eTute 1 - How Drugs Work - A Basic IntroductioneTute 1 - How Drugs Work - A Basic Introduction

Answer 1

describe important routes of drug administration.
distinguish between pharmacokinetics and pharmacodynamics.
describe absorption, distribution, metabolism, excretion, and the plasma concentration-time curve of a drug.
describe the characteristics of four receptor superfamilies.
describe agonists and antagonists with examples (recognising that ligand-receptor interaction is mostly reversible).
describe agonists, antagonists, affinity, efficacy, concentration-response relationship, potency, and EC50 in the context of ligand-receptor interaction.
describe the effectiveness of a drug and its relevance to choosing drug treatments.

Answer 2

drugs typically change how existing biological processes happen - usually they can’t directly rebuild or restore damaged parts of the body, although they sometimes slow down cell damage, or stimulate the body to repair itself.
very often, drugs are used to treat the symptoms, not the cause of a disease. There are some important exceptions to this. For example, antibacterial drugs such as penicillin, or antifungal drugs like itraconazole, are used to kill populations of unwanted pathogenic microorganisms established within the body.
note too that the human body can be a source of drugs: chemists can extract and then synthesise particular hormones that already exist in the body, and use them as treatments, e.g., adrenaline, insulin.

Answer 2

prophylaxis – that is, to prevent the outbreak of sickness or disease in patients who are otherwise healthy.

Question 3

pharmacokinetics

Answer 3

Oral Route: This is the easiest and most common way of administering drugs. Drugs given by the oral route can be formulated in many ways including liquid suspensions, capsules, pills, or tablets. There are various additives and materials that are combined with the drug during the pill manufacturing process, to ensure that drug release occurs at the right time in the right place within the gastrointestinal tract (GI tract). This harsh environment can be a tough place for acid-sensitive drug molecules!
Drugs that are broken down by gastric acids can be surrounded by acid-resistant protective layers (known as enteric coatings) that remain intact in the stomach and then release their payload from the pill core within the upper intestines where the pH environment is less acidic.
With oral dosing, drug molecules may be broken down by enzymes in the GI tract wall and liver before they ever reach the bloodstream, a process known as first-pass metabolism. The resulting drug metabolites usually lose their affinity for their respective drug target, so they are unable to induce a pharmacological response. Another limitation is that it often takes an hour or two for full absorption to occur from the intestines - clearly a problem if patients are in a life-threatening condition and need urgent relief.

Answer 3

A few anti-HIV (human immunodeficiency virus) drugs have also been approved to be used for prophylaxis. In a slightly more unusual case of prophylaxis, oral contraceptives are taken by healthy women of childbearing age to decrease the likelihood of becoming pregnant, not to prevent a disease.

Answer 4

Dermal Route: Also known as topical administration, this involves the application of drugs directly to the skin. Absorption can be limited by the tough epidermal layer and stratum corneum that protects the body against incoming chemical invaders. This can involve mixing the drug into ointments and creams. Adhesive skin patches are also a convenient way to administer drugs such as nicotine or nitroglycerin.

Answer 4

Injection: Drugs that are injected directly into the skin, muscle or bloodstream will bypass the gut and liver, and usually act more quickly than oral medication. Injections can be subcutaneous (under the skin), intradermal (between the top layers of skin), intramuscular (directly into large muscles) and intravenous (directly into the vein). Each of these results in a different time-course of drug release into the blood.
Since these drug delivery methods carry a risk to patients, they require special training and expertise, and their use is often restricted to hospitals and other clinical settings. They are especially useful in emergency settings where a rapid drug response is needed.

Answer 5

​Inhalation: A variety of drugs for asthma and other lung diseases can be inhaled directly into the lungs. Depending on the drug, formulations for delivery via the lungs include gases, aerosol puffers or devices that dispense puffs of finely ground drug particles.

Answer 6

Other Routes: Depending on the condition being treated and the drug in question, a wide variety of methods can be used:

Suspensions like eye or ear drops.
Nasal sprays.
Suppositories inserted into the bowel and absorbed through the bowel wall.
Pessaries inserted into the vagina and absorbed through the vaginal wall.
Sublingual medications that are held under the tongue and dissolved.
Buccal medications which are held against the inside of the cheek and dissolved.

