Receptor theory and pharmacokinetics Flashcards
What is efficacy
A measure of a single agonist receptor complex’s ability to generate a response
What is the efficacy of an antagnoist
0
What is the efficacy of an agnonist
1
What is the concentration of a dug and the size of the response measured using
A bioassay using isolated cells
What does EC50 show
Defines the relationship between the drug and the response in that tissue
What is receptor reserve
100% of receptors don’t need to be occupied to give maximal response
Why is receptor reserve useful
Because the amount of hormones needed can be much lower
Which direction do spare receptors shift the response curve to
To the left of the binding curve
What will the efficacy of the agonist for its receptor influence
It will influence how big and how well it can produce responses
What is the hill slope equation
Response = max[Xa]^n/ ([Xa)n+[EC50]^n)
n is the hill slope factor, measure of the number of molecules that need to bind to a receptor to activate it
What does the drug with the highest potency require
The lowest concentration to produce 50% maximal response
What does the location of the concentration response curve depend on
Affinity, efficacy and spare receptors
What do agonists with different efficacies produce
Different maximal responses
What efficacy does a partial agonist have
between 0-1
What are partial agonists not able to produce
Not able to produce the same maximum response as a full agonist
What does a partial agonist need to achieve to produce the maximum response that it’s capable of?
100% occupancy
What are equal for partial agonists and why is this desirable
KD and EC50. You can’t get a maximum response for partial agonists so you can’t overdose
What 3 properties determine the effect of a drug in a living system
Specificity, affinity and efficacy
Definition of an antagonist
A drug that prevents the response of an agonist
What 5 classes can antagonism be divided into
Chemical, pharmacokinetic, physiological, non-competitive and competitive
What happens in chemical antagonism
Substances in a solution combine so that the effects of the active drug are lost
Example of chemical antagonism
Inactivation of heavy metals reduced with the addition of a chelating agent
What happens in pharmacokinetic antagonism
Refers to the processes that control the concentration of drugs in the body
Example of pharmacokinetic antagonism
some antibiotics stimulate the metabolism of warfarin so reducing its effective concentration in the blood stream
3 kinds of change as a result of pharmacokinetic antagonism
Change in drug metabolism, changes in excretion of an agonist, changes in absorption
What happens in physiological antagonism
The interaction of two drugs with opposing actions on the body
Example of physiological antagonism
Noradrenaline and adrenaline acting in the opposite way to histamine
What happens in non-competitive antagonism and how
Stop the agonist from having its signalling function by indirectly inhibiting the function of the signalling molecule or by binding somewhere different
What is a competitive antagonist
A drug that binds to a receptor to form a complex. It competes with an agonist for occupancy
How does competitive antagonism work
It enters the same site as the agonist, then stabilises the structure of the protein in a way that the activity is not induced
What is competitive antagonism dictated by
By the balance of the forward reaction and reverse reaction
What happens if we increase the concentration of the agonist in terms of competitive antagonism
We will increase the probability that an agonist will bind to the receptor compared to an antagonist
What happens to the concentration response curve with increasing levels of competitive antagonist
the further the shift to the right
What is dose ratio
How many more times agonist is needed in the presence of an antagonist
How do we calculate dose ratio
Concentration of agonist in presence of antagonist/ concentration of agonist in absence of antagonist
What does Schild analysis reveal
The affinity of the competitive antagonist for that receptor. It determines the affinity constant
What kind of scale/ graph is a Schild graph
Linear
What does the Y axis reveal on a Schild graph
Log value of the dose ratio - 1
What does the X axis reveal on a Schild graph
The log value of the concentration of antagonist that was added
What can we determine from the intercept of a Schild plot
The affinity
How do we calculate Pa2
The intercept number multiplied by -1
What does a larger PA2 value show
A higher affinity, more potency
What do partial agonists behave like and which way do they shift the concentration response curve
Competitive antagonists and shift the curve to the right
What is the difference between a partial agonist and a competitive antagonist
Partial agonists can induce some signalling in the absence of full agonists. Competitive antagonists don’t induce any signalling
How do irreversible competitive antagonists work
They bind into the same sites as the agonists, but a chemical reaction occurs which creates a permanent bond
How do we get rid of irreversible competitive antagonists
By creating new receptors
What is pharmacodynamics based on
Based on the mechanism of action and effects on cellular functions e.g. receptors, ion channels, enzymes, transporters
What do the physiochemical properties of drugs affect
Affinity, efficacy and potency
In pharmacokinetics, what do the physiochemical properties have an impact on
Absorption, diffusion, metabolism and excretion (ADME)
What is the main way drugs are delivered around the body
Bulk flow in plasma
What does bulk flow depend on
The cardiovascular system
What’s the first factor we need to consider in terms of drug absorption
How they diffuse across the plasma membrane
What is the diffusion coefficient and what does it mean
1/ sqr of its molecular weight.
