meds2002 ver.ka Flashcards
1
Q
pharmacodynamics
A
the effects of the drug on the body
2
Q
pharmacokinetics
A
the way the body affects the drug
3
Q
drug affinity
A
refers to the drug’s ability to bind to the target
quantified as concentration of drug required to occupy 50% of target proteins
4
Q
Intrinsic efficacy
A
The maximal effect a drug can produce on a specific tissue, expressed as a proportion of the maximal effect of a full agonist on that tissue.
may account for factors such as:
having more than one activated state of a receptor
binding to a small proportion of the total receptors can give a maximum response
5
Q
Potency
A
the concentration of a drug that cause a specified effect
6
Q
selectivity
A
ability of a given drug concentration to produce one effect over another
7
Q
What are the 3 stages of drug action
A
1 binding
2 conformational change and transduction
3 response
8
Q
agonist
A
a ligand that binds to and activates a receptor to produce a response in the cell
9
Q
antagonist
A
a ligand that binds to a receptor but does not activate it
Antagonists reduce the probability of an agonist binding to the receptor
10
Q
allosteric modulator
A
a molecule that binds to an active allosteric site on a macromolecule to enhance or reduce a response to an agonist
No effect on its own
may alter affinity or intrinsic efficacy of the antagonist
11
Q
examples of amino acid transmitters
A
1) GABA
2) Glutamate
3) Glycine
12
Q
examples of monoamines
A
1) catecholamine
indoleamine
histamine
13
Q
example of quaternary amines
A
acetylcholine
14
Q
What is the type of receptor on a preganglionic sympathetic neuron?
A
nAChR
15
Q
What is the type of receptor on a post ganglionic sympathetic neuron
A
variable, can be mAChR for sweat glands
but usually noradrenaline receptors for the rest
16
Q
What kind of ligands are released by the postganglionic sympathetic
A
NA for most stuff
and ACh for sweat glands
17
Q
What is the structure of the adrenal medulla sympathetic system
A
basically one neuron
18
Q
What is the pre and post ganglionic neurons of the parasympathetic nervous system
A
Ach (nAChR)
ACh (mAChR)
19
Q
What is an autoreceptor
A
it is a inhibitory pre synaptic receptor, for example the M2 autoreceptor
20
Q
what kind of receptor is a muscarinic receptor
A
G coupled(metabotropic)
21
Q
what kind of receptor is a nicotinic receptor
A
ligand gated ion channels(ionotropic
22
Q
activation of alpha 1 adrenoreceptors on sympathetic effectors lead to
A
excitation of smooth muscle, genitals, heart, liver, eye, CNS, salivary glands.
all g coupled
23
Q
activation of alpha 2 adrenoreceptor
A
has an inhibitory effect on various stuff. so most likely relaxation
24
Q
What are the effect of stimulating beta adrenoreceptors
A
They are all excitatory.
beta1, 2 and 3 are all excitatory.
For some muscle, excitation actually causes relaxation
So for eye ciliary muscle relaxes for far vision (b2)
bronchi dilate/relax (b2)
coronary vessels relax(b2)
this is actually jjust due to muscle histology
25
What is the law of mass action
rate of reaction is proportional to the molecular concentration of the reactants
rate of reversible chemical reaction is proportional to the product of the concentration of the reactants
26
What is Kd
Kd is a measure of affinity measured as a concentration. Kd measures the concentration of drug that occupies 50% of binding sites at equilibrium
27
What 2 factors is Kd dependent on
electronic/hydrophobic match of drug to receptor (bonding and conformation)
steric match of drug to receptor (conformation and size)
28
how should we change the concentration occupancy curves
originally the pa curve is a rectangular hyperbola if concentration is plotted as a linear scale.
However, we can change this concentration to a log scale to make it a sigmoidal curve
29
what is the law of mass action?
