Pharmacokinetics

This lesson will help you understand the basic principles behind pharmacokinetics and give you some dentistry relevant examples to help put it into context.

What is pharmacokinetics?

• In simple terms pharmacokinetics is thought of as what the body does to the drug. 

• This encompasses absorption, distribution, metabolism and excretion– also known as ADME.

• “Elimination” is also used occasionally. Technically metabolism + excretion = elimination.

Why is it important?

How are drugs administered?

Drugs can be administered in many ways:

• Orally
• Via injection – e.g. intravenously (IV), intramuscularly (IM), subcutaneously (SC) etc
• Transdermally through a patch
• Inhaled
• Nasally via a spray
• Sublingually
• Rectally via a suppository
• Vaginally via a pessary
• You may also see other terms used, such as enteral administration (via the gastrointestinal tract), and parenteral administration (any route other than the gastrointestinal tract)

To keep this lesson simple, we will only consider oral and IV routes of administration when talking about pharmacokinetics.

A.D.M.E

Absorption

How are drugs absorbed from the GI tract?

Four main routes:

1. Passive diffusion through the cell membrane
2. Active transport
3. Facilitated passive diffusion via small pores
4. Pinocytosis – where a drug is engulphed and brought into the cell

Factors that influence absorption from the GI tract:

Some factors may affect absorption, these include:

• Particle size – large molecules are often not absorbed
• Chemical breakdown – e.g. insulin is broken down by the stomach acid
• Concentration – the higher the concentration, the more drug that is absorbed (usually!)
• Ionisation – ionised particles cannot diffuse across membranes – this plays a part in the mechanism of action for local anaesthetics 
• Solubility – drugs that are more polar (see below) are less readily absorbed through the lipid bilayer of the cell membrane 
• Physical state of the drug – e.g. an oral suspension is absorbed more quickly than a modified release tablet
• The effect of first pass metabolism (we will discuss this later)
• Presence/absence of food – for example penicillin must be taken on an empty stomach as the presence of food decreases absorption.
• Health of GI tract.

Polarity vs Ionisation

First Pass Metabolism

• When a drug is absorbed from the GI tract it enters the bloodstream. However, it is not immediately available to the systemic circulation.

• It must first travel through the hepatic portal vein and pass through the liver where it is filtered and exposed to hepatic enzymes which may metabolise it (we will discuss these in more detail later). This is known as “first pass metabolism” and is a way of the body defending itself against anything nasty that we’ve ingested.

• Once the drug has passed through the liver it then reaches the systemic circulation and this is where the concentration can be measured in the blood. This concentration also relates to the therapeutic window which we discussed in the “Introduction To Pharmacology” lesson.

• Some drugs are extensively metabolised during this process and this can decrease the bioavailability of the drug (which we will now discuss).

Route of drug after oral administration:

What is Bioavailability (F)?

• Bioavailability: This is referred to as (F)or the Fraction of drug that is bioavailable. This is the percentage of drug that reaches the systemic circulation when a drug is administered. Normally bioavailability is referenced when discussing drugs administered orally, but it can relate to drugs administered by other methods – such as transdermally.

• Bioavailability varies between drugs and may be 100%, or it could be much less. Some drugs may be poorly absorbed, meaning a large dose may need to be given orally for only a small percentage to actually reach the blood stream.

• When a drug is given IV it is 100% bioavailable. This is because the entire dose is injected directly into the bloodstream, and therefore bypasses the factors listed above (e.g. poor absorption or extensive first pass metabolism). 

How do we calculate the bioavailability (F)?

The equation for bioavailability is: (1)

Don’t worry, this equation looks complicated, but we will break it down:

• We already know F is bioavailability.
• AUC means “area under the curve”.
• Dose is the amount of drug given via each method of administration. For our example we will assume we gave the same amount of drug for each method (IV and oral).

Now let’s explain the equation with a graph:

• On the y axis is the concentration of the drug in the plasma and along the x axis is time. So, this graph shows the amount of drug in the plasma over time.

• For the IV drug (injected directly into the systemic circulation), the concentration starts at the highest point, and over time decreases as the drug is eliminated (remember, elimination means metabolism and excretion).

• For the oral drug the concentration in the blood gradually increases as it’s absorbed, peaks, then gradually decreases as it’s eliminated.

• The area under the curve (AUC) for each line equals the total amount of drug present in the systemic circulation for each administration

The application of the equation:

Now we just need to apply the equation:

In summary the equation for bioavailability (F) is:

For our example: (400/500) x (500/500) = 0.8 x 1 = 0.8, Therefore, F = 0.8

Remember, bioavailability only relates to the drug that reaches the systemic circulation during absorption. The elimination characteristics of the drug are described by its half-life (t_½). We will cover this at the end of the lesson. 

Example question:

A rat was given 60mg of drug via IV injection. The plasma concentration was tested every 30mins and plotted on a graph. The AUC for the IV curve was 60mg. 130mg of the same drug was given to a different rat via an oral solution. The plasma concentration was tested every 30mins and the AUC was 30mg. What is the bioavailability of the drug when given in oral solution?

