PSC 4215 - Exam 2 - Combined set - General principles of drug disposition, Movement across membranes, Review of absorption, Distribution of drugs, PLP plasma proteins

Which substances are absorbed in the stomach, and why?

Weak acids and alcohol remain unionized in the stomach’s low pH (acidic).

• Unionized molecules are lipophilic so it can cross the lipophilic cell membrane by passive diffusion and absorb into tissues

Which drugs act rapidly and why? Provide an example.

• Lipophilic drugs bc it can cross the lipophilic cell membrane quickly

• Anesthesia

Describe oral drug journey from ingestion to excretion.

1. Stomach = Drug dissolution

2. Intestines = Drug absorption

3. Liver = 1st pass metabolism (reduces drug concentration)

4. Systemic circulation/blood = Distributes drug to target tissues

5. Target site = Drug produces effect

6. Excretion = Urine (via kidney filtration), feces (via liver metabolism)

Define onset, duration, intensity of pharmaceutical agents

• Onset = Start time

• Duration = Length

• Intensity = Strength

What determines the magnitude of a drug?

Dose

• The higher the concentration at the target site, the higher the intensity

(Amount of drug taken, ex; 500mg.)

Does higher dose lead to faster onset? Why/why not?

No, onset depends on absorption speed

Pharmacokinetics (PK) vs. Pharmacodynamics (PD)

• PK = What the body does to the drug (ADME)

• PD = What the drug does to the body

ADME

Absorption, distribution, metabolism, excretion

ADME is the study of what pharmacologic process?

PK

Effect of a drug on target cells is called?

PD

What is a xenobiotic? What kind of substance can act like it?

• Foreign substance

• Endogenous substances (ex: Taking thyroxine externally due to thyroid gland removal.)

How are doses established in clinical trials? What 3 factors does testing include.

• Trial & error in phase 2 of FDA approval process

• Testing includes dose, interval, route

T/F: Drug effect is proportional to concentration at site of administration.

False. Drug effect is proportional to concentration at the site of action (where the drug works) not administration (where the drug enters)

What are the two sites where concentration gradients are measured in PK?

Site of administration and site of action

T/F: Drug destroyed post-absorption still has high effect.

False. If a drug is absorbed, then destroyed by first pass metabolism before reaching target site, it will have a low effect.

Why do many drugs cause side effects?

They reach non target sites during distribution

What do acidic drugs bind to?

Albumin (the main plasma protein)

What do basic drugs bind to more?

α1-acid glycoprotein

Define Free drug. How is it eliminated?

• Active drug molecules that can cross cell membranes and bind to receptors.

• Eliminated thru kidney filtration (excreted as urine) or liver metabolism (taken up by enzymes, excreted as bile or feces)

Protein bound drug

Inactive complex that acts like a reservoir bc it slowly releases free drugs

• Increases drug presence in the blood

When plasma proteins bind to drugs, what is the effect on duration and elimination?

• Increases duration bc the complex stays longer in the body

• Reduces elimination bc complex is too large for elimination or absorption

Why exclude albumin-bound drug from effect curves?

Complex is inactive

What are 4 fates of a free drug in plasma?

1. Effect

2. Sequestered (absorbed)

3. Metabolized

4. Eliminated

4 main drug elimination routes?

Urine, feces, sweat, exhaled air

What does concentration vs time curve show?

• X = Time

• Y = Concentration

• Up/down (curve) = Intensity

  • Up = Rising drug levels (Due to drug absorption/injection)

  • Down = Drug elimination (Due to metabolism/excretion)

• Left/right = Half life (The amount of time the drug in the body reduces of half)

  • Left = Narrow width of the curve due to steep slope indicates short half life (good for short exposure)

  • Right = Wide width of the curve due to gentle slope indicates long half life (good for long exposure)

• Left/right = Onset

  • Left curve shift = Faster onset

  • Right curve shift = Slower onset

6 Methods of collecting drug concentration data

Urine, feces, exhaled air, blood, CSF, biopsy

Blood vs. plasma vs. serum — difference?

