Intro to Pharmacology - Dr. Lauver - Exam 1

⭐ Q: What is pharmacology, and how do pharmacokinetics and pharmacodynamics differ?

Pharmacology is the study of how drugs interact with living systems; pharmacokinetics describes what the body does to a drug, whereas pharmacodynamics describes what the drug does to the body.

• Pharmacokinetics (PK): what the body does to the drug

• Pharmacodynamics (PD): what the drug does to the body

⭐ Q: What are physicochemical properties of drugs, and why are they important for pharmacokinetics?

Physicochemical properties are the inherent chemical and physical features of a drug that influence how it dissolves, crosses membranes, distributes, and undergoes absorption, metabolism, and elimination.

Important properties introduced include:

• molecular weight

• pKa

• ionization/charge

• lipid solubility or lipophilicity

• logP

• solubility

• permeability

• plasma protein binding

🔎 What this means:
ADME refers to:

• Absorption

• Distribution

• Metabolism

• Elimination

Before a drug can work, it has to physically get from where it was given to where its target is located.

⭐ Q: What do molecular weight, pKa, logP, solubility, permeability, and plasma protein binding mean?

These properties describe different aspects of a drug's size, acidity, lipid preference, ability to dissolve or cross barriers, and interaction with blood proteins.

Molecular weight

The mass of a molecule, expressed in g/mol or Da.

pKa

The negative log of the acid dissociation constant and a measure related to a molecule's acidity.

logP

A measure of lipophilicity, describing a compound's preference for a nonpolar/fat-like solvent versus a polar/water-like solvent.

Solubility

The ability of a substance to dissolve in a solvent and form a homogeneous solution.

Permeability

The ability of a substance to pass through another substance or barrier.

Plasma protein binding

The reversible attachment of a drug to blood proteins such as albumin or α₁-acid glycoprotein.

⭐ Q: What does logP tell you about a drug?

logP indicates a compound's relative preference for a nonpolar, fat-like environment compared with a polar, water-like environment, and therefore reflects its lipophilicity.

higher logP value = more fat-loving (lipophilic)

• Low logP but still positive → more hydrophilic / water-soluble

logP = 0 → roughly equal preference for fat-like and water-like environments

lower logP value = more water-loving (hydrophilic)

• Negative logP → prefers water more than fat

⭐ Q: What is passive drug diffusion, and what drives it?

Passive diffusion is the movement of drug molecules from an area of higher concentration to lower concentration without requiring energy, driven primarily by the concentration gradient of diffusible drug across a membrane.

Other important factors include:

Drug factors

• ionization

• lipid solubility

• molecular size/shape

Host/membrane factors

• membrane thickness

• membrane surface area

• environmental pH

The lecture calls passive diffusion the most common way compounds move through the body.

⭐ Q: What kinds of molecules cross lipid membranes most easily by passive diffusion?

Small, lipid-soluble and uncharged molecules cross membranes most readily by passive diffusion, whereas large polar molecules and charged molecules require transport mechanisms more often.

The figure shows:

• gases → high permeability

• hydrophobic/lipid-soluble molecules → high permeability

• small uncharged polar molecules → limited permeability

• large uncharged polar molecules → require transporter

• ions/charged molecules → require channel or transporter

🔎 What this means:
The middle of a cell membrane is lipid-like.

So drugs that are both:

uncharged + lipid soluble

have an easier time crossing it.

📝 iClicker Q: Which statement best describes passive drug diffusion across biological membranes?

a) It requires energy and specific transport proteins to move the drug along its concentration gradient.

b) It is driven by a concentration gradient, does not require energy, and favors the unionized, lipophilic form of the drug.

c) It depends only on drug solubility in water, regardless of lipophilicity or ionization state.

d) It occurs equally for all drugs, independent of their molecular weight or polarity.

b) It is driven by a concentration gradient, does not require energy, and favors the unionized, lipophilic form of the drug.

⭐ Q: What does pH represent, and what does the equation

pH = −log[H⁺] mean?

pH is a logarithmic measure of hydrogen-ion concentration, defined as pH = −log[H⁺].

🔎 What this means:
The brackets [H⁺] mean hydrogen-ion concentration.

Because pH uses a base-10 logarithm, a difference of one pH unit represents a 10-fold difference in H⁺ concentration.

⭐ Q: What is an antilog, and why is it useful when solving pharmacology calculations?

An antilog reverses a base-10 logarithm, so the antilog of x is 10ˣ.

Example:

log(100) = 2

Therefore:

antilog(2) = 10² = 100.

If you solve an equation and obtain:

2 = log(ratio)

you can't stop there.