Answer 7

Bioavailability refers to the fraction of the dose ingested by a patient that reaches the bloodstream. It is symbolised using the letter ‘F’ (for fraction), and ranges from 0.1 - 1.0 for most widely used medicines. Obviously, the closer to 1.0 the better, because this means that as much of the drug given to patients reaches the circulation as possible. By definition, a drug that is administered intravenously has a bioavailability of 1.0.

Answer 8

Now that we’ve gotten the drug into the bloodstream, we need to break it down further. These changes to the chemical structure are called metabolism. The changes mostly occur in the liver as it is rich in drug-metabolising enzymes (DMEs), although other tissues/organs, e.g., the gut wall, kidneys, and brain, can also metabolise drugs. Note that orally administered drugs can undergo metabolism as they make their way through the gut wall and the liver before reaching the bloodstream, a process known as first-pass metbolism.

Answer 8

Tiny molecular pumps known as drug transporters control the movement of drugs across most membranes and from one body compartment to another. ​

Answer 9

Transporters (shown as ‘T’s in the diagram) regulate the movement of drugs out of the bloodstream and into a wide range of organs and tissues, including the heart, lungs, liver, brain and mammary tissue.

Answer 10

DMEs within these tissues turn the drug molecules into water-soluble derivatives (metabolites). This is the body’s way of protecting itself against accumulating ‘greasy’ foreign chemicals acquired from outside.

Answer 11

The most common thing to happen to the drug molecule as it is metabolised is that it picks up a new oxygen atom. It does this by interacting with a DME.

Answer 12

The most important family of DMEs are the cytochrome P450 (CYP450) proteins which live mostly in liver cells and the gut wall cells.

Answer 13

Cytochrome P450 is nicknamed ‘Nature’s blowtorch’ because it is a powerful oxidising system that efficiently adds oxygen (O) atoms to foreign chemicals and helps them to be broken down into metabolites.

Answer 13

It’s common for drugs to form multiple metabolites during passage through the liver, with many drugs forming dozens of metabolites within the body.

Answer 13

Some penicillins are excreted mostly via urine.
Metformin, a widely used anti-diabetes drug, also undergoes minimal metabolism in the liver and is excreted as the parent or unchanged drug in urine.

Answer 14

Other drugs are excreted partly through sweat:
lead, mercury and other heavy metals
alcohol

Answer 15

Answer 15

Some are excreted partly through the breath:
alcohol again
some gas anaesthetics

Answer 16

Profile A shows the ‘happy medium’ where we want the drug to have an effect, but not harm the person. This shows when the drug had peak concentration in the person’s blood sample. The area shown in yellow is what we call the therapeutic window - the range of drug concetrations that produces therapeutic effect and does no harm.

Answer 17

Profile B shows the same drug being tested in three different routes, to see how long it lasts and when its concentration peaks in the blood sample. The IV dose shows the highest concentration, as you’d expect, as it’s been injected straight into the bloodstream. By contrast, the oral dose took time to break down, and the subcutaneous dose - injected under the skin - peaked earlier, but wasn’t as concentrated in the bloodstream.

Answer 17

Profile C shows a drug being given in oral doses over time so that its concentration is accumulating and rising in the body. If we keep going like this, we’ll hit toxicity, so we need to stop before we reach that point.

Answer 18

Receptors have what we call ‘binding sites’ for molecules that are present in the body already (known as endogenous ligands), such as neurotransmitters (these are sloshing about in your body all the time naturally). There are four receptor superfamilies.

Question 19

Ligand-gated ion channels

Answer 19

The diagram below shows the structure of a GABAA receptor: a. the structure of one single subunit; b. the structure of a functional GABAA receptor, which consists of five subunits. The GABAA receptor is the drug target for alcohol, benzodiazepines, and some general anaesthetics, all of which will be covered in PHAR1101 lectures.

Question 19

IMPORTANT

Answer 19

Ligand-gated ion channels
G protein-coupled receptors
Kinase-linked receptors
Nuclear receptors

They’re ranked here from the ‘fastest’ to the ‘slowest’ in terms of time scale of action.

