Lecture 6 - Pharmacodynamics

‭Pharmacokinetics‬ ‭Drug Half-Life‬ ‭●‬ ‭Half-life (t‬‭1/2‬‭): Amount of time required for the‬‭drug in the body to decrease by 50%‬ ‭○‬ ‭Varies by drug‬ ‭●‬ ‭Determines the dosing interval of a drug‬ ‭○‬ ‭Short half-life → shorter dosing intervals‬ ‭○‬ ‭Long half-life → longer dosing intervals‬ ‭●‬ ‭Particularly relevant in multi-day drug regiments‬ ‭Multi-Dose Curve‬ ‭‬ R ● ‭ eflects drug accumulation to result in a steady state‬ ‭●‬ ‭Steady-state (plateau)‬ ‭○‬ ‭Amount eliminated = amount administered‬ ‭○‬ ‭Steady-state = t‬‭1/2‬ ‭* 4‬ ‭■‬ ‭It takes roughly four‬ ‭half-lives for a drug‬ ‭to reach a steady‬ ‭state‬ ‭●‬ ‭Decline from plateau: t‬‭1/2‬ ‭* 4‬ ‭○‬ ‭It takes roughly four‬ ‭half-lives for a drug to be‬ ‭eliminated‬ ‭ harmacodynamics vs.‬ P ‭Pharmacokinetics‬ ‭‬ P ● ‭ harmacodynamics: What a drug does to the body‬ ‭●‬ ‭Pharmacokinetics: What the body does to a drug‬ ‭○‬ ‭Absorption‬ ‭○‬ ‭Distribution‬ ‭○‬ ‭Metabolism‬ ‭○‬ ‭Elimination‬ ‭Pharmacodynamics‬ ‭Dose-Response Relationship‬ ‭Determines:‬ ‭●‬ ‭Minimum amount of drug needed‬ ‭●‬ ‭Maximum response a drug can elicit‬ ‭●‬ ‭How much to increase the dosage to produce the‬ ‭desired increase in response‬ ‭Efficacy and Potency‬ ‭Maximal Efficacy‬ ‭●‬ ‭Largest effect‬‭a drug can‬ ‭produce‬ ‭●‬ ‭Height of the dose-response‬ ‭curve‬ ‭Relative Potency‬ ‭●‬ ‭Amount‬‭of drug‬‭needed‬‭to‬ ‭elicit desired effect‬ ‭●‬ ‭X-axis of the dose-response‬ ‭curve‬ ‭Drug-Receptor Interactions‬ ‭Drugs‬ ‭●‬ ‭Chemicals that produce effects by interacting with other chemicals‬ ‭Receptors‬ ‭●‬ ‭A functional macromolecule on a cell to which a‬ ‭drug can bind and produce a response‬ ‭●‬ ‭Found on the cell‬‭surface‬‭and‬‭inside‬‭of cells‬ ‭(steroids, lipid-soluble)‬ ‭●‬ ‭Receptor binding is usually reversible‬ ‭●‬ ‭Normal points of control of physiologic processes‬ ‭●‬ ‭Under physiologic conditions, receptor function is‬ ‭regulated by molecules of the body‬ ‭●‬ ‭Drugs only‬‭mimic or block‬‭the body’s own‬ ‭regulatory molecules‬ ‭●‬ ‭Drugs cannot give cells new functions‬ ‭Receptor Types‬ ‭●‬ R ‭ eceptor site: Where the action‬ ‭happens‬ ‭●‬ ‭4 types:‬ ‭1.‬ ‭Cell-membrane embedded‬ ‭2.‬ ‭Ligand-gated ion channels‬ ‭3.‬ ‭G protein-coupled receptor‬ ‭systems‬ ‭4.