topic 6 (neuroactive drugs)

Question 1

what is a drug?

Answer 1

a chemical which affects physiological function in some way

Question 2

what are the main target proteins of drugs

Answer 2

enzymes
ion channels
receptors
carrier proteins

Question 3

what are the 2 main functions of receptors?

Answer 3

1. recognition or detection of extracellular molecules

2. Transduction, where having recognised a molecule a change in cellular activity is brought about

Question 4

what is the Kd constant and what does it describe

Answer 4

• it is the equilibrium dissociation constant
• it describes the affinity of a drug
• it is defined as the molar concentration of a drug required to occupy 50% of the receptors at equilibrium
• therefore high affinity drugs have low Kd

Question 5

what is BMAX

Answer 5

the total number of receptors expressed in the same units as the y values

Question 6

how does binding relate to the laws of mass action

Answer 6

binding follows the laws of mass action, with most receptor binding interactions being concentration dependent

Question 7

what equation relates receptor occupancy to drug concentration

Answer 7

the hill langmuir equation

Question 8

what are mechanisms of drug antagonism

Answer 8

1. chemical- interaction of two drugs in solution
2. pharmokinetic- one drug affects the absorption, metabolism or excretion of the other
3. competitive antagonism- both drugs bind to the same receptor
4. non-competitve antagonism- the antagonist interrupts the receptor
5. physiologiccal antagonism- two agents producing opposite physiological affects

Question 9

what does EC50 represent

Answer 9

• the efficacy of a molecule

- the drug concentration needed for an amount of receptor binding

Question 10

what is sensitisation?

Answer 10

• increased senstivity to an agonist drug
• occurs after prolonged exposure to an antagonist
• usually reflects an increase in post synaptic receptors

Question 11

what is translocation of a drug?

Answer 11

absorption and distribution

Question 12

what is transformation of a drug?

Answer 12

metabolism and elimination

Question 13

what are the 2 ways drug molecules move around the body?

Answer 13

1. bulk flow transfer (in the blood)

2. diffusional transfer across lipid bilayer

Question 14

how to the chemical properties of a drug affect its transfer

Answer 14

• the chemical properties do not have an impact on the bulk flow transfer
• however they do have an impact on the diffusional transfer

Question 15

what are the 3 routes that drugs can cross lipid bilayers

Answer 15

1. passive diffusion
2. facillitated diffusion (aqueous channel)
3. carrier protein (Active)

Question 16

what is the rate of passive diffusion across the lipid bilayer determined by

Answer 16

lipid solubility

Question 17

what is the PH partition

Answer 17

• most drugs are weak acids or bases
• acids are protonated and bases are unprotonated
• often only the uncharged bases can diffuse across the lipid bilayer
• this can lead to PH accumulation of either side of the membrane

Question 18

what is drug absorption from the gut dependent on?

Answer 18

1. degree of lipid solubility
2. ph range
3. intrinsic gastrointestinal properties
4. drug particle size

Question 19

what is bioavailability?

Answer 19

the fraction of ingested dose of a drug that gains access to systemic circulation

if it is low this may be because absorption is incomplete or the drug is metabolised

Question 20

what is the blood brain barrier?

Answer 20

a continous layer of endothelial cells joined by tight junctions
this means that the brain is innaccessible to many drugs with low lipid solubility

Question 21

what is the effect of inflammation on the blood brain barrier

Answer 21

• inflammation can disrupt the BBB

- this can cause some parts of the BBB to become leaky

Question 22

what area of the brain is naturally leaky?

Answer 22

the chemoreceptor trigger zone

Question 23

what are the major compartments in which drug molecules distribute?

Answer 23

plasma
interstitial fluid
intracellular fluid
transcellular fluid
fats

Question 24

what is the volume of distribution?

Answer 24

the volume of plasma that would contain the total body content of the drug at a concentration equal to that in plasma

Question 25

where do lipid insoluble drugs tend to reside

Answer 25

in the plasma and interstitial fluids, most do not enter the brain

Question 26

what are 3 drug delivery systems that can enhance distribution?

