HUBS week 1

• Agonist


  A compound that binds to a receptor and produces the biological response
• Drug receptor


  • A specialised target macromolecule that binds a drug and mediates its pharmacological action
  • May be enzymes, nucleic acids, or specialised membrane-bound proteins
  • The formation of the drug-receptor complex leads to a biological response
  • The magnitude of the response is proportional to the number of drug-receptor complexes
• Concentration-response curve


  A common way to present the relationship between the drug concentration and the biological response
• Partial agonist


  Produces the biological response but cannot produce 100% of the biological response even at very high doses
• Efficacy


  A term used for comparisons between drugs
• Potency


  • A term used for comparisons between drugs
  • Often expressed as the dose of a drug required to achieve 50% of the desired therapeutic effect (ED50)
• Therapeutic index


  • A measure of drug safety
  • A drug with a higher therapeutic index is safer than one with a lower one
• Therapeutic window


  The range of plasma concentrations of a drug that will elicit the desired response in a population of patients
• Antagonist


  Blocks or reverses the effect of agonists and has no effect of its own
• Competitive antagonist


  Makes the agonist look less potent by shifting the dose-response curve to the right
• Inverse agonist


  • Has opposite effects from those of full agonists
  • Not the same as antagonists, which block the effects of both agonists and inverse agonists
• Therapeutic classification - physiological change induced by the drug

  • Anticoagulants
  • Antihyperlipidemic
  • Antihypertensives
  • Antidysrhythmic/antiarrhythmics
  • Antipsychotics
  • Antidepressants
  • Anticonvulsants
  • Decongestants
  • Hallucinogens
  • Sedatives
  • Stimulants
• Pharmacological classification - mechanism of action on the molecular level

  • Calcium channels blockers
  • Angiotensin-converting enzyme inhibitors
  • Beta-adrenergic blockers
• Chemical name


  • Determined by nomenclature rules designated by the IUPAC (International Union of Pure and Applied Chemistry)
  • A drug will only have 1 chemical name
• Generic name


  Only one generic name per drug, most commonly referred to by this name
• Brand name


  A drug can have any number of trade/brand names
• Combination drugs


  • Drugs with more than one active ingredient
  • 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
• Drug schedules in the US

  • Schedule 1
  • Schedule 2
  • Schedule 3
  • Schedule 4
  • Schedule 5
  • Schedule 6
  • Schedule 7
  • Schedule 8
  • Schedule 9
  • Schedule 10
• Therapeutic Goods Administration (TGA)


  The organisation in Australia that approves drugs for use after assessing their quality, safety and efficacy
• More than 80% of the registered drugs in Australia are available on the Pharmaceutical Benefits Scheme (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 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
• About 36% of Australians over the age of 70 are taking 5 or more different medicines continuously
• Pharmacodynamics


  Selectivity, efficacy, potency
• Lock and key theory

  • Attempts to explain the actions of drugs at specific receptors
  • Likens the drug to a key and the receptor to a lock
  • The drug is shaped to fit a particular lock/receptor
• Receptor


  • When a drug binds to a receptor, it can activate the receptor and produce a change in cellular activity
  • Receptors can be for natural endogenous substances (ligands) or exogenous substances (drugs)
• Drug sites of action

  • Receptor
  • Transporters
  • Ion channels
  • Enzymes
• Receptor


  • When that part locks onto the receptor it will fit due to the profile match -> when it comes down its able to dock onto that receptor and therefore activate the receptor and activate through a series of events, some change in cellular activity
  • When there is receptors naturally existing on cells, to do this cell signalling that purple lump could have been a hormone for eg or neurotransmitter that could've been some other signalling chemical within the body, -> this particular interaction with the natural endogenous substance is activating that receptor = natural ligand
  • Exogenous cell (originated from outside the body eg some kind of drug)
  • The profile of that drug is not exactly the same as that of the receptor, but it is somewhat similar
  • If we allow it to approach the receptor, we can find it sufficiently similar to dock onto the receptor and activate it to produce that same change in cellular activity
  • Although not identically chemically to the receptor, it was sufficiently similar to act as the key in the lock and unlock that particular activity -> this with an exogenous substance is called an agonist at the receptor
  • This one is actually looking down over the receptor, but not matching the receptor as a key would in a lock -> binding to the receptor and preventing the natural ligand or any agonist for that matter getting too the receptor
  • When this happens, you have a drug that can bind to and effectively block a receptor and prevent any ligands getting in and activating it = antagonist
  • When the antagonist binds to the receptor, the change in cellular activity that would be normally triggered by the activation of that receptor doesn't happen
• Transporters


  • Another group of molecules to which drug substances unknown to bind are transport molecules. These are the large proteins that are used as pumps to move substances from one body compartment to another
  • Transporter found on neurons that contain and release them on the way mean 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 transporter
• Ion channels


