , so they would accumulate in fats and phospholipid bilayers
88
What is the general strategy for metabolism of of lipophilic molecules
to convert a
| lipophilic molecule into a more hydrophilic molecule that can be readily excreted.
89
What is the main site of xenobiotic metabolism
Name 6 other sites
liver
```
small intestine,
nasal mucosa
lungs
skin
kidneys
blood
```
90
What is the first site for first pass metabolism
small intestine
91
How can the process of hepatic drug metabolism be divided
into phase 1 (functionalisation) and phase 2 (conjugation)
92
What are the purposes of phases 1 and 2 of hepatic drug metabolism
phase 1: makes a more reactive metabolite
phase 2: Makes a less reactive metabolite that is
(usually) more hydrophilic and higher molecular weight
93
What happens in phase 1 of hepatic drug metabolism
introduces/ unmasks a functional group to alter biological properties of drug
may activate or inactivate the drug
94
Give an example of a pro-drug
codeine - turned on by hepatic drug metabolism
95
What does phase 2 of hepatic drug metabolism do
how does it affect drug activity
uses the reactive functional group to add another molecule. This usually increases
the water solubility of the drug.
Phase 2 can also inactive a drug, though even some
conjugated drugs can have activity
96
name a drug that already has an appropriate functional group so does not require phase 1
paracetamol
97
Which superfamily is very important in phase 1 of drug metabolism
cytochrome P450
98
What does the CYP superfamily comprise
Is it well conserved?
18 CYP families with 57 genes (and 58 pseudogenes) have been identified in the human genome.
no: huge diversity between species, in terms of number of genes,
expression of orthologues, tissue distribution patterns, substrate specificities and activities,
and sensitivity to inhibitors.
99
How many drugs does CYP2D6 metabolised
involved in metabolism of up to 25% of current drugs.
100
How does the presence of CYP2D6 vary between individuals
What does this mean for drug research
Humans carry only one CYP2D6 gene, which is missing or nonfunctional in 7-8% of Caucasian Americans. Mice have nine different, functional Cyp2d genes and rats have six
This makes it difficult to extrapolate drug metabolism studies from animals to humans
101
Which are the most important CYP families
CYP1, 2, 3
102
Which CYP is responsible for metabolism of half of clinical drugs
CYP3A4 is responsible for metabolism of approximately 50% of clinical drugs
103
How can you tell a CYP that deals with metabolism of endogenous products from those which metabolise xenobiotics
CYPs involved
in metabolism of endogenous substrates (such as cholesterol) have very strict substrate
specificity. Xenobiotic metabolising CYPs cannot afford this selectivity. They must accommodate large structural diversity of substrates with a large and fluid substrate binding
site
104
What does the broad scope of xenobiotic metabolising CYP sacrifice
rate - slower than other CYP
105
How does the wide structural diversity of of potential substrates affect drug-drug interactions
makes drugdrug interactions more likely
106
Where are CYPs located
ER membrane
107
Where is a site of lipophilic drug accumulation in the cell
ER membrane where CYPs are located
108
Which molecules do CYPs use to metabolise drugs
O2 and haem.
Haem binds O2 into CYP active site.
CYPs also use H+
from NADPH, supplied by NADPH-cytochrome P450 oxidoreductase
109
What is a potentially harmful outcome of CYP activity
How is this mitigated
Often, more O2 is
consumed than needed, so superoxide is produced.
Superoxide dismutase converts this safely into water
110
How can you inhibit CYPs
Since many drugs can be metabolised by the same CYP isoform, drugs may compete
111
What is Prozac a substrate for
```
Fluoxetine (Prozac) is a substrate of CYP2D6, CYP2C19 and CYP3A4, and can also inhibit
these isoforms (particularly CYP2D6).
```
112
Do drugs react the same way with each isoform of the CYP
Some drugs are metabolised by one CYP isoform but act as competitive inhibitors of other
isoforms. (Quinidine, for example, is a competitive inhibitor of CYP2D6 but not a substrate.)
113
How does ketoconazole react with CYP3A4
forms a complex with the Fe3+ form of haem in CYP3A4
114
How can drugs show mechanism based inhibition of CYPs
The product of
oxidation binds covalently to the CYP, irreversibly blocking the enzyme. This is also called
‘suicide inhibition’.
115
Why can you not have grapefruit juice on certain drugs
Which drugs does this include
A component of grapefruit juice4
(and perhaps some other citrus juices) potently inhibits CYP3A4.
Since CYP3A4 is responsible
for metabolising almost 50% of drugs, this is major problem.
Affected drugs include many dihydropyridine Ca2+ channel blockers (e.g. nifedipine), statins (e.g. simvastatin), antibiotics (e.g. erythromycin) and immunosuppressants (e.g. cyclosporine), amongst others.
116
Which CYP does grapefruit juice affect and where in the body does it happen
CYP3A4
The major site of action appears to be CYP3A4 in the intestinal wall rather than the liver.
