Introduction and Pharmacodynamics
Learning Objectives
1. Define the terms pharmacology, pharmacokinetics and pharmacodynamics 2. Describe how drugs are named and regulated
3. Describe different drug sites of action
4. Understand different types of drug-receptor interactions and how they impact functioning of the target receptors
What is Pharmacology?
Drug Development: Then and Now The study of drugs.
Clinical focus of use of drugs therapeutically.
Definition: anything administered to a person in order to bring a therapeutic or diagnostic effect or control of symptoms.
Two major areas:
1. Pharacodynamics – what the drug is doing, where it’s acting, what effects it’s producing, how it’s producing those effects
2. Pharmacokinetics – what happens to the drug when it’s on its way to its site of action, ie. The process that come to bare on the drug after it has been administered within the body, the way the drug is acted on by the persons own physiological systems, where the drug gets broken down, how quickly it’s broken down, how quickly it’s absorbed, does it arrive at the site of action intact or not.
Both need to be in action to have a useful drug
Global Pharma History.
First discovered in ancient Egypt (6000 BC), found papyrus scrolls bearing names of medicines. Around the same time some South American tribes were discovering some plants had hallucinogenic properties. Opium was also discovered in poppies.
5000 BC, the pharma industry appeared in Greece and the Hippocratic Oath.
First drug stores appeared in the Middle East around AD 754. The first Modern pharmaceutical industry appeared in the late 19th century in the Upper Rhine region and around the same time in the USA. Many drugs at that time were derived purely by accident by discovering the certain antiseptics and dyestuffs and baking powders had pharmacological activity and these accidental discoveries led to the introduction of a huge number of drugs that became household drug names such as aspirin. These small molecule chemical medicines contain an active pharmaceutical ingredient which is known as the generic substance, for example in aspirin this is known as acetyl salicyclic acid and when the original branded medicine eventually reaches the end of its patent life generic copies become available.
Important discoveries insulin was discovered around 1920 around in the same decade Alexander Fleming discovered penicillin the 1960s saw the introduction of the contraceptive pill but then towards the end of that decade a drug cost align cause serious problems to little mind was sleeping tablet prescribed to pregnant women which in animals appeared to be perfectly safe sadly in humans whole generation of children were born with congenital defects that gave rise to a realisation sometimes animal models are not always reliable indicator of safety and human beings and so the declaration of Helsinki was read which eventually many years later became they good chemical practise agreement which improve the safety of patients and healthy volunteers in clinical studies ever since 1970 saw the emergence of the blockbuster which is a drug achieving more than $1 billion per year in sales turnover in those days most blockbusters were for the
management of chronic diseases like asthma or high blood pressure the blockbuster model was then based on fairly high volume fairly low value pricing nowadays blockbuster status is more likely to be the result of a lower volume but higher cost medicines 1980 saw the rapid expansion of biotechnology and biologics I mentioned aspirin earlier as an example of a small molecule chemical drug but larger molecule biologic drugs derived from living process is and these designer drugs are created to deliver a very specific outcomes.
Biotechnology or biopharmaceuticals really is the future of our industry in the 1990s we saw the beginning of a whole rafter mergers and acquisitions where many pharma companies became huge small biotech companies were acquired by large pharma companies who needed to fill the gaps in their pipeline and those small biotech companies then became able to commercialise their products as we entered this decade we saw many of the brand name blockbuster drugs which were patented in 1980s reached the end of their patent protection this sore prescriptions for those conditions being filled instead by generics rather than by the original brands and this resulted in will be referred to as the patent Cliff.
Drug Naming and Categorization
A Drug’s Journey from the Lab to the Market
The story of a medication before it gets to the shelf of a chemist is along one less than 10% of drugs designed by pharmaceutical companies end up making it onto the market that's because most don't pass all the hotels on the way to being approved for sale. Before a drug even comes near being distant humans it's tested on animals this first step help scientists test the effects of the drug on vital organs and how toxic the drug is at different dozens once these hurdles being cleared the drug must go through three phases of human trials known as clinical trials before it's approved for sale.
Base one is the first time the effects of a new drugs are studied in humans at this stage it's all about safety a small sample of up to around 80 healthy volunteers trial the drug to establish his toxicity over a range of doses based on the results of the animal studies if the drug is found to be safe it enters the next phase of testing.
