Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

immu3102 > meds2002 ver.ka > Flashcards

meds2002 ver.ka Flashcards

1
Q

pharmacodynamics

A

the effects of the drug on the body

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

pharmacokinetics

A

the way the body affects the drug

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

Potency

A

the concentration of a drug that cause a specified effect

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

selectivity

A

ability of a given drug concentration to produce one effect over another

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

What are the 3 stages of drug action

A

1 binding
2 conformational change and transduction
3 response

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

agonist

A

a ligand that binds to and activates a receptor to produce a response in the cell

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

examples of amino acid transmitters

A

1) GABA
2) Glutamate
3) Glycine

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

examples of monoamines

A

1) catecholamine
indoleamine
histamine

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

example of quaternary amines

A

acetylcholine

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

What is the type of receptor on a preganglionic sympathetic neuron?

A

nAChR

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

What kind of ligands are released by the postganglionic sympathetic

A

NA for most stuff

and ACh for sweat glands

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

What is the structure of the adrenal medulla sympathetic system

A

basically one neuron

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

What is the pre and post ganglionic neurons of the parasympathetic nervous system

A

Ach (nAChR)

ACh (mAChR)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

What is an autoreceptor

A

it is a inhibitory pre synaptic receptor, for example the M2 autoreceptor

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

what kind of receptor is a muscarinic receptor

A

G coupled(metabotropic)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

what kind of receptor is a nicotinic receptor

A

ligand gated ion channels(ionotropic

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
23
Q

activation of alpha 2 adrenoreceptor

A

has an inhibitory effect on various stuff. so most likely relaxation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
25
Q

What is the law of mass action

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
26
Q

What is Kd

A

Kd is a measure of affinity measured as a concentration. Kd measures the concentration of drug that occupies 50% of binding sites at equilibrium

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
27
Q

What 2 factors is Kd dependent on

A

electronic/hydrophobic match of drug to receptor (bonding and conformation)

steric match of drug to receptor (conformation and size)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
28
Q

how should we change the concentration occupancy curves

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
29
Q

what is the law of mass action?

A

rate of a reaction is proportional to the concentration of the reactants

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
30
Q

competitive antagonists

A

bind to the same site as the agonist on a receptor

Binds reversibly to receptor binding site

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
31
Q

Competitive antagonist quantitative aspects

A

addition of antagonist sets up a second equilibrium reaction which competes with the equilibrium for the agonist receptor binding

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
32
Q

Dose ratio

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
33
Q

new equilibrium rule with competitive antagonists (schild plot)

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
34
Q

what is the x intercept of the schild plot

A

logkb

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
35
Q

insurmountable antagonism

A

includes irreversible and some forms of allosteric antagonism

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
36
Q

irreversible antagonism

A

antagonist binds irreversibly or with very slow dissociation

Effect cannot be reversed by increasing agonist dose

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
37
Q

insurmountable allosteric antagonism

A

antagonist binds to a different site from agonist and reduces receptor activation (intrinsic efficacy) as well as agonist binding (affinity)
negative allosteric modulation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
38
Q

allosteric antagonism

A

antagonist binds to a different site from agonist and reduce agonist binding without affecting receptor activation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
39
Q

physiological antagonism

A

agonists with opposing physiological effects on the same tissue

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
40
Q

partial antagonism

A

use of partial agonists

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
41
Q

chemical antagonism

A

when 2 substances combine to form an inactive compound

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
42
Q

Therapeutic index

A

TD50/ED50
median toxic dose

the therapeutic ratio/index is a quantitative measurement of the relative safety of a drug

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
43
Q

Why is pharmacokinetic analysis important

A

1) accumulation
2) dose proportionality
3) distribution to brain testes, ovaries
excretion and metabolism
potential to interfere with other medications and body functions

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
44
Q

Clearance

A

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+…

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
45
Q

how to calculate clearance with dose and AUC

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
46
Q

volume of distribution

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
47
Q

what is volume of distribution

A

V=dose (mg_/C0(mg/L)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
48
Q

how does drug with high liphophilicity compare to drug which are hydrophilic

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
49
Q

definition of clearance

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
50
Q

most importance clearance

A

Glomulerar filtration rate (renal clearance)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
51
Q

rate of elimination limitation

A

depends on first order kinetics.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
52
Q

what does the volume of distribution tell us

A

it tells us how extensively drug is distributed to the rest of the body compared to the plasma