rate of a reaction is proportional to the concentration of the reactants
30
competitive antagonists
bind to the same site as the agonist on a receptor
Binds reversibly to receptor binding site
31
Competitive antagonist quantitative aspects
addition of antagonist sets up a second equilibrium reaction which competes with the equilibrium for the agonist receptor binding
32
Dose ratio
used to determine the affinity of a competitive antagonist for its receptor can be determined by its concentration dependent liability to shift the dose response curve for agonist to the right
ratio the agonist concentration is increased in presence of antagonist to restore response
33
new equilibrium rule with competitive antagonists (schild plot)
log (DR-1)= log xb-logkb
this is the equation to know for schild plot. If it is competitive antagonism, then the slope =1
affinity and potency are 2 sides of the same coin
34
what is the x intercept of the schild plot
logkb
35
insurmountable antagonism
includes irreversible and some forms of allosteric antagonism
36
irreversible antagonism
antagonist binds irreversibly or with very slow dissociation
Effect cannot be reversed by increasing agonist dose
37
insurmountable allosteric antagonism
antagonist binds to a different site from agonist and reduces receptor activation (intrinsic efficacy) as well as agonist binding (affinity)
negative allosteric modulation
38
allosteric antagonism
antagonist binds to a different site from agonist and reduce agonist binding without affecting receptor activation
39
physiological antagonism
agonists with opposing physiological effects on the same tissue
40
partial antagonism
use of partial agonists
41
chemical antagonism
when 2 substances combine to form an inactive compound
42
Therapeutic index
TD50/ED50
median toxic dose
the therapeutic ratio/index is a quantitative measurement of the relative safety of a drug
43
Why is pharmacokinetic analysis important
1) accumulation
2) dose proportionality
3) distribution to brain testes, ovaries
excretion and metabolism
potential to interfere with other medications and body functions
44
Clearance
drug elimination efficiency
irreversible elimination from circulation
volume of blood cleared per unit time.
One way elimination and or metabolic conversion.
Clearance total=clearance hepatic+clearance renal+...
45
how to calculate clearance with dose and AUC
clearance=dose/AUC
so the drug is often cleared, and so in an in vivo experiment, we need to find a maintenance dose rate in order to find clearance. i.e, what is the dose per unit time needed to maintain plasma concentration. Clearance is usually determined experimentally from AUC following IV administration
46
volume of distribution
relates amount of drug in body to [drug]plasma
indicative of the extent of distribution
used to calculate loading dose
it is back calculated from initial [drug]plasma following given IV dose
47
what is volume of distribution
V=dose (mg_/C0(mg/L)
48
how does drug with high liphophilicity compare to drug which are hydrophilic
drugs with high lipophilicity are able to transverse membranes, so the apparent Vd is greater than 3L
hydrophilic drugs which are trapped in plasma have a Vd of approximately 3L
49
definition of clearance
volume/time it is the volume of plasma that is cleared per unit time. Does not tell us drug. We are not talking about drug elimination. It is the proportionality factor used to determine rate of elimination. Rate of elimination= clearance x concentration
50
most importance clearance
Glomulerar filtration rate (renal clearance)
51
rate of elimination limitation
depends on first order kinetics.
52
what does the volume of distribution tell us
it tells us how extensively drug is distributed to the rest of the body compared to the plasma
53
volume of distribution definition
ratio of the amount of drug in total body to the concentration of drug in plasma
Vd=(amount of drug in body)/(plasma concentration)
54
Half life equation (first order)
Concentration(time)= original concentration x e^(-kt)
k=clearance/volume over distribution
55
Cmax and T max
Cmax is the peak plasma concentration and Tmax is the time taken to reach the peak plasma concentration
56
AUC
```
area under concentration time curve.
average plasma concentration of drug
and overall exposure of drug for people
calculate bioavailability and clearance
calculate steady state
```
57
Bioavailability
difference between plasma concentrations following single oral dose and single injection of the same amount.
It is expressed as a %
F=(AUC oral)/(AUC IV)
58
k(elimination)
is the sum of the rates of excretion from the body and metabolism
59
how do we make sure that the elimination curve is 1 compartment
Plot the same data on log-linear graph. The gradient gives kel
Intercept= Cp(0)
should be a straight line
and the half life should be =0.693/kel
60
two compartment model
drug does not always distribute instantaneously throughout the body
it may distribute unevenly through tissues
peripheral compartments composed of tissues with lower perfusion or affinity
Drugs may bind to tissue types such as melanin or DNA
61
What is the 2 comparment model like as a graph
plasma level time curve declines biexponentially
central compartment= blood, ECF and highly perfused tissues
peripheral compartment= drugs enters more slowly
drug transfer between the 2 compartments assumed to be a first order process
62
log (1 vs 2 compartment)
1 compartment model does not predict drug disposition well if drug behaves in this way
need to find most parsimonious model
2 compartment model has good fit for drug that exhibits such kinetics. Distribution phase more rapid followed by terminal elimination phase
--1st log compartment does not predict the elimination phase well
63
population pharmacokinetics
determination of PK parameters experimentally.
population is unit of analysis
sparse sampling methods
can evaluate importance of parameters affecting drug disposition-e.g: weight, sex, age
64
Fick's law
Drug absorption: passive diffusion into the membranes
flux(across membrane)=permeability coefficient x surface area of membrane (concentration in intestine-concentration in body)
When the membrane is narror and/pr the permeability, surface area or the extracellular concentration are high, then flux across membrane is favoured
65
Is portal blood considered systemic?