Answer 26

1. pro drugs- the parent compound is absorbed and then metabolised to release the active agent 2. liposome packages 3. implantable devices to allow for direct delivery

Question 27

what is drug elimination and what are the two mechanisms by which it occurs?

Answer 27

- the ireversible loss of a drug from the body 1. metabolism 2. excretion

Question 28

what are phase 1 and phase 2 reactions of drug metabolism

Answer 28

phase 1- oxidation, reduction, hydrolysis - this is usually mediated by cytochrome P450 enzymes in the liver - its worth noting that the products of this may be chemically reactive, pharmacologically active or toxic phase 2- conjugation of a reactive group to form inactive and excretable products

Question 29

what is pharmacokinetics

Answer 29

the relatioship between time course of drug adminastration and the drug concentration in different parts of the body

Question 30

what is the Tmax?

Answer 30

the time to maximum effect at the plasma level

Question 31

what is the Cmax?

Answer 31

the maximum plasma level for a given dose of a drug

Question 32

what model does the clearing of drugs from the body usually follow?

Answer 32

- an exponential decay model | - matching the plasma half life (t1/2) of the drug

Question 33

what is the plasma half life (t1/2) proportional to

Answer 33

- it is proportional to the volume of distribution | - it is inversely proportional to the rate of clearance (Kexcretion or Kmetabolism)

Question 34

what are the different levels of drug effect measurement?

Answer 34

- large scale measures e.g epidemiology - clinical trials and clinical pharmacology - physiological, cellular and molecular in drug development

Question 35

what is a bioassay?

Answer 35

the measurement of the potency of a drug or unkown mediator from the magnitute of the biological effect it induces - it involves comparisons of a standard and dose response to estimate potency - this biological effect requires measurement over many levels

Question 36

what types of valitidy from animal drug experiments are we looking for

Answer 36

- CONSTRUCT VALIDITY- the animal model shows the same biological dysfunction - FACE VALIDITY- the model shows strong analogies to the same endophenotypes in humans - PREDICTIVE VALIDITY- the model demonstrates an analagous response to treatment that prevents or reverses symptoms in the human disease

Question 37

in what ways do rodent models have high and low construct validity

Answer 37

PROS - rodent models have high genetic conservation. We can use rodent models with the same genetic mutations as humans - the organizatio, circuitry and brain structure of rodents translates suprisingly well to humans CONS - human brain development is longer and more complex, the same gene may therefore function differently in rodents vs. humans - the brain regions processing emotion and cognition are larger and more complex in humans - conncectivity may be more complex in humans

Question 38

what are the considerations when evaluating face validity in rodent models

Answer 38

- the endophenotype in rodents may not look like the human disease - this is especially the case or behaviour - we can look at dimensions of behaviour where the brain circuitry is well conserved e.g the stress and fear response

Question 39

what is an endophenotype

Answer 39

Endophenotypes are measurable components (e.g., neurophysiological, biochemical, neuroanatomical, cognitive or neuropsychological) that exist between the behavioral symptoms of a disease and distal genotype

Question 40

what should you consider with the predictive validity of rodent drug models

Answer 40

- rodents often behave in a similar way to psychoactive drugs - however cross species measures of drug response may differ - rodents may show differences in distribution, metabolism and pharmokinetics

Question 41

what are the features of a successful animal model?

Answer 41

- not pretend to model the whole illness but focus on specific dimensions or risk factors - acheive a better understanding of the biology underlying these, ensure our understanding is actionable for translation

Question 42

what are two distinct categories of human bioassays?

Answer 42

1. pharmacology with healthy volunteers | 2. Clinical trials with healthy control volunteers and then patient group volunteers

Question 43

what does clinical pharmacology aim to check?

Answer 43

target engagement, pharmacokinetics, safety

Question 44

how do clinical trials avoid bias?

Answer 44

they are controlled, randomized and double blind

Question 45

what do the different phases of clinical trials check?

Answer 45

phase 1- safety phase 2- safety/efficacy phase 3- efficacy