Phase two of the trial process focuses on benefits of the drug whether the drug treats the target condition or minimise effects several hundred patients with the condition are included in the trial sample and if there's evidence of a benefit to patients with an acceptable level of side effects the drug progresses to the third phase. Phase three is the most important phase of drug testing in the last stage before drug developers seek approval from regulatory agencies like the therapeutic goods administration in Australia or the Food and Drug administration in the US before it goes to market where researchers seek the definitive answers on a drug efficacy and safety. The number of participants involved in the duration of the studies very pending on the product and target condition but hundreds or even thousands of participants are often involved and the best way of proving a drug's efficacy against the current standard of care is randomised controlled trial.
Randomised control trials generally divide study participants randomly into two separate groups one group of participants receives the new drug while the other is a control group they receive either no treatment at all it will see which appears to be the treatment but has no active ingredient or the standard treatment available at the time of the trial the two groups are randomly allocated to make sure that affects shown in a trial are the result of the drug itself rather than factors like age lifestyle choices like whether the participants are smokers or living a specific environment or gender and to make sure that effects are boosted or
disadvantaged by the patient knowing which treatment they getting trials are generally what's called blind where possible the researchers and treating doctors are also blinded so no one knows what treatment a participant is receiving until the results are in once the drug clear space three is generally gets approved for sale and hits the market protesting doesn't stop there that's when phase for kicks in its the final safety
measure on a drug and focuses on its long term effects and potential use for treatment in other conditions or new populations like children these studies generally involves a wide population receiving the drug
sometimes thousands and are often a condition of the drug receiving approval so when you take medication you can be safe in knowing that it's gone through a process of testing that can take up to a decade.
How do Drugs get their Names?
All drugs have at least three names,
1. Chemical Name, ie, N-acetyl-para-aminophenol 2. Generic Name, ie, acetaminophen and paracetamol 3. Brand Name, ie, Tylenol
The same drug may have different brand and generic names in different countries. Healthcare professionals will sometimes document use of this drug with the abbreviation APAP. This is derived from the drug’s
chemical name.
As of 2013, the FDA had approved 1,453 drugs since its inception.
Early in drug development a pharmaceutical company may refer to a compound as its chemical name or an abbreviation. During phase one or phase two of the clinical trials they’ll apply for a generic or non-
proprietary name, in United states this is done through the United States Adopted Name Council or US ANC a group of pharmacists and physicians that represent professional organisations and regulatory bodies the council takes into account elements of the drugs chemistry and mechanism of action when assigning the name. The name of drugs with the same mechanism of action will have a common stem usually at the end of the name. Take statins for instance though they all have varying chemical structures and differ in the degree to which the lower cholesterol, drugs like simvastatin, atorvastatin, and rosuvastatin all work the same way in the liver by inhibiting HMG-CoA reductase to reduce cholesterol biosynthesis. Another example are drugs that target viruses ending in vir like valaciclovir sometimes used for shingles or herpes, tenofovir which can be used for hepatitis B or in combination with other antivirals for HIV but it is possible that other countries could give them other names. Thankfully the WHO keeps everyone on the same page by managing and assigning international non-proprietary names or INN. The WHO works closely with national naming
commissions, like the USANC, to develop a suitable international non-proprietary Names for a drug molecule.
This takes a good deal of collaboration but it’s rare a non-proprietary name differs greatly from a national
non-proprietary name. Often the spelling of the international non-proprietary names is no different from country to country when that’s not possible, latinized pronunciations are translated to other languages.
Brand name rules are different from country to country, in the US brand names have to be approved by the FDA before the drug can become to market, this is to ensure that the name is different enough from pre- existing drugs. Aside from the pharmaceutical company has a lot of autonomy and picking the brand name. Brand names often hint at the way a drug works, how it should be taken, or its desired effect.
Categorizing Drugs: Classes, Names, and Schedules
Drugs might be grouped according to the type of molecule they are, or by what it does clinically, or by the mechanism of action. These methods all have their own utilities. The main distinction we want to make is the difference between therapeutic classification, and pharmacological classification.
1. Therapeutic Classification – physiological change induced by the drug, or the main physiological change that is induced by the drug on the organismal level.
