PHAR3306 Notes - Week 1 PDF

PHAR3306 Notes Wk 1: Pharmacodynamics I Drugs An agent that interacts with specific target molecules in the body and produces a physiological effect - Until the 19th Century most drugs were naturally organic dried and...

PHAR3306 Notes Wk 1: Pharmacodynamics I Drugs An agent that interacts with specific target molecules in the body and produces a physiological effect - Until the 19th Century most drugs were naturally organic dried and fresh plant products Pharmacodynamics The mechanism by which drugs exert their effect on the body in order for a therapeutic action to occur. Pharmacodynamics encompasses: - Drug-receptor interactions. - General principle of drug action. Pharmacokinetics is what the body does to the drug. Drugs with activity at high Drugs acting at low concentrations Types of Drugs concentrations. - Structural specificity. - Little structural - Act by chemical rather than physical specificity. interaction (Isoprenaline). - Cause physical change (general anaesthetics). Receptors The site at which a ligand (agonist) can attach Intro Ligands (also known as drugs) may be neurotransmitters, hormones or local factors Activation of receptors by a ligand or agonist produces a response (effect). Affinity: The attraction of a drug for binding. Selectivity: Ligand - Gated ion channels G-protein coupled receptors: Types of Fast neurotransmitters Slow neurotransmitters Receptors e.g. nicotinic, GABA, NMDA, AMPA e.g. Ach, NA, chemokines, opioids Kinase-linked receptors Nuclear receptors Insulin, cytokines and growth factors Steroid hormones, thyroid hormone, retinoic acid and vit D Several subtypes; Receptor - Cholinergic - muscarinic; nicotinic Sub-types - Adrenergic receptor subtypes include 2 (lungs), 1 (heart) and 1 (blood vessels) Development of selective drugs which interact ONLY with specific receptor subtypes has revolutionised pharmacology. Side Effects Because: Receptors for a drug occur in Because: Of the non specificity/selectivity of drugs. several tissues, not just the target tissue. Regulations Until the 1930’s drugs did not need to be tested for safety or effectiveness. ‘Elixir of Sulfonamide Tragedy’ of 1937 led to the requirement that drugs be tested for safety before they reached t– 107 children died. Establishment of the Food, Drug andCosmetic Act of 1938 in the USA; requiring details of a drug’s uses and proof of its safety. Clinical trials were not required. New Regulations required proof of quality, safety and efficacy or effectiveness. The Australian government established: The Australian Drug Evaluation Committee [ADEC]: 1962 Registry of adverse drug reactions: 1962 Adverse Drug reactions Advisory Committee [ADRC]:1971 - It now takes many years of research before a new drug can be registered. - Adverse drug reactions still occur e.g. Rofecoxib Thalidomide Was introduced onto the European market as a safe sedative/hypnotic in the late 1950’s. - Many pregnant women took it for morning sickness. - Tested on male rats only; no teratogen testing. - Thalidomide was found to be a teratogen which causes birth defects. - All drugs capable of crossing the placenta are capable of affecting the foetus. General principles of Drug Action Types of Drug Action Agonists mimic endogenous ligands. They bind to a receptor and cause a secondary effect. Agonists and Antagonists An Antagonist binds to a receptor and prevents the action of an agonist. Most antagonists are competitive and reversible. (No affinity) Locke + Key Model Antagonist is the twig, can't do anything, just locks the effect of the agonist.  Receptor binding can be used to measure effect of drug by measuring efficacy or Drug-receptor effectiveness of drug in producing maximal response Interaction Assumed that the effect of a drug is proportional to the fraction of receptors occupied. Assume that the maximal effects occur when all receptors are occupied. These assumptions are not always true. Properties Efficacy is a measure of the effectiveness of a drug in producing a maximum response Dose ED50 (Effective Dose 50%): The dose of a drug response that produces 50% of its maximum effect in a population EC50 (Effective Concentration 50%): The concentration of a drug that produces 50% of its maximum effect in an individual or a tissue sample. KD (Dissociation Constant): The concentration of a drug at which half of the receptors are occupied. It measures how strongly a drug binds to its receptor. - Assumed: effect is proportional to receptor occupancy and maximal effect occurs when all receptors are occupied. - KD becomes the ED50 i.e. the dose that produces a 50% effect. - Drugs which are highly potent require low dosages The measure of the drug dosage needed to produce a Potency particular therapeutic effect. - It is determined by the strength of binding of a drug to a receptor or the receptor affinity for the drug. ED50: When all receptors are occupied. (For a spare receptor, the presence of spare receptors shifts the dose-response curve to the left of the KD.) Efficacy - The measure of the effectiveness of a drug in producing a maximum response. - Full agonists have high efficacy - Antagonists have no efficacy. Which drug is most potent? Which drug is the most efficacious? Examples Lower Kd = More affinity & potency Dose - Response measurement Determines accurate dosing needed when new drugs are formulated  Cannot use these measurements to calculate affinity only dosing → Agonists bind to receptors causing contractions which are plotted. → Increasing doses = Increasing response until 2 doses have an equal response → Divide everything by that response = max response Practice question  Drug Antagonism Competitive (or surmountable) Antagonism Types Non-Competitive (or