The larger the molecular weight, the slower its diffusion
What are the 4 main mechanisms drugs have to get through the plasma membrane
Diffusion through lipids, diffusion through aqueous pore, carriers/ transport proteins, bulk flow by pinocytosis
What is lipid solubility defined by
Partition coefficient
What is the partition coefficient
How readily a molecule dissolves in water versus oil
What is diffusivity defined by
Diffusion coefficient
Why are drugs weak acids/ bases
They readily form salts so its easier to package them into a tablet/ liquid
What does the Henderson Hussle Puc equation describe
The relationship between the charged and unchanged form of a weak acid or base
What is the Henderson Hussle Puc equation
pKa= pH + log10(HA/A-)
What is the pKA value of weak acids
below 7
What is the intravenous route of administration
Intravenous route, injecting straight in, used in emergancy situations
What is the intramuscular injection used for
Administering molecules that are protein in nature e.g. insulin
What is the intrathecal route of administration
Direct lumber puncture into the cerebral spinal fluid so it has rapid action to the central nervous system.
What is the inhalation route of administration
Used and restricted to drugs localised in the lung where the molecule is a gas
What is the percutaneous route of administration
Administering the drug directly through the skin, avoids the metabolism in the gut
What is the percutaneous route of administration
Administering the drug directly through the skin, avoids the metabolism in the gut
What is the oral route of administration and what do you need to consider
Oral is swallowing tablet. Need to consider the particle size
What is bioavailability
Only a fraction of ingested dose gains access to circulation
What are the overall factors affecting absorption
Site/ method of administration, molecular eight, lipid solubility, pH and ionization
What % of body weight does plasma make up
4.5%
What % of body weight does interstitial fluid make up
16%
What % of body weight does lymph make up
1-2%
What % of body weight does intracellular fluid make up
30-40%
What % of body weight does transcellular fluid make up
2.5%
What % of body weight does fat make up
20%
What is the volume of distribution of a drug
A measure of the volume of fluid that would be required to hold the amount of drug in the body as measured in the plasma
What is the volume of distribution equation
Vd= Dose/ CP
Which drugs have a high volume of distribution
Propranolol and ethanol
Which drugs have a low volume of distribution
Herapin
What is meningitis
The breakdown of tight junctions in the brain caused by a bacterial infection
How can we treat meningitis
IV penicillin
What other factors influence drug distribution and example
Binding to plasma proteins e.g. albumin binds mainly acidic and highly charged proteins
What does body fat act as
Acts as a reservoir on the drug causing the drug to stay in the body for longer
Where does metabolism take place
In the liver
What is the phase 1 reaction of metabolism
Catabolic reaction- changes the composition of the drug to produce a more active compound
What is the phase 2 reaction of metabolism
Anabolic reaction - involves the conjugation of large molecules with a more reactive compound to produce inactive product
What are the enzymes involved in metabolism
Microsomal
What are the largest family of microsomal enzymes
Cytochrome P450
What are prodrugs
When the molecule in the phase 1 reaction may still have activity
What are the factors influencing drug metabolism
Route of administration
What is the most common way of eliminating drugs
Metabolism of the liver
What occurs during the elimination of aspirin
1: Hydroxylation reaction at the acetyl group carried out by cytochrome p450 enzyme
2: Salicylic acid is conjugated with glucuronide which is transported through the body via bulk flow
How many genes in the human genome can code for the p450 enzymes
57
What can you not take while taking warfarin and why
Grape fruit juice because it inhibits the activity of the enzyme involved in warfarin
What do different isoforms of P450 do
They react with different drugs
What do inducers of P450 do
Increase drug metabolism and therefore lower the plasma concentrations of the drug to the point where it can’t achieve therapeutic concentrations
Types of renal excretion
Glomerular filtration, active tubular secretion, passive diffusion
Is diazepam cleared quickly or slowly and why
Highly lipophilic, so active metabolites are cleared slowly