• Examples: anticoagulants (help prevent blood clots), antihyperlipidemics (lower blood- cholesterol levels), antihypertensives (lower blood pressure), antidysrhythmics/antirrhythmics (treat an abnormal heartbeat), antipsychotics, antidepressants, anticonvulsants,
antinauseants
This type of classification describes the clinical purpose, or the physiological change induced by the drug. It does not describe anything about the way the drug achieves this change. A large percentage of these categories begin with the prefix ‘anti’, because it means against and these categories describe the
condition that the drug is working against. Some of their functions are immediately apparent from the name, while others require a little more background information. There are other classes that don’t begin with this prefix;
• Examples: decongestants, hallucinogens, sedatives, stimulants
2. Pharmacological Classification – mechanism of action on the molecular level, or what the drug does on the molecular level.
• Examples: calcium channel blockers (block calcium channels in the heart and limit the passage of calcium ions through the cell membrane), angiotensin-converting enzyme inhibitors – ACE inhibitors (discourage formation of angiotensin II by inhibiting its production from angiotensin I), beta-adrenergic blockers – beta blockers (inhibit proteins that receive epinephrine [adrenaline] which slows the heartbeat and lowers blood pressure)
• Typically involves a drug interacting with some protein such as an enzyme receptor.
A specific drug could be describe as either a beta blocker or an antihypertensive, this classification will simply depend on the context and what it is that is being examined or described at any particular moment, and depending on the efficacy of any particular drug, one label may be more appropriate or at least more commonly used. With pharmacological classifications we are typically dealing with the way that drug interacts with some biomolecule, usually protein. This protein may be an enzyme, it may be a receptor, or otherwise, but there is typically some interaction between the drug and this protein that modifies the activity of that protein. For this reason, pharmacological classification is more specific than therapeutic classification and significant knowledge of the biochemistry is absolutely crucial in order for pharmacological
classification to make any sense whatsoever.
Drugs can have three names:
1. Chemical Name
• Determined by nomenclature rules designed by the International Union of Pure and Applied Chemistry
• The purpose of the naming rules is to give any molecule a completely unambiguous name 2. Sometime causes the public to exhibit chemophobia
Is quite straightforward, this is determined by the rules of chemical nomenclature designated by the IUPAC.
A drug will only have one chemical name because the rules are highly specific and exist precisely for the purpose of giving any molecule one unambiguous name and impractical for general use. Because of the way these names are derived, they tend to be “chemically” sounding which causes many sectors of the public to recoil strictly due to chemophobia – an irrational fear of chemicals and chemical sounding things.
For example, this drug is called 2-acetoxybenzoic acid, X’s and Z’s are particularly scary sounding as is the word “acid”, so some people may presume that this is a harmful chemical. However, in the US this drug is commonly known by its generic name, aspirin.
2. Generic Name
• Assigned by US Adopted Name Council to give drugs names that are short and easy to remember
• Only one generic name per drug and they are most commonly referred to by this name
Generic names are typically assigned by the US Adopted Name Council, specifically for the purpose of giving drugs with long chemical names another name that is short and easy to remember, even though it does not actually describe the composition of the molecule. There is only one generic name for any drug, so drugs are most commonly referred to by their generic names since non-chemists do not have the vocabulary required to pronounce or understand most chemical names. Generic names should be memorised and they are useful.
3. Brand/Trade Name
• The brand/trade name is trademarked and can be advertised in any manner desired
• These may be more recognisable than the generic name
• Pharmaceutical companies try to produce a bias in consumer trends towards their version A drug has only one chemical name and one generic name, it can have any number of brand names. That’s because anyone who makes the drug can call it whatever they want, and the name that is chosen is
completely meaningless outside of the context of marketing. For example, Empirin, this is aspirin. They are completely synonymous. Empirin is a brand name that is trademarked and can be advertised in any manner desired by its producers. Anyone else can mass produce aspirin and call it whatever they want as well.
Another generic name for a drug is Ibuprofen. Now consider the brand names Advil and Motrin, these are also Ibuprofen. The pill itself may look different cosmetically but the active ingredient is identical. Pharmaceutical companies rely on brand recognition as a result of advertising efforts in order to produce a bias in consumer trends towards their version of the drug, resting on the fact that most people do not realise that there is no difference apart from dosage.
Generic vs Brand Name
• Generic vs Brand/Trade Name – active ingredient is 100% identical
• There can be a discrepancy in bioavailability or the ability of the drug to reach its target
• Inactive ingredients may slightly affect absorption or other factors
A difference does arise when it comes to combination drugs (drugs with more than one active ingredient).