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
53
Q

volume of distribution definition

A

ratio of the amount of drug in total body to the concentration of drug in plasma

Vd=(amount of drug in body)/(plasma concentration)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
54
Q

Half life equation (first order)

A

Concentration(time)= original concentration x e^(-kt)

k=clearance/volume over distribution

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
55
Q

Cmax and T max

A

Cmax is the peak plasma concentration and Tmax is the time taken to reach the peak plasma concentration

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
56
Q

AUC

A 
area under concentration time curve.
average plasma concentration of drug 
and overall exposure of drug for people
calculate bioavailability and clearance
calculate steady state
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
57
Q

Bioavailability

A

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)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
58
Q

k(elimination)

A

is the sum of the rates of excretion from the body and metabolism

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
59
Q

how do we make sure that the elimination curve is 1 compartment

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
60
Q

two compartment model

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
61
Q

What is the 2 comparment model like as a graph

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
62
Q

log (1 vs 2 compartment)

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
63
Q

population pharmacokinetics

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
64
Q

Fick’s law

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
65
Q

Is portal blood considered systemic?

A

No, it is not considered part of the systemic circulation.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
66
Q

SLC influx transporters

A

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)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
67
Q

ABC efflux transporters

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
68
Q

How are drugs sorta absorbed after being taken in orally

A

Some drug found in the lumen, gets absorbed by enterocyte (where some are metabolised) then the drug is absorbed into portal circulation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
69
Q

plasma protein binding

A

plasma protein could bind with drugs.
and only unbound drug in plasma can enter tissues

These drugs are subject to protein binding equilibrium

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
70
Q

What kind of drugs does serum albumin bind to

A

acidic drugs

like paclitaxel

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
71
Q

What kind of drugs does acidoglycoprotein bind to?

A

many basic drugs

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
72
Q

Bioavailability

A

the fraction of an administered drug that reaches the systemic circulation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
73
Q

how is bioavailability of a substance decreased

A

presystemic metabolism occurs in the intestine

first pass hepatic clearance occurs

The drug is not absorbed

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
74
Q

What are some roles of biotransformation enzymes

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
75
Q

phase 1 reactions

A

chemical conversion of a lipophilic chemical into a more polar analogue.
Inclusion of a new functional group usually by oxidation, reduction or hydrolysis

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
76
Q

what is CYP450

A

is the major class of phase 1 biotransformation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
77
Q

What are some properties of CYPs

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
78
Q

What are some other important properties of CYPs that can influence therapy

A

They are readily inhibited
Some are easily inducible

Many are often subject to extensive pharmacogenetic variation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
79
Q

CYP3A4

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
80
Q

consequences of CYP3A4 inhibition

A

increase in absorbed drug and bioavailability

Increased Cmax

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
81
Q

How did we know that CYP3A4 was inhibited by grape juice felodipine

A

ethanol concentrations were normal when felodipine from grape juice is administered intravenously

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
82
Q

PXR

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
83
Q

CYP2D^ is also known as

A

debrisoquine hydroxylase.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
84
Q

What is the most common form of gene polymorphism

A

single nucleotide polymorphism

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
85
Q

What are the 2 most common types of gene polymorphism

A

single nucleotide polymorphism

and variable number of tandem repeats

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
86
Q

What happens when there is a defective SNP on coding region of CYP

A

affect protein function

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
87
Q

What happens when there is a defective SNP on regulatory region variants

A

affect amount of protein synthesised

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
88
Q

extensive metabolisers (CYP2D6)

A

carry 2 active metabolites

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
89
Q

poor metabolisers (CYP2D6)

A

carry 2 nonfunctional alleles-they exhibit slow clearance of CYP2D6 substrates and poor activation of drugs like codeine

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
90
Q

Intermediate metabolisers

A

carry 2 low activity alleles or one active and one inactive allele

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
91
Q

Ultrarapid metabolisers

A

carry multiple copies of the CYP2D6 gene

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
92
Q

phase II metabolism

A

phase I metabolites are conjugated with very polar endogenous molecules such as glucuronic acid and sulfate

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
93
Q

UGT1A1

A

is a gene that provides instructions for making enzymes called UDP glucuronosyltransferases

