intro to pharmaceutics exam 2

oral absorption and drug bioavailability

Drug resistance (MDR) and toxicity

excretion of drugs/metabolites by kidney/liver transporters

drug pharmacokinetics and pharmacodynamics

What is the role of transporters?

monocarboxylate transporters

transports molecules with 1 carboxylate group

organic cation transporters

transports positively charged organic molecules

nucleoside transporters

transports nucleosidespe

peptide transporters

transports small peptides

primary active transport

transports a substance against conc gradient with use of ATP

secondary active transport

occurs when a cell uses energy indirectly to move a substance against its conc gradient by using the energy stored in another substance’s conc gradient

symport

2+ substances that are transported in the same direction on a simple transporter

antiport

counter-exchange system, moving two solutes in opposite directions

facilitated diffusion

transports a substance down conc gradient using a protein

• glycosylation

• phosphorylation

• disulfide bonds

• oligomerization

• trafficking

• pH

What factors affect transporter activity and ADME?

glycosylation

addition of sugar moiety to ASPARAGINE residues of a transporter

• helps with proper sorting and translocation of polypeptides into membranes

phosphorylation

addition of phosphate group to a transporter

• decreases transport function (uptake of substrate)

disulfide bonds

strong covalent bonds form between 2 CYSTEINE residues of amino acid

• helps stabilize structure and support proper folding

oligomerization

2+ protein molecules join together to form a larger protein complex

• affects transport activity, stability, and membrane localization

• primary active transport

• secondary active transport

• facilitated diffusion

3 transport mechanisms

• simple diffusion

• paracellular transport

• facilitated diffusion

• active transport

• receptor-mediated endocytosis

5 pathways of drug transport across membrane

small molecules

organic ions, water, and monosaccharides

What kind of molecules use transporters to move across membrane?

macromolecules and particles > 100 Da

proteins, polynucleotides, and polysaccharides

What kind of molecules use endocytosis and exocytosis to move across membrane?

Ingested or secreted macromolecules are sequestered in vesicles and do not mix with most of the other macromolecules or organelles in cytoplasm

Shared feature of endocytosis and exocytosis

1. Adherence: 2 bilayers come into close apposition

2. Joining: 2 bilayers fuse

2 steps to both endocytosis and exocytosis

secretory cells: hormones and neurotransmitters

What kind of cells use the regulated pathway of exocytosis?

all eukaryotic cells

What kind of cells use the constitutive pathway of exocytosis?

constitutive pathway

Secreted proteins are packed in transport vesicles and secreted continuously

Regulated pathway

Secreted proteins are stored in special secretory vesicles and released only when the cell is triggered by an extracellular signal

retrieved by endocytosis and reincorporated into new secretory vesicles

What happens to the protein and lipid components that are in membrane vesicles during the regulated pathway?

receptor-mediated endocytosis

serves as a concentrating device for internalizing specific extracellular macromolecules

• deliver nutrients to cells

• clear molecules from circulation

• efficient neurotransmission

• precisely regulate signal transduction

• immune function

Functions of receptor-mediated endocytosis

plasma membrane process

cytosol process

General processes of receptor-mediated endocytosis

Binding at plasma membrane

Coated pit formation

2 steps of plasma membrane process of receptor-mediated endocytosis

Extracellular ligand binds to receptor at membrane

concentrates ligand at plasma membrane to increase efficiency of uptake

What happens during binding at plasma membrane of RME?

1. Coated pits are formed from clathrin

2. Plasma membrane receptors migrate into pits

3. Pits invaginate and bud off plasma membrane to form coated vesicles

4. Clathrin coat surrounding vesicle disassembles —> reuse coat proteins

5. forms endosome: coatless vesicle that remains

What happens during coated pit formation of RME?

Acidifcation of endosome

Proteolysis using lysosomes

2 steps of cytosol process of receptor-mediated endocytosis

Lumen of endosomes become acidic (pH 6 to pH 5)

If the receptor-ligand complex dissociates in early endosome, the receptor recycles back to plasma membrane

If the receptor-ligand complex does not dissociate in early endosome, the complex moves to lysosome for degradation

What happens during acification of endosomes?

lyososomes

membrane-bound vesicles involved in intracellular digestion that contain many hydrolytic enzymes that are active under acidic conditions

Hydrolytic enzymes degrade receptor-ligand complex

What happens during proteolysis during RME?

LDL receptor binds to a cholesterol-rich LDL particle —> lysosomal degradation of LDL and release of cholesterol into cell

How does receptor-mediated endocytosis affect LDL receptor?

pharmacogenetics

the study of hereditary variations in drug response (genetic polymorphism of drug transporters, drug metabolizing enzymes, and drug receptors)

mutation

a change in the sequence of the nucleic acid

genotype

the fundamental assortment of genes of an individual

phenotype

the outward characteristic expression of an individual

1. substitution

2. addition/insertion

3. deletion

3 mechanisms of mutation

provides patients with information that could facilitate an individualized therapy with choice and dose of drugs

Application: Why are pharmacogenetics important?

