Basics of Pharmacology

What does pharmacokinetics describe?

What the body does to the drug

What are the four main pharmacokinetic processes?

1. Absorption

2. Distribution

3. Metabolism

4. Excretion

Are pharmacokinetic processes common to all drugs?

Yes

What does systemic absorption of a drug into circulation depend on?

1. Drug’s solubility

2. Blood flow to the site of absorption

3. Area of absorbing surface available

The relative amount of drug that reaches systemic circulation

Bioavailability

What is the bioavailability of drugs given intravenously (IV) or intramuscularly (IM)?

1 (100%)

Why is bioavailability usually less for oral or rectal (enteral) drugs?

First-pass metabolism by the liver

In anesthesia, why do most drugs have 100% bioavailability?

Because they are given IV and instantly reach systemic circulation

Metabolism that occurs before a drug reaches systemic circulation or its target site

First-pass metabolism

How does first-pass metabolism affect bioavailability?

Significantly reduces the bioavailability of drugs

→ Especially when taken orally

Which organ is the primary site of first-pass metabolism for enteral drugs?

Liver

In which organs can first-pass metabolism occur?

1. Liver

2. Lungs (Ex: Fentanyl uptake/metabolism)

3. Plasma esterases/pseudocholinesterase

Succinylcholine is metabolized by

Pseudocholinesterase

What is pseudocholinesterase also known as?

1. Butyrylcholinesterase

2. Plasma cholinesterase

Which tissue group gets the largest share of cardiac output despite being a small % of body weight?

Vessel-Rich Group (VRG)

Which tissue group gets almost no cardiac output?

Vessel-Poor Group (VPG)

Examples of VPG

1. Bones

2. Ligaments

3. Cartilage

Percentage of CO for:

1. Vessel-rich group

2. Muscle and skin

3. Fat

4. Vessel-poor group

1. Vessel-rich group → 75%

2. Muscle and skin → 19%

3. Fat → 6%

4. Vessel-poor group → 0%

After an injection, where does a drug initially distribute?

Vessel-rich group (VRG) tissues

→ Because most cardiac output goes there

__________ rapidly equilibrate into CNS tissue but are also avidly taken up into fat

Lipophilic drugs

The movement of a drug from vessel-rich tissues (Ex: Brain/CNS) into less perfused tissues (Ex: Fat or muscle), reducing its clinical effect

Redistribution

For lipophilic drugs, _______ will gradually absorb the drug over time due to redistribution

Fat

Why does redistribution cause drug effects to wear off?

Because drug concentration in the target organ falls as it moves into fat and muscle, even though the drug is still present in the body

What happens with repeated doses of lipophilic drugs?

Peripheral tissues accumulate the drug

→ Impact of redistribution is reduced, leading to prolonged drug effects

After redistribution has occurred, what mainly determines the fall in plasma drug concentration?

Elimination by metabolism and excretion

What causes the major initial drop in plasma drug concentration after injection?

Rapid distribution of the drug into vessel-rich group (VRG) tissues

True or false: Most drugs are bound to plasma proteins and unavailable for uptake or excretion

True

Which plasma protein mainly binds acidic or neutral drugs?

Albumin

Which plasma protein mainly binds basic drugs?

α1-acid glycoprotein

What is the effect of low plasma protein levels on drug availability?

Increased availability

→ Higher amount of free drug in serum, since less is bound to proteins

What conditions lower plasma protein levels, leading to more free drug in plasma?

1. Age

2. Hepatic disease

3. Renal failure

4. CHF

5. Major burns

6. Pregnancy

Does plasma protein binding significantly affect propofol?

No, because propofol is given in a lipid emulsion that provides its own binding

In theory, how should higher free drug levels affect drug action?

Increase the drug’s effect

→ However, in practice, this relationship is unclear

Do plasma proteins account for most drug binding in the body?

No

→ Plasma proteins only account for small portion of total binding sites for a drug in the body

How much do changes in plasma protein concentration influence drug action at receptor sites?

Generally very little

Are most drugs weak or strong acids/bases?

Most are weak acids or weak bases

→ Existing in both ionized and non-ionized forms

Which form of a drug is usually lipid-soluble?

