Pharmacokinetics /2

Pharmacokinetics:

Pharmaco = drugs

Kinetics = movement

So essentially, pharmacokinetics is the way a drug moves through the body, or more precisely, the way drugs enter the body, move through the body, and then leave the body.

That is essentially pharmacokinetics. Now how does it do this? What are the four processes?

We have absorption, which refers to the way the drug goes from administration into the blood. Then we have distribution, which is how the drug, once in the blood, moves in, out, and around tissues, and how widely it distributes. Then we move to metabolism, which is how the body chemically alters the drug, predominantly in the liver. This determines whether the drug becomes activated, inactivated, or less active. Finally, we have elimination, also called excretion, which is the way the drug moves out of the body.

All right, so let’s start with absorption.

Absorption is the way the drug gets into the blood. There are many different routes, or ways, that we can administer drugs, which I will come to in a moment. But first, the main principle to understand is the different transport methods drugs use to get into the blood.

This takes us back to cellular biology and the different types of transport:

Passive transport

Facilitated transport

Active transport

Bulk transport, or endocytosis

These are the four ways drugs can be absorbed and move into the blood.

Let’s look at an example. Imagine this is a capillary bed and just one cell layer thick. We know that cells have a membrane called a phospholipid membrane, because it contains phospholipids and has two layers. That is why it is called a bilayer.

The phosphate heads are water-loving, while the tails are lipid-like and do not like water, so they are hydrophobic. Therefore, we have a phospholipid bilayer, and this means certain things move differently across the membrane.

The first type of transport is passive transport. Certain drugs can passively move through the membrane from a high to a low concentration gradient. It will be higher where the drug is given and lower where we want the drug to go in the blood.

A good example of passive transport would be a fat-soluble drug. Fat-soluble drugs can move straight through the membrane because most of the membrane is made of fat itself.

If the drug is water-soluble but very small, it may move through aquaporins, which are water channels in the membrane. These drugs still passively move from high to low concentration. It does not need energy, but it needs some help.

The next situation is where the drug is water-soluble but larger, so it needs more assistance. In this case, a channel helps carry it across, but it is still following its concentration gradient and so still does not use energy.

When transport requires energy, we need ATP. This is usually for a bigger, water-soluble drug, and it will require a transporter using ATP to pull it across.

Lastly, we have endocytosis, where a really large drug molecule is engulfed by the membrane, brought in, and then moved through. This is the largest type of transport.

These transport methods all affect the absorption of the drug.

Now let’s look at the most common route for administering medication: the gastrointestinal tract (GIT).

We often give drugs such as capsules, tablets, and syrups through the GIT because it is convenient. It is much easier than injecting into a muscle or a vein. How well the drug gets into the blood depends on the type of drug and how well it can cross the membrane.

Let’s say drug X is 100 mg. How much gets into the blood? This depends on the chemical nature of the drug and how well it crosses the membrane.

The gastrointestinal tract has several features that help absorption:

It has a very large surface area

The intestines are long

Villi and microvilli increase the surface area even more

It has a rich blood supply

However, everything absorbed from the GIT must first go through the liver, which acts as a gatekeeper. All that blood carrying the drug passes first through the liver via the portal venous system. The liver may metabolise the drug before it reaches the systemic circulation. This is called first-pass metabolism.

Depending on this first pass, the amount of drug reaching the blood can vary. For example, if you give a 100 mg dose and only 50 mg reaches the blood, then the drug has 50% bioavailability.

This is an important concept. Bioavailability refers to how much of the administered dose reaches the plasma.

If we compare this with intravenous (IV) administration, where 100 mg is injected straight into the blood, then 100 mg reaches the plasma. That gives 100% bioavailability.

So, with absorption, bioavailability means: from the dose given, how much reaches the plasma.

What things could affect the GIT?

One factor is the liver, which can remove a lot of the drug. A good example is GTN, which does not pass through the liver very well, so it has poor oral bioavailability if swallowed.

Other factors include:

Different pH levels in different tissues

The acidic environment of the stomach

The alkaline environment of the intestines

Surface area

Blood supply

The time the drug is exposed to the area

For example, if a patient has diarrhoea, the drug passes through quickly, which reduces absorption. If they have constipation, or if the drug is taken with food, absorption can also be affected.

The GIT also contains enzymes, which can interfere with drugs. For example, insulin is a protein, and GIT enzymes would break it down before it could be absorbed. That is why insulin is not given orally.

Now, back to GTN. Although we do not usually swallow it, we do give it sublingually (under the tongue). Under the tongue, the mucous membrane has a rich blood supply, so GTN is absorbed directly into the blood and avoids first-pass metabolism. This gives it much better bioavailability.

What about the skin?

Drugs can be given topically. Because the skin is waterproof, water-soluble drugs usually do not cross it well. Fat-soluble drugs are better absorbed through the skin.

Some drugs are applied to act locally, such as cortisone for inflamed skin like dermatitis. Others, such as nicotine, fentanyl, and GTN, can be absorbed through the skin into the blood.

