01a: Pharmacokinetics Flashcards by Nuna H

List the pharmacologic phenomena that describe time course of drug in body.

Absorption
Distribution
Elimination

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Passive diffusion follows (0/1/2)-order kinetics. Thus, rate of transport depends on (X).

X = conc gradient

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List the physicochemical features of drug molecules that affect drug transport.

MW
Lipophilicity (oil:water partition coeff)
pKa (ionizable groups)
Physical form (solid/liquid/gas)
Stability in aqueous soln
Affinity for proteins

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Active transport follows (0/1/2)-order kinetics. Thus, (X) is constant.

X = rate of transport

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(X) method of drug transport is especially important for high MW compounds, such as protein therapeutics.

X = endocytosis

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Ionization markedly increases (X), thus (increasing/decreasing) lipophilicity.

X = hydrophilicity

Decreasing

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Drugs with (X) groups act as acids and become (pos/neg)-charged as pH (increases/decreases).

X = carboxylate
Neg
Increases

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Drugs with (X) groups act as bases and become (pos/neg)-charged as pH (increases/decreases).

X = amine
pos;
Decreases

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A drug that’s a weak base is able to cross cell membrane via diffusion at (high/low) pH.

High (loses H, becomes neutral)

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Aspirin is a (strong/weak) (acid/base) with pKa of 3.5. At physiological pH, can it cross membrane via diffusion?

Weak acid;

No - neg charged (lost H)

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(X) is the transport of small molecule drugs in bulk flow of aqueous fluid. What does the rate of this transport depend on?

X = filtration

Hydrostatic P
Drug properties (MW, size, charge, binding)
Tissue porosity

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List some organs/structures that use filtration as method of drug transport.

Glomerulus, liver sinusoids, choroid plexus

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(X) transport is an important mechanism for mAb transport. In the body, mAb are transported from (Y) into (Z) spaces.

X = convective
Y = lymph or blood
Z = tissue spaces

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Convective transport depends on:

Fluid flow rate (into tissue)
Sieving effect of paracellular pores
Hydrostatic P gradient

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The sieving effect in (X) transport depends on:

X = convective

Size/shape of pores
Size/shape/charge of Ab

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P-glycoprotein1 (Pgp) is a drug transporter belonging to (X) family. Which types of substrates does it transport?

X = ABC

Neutral, cationic, and amphipathic substrates (multidrug/variable)

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OAT1, aka (X), is a drug transporter belonging to (Y) family.

X = Organic anion transporter;
Y = solute carrier

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Rate of receptor-mediated endocytosis is dependent on:

Receptor expression

2. Membrane insertion of receptor

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T/F: All transport of Ab via endocytosis involves specific binding.

False - fluid phase endocytosis is nonspecific (no ligand binding)

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Fluid-phase endocytosis is a process driven by (X). It’s responsible for entrance of which drugs into (Y) tissues?

X = mAb concentration on extracellular side
mAb
Y = endothelial and peripheral

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Absorption kinetics: how long it takes for….

Transport of drug from site of admin to systemic circulation

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Absorption kinetics are characterized by:

Absorption half-life

2. Bioavailability

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Define bioavailability.

Percent of the administered dose that’s absorbed (reaches circulation in SAME molecular form)

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T/F: Fastest possible input rate is seen in oral route of drug administration.

False - IV

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IV drug administration: in addition to sterility, which two characteristics are important to consider?

1. Lack of particulates | 2. Aqueous solubility

IV administration is a good route for (low/high) MW, (polar/nonpolar) molecules.

High; polar

T/F: Enteral administration of drugs is simply another way to say "oral" admin.

False - enteral can be via mouth or rectum

"First-pass effect" influences (bioavailability/abs half-life) when drugs are administered via (X) route. Briefly describe this effect.

Bioavailability; X = enteral (oral) Lumenal, mucosal, and/or hepatic biotransformation

Oral administration of drug: absorption half-life affected by which three things?

1. Formulation of drug (dissolution from solid) 2. Gastric emptying time 3. Interactions with diet/other drugs in GI lumen

The GI mucosa could serve as a barrier, affecting (bioavailability/abs half-life) of drugs with which characteristics?

Bioavailability; High MW, low lipophilicity, carrier-mediated extrusion (back to lumen)

Parenteral admin of drugs includes which specific method(s)?

1. IV injection | 2. Intramuscular or subcutaneous injection

Uptake of high MW compounds into (X), when administered via I.M./S.C. injections, provides (fast/slow) absorption rate.

X = lymphatics | Slow

Inhalation route of admin provides (fast/slow) absorption of gases/vapors into circulation. Why?

Fast; 1. High pulmonary blood flow 2. Low diffusional distance from alveolus to blood

Distribution kinetics: rate and extent of drug distribution from (X) to (Y).

``` X = vascular fluid Y = tissue space ```

Distribution kinetics: the equilibration rate is based on (X).

X = blood flow/tissue perfusion rates

Distribution kinetics: list some tissue factors that affect equilibrium gradient.

1. Vascular permeability 2. Macromolecular and plasma protein binding 3. Dissolution of lipid-soluble drugs in adipose

V(d), the apparent volume of distribution, refers to:

volume of body into which drug appears to have distributed

T/F: Drugs will distribute into their V(d) depending on their chemical characteristics.

True

TBW (total body water) in 70 kg subject is (X) L and (Y)% body weight.