Non-ionized form

Which form of a drug is usually water-soluble?

Ionized form

Which form of a drug is usually pharmacologically active?

Non-ionized form

Which form of a drug can easily cross cell membranes, such as BBB, placenta, renal tubular epithelium, and hepatocytes?

Non-ionized form

How does ionization affect drug handling in the body?

1. Reduces GI absorption

2. Limits hepatocyte metabolism

3. Promotes renal excretion

What is the general equilibrium equation for a weak acid and a weak base?

Weak acid: H⁺ + A⁻ ⟷ HA

Week base: H⁺ + B ⟷ HB⁺

According to Le Chatelier's principle, what happens when [H⁺] increases (acidic environment)?

The equilibrium shifts to the right

→ Adding more reactants = Right shift

H⁺ + A⁻ ⟷ HA

H⁺ + B ⟷ HB⁺

What does the pKa of a drug represent?

pH at which the drug is 50% ionized and 50% nonionized

→ Henderson-Hasselbalch equation

pH = pKa + log([A-]/[HA])

→ At 50% ionized and 50% non-ionized, [A-]/[HA] is 1

→ Log1 = 0, so pH = pKa

If serum pH is lower than the drug's pKa, which way does equilibrium shift?

To the right (more protonated forms)

→ More H+/reactant in serum

H⁺ + A⁻ ⟷ HA

H⁺ + B ⟷ HB⁺

If serum pH is higher than the drug's pKa, which way does the equilibrium shift?

To the left (more deprotonated forms)

→ Environment is more basic than the drug. Left shift to maintain equilibrium

H⁺ + A⁻ ⟷ HA

H⁺ + B ⟷ HB⁺

Midazolam is a Base (H⁺ + B ⟷ HB⁺)

• pKa = 6.2

• Blood pH = 7.4

Which side will the equation shift?

Is midazolam ionized or non-ionized in the blood?

1. Left shift

2. Midazolam is mostly non-ionized in blood

Propofol is an Acid (H⁺ + A⁻ ⟷ HA)

• pKa = 11

• Blood pH = 7.4

Which side will the equation shift?

Is propofol ionized or non-ionized in the blood?

1. Right shift

2. Propofol is mostly non-ionized in blood

When are weak bases mostly nonionized?

When the pH is greater than their pKa

When are weak acids mostly nonionized?

When the pH is lower than their pKa

What is the main purpose of drug metabolism?

Convert pharmacologically active, lipid-soluble drugs into water-soluble, usually inactive metabolites

Can metabolites be more potent than the parent drug? Examples?

Yes

→ Morphine’s metabolite M6G is more potent

What is a prodrug? Example?

An inactive compound that becomes active after metabolism

→ Codeine to morphine

What are the four basic pathways of drug metabolism?

Phase I

1. Oxidation

2. Reduction

3. Hydrolysis

Phase II

4. Conjugation

Which phase of metabolism introduces or unmasks a polar group on the drug?

Phase I reactions

Which phase of metabolism adds an endogenous substrate to make the drug more water-soluble?

Phase II reactions

Where do oxidation and reduction occur in Phase I of metabolism?

Liver

What is the role of oxidation and reduction in Phase I metabolism?

Increase the polarity of drug molecules before Phase II

Where does hydrolysis often occur?

Outside the liver, commonly in plasma and tissues

Give examples of drugs metabolized by ester hydrolysis in plasma/tissues

1. Remifentanil

2. Succinylcholine

3. Esmolol

4. Ester local anesthetics

Why do most drugs need to become polar (hydrophilic)?

To allow excretion

A large family of membrane-bound enzymes responsible for metabolizing many drugs

Cytochrome P450 enzyme system

Which CYP enzyme metabolizes more than half of all drugs?

CYP3A4

What happens when drugs induce CYP enzymes?

Metabolism increases → Drug effects and duration decrease

What happens with ongoing drug exposure that induces CYP enzymes?

Enzyme activity rises → Metabolism of other drugs handled by the same enzyme subtype is altered

What happens when drugs inhibit CYP enzymes?

Metabolism decreases → Drug effects and duration increase

What is the purpose of forming conjugates in Phase II metabolism?

