Drug Delivery Flashcards
Maximum Effect
when the logarithm of concentration is plotted versus effect, the concentration above which no greater effect is achieved
EC50, UNITS
50% Effective Concentration (EC50): the concentration at which 50% of the maximum effect is achieved mg/L
Single compartment model, UNITS
XO->[X1]->K
X0 in mg, X1 in mg,K in (fraction) per hour
V=X/C, UNITS
Volume of distribution (L) is equal to dose (mg) divided by concentration (mg/L)
What types of bonds are degradable? Which are not?
Carbon-carbon bonds and amides are not, those with heteroatoms in their backbones are
Step Growth Polymerization
React functional groups to form chains, place heteroatoms in backbone
Functional groups can be hydrolyzed or degraded by an enzyme
Chain Polymerization or Free Radical Polymerization
Use radicals to initiation polymerization of double bonds
Produces polymers with carbon-carbon backbones, not degradable
Poly(2-hydroxypropyl methacrylamide) or Poly(HPMA)
the first polymer drugs were attached to
Poly(lactic-co-glycolic acid) or PLGA
the most famous polymer after PEG/PEO and has esters in its backbone that make it degrade into lactic acid and glycolic acid
Amount of each monomer type can change hydrolysis rates
Polyethylene Glycol (PEG) and Polyethylene Oxide (PEO)
Hydrophilic and biocompatible, but not biodegradable
Oxygens in backbone increase solubility by forming a water shell to shield from immune system
Easy to make and control size
Polymer-Drug Conjugates, components
Connect hydrophilic (sugar, hydroxyl, amides) polymer with drug using degradable linkage
Drug release rates for amides, peptides, phenyl esters, and alkyl esters
Peptides → Phenyl Esters → Alkyl Esters → Amides
Polymer-Drug Conjugates, advantages and disadvantages
Easier to make than liposomes
May be difficult to attach certain drugs or certain combinations of drugs, may produce side reactions, hard to make in large quantities
Hydrazone bonds
Ketone + Hydrazide → Hydrazone bond that is stable at pH 7.4 (blood) but unstable when in the acidic conditions of an endosome or lysosome
Polymerizable Prodrug Monomers, components
Polymerizable Group + Cleavable Linkage (hydrolyze or enzyme) + Therapeutic Agent all held together by hydrophilic comonomer spacers
Polymerizable Prodrug Monomers, advantages and creation
Avoid cross-reactivity with functional groups, easier to control amount of drug
Created in a single polymerization by free radical chain growth
Micelles, hydrophobic/hydrophillic
Cores are hydrophobic, accept hydrophobic drugs (no charge or polar groups)
Hydrophilic outside with positive charges
Micelles, bilayer, tails, possible components
Do not have a bilayer
Prepared from single tailed species (heads on outside)
Can be formed from surfacants or by polymers with a hydrophobic and hydrophilic side (these may also form polymersomes)
Liposomes, hydrophobic/hydrophillic
Cores are aqueous, accept hydrophilic drugs
Liposomes, bilayer, tails, possible components
Require twin tails
Contain bilayer (head-tail-head, philic-phobic-philic)
Lipids or polymers
Liposomes, possible additions
Can be coated with PEG to hide from immune system
Can be attached to targeting groups like antibodies, vitamins, folic acid, peptides
Can increase circulation time and change destination (ex: targeting, large size)
Liposomes, advantages and disadvantages
Hard to make, but still common
Nucleic Acids, examples, charges, carriers, active in
mRNA, siRNA
Only active in the cytoplasm, cannot enter the cell due to polarity
High negative charge (hard to attach to carrier), large and hydrophilic
NP or +/- ratio with nucleic acid biologic drug
DNA is -, Cation is +
NP ratio or +/- ratio
May not want to unstick, need to mess with ratio
Net positive is active/stable/toxic, net negative is as stable but less active/toxic
Nucleic acid biologic drug, circulation, additions
Adding PEG decreases both the toxicity and activity
Vulnerable to nucleases
Short circulation times
Nucleic acid biologic drug, carriers
Liposomes with cationic lipids (NH3+), polyelectrolyte complex
Cationic polymers (still toxic, lyse cell membranes and endosomes)
Protein biologic drugs
Antibodies, Enzymes
Can be involved in protein-protein interactions considered undruggable
A bit more stable and less charge than nucleic acids
Very effective and specific
Viral and special carriers of biologic drugs
Viruses are non-specific and may cause cancer
Carriers should sense pH change
Viruses can change from a stable conformation to one that lyses the endosomes and enters the cytoplasm
Three challenges of drug delivery
solubility, stability, physical barriers
Low Molecular Weight Drugs
Include antibiotics, worried about getting into solution and first pass, usually diffuse well if not too polar
Protein Therapeutics
Can modify protein-protein interactions, great specificity, cannot diffuse past membranes, without vehicle will go through endocytosis (bad), proteases (not as big as a deal)
Nucleic Acid Therapeutics
Vulnerable to nucleases, viral carriers are nonspecific
What groups are polar/hydrophilic?
