Pharmacodynamics Lecture Notes PDF

1  Pharmacodynamic Terms Pharmacodynamics: relationship between the concentration of drug at its site of action and its ensuing physiological effect What the Drug does to your Body...

1  Pharmacodynamic Terms Pharmacodynamics: relationship between the concentration of drug at its site of action and its ensuing physiological effect What the Drug does to your Body 2  Pharmacodynamic Terms A drug’s… Affinity vs. Potency vs. Efficacy 3  Pharmacodynamic Terms Affinity - ability of drug to bind to a receptor or channel (how well the drug interacts with its receptor/channel) Binding affinity typically reported as the equilibrium dissociation constant (KD) - equilibrium dissociation constant (KD) = likelihood that an interaction between two molecules will break - the smaller the KD value, the greater binding receptor receptor affinity (drug is tightly bound) “perfect fit”: Higher Affinity “less perfect fit”: Lower Affinity 4 Which drug has greater affinity based on KD values? Red is the winner!! lower KD value indicates that the “red” drug is less likely to have it’s interaction (binding) to the receptor broken 5  Pharmacodynamic Terms Potency - potency is a measure of the quantity of drug needed to induce a desired effect A more potent drug does not use as much to reach a predetermined XX% of effect compared to a less potent drug Often characterized as a concentration (x-axis) to reach the desired effect (y-axis): inhibitory or excitatory effect - typically in a cellular assay (functional readout) - effective (or excitatory) concentration (for 50% “excitatory” effect = EC50): typically used for agonists - inhibitory concentration (for 50% “inhibitory” effect = IC50): typically used for antagonists - EC50 and IC50 values can be used to compare drugs - other levels of potency other than a 50% effect can also be used to compare drugs (e.g., EC75, IC40) 6  Pharmacodynamic Terms Efficacy - a measure of specific drug effect once it interacts with its target A more efficacious drug has a higher degree of pharmacological effect on specific endpoints (e.g., affecting cognition, pain, mood…) Some drugs, despite fully acting at their target, can only achieve partial efficacy - the maximum efficacy of that specific drug- target pairing is, thus, limited (plateau in curve as shown in “B” and “C” curves in graph) - typically indicates that the target has only a partial role in the particular readout 7 Which is Most Potent and Which is Most Efficacious? Most Potent Most Efficacious 8  Pharmacodynamic Terms Selectivity - ability of drug to only affect the target (e.g., receptor or channel) of interest The more selective a drug is for its target, the less chance that it will have “off-target” side effects “off-target” = any target other than the desired one (non-desired target) Drugs can be relatively selective - drug X has an IC50 for D1 receptors of 2 nM, while it’s IC50 for D2 is 100 nM and D3 is 25000 nM - thus, drug X is 50-fold selective for D1 over D2, and 12500-fold selective for D1 over D3 - a dose can be picked to avoid reaching drug levels that affect the non-desired receptors - the higher the dose that is administered increases the likelihood of affecting non-desired targets - very non-selective drug has somewhat equivalent potencies at the desired target vs. non-desired target(s): dirty drug - a very selective drug has a wide potency separation between activity at desired target vs. any other target 9  Which is Most and Least Selective Drug for the CB1 Receptor? MOST LEAST Drug ABC Drug Q R S Drug XYZ - EC50 at CB1 = 1 nM - EC50 at CB1 = 20 nM - EC50 at CB1 = 0.5 nM - EC50 at CB2 = 90 nM - EC50 at CB2 = 90 nM - EC50 at CB2 = 90 nM - no activity at any other receptor - EC50 at H3 = 1200 nM - EC50 at H3 = 1500 nM - EC50 at D2 = 35 nM - EC50 at D2 = 350 nM - EC50 at Gabab = 30000 nM - EC50 at Gabab = 95 nM - EC50 at D3 = 27000 nM - EC50 at 5-HT7 = 900 nM - EC50 at µ = 8100 nM - EC50 at Gabaa = 10000 nM 10  Pharmacodynamic Terms Receptor Occupancy - quantifying the number of receptors/target that are bound by your drug - typically a percent (fully occupied = 100 % occupancy) In theory, if your drug reaches 100% occupancy of its target it should have maximized its efficacy 11 12  Pharmacodynamic Terms Dose response curve - plot of effect vs. dose Dose that gives a 50% effect - 50% effective dose (ED50) 100 ED80 = 65 mg/kg ED50’s can be used to compare drugs May “raise the bar” on the degree of efficacy desired ED50 = 29 mg/kg (e.g., ED80) to treat the disease 5 % effect 0 - if there is an existing drug that has a 60% effect, may want to increase the efficacy of “next Gen” drugs to be better than older drug (want at least 80% efficacy) 0 10 30 100 13 Dose (mg/kg)  Pharmacodynamic Terms Not all dose-response curves are linear As doses of a drug escalate, the body may quickly adapt - U-shaped curve to mask or eliminate the drug effect - receptor is internalized into the neuron (nowhere for drug to bind) Inverted U-shaped curve - another system/target takes over the role negating the drug’s effect 100 (compensation or redundancy in systems) Problem with 1 or 2 dose studies: - does this drug have a U-shaped curve? - where on the curve does this 5 dose fit? % effect 0 - hard to interpret data with only 1 What is it’s ED50? dose is that particular dose the max effect? does a lower or higher dose have the max effect? has the body adapted in response to the drug (e.g., receptor internalization)? 