Drug Disposition and Pharmacokinetics Flashcards
Qualitative description of how the body handles the drug; includes how the drug is absorbed, where it is distributed, how it’s metabolized, and how it is eliminated in the body
Drug disposition
Quantitative description of drug disposition
Pharmacokinetics (PK)
Parameters that describe drug disposition
Absorption, distribution, metabolism, excretion (ADME)
Drug must be present at adequate concentration at its site of action to produce a pharmacological effect. (T/F)
True.
Route of administration and the conditions at the route of administration:
Absorption
Route influences extent and speed that drug is absorbed, thus influencing what?
The efficiency of therapeutic effect
Major site of oral drug absorption:
Intestine
Oral route of drug administration have what issues
?
slower rate of absorption and subject to LIVER FIRST-PASS METABOLISM
Bypasses first pass metabolism:
Parenteral (“beyond” the alimentary tract) - injection, inhalation, intranasal
Quicker absorption –>
quicker time to effect (intravenous, inhalation, sublingual, intramuscular, subcutaneous, rectal, oral, transdermal)
Fraction of the dose of unchanged drug that reaches systemic circulation by any route
Bioavailability
Drugs give by IV have bioavailability of what? Other routes will be what?
IV = 100%, other = <100%
For routes other than IV, bioavailability depends on:
Chemical form of drug, contact time with the absorbing surface, presence of drug metabolizing enzymes and efflux transporters can change or eliminate the drug before it reaches the systemic circulation
Drug has to ENTER circulation after administration:
Absorption
Drug has to traverse WITHIN the body:
Distribution
Drug has to move INTO liver and hepatocytes:
Metabolism
Drug/metabolites must be ELIMINATED:
Excretion
Mechanisms by which drugs are transported after administration:
- passive transfer
2. carrier-mediated transport
Passive transfer consists of:
- bulk flow (filtration)
2. passive diffusion
Carrier-mediated transfer consists of:
- facilitated diffusion
- active transport
- receptor-mediated endocytosis
Passage of compounds through intercellular pores:
Bulk Flow (peripheral capillaries and kidney)
Passage of drugs by dissolving into and diffusing across lipid membranes:
Passive Diffusion
What is the most important transport processes?
Passive diffusion; most drugs are targeted for the enteral route that utilizes passive diffusion as a primary mechanism for absorption.
Properties of molecules that cross by passive diffusion:
- uncharged, non-ionized
2. lipid soluble (lipophilic or hydrophobic)
Measured by the distribution in an immiscible mixture of an organic-aqueous solvent:
Lipophilicity
The greater the permeability, the greater the lipophilicity. (T/F)
True.
Diffusion of drug from a high to low gradient is known as which law?
Fick’s 1st law of diffusion
Most drugs are small molecular weight organic acids or bases that exist just as ionized forms. (T/F)
False. they exist in both ionized and non-ionized forms
Neutral molecule which can reversibly dissociate into an anion to yield a proton
Acidic Drug
Proton Donor
Acidic drug
Neutral molecule which can form a cation by combining with a proton.
basic drug
Proton acceptor
basic drug
Difference between cation and anion:
Cation = positively charged, Anion = negatively charged
Non-ionized form of drug passively diffuses. (T/F)
True. Diffuse until equal concentrations of uncharged are attained on both sides of membrane (equilibrium).
Total amount of drug on either side of the membrane equals:
non-ionized + ionized forms
Amount of non-ionic and ionic species depends on:
- whether the drug is an acid or base
- pKa of the drug
- pH of the environment
Term used for pH where 50% is ionized and 50% is non-ionized:
pKa = percent ionization is 50%
Accumulate at high pH side of membrane:
Weak acidic drugs (or bases)
Accumulate at low pH side of membrane:
Weak basic drugs (or acids)
For each pH unit from the pKa, it changes the N/I ratio by what?
10
For a weak acid what happens as pH increases/decreases in regards to ionization?
pH increases for weak acid: favors ionized.
pH deceases for weak acid: favors non-ionized.