What about subcutaneous administration?

The subcutaneous layer contains a lot of fat, and fat has a poor blood supply. Only about 5% of total blood flow goes to fat, so drugs are not absorbed very quickly there. However, this can be useful if you want a drug to be absorbed slowly over time. Examples include insulin and some contraceptive medications.

What about intramuscular administration?

Muscle is about 75% water, so water-soluble drugs work well here. Muscle also has a fairly good blood supply, so absorption is better. Some drugs therefore work well when injected intramuscularly.

Finally, with IV administration, the drug goes straight into the vein, giving complete bioavailability.

Once the drug is in the blood, we move on to distribution.

Distribution means how well the drug moves from the blood into tissues, and how widely it spreads through different body compartments. Does it stay in the blood? Does it move into extracellular fluid, intracellular fluid, fat, or other tissues?

The greater it moves, the greater its apparent volume of distribution.

This is worked out as:

Dose ÷ plasma concentration

For example, if you gave 100 mg and one hour later found 80 mg still in the blood, that tells you most of the drug is still in the plasma, so it has a poor distribution.

As the plasma concentration goes down, the distribution goes up, because more drug has moved out of the blood and into tissues.

Factors that affect distribution include:

Blood flow to tissues

Drug properties

Protein binding

Tissues such as the brain, lungs, heart, liver, and kidneys have a very good blood supply, so drugs distribute there more quickly.

If a drug is fat-soluble, it moves through membranes more easily and distributes more widely into tissues.

In the blood, there are proteins such as albumin, which can bind drugs. If a drug is bound to plasma proteins, it is not free to move into tissues or exert its action. This lowers the volume of distribution and increases plasma concentration.

An example is warfarin, which has a poor volume of distribution because much of it remains in the plasma bound to proteins. That is fine, because warfarin works in the blood to reduce coagulation.

If a drug needs to work in tissues such as the brain, it often needs to be fat-soluble so it can cross membranes and the blood-brain barrier more easily.

Next is metabolism.

Metabolism refers to the chemical alteration of the drug. This may activate the drug, as with a prodrug, or inactivate it.

For example, codeine can be converted into morphine. Other drugs may be altered to become less effective.

Although tissues such as the intestines, lungs, and kidneys can metabolise drugs, the liver is the main organ involved.

The liver carries out metabolism in two phases:

Phase 1

The aim of phase 1 is to make the drug less lipid-soluble and more water-soluble. This uses enzymes called cytochrome P450. The main reactions are:

Oxidation

Hydrolysis

Reduction

This helps prepare the drug for elimination by the kidneys.

Phase 2

This is called conjugation. A group is added to the drug, such as:

A methyl group

A sulfur group

A glucuronide group

An amino acid

This makes the drug more polar and easier to eliminate.

These enzymes can be affected by other substances. For example, grapefruit juice can interfere with drug metabolism. Some drugs can speed up or slow down liver enzymes, which can affect how quickly drugs are metabolised. If metabolism slows down, drugs may build up in the blood.

Other things that affect metabolism include:

Age: infants have immature livers, and older adults may have reduced liver function

Liver disease or liver failure

Finally, we move to elimination.

Elimination works alongside metabolism. It may involve:

Removing the active drug from the body (excretion)

Chemically inactivating it as part of metabolism

The primary organ for excretion is the kidney.

Since the kidneys filter blood and produce urine, which is water-based, drugs usually need to be made more water-soluble to be excreted effectively.

The three main ways the kidneys eliminate drugs are:

1. Glomerular filtration

Small drug molecules, whether fat-soluble or water-soluble, can pass into the filtrate. If they are lipid-soluble, they may be reabsorbed back into the blood. If they are water-soluble, they are more likely to stay in the filtrate and be excreted.

2. Tubular secretion

As the filtrate moves through the nephron, drugs can be actively secreted from the blood into the nephron. This is especially important for conjugated drugs with large polar groups. Once in the urine, they are less likely to be reabsorbed.

3. Reabsorption

Some molecules in the urine can move back into the blood if they are small enough or lipid-soluble. However, urine pH can affect whether a drug is reabsorbed or excreted. For example:

A weak acid is more likely to be excreted in alkaline urine

A weak base is more likely to be excreted in acidic urine

Other ways drugs can leave the body include:

Through the skin

In sweat

In tears

In breast milk

Through the lungs

Via the liver into bile, which enters the digestive tract and is excreted in faeces

Some drugs excreted in bile can be reabsorbed again in the GIT. This is called enterohepatic circulation, and it can prolong the drug’s presence in the body and affect its half-life.

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Learning Outcomes

To understand the absorption, distribution, metabolism and excretion of drugs (ADME)

To understand and describe the principles of pharmacokinetics

To develop knowledge that underpins routes of drug administration, drug–nutrient interactions and dietetic patient management

By the end of this session, you should be able to:

Understand absorption, distribution, metabolism and excretion of drugs

Understand and describe the principles of pharmacokinetics

Develop knowledge that underpins routes of drug administration, drug–nutrient interactions and dietetic patient management

You should also have awareness of:

The likely effect of a drug

How long it takes to enter and act in the body

Whether it can be taken orally, injected, or administered via other routes

How dosing and timing influence effectiveness and safety

Why we are interested in Pharmacokinetics

Pharmacokinetics is essential because a drug is only useful if it can reach and remain at its target site at the correct concentration.