irreversible) Antagonism Physiological Antagonism Competitive Occurs when agonists and Antagonism antagonists compete for the same receptor sites. Maximal effect unchanged (ie antagonism is surmountable). Parallel shift to the right leading to increase in dosage to overcome the antagonism Produce irreversible changes Non- Competitive by acting on the receptor itself Antagonism to change it and make binding impossible Cause a change in the receptor so that the agonist can no longer bind. A maximum effect is no longer produced Spare receptors Are important in non-competitive antagonism as a receptor reserve can allow a maximum response to be reached. Spare receptors occur because there are several amplification steps downstream from the initial drug-receptor interaction. ED50 for a drug effect with spare receptors may not be equal to KD and this shifts the dose response curve to the left of KD as in classical theory, half receptors bound should lead to half of the maximal effect but this is not the case with spare receptors Physiological Occurs when 2 agonists act on different receptors to produce opposite effects. Antagonism The drugs have different mechanisms of action. Eg bronchoconstriction due to histamine can be treated with adrenaline which acts as a vasodilator. Practice question i) T ii) F iii) T iv) F Agonists in-vivo: The effect of an antagonist relies solely on blocking the action of an agonist which is Concept of tone already producing a certain effect ie there must be an agonist induced tone Partial agonists are less ‘efficacious’ - Partials Agonists 1. Never achieve maximum effect. 2. Also act as an antagonist (locking full agonist from binding) Inverse Agonists Some receptors are constitutively active, even in the absence of any agonist. An Inverse agonist restores the receptor to its inactive state. Mechanism: 1. Receptors exist in equilibrium between active and inactive forms 2. The presence of an agonist will increase the proportion of active receptors 3. The presence of an inverse agonist will increase the proportion of inactive receptors 4. Mechanism of action of inverse agonists is thought to involve the destabilisation of G-protein receptor coupling. Potentiation of Occurs due to the decreased inactivation of an agonist i.e the breakdown of the drug is Agonists reduced. The drug will be able to accumulate to higher concentrations and have a more potent effect - Acetylcholine in the presence of anticholinesterase (neostigmine; physostigmine). - Noradrenaline in the presence of an uptake blocker (cocaine, tricyclic antidepressants). Allosteric These compounds bind to a separate site on the receptor from agonists called an Modulators allosteric site. Occupation of this site can either increase or decrease the response to endogenous agonists, depending on whether it is positive or negative modulation. Qualitative and Quantitative response: is measured in gradual steps, eg fall in blood pressure Quantal response Quantal response: is all or none e.g. responders or non- responders. Quantal dose - Response curve Tells us the therapeutic range and safety of a particular drug. - Smaller distance between curves indicating less safe drug - ED50 refers to dose that results in response in 50% of population - LD50 refers to the dose that results in death in 50% of the population. Therapeutic aka Toxic ratio A measure of the safety of the drug. The dose that is lethal in 50% of the population divided by the the effective dose, in 50% of the population. Higher ratio = safer - Problems with the therapeutic ratio is that it’s not ethical to kill 50% of animals and does not reflect sublethal toxicity and presence of differences in animal and human data Risk Vs Benefit: A contraindication is an existing condition or situation that alters the use of a drug Contraindications because of increased risk of adverse effects. Contraindications may be absolute (i.e. drug should not be used at all) or relative (i.e. drug can be used with caution – may require increased monitoring or dose adjustment) Molecular Aspects The number of receptors in a cell is not static but dynamic. of Drug Action: There is a high turnover of receptors as they are continuously removed or Receptor replaced. numbers Repeated drug treatment may up-regulate or downregulate the receptor numbers. Tolerance The same dose of drug, on repeated administration, produces less effect. - Tachyphylaxis: Tolerance which develops very rapidly. Desensitisation Desensitisation: Less effect is produced the longer the agonist remains in contact with the receptor. Causes of desensitisation / tachyphylaxis / tolerance Change in receptors (phosphorylation) Downregulation of receptors (internalisation /reduced expression) Depletion of mediator Increased metabolic breakdown Pharmacology Food as drugs – nutraceuticals and lifestyle - Food-drug interactions Exercise:  - Effect of exercise on drugs; pharmacokinetics and pharmacodynamics - Activation or induction of antioxidant systems - Effect of drugs on exercise The role of Provides information regarding dose/dosage regimen vs response. pharmacodynamics - Factors affecting pharmacodynamics together with pharmacokinetics are in pharmacology considered when a dose is individualised for special populations such as the elderly - Useful tool for introducing new indications, new dosages or new treatment populations contributing to valuable information for drug development. Practice question =D - Sites of Drug Action Receptor A protein that responds to a molecule (e.g., hormone or neurotransmitter) and causes a consequent change in cellular or biological function. The Locke and Key - Key is the Endogenous Model Agonist while Lockpick can be considered the Exogenous Agonist and both can open the lock