Excedrin is a mixture of acetaminophen, aspirin, and caffeine, intended to combine the effects of these three drugs to produce a more effective pain relief. In addition, while the active ingredient in a brand name drug and its generic counterpart is 100% identical, there can potentially be a discrepancy in bioavailability or the ability of the drug to move through the body to reach its target and elicit the desired effect. This is due to inactive ingredients when can influence the degree of absorption and other related factors but typically these discrepancies are minimal or even completely negligible.
Scheduled Drugs
• Drug abuse/addiction
• Physical dependency
• Psychological dependency
• Classified according to the degree of potential abuse
• Greater abuse potential = less therapeutic application
• Some drugs that can cause addiction are not included in the classification (alcohol, caffeine)
• There can be propaganda with the placement of certain drugs (marijuana and LSD are schedule I
These are drugs that have some likelihood of resulting in either physical or psychological dependency, or both.
Drugs with this quality are called scheduled drugs, and they are classified according to the degree of their potential for abuse.
Schedule I drugs have the highest potential for abuse, followed by II, III, IV, and then schedule V drugs have the lowest potential for abuse. The greater the abuse potential, the less therapeutic application a drug typically has.
1. Schedule I Drugs:
• Heroin – the most addictive substance known to man 2. Schedule II Drugs:
• Morphine, cocaine
Have some therapeutic purpose but still a very high dependency potential such as morphine and cocaine.
3. Schedule III Drugs
• Ketamine, anabolic steroids, low levels of codeine
Include ketamine, anabolic steroids, and products with low levels of codeine.
4. Schedule IV Drugs
• Valium and Xanax 5. Schedule V Drugs
• Cough medicines
Regulation of Drugs in Australia
Include things like cough medicines and are often available over the counter. These have very low dependency potential.
We should note that some drugs that do cause addiction are not included in this classification, such as alcohol and caffeine. There can be propaganda associated with the placement of certain drugs in a particular schedule, such as marijuana and LSD qualifying as schedule I drugs, given that there is little to no evidence that these substances produce any kind of dependency that could be comparable to a
substance like heroin.
How are drugs made available in Australia
For a drugs to be available in Australia, it has to be approved by the Therapeutic Goods Administration (TGA), after assessment of its quality, safety and efficacy. Once a drug is registered with the TGA for sue, the drug company can apply to have it listed on the pharmaceutical Benefits Scheme (PBS), so that the cost is subsidised by the government. The decision is made based on need and cost-effectiveness. Moe than 80%
of the registered drugs in Australia are available on the PBS, so that people can get them for the cost of the prescription, rather than having to pay the whole cost of the drug.
As of June 2020, there were 902 different individual medicines available on the PBS. This does not include the drugs that are registered by not subsidised by the PBS. These medicines were used in 5371 different
formulations/brands. The number of prescriptions issued under the PBS during the year was 208.5 million, at a total cost of $12.6 billion. Not surprisingly, drugs used to treat chronic disorders account for the largest
number of prescriptions.
The pharmacological management of chronic conditions has increased the quality of life and longevity of many Australians, but it has also resulted in a high rate of polypharmacy – taking multiple medicines long term. One recent study using 2016-2017 figures estimated that about 36% of Australians over the age of 70 are taking 5 or more different medications continuously. Those figures are consistent with studies conducted in the UK. This is fine as long as all the medications are clinically necessary, but it can also be responsible for more adverse drug events and failure to take medicines as prescribed, both which can cause problems of their own.
Science has made huge advances in the prevention and treatment of the most deadly diseases, but it is lifestyle-related preventable disease, some of which were almost unknown a few decades ago, that are now taking lives.
The role of the TGA in Australian drug regulation
The TGA regulate therapeutic goods in Australia, including how they are manufactured and advertised. They are a part of the Australian Government Department of Health.
Therapeutic goods are used for:
• Preventing, diagnosing, curing, or alleviating a disease, ailment, defect or injury
• Influencing, inhibiting, or modifying a physiological process
• Testing the susceptibility of people to a disease or ailment
• Influencing, controlling, or preventing conception
• Testing for pregnancy Therapeutic goods include:
• Prescription medicines, including vaccines
• Biologicals Blood and tissue products
• Over the counter medications
• Complementary medicines
• Medical devices, including in vitro diagnostic devices They also regulate the manufacturing and advertising of all these products.