0 10 30 100 Dose (mg/kg) 14  Pharmacodynamic Terms Not all dose-response curves are linear - U-shaped curve As doses of a drug escalate, the selectivity of the drug may not be as good Non-Inverted U-shaped curve - may have an effect due to activity at another target other than the target of interest 100 - more seen with antagonists 5 % effect 0 What is it’s ED50? 0 10 30 100 Dose (mg/kg) 15  Pharmacodynamic Terms Tolerance - a drug becomes less effective with repeated administration (the body slowly adapts) 100 n a ti o r ug i s tr t d in c m je a d in d e te t i m a t e 1s rep 50 r % effect fte A ED50 = 29 mg/kg ED50 = 75 mg/kg 0 10 30 100 Dose (mg/kg) 16  Pharmacodynamic Terms Sensitization - a drug becomes more effective that it had been previously (the body has changed/adapted to enhance efficacy of drug) 100 t ed c je in ED50 = 13 mg/kg rug g d dru e ect d t im in j r 3 e o r t i m n d s t 50 2 1 % effect ED50 = 29 mg/kg 0 10 30 100 Dose (mg/kg) 17  Pharmacodynamic Terms Effective concentration (also indicated as EC50 or EC80…) of drug in the plasma/blood - what your body “sees” in terms of amount of drug is more important than dosage Dosages (mg or mg/k g) of a specific drug are given to a person in order to reach a certain concentration in blood (mg/L) that has been shown to be effective on specific disease endpoints - goal is to find the dosage that reaches a certain level of drug concentrations in plasma/blood Minimum effective concentration (MEC) is the lowest concentration in blood needed to observe a desired pharmacological effect Maximum tolerated concentration (MTC) is the concentration in blood that is still safe (limited side effects) - go above MTC and likely to have an increased chance of side effects 18 19  Types of Drug Interactions With Its Target Agonists - a drug that is a full agonist: binds to and maximizes activation of receptor 20  Types of Drug Interactions With Its Target Agonists - a drug that is a partial agonist: binds to, but lacks chemical properties to fully activate receptor  Types of Drug Interactions With Its Target Agonists - a drug that is a partial agonist: binds to, but lacks chemical properties to fully activate receptor - may interfe with action of full agonist, thus can be an antagonist to the full agonist - the partial agonist occupies the target receptor preventing binding of the full agonist = antagonist - if full agonist and partial agonist are administered at the same time, need more of the full agonist to get same effect (partial agonist acts like an antagonist) 22  Types of Drug Interactions With Its Target Antagonists - binds receptor but is not active - interferes with activation of receptor by agonist - 2 types: competitive (same site as agonist) and non-competitive (alternative site to agonist) 23  Agonist vs. Competitive Antagonist Competing for the same site to bind on the receptor 24  Agonist vs. Non-Competitive Antagonist Non-competitive antagonist binds to different site than the agonist, but still interferes with agonist action Agonist effect in presence of non- competitive antagonist - interferes with agonist induced conformational changes in the receptor (needed for receptor activation) 25  Types of Drug Interactions With Its Target Inverse agonists - does not “activate” the receptor like a typical agonist - it actively induces the opposite of an agonist (needs some basal biological function) - not an antagonist, since it has an active process 26  Types of Drug Interactions With Its Target Allosteric modulators - bind to the receptor/channels at a site away from the typical agonist - may not do anything on its own but can augment or decrease signaling (of an agonist) - affects the affinity of the agonist for the receptor (changes conformation of receptor) - typically through intracellular processes - can be negative or positive - positive allosteric modulator (PAM) - negative allosteric modulator (NAM) 27 Allosteric Modulation - NAM decreases efficacy and/or potency of full agonist - PAM increases efficacy and/or potency of full agonist 28  Types of Drug Interactions With Ion Channels Activators - can trigger opening of the ion channel - may be called an agonist 29  Types of Drug Interactions With Ion Channels Blockers - blocks the pores of the ion channel - may be called an antagonist 30  Types of Drug Interactions With Its Target Antibodies (can be called “biologics”) - protein that neutralizes/binds to another peptide/protein (e.g., receptor, cytokine, peptide..) - binds to peptide/protein to interfere with its function (with binding changes shape of protein) 31  Take home message Pharmacodynamics represents a diverse set of interactions between a ligand or drug and the body There are a diverse set of interactions between a drug and the target/receptor that can dictate the type and degree of response 32  To do for next week Read text chapter 19: LO 19.1-19.2, 19.11 Opioid Substance Use Disorder: Addiction/Physical Dependence Read Journal Club papers: Ryan + Farhan + Janitza: “TRPA1 participation in behavioral impairment induced by chronic corticosterone administration” by Pereira et al., 2023 Kate + Daniel D. + Teresa: “Efficacy assessment of novel methanimine derivatives in chronic constriction injury-induced neuropathic model: An in-vivo, ex-vivo and In- Silico approach” by Khan et al., 2024 33 Final thoughts… “Like what you do, and then you will do your best.” Katherine Johnson NASA 34