Pharmaceutical Chemistry Flashcards
Ligands
Compounds that bind to a receptor
Potency
The amount of drug that must be administered in order to produce a desired effect
What is ED50?
The dose which produces the effect in 50% of the population
Receptor
Any cellular macromolecule to which a drug binds and thereby initiates its characteristic biological effect
Extraction
Separation of substance from a matrix
Bio guided fractionation
Reduces wide range of chemicals present in an extract through removal of substances based in similar chemical properties
Ethnopharmacology
the traditional use of natural products
Biodiversity
degree of variation of life
In vitro
conducted using components of an organism that have been isolated from their usual biological surroundings in order to permit a more detailed or more convenient analysis that can be done with whole organisms
In vivo
conducted with living organisms in their normal intact state
In silico
performed on a computer or via computer simulation
computational chemistry
target directed modeling of a compound to elevate the interaction between a receptor and the chemical structure
High Throughput Screening (HTS)
a method for scientific experimentation especially used in drug discovery. Allows a researched to quickly conduct millions of chemical, genetic, or pharmaceutical tests. You can rapidly identify active compounds, antibodies, or genes which modulate a particular biomolecular pathway.
pharmacophore
necessary structure for binding to the target
Human studies are divided into what three stages?
Phase I clinical trials (healthy volunteers)
Phase II clinical trials (patients-small population)
Phase III clinical trials (patients-large population)
Phase IV trials (patients-for evaluation of rare side effects and monitoring of efficacy)
parenteral administration
delivers drugs directly into bloodstream
enteral administration
oral route
physicochemical properties include?
ionizable functional groups
solubility
lipophilicity
molecular weight
pharmacokinetics
process by which a drug enters the body, distributes through it, is altered through metabolism and is excreted
LADME model
Liberation Absorption Distribution Metabolism Excretion
Liberation
important for ideal absorption into the body
extended release
drug formulated to slowly dissolve over an extended period of time
Absorption
when an unionized substance is dissolved in an aqueous solution, it can either passively diffuse across a lipophilic membrane to cross into the body or be actively transported across the membrane
Passive diffusion
concentration gradient; high concentration to low concentration across a membrane
active transport
involves a carrier protein located inside the membrane and utilizes energy to actively transport a substance across the membrane
bioavailability
the fraction of the total drug amount given that will be available in the body
Lipinski’s Rule of 5
not more than 5 H bond donors not more than 10 H bond acceptors MW below 500 Dalton Partition coeff. logP below 5 rough estimate of the likeliness of a drug to show a high bioavailability if given orally
Distribution
if the drug is very hydrophilic, it will not distribute into certain tissues and is less likely to cross the blood brain barrier without a specific transporter. the more lipophilic a drug is, the easier it will distribute throughout the body
Metabolism
set of life-sustaining chemical transformations within the cells of living organisms
cytochrome P450
metabolizes drugs to more soluble metabolites
Excretions
when a drug gets secreted from the body. Water soluble=secreted through urine (kidneys); lipid-soluble= secreted through feces (gall bladder)
Van der Waals interactions
occurs between alkyl groups on the receptor and on the drug molecule caused by polarization of C-C bonds in close proximity of each other
Hydrogen bonding
interaction between polar molecules
Ionic interactions
occur between two charged species that carry an actual charge instead of just a polarization. Electrostatic attraction between opppositely charge ions
Covalent bond
formed when one electron from each of two atoms contributed to form a bond between the two atoms
Arrhenius acid
increases the concentration of [H+] ions
Arrhenius base
increases the concentration of [OH-] ions
Bronsted-Lowry acid
proton donor
Bronsted-Lowry base
proton acceptor
ionization
mechanism by which an acid transfers a proton to a base
dissolution
process of dissolving a solute in a solvent to form a homogeneous solution
pH=
-log[H+]
pKa=-logKa
for strong acids: Ka>1
for strong bases: Ka
pKa+pKb=
pKw=14
electron withdrawing groups
halides aldehyde ketone carboxylic acid esters halide acids cyanide sulfate quaternary amine nitrite
weak acid
pHpKa; lower [H+]; equilibrium shifts towards more ionized species (shift right)
