Exam 1 Flashcards by Brooklyn Underwood

What is drug discovery

Early sources of drugs
-Natural products derived from plants

Based on observation of medicinal properties (discover)

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What is drug invention

Modern approach is a process (inventive)
Chemical synthesis, experimentation and optimization

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What is rational drug design

Starting from a known molecule and optimizing it through synthsis to improve its potency, selectivity, stability

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What is screening

Random process
-identify a target
-develop a screen that identify active compound
-test large library of compounds to get a hit
-modify hits to get a lead molecule

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What are screening library approach refined through

Combinatorial chemistry
Increased chemical diversity of compound libraries
High-throughput screening (well plate test)
Virtual screening (big chemical databases)

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Small vs large molecules

In the past many were small, but now recombinant DNA technology permitted development of large molecules

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Targets of drug action critical questions to ask

-can one find a drug that will have the desired effect against its target
-does modulation of the target protein affect the course of disease
-does this project make sense economically

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What are druggable targets

Does it have known binding sites
-Do other small ligands interact with target
-What type of molecules interact (smaller are ideal)

Are binding sites extracellular or intracellular
-Extracellular are better because they don’t have to go through membranes

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Valid drug target

Is the target critical for disease process (or normal function)
-What happens if the target is disrupted
-Redundancy of biological systems
-Adaption to presence of drugs

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Economically viable targets

Biotech start-ups and university spin-offs
-Funded by small investors or grants
Big Pharma (large companies)
-Well funded, lots of resources
Private foundations and non-profits
-Special interests
Federal Agencies (NIH, FDA)
-Help support university and small business efforts
-Support rare diseases (ophans)

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Preclinical Research

Medicinal Chemistry
-synthesis of novel compounds
Pharmacology
-Measure affinity, selectivity, activity
-Pharmacokinetic properties (ADME)
Pharmaceutics
-Pharmaceutical properties (stability, solubility, formulation)
Toxicology
-safety

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Preclinical safety data required

Acute toxicity studies
-several doses
-at least two species (one non-rodent)
Chronic tox studies
-period related to extent of proposed human use
-two species (one non-rodent)
Genotoxicity, cardiotoxicity, respiratory safety, other systems
-In vitro
-In vito

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What is in the investigational new drug application (IND)

Chemistry, manufacturing (API)
Pharmacological, pharmokinetics, tox data
Human study rational
Protocol plan

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How long does the FDA have to approve the IND application

30 days
If no contact before then trails can start

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Role of US food and drug administration

Responsible for protecting public health by assuring safety, efficiency, and security of drugs

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What were some setbacks of the pure food and drug act

No restrictions on what was in the medications
Needed to implement tox testing
Resulted in NDA (new drug application)

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Food drug and cosmetic act
Kefauver-Harris amendments

Ads that have side effects listed

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What is an IRB (institutional review board)

It is a board at a university to approve trials
they review protocols, address privacy concerns, requires informed consent to participate in clinical trials

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What do phase 1 and 2 do in clinical trials

Phase I: 10-100 healthy volunteers, emphasis on safety
Phase 2: 50 -500 people with disease, focus on efficacy

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What are phase 3 and 4 in clinical trials

Phase 3: 200 - 2,000 patients, full drug approval
Phase 4: 10,000+ patients

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What are the seven ethical principles for conducting clinical trails

social and clinical value
scientific validity
fair selection of subjects
informed consent
favorable risk-benefit ratio
independent review
respect for potential and enrolled subjects

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What is the importance of hypothesis testing for clinical trials

identify primary endpoint for assessing outcomes
surrogate endpoints
biomarkers

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What is the importance of sample size for clinical trials

small size for initial studies of safety
large size for studies of efficacy

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What is the belmont report outlines ethical framework for studies with human subjects

respect for persons
beneficence
justice

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What are biomarkers

a characteristic that is measured as an indication of a physiological process or pathological state

What is type for biomarkers

target mechanism outcome

What is linkage to efficacy or outcome for biomarkers

low - no consistent linage medium - some information high - reproducibility demonstrated

Why is it important for biomarkers to have predefined criteria and qualification of biomarkers

predefined criteria: similar to considerations about primary clinical endpoints qualification of biomarkers: assay or measure reliably established and reflects outcome or safety