Include neutral groups such as hydroxyls and amides as well as charged particles
What groups are nonpolar/hydrophobic?
c-c bonds
What are lipids/surfactants?
Organic molecules that are amphiphilic containing both hydrophobic tails and hydrophilic heads
Different head possibilities for lipids/surfacants
Cationic polar heads are toxic, but can deliver nucleic acids
Anionic polar heads are vulnerable to kupffer cells in liver
→ Want neutral hydrophilic heads
What are the types of neutral hydrophilic heads?
Include zwitterions (+ attached to -, include cell membranes), PEG chains, hydroxyls, amides
Structure of phosphatidylcholine
twin tails with single double bond, esters, PO4, NC3+
Absorption
the process of a substance entering blood circulation
Very important for oral drugs to get through liver first pass
Distribution
dispersion throughout the fluids and tissues of body
Metabolism
recognition by organism and transformation into daughter metabolites, usually by adding polar groups
May make the drug more toxic
Excretion
the removal of substances from the body
Pharmacokinetics
the study of how the organism affects the drug
or
the study of the time course of drug absorption, distribution, metabolism, and excretion
Pharmacodynamics
the study of how the drug affects the organism (factors include density of receptors, second messengers, regulatory factors)
relates drug concentration to drug effect
First Pass Effect
the phenomenon of drug metabolism whereby the concentration of a drug is greatly reduced (by the liver) before it reaches the systemic circulation
Clinical Pharmacokinetics
the application of pharmacokinetic principles to safely and effectively administer drugs to patients by developing correlations between drug concentration and pharmacologic response
Clinical Pharmacokinetics, goals
Want to increase efficacy and decrease toxicity
Kinetic Homogeneity
the description of the predictable relationship between plasma drug concentrations and concentrations at the receptor site
Plasma
the fluid portion without the formed elements
Serum
plasma without fibrinogen
Fibrinogen
soluble protein that produces fibrin by the enzyme thrombin
Fibrin
insoluble protein formed from fibrinogen during blood clotting that forms a fibrous mesh
Distribution of water: % in body
60
Distribution of water: Intracellular v Extracellular
58% is intracellular and 42% is extracellular
Distribution of water: Extracellular components
Of the extracellular fluid, 16% is plasma and 84% is interstitial
One-compartment model, describes and assumes
All body tissues are fluids are part of the compartment
After a drug is administered, it distributes instantaneously to all body areas
Intravenous bolus dosing
administering a dose of drug over a very short time period
First-Order, Ln (concentration) v time
line
V = XC, meaning of V
V is volume to account for all drug if concentrations in tissues are the same as the plasma drug concentrations
Volumes below extracellular fluid is mostly in fluid, volumes higher is mostly in tissues (sources of error are from diff con in tissues/plasma)
Therapeutic Drug Monitoring
the use of assays to determine the plasma drug concentration and application of these data to develop safe and effective drug regimens
Therapeutic Drug Monitoring, uses
Used when there is a good correlation between response and plasma concentration, wide intersubject variation, and narrow therapeutic index (and effects that cannot be assessed by other means)
Plots probability (%) by drug concentration (mg/L) for response and toxicity
Clearance, meaning
Clearance includes renal (kidneys), liver, biliary (bile duct), and other routes
Volume/time
a measure of the removal of drug from a volume of plasma in a given unit of time (volume that would be drug-free if concentration were held constant)
Clearance, blood flow, excretion ratio
Equal to excretion ratio by blood flow → Cl = QE
Q is blood flow in mL/min
E is excretion ratio, unitless
Cl is clearance in volume/time
Model independent, summation of all organs (liver/kidneys)
Excretion ratio
E is excretion ratio (concentration in-concentration out)/(concentration in), unitless
Fraction removed constant, amount different ->
Fraction removed different, amount constant ->
First-order, Ln concentration v time linear
Zero-order, concentration v time linear