``` X = 40-42 Y = 58 ```

Majority of total body water, about (X)%, is (Y) fluid compartment.

``` X = 67 Y = intracellular ```

Extracellular fluid compartment in 70 kg subject is (X) L and (Y)% body weight.

``` X = 12-14 Y = 17 ```

Plasma fluid is part of (intra/extra)-cellular fluid compartment. In 70 kg subject, this is (X) L and (Y)% body weight.

Extracellular; X = 3-4 Y = 4

High MW drugs (ex: therapeutic proteins) will likely have V(d) equal to:

Plasma V

Low MW, polar drugs will likely have V(d) equal to:

Extracellular fluid

Low MW, non-polar/lipophilic drugs will likely have V(d) equal to:

TBW (or greater; stored in adipose)

Patient variability: V(d) is generally (directly/inversely/un)-proportional to body weight.

Directly

T/F: A drug's V(d) is always larger in obese patients.

False - depends on its characteristics/where it's distributed (TBW v adipose)

Clearance of an organ depends on which two key factors?

1. Plasma flow | 2. Extraction ratio (how readily organ extracts drug)

Total clearance is the (sum/product) of:

Sum; | Renal and non-renal clearances

T/F: Renal clearance of drug involves its elimination in an unchanged form.

True

Fc-mediated elimination pathways is for (endogenous/therapeutic) (X). Which receptors are involved?

Either; X = IgGs or mAbs FcRn or Fc(gamma)

In (X) method of drug elimination, (Y) complex forms in the (acid/neutral/basic) environment of the early endosome.

X = FcRn-mediated elimination/recycling Y =FcRn-mAb Acid

FcRn-mediated elimination/recycling: large fraction of endosomes end up where?

Not delivered to lysosome, but sorted to cell surface for Ab recycling

Administration of mAb can trigger immune response, generating (X), which then form (Y). How are these eliminated?

``` X = endogenous Ab (antidrug Ab/ADA) Y = immune complexes ``` Via RES (reticuloendothelial system, predominantly phagocytes)

Non-renal clearance via (X) system(s) involves excretion of the unchanged drug.

X = lungs or bile

Non-renal clearance: biotransformation of drug involves Phase I, which involves (X) processes.

X = ox, red, or hydrolysis

Non-renal clearance: biotransformation of drug involves Phase II, which involves (X) processes.

X = conjugation

Mechanisms of renal clearance of drugs, (same/different) as clearance of endogenous substances.

Same; 1. Glomerular filtration 2. Prox tubule carrier-mediated/active secretion 3. Passive reabsorption

Glomerular filtration: (X)% renal blood flow is filtered.

X = 20

T/F: Protein-bound drugs of any size are not filtered at the glomerulus.

True

Acid drugs excreted into urine via (X) process in (Y) part of renal clearance.

``` X = active transport (via organic anion transporter); Y = proximal tubule secretion ```

T/F: Protein-bound drugs of any size are not secreted at the proximal tubule.

False - protein binding doesn't affect secretion

T/F: Renal clearance: distal tubule reabsorption is passive and involves lipophilic, unionized drugs.

True

Acid drug in alkaline urine has (increase/decrease) excretion.

Increase (ionized at high pH, so not passively reabsorbed at distal tubule)

Renal clearance, Cl(R), is determined by: (equation)

Urine excretion rate/Cp

When calculating renal clearance, the plasma conc (Cp) is taken at (beginning/middle/end) of time interval during which urine excretion is measured.

Middle

Renal clearance (increases/decreases) with body weight and (increases/decrease) with age.

Increases; decreases

(X)-mediated recycling results in long elimination half-life of IgG and many mAbs.

X = FcRn

Elimination in first-order kinetics: the plot of Cp v time has which shape?

Curvilinear

Elimination kinetics: in first-order kinetics, therapeutic drug levels tend to be (higher/equal/lower) than Km. List some exceptions.

Much lower; Aspirin, Acetaminophen, EtOH

Elimination kinetics: in first-order kinetics, rate of biotransformation is proportional to:

Concentration

Why do elimination kinetics of EtOH and aspirin follow (X)-order?

X = zero Effective drug conc is much higher than Km of enzyme of biotransformation

Biotransformation (for elimination): Drug becomes (X) after phase 1 and (Y) after phase 2. (Y) is typically (more/less) active and (more/less) polar than parent compound.

``` X = metabolite Y = conjugated metabolite ``` Inactive and more polar

T/F: Absorption and elimination half-lives are typically first-order, meaning a constant amount of dose eliminated/absorbed per unit time.

False - constant FRACTION (first-order)

Phase 1 biotransformation carried out by (X) enzymes, which catalyze (Y) process. These are most typically located where?

``` X = cytochrome p450 Y = addition of molecular oxygen ``` sER membrane (with highest activity in liver)

Phase 2 biotransformation involves (X) process. List some moieties involved.

X = conjugation 1. Glucaronic acid 2. Sulfate 3. Methyl groups 4. Glutathione 5. Acetyl groups 6. Glycine

T/F: Renal clearance of drugs would be reduced by renal disease.

True

SC/IM drug administration: more extensive absorption of (high/low) molecular weight, (polar/nonpolar) molecules than by p.o. route.

High; polar

(X) is an enzyme that hydrolyzes succinylcholine. Rare gene mutation in this enzyme results in markedly (faster/slower) clearance and (longer/shorter) elimination half-life.

X = Pseudocholinesterase Slower; Longer