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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

  1. Formulation, stability scale-up synthesis, chronic safety in animals
  1. company files investigational new drug (IND) application with FDA
  1. Chemicals tested for efficacy and safety in tubes and animals. Results used to choose drug candidate
  1. Novel chemicals synthesized
  1. 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

  1. LogP<=5
  1. H-bond acceptors <= 10 (expressed as the sum of Ns and Os)
  1. Moleccular weight <= 500DA
  1. Good in vivo drug absorption and permeation
  1. 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