For a weak base what happens as pH increases/decreases in regards to ionization?
pH decreases for weak base: favors ionized.
pH increases for weak base: favors non-ionized.
Three examples of carrier-mediated transport:
- facilitated diffusion
- active transport
- receptor-mediated endocytosis
Protein transporter moves drug DOWN a chemical/concentration gradient until equilibrium is achieved:
facilitated diffusion
This type of diffusion is energy INDEPENDENT:
facilitated
This type of diffusion is bi-vectorial; same protein can transport in both directions across the membrane but down the concentration gradient:
facilitated
SLC =
solute carrier proteins, facilitated diffusion
Transports drug AGAINST its concentration gradient (from lower to higher amount of drug).
Active transport
This type of transport is energy DEPENDENT and uses what?
Active transport; uses ATP (requires energy to transport against its concentration gradient)
Difference between primary and secondary transporters:
Primary: energy machinery contained within the transporter; ATP Binding Cassette, ATP as energy.
Secondary: energy source is provided from other sources not within the transporter; Solute Carrier
OAT stands for:
Organic Anion Transporter
OCT stands for:
Organic Cation Transporter
3 examples of neurotransmitter re-uptake transporters:
NET, DAT, SERT (all are Na+ symporters)
MDR stands for:
multi-drug resistance
MRP stands for:
Multidrug resistance-associated proteins
Selectivity is based on size, it is not saturable, and not energy dependent:
bulk flow (filtration)
Selectivity is based on non-ionized/lipophilic, it is not saturable, and not energy dependent:
passive diffusion
Has broad Selectivity, it is saturable, and not energy dependent:
Facilitated diffusion
Has broad Selectivity, it is saturable, and is energy dependent:
active transport
Highly ionized drugs (N/I <0.001) will not ever be absorbed to some extent. (T/F)
False, they will eventually be absorbed to some extent.
Equilibrium os non-ionic species is never attained where?
In the gut/GI tract
6 factors that determine rate and extend of drug distribution:
- blood flow and tissue mass/volume
- capillary permeability
- lipid solubility of the drug
- extend of drug ionization and tissue pH
- transport mechanisms available
- extent of drug binding to proteins
In regards to tissue vascularization, give examples of high equilibrate that happens quick and first compared to poor equilibrate that occurs slowly:
Highly equilibrate quicker and first: liver and brain
Intermediate: muscle, skin
Poorly equilibrate very slowly: adipose, bone
What occurs when the concentration of charged species is higher in tissue than in plasma and the drug accumulates in tissue?
Ion trapping
Compounds that are charged at all physiological pHs diffuse poorly across lipid membranes and rely on carrier-mediated transport to cross membranes. (T/F)
True.
Which would provide the fastest, greatest distribution of drug?
Bulk flow.
Equation for Apparent volume of distribution (Vd) =
Vd (L) = X0 (mg) / Cp (mg/L); the amount of drug in body/the concentration of drug in the plasma immediately after IV administration.
Volume of distribution and concentration of drug in plasma are inversely related. what does this mean?
If concentration decreases, then volume of distribution increases; if concentration of drug in plasma increases, then volume of distribution decreases
The volume that X0 occupies in body to yield Cp is known as:
Apparent volume of distribution (Vd).
What is the volume of fluid for the following: plasma, extracellular fluid, total body water?
plasma: 3 L, extracellular fluid: 12 L, total body water: 42 L.
If Vd > 100, what does can we assume this means?
volume of distribution is considered stored in fat.
What is the significance of volume of distribution?
utilized in the calculation of doses and dose rates
Compare larger Vd to smaller Vd.
Larger Vd = more lipophilic, easier to cross BBB, accumulate in tissues or fat, maintained longer in body, typically require hepatic metabolism for elimination;
Smaller Vd = more hydrophilic, more rains in the blood with little accumulation in fat, tissue or brain, may be large MW or bind to plasma proteins, eliminated primarily in kidney