No, it is not considered part of the systemic circulation.
66
SLC influx transporters
solute carrier transporters
they have a physiological role in anion and cation transport across membranes
They also increase intestinal uptake of numerous drugs
just gotta the major classes for organic anions are (OATs and OATPs) and cations (OCTs and OCTNs)
67
ABC efflux transporters
found in intestine
some called multidrug resistance protein
an example is p glycoprotein
They basically pump drugs out and decrease drug uptake into the portal circulation
68
How are drugs sorta absorbed after being taken in orally
Some drug found in the lumen, gets absorbed by enterocyte (where some are metabolised) then the drug is absorbed into portal circulation
69
plasma protein binding
plasma protein could bind with drugs.
and only unbound drug in plasma can enter tissues
These drugs are subject to protein binding equilibrium
70
What kind of drugs does serum albumin bind to
acidic drugs
| like paclitaxel
71
What kind of drugs does acidoglycoprotein bind to?
many basic drugs
72
Bioavailability
the fraction of an administered drug that reaches the systemic circulation
73
how is bioavailability of a substance decreased
presystemic metabolism occurs in the intestine
first pass hepatic clearance occurs
The drug is not absorbed
74
What are some roles of biotransformation enzymes
convert lipid soluble chemicals into more polar products
These are more readily eliminated
Usually metabolites are also less active
However, some important drugs are prodrugs that themselves have low activity
prodrugs are activated by metabolism
75
phase 1 reactions
chemical conversion of a lipophilic chemical into a more polar analogue.
Inclusion of a new functional group usually by oxidation, reduction or hydrolysis
76
what is CYP450
is the major class of phase 1 biotransformation
77
What are some properties of CYPs
unlike most enzymes, they have low substrate specificity and can act on diverse substrates
All cyps have a haem group involved in oxygen activation
The polypeptide chain differs between CYPs and controls substrate specificity
78
What are some other important properties of CYPs that can influence therapy
They are readily inhibited
Some are easily inducible
Many are often subject to extensive pharmacogenetic variation
79
CYP3A4
major Cyp in human liver
60% of drugs metabolised by this enzyme
readily inhibited by stuff like grapejuice
highly inducible by stuff like St Joh's wort
80
consequences of CYP3A4 inhibition
increase in absorbed drug and bioavailability
| Increased Cmax
81
How did we know that CYP3A4 was inhibited by grape juice felodipine
ethanol concentrations were normal when felodipine from grape juice is administered intravenously
82
PXR
basically a nuclear receptor that could activate the CYP genes
A drug xenobiotic activates PXR (pregnane X receptor). The pregnane X receptor then forms dimers with the RXR and then the RXR can do stuff
Similarly a receptor called constitutive androstane receptor (CAR) could also activate CYP genes
83
CYP2D^ is also known as
debrisoquine hydroxylase.
84
What is the most common form of gene polymorphism
single nucleotide polymorphism
85
What are the 2 most common types of gene polymorphism
single nucleotide polymorphism
| and variable number of tandem repeats
86
What happens when there is a defective SNP on coding region of CYP
affect protein function
87
What happens when there is a defective SNP on regulatory region variants
affect amount of protein synthesised
88
extensive metabolisers (CYP2D6)
carry 2 active metabolites
89
poor metabolisers (CYP2D6)
carry 2 nonfunctional alleles-they exhibit slow clearance of CYP2D6 substrates and poor activation of drugs like codeine
90
Intermediate metabolisers
carry 2 low activity alleles or one active and one inactive allele
91
Ultrarapid metabolisers
carry multiple copies of the CYP2D6 gene
92
phase II metabolism
phase I metabolites are conjugated with very polar endogenous molecules such as glucuronic acid and sulfate
93
UGT1A1
is a gene that provides instructions for making enzymes called UDP glucuronosyltransferases
94
Irinotecan metabolism
Irinotecan is activated by hydrolysis to SN38,
| then it is deacted by UGT1A1 by glucuronide conjugation and effluxed into bile
95
UGT1A1 pharmacogenetics
28 star variant has an extra TA in the regulatory region
| Seven TA repeats instead of six
96
28* variant of UGT1A1
28* variant has an extra TA in regulatory region.
this causes seven TA REPEATS INSTEAD OF 6.
THIS CAUSES LESS N38 Conjugation
making them more likely to get neutropenia.