Tip: You have been given lots of excess information, read through carefully and identify what is important for the equation.

Answer at the end of the lesson.

Distribution

This is concerned with the distribution of the drug amongst the tissues in the body, after absorption.

Things to consider:

• We can only measure the concentration of the drug in the blood plasma.
• We do this by taking a sample of blood and measuring the amount of drug in this known volume.
• Concentration of drug in blood = mass of drug/volume or C = M/V
• However, we recognise that the body is made up of more than just blood – there are various other areas in the periphery the drug could diffuse into – for example:
• Intracellular water
• Adipose tissues (fat)
• Interstitial water
• These other areas are known as compartments.

Volume of Distribution (V_D)

In many cases the concentration of the drug in the blood might be lower than expected - because some of the drug has diffused into compartments, and we can only measure what is in the blood plasma.

This is called the apparent volume of distribution (V_D). 

Apparent V_D

• Drugs with a low V_D are primarily distributed in the blood, so may be more hydrophilic.

• Drugs with a high V_D have diffused more into the surrounding tissues and so may be more lipophilic.

• Drugs with a high V_D may also take longer to eliminate (have a longer half-life – t_½) as they can only be eliminated when in the blood stream – more of the drug is hiding in the tissues when the V_D is high. The drug can be slow to diffuse out of the tissues and back into the blood.

What happens to the drug when it’s in the circulation?

Bound to tissues

• Adsorbed onto bone
• Partitioned into adipose tissue

Bound to plasma proteins e.g. albumin

It is important to note that it is only the unbound drug that can exert an effect – each of the above would render the drug inactive.

Drugs may compete for the same protein – i.e. Two drugs administered at the same time may compete to bind to the same plasma protein. One of them will have a higher affinity for the protein and will displace the other. This means that there will be more of the other drug free in the plasma to exert its effects.

Clinically, there are very few plasma protein displacement interactions that are significant. This is thought to be because the displaced drug tends to redistribute throughout the body.

Plasma Protein Drug Binding

Metabolism

This is the processing and breakdown of the drug by the body.

Not all drugs are fully metabolised, and often a percentage of a drug is excreted unchanged.

• Example: Up to 70% of amoxicillin is excreted unchanged in urine during the first 6 hours after administration of one 500mg dose. (2)

What are the main methods of metabolism?

A large percentage of drugs are metabolised by the liver.

• Example: Amide local anaesthetics, such as Lidocaine.

Some drugs can be metabolised in the blood.

• Example: Ester local anaesthetics, such as benzocaine. These are metabolised by plasma esterases.

The kidneys also contain enzymes and often play a part in phase II metabolism – we will discuss this later.

There are some other minor methods of metabolism such as enzymes present in the lungs.

How does the liver metabolise drugs?

Cytochrome P450 Enzymes

Within the liver, are an important group of enzymes called cytochrome P450 (CYP450). They’re found in the hepatic smooth endoplasmic reticulum within the hepatocytes.

The family of enzymes is broken down into subcategories – important examples are CYP450 3A4, 2D6, 2C19 and 2C9.

These enzymes can also be inhibited or induced by drugs and can be involved in drug interactions.

Dentally relevant examples (not by any means exhaustive): (3)

Inducers CYP450 3A4:

• Phenytoin (epilepsy)
• Carbamazepine (epilepsy, trigeminal neuralgia)
• Rifampicin (TB)
• St John’s Wort (an over-the-counter supplement)

Inhibitors CYP450 3A4:

• Grapefruit juice
• Clarithromycin (antibiotic)
• Erythromycin (antibiotic)
• Fluconazole (antifungal)

Drugs metabolised by CYP450 3A4:

• Clarithromycin (antibiotic)
• Erythromycin (antibiotic)
• Warfarin (anticoagulant)
• Some statins e.g. Simvastatin (to treat high cholesterol)

Inducers CYP450 2D6:

• Rifampicin (TB)

Inhibitors CYP450 2D6:

• Many selective serotonin reuptake inhibitors – e.g. citalopram, fluoxetine, sertraline (anxiety and depression)

Drugs metabolised by CYP450 2D6:

• Codeine (opioid painkiller)

Inducers CYP450 2C19:

• Rifampicin (TB)
• Carbamazepine (epilepsy, trigeminal neuralgia)

Inhibitors CYP450 2C19:

• Lansoprazole, omeprazole (reflex and heartburn)

Drugs metabolised by CYP450 2C19:

• Warfarin (anticoagulant)
• Diazepam (sedative, anxiolytic) 
• Phenytoin (epilepsy)

Inducers CYP450 2C9:

• Rifampicin (TB)
• Carbamazepine (epilepsy, trigeminal neuralgia)

Inhibitors CYP450 2C9:

• Miconazole (antifungal)
• Fluconazole (antifungal)

Drugs metabolised by CYP450 2C9:

• Warfarin (anticoagulant)
• Non-steroidal anti-inflammatories
• Clopidogrel (antiplatelet)

Genetical variations

Genetic variations can lead to altered CYP450 polymorphisms and so altered metabolism of drugs.