• Blood = Whole blood cells (RBC, WBC, Platelets) + Plasma (liquid portion)

• Plasma = Liquid portion only + Clotting factors (No blood cells)

• Serum = Clotted plasma

T/F: Drugs in blood are in the water portion.

True, unbound drugs (free drugs) remain in the plasma

T/F: Total body drug amount can be measured directly.

False, only estimates are possible by measuring plasma

Positive vs. negative slope in concentration-time curve?

• Positive = Absorption > Elimination

• Negative = Elimination > Absorption

What does a plateau in the concentration-time curve mean?

Absorption = Elimination

Why does plasma concentration reflect tissue concentration?

They are in equilibrium

• Free drugs move freely between plasma and tissues, so plasma concentration mirrors tissue concentration

MEC

Minumum effective concentration

• Below this, there is no therapeutic effect

MTC

Minimum toxic concentration

• Lowest level for toxicity

How to find drug duration on a conc-time graph?

The start and end time of the drug concentration that reached MEC

How to find drug onset on a conc-time graph?

The time that drug concentration reaches MEC

T/F: MEC always gives desired response.

False. MEC marks the start of the therapeutic response not the max

Response intensity is proportional to what?

Plasma concentration

AUC

Area under the curve

• Total amount of the drug that is absorbed systemically

On a conc-time curve, does the curve shift right/left with IM injection?

It shifts the curve left which indicates faster onset

Tmax vs. Cmax

• Tmax = The time it takes to reach max (peak) concentration in the plasma

• Cmax = Max (peak) concentration in the plasma

Effect of IV bolus on conc-time curve?

It starts very high with a steep negative slope

Effect of infusion on conc-time curve?

Rises slowly then plateau

T/F: A single curve typically represents the pharmacokinetics of one dose of a drug (the graph represents oral administration).

True

Graded vs. quantal effect curves — difference?

• Graded curve = The magnitude (intensity) of a response

• Quantal curve = The % of a population that had a response

Is the graded response reversible?

Yes, at a lower dose

Which response is all-or-none?

Quantal response

3 Examples of quantal responses

Toxicity, death, hypotension

Does plateau on conc-effect curve guarantee safe effect?

No, it could be toxic

T/F: Conc-time curve shape is unchanged by dose and same route

True, only Cmax changes

T/F: Higher dose changes half-life

False, half life is constant

Does the Rate of drug elimination increase/decrease/stay the same at higher doses?

The rate stays the same

• First order kinetics: The body eliminates a constant fraction of the drug per unit time (ex; 50% per hour)

Therapeutic index (TI)

Toxic dose / Therapeutic dose

T/F: The larger the TI the safer the drug

True

When is response-time curve preferred?

When the plasma concentration does not match the effect

(Ex; It is difficult to measure the plasma levels when taking topicals but the affect can be observed, like reduced inflammation)

4 Reasons why plasma concentration may not reflect the drug effect?

1. Tolerance; reduced drug response despite same dose

2. Delays; takes time to equilibrate at the target site

3. Active metabolites

4. Chirality; one isomer may be active/inactive

Prodrug

Inactive form of a drug that gets activated inside the body which is usually by metabolism

If an oral dose has a greater effect than IV, what does it suggest?

The oral route activated the prodrug

• The drug gets absorbed in the GI tract then metabolized by the liver where liver enzymes converts it from inactive to active

Tolerance vs. Resistance

• Tolerance = Host adapts, decreased response to a drug over time

• Resistance = Pathogens/cells adapt, drugs become less effective against it (ex; bacteria, cancer cells)

3 Mechanisms of tolerance

1. Increased Clearance

2. Decreased Receptors

3. Decreased Absorption

T/F: Plasma conc. does not reflect response in single-dose therapy

True

Is slow or fast absorption preferred for treating Helicobacter pylori infection?

(H. pylori is a stomach bacteria that can damage stomach and duodenal tissue, causing pain and inflammation.

Slow absorption, it helps keep the drug in the stomach longer

Methotrexate is used to treat cancer and autoimmune diseases. What does its affect depend on?