28* and 6* variant of allele both pretty awful.
heterozygous seems ok
6* variant found in asians.
97
ABC transporter mechanism
ABCtransporters exist in the membrane as dimers.
In the open dimer form, the transporter accepts substrate.
Binding of ATP produces a conformational shift.
the substrate is effluxed and ATP is dephosphorylated to produce ADP
the starting conformation is restored to accept further substrate present in cells.
98
glomerular filtration
removal of free drug (not bound to plasma proteins) at the glomerulus
99
active tubular secretion
drug is transported from blood into urine by tubular transporter proteins
100
tubular reabsorption
passive process in which drug in urine diffuses back into blood
favours unionised drug
therefore urinary pH important
101
physiological role of bile
Excretion of cholesterol
absorption of lipids
stimulation of intestinal motility
102
what is the function of bile
bile may be produced in liver and may be stored in gall bladder
103
What are 2 major mechanisms for drugs to appear in faeces
By not being absorbed into the systemic circulation- so drug passes along the intestine
By being absorbed, excreted in bile
Being deposited back into the intestine
104
What are the functions of biliary cells
they could influx the conjugates that are then excreted in bile -molecular weights of 500DA or greater
105
intestinal cleavage of phase II drug conjugates
after biliary excretion, gut bacteria can cleave phase II drug conjugates.
The polar sugar residue in the glucuronide here is removed
This restores the drug or phase I metabolite in the intestine
The drug or metabolite can be reabsorbed
106
enterohepatic recycling
reabsorption of the drug or metabolite can boost blood levels again
This may produce a secondary phase of therapeutic effect for some drugs
with further rounds of enterohepatic recycling there is gradual loss of drug
107
pulmonary elimination
the lung is the major organ of excretion for gases and volatile substances that do not require metabolism
the brethalyzer test quantifies the pulmonary excretion of ethanol
108
erythromycin breath test
small dose of erythromycin administered
breath collected at intervals and radioactivity measured
can be used in patients to measure the activity of liver phase 1 enzymes
109
breast milk
yuh some are lost through breast milk
110
What is the sequence of events in the preclinical drug development pipeline
1) high throughput screening
2) hit to lead
3) lead optimisation
4) candidate seeking
111
How many compounds are in high throughput screening
1000s of compounds
112
How many compounds are in hit to lead
100s of compounds
113
How many compounds are in lead optimisation
dozens of compounds
114
How many compounds are in candidate seeking?
1 or 3
115
What happens in high throughput screening
high throughput screening, IC50 determination. Hit triage
116
What happens in hit to lead
selectivity assays, in vitro efficacy assays, tier 1 ADME/physical chemistry assays
117
What happens in in vivo efficacy assays
tier II ADME/physical chemistry assays
118
What happens in candidate seeking
second species PK, PK/PD MODELLING
119
what happens after candidate seeking
GLP toxicology studies, genetic toxicology, safety pharmacology, in vivo toxicology
120
why do we use animals in medical research
to understand anatomy and physiology
as models to study disease
to test potential treatments
to test drugs for efficacy
121
Which 4 people are on the animal ethics committee
Vet
person with current animal research involvement
animal welfare representative
lay person.
122
All projects with animals require the 3Rs
replacement of animals with other methods
reduction in the number of animals used
refinement of techniques to reduce adverse impact on animals
123
Conflict of interest
funding needed for project but researchers need to remain independent
Scientists need to stay open and transparent
disclosure of all interactions with potential sources of conflicts of interest must be revealed at all points of publication
124
tenets of drug registration
all pharmaceuticals must be registered in OECD countries before they can be marketed
each country has its own regulatory authority
companies must apply for market authorisation
125
Common technical document
internationally agreed set of specifications for a submission dossier
consists of 5 modules
studies on pharmacology, pharmacokinetics and toxicity in animals
module 4 contains non clinical
126
What are the modules in the CTD
mod1: regional administrative information
mod2: quality overall summary, non clinical overview, non clinical summary, clinical overview, clinical summary
mod3: quality
mod4: non clinical study repoirts
mod5: clinical study reports
mod 2 through to 5 form the CTD
127
Why do we need non clinical data in the CTD?
What experiments could be conducted to determine the safety of a new pharmaceutical
considerations: appropriate species? BSA? pharmacology??