  • The difference b/w ion channels and transporters can be confusing. They're both transmembrane proteins that help molecules pass through cell membranes more efficiently (eg if they are charged)
  • Ion channels provide a pore that permits often rapid, highly selective, and tightly regulated movement of ions down their electrochemical gradient
  • In contrast, active transporters can move or "pump" ions or other larger molecules. This movement via transporter occurs against the molecules electrochemical gradient, a process which requires energy
  • In the image the potassium channels are opening and closing in order to either allow or not allow the ions to pass through
  • There are binding sites for ligands to gate those channels and a number of drugs bind at various ion channels to have their effects
• Enzymes


  • Enzymes are named by adding the suffix -ase to the name of the substrate that they modify (ie urease and tyrosinase), or the type of reaction they catalyse (dehydrogenase, decarboxylase). This can be helpful for determining if a drug acts on an enzyme (eg decarboxylase inhibitors are a class of medications used to treat symptoms of Parkinson's disease)
  • The large proteins that catalyse hundreds of thousands of biochemical reactions that go on inside ourselves on a daily basis
• Affinity


  • This is essentially the readiness with which a drug will bind to a binding site and the tightness with which it will bind -> how readily it will come off again once its bound
  • The green drug is occupying ¾ receptors and the yellow drug is only able to occupy 1
  • The green drug therefore has the higher affinity for the purple receptors than the yellow drug
  • This concept of affinity is important when it comes to thinking about whether a drug will be useful or not as the higher the affinity the more sites the drug is likely to be able to occupy -> if competition occurs b/w the drugs, the higher affinity drug will be more competitive (jostle other substances off the binding sites and replace them on the sites)
  • If you have an extremely high affinity binding, then the drug will stick to the receptor of the binding site and won't move (and opposite) non-competitive finding
• Selectivity


  • Selectivity plays a big role in the usefulness of a drug
  • The yellow drug is binding preferentially to the purple receptors, which means hat it is selecting for the purple receptors
  • The selectivity of a drug is about the difference in affinity that it 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. If it binds to other receptors or another binding site, it is doing so with a much lower affinity and therefore at a lower concentration -> binding mainly to that one type of receptor that it has a higher selectivity for
  • The selectivity of a drug for a particular receptor type is about its affinity for that receptor versus its affinity for other receptors
  • If a drug binds to multiple receptors -> producing array of effects (may only want one) -> side effects
  • If the drug is quite selective for a particular receptor type, it would only be at very high doses that you might expect to get effects from it binding to other receptors for which it has a lower affinity
• Efficacy


  • The first cell has a pink agonist coming down, looking on and producing its effect after it interacts with the receptor
  • The purple agonist produces a much smaller effect
  • Efficacy is about the side of the effect that you can get after a drug interacts with its receptor (agonist)
  • The natural ligand in this case would effectively produce a 100% response. If an agonist is able to match that response when it locked onto the receptor, then it's called a full agonist
  • As you ^ the dose of the agonist, you ^ the response which can be up to 100%
• Comparing Agonists and Antagonists


  • Agonists – affinity, selectivity and efficacy
  • Antagonists – affinity, selectivity but no efficacy
• Competitive Antagonists


  • Can have competitive antagonism -> can have an agonist and an antagonist competing for the same receptor -> competing effects (one blocking and one activating)
  • From a therapeutic view – if you're using an antagonist as a drug and you want to remove that drug or you want to stop the action of the drug you can do so by adding the agonist in order to compete that drug off its receptor. If you don't want that to happen you need to be careful you don't diminish the effects of the drug by adding a lot of agonist
  • Need to use more of the agonist to get any response at all
  • Eg heroin (opioid) overdose -> give Narcan which is an antagonist at the opioid receptor and it will compete with the agonist with the heroin and it will start to remove the agonist from its receptors -> start to reverse the effects of the opioid = competitive antagonism
• Non-competitive antagonism


  • Where you have an antagonist that binds so tightly to a receptor that absolutely nothing can shift it -> if you try to use an agonist at that receptor, won't be able to get the same effects the agonist will only be able to get at activate any unoccupied receptors
  • The total maximal effect that the agonist can give you in the presence of a non-competitive antagonist is just going to be a lot less
  • All the agonist can do is get at the receptors that are currently unoccupied by the non-competitive antagonist
  • The agonist is unable to knock the non-competitive antagonist off its receptor sites -> get whatever is left over
• Changes in drug action after long term use

  • Desensitisation and tolerance refer to reduction in the response (or decreased sensitivity) of the system to an agonist due to receptor downregulation with long-term use
  • Sensitisation refers to an increase in the response (or increased sensitivity) of the system to an agonist/endogenous ligand, BUT the antagonist is less effective (because there are more receptors available for the endogenous ligand)
  • Long term agonist use can -> receptor downregulation (removal of receptors from the cell membrane -> don't get such a big response to the agonist anymore)or desensitisation result in tolerance
  • Long term antagonist use can -> receptor upregulation or sensitisation to the agonist -> reduction in the effect of your antagonist (doesn't happen with all drugs)
  • If you stop taking the drugs for a while , you then aloe the situation to reverse and the dynamic system will respond to the fact that the drugs are no longer in the system and will reset itself to its pre-drug levels