To regulate, they have systems in place to:
• Ensure manufacturers meet standards for producing goods
• Authorise supply
• Monitor products once they are on the market and take action if there are problems
• Identify illegal activities like counterfeiting and take action to stop these occurring The TGA review:
• The manufacturing information for every batch of vaccine
• Test the first five batches of most biological medicines
• Perform targeted investigations of medicines for suspected non-compliance
• Seek advice from experts on their advisory committees
• Test devices for sterility and when they have been involved in adverse events
Dynamics and Kinetics
Drugs Sites of Action
To identify medicines that have been regulated by the TGA
• Lower risk medicines, such as vitamins or herbal supplements have an AUST L number on the label
• Higher risk medicines, such as prescription medicines or painkillers have an AUST R number on the label. These medicines are tested for efficacy
Therapeutic goods must be entered on the Australian Register of Therapeutic Goods (ARGT) before they can be lawfully supplied in Australia unless there is an exemption. The TGA continues regulating the goods
throughout their lifecycle in several ways:
• Manufacturing
• Marketing
• Supply
• Hazards
• Adverse events
TGA only regulate therapeutic goods, other government agencies regulate:
• Veterinary Medicines – Australian Pesticides and Veterinary Medicines Authority
• Health Professionals – Australia Health Practitioner Regulation Agency
• Health Insurance – Private Health Insurance Administration Council
• Food Regulation – States and Territories and Food Standards Australia New Zealand
• Cosmetic and Chemical Standards – National Industrial Chemicals Notification and Assessment Scheme
The TGA do not:
• Research and develop new therapeutic goods
• Provide clinical advise to individuals
• Consider cost effectiveness or recommend one product over another
• Make decisions about subsidy of therapeutic goods. The PBS and other areas of government have this responsibility
We divide drug characteristics into Dynamics and Kinetics 1. Pharmacodynamics
• Selectivity
• Efficacy
• Potency
What the drugs does once it’s in the body is very much dependant on its chemical structure, the shape of its molecule and the various reactive groups that the molecule has on it. The reason that a chemical is having its action by interacting with our own chemical structures in some way and the lock and key theory is an attempt to explain the actions of drugs and specific receptors. It likens the drug to a key, and the receptor, the place that the drug is binding is the lock. This idea of the drug is shaped to fit into particular locks, or receptors, or similar receptors and once in the lock the drug or key can either unlock it or may jam it and prevent any other keys from getting in there. This theory helps explain the observations that certain classes of chemical tend to bind to the same types of receptors and they have similar actions once they are bound.
Receptors
Once a drug binds to a receptor it will activate the receptor which is activated through a series of events and some change in cellular activity. Receptors naturally exist on cells to create cell chemical signalling which could be a hormone, neurotransmitter, etc and when the interaction is identified where the natural endogenous substance, which is the substance that originates from within the body, is activating the receptor it is called the natural ligand.
When you have the same cell and the same receptor but a drug (exogenous – originated from outside the body), the drug may not be a ‘perfect fit’ for the receptor, but it is similar and if the cell allows the drug to interact with the receptor it can be sufficient to bind and active the receptor and still produce the same cellular activity. Although, the drug isn’t identical to the receptor it was sufficiently similar to act as the key in the lock and unlock the particular activity. When this occurs with an exogenous substance, this substance is called an agonist.
If something approaches the receptor that does not look like or similar to the profile of the receptor, it can cover the receptor/lock the receptor but does not match to activate cellular activity. However, it can still bind to the receptor sometimes quite tightly to prevent the natural ligand or agonist – effectively preventing the receptor from activating. This substance is called an antagonist.
Drug Receptor Interactions Transporters
Large proteins used often as pumps to move substances from one body compartment to another, located on cell membranes and usually transporting substances against their concentration gradient. When they require energy (which they usually do) to transport those substances, it is known as active transport
molecules. There are a number of drugs that are used therapeutically that bind to these types of molecules in order to have their effect. Monoamine transporters are a good example, they are usually found on neurons that contain and release the monoamine neurotransmitters (serotonin, noradrenaline, dopamine). After the transmitters have been released and have had their effect, they are actively pumped back into the nerve ending by an active transport molecule.