You need to undo the log:

ratio = 10² = 100

⭐ Q: How are low and high pH related to hydrogen-ion concentration?

A lower pH means a higher H⁺ concentration and a more acidic environment, whereas a higher pH means a lower H⁺ concentration and a more basic environment.

🔎 What this means:

Low pH → lots of H⁺

High pH → fewer H⁺

⭐ Q: How do acids and bases differ in how they interact with H⁺?

An acid donates a proton, whereas a base accepts a proton.

Acid

HA → A⁻ + H⁺

After donating H⁺:

HA → A⁻

The acid becomes negatively charged.

Base

B + H⁺ → BH⁺

After accepting H⁺:

B → BH⁺

The base becomes positively charged.

⭐ Q: Which forms of weak acids and weak bases are ionized versus unionized?

A weak acid is unionized when protonated as HA and ionized when deprotonated as A⁻, whereas a weak base is unionized when deprotonated as B and ionized when protonated as BH⁺.

a Weak Acid is written as HA

• think of it has an acid (A) holding a proton (H⁺)

• while the acid (A) is holding the H⁺, it is neutral aka unionized

• once the acid (A) gives the H⁺ away, it becomes negative and is now ionized

HA = has H⁺ = unionized/neutral = happy

A⁻ = deprotonated, now has a neg charge = ionized

a Weak Base is just B

• B is neutral/unionized

• but once B accepts an H⁺, it becomes positive

  • B + H⁺ → BH⁺

B = no proton = unionized/neutral

BH⁺ = protonated = ionized/positive

💡 For weak bases: gaining H⁺ creates the charge
💡 For weak acids: having an H⁺ makes it neutral

Protonation does NOT mean the same thing for acids and bases in terms of charge.

📝 iClicker Q: Fill in the blanks:

An acid is ionized when it is in the ______ form, whereas a base is ionized when it is in the ______ form.

An acid is ionized when it is in the deprotonated form, whereas a base is ionized when it is in the protonated form.

⭐ Q: What is pKa, and what does it mean when pH = pKa?

pKa is the pH at which a drug or chemical functional group is present in equal ionized and unionized amounts.

Therefore:

when pH = pKa

50% ionized = 50% unionized

⭐ Q: What happens to protonation when environmental pH is below, equal to, or above pKa?

When pH < pKa the protonated form predominates, meaning there is more H⁺ around

• majority of weak acids would be in the form HA

• and weak bases would be in the form BH⁺

  • because there are more protons in solution in low pH, it is more acidic

When pH = pKa the forms are equal

When pH > pKa the deprotonated form predominates, meaning there is less H⁺ around

• majority of the weak acids would be in the form A⁻

• and majority of weak bases will be in the form B

  • because there are less protons in solution in high pH, it is less acidic

⭐ Q: How does environmental pH affect ionization of weak acids and weak bases?

Weak acids become more unionized in acidic environments and more ionized in basic environments, whereas weak bases become more ionized in acidic environments and more unionized in basic environments.

🔎 What this means:
Another way the lecture frames this is the “like environment” rule:

acidic drug + acidic environment → more unionized

basic drug + basic environment → more unionized

Q: For a weak base, how do B and BH⁺ compare when pH is below, above, or equal to pKa?

For a weak base,

BH⁺ predominates below pKa,

B predominates above pKa,

and the two forms are equal at pKa.

• pH < pKa: B < BH⁺

• pH > pKa: B > BH⁺

• pH = pKa: B = BH⁺

⭐ Q: Why does ionization influence drug absorption and distribution?

Ionization affects drug absorption because unionized drugs cross lipid membranes more easily, whereas ionized drugs are more water-soluble and cross membranes less readily.

Unionized / uncharged

• more lipid soluble

• favors diffusion/absorption

Ionized / charged

• more water soluble

• poorer passive membrane diffusion

• favors dissolution and excretion

📝 iClicker Q: Why is pH important for drug absorption and distribution?

pH is important because it determines whether a drug is predominantly ionized or unionized, which affects its membrane permeability.

⭐ Q: Why are weak acids generally more diffusible in acidic environments and weak bases more diffusible in basic environments?

Weak acids are more diffusible in acidic environments and weak bases in basic environments because those “like” environments favor their unionized forms, which cross lipid membranes more readily.

Q: How does aspirin illustrate the pH–pKa relationship for a weak acid?

Aspirin behaves as a weak acid, so it is more unionized below its pKa and more ionized above its pKa.

The lecture gives aspirin a pKa around 3.4–3.5.