128
What is the PBS
pharmaceutical benefits scheme that provides a schedule of all of the medicines available to be dispensed to patients at a federal government subsidised price
129
What is the PBAC
it is the committe which decides which medicines go on the PBS
If the PBAC considers a medicine cost effective, then it will approve the addition to PBS
130
What do we do to try identify the lead drug
high throughput screening
QSAR (structure based design)
molecular docking studies
and quantitative drug target assay
131
What do we do to try quantify drug target response (drug target pharmacology)
biomarker and assay development
companion diagnostic assay, surrogate endpoint
132
What are the three steps we need to find basic science and drug target identification
disease pathophysiology
experimental design
biospecimens
development of new bioassays or methods, big
133
what are the main reasons for preclinical pharmacology failures
40% of drugs failed due to PK issues and toxicity
134
What do we need to consider in animal in vivo testing
is the animal healthy or does the disease model be needed
Is the mice young or old
Is the treatment time frame appropriate
How should we dose the animals?
135
what do we need to consider for cancer
who what where why?
tumour type=mouse/human cancer cell line
tumour location=
treatment time
immune regulation- are the animals immunocompetent or immunocompromised
136
What is the size of the active site of CYP3A4
1440
137
What is the size of the active site of CYP2E1
585
138
Which 5 CYPS account for 90% of human drug metabolism?
```
CYP1A2
2c9
2c19
2d6
3a4
```
139
How does cyp metabolism work
they basically have
140
What are the most likely in vitro cyp inducier
just guess rifampicin
Cyp1A2 has omeprazole, lansoprazole
but CYP2B6 also has phenobarbital
141
What are anti-sense oligonucleotide therapies
they are nucleic acid oligomers complementary to a gene's mRNA. They can bind to mRNA and inhibit its actions in various ways
142
In vivo 2 year carcinogenicity study
use a rat or a mouse,
and basically give it the drug at whatever dose you want
examine for clinical signs of tumour
143
micronucleus assay
look for the presence of micronuclei. It can be produced by bits of DNA being broken off during mitosis.
We give the rodent drug, wait 24 hours then harvest the bone marrow and look for micronuclei
144
mammalian cell transformation assay
untransformed cells do not attach to substrate and cannot proliferate in soft agar, you then treat it with a carcinogen and let it grow for over 1 week. The transformed cells are anchorage independent
145
AMEs test
you have a culture of histidine dependent salmonella, add a s9 rat liver extract then add your xenobiotic of interest
146
What are the 2 main options of standard testing from ICH
option 1 include:
AMEs test
cytogenetic test for chromosomal damage
an in vivo test for genotoxicity in rodent haemopoietic cells
In option 2:
a bacterial mutation test
and an in vivo test for genotoxicity with 2 different tissues
147
What is the primary and secondary safety studies
primary studies look at mechanisms of action and effects in relation to desired therapeutic target
secondary: studies the mode of action/effects not related to the desired therapeutic target
148
What are the safety core battery
cardiovascular
CNS
Respiratory
149
acute toxicology studies vs repeat dose studies
both use 2 species
for acute we use intravenous and proposed route wherease for repeat dose we use proposed route only
in acute we are looking for overdose info and PK data, therefore we often exceed anticipated clinical exposure.
Repeat dose studies
up to maximum tolerated dose
limited by solubility etc
150
dose
amount of drug that is given to the individual
151
Which route provides the fatest route to the plasma?
Intravenous
152
The initial concentration of chlorine in the pool was 0.005g/L
You add 0.6kg of chlorine and measure a new chlorine concentration of 0.02g/L what is the pool volume?
0.6kg changed concentration by 0.015g/L, i.e 0.02-0.005
Therefore, 0.015g/1L=0.6kg/X L
rearrange all this to give 40000L
153
You know that the current level of a 40000L pool's concentration is 0.02g/L. how much more chlorine do you need to add to achieve a final concentration of 0.05g/L
1. 2 kg
| 0. 05-0.02/L=x/40000
154
what is the total body water
45L
155
What is the intracellular volume
30,
since total body water=intracellular+extracellular volume,
you know that extracellular volume is 15
156
What is the interstitial volume
extracellular volume=interstitial volume+plasma volume
interstitial volume =11
extracellular=15
plasma=4
157
What is volume of distribution
dose/initial plasma concentration
158
What does a Vd greater than total body water indicate?
The drug is selectively bound to or taken up into tissues outside of the blood stream
159
what does a Vd of 4L indicate
the drug is found only in plasma
160
what does a Vd of 45 L indicate
even distribution in body water
161
what is clearance (definition from tutorial)
measure of the efficiency of drug elimination from the body. The processes of metabolism and elimination contribute to the clearance of a drug to the body.
162
what are the 3 pharmacokinetic parameters
1) dose
2) clearance
3) volume of distribution
163
when does elimination proceed at the fastest rate?
when the plasma concentration was greatest
164
Does initial plasma concentration affect half life?