“A chemical cannot be a drug… unless it is also taken appropriately into the body (absorption), distributed to the right parts of the body, metabolized in a way that does not instantly remove its activity, and eliminated in a suitable manner – a compound must get in, move about, hang around, and then get out.”

— Hodgson J (2001)

Key Concept Added (from lecture):

The goal is to maintain drug levels within the therapeutic range

Too low → ineffective

Too high → toxic

This balance is achieved by matching drug input (dose) with drug elimination (clearance)

Pharmacokinetics

Describes how the body handles a drug (what the body does to the drug)

Covers the entire duration of drug exposure

Concerned with movement, transformation, and removal of drugs

Provides the underpinning principles needed to understand:

Routes of drug administration

Drug–nutrient interactions

Safe and effective dietetic patient management

Key distinction

Pharmacokinetics = movement of drug (ADME)

Pharmacodynamics = effect of drug at receptor/site

Core Components (ADME ± Toxicity)

Absorption – entry into systemic circulation

Distribution – movement around the body

Metabolism – chemical modification (activation/inactivation)

Excretion – removal from the body

Toxicity – occurs when concentration exceeds therapeutic range

Routes of Administration

Drugs can be administered via:

Oral (tablets/liquids)

Topical (creams)

Inhalation

Transdermal patches

Injections:

Intravenous (IV)

Intramuscular (IM)

Subcutaneous (SC)

Intradermal (ID)

Key concept added:

Route affects bioavailability, speed of action, and overall pharmacokinetics

Example:

Insulin cannot be taken orally → destroyed in GI tract → low bioavailability

Therapeutic Range & Steady State (NEW – from lecture)

Drugs must stay within a therapeutic window

Achieved through repeated dosing → leads to steady state

Steady state reached after ~4–5 half-lives

Dose adjustments occur via:

Changing dose amount

Changing dosing interval

Considering clearance changes

Important clinical concept:

Drug therapy is often individualised (titration)

Patients respond differently → requires monitoring and adjustment

Therapeutic Drug Monitoring (Expanded)

Plasma used as a proxy for drug levels at the target site

Cannot directly measure drug concentration at receptor sites

Used for:

Narrow therapeutic window drugs

Avoiding toxicity

Ensuring effectiveness

Monitoring compliance

Example (added):

Isotretinoin

Requires monitoring due to hepatotoxicity risk

Absorption

Movement from administration site → systemic circulation

Influences:

Drug concentration at site of action

Onset of action

Mechanisms

Passive diffusion (concentration gradient)

Active transport (saturable)

Bioavailability

Fraction reaching circulation

IV = 100% (gold standard)

Oral ↓ due to:

Stomach acid

Enzymes

First-pass metabolism

Food–Drug Interactions (Expanded importance)

Food affects:

Gastric emptying

Bile salts

Enzyme activity

Drug metabolism (e.g. CYP450)

Example

Tetracyclines + calcium → ↓ absorption

Dietetic importance

Small changes can:

Reduce effectiveness

Cause toxicity

Especially critical for narrow therapeutic window drugs

Distribution

Movement of drug through body compartments

Influenced by:

Polarity

Size

Protein binding

Hydration

Key principle

Only free (unbound) drug is active

Metabolism

Mainly occurs in liver

Converts drugs → more water-soluble

Includes:

Activation (prodrugs)

Inactivation

Clinical relevance

Enzyme systems (e.g. CYP450)

Affected by diet (e.g. grapefruit juice)

Excretion

Removal via:

Kidneys (main route)

Lungs

Skin

GI tract

Key processes:

Filtration

Secretion

Reabsorption

Key Pharmacokinetic Parameters (Expanded)

Half-life → time for 50% reduction

Clearance → rate of elimination

Volume of distribution → extent of distribution

Bioavailability → fraction reaching circulation

Drug Kinetics

First-order → most drugs (proportional elimination)

Zero-order → fixed elimination rate (e.g. alcohol)

Importance for Dietetic Practice (Strengthened)

Pharmacokinetics is crucial for dietitians because:

Nutrition can alter:

Absorption

Metabolism

Excretion

Can lead to:

Drug inefficacy

Toxicity

Particularly important for:

Enteral feeding

Oral nutritional supplements

Patients with:

Liver disease

Kidney disease

Malnutrition

Final Summary (Improved)

Pharmacokinetics = how drugs move through the body (ADME)

Focus is on drug journey, not drug effect

Drugs must remain within a therapeutic range

Steady state achieved after ~4–5 half-lives

Dosing is individualised and often adjusted

Plasma drug levels are used as a proxy for effect

Dietitians play a key role in:

Preventing drug–nutrient interactions

Supporting safe and effective therapy