To create highly polar compounds that are easily excreted in urine or bile

Is drug metabolism always strictly Phase I followed by Phase II?

Usually sequential, but not always

→ Some Phase I metabolites are excreted directly

→ Some Phase II reactions can occur before Phase I

→ Some drugs undergo Phase II without Phase I at all

How does drug metabolism differ in neonates (<1 year old)?

They have reduced Phase I and Phase II enzyme activity

→ Slower drug clearance

What is hepatic clearance? Equation?

Volume of blood cleared of a drug per unit time

→ Hepatic blood flow × Extraction ratio

1. How are drugs with a low hepatic extraction ratio cleared?

2. What factor increases clearance for low extraction ratio drugs?

3. How does hepatic blood flow affect clearance?

1. They are capacity-limited

→ Clearance depends on liver enzyme activity

2. Enzyme induction = Proportional increase in clearance

3. Minimal effect on clearance

→ Liver can only handle a fraction of the drug at a time, regardless of the amount of blood flow

1. How are drugs with a high hepatic extraction ratio cleared?

2. What factor increases clearance for low extraction ratio drugs?

1. They are flow-limited

→ Clearance depends on hepatic blood flow

2. Increased/decreased blood flow = Proportional change in clearance

True or false: For high hepatic extraction ratio drugs, the liver removes almost all of the drug delivered by the blood

True

What is renal clearance? Equation

The rate of drug elimination by the kidneys

→ Renal blood flow × Renal extraction ratio

Which form of a drug is excreted in urine?

Ionized form

Which form of a drug is more likely to be reabsorbed in the renal tubules?

Non-ionized, lipophilic form

→ They cross membranes readily and diffuse back into the blood

How should drug dosing be adjusted in patients with severe renal disease?

Doses should be reduced to prevent buildup of drugs and their metabolites

What is the Cockcroft-Gault equation used for?

Estimating creatinine clearance

How is creatinine clearance related to GFR?

It closely reflects GFR but is not identical

→ Slightly overestimates true GFR (about 10–20%)

Why is creatinine useful for estimating clearance?

1. Water-soluble

2. Not reabsorbed in the renal tubules

What causes the rapid decline in plasma drug concentration (α phase)?

1. Distribution from central compartments → peripheral compartments

2. Hepatic clearance of high-extraction drugs

3. Plasma metabolism by enzymatic hydrolysis

What causes the slower decline in plasma drug concentration (β phase)?

1. Redistribution of drug from peripheral → central compartments

2. Drug removal by metabolism and elimination

What is the α phase also called?

Distribution phase

What is the β phase also called?

Elimination phase

A constant percentage of the drug is removed per unit time

First-order kinetics drug elimination

A constant amount of drug is removed per unit time

Zero-order kinetics drug elimination

Which type of drug elimination depends on serum concentration, and which type does not?

Depends on serum concentration → First-order kinetics

Independent of serum concentration → Zero-order kinetics

When can zero-order kinetics occur for drugs that usually follow first-order?

At high serum concentrations

→ Metabolic pathways are saturated and cannot increase clearance

Time required for serum concentration to decrease by half

Half-life

After 5 half-lives, ____% of drug is gone

97%

True or false: Drugs with shorter half-life require less frequent dosing

False

→ Drugs with shorter half-life require more frequent dosing

The extent that drug is distributed

Volume of distribution (Vd)

Describes capacity of tissues to absorb a drug

Volume of distribution (Vd)

Which type of drug has a higher volume of distribution, lipophilic or hydrophilic drugs?

Lipophilic drugs

What does context-sensitive half-time mean?

The time for plasma concentration to fall by half after stopping an infusion, where “context” refers to the infusion duration

Why does context-sensitive half-time increase with longer infusions?

Because more drug accumulates in peripheral tissues, which then redistribute back into plasma after the infusion stops

→ INCREASES as a function of the duration of the infusion

What the drug does to the body

Pharmacodynamics

Maximum possible drug effect (Emax)

Efficacy

→ More efficacy = Higher max effect

The dose required to produce a therapeutic effect in 50% of the population

ED₅₀

Dose required to cause death or toxicity in 50% of the population

LD₅₀ or TD₅₀