No
the time taken for plasma concentration to fall by half was the same for each concentration. THIS IS KNOWN AS THE HALF LIFE OF A DRUG.
dose does not affect halflife
165
How does the volume of distribution affect the half life of a drug
The volume of distribution is an apparent volume into which the drug appears to distribute to achieve a given concentration in the plasma
The higher the Vd, the greater the proportion of the drug that is distributed outside of the blood stream. Thus less is in the plasma and therefore elimination proceeds at a slower rate giving a longer half life.
166
is it possible to derive a half life for a drug that works under zero order kinetics?
Nope. This is because the time for plasma concentration to fall by half depends on the concentration. Therefore it is not possible to determine a half life for phenytoin
167
zero order usually means that the enzyme is saturated, this means that
it could possibly lead to drug overdose
168
in occupancy, what is the equation for the forward rate (according to law of mass action)
(K+1)[A][B]
169
in occupancy what is the equation for the reverse rate (according to law of mass action)
(K-1)[C][D]
170
High Ka/Kd
the occupancy concentration curve would move more to the right the larger Ka
171
Relationship between Ka and affinity
As Ka increases, affinity decreases
172
Numerically Ka is defined as the concentration of agonist needed to ensure that a certain proportion of the receptors is occupied. What is this proportion expressed as a percentage
50%5
173
why is (%max) response curves more important than response curves
ratios means that comparisons can be made between experiments
174
Why is it that some agonists can produce a maximum response and others can't
several factors affect the maximum size of response an agonist can elicit
1) Characteristics of the tissue involved
- the total number of receptors present
- the nature of the receptor and response coupling
2) the agonist receptor complex itself
175
Consider 2 agonists which complex with the same receptor and which have the same affinity for the receptor. You find that one of the agonists produce a bigger response than the other. What does this imply?
Difference in intrinsic efficacy
176
equation of occupancy and Ka
occupancy=(xa)/(xa+ka)
177
What is the rare case in which the dose response curve does shift when there is a low concentration of an irreversible competitive antagonist
when there are spare receptors and a very low concentration of antagonists
Irreversible antagonist does not cause the dose response curve to shift along the x axis
178
what kind of antagonist is salbutamol
physiological antagonism
179
What are the issues of ionic bonds in drugs
ionic bonds can lead to strong interactions with target
ionic forms of drugs penetrate membranes slowly
180
Acids and bases
when bases become more basic, they could basically attract protons due to their lone pairs and form BH+, which is used to make a more alkaline system
181
henderson hasselbalch equation for a weak acid
pH-pKa=log(A-)-log(AH)
e.g what is the distribution between AH and A- at a pH of 7.4 for an acid with a pKa of 5.4?
```
7.4-5.4=log[A-]/[AH]=2
2=log [A}/[AH]
10^2=100
SO 100:1 ratio between A- and AH
for 101 molecules, 100 are -, 1 is AH
```
182
henderson hasselbalch equation for a base
pH-pKA=log(B)/(BH)
| LITERALLY SAME THING AS the henderson hasselbalch equation for an acid.
183
what is the influence of pH on drug passage through membranes
lipid bilayer creates a barrier between compartments pH may differ between compartments. Only the neutral or uncharged form will pass through the membrane and each compartment will have its own equilibrium.
184
optical isomers
have same physiochemical properties
have the same chemical groups but are in different 3D positions
do not have the same activity
usually optically pure drugs (the more active isomer) are preferred to racemic mixtures
185
give an example of an optical isomer
methacholine is a muscarinic acetylcholine receptor
| S acetyl methylcholine is 240 times more potent than the R isomer at muscarinic acetylcholine receptors
186
nicotinic acetylcholine receptor
ligand gated ion channel
5 subunits come together to form an ion channel
multiple subtypes of a subunits and beta subunits
187
muscarinic receptor
G protein coupled receptor
7 transmembrane domain protein coupled to a trimeric G protien
5 subtypes
188
amino side chains with aromatic R groups
phenylalanine
tyrosine
tryptophan
189
positively charged R group amino acid
lysine
arginine
histidine
hellboy accepted leia
190
negatively charged R groups
aspartate
glutamate
AG
191
nonpolar aliphatic R groups
glycine, alanine, valine, leucine, methionine
| isoleucine
192
polar uncharged R groups
serine, threonine, cytseine, proline, asparagine, glutamine
193
hydrogen bond examples
hydrogen atom from a hydroxyl group and oxygen atom from a carbonyl group from either glutamate, aspartate, aspargine, glutamine or a peptide backbone
hydrogen bonds are GAGA
194
example of a cation pi bond
quaternary amine of acetylcholine and aromatic group of a tyrosine residue
195
example of a pi pi bond
aromatic group of nicotine and aromatic group of a phenylalanine residue
196
hydrophobic interatcation example
side chains of aliphatic and whatever
leucine residue and aromatic group of nicotine.