117
How can xenobiotics affect the impact of CYPs in the long term
can affect expression via nuclear receptors
118
Are the nuclear receptors which control CYP expression promiscuous?
yes
The flexible ligand binding site of these nuclear receptors allows them to be activated by structurally diverse molecules (usually small and lipophilic)
119
Describe the pathway for activation of CYP genes via nuclear receptors
pregnane X receptor (PXR) and constitutive androstane receptor (CAR) heterodimerise
with the retinoid X receptor (RXR), allowing them to bind to xenobiotic response elements (XREs) in upstream promotor regions
CYP3A4 is upregulated
120
Name 2 drugs that can activate PXR
Name a herbal xenobiotic that also does so
phenobarbital
rifamycin
St John's Wort
121
What is St John's Wort used to treat
mild/ moderate depression
122
Which CYP is especially unregulated by XRE
Why is this important for pharmacologists to know
CYP3A4
CYP3A4 metabolises 50% of all clinical drugs
123
What is FMO
What does it do
Flavin-containing monooxygenases (FMO) in the liver
catalyse oxidation reactions, using FAD rather than haem
124
What is the most abundant FMO in the liver
What can it metabolise (3)
FM03
FMO3 can metabolise
structurally diverse drugs, including amphetamines, the anti-psychotic clozapine, and the
histamine H2 receptor antagonist ranitidine
125
What kind of drugs are clozapine and ranitidine? What is the common denominator
clozapine: anti-psychotic
ranitidine: H2 histamine receptor antagonist
both metabolised by FMO3
126
What causes fish odour syndrome
mutations in FMO3 so TMA is not metabolised and builds up to be released into the sweat and urine causing a fishy smelll
127
What can be released from CYPs
what happens to them
highly reactive epoxides
epoxide hydrolases detoxify them
128
What is carbamazepine
a prodrug activated by CYPs used to treat epilepsy
129
How is carbamazepine activated and deactivated
activated by CYPs to generate a
| reactive (and active) epoxide. This is hydrolysed by microsomal EH, which also inactivates the drug.
130
What is often used in conjunction to carbamazepine
why
valproic acid (an anticonvulsant)
inhibits microsomal EH, increasing the
concentration of the active metabolite of carbamazepine and delaying its elimination.
131
What is the importance of alcohol dehydrogenase
oxides ethanol to ethanal (a toxic acetaldehyde)
this must then be converted to acetate by acetaldehyde dehydrogenase
132
What does disulfiram do in alcohol metabolism
inhibits acetaldehyde dehydrogenase
133
Where are esterases found (2)
Name a drug these are important for
in the intestinal wall and liver
Aspirin is
hydrolysed to salicylic acid by esterases
134
What is one of the most common Phase 2 reactions
Glucuronidation (addition of glucouronic acid)
135
What is glucuronidation in phase 2 catalysed to
why is this reaction important
by UDP-glucuronosyltransferases (UGTs)
Many drugs are excreted as glucuonides in urine or bile
136
Which functional groups can glucuronidation occur with
therefore...
hydroxyls, carboxyls, sulfuryl, carbonyl, and amide groups, so can occur with many structurally diverse drugs
137
What is the pKa of the carboxylic acid in glucuronic acid
what does this mean
pKa of 3-3.5.
It is mostly ionised at physiological pH in cells, in the blood, and in urine.
138
Describe phenytoin metabolism (phases 1 and 2)
m involves CYP-dependent hydroxylation (phase 1) followed by
glucuronic acid conjugation (phase 2)
therapeutic doses of phenytoin are close to saturation of this pathway
139
What can phenytoin act as an inhibitor of (2 things involved in drug metabolism)
as an inhibitor of CYP2C9 and of glucuronidation.
140
Give 3 uses of codeine and morphine
give 4 side effects
pain relief
cough suppression
antidiarrheal
depression,
constipation,
sedation
addiction.
141
Through which receptor does the analgesic effect of codeine and morphine arise
µ-opioid receptor
142
True or false
| codeine is a prodrug
true -
it is a weak µ-opioid agonist, and ineffective at plasma
concentrations usually achieved. It is considered to be a prodrug
143
How does the affinity of codeine to the µ-opioid receptor compare to morphine compare
Morphine has a much greater affinity (200-300x).
144
What happens to codeine in the liver
Most is directly glucuronidated to codeine-6-glucuronide, and some
converted to norcodeine by CYP3A4
5-15% of the codeine is coverted to morphine
145
How does the affinity of the products of codeine metabolism compare to codeine itself
Codeine-6-glucuronide and norcodeine have a similar
affinity for the µ-opioid receptor to codeine
Morphine has a much greater affinity (200-300x).
Morphine and norcodeine are also
glucuronidated. Morphine-6-glucuronide is a high affinity µ-opioid agonist (similar to
morphine) and may be responsible for the some of the actions and side effects of codeine
and morphine. Morphine-3-glucuronide is ineffective at the µ-opioid receptor, but may also
contribute to side effects and toxicity.
146
Why might heroin be considered a prodrug?
| the handout does NOT call it this, it's just for the purpose of this flashcard
Heroin (diacetylmorphine) is also converted to morphine for its action
147
What allows heroin to cross the BBB
ts acetyl groups
| increase its lipophilicity, which means that it can readily cross
148
Where is heroin converted to morphine
in the brain (after crossing the BBB)
149
Name a CYP2D6 inhibitor
fluoxetine
150
What effect does fluoxetine have on codeine
it is a CYP2D6 inhibitor so reduces morphine formation from it
prevents the analgesic effect
151
How do individuals' abilities to metabolise codeine (5 points)
CYP2D6 expression levels vary in humans.