1. specificity of uptake

2. targeted delivery and cellular distribution

3. access to endogenous regulatory mechanism of subcellular distribution

4. Capitalizing on genetic polymorphism of drug transporters by designing drugs towards specific segments of patient population

4 advantages of using transporters for drug delivery

1. drug-drug interaction

2. drug-endogenous ligand interaction

3. sensitivity to changes in microenvironment of transporter as may occur during inflammation and infection

3 challenges of using transporters as drug delivery system

liquid-liquid interface

type of interface for emulsion

liquid-solid interface

type of interface for suspension

interface

the boundary between 2 phases which exist together

surfactants

amphiphilic molecules/ions that are absorbed at interfaces

monolayers

soluble layers or insoluble films formed after a material is absorbed in the liquid subphase

surface tension

the tension of the surface film of a liquid caused by the attraction of particles in the surface layer by the bulk of liquid, which tends to minimize surface area

difference between surface tension of pure supporting liquid (y0) and that of the liquid with an absorbed film (y)

surface pressure of a monolayer film

1. Work of cohesion

2. Work of adhesion

2 forces required for spreading of one liquid over another

work of cohesion

work required to separate the molecules of the spreading liquid

work of adhesion

work required to break the attraction between unlike molecules

newly created surface tensions (yL + ys) minus the

interfacial tension (yLS) that has been destroyed in the process.

How to calculate work of adhesion (separate two sections of liquid)

2 newly created surface tensions (2yL)

NO interfacial tension

How to calculate work of cohesion (separate molecules of spreading liquid so that it can flow over sublayer)

work of adhesion - work of cohesion

Spreading coefficient (S)

Liquid will spread over another liquid surface

What happens is spreading coefficient is positive?

Liquid will coalescence of the excess material into a lens

What happens if spreading coefficient is negative?

• chemical nature of absorbent and absorbate\

• surface area of absorbent

• temperature

• partial pressure of absorbed gas

What does the degree of gas by a solid depend on?

physical and chemical absorption

Types of absorption

physical absorption

reversible

associated with Van der Waals forces

chemical absorption

irreversible

Absorbate is attached to absorbent by primary chemical bonds

soaps and detergents

Examples of surfactants

soaps

fatty acids salts that contain a long hydrocarbon chain and a carboxylate group

form emulsions using a property known as detergency

How do soaps and detergents remove oils and greases

emulsions

a dispersion of one liquid in a second, immiscible liquid

multiphase systems: continuous and dispersed phase

detergents

Surfactants that are used for the removal of dirt

1. Hydrocarbon tails of detergent anions dissolve grease

2. The grease spot gradually breaks up and becomes pincushioned by detergent anions

3. Small bits of grease are held in colloidal suspension by detergent. Anionic heads keep grease from coalescing

How do detergents work?

decreases the surface tension at the air-alveoli interface to:

prevent collapse of alveoli

decrease pressure inside alveoli to allow us to breathe

How do lung surfactanst work?

dispersed systems

consist of dispersed phase distributed throughout a continuous medium

molecular dispersion

colloidal dispersion

coarse dispersion

3 classifications of dispersed systems

size: < 1 nm

Invisible in electron microscope

Pass through ultrafilter and semipermeable membrane

Rapid diffusion

Characterstics of molecular dispersion

size: 1 nm - 0.5 micrometers

not detected by ordinary microsocpe but visible in electron microscope

passes through filter paper but not semipermeable membrane

very slow diffusion

characteristics of colloidal dispersion

size: > 0.5 micrometers

visible under microscope

does not pass through normal filter paper or semipermeable membrane

does not diffuse

Charactersictis of coarse dispersion

dialysis

technique that separates colloidal particles from molecular particles (electrolyte) using a semipermeable membrane of collodion/cellophane

Ultrafiltration: negative pressure

electrodialysis: electric potential across membrane

Types of separate of colloidal particles

forms SOLUTIONS (no dispersion)

Gas-gas combination

Figure out continuous phase by adding drop of water-soluble dye

If normal emulsion: Dye will dissolve in water and emulsion will take color of dye

If inverse emulsion: Dye stays a large glob separated from water droplets by surfactant and continuous phase

How to test if emulsion is an inverse or normal emulsion?

determined on basis of interaction of particles of dispersed phase with the molecules of dispersion medium:

lyophilic

lyophobic

association

Types of colloidal systems

lyophilic colloids

systems containing colloidal particles (organic molecules) that interact to an appreciable extent with the dispersion medium

lyophonic colloids

composed of materials (inorganic particles) that have little attraction for the dispersion medium

association colloids

Amphiphiles/surface-active agents have 2 distinct regions with opposite solution affinities within the same molecule or ion

micelles

aggregates that occur when presented in a liquid medium at low concentrations

critical micelle conc

the conc at which micelles form in solution

stability

“extent to which a product retains,within specified limits, & throughout its period of storage and use (i.e. its shelf life), the same properties & characteristics that it possessed at he time of its manufacture

conc, temp, light, and catalysts

Important factors in chemical kinetics

k = -dA/dt

moles / (liter sec)

k and Units of Zero Order reactions

k = -dA/dt x 1/A

1/sec

k and units of first order

liter/ (sec mol)

k and units of second order reaction

C = C0 - kt

Equation for Zero Order Reactions

C VS t

Graph that gives straight line for zero order

k

(independent of conc)

in zero order, rate is dependent on ____

t1/2 = 0.5 A0 / k0

Half life for zero order

As drug decomposes in solution, more drug is released from suspended particles, keeping the overall conc. in solution relatively constant

First order expression becomes: -d[A]/dt = k[A]

when A is constant: -d[A]/dt = k0 —> ZERO ORDER

Why are suspensions a zero order case?

concentration C

-dc/dt = kc

In first order, rate is dependent on ____

ln C = ln C0 - kt OR
k = 2.303/t log a/(a-x)

equation for first order

t1/2 = 0.693/k

First order equation for half life

dx/dt = k(a-c)²

k = 2.303/t(a-x) logb(a-x)/a(b-x)

Equation for second order