What does ADME stand for in pharmacokinetics

Absorption Distribution Metabolism Elimination

What properties determine the nature of drug action of pharmacodynamics

Binding and activity at therapeutic target Toxicity (bind and activity at other targets)

What is pharmacokinetics

the study of biochemcial and physiological effects of drugs and their mechanism of action

What are drug targets

Cell surface Intracellular Nucleus DNA Protein

What are chemical messengers

Cell to cell communication -Hormones (distal) -Neurotransmitters (local) Modulate activity at receptor represents important target for therapeutic intervention

How are receptors named

For endogenous compound

Cholinergic receptors are activated by acetylcholine

Muscarinic - GPCR Nicotinic - ligand gated

Called ________ receptors when endogenous compound is unknown

orphan

Agonists

Activates receptors -produces physiological responses (full vs partial) -Endogenous compounds are agonists (acetylcholine) -Synthetic compounds or natural products may be agonists

Antagonists

Inhibit physiological responses produced by agonists -shift agonist dose response to right in parallel manner

Inverse agonists

Produce opposite effect of agonist -may inhibit agonist response

Allosteric Ligand

modify agonist activity bind to site outside agonist binding site (orthosteric site)

Orthosteric site vs Allosteric site

Orthosteric: site for endogenous ligand, competitive inhibitor, highly conserved amino acid residue Allosteric: modulate binding to orthosteric site, may activate or inhibit receptors, less highly conserved

Drug affinity and intrinstic activity related to chemical structure

-small changes in structure may lead to large changes in pharmacological properties -stereoselectivity -pharmacophore (functional groups, chem properties)

How has drugs interaction with receptors been enhanced by several recent developments

-Molecular modeling of drug molecules combined with structure activity relationship studies -Site-directed mutagenesis -Structural data for receptors

G protein coupled receptors

-Mediate slow onset, long duration responses -Target for many best-selling drugs

What does Gi, Gs, Gq, G(olf), Gt do

Gi: inhibits adenylyl cyclase Gs: stimulates adenylyl cyclase Gq: stimulates phospholopase C G(olf): olfactory G protein mediates olfactory sensation Gt: transducen mediates sensitivity to light

What do odd and even muscarinic receptors do

odd: activate Gq (promote phosphoinositide metabolism) even: activate Gi/o (inhibit adenylyl cylase, decrease cAMP)

What do ligand-gated channels do

regulate ion flow in response to extracellular signals can be excitatory or inhibitory depending on ion flow

What do nicotinic receptors do

mediate fast-onset, short duration responses to acetylcholine

What are GABA receptors

predominant inhibitory receptor in the CNS

How long are patents good for

20 years about date filed (5 years on market)

Generic vs brand name

generic: assigned by USAN council brand: assigned by manufacturer

Tyrosine kinases and growth hormones activate ________ signals that alter cellular function

intracellular

Nuclear receptors regulate gene ________ and __________ of proteins

transcription and translation

What is quantification

interaction between drugs and receptors *important for understanding relationship between dose and response of drug

What are dose-response curves

Permit a measure of receptor binding or activity as a function of drug concentration

What is KD and EC50

KD: affinity EC50: potency

What is B(max) and S(max)

B(max): binding S(max): activity

What is the difference between linear and log plots

linear is closer together and can not see the curve while log you can

Stats for mean values are converted to what

convert to log units then calculate mean then convert back

When KD is low it indicates ______ affinity

high affinity (low concentrations are needed to occupy half the receptors)

What are competitive antagonists

Indicated when agonist and antagonist compete for same binding site on receptor -shift to right

What are irreversible antagonists

Antagonist dissociates slowly from receptor *agonist can not overcome presence of antagonist -shift to right

Increasing concentrations of ______ cannot fully overcome the effects of allosteric inhibitors

agonsists

Endogenous ligands bind to what sites

orthosteric sites

Orthosteric binding sites are more highly conserved than _________ sites

allosteric

Allosteric ligands can enhance or inhibit activity of ________

agonists

Allosteric ligands can directly activate or inhibit ________

receptors

Positive allosteric modulators (PAMs) can enhance agonist potency (PAM __) or agonist efficacy (PAM __)

potency: X efficacy: Y