pencils DDS intro to biopharmaceutics

drug targets

most drugs exert their effects by interacting w targets 

IV. mannitol

topical zinc oxide 

osmotic agent

reflective agent (

location

diff. targets can be found @ diff sites in the body

at these sites the specific targets may be in diff locations

various organs, tissues, or cells

specific target molecule in diff locations- inside cells, in cell membrane, or in extracellular fluid

excipients and purpose 

excipient purposes are to improve stability, dissolution, & taste 

when the drug is formulated into its dosage form, it may be present in diff physical forms

the diff physical forms may be crystal or molecules

take home 1

in most cases, it is intended that the administered drug is transported by the systemic circulation to the target areas

in some cases the drug is administered directly into the circulation

IV administration

most commonly, drug reaches the systemic circulation INDIRECTLY by other routes

oral, buccal, rectal, IM injection, inhalation, intranasal

bioavailability 

a drug administered through an IV is 100% bioavailable 

incomplete dissolution

only dissolved drug is absorbed

inadequate time at the primary absorptive area

bypassing the important absorptive area ex: w/ GI hypermotility (effects can vary)

pushes the drug too quickly thru the GI. tract= cutting down of what is absorbed

incomplete absorption through epithelia

“get inside but pushed right out”

some drugs can be transported out of the epithelial cells (efflux)

pre systemic metabolism

one of the most common factors that reduces bioavailability for extravascular routes 

most common for enzymes that destroy drugs 

ex: enterocytes & hepatocytes

chemical degradation proton pump inhibitors

omeprazole degrades under acidic chemical conditions in the stomach

take delay in rise & progressive loss over time (plot) 

delay in rise & progressive loss over time

specific nature of LADME processes

LADME is affected by enzymatic activity

route of administration

diff routes have diff absorption barriers

dosage form

diff dosage forms release drugs differently

physiochemical properties that affect the fate of the drug: ionization 

most drugs are weak acids/bases therefore they are pH dependent meaning good for ionization 

the degree of a drugs ionization can be important for many biopharmaceutical properties

ionization & biopharmaceutical properties = dissolution & absorption

take home physiological phenomena

physiological phenomena that can affect the fate of a drug in the body are MEMBRANE PASSAGE & COMPLEXATION

membrane can be interpreted in diff ways

multiple layer of cells (skin & eyeball multi layer)

single layer (intestinal epithelium)

lipid bilayer of individual cells (phospholipid bilayer)

take home membrane passage 

a drug will cross a membrane by passive diffusion or by transporter mediated mechanisms 

the importance of the environments pH for an ionizable drug to pass through lipid bilayers as the pH of the environment determines the fraction of an ionizable drug in the nonionized form pH can be critical for MEMBRANE PASSAGE

the nonionized or “non charged” is less polar meaning it is greater for passing through

passive diffusion

continuous

fenestrated “pores” travel through the pores

sinusoid “larger gaps”

these passive processes, drugs will move down their concentration gradient i,e., high to low

transported mediated mechanisms

some drugs are transferred into, and/or, out of the cells w the aid of drug transporters, which are membrane bound proteins

active transport

moving against concentration gradient requires ENERGY ATP

facilitated diffusion 

w/concentration gradient (passive process) 

xenobiotics

foreign chemicals including drugs

drug transporters and their role in resistance to some drugs

efflux transporters in cancer cause resistance

drug transporters and their role in adverse effects to some drugs

uptake transporters can cause drug accmulation in cells

drug transporter classification 

two superfamilies: ABC & SLC

ABC (ATP binding cassette) transporters

in eukaryotes are used for efflux=pushing things outta the cell

SLC (solute carrier) transporter

some are efflux & some are uptake

-include facilitated transporters & ion coupled active transporters… they require coupling w the transport of a 2nd solute for their energy

many times this 2nd solute is Na+ glucose

uptake & efflux transporters 

location in the cell determines where the drug will end up 

complexation or binding of a drug

complexation/binding w/Ca++ or Mg++ can reduce the absorption

in regard to plasma proteins

generally should be free (unbound)

interacts w/other molecules (targets & enzymes)

be renally excreted (proteins too big to pass through glomerulus)

common way for excretion through the kidneys

drug or metabolite in urine or other excretory medium

take home liberation 

for a drug to be absorbed through biological membranes the drug must be liberated from its dosage form and if it is in the solid state, it must DISSOLVE in body fluids (DRUG MUST BE IN MOLECULAR FORM) 

dosage forms and release take away

drug in an aqueous suspension of crystals, the crystals must dissolve

absorption

for the drug to be delivered through extravascular routes, after it dissolves, it most often needs to be absorbed to reach its target= once a drug reaches the target the transporting fluid is the bloodstream for most drug routes

notable exception to easy passage

found w/in the CNS

endothelial cells of the capillaries supplying the brain and spinal cord are held together by tight junctions that restrict easy passage THINK BBB, tight junctions, efflux transporters

plasma protein binding & tissue binding 

for plasma protein binding an important point is that only free drug is able to leave the vasculature 

tissue binding- drugs can also bind to tissue components, these components are cell membrane phospholipid & proteins

TB- tissue bounding drug can act as a reservoir that can slowly release the drug and prolong its effect but can lead to ADEs if the drug is toxic to a particular tissue

metabolism take home

the primary function of metabolism is to transform compounds into more hydrophilic and therefore more excretable metabolites

DRUGS ARE MORE EXCRETABLE WHEN THEY ARE MORE HYDROPHILIC

pre systemic metabolism (first pass metabolism)

a lot of drug can be taken out before reaching target

metabolism that occurs before reaching systemic circulation

pre systemic metabolism (first pass metabolism) cont.

first pass metabolism can limit a drugs bioavailability, sites such as the skin & lungs can exhibit first pass metabolism but to LESSER degree

excretion (renal excretion) 

involves three major processes

1. glomerular filtration 

2. secretion from the blood into filtrate

   1. reabsorption from filtrate back into blood stream 

other excretion sites (biliary/fecal)

upon reaching the intestinal lumen, drug (metabolite) can be excreted in feces, but some can be reabsorbed back into the blood stream and this is known as ENTEROHEPATIC CIRCULATION

other excretion sites (saliva, breast milk)

drug excretion by these routes is insignificant to the pt but can be good for clinical importance

saliva- can be used to assay (test) drug lvls

breast milk- for breast fed children