Normal (‘extensive’) metabolisers have one or two functional copies of the CYP2D6 gene.
Ultra-rapid metabolisers have >2 functional copies, and are at high risk of morphine toxicity at normal doses of codeine.
Codeine should also be avoided in breast-feeding mothers who are ultra-rapid metabolisers.
Poor metabolisers lack functional CYP2D6, and do not obtain adequate
pain relief from codeine.
152
What is the effect of CYP3A4 inhibitors on codeine metabolism
Codeine metabolism via CYP3A4 is a minor pathway in most people, so CYP3A4 inhibitors have little effect.
However, strong CYP3A4 induction may reduce formation of morphine.
153
What are the 3 routes of paracetamol metabolism following a therapeutic dose
major routes:
glucuronidation and sulfonation (both phase 2)
A minor fraction is oxidised to NAPQI, a
reactive metabolite, which is detoxified by conjugation to glutathione (GSH).
154
What happens to the different metabolism pathways in a supratherapeutic dose of paracetamol
sulfonation pathway is saturated.
At higher toxic doses gluruonidation is also saturated
thus a higher proportion is converted to NAPQI, leading to depletion of GSH and hepatic cell injury or cell death
155
Which molecule do you want to replace in paracetamol overdose
How can you do this
GSH
by exogenous NAC
156
Why might phenytoin lead to paracetamol hepatic injury
what else might increase risk of this
phenytoin and pentobarbital are glucuronidation inhibitors
Induction of CYP2E1 by chronic alcohol consumption may also increase hepatotoxicity risk.
157
What is the principle site for excreting water soluble drugs
kidneys
(Drugs can be passively filtered from plasma and secreted into the renal tubules. They can also be reabsorbed from the tubules. )
158
What is normal plasma flow
what is normal GFR
625ml/min
125ml/min
159
What 2 features must a drug have to be freely filtered by the kidneys/ readily cleared by glomerular filtration
polar
| not heavily bound to plasma proteins
160
f𝑖𝑙𝑡𝑟𝑎𝑡𝑖𝑜𝑛 𝑟𝑎𝑡𝑒 𝑜𝑓 𝑑𝑟𝑢𝑔 =
𝐺𝐹𝑅 × 𝐶𝑓𝑟𝑒e
161
Why does glomerular filtration not immediately change plasma [drug]
water and drug filtered in proportion
162
How does the number of binding sites for drugs, and bound drugs themselves change from afferent to efferent arterioles in the kidney
both 20% higher in the efferent arterioles than in the afferent arterioles
163
What factors preserve the
| equilibrium between bound and free drug in the kidney (before and after glomerulus)
Glomerular filtration does not immediately change the plasma concentration of a drug, since water and drug are filtered in proportion. In addition, the loss of water means that the number of binding sites for drugs, and bound drugs themselves, are 20% higher in the efferent arterioles than in the afferent arterioles
164
How does an increase in plasma protein binding affect clearance of a drug if the drug is ONLY filtered
decreases clearance
165
Which transporters secrete drugs from peritubular capillary plasma to the tubule
two families of SLC transporter: OATs and OCTs
166
What do OATs in the nephron transport
```
acidic drugs in their negatively charged anionic form (eg, penicillin)
endogenous acids (eg uric acid.) Glucuronide and sulphide conjugates (such as conjugates of paracetamol
```
167
What do OCTs transport
organic bases in their protonated cationic form (eg morphine)
168
True or false
| drugs can compete at OATs and OCTs
true
Probenecid and penicillin are both transported by OATs.
Probenecid prolongs the action of penicillin by reducing its tubular secretion.
169
How does drug secretion into the tubule affect plasma [drug]
what is the effect of secretion on drug bound to plasma protein
lowers the free concentration in the plasma, since drug movement is not accompanied by water.
shifts the equilibrium between bound and free drug. More drug is released from the plasma proteins.
If secretion is fast enough the newly released drug is also secreted
170
If secretion is fast enough the drug newly released from plasma protein is also secreted. what does this mean for renal clearance
an increase in plasma protein binding has little effect on renal clearance.
171
When can a drug have a clearance greater than GFR
Drugs that are rapidly secreted and not reabsorbed have clearance greater than GFR and can approach RPF
172
What is required for drugs to be reabsorbed from the tubule
If the drug can cross the renal tubule then it will diffuse down its concentration gradient (out of tubule)
173
Which drug traits mean they are poorly or well reabsorbed from the renal tubule
Lipid soluble drugs are poorly excreted by the kidney since they are readily reabsorbed.
In contrast, polar drugs are poorly reabsorbed and are readily excreted
174
How does urine pH affect excretion of drugs
alters the dissociation of acidic and basic drugs in the tubular lumen. This can lead to ion trapping
175
How does urine pH compare to plasma pH
how does this affect excretion of drugs
urine is usually more acidic
favours excretion of basic drugs in their cation form, and reabsorption of acidic drugs
176
How can you increase the excretion of acidic drugs in urine
what is this used for
by increasing urine pH through infusion of NaCO3
following an overdose of eg aspirin, barbiturates
177
How does increasing urine pH affect excretion of basic drugs
increases reabsorption, so decreases excretion, of basic drugs
178
Why do the effects of urine pH on drug excretion explain the importance of hepatic metabolism for renal excretion
conjugated metabolites are usually more water soluble, so freely filtered.
