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DRUG
Development Process
Drug Types
Partial Agonist
Competitive Antagonist
Full Agonist
Inverse Agonist
Parameters
Efficacy
IC50
LD50
EC50
the effective concentration of agonist for 50% response
the inhibitory concentration for 50% inhibition
the lethal dose that kills 50% of the sample population
Bioavailability
AUC is used to calculate the bioavailability of a drug
Therapeutic Window
The range of concentrations between efficacy and toxicity.
Therapeutic Index
The ratio of the LD50 to the ED 50, is an indication of how selective a drug is in producing its desired effects relative to its toxicity.
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Receptor Types
ion channels
nuclear receptors
GPCR
intracellular enzymes
transmembrane enzymes
transmembrane (nonenzyme) proteins
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Pre-clinical studies
- Formulation, stability scale-up synthesis, chronic safety in animals
- company files investigational new drug (IND) application with FDA
- Chemicals tested for efficacy and safety in tubes and animals. Results used to choose drug candidate
- Novel chemicals synthesized
- Research team formed and objectives set
Clinical Studies
Phase II
Phase I:
Phase III
Testing of drug on healthy volunteers for safety, involves testing multiple doses
Testing of drug on patients to assess efficacy and side effects in small scale
Testing of drug on patients to assess efficacy, effectiveness and safety in large scale
Phase IV
Market Approval. This phase is the most significant one due to the population effect.
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drug delivery systems and strategies
Nanoparticles (NPs)
Prodrugs
Material
polymer particle
hydrogel particle
dendrimer
protein-drug conjugate
metal particle
liposome
Carbon nanotube
solid-lipid hybrid particle
shape
sphere
star
plate
rod
cube
surface
Surface functional group
surface charge
PEGylation or other coatings
targeting ligand (antibody, peptide, aptarmer)
size: 1nm-100nm
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Barriers
Social barriers
Political Barriers
Financial Barriers
Physiological Barriers
Body level
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Route of administration
Sublingual delivery
Oral delivery
Buccal delivery
Intravenous delivery
Ocular deliver
intramuscular delivery
Subcutaneous delivery
Transdermal deliver
Pulmonary/Nasal delivery
Vaginal/rectal deliver
Organ system level
muscular system
skeletal system
excretory system
integumentary system
digestive system
immune system
circulatory system
endocrine system
Respiratory system
reproductive system
Nervous system
Tissue level
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Connective
Muscle
Epithelial
Extracellular Matrix: Small Amount
Main Functions: Lining of surface or body cavities; glandular secretion
Cells: Aggregated polyhedral cells
Extracellular Matrix: Abundant amount
Main Functions: Support and protection of tissues/organs
Cells: Several types of fixed and wandering cells
Extracellular Matrix: Moderate amount
Nervous
Extracellular Matrix: Very small amount
Main Functions: Strong contraction; body movements
Cells: Elongated contractile cells
Main Functions: Transmission of nerve impulses
Cells: Elongated cells with extremely fine processes
Blood Brain barrier
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Characteristics
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Types
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Stratified epithelium
transitional epithelilum or urothelium
Simple columnar epithelium
pseudostratified epithelium
Simple cuboidal epithelium
secretory epithelia and glands
Simple squamous epithelium
Regulated and responsive intracellular space between the epithelial or endothelial cells
Underlying stroma (lamina propria in digestive, respiratory, urinary systems)
Apical secretions and/or restrictive apical membranes and transporters
Tight junctions between cells (and mostly ordered junctions discussed below)
Specialized polarized cells
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Neurovascular unit
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BBB supporting systems
endothelial cells
extracellular base membrane
brain capillary
adjoining pericytes
astrocytes
microglia
Surrounding neurons
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Pathways
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efflux pumps
receptor-mediated transcytosis (RMT)
transport proteins
Adsorptive transcytosis (AMT)
transcellular lipophilic pathway: small lipid soluble substances
Cell mediated transcytosis
Paracellular aqueous pathway: small water-soluble molecules
Cell and Molecular levels
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Diffusion
Transport barriers
Extracellular Matrix
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Multidrug Resistance (MDR)
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Increased drug efflux
Drug modification
Decreased drug influx
Target Modification
DNA repair and blocked programmed cell death
Mutational response and selection
Barriers to drug delivery
Biochemical barriers
Physiological barriers
Chemical Barriers Physiochemical properties of the drug
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BBB
interstinal epithelium
Skin
crossing biological membranes
Transporters
Efflux pumps
Metabolizing enzymes
Lipinskl's rule of 5
- LogP<=5
- H-bond acceptors <= 10 (expressed as the sum of Ns and Os)
- Moleccular weight <= 500DA
- Good in vivo drug absorption and permeation
- H-bond donors <= 5 (expressed as the sum of OHs and NHs)
- Only a general guide and applied to orally adminstered drugs
Barriers
Financial Barrier
Social/Political Barrier
Physiological Barrier
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Body Level
Directly responsible for the absorption phase in PK ADME
Associated with the route of administration
Organ Level
Depending on the target tissue and receptor, each of the 11 organ systems possess unique challenges
Dependent on the route of administration
Tissue Level
Connective
Epithelia:
Muscle
Nervous
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Cell and Molecular Level
Diffusion Barriers
Transport Barriers
Extracellular Matrix Barriers