OPTOM 345 Flashcards
What is a drug
Chemical substance that produces a biological effect and interacts with Receptors, Ion channels, Carriers and Enzymes
What is Pharmacokinetics
How drug moves in body and how well it reaches parts of the body
What is pharmacodynamics
The effect the drug has on the body
Name the axis on a Dose Response Curve
X axis = Drug Concentration
Y axis = Drug Response
What does a dose response curve tell us
Measures how well a drug binds to a receptor, and the point where it reaches maximum effect
What is maximum effect
The point where increasing drug concentration does not increase drug response
What is affinity
Drug interaction strength at the target site
What is Potency
Drug concentration needed for 50% maximal effect
Efficacy
The ability of the drug to produce a response once bound to a target site
When to use Bioequivalence
Used to determine which drug is better to use when compared to each other
How do we compare drugs
Risk v Benefit ratio
How does the risk v benefit ratio work
Uses the Toxic dose and Effective dose to calculate a therapeutic index
How to calculate the therapeutic index
TI = TD50 / ED50
The higher TI the safer the drug
What is the toxic dose
The toxic dose in 50% of the population
What is the effective dose
The effective dose in 50% of the population
What is the Therapeutic window
The dose range where the drug effect has minimal adverse effect
Different between specificity and selectivity
Specificity is where the drug targets in the body
Selectivity is how exclusive the drug is to certain receptors
Important of binding specificity
A drug must be specific for certain cells and tissues but in reality, no drug is completely specific.
Importance of binding selectivity
important for drugs to bind exclusively to certain receptors to reduce unwanted effects
What happens if we increase drug dose
It decreases drug specificity resulting in adverse effects
How do we make a drug more selective
By changing its size or having stereoisomerism where a drug has a different geometric structure so it will be selective to certain receptors increasing the potency for that receptor
What do Bioassays do
compare new drugs to existing drugs
What are the requirements for an assay
Should be reproducible, reliable indicator of its response and able to effectively comapre two or more drugs/formulations
Describe In-Vitro, Ex-Vivo and In-Vivo
In-vitro = Outside of body in Petri dish
Ex-vivo = Extract tissue from living organism
In-vivo = Perform study inside living organism
Explain the Transgenic animal models
They are use genetic manioulation to inactivate individual genes, mutate genes to pathological genotypes, introduce new genes and to over express genes such as parkinsons with increased synuclein expression
What is a requirement for animal models
Should be similar to human disease model where the pathophysiological phenotypes, causation and response to the treatment are similar
Why do many drugs fail clinical trials
Due to lack of clinical efficacy unmanageable toxicity, poor drug like properties, lack of commercial interest and poor strategic planning
What are clinical trials
Research studies that see if a medical strategy, treatment or device is safe and effective for humans
Briefly explain the procedures in clinical testing
Preclinical testing, 4 phases of clinical research and final data analysis with followups
What occurs in Phase 1 trial
Determine drug safety in healthy volunteers
What occurs in phase 2 trials
Pharmaco-kinetic/dynamic studies in healthy volunteers. There is also intital assessment of efficacy and continued assessment of safety in volunteers
What occurs in phase 3 trials
Assess longer-yerm efficacy and safety of the drug in the patient
What occurs in phase 4 trials
Post-marketing surveillance, ongoing assessment of safety and the likelihood of approval
What is a biomarker
Something that is objectively measured and evaluated as an indicator of normal biological process, pathogenic process or pharcologic response to a therapeuti intervention
What do biomarkers do
Indicate the prognosis of disease and monitor clinical response to an intervention
What do we measure in Bioassays when comparing drugs
The drugs efficacy, not potency
Strategies to avoid bias in drug testing
Controlled, Randomised and Double-blind testing
What is controlled testing
Compare A with B ( B is a control or placebo )
What is randomised testing
Patients assigned to group A or B randomly
What is double blind testing
Common in Phase 1-3 and sometimes 4, here neither participants or researchers know which participants belong to the control or test group. This minimises subjective bias
What is simple randomisation
When patients are assigned randomly to each group
What is stratified randomisation
When you divide participants into smaller group, then randomise each group with both the treatments and allocated similar overall demographics
What is Pharmacogenomics
Study the role of genes in drug response
Why do we do Pharmacogenomics
People of different ethnics have different genetic backgrounds that changes how the drug is metabolised and varies its efficacy
How to calculate Risk and Odds in a test
Risk for patients = Number of affected divided by the total number of paticipants
Odds for patients = Number of affected divided by the difference between the total number of participants and the affected
How to calculate relative risk ( RR )
Ratio of risk in treatment group and the risk in the control
How to calculate relative risk reduction ( RRR )
1 - RR
How to calculate Absolute Risk Reduction ( ARR )
Control risk - Treatment risk
How to calculate the number needed to treat ( NNT )
1/ARR
What is the number needed to treat ( NNT )
Number of people needed to treat to show the given effect of the drug
Lower NNT is more valuable
