621 unit 1 LOs Lec 1-2

Pharmacokinetics

Pharmacokinetics

the relationship between drug input (dose, dosage, frequency) and how the concentration of drug changes with time

Pharmacodynamics

the relationship between concentration at an active site & effects with time on the body

Systemic Absorption

the process by which unchanged drug proceeds from the site of administration to site of measurement

Distribution

Process of reversible transfer of the drug to and from the site of measurement and the peripheral tissues.

Disposition

sum of all kinetic processes that occur to a drug after systemic absorption

•elimination and distribution

ADME

Absorption Distribution Metabolism Excretion

Therapeutic Window

• Exposure high enough to get desired response from drug but not too high to cause adverse effects

Transcellular vs Paracellular Transport

Trans: transport through a cell membrane

Para: Transport between cells

Intravascular Dosing

Drug is placed directly in the blood. Ex; intra venous

1)Distribution from blood to tissue across capillary membrane

2)Hepatic Elimination (metabolism) - transfer from  blood to intracellular compartment of hepatocytes

3. Renal elimination (excretion)

Extravascular Dosing

same steps as intra w addition of absorption step from admin site to blood

Systemic pathways for Extravascular dosing

oral, intramuscular, subcutaneous, sublingual, buccal, dermal, pulomnary, rectal

Regional pathways for Extravascular dosing

ventricular delivery to brain, pleural delivery to the lungs, peritoneal delivery to abdomen

Passive Diffusion

(most drugs)

molecules transfer from regions of high to low concentrations

Passive Facilitated Diffusion

Movement across the membrane facilitated by a transporter

Active transport

Can move drugs against an opposing gradient, The direction of movement can be either influx (into the cell) or efflux (out of the cell)

Which types of diffusion follow the concentration gradient

Passive & Facilitated

Which types of diffusion are structure specific

Facilitated & Active because of the transporters

Which types of diffusion have saturable transport

Facilitated & Active because of the transporters

Which types of diffusion can be inhibited by structurally related compounds

Facilitated & Active because of the transporters

Which types of diffusion require energy

Active transport

Which types of diffusion can be inhibited by metabolic poisons

Active transport

Because active transport mechanisms depend on cellular metabolism for energy, they are sensitive to many metabolic poisons that interfere with the supply of ATP

What types of diffusion can go from lower to higher concentrations

Active transport

What does the transport maximum look like graphically

What factors affect drug transport across a membrane barrier

1. Molecular Size

2. Lipophilicity

3. Degree of protein binding

4. Charge (degree of ionization)

Ficks First Law

Rate= [ (D K SA)/ h] (Cside1-Cside2)

amount/time

D= diffusion coef

K= lipid/water partition coef

SA= Surface area (cm^2)

h= membrane thickness

c= drug concern on each side

Describes the passage of drugs through membranes by Diffusion

Permeability

(D * K)/ h = P in distance/time

expression of ease of membrane penetration

Diffusion Coefficient D (Stokes Einstein)

D= ( R * T) / (6 * N * pi * r *n)

R= gas constant

N= avogadro number

r= radius

n= viscosity

As the membrane SA increases the rate of absorption….

increases

As the functional membrane height increases the rate of absorption….

decreases

As the lipid water partition coefficient increases the rate of absorption…

increases

As molecular size increases, the rate of absorption…

decreases

As concentration on side 1 increases, the rate of absorption…

increases

As viscosity increases, the rate of absorption …

decreases

Cite active transport example of particularly p-glycoprotein

Active transporters play major roles in removing drug metabolites and foreign substances from cells and tissues

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EX: Tumor resistance to specific anticancer drugs

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•MDR1 was found to efflux many drugs that had entrees cancer cells, P-glycoprotein was found to be responsible, it is located in many organs and tissues and plays a big role in the hepatic secretion of many drugs into bile

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•P-gp recognizes hundreds of compounds, it works as a hydrophobic vacuum cleaner, pulls substances from the lipid bilayer, expelling them to promote multi drug resistance

Protein binding- lipophilic drugs

•Only unbound, nonpolar drugs are able to cross lipid membranes

•Unbound concentration provides the driving force for drug transport

•At distribution equilibrium, Unbound drug concentration will be equal on both sides of the membrane

Degree of Ionization

•pH partition hypothesis: only un ionized nonpolar drugs are able to cross lipid membranes

•pH partition hypothesis applies @ equilibrium- used to predict the influence of pH on the rates of absorption and distribution

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For 2 drugs with equal lipophilicity/molecular size/ protein binding that are not subject to carrier-mediated transport, the drug which is more unionized at a given pH will nearly always exhibit a faster rate of penetration across the membrane

Henderson Hasselbalch equation

pH= pka + log [unpronotated / protonated]