197
what aliphatic amino acid could form ion dipole and hydrogen bonds
only methionine
198
what is the only polar amino acid that can form ionic bonds
cysteine
199
what is the only polar amino acid that can form hydrophobic bonds
threonine
200
can aromatic amino acids form ionic bonds
no
201
could aromatic amino acids form ion dipole bonds
only tyrosine and tryptophan
202
could aromatic amino acids form hydrogen bonds
yes, except for phenylalanine
203
why is muscarine and nicotine selective while ACh is not selective
ACh is free to rotate many conformations, so it can bind to both mAChR and nAChR.
As for muscarine, and nicotine, they have rings which restrict the number of conformations they could have
204
structure activity for mAChR ligands
there is a maximum length for mAChR ligands.
The quaternary nitrogen is important.
The length of the chain should be 5 atoms max
beta methyl group can fit,
alpha methyl group cannot fit well.
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biosteric replacement
replacement of a binding group in adrug with another group such as replacing CH3 in ACh with NH2 in carbachol.
206
What is the receptor specificity of methacholine for muscarinic and nicotinic
methacholine is much more selective for muscarinic, and slightly selective for nicotinic.
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what is the receptor specificity of bethanechol for muscarinic and nicotinic
bethanechol is specific to muscarinic but not at all specific to nicotinic
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is carbachol hydrolysed by AChE
no
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Is bethanechol hydrolysed by AChE
no
210
Where are acetylcholinesterase distributed
cholinergic nerve terminals, muscle (motor end plates), red blood cells
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Where are butyrylcholinesterase distributed
liver, skin, brain, gastrointestinal smooth muscle
212
What are poor substrates of acetylcholinesterase
carbachol, benzylcholine, suxamethonium
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what are poor substrates of butyrylcholinesterase
methacholine, carbachol
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what are substrates of butyrylcholinesterase
butyrylcholine, acetylcholine, benzylcholine, suxamethonium
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what are substrates of acetylcholinesterase
acetylcholine or methacholine
216
what is the structure of acetylcholinesterases?
collagen-like trunk to anchor the protein to the membrane
close to ACh receptors
3 branches with separate enzymes of each branch
each enzyme consist of 4 subunits
butyrylcholinesterase is soluble form that lacks collagen like anchor
217
what is the function of the peripheral binding site
attracts acetylcholine into the site N methyl group of acetylcholine forms a pi chation bond transferred down the gorge into the active site by a series of pi cation interactions
218
What is the function of the catalytic site
N methyl group stabilised by a tryptophan,
catalytic triad
219
what are 3 examples of reversible inhibitors given in the lecture
physostigmine
carbamates
donepezil
220
what does physostigmine do?
forms a carbamylated form of the enzyme (rather than an acetylated form for acetylcholine)
221
what does donepezil do
it forms a number of pi pi interactions in the gorge of the active site and does not directly interact with the catalytic triad
222
why is malathion inactive in mammalian acetylcholinesterases
P=S bond is metabolised to P=O which creates a toxic irreversible acetylcholinesterase inhibitor
223
what is an antidote to organophosphate
pralidoxime
224
parasympathetic
craniosacral (from brain and the sacrum)
225
sympathetic
thoracic-lumbar
226
what is the function of the ANS?
maintenance of homeostasis
smooth muscle
exocrine and endocrine
metabolism
heart rate
227
pre and post ganglionic receptors for parasympathetic
pre ganglionic: nAChR
| post ganglionic: mAChR
228
noepinephrine receptors
G protein coupled
229
acetylcholinesterase breaks acetylcholine down to
choline and coenzyme A
The choline gets reabsorbed to the pre synaptic cell by a choline transporter where it helps form more acetylcholine.
The M2 autoreceptor
230
basically all nicotinic ACh receptors are
all excitatory
| and they all increase sodium permeability.
231
muscarinic receptors
| mostly
mostly could be split into M1 and M2.
M1, M3 and M5 are all excitatory G coupled.
M2 and M4 are inhibitory. So M4 is a kind of M2..