• An example of this is a variation in the CYP450 2D6 enzyme. Some people may possess a variation of this enzyme that does not work as efficiently (poor metabolisers). Others have a variation which results in the enzyme working much more quickly (rapid or ultra-rapid metabolisers).

• Codeine is a prodrug which means it must be metabolised into its active form (morphine) to work. This occurs via the CYP450 2D6 enzyme. Poor metabolisers may not metabolise codeine effectively and may be resistant to its effects. Ultra-rapid metabolisers may be the opposite and experience large conversion to morphine rendering them sensitive to the drug.

Phases of metabolism:

Phase I metabolism:
Oxidation, reduction or hydrolysis

• Occurs in the liver
• Usually involves CYP450
• Often involves breaking down chemical bonds
• Makes the molecule more polar. We covered polarity above, drugs that are more polar are more water soluble and so are more easily excreted in the urine.
• Often creates active metabolites

Phase II metabolism:
Conjugation, glucuronidation, acetylation etc

• Occurs in the liver and kidneys
• Involves other enzymes to CYP450 (various transferases)
• Often involves the addition of polar groups
• Often deactivates metabolites

Excretion

• This involves the removal of the drug from the body.

• It usually relates to the kidneys; but can also involve the lungs and liver (excretion via exhalation, or via bile into faeces).

What is Clearance (CL)?

• This is the rate at which the organ involved removes the drug.

• It can refer to total clearance (CL_Total), or as clearance of the individual organ e.g. CL_Liver, CL_Renal

Excretion in the kidney

Occurs via three main methods: (4)

Glomerular filtration – filtration of soluble drugs free in the plasma.

Active secretion of drugs in proximal tubules – the drug is actively pumped into the urine, against its concentration gradient.

• Note: Some drugs may compete for the same transporter.

Passive reabsorption from the distal tubule – The drug passively diffuses back into the plasma from the distal tubule.

• A high urine flow rate may lead to larger clearance of the drug and a low flow rate (e.g. in dehydration) may lead to lower clearance.

• Acidity of the urine may also play a part, with drugs becoming ionised and trapped in the distal tubule – this is the same principle that occurs in neurons in the mechanism of action for local anaesthetics (LA). We will cover this in the LA lesson.

What is half-life (t_½)?

Half-life is the time it takes for the drug concentration to reduce by half. This depends on both metabolism and excretion, and so each drug will have a different half-life. 

Drugs with short half-lives tend to wear off more quickly and may require more frequent dosing. Drugs with a long half-life can sit in the body for extended periods after the medication has been stopped; meaning they can still interact with other prescribed medication. This is why it is important to have a full medical history, including recently stopped medications. 

A Graph to show the half life of a drug

On this graph we can see that it takes one hour for the drug concentration in the plasma to decrease by half. Therefore, the half-life is 1 hour.

A graph to show drugs with different half lives

On this graph we can compare drugs with different half-lives and how that relates to the frequency of dosing. The drug with the short life is eliminated quickly and we must give frequent doses to keep the concentration within the therapeutic window. The drug with the long half-life takes longer to be eliminated and so the concentration stays within the therapeutic window for longer. For this drug we do not need to dose as frequently.

• Examples of this in dentistry are the antibiotics penicillin (phenoxymethylpenicillin is the full name) and doxycycline. Penicillin has a short half-life of approximately 45mins and so is usually dosed 4 times a day. (5) Doxycycline has a comparatively long half-life of 16-22hrs and so is often dosed once or twice a day. (6)

How does pharmacokinetics relate to treating patients?

When prescribing you need to be aware of the properties of the drug you are using and how they may affect your patient. Certain medical conditions can influence how a patient’s body processes a drug, and interactions between medications can be important. Understanding the pharmacokinetic principles will allow you to make informed decisions about how to modify your prescribing or find alternative drugs when necessary.

Relevant examples (not exhaustive): (7)

Absorption:

• Penicillin should be taken on an empty stomach but amoxicillin and co-amoxiclav can be taken with or without food. Penicillin is not absorbed efficiently in the presence of food, whereas amoxicillin is not affected.

Metabolism:

• Miconazole increases conc. warfarin
• Metronidazole increase conc. warfarin
• Erythromycin increases conc. warfarin
• Erythromycin increases conc. simvastatin
• Clarithromycin increases conc. warfarin
• Clarithromycin increases conc. simvastatin
• Fluconazole increases conc. warfarin
• Fluconazole increases conc. simvastatin
• Codeine + hepatic impairment: Manufacturer advises dose reduction in mild to moderate impairment.

Answer to bioavailability question:

This question was designed to be wordy to give excess information. It might help to highlight or jot down the key information when reading.

F = (30/60) x (60/130) = 0.5 x 0.46 = 0.23, Therefore, F = 0.23