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
94
Q

Irinotecan metabolism

A

Irinotecan is activated by hydrolysis to SN38,

then it is deacted by UGT1A1 by glucuronide conjugation and effluxed into bile

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
95
Q

UGT1A1 pharmacogenetics

A

28 star variant has an extra TA in the regulatory region

Seven TA repeats instead of six

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
96
Q

28* variant of UGT1A1

A

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.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
97
Q

ABC transporter mechanism

A

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.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
98
Q

glomerular filtration

A

removal of free drug (not bound to plasma proteins) at the glomerulus

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
99
Q

active tubular secretion

A

drug is transported from blood into urine by tubular transporter proteins

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
100
Q

tubular reabsorption

A

passive process in which drug in urine diffuses back into blood

favours unionised drug

therefore urinary pH important

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
101
Q

physiological role of bile

A

Excretion of cholesterol
absorption of lipids
stimulation of intestinal motility

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
102
Q

what is the function of bile

A

bile may be produced in liver and may be stored in gall bladder

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
103
Q

What are 2 major mechanisms for drugs to appear in faeces

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
104
Q

What are the functions of biliary cells

A

they could influx the conjugates that are then excreted in bile -molecular weights of 500DA or greater

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
105
Q

intestinal cleavage of phase II drug conjugates

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
106
Q

enterohepatic recycling

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
107
Q

pulmonary elimination

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
108
Q

erythromycin breath test

A

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
Q

breast milk

A

yuh some are lost through breast milk

110
Q

What is the sequence of events in the preclinical drug development pipeline

A

1) high throughput screening
2) hit to lead
3) lead optimisation
4) candidate seeking

111
Q

How many compounds are in high throughput screening

A

1000s of compounds

112
Q

How many compounds are in hit to lead

A

100s of compounds

113
Q

How many compounds are in lead optimisation

A

dozens of compounds

114
Q

How many compounds are in candidate seeking?

A

1 or 3

115
Q

What happens in high throughput screening

A

high throughput screening, IC50 determination. Hit triage

116
Q

What happens in hit to lead

A

selectivity assays, in vitro efficacy assays, tier 1 ADME/physical chemistry assays

117
Q

What happens in in vivo efficacy assays

A

tier II ADME/physical chemistry assays

118
Q

What happens in candidate seeking

A

second species PK, PK/PD MODELLING

119
Q

what happens after candidate seeking

A

GLP toxicology studies, genetic toxicology, safety pharmacology, in vivo toxicology

120
Q

why do we use animals in medical research

A

to understand anatomy and physiology
as models to study disease
to test potential treatments
to test drugs for efficacy

121
Q

Which 4 people are on the animal ethics committee

A

Vet
person with current animal research involvement
animal welfare representative
lay person.

122
Q

All projects with animals require the 3Rs

A

replacement of animals with other methods
reduction in the number of animals used
refinement of techniques to reduce adverse impact on animals

123
Q

Conflict of interest

A

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
Q

tenets of drug registration

A

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
Q

Common technical document

A

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
Q

What are the modules in the CTD

A

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
Q

Why do we need non clinical data in the CTD?

A

What experiments could be conducted to determine the safety of a new pharmaceutical
considerations: appropriate species? BSA? pharmacology??

128
Q

What is the PBS

A

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
Q

What is the PBAC

A

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
Q

What do we do to try identify the lead drug

A

high throughput screening
QSAR (structure based design)
molecular docking studies

and quantitative drug target assay

131
Q

What do we do to try quantify drug target response (drug target pharmacology)

A

biomarker and assay development

companion diagnostic assay, surrogate endpoint

132
Q

What are the three steps we need to find basic science and drug target identification

A

disease pathophysiology
experimental design
biospecimens
development of new bioassays or methods, big

133
Q

what are the main reasons for preclinical pharmacology failures

A

40% of drugs failed due to PK issues and toxicity

134
Q

What do we need to consider in animal in vivo testing

A

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
Q

what do we need to consider for cancer

A

who what where why?
tumour type=mouse/human cancer cell line

tumour location=
treatment time
immune regulation- are the animals immunocompetent or immunocompromised

136
Q

What is the size of the active site of CYP3A4

A

1440

137
Q

What is the size of the active site of CYP2E1

A

585

138
Q

Which 5 CYPS account for 90% of human drug metabolism?