‬ ‭Intracellular (transcription)‬ ‭Drug-Receptor Characteristics‬ ‭Affinity (Fondness)‬ ‭●‬ ‭Strength of the interaction‬‭between a drug and its‬‭receptor‬ ‭●‬ ‭High affinity = high‬‭potency‬ ‭Intrinsic Activity (Efficacy)‬ ‭●‬ ‭A drug’s capacity to‬‭produce an effect‬‭after binding‬ ‭●‬ ‭High intrinsic activity = high‬‭efficacy‬ ‭Selectivity‬ ‭●‬ ‭Drug ideally selectively binds with a specific receptor to produce an effect‬ ‭●‬ ‭The more selective the drug, the fewer side effects‬ ‭●‬ ‭Receptors can be responsible for more than one physiologic response‬ ‭Drug Types‬ ‭Agonists (Mimetics)‬ ‭●‬ ‭Mimic endogenous molecules‬ ‭●‬ ‭Speed up or slow down processes‬ ‭●‬ ‭Have both affinity and high intrinsic activity‬ ‭Antagonists (Blockers)‬ ‭●‬ ‭Prevent receptor activation‬ ‭●‬ ‭No effect of their own‬ ‭●‬ ‭Affinity but no intrinsic activity‬ ‭Competitive vs. Non-Competitive Antagonists‬ ‭Non-Competitive Antagonists‬ ‭Competitive Antagonists‬ ‭Irreversible binding (but w/ turnover)‬ ‭Reversible binding‬ ‭Rarely used therapeutically‬ ‭Effect is surmountable‬ ‭Decrease‬‭maximal response‬‭(‭e‬ fficacy‬‭)‬ ‭Affinity‬‭to receptor based on‬‭highest‬ ‭concentration‬ ‭Impact‬‭potency‬ ‭Partial Agonists‬ ‭●‬ ‭An agonist with moderate intrinsic ability/reduced effect‬ ‭●‬ ‭Acts as both an antagonist and agonist‬ ‭●‬ ‭Reduces maximal effect‬ ‭Variable Drug Responses on People‬ ‭‬ P ● ‭ eople are individuals‬ ‭●‬ ‭Dose to produce therapeutic response varies‬ ‭●‬ ‭Monitoring individual pt response to drugs is imperative‬ ‭Therapeutic Index‬ ‭‬ S ● ‭ tandard dose (ED‬‭50‬‭)‬ ‭●‬ ‭Lethal dose (LD‬‭50‬‭)‬ ‭●‬ ‭Therapeutic index = LD‬‭50‬‭/ED‬‭50‬ ‭Question:‬‭A patient is taking amlodipine. The prescriber‬‭orders an additional drug (rifampin).‬ ‭1.‬ ‭What are the primary indications for these drugs?‬ ‭a.‬ ‭Amlodipine: Angina, chronic‬‭HTN‬‭, Raynaud phenomenon‬ ‭2.‬ ‭3.‬ ‭4.‬ ‭5.‬ ‭b.‬ R ‭ ifampin: Symptomatic anaplasmosis,‬‭Bartonella‬‭spp. Infection, brucellosis,‬ ‭cholestatis prutitus, endocarditis, hidradenitis suppurativa, postexposure‬ ‭prophylaxis leprosy, leprosy, meningococcal disease, mycobacterial infection,‬ ‭Staphylococcus‬‭spp. infections,‬‭Streptococcus‬‭chronic‬‭carriage,‬‭tuberculosis‬ ‭(active or latent)‬ ‭Are either of the drugs affected by the P450 enzymes?‬ ‭a.‬ ‭Yes, both‬ ‭If so, in what way?‬ ‭a.‬ ‭Amlodipine is a substrate and weak inhibitor of CYP3‬ ‭b.‬ ‭Rifampin is an inducer of CYP1, CYP2, and CYP3‬ ‭What do these terms mean?‬ ‭a.‬ ‭Substrate: Metabolized by P450‬ ‭b.‬ ‭Inducer: Increases metabolism, decreasing serum levels of substrates‬ ‭c.‬ ‭Inhibitors: Decreases metabolism, increasing serum levels of substrates‬ ‭How will being on these two drugs affect the metabolism of each other?‬ ‭a.‬ ‭Rifampin would increasing metabolism,‬‭decreasing serum‬‭levels of Amlodipine‬ ‭i.‬ ‭High blood pressure‬ ‭b.‬ ‭Amlodipine could also be an inhibitor to itself, decreasing metabolism and‬ ‭increasing its own serum levels‬ ‭i.‬ ‭Low blood pressure‬