Below pKa

pH < 3.4
→ its neutral HA predominates aka its unionized form

Above pKa

pH > 3.4
→ the deprotonated A⁻ form predominates aka the ionized form

Q: How does the caffeine example illustrate the pH–pKa relationship for a weak base?

In the lecture's caffeine example, the caffein is a weak base, so

B is the neutral form

BH⁺ is the ionized form

at pH < its pKa

→ protonated form predominates
→ ionized

at pH > its pKa

→ deprotonated base predominates
→ unionized/neutral

📝 iClicker Q: A weak acid has a pKa of 4.5. At which pH would it have the greatest fraction in the ionized form: pH 3, 4.5, or 6?

The weak acid would have the greatest ionized fraction at pH 6.

• we want the ionized form, aka the unprotonated form of HA which is A⁻

• So if we want A⁻ to predominate, we need it to be at the highest pH that is listed, which is 6

⭐ Memorize this!! Q: What is the Henderson–Hasselbalch equation and what does it tell us in pharmacology?

The Henderson–Hasselbalch equation relates pH, pKa, and the ratio of ionized to unionized drug, allowing us to predict drug ionization, membrane diffusion, ion trapping, and excretion.

For a weak acid:

pH = pKa + log([A⁻]/[HA])

1. if pH is equal to pKa

2. then [A⁻]/[HA] = 1 aka a 1:1 ratio

For a weak base:

pH = pKa + log([B]/[BH⁺])

• if pH is equal to pKa

• then B/BH⁺ = 1 aka its a 1:1 ratio

Short cut that works for both equations: Think

pH = pKa + log(non-protonated / protonated)

• HA = protonated weak acid

• A⁻ = deprotonated weak acid

• B = deprotonated weak base

• BH⁺ = protonated weak base

⭐ Q: Aspirin is a weak acid with pKa 3.5 in the stomach at pH 1.5, what is the unionized-to-ionized ratio and is passive absorption favored?

Given:

pKa = 3.5

pH = 1.5

Difference:

pKa − pH = 2

So:

10^(pKa − pH)

10² = 100

For a weak acid at low pH:

HA = protonated = unionized

Therefore:

unionized : ionized = 100 : 1

🔎 What this means:
The math matches the conceptual prediction:

pH < pKa
→ lots of H⁺
→ weak acid stays protonated
→ HA
→ unionized
→ membrane diffusion favored.

⭐ Q: For aspirin, a weak acid, with pKa 3.5 in the small intestine at pH 6.5, what is the unionized-to-ionized ratio?

Given:

pKa = 3.5

pH = 6.5

Difference:

pKa − pH = −3

Therefore:

10^(pKa − pH)

10⁻³ = 0.001 = 1/1000

So:

unionized : ionized = 1 : 1000

🔎 What this means:

pH > pKa
→ weak acid loses H⁺
→ A⁻ predominates
→ ionized.

⭐ Q: What is ion trapping, and why does it cause drugs to accumulate in certain body compartments?

Ion trapping is the accumulation of a drug in a compartment after an initially unionized drug crosses a membrane and then becomes ionized because of a different local pH.

General mechanism:

1. Unionized drug crosses membrane
→ 2. Drug enters compartment with different pH
→ 3. Drug becomes ionized
→ 4. once charged, the membrane becomes much harder to cross again
→ 5. causing the Drug to accumulate/ aka “trapping” it there

💡 Analogy:
Someone walks through a door while carrying nothing.

Once inside, you hand them a giant couch.

Now getting back through the door is much harder. 😭

⭐ Q: Where are weak acids and weak bases preferentially ion-trapped?

Weak acids are preferentially trapped in more basic compartments, whereas weak bases are preferentially trapped in more acidic compartments.

• Basically the tend to get trapped in their opposite/unLIKE environment

Weak acid

Basic environment
→ loses H⁺
→ A⁻
→ ionized
→ trapped

Weak base

Acidic environment
→ gains H⁺
→ BH⁺
→ ionized
→ trapped

⭐ Q: How can clinicians use urine pH to alter drug or toxin excretion?

Clinicians can manipulate urine pH to increase ionization of a drug in the tubular fluid, reducing reabsorption and trapping more drug in the urine for excretion.

Because remember the more ionized a drug is, the harder it is for it to cross a membrane

• therefore it reduces reabsorption

• and traps the drug in urine to be excreted

An example of a veterinary drug that does this is phenobarbital

• phenobarb is a weak acid, so if a dog ever gets overdosed on phenobard (an anti-seizure medication)

  • clinicians can increase the alkilinity of urine to make more ionized phenobarb => less reabsorption => more is excreted in urine