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Summary study guide drug discovery and development final year exam
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Lecture list including learning outcomes2022-23
The Drug Discovery & Development Pipeline Parts 1 and 2;
• Recall the stages of the drug discovery and development pipeline
• Describe the purpose of each stage.
Very costly, very leaky – inefficient not many drugs pass, slow, 2 dimensional – could have
to stop turn back drug process
1. Therapeutic concept
a. Can it be done, tested and sold?
b. Will it make money? Better than the competitions?
c. Research, development and commercial view
d. Mechanisms of action of existing drugs, info from genes, analysis of pathogen
– 3 ways to select target
e. Target validation, then drug but not always
2. Lead finding
a. Molecular target known
b. Refining the desirable drug and improving specificity
c. Strategies like virtual screening, natural ligands, known drugs with overlapping
activity etc
3. Lead optimization
a. Look at what makes a drug better
a. Physical properties- pkA, lipid solubility (octanol vs aqueous non ionized
form) – log P
b. Pharmacodynamic properties – affinity, specificity, efficacy
c. Pharmacokinetics properties – stability of drug, absorbance into blood
stream (through gut wall) , volume of distribution, metabolism
- Have to keep drug conc. between therapeutic window for maximum effectiveness
and no adverse effects caused
b. Log D – for ionizable drugs – distribution coefficient – all forms of drug in
octonal vs aqueous
4. Pre-clinical development
a. Formal safety testing to
create safety window –
define maximum
tolerated dose
b. Assessment of toxicity
c. Broader and more
speculative specificity
, 5. Clinical development
a. Market authorisation – reg authorities
b. Benefit
c. Risk – adverse effects
Clinical trials:
a. Phase 1: exploratory in human
- Safety and tolerability
- Small numbers of volunteers
- Placebo controlled
b. Phase 2 – efficacy
- exclusion and inclusion criteria of patients set up; patients divided into groups
- Control and treatment group- has to be random
- 50-200 patients
- Exploratory still or confirmatory 200-500 patients where you can confirm dose and
treatment
- 1 year
c. Phase 3 – confirmatory
- Full scale evaluation of how safe and effective it is
- 2000-10000 patients
- Lasts several years
- Once complete can apply for registration
d. Phase 4 – post marketing surveillance
- Drug licensed and on the market
- Monitor consequences of increasing exposure
6. Regulatory approval
a. a contract between health authority, FDA, EMEA, MHRA
a. protects public health and safety
b. pharmaceutical company
a. permission to market drug for specific indication
b. owns document used for assessment
c. Collects compiles and evaluates data
c. Regulatory document
a. Describes quality, toxicology, pharmacokinetics and dynamics, efficacy
b. In standardized form
c. If successful with an approvable letter
- In relevant territory
Receptors as drug targets – measuring agonist and antagonist activity
• Distinguish between pharmacology and homeopathy
1. Homeopathy
a. Plant based
b. Myth based
c. Alternative medicine
d. No actual medicine
2. Pharmacology
a. Drug composition
b. Mechanisms of action on receptors and whole organisms
, c. Binding of drugs to receptors
• Define the terms “drug” and “receptor”
1. Drug – chemical substance of known structure other than a nutrient which when
administered to a living organism produces a biological effect, stereo-specificity
2. Receptor- pharmacological meaning from its physiological role in cell signalling
that involves recognition and transduction (produce conformational changes)
a. Interact with agonists
b. Drug binding site
c. Drug leaves receptor unaltered
d. gpcrs, ligand gated, intrinsic enzyme receptors and dna binding receptors
• Identify the properties of an agonist (affinity & efficacy) and how they are measured
Two elements of agonist
• Bind to receptor - how good is it at binding – affinity or kA
• k+1 = how quickly it binds to receptor
• k-1 = how quickly it detaches
• Kd = k-1/ k+1
• Bmax=number of Receptors, B= number of receptors bound
• Activate receptor - how good is it at activating - efficacy
• Describe the types of agonist
a. Types:
Partial – but has affinity
• Distinguish an antagonist from an agonist
a. Agonist: Elicits a response by binding to receptor, has both affinity (kA) and efficacy
which can be quantified
b. Antagonist: a type of receptor ligand or drug stops or slows a biological response by
binding to and blocking a receptor
• Describe what a Schild plot measures
It measures pA2 – 50% of receptors bound by antagonist, shift agonist
concentration 2-fold to the right
• Explain which parameters alter the pA2 and which do not.
It is independent of the agonist used
Does not change with tissue location for each receptor
It DOES change with different antagonists
It DOES change with different receptors
• Explain why competitive antagonists are better at defining receptors than agonists
, • Explain why different types of antagonist have different effects on agonist responses
1. Competitive reversible antagonist
• affinity but zero efficacy but competes with agonist for binding site
• Can be overcome by adding agonist
• Parallel shift
2. Competitive irreversible antagonist
• Affinity but zero efficacy
• Permanently bound- can´t be overcome
3. Non-competitive antagonist
• Not competing with the agonist but agonist can’t do anything
because it blocks the channel
• appears downstream from binding site
Pharmacokinetics in drug development
• Understand the principles of ADME and the Pharmacokinetics (PK) of drugs
Pharmacokinetics: what the body does to a drug
ADME - journey of drug through the body
1. absorption – site of administration to site of action
• first order process – across first barrier
• proportional to conc of drug
• Needs to retain sufficiently lipophilic to permeate through membrane
• be water soluble enough to dissolve in plasma
• If you changhe pH you get diff rates of absorption in diff parts of body
• If you want it to absorb in stomach drug needs to be soluble and acidic in
pH
2. distribution – drug moves from bloodstream into peripheral tissues
• Quantified by volume of distribution – ratio between amount of drug in
body and amount of drug in plasma
• It’s not a real volume – eg its just telling u you can find 10% of blood in
plasma and 90% somewhere else
• YOU CANT SAY WHERE ELSE IT WENT- YOU ONLY KNOW WHERE ITS NOT -
AKA THE PLASMA
• HIGH VOLUME= LESS IN PLASMA = more its distributing out of blood
3. Metabolism – irreversible chemical alteration of a drug by a biological system
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