A drug that halves a mortality from 50% to 25% is more valuable than a drug that halves a mortality from 5% to 2.5%
What is the null hypothesis
States that there is no effect between comparisons
What is the P-Value
The probability that the null hypothesis is true. A statistically signficant P value is a value less that 0.05. When significant, we can reject the null hypothesis ( Ho )
What is the confidence interval
Range of values where the true parameter falls in, usually at 95%
What is Type 1 error
Rejection of a null hypothesis when it is true in the population
What is Type 2 error
Accepting null hypothesis when it is false in the population
What is power in statistics
The probability of detecting a difference when present where a larger sample size gives more power
What is the goal in a statistical tests regarding the number of participants
Recruit the minimum number of subjects to reject the null hypothesis ( usually 80% power )
How to calculate the power of a study
1 - Beta
Beta is the probability of a type 2 error
What does sample size of a study depend on
Power, magnitude of the difference you want to see and the statistical tests you plan to run
What are the 4 main targets for drugs
Receptors, Ion Channels, Carriers and Enzymes
Function of a receptor
Recognise and respond to endogenous chemical signals known as ligands and are found on cell surfaces
What happens when a receptor is bound
It activates and causes downstream effects
How do GPCRs work
Ligand binds giving conformational change in the GPCR causing the Alpha subunit to exchange GDP for GTP resulting in the alpha subunit and the beta-gamma dimer to dissociate and regulates the target proteins. Then the GTP hydrolyses to GDP and the cycle continues
How do Receptor Tyrosine Kinases work ( RTKs )
These have two receptors, when both are bound they come together forming one receptor causing the tyrosine residue to phosphorylate causing downstream effects
Name the 4 receptor types
Ligand gates ion channels, GPCRs, Kinase linked receptor and Nuclear receptors
How quickly do Ligand gated ion channels act
Milliseconds
How quickly do GPCRs act
Seconds
How quickly do Kinase linked receptors act
Hours
How quickly do nuclear receptors act
Hours
Why do nuclear receptors take so long to act
They are intracellular receptors so the ligand has to diffuse into the cell membrane to bind to the receptor
Function of ligand gated ion channels
When bound, the gate open or closes which either increases or decreases permeability to select ions. When membrane potential is changed by depolarisation or hyperpolarisation
Function of GPCRs
In eurkaryotes with 7 transmembrane domains coupled with G proteins which bind to GDP or GTP. These are also Muscarinic ACH receptors. It is for therapeutic drugs and causes downstream activation of other membrane targets
Structure of GPCRs
These are heterotrimeric so it has 3 subunits known as alpha, beta and gamma subunits which interact with GDP and GTP
Function of Kinase Linked Receptors
Includes RTKs, and Cytokine receptors. When bound is cuases phosphorylation of the intracellular domain and signals downstream processes
Also mediates growth factors, cytokines and hormones. The effects are exerted at the gene transcirption level and controls cell division, growth, differentiation, inflammation, immune responses, tissue repair and apoptosis
Function of Nuclear receptors
Found in cytoplasm ( Class 1 ), Nucleus ( Class 2 ) and Endocrine system ( Hybrid class ) known as steroid receptors
Activated by cell-permeating or lipophilic molecules and leads to the signalling cascades affecting gene expression
What is affinity and what does it depend on
The tendency of the drug to bind to a receptor, it depends on the Van der waals forces, hydrophobic, ionic, hydrogen and covalents
What is an agonist
acts as ligand and can activate or deactivate receptors
What is an antagonist
Acts as ligand and binds to receptor and causes no change in activity as it stops other molecules binding to the receptor but does not interact with active site
What is a partial agonist
Has an intermediate efficacy when bound even when all receptors are occupied
What are full agonists
Has full efficacy
What are inverse agonists
Drug that shows selectivity for resting states instead of activation of a receptor
What are antagonists
Have affinity but zero efficacy
Classes of Antagonists
Competitive reversible, Competitive irreversible and Non-competitive
What are competitive reversible antagonists and its effect on the dose respone curve
Competes with agonist, whichever concentration is higher will be favoured
Curve shifts to the right as more agonists needed to displace antagonist
What are competitive irreversible antagonists and its effect on the dose response curve
Competes with agnostic but has higher affinity for receptor so it requires new receptors to reverse its effects. Increasing concentration of agonist does not reverse its effect
Shifts curve to the right and reduces efficacy on the curve
What is a non-competitive antagonistm and its effect on the dose response curve
Does not bind to active site, binds to allosteric site
Shifts curve to the right and decreases efficacy
What are secondary messengers
Have receptors for ligand gated ion channels. When bound it causes a conformational change in the channel and ions move down their concentration gradients causing hyper or a depolarised state giving a cellular effect
Name the two ligand gated ion channels
Nicotinic acetylcholine receptor and the GABA receptor
What is the Nicotinic Acetylcholine receptor
ACH or Nicotine bnids giving influx of sodium which depolarises the cells increasing the chance of an action potential
What are GABA receptors
GABA binds causing influx of chloride ions into the cell and hyperpolarises the membrane reducing chance of an action potential