pH=pKa; 50% of molecules ionized, 50% of molecules unionized
weak base
pHpKa; [H+] ion decreases; molecules will mainly unionize
% ionized=
100/1+10^pH-pKa
Hydrophilicity
increases water solubility; optimizes drug formulations; important for dissolution after oral administration
lipophilicity
increases lipid solubility; penetration through cell membranes; longer circulation in the body
Pro-drugs
temporarily alters the physicochemical properties of a drug to provide it with more desirable properties for its administration
logP
indicator of a substances lipid solubility in its unionized state
logP=
sum[pi(organic fragments)]
diffusion layer
consists of tightly bound molecules of water which are not easily disrupted by stirring
Noyes-Whitney equation
dw/dt=k (cs-ct) dw=amount of drug going into solution dt=time k=time dependent constant Cs= saturated solubility of the compound Ct=concentration at any time t
Hansch analysis
predicts how well a molecule will likely fit and interact with its intended target
Quantal dose response
simple model to express the response of an enzyme, receptor, or animal to a drug is to correlate number of responses to the dose
log-dose response curve
Provides a sigmoidal curve. The activity of a drug is displayed on the y-axis and the potency is displayed on the x-axis
Activity
activation of the receptor or enzyme upon binding of the drug with subsequent physiological or pharmacological changes.
Potency
How strong a drug binds to its target. A drug with high potency binds very strongly to the target and therefore requires less of the drug for the physiological or pharmacological change to occur.
Agonist
An agonist binds to its target and activates it resulting in the physiological or pharmacological response
Antagonist
binds to its target but does not activate it. Instead, antagonists prevent binding of agonists to the target.
Partial agonists/antagonists
not all agonists lead to the activation of all targets that are occupied-in some cases only some of the occupied targets will be activated while other are only occupied
Competitive antagonist
binds to the same site on the target as the agonist. The potency of the agonist decreases-a shift to the right on the log-dose response curve is observed
Non-competitive antagonist
the antagonist binds to a different site than the agonist and prevents activation of the target. The agonist can still bind but the activity is reduced in the presence of a non-competitive antagonist while potency is not affected.
Michaelis-Menten kinetics
The interaction between a drug [D] and a receptor [R] are the same as between a drug (S) and an enzyme (E)
Lineweaver-Burke (double-reciprocal plot)
Allows for determination of the maximum velocity or activity Vmax/Emax of the reaction as well as Km/Kd
Lineweaver-Burke equation
1/V=1/Vmax + 1/[S] x Km/Vmax for enzyme-substrate interaction
1/E=1/Emax + 1/[D] x Kd/Emax for medicinal chemistry
Isoterism
The replacement of functional groups or parts of a molecule to alter the size and shape is often utilized to wither design structurally closely related drugs that maintain the pharmacological activity or to improve the binding and positioning affinity for the drug with the target
Isoters
functional groups that function similar to one another
1906 Pure Food and Drug Act
prohibited the interstate commerce of mislabeled food and drug products
1911 Sherley amendement
required the label claims to be accurate-although the government had to proof intentional mislabeling
1938 Federal Food, Drug, and Cosmetic Act
required that drug manufacturers evaluate the safety of a drug before it is being marketed and submit a new drug application for review to the FDA, had labeling requirements that had indicate adverse effects and potential hazards that has been observed before, and authorized the FDA to conduct unannounced inspections of dru manufacturing facilities
1962 Kefauver-Harris Act
closed many of the loopholes in drug regulation
Federal Controlled Substances Act
provided drug scheduling for drugs that could potentially lead to abuse and addiction
Orphan Drug Act
intended to provide incentives to drug manufacturers to invest in drug development for rare diseases
Extrinsic pathway
tissue damage leads to release of tissue factor
Intrinsic pathways
tissue damage leads to release of kallikrein
Plasminogen
can prevent or resolve a blood clot
Pro-drugs
rapidly metabolized after absorption into the body to the active drug
isoters
functional groups that function similar to one another
bioisoters
share similar physical and chemical properties with one another and are used to optimize pharmacodynamics and pharmacokinetics
Replacement of a carboxylic acid with a sulfonamide group does what?