A 
CYP1A2
2c9
2c19
2d6
3a4
139
Q

How does cyp metabolism work

A

they basically have

140
Q

What are the most likely in vitro cyp inducier

A

just guess rifampicin

Cyp1A2 has omeprazole, lansoprazole
but CYP2B6 also has phenobarbital

141
Q

What are anti-sense oligonucleotide therapies

A

they are nucleic acid oligomers complementary to a gene’s mRNA. They can bind to mRNA and inhibit its actions in various ways

142
Q

In vivo 2 year carcinogenicity study

A

use a rat or a mouse,
and basically give it the drug at whatever dose you want

examine for clinical signs of tumour

143
Q

micronucleus assay

A

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
Q

mammalian cell transformation assay

A

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
Q

AMEs test

A

you have a culture of histidine dependent salmonella, add a s9 rat liver extract then add your xenobiotic of interest

146
Q

What are the 2 main options of standard testing from ICH

A

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
Q

What is the primary and secondary safety studies

A

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
Q

What are the safety core battery

A

cardiovascular
CNS
Respiratory

149
Q

acute toxicology studies vs repeat dose studies

A

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
Q

dose

A

amount of drug that is given to the individual

151
Q

Which route provides the fatest route to the plasma?

A

Intravenous

152
Q

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?

A

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
Q

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

A
  1. 2 kg

0. 05-0.02/L=x/40000

154
Q

what is the total body water

A

45L

155
Q

What is the intracellular volume

A

30,
since total body water=intracellular+extracellular volume,
you know that extracellular volume is 15

156
Q

What is the interstitial volume

A

extracellular volume=interstitial volume+plasma volume
interstitial volume =11
extracellular=15
plasma=4

157
Q

What is volume of distribution

A

dose/initial plasma concentration

158
Q

What does a Vd greater than total body water indicate?

A

The drug is selectively bound to or taken up into tissues outside of the blood stream

159
Q

what does a Vd of 4L indicate

A

the drug is found only in plasma

160
Q

what does a Vd of 45 L indicate

A

even distribution in body water

161
Q

what is clearance (definition from tutorial)

A

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
Q

what are the 3 pharmacokinetic parameters

A

1) dose
2) clearance
3) volume of distribution

163
Q

when does elimination proceed at the fastest rate?

A

when the plasma concentration was greatest

164
Q

Does initial plasma concentration affect half life?

A

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
Q

How does the volume of distribution affect the half life of a drug

A

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
Q

is it possible to derive a half life for a drug that works under zero order kinetics?

A

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
Q

zero order usually means that the enzyme is saturated, this means that

A

it could possibly lead to drug overdose

168
Q

in occupancy, what is the equation for the forward rate (according to law of mass action)

A

(K+1)[A][B]

169
Q

in occupancy what is the equation for the reverse rate (according to law of mass action)

A

(K-1)[C][D]

170
Q

High Ka/Kd

A

the occupancy concentration curve would move more to the right the larger Ka

171
Q

Relationship between Ka and affinity

A

As Ka increases, affinity decreases

172
Q

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

A

50%5

173
Q

why is (%max) response curves more important than response curves

A

ratios means that comparisons can be made between experiments

174
Q

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

A

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
Q

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?

A

Difference in intrinsic efficacy

176
Q

equation of occupancy and Ka

A

occupancy=(xa)/(xa+ka)

177
Q

What is the rare case in which the dose response curve does shift when there is a low concentration of an irreversible competitive antagonist

A

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
Q

what kind of antagonist is salbutamol

A

physiological antagonism

179
Q

What are the issues of ionic bonds in drugs

A

ionic bonds can lead to strong interactions with target

ionic forms of drugs penetrate membranes slowly

180
Q

Acids and bases

A

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
Q

henderson hasselbalch equation for a weak acid

A

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
Q

henderson hasselbalch equation for a base

A

pH-pKA=log(B)/(BH)

LITERALLY SAME THING AS the henderson hasselbalch equation for an acid.