232
Heart
M2 so obviously you get a decreased rate of contraction and decrease force
233
Bronchi
M3 -excitatory
| so you get contraction of smooth muscle and gland secretion
234
Gastrointestinal tract
M1, M3 so excitatory
| contraction, gland secretion, relaxation of sphincters
235
sympathetic/parasympathetic length
The parasympathetic have a much longer preganglionic neuron.
(and much shorter postganglionic neuron)
236
precursor of noradrenaline
| and differences between noradrenaline vs cholinergic
dopamine
acts on alpha beta receptor
Noradrenaline unlike cholinergic is completely taken back in the cell or taken up and broken down into a metabolite
237
adrenaline affinity
adrenaline: beta2>b1/b3/a
238
noradrenaline
alpha>beta1>>beta2
239
alpha 2 adrenoreceptors
all inhibitory
240
alpha 1 adrenoreceptors
basically excitatory except for intestinal
241
excitatory lung
relaxation beta2
242
heart excitation
beta 1 increasw contaction
243
blood vessel excitation
constriction of smooth muscle
244
gastrointestinal tract excitation
relaxation
245
salbutamol
agonises beta 2 adrenoceptors to relax bronchial smooth muscle
246
phenylephrine
phenylephrine used in nasal congestion, agonises a1 adrenoceptors to restrict blood flow hence mucosal secretion.
247
timolol
blocks beta adrenoreceptors to prevent heart rate and force of contraction in hypertension
248
prazosin
blocks a1 adrenoceptors to dilate vascular smooth muscle and reduce arterial blood pressure
249
imatinib is used for what kind of cancer?
Chronic myelogenous leukaemia
250
how does Chronic myelogenous leukaemia (CML work)
There is an extra gene that is not present in healthy cells called BCR/Abl which encodes for kinase activity that promotes tumour growth
There is shortened chromosome 22 and a lengthened chromosome 9
251
c-kit
a kinase that regulates haemotopoiesis and is expressed in some cells of the GI mucosa
252
haepatocellular carcinoma
hepatitis B and C and nonalcoholic fatty liver disease.
253
tumour angiogenesis
oxygen and delivery of nutrients are essential for normal cell function and survival. In cancers we see angiogenesis initiating signals including vascular endothelial and fibroblast growth factors that activate receptors on endothelial cells, are released by tumours.
254
Sorafenib
orally active kinase inhibitor used in the treatment of advanced hepatocellular carcinoma
Sorafenib inhibits multiple dysregulated kinases including RAF kinase, or VEGDF receptor
basically this means sorafenib decreases tumour growth by decreasing angiogenesis
255
What are some of the adverse effects of imatinib and sorafenib
Several kinase inhibitors may cause hand-foot syndrome and other dermal toxicities as well as gastrointestinal toxicity
256
imatinib metabolism
imatinib in the presence of CYP and NADPH turns into N-desmethylimatinib.
257
What CYP metabolises imatinib
CYP3A4
| CYP2C8
258
WHAT IS THE POINT OF THE ERYTHROMYCIN BREATH TEST
the breath basically sees what is the erythromycin clearance and measures CYP3A4 activity.
259
imatinib
inhibition increases with time which may suggest that an inhibitory metabolite is forming
260
Sorafenib metabolism
Sorafenib is principally metabolised by CYP3A4 where N oxide and N hydroxymethyl are formed
possibly causes its own inhibition
261
Why is combo drugs used in cancer
combo drugs can increase the Cmax and AUC of the coadministered drugs.
262
What does alcohol dehydrogenase and aldehyde dehydrogenase do?
Ethanol=> Acetaldehyde=> acetate
| alcohol dehydrogenase turns ethanol to acetaldehyde
263
ALDH2*1
high activity of this enzyme
264
ALDH2*2
encode low activity forms of this enzyme.
| this causes flushing response
265
ADH1B*2
a small change from arginine to histidine. This causes a more rapid rate of oxidation of ethanol, leading to a faster buildup. acetaldehyde.
266
Three steps of DNA amplification
1-DNA denaturation
when samples are heated in the thermocycler to 94-98 C they separate the double stranded DNA
2-annealing of primers to DNA
by lowering the temperature to approximately 55-65C forward and reverse primers can anneal
3-DNA extension
The third step involves raising the temperature to 68 to 72 C, the polymerase attaches to each primer site and extends, or synthesises a new DNA strand complementary to the existing strand.
267
RFLP
Restriction fragment length polymorphism, where a particular restriction enzyme will either cut or not cut at a designated SNP site
268
SYBR green, gelred, ethidium bromide
DNA strain
269
What are factors which affect the speed at which migration occurs
1) size of the molecule,
2) the concentration of agarose in the gel
3) the voltage applied to the gel