They can also be secreted via OATs.
Since they are more polar than their parent drug, they are less likely to be reabsorbed from the tubule.
179
How are drugs excreted in faeces
hepatocytes secrete drugs and their metabolites from plasma into bile using similar transporters to the renal tubules. Bile is delivered to the small intestine. There, the drug can be excreted in faeces
180
Are all drugs that enter the small intestine in bile excreted in feces?
no
once they have entered the small bowel they can be excreted in faeces; unmodified drugs can be reabsorbed; and conjugates can be hydrolysed, potentially regenerating an active drug
181
which drug conjugate is particularly likely to be hydrolysed once it has entered the small bowel in bile
Glucuronides
182
What happens to drug conjugates that are hydrolysed after entering the small bowel in bile
hydrolysed drug can then be either excreted in faeces or reabsorbed.
If it is reabsorbed then is called enterohepatic circulation. This slows the rate of elimination of a drug from the plasma, prolonging the effect of the drug
183
What must pharmacologists be aware of when studying dosing patterns for animals that perform coprophagy
active drugs can enter the feces and so be taken into the animal that ingests the feces
184
Given 2 examples of coprophagy causing problems for pharmacologists
Give a further example of a similar problem that did not arise from coprophagy
In one study, foals were treated with erythromycin to treat an infection. Mares practising coprophagy with their foal’s faeces had a high incidence of colitis because of the erythromycin.
In another study, rabbits showed a rebound in plasma concentration of a drug 24 hours after i.v. injection.
untreated horses were housed in a box previously used for naproxen-treated horses. The untreated horses were found to excrete naproxen in their urine.
caused by cross-contamination of bedding and ingestion of contaminated straw
185
What does first order kinetics refer to
the rate of elimination is directly proportional
to the plasma concentration.
A chart of rate of elimination versus plasma concentration would give a straight line.
186
Which drug elimination methods follow Michaelis Menten kinetics
Elimination by metabolism and carrier-mediated drug transport (e.g. tubular secretion) which are both dependent on enzymes
187
For many drugs, the therapeutic concentration is much lower than Km, so the rate of
elimination is linear with respect to concentration. Why?
𝑟𝑎𝑡𝑒 𝑜𝑓 𝑟𝑒𝑎𝑐𝑡𝑖𝑜𝑛 =
𝑉𝑚𝑎𝑥. 𝐶
-------------
𝐾𝑚 + C
if C
188
True or false
| renal filtration will always be linear
true
Renal filtration is not enzyme dependent and cannot be saturated.
The rate of elimination in this manner with always be linear.
189
Compare a first order and zero order reaction
A first order reaction has a rate proportional to concentration of a single reactant.
a zero order reaction is independent of the concentration of the reactant. (When elimination is saturated and has reached the fixed, maximum rate, the elimination is zero order.)
190
What is clearance considered a measure of (2)
a measure of the body’s ability to eliminate a drug, normalised to plasma concentration
s sometimes thought of as the flow of arterial blood that would be completely cleared of a drug at that rate of elimination
191
If a rug is cleared through different routes, how do they relate?
Clearances through different routes are additive:
𝑡𝑜𝑡𝑎𝑙 𝑐𝑙𝑒𝑎𝑟𝑎𝑛𝑐𝑒 = ℎ𝑒𝑝𝑎𝑡𝑖𝑐 𝑐𝑙𝑒𝑎𝑟𝑎𝑛𝑐𝑒 + 𝑟𝑒𝑛𝑎𝑙 𝑐𝑙𝑒𝑎𝑟𝑎𝑛𝑐𝑒 + ⋯
192
If elimination is first order, clearance will be...
constant
193
What does the single compartment model assume
the body behaves
like a single, well-mixed container into which a dose of drug, D, is rapidly added by IV injection.
i.v. injection means that the model ignores absorption.
The [drug] in the plasma, C, is in rapid equilibrium with the drug in any extravascular tissues that the drug can access
Since 'well mixed', we can ignore distribution
assumes elimination is 1st order kinetics
194
In the single compartment model, concentration of drug in the plasma, C, is in rapid equilibrium with the drug
in any extravascular tissues that the drug can access. Does this mean [drug] everywhere is equal to plasma [drug]
no
| rather that these concentrations are proportional to the plasma concentration at all times
195
What does the single compartment model assume for elimination
what does this mean
assumes that the drug elimination follows first order kinetics.
This means that the rate of elimination is proportional to the plasma concentration.
Elimination may be via metabolism or excretion, or both
196
How does Vd change over time in the single compartment model
Since the compartment is well mixed, Vd remains constant throughout
197
How to work out [drug] in plasma at any time in the single compartment model
C=X/Vd
X=The amount of drug remaining in the compartment
Vd= volume of distribution
198
How to calculate rate of change of plasma concentration in single compartment model
dC
----- =-Ke.C
dt
199
How to workout the rate of increase in amount of drug in the body in single compartment model?
dX
----- = -Ke.X
dt
200
How do work out Vd in single compartment model
Vd=CL/Ke
201
What is the equation you should use to plot plasma concentration against time (single compartment model)
How is this made into a straight line
What is the important information that can be gathered from this line?