preserves ionization but leads to inhibition of target due to change in topology
Replacement of an ester with an amide does what?
reduces metabolism and increases half-life of the compound
central compartment
the blood and highly perfused organs such as the liver lungs and kidneys(one compartment model) Ex. intravenous injection
apparent volume of distribution (Vd)
reflects the volume that would be needed to achieve the same plasma concentrations of a substance in the body
clearance (Cl)
links elimination of a drug from the body to its concentration over time
area under the curve (AUC)
the total body exposure to the drug over the course of time from administration to elimination of the whole dose or after repeated dosing
The most common phase 1 reactions of drugs:
oxidation and hydroylsis
Phase II pathways
Glucuronide conjugation Sulfate conjugation Glutathione Acetylation Amino acid conjugation Methylation Fatty acid conjugation Cholesterol esters
minimum effective concentration (MEC)
minimum concentration of drug in plasma required to produce the therapeutic effect. It reflects the minimum concentration of drug at the receptor site to elicit the desired pharmacological response.
minimum toxic concentration (MTC)
minimum concentration in which toxicity usually occurs
Therapeutic window
blood concentration range between MEC and MTC
biotransformation
the process of conversion of a drug into metabolites
xenobiotic
low molecular weight organic molecules that are not used by the human body for nutritional or other physiological purposes
Phase 1 reactions
introduce or uncover a hydrophilic functional group
Phase 2 reactions
an endogenous, usually water soluble, small molecule combines with a functional group of the drug or drug-metabolite
The most abundantly expressed CYP in human intestines and liver is?
CYP3A4
transporters
proteins that facilitate the elimination of drugs and drug metabolites out of cells
Factors affecting drug biotransformation and duration of drug action:
amount of enzyme
affinity
availability of co-factors and co-substrates
inhibition
Bloodborne pathogen
any pathogenic (disease causing) microorganism present in human blood that causes disease
developmental validation
includes characterization of the locus, species specificity studies, sensitivity, stability, and mixture studies.
internal validation
must be conducted by any lab when delveloping validation has been performed by another lab or at another site of a multi-site lab
Good Manufacturing Practice (GMP)
intended to provide a set of processes that are validated to result in consistent and repeatable quality of the product at every stag of the manufacturing process
Good Laboratory Practice (GLP)
adequate testing of intermediates and final drug products to ensure continuous high quality and detect deviations from the predetermined standards ASAP.
Good Clinical Practice (GCP)
involves all activities related to human subject research, especially in regards to ethical standards, adequate protocol development for research projects, safety, and oversight of clinical trials.
What factors are considered before purchasing instruments for a lab?
Technical and service support provided Price Lab environment Number and size of samples Installation Operation Number of units required Special reqs
Equipment qualification
process by which an instrument is checked for compliance with previously determined standards of function and performance
Validation
establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality attributes
Inspections
the examination or measurement of an item or activity to verify conformation to specific requirements
Calibration
a comparison of a measurement standard, instrument, or item with a standard or instrument of higher accuracy to detect and quantify inaccuracies and to report or eliminate those inaccuracies by adjustments
Chain of Custody (COC)
an unbroken trail of accountability that ensures the physical security of samples, data and records
A chain of custody must include:
the signature or initials of each individual receiving or transferring evidence, the date for each transfer with a corresponding identifier which specifies each evidentiary item
Required information on sample collections include:
date and time of sample collection
name of person collecting samples
unique identification number for each individual sample
documentation that sample collection equipment and containers are clean
secure storage of all samples under specified conditions while awaiting transport
