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brain form and function > topic 6 (neuroactive drugs) > Flashcards

topic 6 (neuroactive drugs) Flashcards

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1
Q

what is a drug?

A

a chemical which affects physiological function in some way

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2
Q

what are the main target proteins of drugs

A

enzymes
ion channels
receptors
carrier proteins

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3
Q

what are the 2 main functions of receptors?

A
  1. recognition or detection of extracellular molecules

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

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4
Q

what is the Kd constant and what does it describe

A
  • 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
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5
Q

what is BMAX

A

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

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6
Q

how does binding relate to the laws of mass action

A

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

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7
Q

what equation relates receptor occupancy to drug concentration

A

the hill langmuir equation

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8
Q

what are mechanisms of drug antagonism

A
  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
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9
Q

what does EC50 represent

A
  • the efficacy of a molecule

- the drug concentration needed for an amount of receptor binding

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10
Q

what is sensitisation?

A
  • increased senstivity to an agonist drug
  • occurs after prolonged exposure to an antagonist
  • usually reflects an increase in post synaptic receptors
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11
Q

what is translocation of a drug?

A

absorption and distribution

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12
Q

what is transformation of a drug?

A

metabolism and elimination

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13
Q

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

A
  1. bulk flow transfer (in the blood)

2. diffusional transfer across lipid bilayer

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14
Q

how to the chemical properties of a drug affect its transfer

A
  • the chemical properties do not have an impact on the bulk flow transfer
  • however they do have an impact on the diffusional transfer
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15
Q

what are the 3 routes that drugs can cross lipid bilayers

A
  1. passive diffusion
  2. facillitated diffusion (aqueous channel)
  3. carrier protein (Active)
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16
Q

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

A

lipid solubility

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17
Q

what is the PH partition

A
  • 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
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18
Q

what is drug absorption from the gut dependent on?

A
  1. degree of lipid solubility
  2. ph range
  3. intrinsic gastrointestinal properties
  4. drug particle size
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19
Q

what is bioavailability?

A

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

20
Q

what is the blood brain barrier?

A

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

21
Q

what is the effect of inflammation on the blood brain barrier

A
  • inflammation can disrupt the BBB

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

22
Q

what area of the brain is naturally leaky?

A

the chemoreceptor trigger zone

23
Q

what are the major compartments in which drug molecules distribute?

A 
plasma
interstitial fluid
intracellular fluid
transcellular fluid
fats
24
Q

what is the volume of distribution?

A

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

25
Q

where do lipid insoluble drugs tend to reside

A

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

26
Q

what are 3 drug delivery systems that can enhance distribution?

A
  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
27
Q

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

A
  • the ireversible loss of a drug from the body
  1. metabolism
  2. excretion
28
Q

what are phase 1 and phase 2 reactions of drug metabolism

A

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

29
Q

what is pharmacokinetics

A

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

30
Q

what is the Tmax?

A

the time to maximum effect at the plasma level

31
Q

what is the Cmax?

A

the maximum plasma level for a given dose of a drug

32
Q

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

A
  • an exponential decay model

- matching the plasma half life (t1/2) of the drug

33
Q

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

A
  • it is proportional to the volume of distribution

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

34
Q

what are the different levels of drug effect measurement?

A
  • large scale measures e.g epidemiology
  • clinical trials and clinical pharmacology
  • physiological, cellular and molecular in drug development
35
Q

what is a bioassay?

A

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
36
Q

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

A
  • 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
37
Q

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

A

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
38
Q

what are the considerations when evaluating face validity in rodent models

A
  • 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
39
Q

what is an endophenotype

A

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

40
Q

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

A
  • 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
41
Q

what are the features of a successful animal model?

A
  • 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
42
Q

what are two distinct categories of human bioassays?

A
  1. pharmacology with healthy volunteers

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

43
Q

what does clinical pharmacology aim to check?

A

target engagement, pharmacokinetics, safety

44
Q

how do clinical trials avoid bias?

A

they are controlled, randomized and double blind

45
Q

what do the different phases of clinical trials check?

A

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

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