C=Co.e^(-Ke.t)
where C0 is the plasma concentration at time zero
ln(𝐶) = ln(𝐶o) − 𝑘𝑒.t
The slope is –ke and the vertical intercept is ln(C0).
202
What is the equation for half life in the single compartment model
t0.5= 0.693/Ke
203
How can you find the clearance from a graph of conc vs time (SINGLE COMPARTMENT MODEL)
area under the curve
AUC=Co/Ke
CL=D(i.v.)/AUC
204
What is the 2 compartment model used to model
describes a situation where the drug does not appear to distribute instantaneously.
Instead, the drug appears to distribute to some parts of the body more rapidly than others
205
How does distribution work in the 2 compartment model
drug is injected into a central compartment.
This represents the blood (and therefore plasma), and often represents other well-perfused tissues, such as the liver, kidney, heart, brain and lungs.
The drug is eliminated from this
compartment by metabolism or excretion. The drug can also slowly distribute into a peripheral compartment.
This often represents poorly-perfused tissues, such as skin, fat and skeletal muscle (at rest).
206
What is the time course for drug distribution through the 2 compartments in the 2 compartment model
When the drug is injected, it rapidly distributes through the central compartment.
It will be at a high plasma concentration as the volume of distribution is relatively low.
Over time, it will also slowly distribute into the peripheral compartment. This increases the volume of distribution.
This will affect the plasma concentration and the rate of elimination.
Drug in the peripheral compartment must return to the central compartment to be eliminated
207
How does plotting C against time in 2 compartment model differ from 1 compartment
may be difficult to see any difference from the single compartment model.
However, when ln(C) is plotted against time the chart is no longer a straight line. This is indicative of a distribution phase
208
Why is ln(C) plotted against time in 2 compartment model different from single compartment
indicative of a distribution phase. The plasma
concentrations soon after injection are higher than would be predicted by a straight line
from the later data. The later, straight-line phase is called the terminal phase
209
How do you know if a parameter refers to the terminal phase of the ln(C) vs time graph in 2 compartment model
often given the subscript z
210
When does graph of ln(C) vs t show that elimination is entirely dictated by first order kinetics
when distribution is complete (terminal phase)
211
How do you work out the Ke and half life from the terminal phase of ln(C) vs t graph (2 compartment)
How do you find AUC in terminal phase
gradient = -Kz
t0.5=0.693/Kz
AUCz=C1/Kz
where C1 is the plasma concentration at the start of the terminal phase
212
How do you find the total AUC for ln(C) vs t in 2 compartment model
divide AUC before terminal phase into trapezia and work out area of each:
1/2(h1+h2)b
𝐴𝑈𝐶𝑡𝑜𝑡𝑎𝑙 = 𝐴1 + 𝐴2 + ⋯ + 𝐴n + 𝐴𝑈𝐶z
213
How do you find the volume of distribution of the terminal phase (2 compartment model)
Vz=CL/Kz
Vz refers to the terminal phase volume of distribution, i.e, once the drug has distributed between the central and peripheral compartments.
214
How is single oral dose added to 1 or 2 compartment models
what is absorption affected by
dose is added to a separate G.I. compartment
Absorption from the G.I. compartment is proportional to the amount of dose remaining, so the rate of absorption decreases with time. The rate of absorption will also be affected by the formulation of the drug.
215
In a single oral dose model, how can you show slower absorption
Sustained release preparations can be used for slower absorption and more sustained effect
216
Is all of a drug given orally usually absorbed?
no
First pass metabolism is a major cause of loss of drug.
The proportion of drug that is absorbed is the factional bioavailability, F.
217
In the 2 compartment model with a single oral dose, which compartment is the drug absorbed into
central
It is possible to model absorption into a central compartment with distribution into a peripheral compartment, but this is often not necessary unless absorption is much more rapid than distribution between central and peripheral compartments
(does not change approach to analysis)
218
|Describe the graph of Plasma concentration against time for a drug taken as a single oral dose (5)
C shows dramatic initial increase as drug is absorbed
rate of elimination also increases as plasma concentration increases.
As drug is absorbed, the amount of drug remaining in the G.I. tract is reduced, so rate of absorption decreases.
The maximum concentration occurs when the absorption has decreased and elimination has decreased sufficiently for them to balance.
As absorption continues to decrease the kinetics become dominated by the rate of elimination.
During the terminal phase there is no further absorption and only elimination
219
How is Kz found for a single oral dose of a drug
How is AUC found?