Ion Channels
Sodium and Potassium channels open and close to either allow or not allow their ions to pass through. There are binding sites for ligands to gate the channels as well as a number of drugs bind with ion channels to have their effects.
Enzymes
Large proteins that catalyse biochemical reactions that go on inside our cells daily. Similar to the receptors, ligand interaction, there is a fitting of substances that are reacting in to the enzyme that is causing the reaction to speed up – catalysing the action. Catalysing is the role of the enzyme.
To summarise, the majority of the drugs that are used therapeutically have their action at one and or other of these major binding sites for drug receptors, transporters, ion channels, or enzymes. This doesn’t cover all of the drugs and there are other areas that some drugs will have their action and there are also a number of drugs that we use that don’t actually bind to a particular site. For example: antacids that reduce acidity in the stomach are simply helping to neutralise the acid in the stomach. There are various resins and binders for example that don’t act as a particular site in order to bring about the effect that you want but those four areas cover majority of drugs that we use
Pharmacodynamic Variables 1. The concept of Affinity
The readiness of which a drug will bind to a binding site and the tightness of which it will bind – how readily it will come off again once its bound. If there are two drugs present in the same concentration, but one of the drugs (green) is occupying three out of the four receptors while the other drug (yellow) is only able to
occupy one. In this situation, the drug occupying more receptors has the higher affinity. The concept of affinity is important when it comes to considering if a drug will be useful or not because the higher the affinity, the more sites the drug is likely to occupy and if there is competition for those binding sites with other substances than the higher affinity drug will be more competitive – will be able to justly other substances off the binding site to replace them. Drugs binding to the receptor sites are a dynamic process. The drug doesn’t usually attach to the binding site and then stay there forevermore, it is more likely the drug will be binding and unbinding. During this unbound phase, there is an opportunity for any other substances that are in the area that also bind to that receptor to sneak in to the binding site instead. When there is a lower affinity drug, other drugs that bind to the same receptor can remove it from the receptor. If there is an extremely high affinity binding then the drug will stick to the receptor/binding site and it won’t move for the life of the receptor, for the life of the binding site. They are known as non-competitive binding as they do not allow any other substance to compete for the site but it is more usual for two drugs to compete for a binding site and the drug with the higher affinity will win to occupy most of the receptors.
2. Selectivity
The selectivity of a drug for a particular receptor site over another, this plays a bit part of the usefulness of a drug. When there are two types of receptor sites, a drug or substance will bind preferentially to one site over another (yellow drug preferentially selecting purple over red), this means the drug is selecting one receptor site over the others. Selectivity is about the affinity of a drug that is has for different types of receptors, if a drug is highly selective for one particular type of receptor then it means it has a high affinity for that receptor and if it binds to other receptors or other binding sites it is doing so with a much lower affinity. Therefore, at a lower concentration you would expect it would be binding mainly to the one type of receptor that it has a high selectivity for. The selectivity of a drug for a particular receptor site is about its affinity for that receptor verses the affinity for other receptors. This has an impact on how useful a drug is because if a drug binds to lots of different receptors then the drug is going to be producing a higher rate of effects and you may only want those effects as a therapeutic effects. If a drug binds in a lot of different places the chances are it will
Agonists and Antagonists
produce a lot of side effects and in particular, if it binds with similar affinities to different receptors that means at a therapeutic dose you will be receiving those other side effects coming in as the drug is binding to all receptors. If the drug is quite selective for a particular receptor type it will only be at very high doses that you’d see those effects of it binding to other receptors for which it has a lower affinity. The concept of the selectivity of a drug with particular receptors tells us about how ‘dirty’ or ‘clean’ the drug will be, how many different effects you’d expect it to produce.
Efficacy
The size of the effect that you can get after an agonist (drug) interacts with its receptor. If the natural ligand was to bind with the receptor, you would expect the natural ligand would produce a 100% response but if an agonist was to match that response when binding with a receptor it would be known as a full agonist. If the agonist isn’t able to produce a 100% response after binding with the response it would be known as a partial agonist. This is because the efficacy of the partial agonist is much less than the efficacy of the natural ligand of that receptor. For the partial agonist by increasing the dose, it will only reach a fraction of the total maximum response that you could receive from a full agonist or natural ligand of that receptor.