and cause an effect - Object jammed in the lock is analogous to the antagonist which prevents the agonist from acting on it Sites of Drug Action Main Drug targets The estimated proportion of genes from different gene families that are targets for approved drugs, but you can see there are a number of ‘usual suspects’ Transporters Occurs when 2 agonists act on different receptors to produce opposite effects. - Not strictly defined as receptors as they don’t bind endogenous agonists - Transporters actively move substances from one side of a cell membrane to the other ATP-binding Primary active transporters: use ATP cassette (ABC) hydrolysis to actively pump substrates transporters against a concentration gradient - Examples include P-glycoprotein (P-gp; multidrug resistance protein 1) or cystic fibrosis transmembrane regulator (CFTR) Solute-linked carrier Secondary active transporters: One or more (SLC) transporters molecules travel down their concentration gradient so that the solute can travel against its concentration gradient - Examples include the monoamine transporters DAT (dopamine), NET (noradrenaline) and SERT (serotonin)  Receptors are classified into different Cellular location families, primarily based and structural on their structural similarities. features - Three of these receptor of receptors families are cell surface receptors, which means that they are embedded in the plasma membrane. - While the nuclear receptors are soluble proteins that are present either in the cytosol or the nucleus. Ligand-gated ion channels (are also receptors!) Ligand-gated ion - Essential for synaptic transmission channels: in the central and peripheral nicotinic nervous system in humans. acetylcholine (ACh) - Has 2 alpha subunits which ligand receptor binds between and requires 2 ligands to open the channel - Each subunit is made up of 1 polypeptide chain that has 4 transmembrane helices - 5 Receptor subunits form the active channel G protein-coupled 7 transmembrane helices with N-Terminus receptors that is Extracellular and a C-Terminus that is intracellular Largest family of cell surface proteins Conserved throughout evolution >800 GPCRs in human genome (~3% total genome) ~250 have been matched to a ligand and the rest are ‘orphans’ Most drugged family of proteins with >35% market share. Heterotrimeric protein with 3 parts, one alpha, beta and gamma subunit G protein-coupled When a ligand binds to the GPCR, a conformational change receptor signalling occurs that immediately disrupts the G protein heterotrimer, so it dissociates from the GPCR and the alpha subunit also dissociates from the beta and gamma subunits. - The alpha Subunit then goes down to have downstream signalling effects, and so does the beta and gamma heterotrimer Catalytic receptors AKA Kinase-linked/enzyme-linked receptors dimerise when bound to ligands to form the functional receptor. - Extracellular Binding Domain, 1 transmembrane helix and an intracellular catalytic domain forming the C Terminus with an attached enzyme which is where signalling occur - Cross Phosphorylation of the C-Terminus initiates signalling to allow Catalytic receptors to dimerise when bound to a ligand to form the functional receptor Types of Catalytic 1. Receptor Tyrosine Kinase (RTK): receptors Have intrinsic tyrosine kinase activity (EGF, VEGF, Insulin) 2. Receptor Serine/Threonine Kinase: Contain intrinsic serine/threonine kinase activity (TGF- ) 3. Cytokine Receptors: Receptors that associate with proteins that have tyrosine kinase activity (Interleukin Receptors) 4. Receptor Guanylyl Cyclases: Have intrinsic cyclase activity (ANP receptors) 5. Receptor Protein Tyrosine Phosphatases: Have intracellular phosphotyrosine phosphatase activity (PTEN, a tumour suppressor) Receptor tyrosine Activation of receptors leads to dimerisation that kinase signalling causes autophosphorylation of the C-Terminus of each receptor allowing other proteins to bind and initiate a kinase cascade Nuclear receptors - Live within the cytoplasm or nucleus and their ligands therefore need to be able to cross the plasma membrane and sometimes the nuclear membrane to get to their receptor meaning they need to be lipid soluble - Basic Structure contains Ligand binding domain, DNA binding domain and variable N-terminal activation domain and activation function 1 (AF1) - Bind inhibitory proteins (co-repressors) in their inactive conformation. - Agonist binding causes conformational change in the ligand-binding domain, → co-repressor(s) dissociation and coactivator recruitment, → increasing gene transcription. - Zinc fingers, dimer pair needed for functional receptors. Class I nuclear Are steroid receptors that act as Homodimers with receptors mainly endocrine ligands present in the Cytoplasm High affinity ligands Synthesised in inactive forms bound to Heat Shock Protein which upon ionisation will allow for ligand binding → conformational change that causes dissociation from the HSP complex and translocation into the nucleus with dimer pair binding to response element at gene to initiate gene modulation Class II nuclear Act as heterodimers with mainly lipid ligands. receptors Low affinity and are located within the nucleus Exist as retinoic acid receptor (RXR) In absence of Agonist, corepressors/inhibitory proteins bind to nuclear receptors resulting in inactivated conformation preventing transcription Binding of Agonist causes conformational change in ligand-binding domain causing corepressor to dissociate and coactivator protein to bind to receptor transcription activating domain leading to increased gene transcription This occurs as part of a slow process so we won’t target a nuclear receptor expecting a rapid effect Receptor signalling over time Practice question