How is CL found?
slope of the chart of ln(C) against time = -Kz
AUCz= C1/Kz
total AUC = trapezia + AUCz
Oral Dose.F
-----------------
AUCtotal
220
In the equation:
Oral Dose x F
-------------------- = CL
AUC total
what does F represent
How does F affect the dose
how is F determined
F= fractional bioavailability
reduces the dose reaching the central compartment
can be determined by comparing the pharmacokinetics of a single i.v. dose and a single oral dose
221
What is the equation to find F
AUC oral dose(iv)
--------------x------------
AUC(iv) oral dose
222
During i.v. infusion at a constant rate, what is the rate at which the drug accumulates in the body?
difference between the rate of infusion and the rate of elimination.
at steady state rate of infusion is equal to the rate of elimination
223
During i.v. infusion at a constant rate, the rate at which drug accumulates in the body is the difference between the rate of infusion and the rate of elimination. Give this in equation format
dX/dt= rate in - rate out
=Rin - CL.C
224
Give the equation for plasma concentration of drug at steady state
what should be noted
Rin
----- =Css
CL
Css is only determined by the rate of infusion and by the clearance. Vd has no effect.
If the Rin is doubled, the Css is also doubled.
225
How do you calculate the time taken to reach a desired conc when you are constantly infusing the drug?
𝐶𝑡 = 𝐶𝑠𝑠(1 − 𝑒^−𝑘𝑒.𝑡)
thus
t= (-1/Ke).ln[1-Ct/Css]
226
What is a loading dose
what is a draw back of this
To get to Css immediately, we could give a large, bolus i.v. injection in addition to slow infusion.
dose needs to be sufficient to give a plasma concentration of Css when it is distributed throughout the volume of distribution.
might not be the best approach as it could give very high peak concentrations in the brain and heart.
227
What is the equation for loading dose
𝐿𝐷 (𝑖𝑛𝑓𝑢𝑠𝑖𝑜𝑛) = 𝐶𝑠𝑠 × 𝑉d
228
What happens to a drug after it has stopped being infused constantly?
How does it behave
drug will be eliminated from the body by metabolism and/or excretion.
behaves in the same way as exponential decay after i.v. injection in the single compartment model, as distribution has already occurred during the infusion.
229
Relate AUC, Css, and Ke in an equation
Css
------ = AUC
Ke
230
How can you determine steady state volume distribution from CL
CL
----- = Vss
Ke
231
How can you achieve Sustained, effective plasma concentrations
constant iv infusion
| multiple dose regimen, either of i.v. bolus injections, or oral tablets.
232
How does multiple dose regime reach effective sustained plasma conc of drug
dose is repeated with a dose interval, τ
If the second dose is given before all of the first dose has been eliminated then the drug will accumulate, achieving a higher peak concentration with the second dose and so on.
Assuming that drug elimination follows first order kinetics, average rate of elimination will increase as drug plasma concentration increases. Css is reached when the amount of drug eliminated in each dose interval is equal to the amount of the dose.
From this point, the C will vary between the Cmax ss and minimum concentration (Cmin, ss; immediately prior to the next dose).
233
How does changing dose frequency and amount in multiple dose regime change the steady state
Half the dose, twice as often (same dose rate) will produce the same Cav, ss, but with less
variation about above and below this value.
234
What is Cav ss
average concentration at steady state (Cav, ss) that is achieved by multiple dosing
v similar to Css from constant infusion
235
True or false
| At Css, the entire dose must be eliminated just before the next doser
true
| average rate of absorption (Rav, in) must equal the average rate of elimination
236
average rate of absorption (Rav, in) must equal the average rate of elimination. Express this as 2 equations
Rav,in=
Dose iv
-----------
tau
or
CL.Cav,ss
237
Give a formula for Cav,ss in terms of AUC and tau
AUCss
----------- = Cav,ss
tau
238
Assuming first order kinetics, how does AUCss compare to AUC for an equivalent single iv dose? Why?
AUCss is the same as AUC for an equivalent single i.v. dose
because AUC = Dose/CL in both circumstances. If the elimination is still first order, the clearance will be the same
239
Give an equation for Cmax,ss involving dose iv, Vd and an exponential
Cmaxss=...
dose iv 1
----------x ---------------
Vd 1-e^(-Ke.τ)
240
How do you calculate loading dose to reach Css for multiple doses
𝐿𝐷 (𝑚𝑢𝑙𝑡𝑖𝑝𝑙𝑒 𝑑𝑜𝑠𝑒𝑠) = 𝐶𝑚𝑎𝑥,𝑠𝑠. 𝑉𝑠s
241
What is the problem with using Vss in calculations
s if the drug undergoes extensive redistribution between compartments
The initial Vd will be smaller than Vss, making the initial plasma concentration much higher than predicted and risk of toxicity.
242
How does achieving Css with multiple oral doses differ from multiple iv doses
absorption after an oral dose will be slower than direct i.v. injection.
Without knowing the rate constant for absorption, we cannot predict the Cmax ss and Cminss
However, if absorption is fairly rapid, we might use the i.v. as an approximation
243
Describe behavior of elimination in zero order kinetics
elimination rate is constant and is not dependent on plasma concentration.
244
How does plasma concentration of drug differ between first order and zero order kinetics
in zero order, If we infuse at a constant rate, plasma concentration will continue to increase.
Compare with first order kinetics, where constant infusion leads to a steady state plasma concentration, Css.
If we increase the rate of infusion then Css does not increase
proportionally, as in first order kinetics, but increases exponentially.