Comparing Agonists and Antagonists 1. Agonists
• Affinity
• Selectivity
• Efficacy 2. Antagonists
• Affinity
• Selectivity
• No efficacy – the antagonist’s job is to block the receptor Competitive Antagonists
Agonists and antagonists can compete for the same receptor and they will have competing effects on that receptor – one competing to block the receptor and the other will be wanting to activate the receptor.
Competitive antagonism is when an antagonist can bind and block a receptor but its affinity is not so high that it could come off the receptor and therefore if an agonist is present it can compete for a position on the receptor. From a therapeutic point of view, if you are using an antagonist as a drug and you want to remove the drug or want to stop the action of the drug you can do so by adding the agonist in order to compete the drug off their receptors. On the other hand, if you don’t want that to happen then you need to be careful that you don’t diminish the effects of the drug by adding a lot of agonists. An agonist alone can achieve the maximum response, by adding a competitive antagonist it will block the same receptors that the agonist is working on and then try the agonist again the presence of the antagonist you will find that you will require a higher dose, more of the agonist to get any kind of response and an even greater dose on top of that to have higher response. In order to overcome the effects of the antagonist you are going to have to put more of the agonist around to compete for the receptor when the antagonist removes from the receptor briefly.
An example of this in therapeutic use is when there are people with opioid addicts (ie heroin overdose) the emergency treatment for this is by giving narcan or a similar drug that is an antagonist at the opioid
receptors, this will compete with the agonist, with the heroin and will start to remove the agonist from the receptor which will reverse the effects of the opioid.
Non-competitive Antagonists
When you have an antagonist that binds so tightly to a receptor that absolutely nothing will shift it, in the case it if you try to use an agonist at this receptor you will not be able to get the same effects of the agonist as you would if the antagonist wasn’t there. This is because whatever receptors are occupied currently by the non- competitive antagonists, they will remain occupied and the agonist will only be able to activate the
unoccupied receptors. The total maximal effect that the agonist will provide in the presence of a non- competitive antagonist is going to be a lot less.
Changes in drug action after long term use depend on the drug type Regulation of Receptors
Taking drugs long term will eventually cause a change to the physiological system. Your physiological system will put in place mechanisms that counteract what the drugs are doing, this has a profound effect on the effectiveness of the drug/s over time. By taking a drug daily for an extended period of time, this drug will be
at a higher concentration than the natural ligand and this means there is an unnaturally high level of stimulation of receptors in that cell. Body systems will respond by adjusting the response to the agonist. One way this is done is by removing some of the receptors from the membrane so the sensitivity of the cell is lowered when there appears to be an excessive agonist activity on that cell. When agonist drugs are taken long term, there can be down-regulation or desensitisation that remove receptors resulting in tolerance/a reduction in response to the drug.
Taking an antagonist long term, they are blocking cell receptors long term. When the natural ligand comes along, they no longer have the same effect as they would have had before as some of the receptors are blocked. If this is continued long term, the cell will detect that there is an unnatural/abnormal reduced number of agonist activity on that cell. This cell will increase its sensitivity by producing more receptors on the member for the agonist to bind to. Long term antagonist use can lead to receptor upregulation or
sensitisation that results in a decreased effect of the antagonist.
A drug holiday is known when people stop taking their drugs for a period of time, this can reverse the
dynamics by the cell responding to the fact that the drugs are no longer in the system and it will reset itself to pre-drug levels. The risk of this is when people stop taking the drug suddenly it causes a rebound effect.
Summary 1. Agonist
• Any drug that binds to a receptor and activates the receptor.
• In most cases, the agonist leaving the binding site deactivates the receptor.
• In some receptors, agonists permanently activates the receptor until the protein receptor is recycled.
2. Pharmacological Antagonist
• Is any pharmacological drug that binds to a receptor and prevents the activation of the receptor.
• Competitive antagonists is any pharmacological antagonist that ‘competes’ with the binding of an agonist at the binding site.
• Non-competitive antagonist is any pharmacological antagonist that binds to a site on the receptor other than the agonist binding site.
3. Chemical Antagonist
• Is any drug that binds directly to an agonist and deactivates the agonist.
4. Physiologic Antagonist
• Any drug or chemical that has an opposite effect, but through completely different physiologic pathways
• Histamine – anaphylaxis is a severe systemic allergic reaction. Excess histamine released by the body is part of the problem
• Epinephrine – given to counteract the effect of excess histamine, but they work by completely different receptors and physiologic pathways.