Question 20

Ligand-gated ion channels

Answer 20

Ion channels act as tiny molecular turnstiles to allow the movement of ions such as Na+, K+, Ca2+ or Cl- into cells. Ligand-gated ion channels are very important in neurotransmission (the mechanism by which neurons communicate with each another, or neurons relay signals to muscles).

Question 20

Ligand-gated ion channels

Answer 20

Drugs that block ligand-gated ion channels or alter the rate at which they open or close are used to treat many diseases of the nervous and cardiovascular systems. Changes in activity of ligand-gated ion channels are the fastest - typically evident within a few milliseconds (i.e. one thousandth of a second) of a drug binding to the receptor.

Question 21

Ligand-gated ion channels

Answer 21

Question 22

G protein-coupled receptors

Answer 22

These are arguably the most important receptor superfamily in modern pharmacology. G proteins receive their name because they interact with important cell signalling molecules known as guanine nucleotides (known by their abbreviations of GTP and GDP). These receptors live in cell membranes and help the cell to communicate with the outside world - they can signal for hormones, for example.

Question 23

G protein-coupled receptors

Answer 23

It’s like pressing an app icon on your screen: we activate many interesting electronic reactions inside the ‘box’. When a drug molecule binds to G-protein coupled receptors in cell membranes, they set off a complex array of processes (known as signal transduction) that can stimulate or suppress the body’s responses. Responses mediated by G-protein coupled receptors take longer to observe than those via ligand-gated ion channels: in this case, the responses take a few seconds or so to be observable.

Question 24

G protein-coupled receptors

Answer 24

The diagram below shows the μ opioid receptor (MOR) and associated signal transduction. The μ opioid receptor is the drug target for opioids, such as morphine, which will also be covered in a PHAR1101 lecture.

Question 25

G protein-coupled receptors

Answer 25

Question 26

Kinase-linked receptors

Answer 26

These are key targets for many innovative drugs that are now used to treat cancers. A kinase is an enzyme that transfers a phosphate group to a target protein (this process is known as phosphorylation), often changing the activity or function of the newly ‘phosphorylated’ protein.

Question 27

Kinase-linked receptors

Answer 27

Question 27

Kinase-linked receptors

Answer 27

The diagram below shows the epidermal growth factor receptor and associated signal transduction. You will learn about small molecule tyrosine kinase inhibitors in the PHAR1101 Treating cancer lecture.

Question 27

Nuclear receptors

Answer 27

The diagram below shows the glucocorticoid receptor (GR) and its regulation of gene transcription.

Question 27

Kinase-linked receptors

Answer 27

Kinases can abnormally stimulate the growth of tumour cells, causing the uncontrolled expansion we associate with cancer. Drugs that inhibit kinases are very useful in slowing the growth of certain tumours. However, they often take minutes before we can observe them at work.

Question 28

Nuclear receptors

Answer 28

Nuclear receptors are responsible for producing the effects of steroid hormones, including anabolic steroids or sex hormones such as estrogen. For example, the nuclear factor-mediated activation of gene expression by anabolic steroids causes the increased muscle bulk that is typical of steroid use and abuse. These can take several hours to show a response.

Question 28

Nuclear receptors

Answer 28

As the name implies, these receptors act within the nucleus of cells, typically by altering the expression of particular genes or sets of genes. The nuclear receptors are essentially ligand-activated transcription factors that bind to regions in DNA known as gene promoters - so they can make the gene get more or less busy.

Question 28

Nuclear receptors

Answer 28

Answer 29

the strong painkiller morphine is an agonist at the μ opioid receptor in the brain, spinal cord, and peripheral tissues.
the asthma drug salbutamol is an agonist at the β2 adrenoceptor: it is administered via aerosol inhalers to relax smooth muscles in the lungs of asthma sufferers.

Answer 30

an agonist mimics the effects of endogenous molecules (the ones inside your body already) by binding to and activating the receptor. An agonist produces much the same biological or physiological response as the endogenous molecules. Agonist drugs are useful for treating diseases where stimulation of a specific receptor is desirable.