245
Why must you be careful when increasing doses of phenytoin
when can it be dangerous at normal doses
Therapeutic concentrations of phenytoin are close to saturation for hydroxylation by CYP2C9. A small increase in dose rate can lead to a much greater plasma concentration and toxicity.
Polymorphisms in CYP2C9 that reduce its reaction rate, and inhibitors of CYP2C9
(e.g. valproic acid), can make this more likely at ‘normal’ dose rates
246
Can zero order kinetics become first order kinetics
In zero-order kinetics, the rate of elimination is constant. A constant amount of drug is eliminated per unit time. The concentration declines at a constant rate until the concentration is sufficiently low for first order kinetics to be re-established
247
Give an example of first order kinetics becoming zero order kinetics
ethanol
Metabolism of ethanol saturates at fairly low alcohol intake.
Above this, elimination follows zero order kinetics.
Chronic alcohol consumption can increase the rate of ethanol metabolism through induction of CYP2E1.
248
What does general anaesthesia involve (4)
loss of consciousness
loss of reflexes,
muscle relaxation,
inability to feel pain (analgesia).
249
Give 6 attempts at producing analgesia used through the ages
what were the earliest inhalation anaesthetics (2)
```
poppy extracts (opioids),
henbane,
acupuncture,
carotid compression,
boiled mandrake
coca leaves
```
ether and nitrous oxide
250
What did Queen Victoria use to reduce labour pains
chloroform
251
What does the Meyer-Overton correlation suggest about the MOA of anaesthetics
what properties of GAs do not fit (3)
general anaesthetics act through a common and non-specific mechanism by accumulating in lipid bilayers and altering membrane function
maximum molecule size cut-off, discovery of some lipid soluble molecules that did not cause anaesthesia, and stereo-specificity of some anaesthetics such as isoflurane.
252
What did Franks discover about the potency of anaesthetics
demonstrated that anaesthetic potency also correlated with their ability to
inhibit a lipid-free protein (luciferase)
253
What conclusion have the observations of Franks, Meyer and Overton lead to about the binding os GAs
general anaesthetics bind to a hydrophobic pocket in one or more target proteins
254
What is the Meyer-Overton correlation
Meyer (1899) and Overton (1901) independently demonstrated a strong correlation between anaesthetic potency and its solubility in olive oil (oil:water partition coefficient in experiments on tadpoles, or oil:gas partition coefficient for delivery by alveolar ventilation)
255
Which receptors/ channels are GAs thought to act on
3 main ones:
GABA A
K2P family
NMDA receptors
additional protein targets:
glycine receptors
HCN channels
Nav channels
256
Name 3 things that act on the Cl- current through GABA A receptors
many general anaesthetics
ethanol
barbiturates
257
What does activation of GABA A receptors result in
hyperpolarises the post-synaptic membrane and reduces neuronal activity
258
Describe the structure of GABA A receptors
How does this relate to the action of different anaesthetics
pentomeric with a variety of different combinations, usually with 2α, 2β and γ isoforms.
i.v. anaesthetics propofol and etomidate act on the β subunits, at related but distinct sites, whereas volatile anaesthetics appear to act on α and β subunits
259
How are mutations in GABA A receptors related to GA potency
Point mutations in GABAA α and β subunits have been shown to reduce anaesthetic potency.
Notably, mutations in the α subunit reduce or abolish the effect of many volatile anaesthetics with no effect on propofol or etomidate, whereas mutations in the β subunit affect both volatile and i.v. anaesthetics (e.g. the β3 mutation N265M).
However, not all anaesthetics are affected by mutations in GABAA subunit.
260
Which ion channel does isoflurane activate
Some volatile anaesthetics, such as isoflurane and nitrous oxide, activate members of the Two pore domain K+ channel (K2P) family, leading to hyperpolarisation and reduced neuronal activity
261
Give a mutation study that involves halothane
mutation in TASK3 (M159A) abolished the effect of halothane and isoflurane, suggesting that this amino acid may be involved in binding of these anaesthetics.
262
What normally activates NMDA receptors
Which GAs affect them? \What is a possible MOA here?
glutamate
Some general anaesthetics, particularly nitrous oxide and xenon, may also inhibit the excitatory NMDA receptors
competition with glycine, an essential co-agonist for NMDA receptor activation.
263
Which area of the brain is responsible for all the clinical effects of GAs
There may be no one area of the brain that is target site for anaesthetics, responsible for all the clinical effects, although the thalamus seems to be an important site
264
Why must anaesthesia
| be carefully monitored and controlled
Increasing concentrations progressively affect many brain functions.
Higher concentrations can lead to respiratory failure and death
265
Name 3 GAs that are administered iv
what are they good for
Thiopental (thiopentone),
propofol
etomidate
effects have rapid onset so used for rapid induction
266
Where does thiopental act
it's lipophilic so can cross BBB to induce anaesthesia in 10s of seconds
267
Describe the pharmacokinetics of thiopental
binds to plasma proteins. It is metabolised in the liver. This metabolism is close to saturation, so can show zero order kinetics of metabolism if maintained by infusion or repeated injection.
However, consciousness is rapidly recovered after a single i.v. injection. This is because the initial fall in plasma concentration is caused by redistribution, not metabolism
268
Describe the distribution of thiopental
Following injection, the plasma concentration is immediately high.