Duration of exposure not concentration

IV bolus vs infusion

• IV bolus = Entire dose is given all at once

• Infusion = Steady dose

Why does warfarin take days to work? (Warfarin prevents blood clots)

Clotting factors already in the blood circulation need to degrade

T/F: Fluctuating antibiotic levels may be preferred

True

Ceftazidime shows what kinetics and concentration–time curve shape? (Ceftazidime treats bacterial infections)

• First order kinetics

• Flat curve

Define First order kinetics. What kind of curve does it have?

• The body eliminates a constant fraction of the drug per unit time, so drug elimination increases with concentration (ex; 50% per hour)

• Exponential decline curve

Define Zero order kinetics. What kind of line does it have on a graph?

• The body eliminates a constant amount of the drug per unit time (ex; 10 mg per hr)

• Linear decline

Which kinetic type is most common in body?

First order kinetics

First-order kinetics equation before and after integration?

• Before integration: Rate = -K[C]

• After integration: C = C₀e⁻ᵏᵗ

Slope & y-int of log conc-time graph?

• Slope = -K/2.303

• Y-int = log C₀

How does half-life differ in first order vs. zero order kinetics?

• First order kinetics = Constant

• Zero order kinetics = Increases with dose

Which kinetics appears linear on semi-log plot?

First order kinetics

What does slope of semi-log plot represent?

Elimination rate

What is the key difference between transcellular and paracellular transport?

• Transcellular: Lipophilic drugs passes through cells

• Paracellular: Small drugs with low molecular weight (MW) passes between cells, limited by tight junctions

Why does inflammation increase paracellular transport?

It loosens tight junctions, allowing larger/small drugs to pass.

What does paracellular transport depend on?

Molecular weight of the drug (must fit through junctions).

What does transcellular transport depend on most?

Lipophilicity of the drug

Which drugs diffuse best through membranes?

Highly lipophilic drugs.

True or False: Human cells have cell walls.

False — they have cell membranes.

What 3 things can cross the semi-permeable membrane?

1. Lipophilic drugs

2. Small hydrophilic molecules

3. Water

What does the fluid mosaic model describe?

Structure of cell membrane = Fluid lipid bilayer + Embedded proteins for transport

What drives passive diffusion?

• Concentration gradient (high → low)

• No energy required

True or False: At equilibrium, molecules are equal on both sides (blood vs tissues)

False — only the rate is equal, not the amount.

How can drug absorption be increased at equilibrium?

Increase blood flow to restore concentration gradient

What effects of polycythemia on drug equilibrium and diffusion?

(Polycythemia = Abnormally high RBCs = Thick blood flow)

• Increases equilibrium due to less plasma volume

• Decreases diffusion due to less blood flow

  (which lowers concentration gradient)

What is the simplified form of Fick's Law?

Rate = P × [conc. at absorption site].

Why is Cp (plasma concentration) negligible in Fick's Law?

Absorption site concentration > Plasma concentration

Do lipids follow Fick’s law?

(Fick’s law: Rate of drug diffusion across a membrane)

No — they diffuse freely.

What order of absorption does Fick’s Law describe?

First-order absorption, Higher concentration = Faster absorption rate

Why is absorption usually faster than elimination?

There is a larger concentration gradient between the absorption site (e.g. gut) and the blood

Most drugs are weak. What is the implication?

Weak electrolytes — they are both hydrophilic and lipophilic.

What is the solubility difference between ionized and unionized drugs?

• Ionized = Water-soluble

• Unionized = Lipid-soluble

Where do weak acids accumulate — stomach or plasma? Why?

• They get ionized in plasma so they accumulate

• They remain unionized in the stomach so they get absorbed

Where do weak bases accumulate and why?

In the stomach — they become ionized there = ion trapping

Key Concept: "Like absorbs like"

• Acidic environment (e.g. stomach): favors _____ → better absorption

• Basic environment (e.g. intestines): favors _____ → better absorption

• Unionized weak acids

• Unionized weak bases

Which pharmacokinetic phase is influenced by protein binding?

Distribution.

What is the effect of plasma protein binding on drug half-life and tissue affinity?

• Increases half life

• Decreases tissue binding

How does tissue binding affect half-life?

It decreases half-life — the drug is pulled into tissue.