topic 6 (neuroactive drugs) Flashcards
what is a drug?
a chemical which affects physiological function in some way
what are the main target proteins of drugs
enzymes
ion channels
receptors
carrier proteins
what are the 2 main functions of receptors?
- recognition or detection of extracellular molecules
2. Transduction, where having recognised a molecule a change in cellular activity is brought about
what is the Kd constant and what does it describe
- 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
what is BMAX
the total number of receptors expressed in the same units as the y values
how does binding relate to the laws of mass action
binding follows the laws of mass action, with most receptor binding interactions being concentration dependent
what equation relates receptor occupancy to drug concentration
the hill langmuir equation
what are mechanisms of drug antagonism
- chemical- interaction of two drugs in solution
- pharmokinetic- one drug affects the absorption, metabolism or excretion of the other
- competitive antagonism- both drugs bind to the same receptor
- non-competitve antagonism- the antagonist interrupts the receptor
- physiologiccal antagonism- two agents producing opposite physiological affects
what does EC50 represent
- the efficacy of a molecule
- the drug concentration needed for an amount of receptor binding
what is sensitisation?
- increased senstivity to an agonist drug
- occurs after prolonged exposure to an antagonist
- usually reflects an increase in post synaptic receptors
what is translocation of a drug?
absorption and distribution
what is transformation of a drug?
metabolism and elimination
what are the 2 ways drug molecules move around the body?
- bulk flow transfer (in the blood)
2. diffusional transfer across lipid bilayer
how to the chemical properties of a drug affect its transfer
- the chemical properties do not have an impact on the bulk flow transfer
- however they do have an impact on the diffusional transfer
what are the 3 routes that drugs can cross lipid bilayers
- passive diffusion
- facillitated diffusion (aqueous channel)
- carrier protein (Active)
what is the rate of passive diffusion across the lipid bilayer determined by
lipid solubility
what is the PH partition
- 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
what is drug absorption from the gut dependent on?
- degree of lipid solubility
- ph range
- intrinsic gastrointestinal properties
- drug particle size
what is bioavailability?
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
what is the blood brain barrier?
a continous layer of endothelial cells joined by tight junctions
this means that the brain is innaccessible to many drugs with low lipid solubility
what is the effect of inflammation on the blood brain barrier
- inflammation can disrupt the BBB
- this can cause some parts of the BBB to become leaky
what area of the brain is naturally leaky?
the chemoreceptor trigger zone
what are the major compartments in which drug molecules distribute?
plasma interstitial fluid intracellular fluid transcellular fluid fats
what is the volume of distribution?
the volume of plasma that would contain the total body content of the drug at a concentration equal to that in plasma
where do lipid insoluble drugs tend to reside
in the plasma and interstitial fluids, most do not enter the brain
what are 3 drug delivery systems that can enhance distribution?
- pro drugs- the parent compound is absorbed and then metabolised to release the active agent
- liposome packages
- implantable devices to allow for direct delivery
what is drug elimination and what are the two mechanisms by which it occurs?
- the ireversible loss of a drug from the body
- metabolism
- excretion
what are phase 1 and phase 2 reactions of drug metabolism
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
what is pharmacokinetics
the relatioship between time course of drug adminastration and the drug concentration in different parts of the body
what is the Tmax?
the time to maximum effect at the plasma level
what is the Cmax?
the maximum plasma level for a given dose of a drug
what model does the clearing of drugs from the body usually follow?
- an exponential decay model
- matching the plasma half life (t1/2) of the drug
what is the plasma half life (t1/2) proportional to
- it is proportional to the volume of distribution
- it is inversely proportional to the rate of clearance (Kexcretion or Kmetabolism)
what are the different levels of drug effect measurement?
- large scale measures e.g epidemiology
- clinical trials and clinical pharmacology
- physiological, cellular and molecular in drug development
what is a bioassay?
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
what types of valitidy from animal drug experiments are we looking for
- 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
in what ways do rodent models have high and low construct validity
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
what are the considerations when evaluating face validity in rodent models
- 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
what is an endophenotype
Endophenotypes are measurable components (e.g., neurophysiological, biochemical, neuroanatomical, cognitive or neuropsychological) that exist between the behavioral symptoms of a disease and distal genotype
what should you consider with the predictive validity of rodent drug models
- 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
what are the features of a successful animal model?
- 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
what are two distinct categories of human bioassays?
- pharmacology with healthy volunteers
2. Clinical trials with healthy control volunteers and then patient group volunteers
what does clinical pharmacology aim to check?
target engagement, pharmacokinetics, safety
how do clinical trials avoid bias?
they are controlled, randomized and double blind
what do the different phases of clinical trials check?
phase 1- safety
phase 2- safety/efficacy
phase 3- efficacy