Thiopental rapidly equilibrates into high blood flow tissues, such as the brain, heart, kidney and liver.
The initial Vd is relatively low. Over the course of minutes, thiopental equilibrates into lower blood flow tissues, such as the skin and muscle. This change in drug distribution increases the Vd, decreasing the plasma concentration.
High blood flow tissues rapidly equilibrate with the decreasing plasma concentration. The consequence is that brain concentration falls, and consciousness is regained.
Equilibration into fat is even slower because it has very low blood flow. However, because thiopental is so lipophilic, it readily accumulates in fat.
269
Why can thiopental give an anaesthetic hangover
slowly, thiopental is metabolised by the liver. As it is metabolised, thiopental slowly equilibrates back from the low blood flow tissues and the fat. This leads to a very slow decrease in plasma concentration. The plasma concentration is sub-anaesthetic but can be high enough to give side effects
270
why does thiopental require >1 injection or constant infusion
what must you be aware of
consciousness is rapidly recovered
With each additional injection, the rapid fall in C by redistribution ends at a higher level and may be above the minimum conc for anaesthesia. Recovery is then dependent on metabolism and slow accumulation in fat.
The time to waking can become hours rather than minutes.
271
What has replaced thiopental
why (3)
Propofol
has more rapid redistribution than
thiopental, and has more rapid metabolism. may also have an anti-emetic effect.
272
How does etomidate compare to Propofol
Etomidate has a wider therapeutic window for anaesthesia over cardiovascular depression, but a higher rate of vomiting and nausea during recovery has been reported compared to propofol.
273
How are volatile GAs administered
inhalation
274
What is a key determinant of rate of induction of volatile GAs
They must cross the alveoli epithelium into the blood then cross into the brain.
The blood:gas partition co-efficient is key determinant of rate of induction because it affects how quickly the alveoli air comes into equilibrium with the inspired air.
275
What does the blood: gas partition coefficient describe
the ratio of the concentration of the anaesthetic in blood to alveolar gas when the partial pressures are in equilibrium.
276
How can you increase the blood: gas partition coefficient
by increasing solubility by increasing the binding to the lipids and proteins in blood that GAs can bind to (eg albumin, triglycerides, serum cholesterol and RBC membranes)
277
Describe how the partial pressure of anaesthetic gas changes as it is inhaled and absorbed
The partial pressure of anaesthetic gas in inspired air (Pinsp) is high. During inhalation it is diluted by the residual air in the alveoli, leading to a lower partial pressure in the alveoli (Palv).
Anaesthetic gas diffuses into the blood in pulmonary capillaries, increasing the Pblood, bringing it rapidly close to equilibrium with Palv.
Blood circulates around the body, perfusing the tissues (particularly high blood flow tissues, including the brain. Anaesthetic gas diffuses from capillaries into tissues, increasing the partial pressure there (e.g. PCNS).
278
What does induction of volatile anaesthetics require
equilibration between P(insp) and P(CNS)
this involves many equilibria
Pinsp↔Palv, Palv ↔Pblood, and Pblood ↔PCNS.
diffusion between compartments is rapid
279
what does the rate of approach to equilibrium between Pinsp and Palv depend on
use 2 contrasting scenarios to demonstrate
blood:gas partition coefficient.
If the blood:gas partition coefficient is high, more gas in the alveoli crosses into the blood to approach equilibrium. The alveoli partial pressure stays relatively low and it takes longer for equilibrium between Pinsp and Palv to be achieved. Induction is relatively slow.
In contrast, if the blood:gas partition coefficient is low, less gas crosses to achieve equilibrium, so Palv rapidly increases. Equilibrium between inspired air and alveoli is rapidly achieved, and induction is rapid.
280
How does cardiac output affect induction rate of volatile GAs
How does alveolar ventilation rate affect it?
slows induction rate, since more gas is removed during each breath.
Low alveolar ventilation rate also slows induction rate, since less anaesthetic is delivered to the alveoli in a given time
281
Do volatile GAs accumulate in fat?
yes
This is slow since fat blood flow is very low. Complete redistribution equilibrium can take a long time to achieve. The extent of accumulation depends on the length of the procedure.
282
What affects the rate of recovery from volatile GAs
The rate at which Palv equilibrates with Pisnp (now equal to 0 when the pump is turned off)
blood:gas partition coefficient
283
How are volatile GAs removed from the body
delivered to the lungs by blood flow and is removed from the alveoli on each breath
Anaesthetic in the body (blood and tissues) is acting as a reservoir of gas to keep Palv > Pinsp
284
How does e blood:gas partition coefficient affect recovery from volatile GAs
If the blood:gas partition coefficient is low (poorly soluble), most of the anaesthetic rapidly crosses into the alveoli and is removed (i.e. at
equilibrium between Pblood and Palv, the concentration of gas in the blood is low). The amount of anaesthetic in the body falls quickly and recovery of consciousness is rapid.
If blood:gas partition coefficient is high, Pblood and Palv rapidly equilibrate, but at this equilibrium the concentration of anaesthetic gas in the blood is high. This is a greater reservoir to maintain Palv > Pinsp for longer. Therefore, recovery is slow.