Answer 31

Antagonist drugs are more commonly used in modern pharmacology. These drugs bind to the same site as endogenous molecules on a particular receptor, but do not provoke a physiological response. Antagonists are useful in treating diseases in which reducing the action of a particular receptor is desirable, as they work by preventing endogenous molecules from binding to the receptor to induce a response.

Answer 32

metoclopramide, a drug used to treat vomiting, is an antagonist at the dopamine D2 receptor.
metoprolol, a drug used to treat high blood pressure, is an antagonist at the β1 adrenoceptor.

Answer 33

Answer 34

Aspirin (acetylsalicylic acid) irreversibly donates an acetyl group (-CHOCH3) to the active site of cyclooxygenase (COX), a key enzyme in prostaglandin production during tissue inflammation (prostaglandin is a hormone that is involved when we experience cramping pain, like menstrual cramps).

Answer 34

​Usually, interactions between drugs and their target are reversible as weak chemical forces are involved.

Answer 35

There are however a few important drugs that work by irreversibly binding to their drug target.

Answer 35

Drugs like aspirin are sometimes called covalent drugs because they permanently change the chemical structure of their target.

Answer 35

If a particular drug binds to a receptor strongly, we say it has high affinity, but if it binds weakly it has low affinity. It simply tells us about the ‘stickiness’ of a drug for its receptor, or how strongly it binds to any receptor.

Answer 36

Efficacy is a measure of the MAGNITUDE of response produced by drug-induced receptor activation. A drug that causes a strong response has high efficacy, while a drug that produces a weak response has low efficacy.

Answer 36

​Affinity describes the TENDENCY of a drug to bind to its target. Without affinity, drugs do not bind and do not act: a molecule with zero affinity for any target within the body will likely have zero potential as a drug. It just won’t work.

Answer 37

Potency is a measure of the amount of a drug required (expressed as the concentration or dose) to produce a given response. A high potency drug will produce a given response at lower drug concentrations or doses.

Answer 37

Answer 38

An antagonist binds to but does not activate a receptor, so it has affinity for that particular receptor, but lacks efficacy as it does not produce a response. Antagonist also has potency - this can be measured as the concentration that reduces the response to an agonist.

Answer 38

To summarise,
Affinity = Tendency
Efficacy = Magnitude
Potency = Amount

Answer 39

As we learned in an earlier section, an agonist binds to and activates a receptor to produce a response, so it has affinity for that particular receptor, and efficacy since it leads to a response. Agonist has potency - this is commonly measured as EC50 (effective concentration, 50%) in in vitro experiments - this will be discussed further in the next section.

Answer 40

A concentration-response curve describes the relationship between the magnitude of response produced by a drug and the drug concentration. A concentration-response curve is typically S-shaped - at low agonist concentrations, few receptors are occupied, so the drug is unable to produce a response. As the agonist concentration increases, the magnitude of response rises as more receptors are occupied, until we hit a point at which all available receptors are occupied and a maximum response is achieved. At this point, administering extra amounts of the drug doesn’t cause a greater response.

Answer 41

What is ultimately important in patient treatment is whether the drug is effective (not to be confused with efficacy). Effectiveness measures the MAXIMUM LEVEL of therapeutic effect a drug can produce. Both agonists and antagonists can be effective because they produce the desired therapeutic effect, whether it be achieved through activating or blocking receptors.

Answer 42

The level of effectiveness is also an important consideration, as not all drugs that produce the same therapeutic effect produce the same maximum level of effect. For example, morphine and ibuprofen provide pain relief, but morphine can be used for severe pain, not ibuprofen - morphine is therefore more effective than ibuprofen in providing pain relief. This difference in effectiveness is due to the fact that morphine and ibuprofen bind to different drug targets.

Answer 43

Pharmacokinetics has also provided insight into how different people react differently to the same drug and dose. In recent decades, scientists have learned that we all carry inherited variants of many genes involved in drug metabolism or membrane transport, and that these genetic differences can underlie unusual sensitivities to drug toxicity or drug responses. This can guide doctors and other prescribers to choose one drug over another if they expect that it will have fewer ‘pharmacokinetic issues’ in patients.