183
Q

what is the influence of pH on drug passage through membranes

A

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
Q

optical isomers

A

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
Q

give an example of an optical isomer

A

methacholine is a muscarinic acetylcholine receptor

S acetyl methylcholine is 240 times more potent than the R isomer at muscarinic acetylcholine receptors

186
Q

nicotinic acetylcholine receptor

A

ligand gated ion channel

5 subunits come together to form an ion channel

multiple subtypes of a subunits and beta subunits

187
Q

muscarinic receptor

A

G protein coupled receptor
7 transmembrane domain protein coupled to a trimeric G protien
5 subtypes

188
Q

amino side chains with aromatic R groups

A

phenylalanine
tyrosine
tryptophan

189
Q

positively charged R group amino acid

A

lysine
arginine
histidine
hellboy accepted leia

190
Q

negatively charged R groups

A

aspartate
glutamate
AG

191
Q

nonpolar aliphatic R groups

A

glycine, alanine, valine, leucine, methionine

isoleucine

192
Q

polar uncharged R groups

A

serine, threonine, cytseine, proline, asparagine, glutamine

193
Q

hydrogen bond examples

A

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
Q

example of a cation pi bond

A

quaternary amine of acetylcholine and aromatic group of a tyrosine residue

195
Q

example of a pi pi bond

A

aromatic group of nicotine and aromatic group of a phenylalanine residue

196
Q

hydrophobic interatcation example

A

side chains of aliphatic and whatever

leucine residue and aromatic group of nicotine.

197
Q

what aliphatic amino acid could form ion dipole and hydrogen bonds

A

only methionine

198
Q

what is the only polar amino acid that can form ionic bonds

A

cysteine

199
Q

what is the only polar amino acid that can form hydrophobic bonds

A

threonine

200
Q

can aromatic amino acids form ionic bonds

A

no

201
Q

could aromatic amino acids form ion dipole bonds

A

only tyrosine and tryptophan

202
Q

could aromatic amino acids form hydrogen bonds

A

yes, except for phenylalanine

203
Q

why is muscarine and nicotine selective while ACh is not selective

A

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
Q

structure activity for mAChR ligands

A

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.

205
Q

biosteric replacement

A

replacement of a binding group in adrug with another group such as replacing CH3 in ACh with NH2 in carbachol.

206
Q

What is the receptor specificity of methacholine for muscarinic and nicotinic

A

methacholine is much more selective for muscarinic, and slightly selective for nicotinic.

207
Q

what is the receptor specificity of bethanechol for muscarinic and nicotinic

A

bethanechol is specific to muscarinic but not at all specific to nicotinic

208
Q

is carbachol hydrolysed by AChE

A

no

209
Q

Is bethanechol hydrolysed by AChE

A

no

210
Q

Where are acetylcholinesterase distributed

A

cholinergic nerve terminals, muscle (motor end plates), red blood cells

211
Q

Where are butyrylcholinesterase distributed

A

liver, skin, brain, gastrointestinal smooth muscle

212
Q

What are poor substrates of acetylcholinesterase

A

carbachol, benzylcholine, suxamethonium

213
Q

what are poor substrates of butyrylcholinesterase

A

methacholine, carbachol

214
Q

what are substrates of butyrylcholinesterase

A

butyrylcholine, acetylcholine, benzylcholine, suxamethonium

215
Q

what are substrates of acetylcholinesterase

A

acetylcholine or methacholine

216
Q

what is the structure of acetylcholinesterases?

A

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
Q

what is the function of the peripheral binding site

A

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
Q

What is the function of the catalytic site

A

N methyl group stabilised by a tryptophan,

catalytic triad

219
Q

what are 3 examples of reversible inhibitors given in the lecture

A

physostigmine
carbamates
donepezil

220
Q

what does physostigmine do?

A

forms a carbamylated form of the enzyme (rather than an acetylated form for acetylcholine)

221
Q

what does donepezil do

A

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
Q

why is malathion inactive in mammalian acetylcholinesterases

A

P=S bond is metabolised to P=O which creates a toxic irreversible acetylcholinesterase inhibitor

223
Q

what is an antidote to organophosphate

A

pralidoxime

224
Q

parasympathetic

A

craniosacral (from brain and the sacrum)

225
Q

sympathetic

A

thoracic-lumbar

226
Q

what is the function of the ANS?

A

maintenance of homeostasis
smooth muscle

exocrine and endocrine
metabolism
heart rate

227
Q

pre and post ganglionic receptors for parasympathetic

A

pre ganglionic: nAChR

post ganglionic: mAChR

228
Q

noepinephrine receptors

A

G protein coupled

229
Q

acetylcholinesterase breaks acetylcholine down to

A

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
Q

basically all nicotinic ACh receptors are

A

all excitatory

and they all increase sodium permeability.

231
Q

muscarinic receptors

mostly

A

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
Q

Heart

A

M2 so obviously you get a decreased rate of contraction and decrease force

233
Q

Bronchi

A

M3 -excitatory

so you get contraction of smooth muscle and gland secretion

234
Q

Gastrointestinal tract

A

M1, M3 so excitatory

contraction, gland secretion, relaxation of sphincters

235
Q

sympathetic/parasympathetic length

A

The parasympathetic have a much longer preganglionic neuron.
(and much shorter postganglionic neuron)

236
Q

precursor of noradrenaline

and differences between noradrenaline vs cholinergic

A

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
Q

adrenaline affinity

A

adrenaline: beta2>b1/b3/a

238
Q

noradrenaline

A

alpha>beta1»beta2

239
Q

alpha 2 adrenoreceptors

A

all inhibitory

240
Q

alpha 1 adrenoreceptors

A

basically excitatory except for intestinal

241
Q

excitatory lung

A

relaxation beta2

242
Q

heart excitation

A

beta 1 increasw contaction

243
Q

blood vessel excitation

A

constriction of smooth muscle

244
Q

gastrointestinal tract excitation

A

relaxation

245
Q

salbutamol

A

agonises beta 2 adrenoceptors to relax bronchial smooth muscle

246
Q

phenylephrine

A

phenylephrine used in nasal congestion, agonises a1 adrenoceptors to restrict blood flow hence mucosal secretion.

247
Q

timolol

A

blocks beta adrenoreceptors to prevent heart rate and force of contraction in hypertension

248
Q

prazosin

A

blocks a1 adrenoceptors to dilate vascular smooth muscle and reduce arterial blood pressure

249
Q

imatinib is used for what kind of cancer?

A

Chronic myelogenous leukaemia

250
Q

how does Chronic myelogenous leukaemia (CML work)

A

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
Q

c-kit

A

a kinase that regulates haemotopoiesis and is expressed in some cells of the GI mucosa

252
Q

haepatocellular carcinoma

A

hepatitis B and C and nonalcoholic fatty liver disease.

253
Q

tumour angiogenesis

A

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
Q

Sorafenib

A

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
Q

What are some of the adverse effects of imatinib and sorafenib

A

Several kinase inhibitors may cause hand-foot syndrome and other dermal toxicities as well as gastrointestinal toxicity

256
Q

imatinib metabolism

A

imatinib in the presence of CYP and NADPH turns into N-desmethylimatinib.

257
Q

What CYP metabolises imatinib

A

CYP3A4

CYP2C8

258
Q

WHAT IS THE POINT OF THE ERYTHROMYCIN BREATH TEST

A

the breath basically sees what is the erythromycin clearance and measures CYP3A4 activity.

259
Q

imatinib

A

inhibition increases with time which may suggest that an inhibitory metabolite is forming

260
Q

Sorafenib metabolism

A

Sorafenib is principally metabolised by CYP3A4 where N oxide and N hydroxymethyl are formed

possibly causes its own inhibition

261
Q

Why is combo drugs used in cancer

A

combo drugs can increase the Cmax and AUC of the coadministered drugs.

262
Q

What does alcohol dehydrogenase and aldehyde dehydrogenase do?

A

Ethanol=> Acetaldehyde=> acetate

alcohol dehydrogenase turns ethanol to acetaldehyde

263
Q

ALDH2*1

A

high activity of this enzyme

264
Q

ALDH2*2

A

encode low activity forms of this enzyme.

this causes flushing response

265
Q

ADH1B*2

A

a small change from arginine to histidine. This causes a more rapid rate of oxidation of ethanol, leading to a faster buildup. acetaldehyde.

266
Q

Three steps of DNA amplification

A

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
Q

RFLP

A

Restriction fragment length polymorphism, where a particular restriction enzyme will either cut or not cut at a designated SNP site

268
Q

SYBR green, gelred, ethidium bromide

A

DNA strain

269
Q

What are factors which affect the speed at which migration occurs

A

1) size of the molecule,
2) the concentration of agarose in the gel
3) the voltage applied to the gel

immu3102 (12 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions