Drug Receptor Interactions PDF

Drug receptor interactions ~ 10 1) Drug. has to kind to a receptor -...

Drug receptor interactions ~ 10 1) Drug. has to kind to a receptor - Intracellular or Extracellular 1. Understand how drugs interact with their targets 2) Either Activates Inhibits cascade of and the di3ering types of targets or =. events 3) produces a cellular Response Drug targets are molecules in the body, often proteins, that drugs bind to in order to produce their effects. o Receptors o Enzymes o Ion channels o Transport proteins. Receptors: o Receptors are protein structures that bind to a drug and trigger a cellular response. o They are found on the surface or inside cells. o For example, GABA_A receptors are targets for benzodiazepines, which enhance inhibitory neurotransmission【18†source】. Enzymes: o Enzyme inhibitors are drugs that bind to and inhibit the action of enzymes. o For example, monoamine oxidase inhibitors (MAOIs) bind to enzymes involved in the breakdown of neurotransmitters to treat depression【18†source】. Ion channels: o Ion channels are proteins that allow ions like sodium (Na+) or calcium (Ca2+) to move in and out of cells. o Drugs can block or open ion channels, aBecting the flow of ions and altering cellular activity. o For example, calcium channel blockers like nifedipine are used to treat hypertension【 18†source】.  Transport proteins: o These proteins help move substances across cell membranes. o Drugs may inhibit transport proteins, preventing the movement of molecules like glucose or neurotransmitters into cells. 2. Understand the receptor occupancy theory of drug function The Receptor Occupancy Theory explains how drug effect is related to the number of receptors occupied by the drug. o Law of Mass Action: The interaction between drug and receptor follows the law of mass action, where the response is proportional to the amount of drug and number of receptors available for binding【18†source】. Full occupancy: o Maximal response occurs when all receptors are occupied by the drug. o However, in some tissues, not all receptors need to be occupied for the maximum response to occur due to spare receptors【18†source】. Spare receptors: o Some receptors are "spare" and do not need to be occupied to produce a full response, meaning a lower drug concentration can still produce a maximal eBect Elso will be lower than Kd 3. Know the types of receptors, how they are similar, how they di3er, and how they transduce signals Receptor types include: o Intracellular receptors: § Located inside the cell, requiring drugs to cross the cell membrane to bind. § Examples: Steroid hormone receptors, such as for cortisol or estrogen【 18†source】. o Ligand-gated ion channels: § When a drug binds to these receptors, the channel opens or closes, allowing ions to move across the membrane. § These receptors are fast-acting and opens ligand-gated channel to open and Both are for involved in rapid processes like muscle allow (L-to enter G Hydrophilic contraction. molecules Large § Example: The GABA_A receptor allows chloride ions to pass through the membrane when activated by GABA or drugs like diazepam【18†source】. o G-protein coupled receptors (GPCRs): 7-pass receptors § These receptors have seven or serpentine transmembrane regions and are receptors activated by ligands to initiate Ga intracellular signaling via G-proteins. phospholipase C (PLC) ↓ § GPCRs are the target of approximately PIP2 Das Eps pic 50% of all therapeutic drugs. § Example: Beta-adrenergic receptors 6s mediate the eCects of adrenaline Adenylate cyclase (Stimulate) ↓ ↑CAMB , APKA Gi Adenylate cyclase (inhibit)  o Enzyme-linked receptors: § Binding of a ligand to these receptors activates an enzyme, leading to downstream cellular eBects. § Example: The insulin receptor, which is activated by insulin to regulate glucose uptake【18†source】. 4. Understand selectivity, a3inity, and intrinsic activity Selectivity: "picky" o Refers to a drug's ability to aQect a specific receptor or target without influencing others. o The more selective a drug is, the fewer side eBects it tends to have. Affinity: "Tightness" o Describes the strength of binding between a drug and its receptor. o A drug with high aBinity will tightly bind to its receptor, but this does not necessarily mean it will have a strong eBect (this is measured by intrinsic activity)【18†source】. Intrinsic activity: "Turn on receptor" o Refers to a drug’s ability to activate the receptor once bound. o A drug with high intrinsic activity can produce a full biological eQect, while one with low intrinsic activity (such as partial agonists) produces only a submaximal eBect. o For example, buprenorphine is a partial agonist at opioid receptors, meaning it produces pain  relief without the full eCect of a stronger opioid Potency ↑ potency Right shift like morphine【18†source】. = ↓ potency = Leftshift SS 5. Know the major landmarks of dose-e3ect curves and how to use them to compare and contrast the e3ects of drugs Dose-effect curves plot the relationship between drug dose and the biological response. o These curves help compare the potency and eQicacy of drugs. Landmarks include: o EC50: The concentration at which 50% of the maximal eBect is observed. o Kd: The concentration at which 50% of receptors · "S" shaped curve v, sigmoidal are occupied by the drug. ↑affinity · - > ↑ potency · ECSO measurement of o Emax: The concentration at which the maximal potency NEC5O 1 potency - = - eBect is achieved. - tECSo = ↑ potency o Bmax: The concentration at which maximum ↓ efficacy Down Shift Nefficacy receptor binding occurs【18†source】. = = Upshift Potency vs Efficacy: o Potency is how much drug is needed to produce a given eBect. o EQicacy is the maximum eBect the drug can · potency does NOT A produce, regardless of the dose. · ONLY how effective drug A is o Two drugs can have the same eCicacy but diCer in potency. For example, heroin has a higher potency than morphine but both can produce a similar maximal eCect【18†source】. 6. Understand the two ways in which a dose- response curve can be generated Graded dose-response curves: o Measure the magnitude of a response in an individual as the dose increases. o For instance, the amount of pain relief in response to increasing doses of an analgesic【 18†source】. Quantal dose-response curves: o Measure the frequency of a particular response in a population. o Responses are binary (yes/no), such as whether or not a patient experiences pain relief. o ED50 in this context refers to the dose at which 50% of individuals show the desired response【 18†source】. 7. Know the di3erences between agonists, antagonists, and modulators Agonists: o Full agonists bind to receptors and produce the maximum possible response. o Partial agonists bind to receptors but produce a submaximal response, even if all receptors are occupied. o Example: Morphine is a full agonist at opioid receptors, while buprenorphine is a partial agonist【18†source】.  Antagonists: o Bind to receptors but do not activate them, eBectively blocking the action of agonists. o Competitive antagonists compete with agonists for the same receptor binding site. o Non-competitive antagonists bind to diBerent sites on the receptor. o Example: Naloxone is a competitive antagonist that reverses opioid overdose by blocking opioid receptors【18†source】. Modulators: o Modulate the activity of receptors but do not bind to the same site as the endogenous ligand. o Positive modulators enhance receptor activity o Negative modulators decrease it. o Example: Benzodiazepines are positive modulators of the GABA_A receptor, increasing its inhibitory eCects【18†source】. 8. Understand the concept of spare receptors Spare receptors are receptors that are not needed to be occupied for a drug to produce its maximum effect. o These receptors allow for amplified responses; fewer receptors need to be occupied to generate a maximal response【18†source】. Effect on EC50: o When spare receptors are present, the § EC50 is LOWER than the Kd § EC50-the concentration needed to produce 50% of the maximal eBect § Kd-the concentration required to occupy 50% of the receptors)  o Example: If a tissue has 100 receptors, but only TD50 - 50 % TOXIC Effects 10 are needed for the full eCect, the drug can produce the same response at a lower J concentration【18†source】. Narrow TI = BAD GWTDAL (Guys , Waring , These Drugs Are Lethal) 9. Understand the importance of therapeutic index Gentamicin and how it is calculated Warfarin ENR) Theophylline The Therapeutic Index (TI) is a ratio that compares the Digoxin lethal dose (LD50) to the eQective dose (ED50). AED's o LD50: The dose that causes death in 50% of a Lithium population. o ED50: The dose that produces a desired therapeutic eBect in 50% of a population. TI = LD50 / ED50: EDSO - 50% DESIRED Effects o A high TI indicates a drug is relatively safe, as there is a large gap between the eBective and lethal doses. ↓ o A low TI means the therapeutic dose and lethal · WIDE TI = GOOD dose are close, making the drug riskier. · Penicillin G o For example, drugs like warfarin have a narrow · Steroids therapeutic index, requiring careful dosing【 18†source】. Narrow TT ↑ = risk of side effects Wide TI = ↓ risk of side effects Second messengers/signal transduction ~ 5 1. Describe the basic structure and function of GPCRs and G-proteins, including α vs. βγ subunits GPCR Structure: o GPCRs are single subunit proteins with 7 transmembrane domains that span the cell membrane. o The extracellular domain interacts with ligands such as hormones or neurotransmitters. o The intracellular domain interacts with G- proteins, transmitting the signal inside the cell. G-proteins: o G-proteins are heterotrimeric proteins, composed of three distinct subunits: § α (alpha): Binds GTP or GDP, determining whether the G-protein is active (GTP-bound) or inactive (GDP- bound). § β (beta) and γ (gamma): Form a stable dimer and play a role in signaling after dissociation from the α subunit. o Function: § Upon ligand binding, the GPCR undergoes a conformational change, activating the associated G-protein. § The α subunit exchanges GDP for GTP, triggering dissociation from the βγ complex, creating two active signaling units. § The α-GTP and βγ dimer can now interact with their respective eBectors to propagate the signal inside the cell*. 2. Describe the steps in the receptor-G-protein cycle, including the role of guanine nucleotides Ligand Binding: o A ligand (e.g., a hormone or neurotransmitter) binds to the GPCR, inducing a conformational change in the receptor. Guanine Nucleotide Exchange: o The α subunit of the G-protein is initially bound to GDP, keeping it in an inactive state. o Upon receptor activation, GDP is exchanged for GTP, converting the α subunit into its active form. Subunit Dissociation: o The α-GTP complex dissociates from the βγ dimer. o Both the α subunit and the βγ dimer are now free to interact with downstream eBectors, initiating separate signaling pathways. Effector Activation: o The α-GTP complex can activate or inhibit target Gg = PLC enzymes like adenylyl cyclase or phospholipase C, depending on the type of G- Gs = ↑ A cyclase. , ↑ CAMP protein. o The βγ dimer can also regulate other proteins, Gi if A. cyclace , o CAMP such as ion channels or kinases.  Inactivation: o The α subunit has intrinsic GTPase activity, meaning it can hydrolyze GTP to GDP, returning to its inactive form. o Once GTP is hydrolyzed, the α subunit re- associates with the βγ dimer, forming the inactive heterotrimeric G-protein once again*. 3. Identify the types of G-proteins (Gαs, Gαi, Gαq, Gαt), their e3ectors, and second messengers Gαs (Stimulatory G-protein): o Activates adenylyl cyclase (AC), increasing the conversion of ATP to cAMP. o cAMP acts as a second messenger and activates Protein Kinase A (PKA). o PKA phosphorylates various downstream targets, including enzymes and transcription factors. Gαi (Inhibitory G-protein): o Inhibits adenylyl cyclase (AC), reducing cAMP levels. o Decreased cAMP levels reduce PKA activity, lowering phosphorylation of downstream targets. o Example: Gαi-coupled receptors can reduce the activation of signaling pathways, such as those related to metabolism or gene expression.  Gαq: o Activates phospholipase C (PLC), which cleaves PIP2 (phosphatidylinositol 4,5- bisphosphate) into two second messengers: § Diacylglycerol (DAG): Activates Protein Kinase C (PKC). § Inositol triphosphate (IP3): Binds to IP3 receptors on the endoplasmic reticulum, causing Ca2+ release into the cytoplasm. Gαt (Transducin): o Found in the visual system and activated by rhodopsin. o Gαt activates phosphodiesterase (PDE), which hydrolyzes cGMP into GMP. o This process is critical in phototransduction by controlling the cGMP-gated ion channels involved in visual signaling*. 4. Describe short- and long-term signaling by GPCRs Short-Term Signaling: o Involves the activation of second messengers like cAMP, IP3, and DAG. o These second messengers cause rapid cellular responses, such as the activation of kinases (PKA, PKC) or the modulation of ion channels. o Short-term responses are typically reversible and occur within seconds to minutes. o Example: The activation of PKA by cAMP leads to the phosphorylation of target proteins, which alters their activity in the short term*.  Long-Term Signaling: o Can lead to more persistent changes in cell function through the regulation of gene expression. o Activated kinases (e.g., PKA, PKC) can phosphorylate transcription factors such as CREB. o Phosphorylated CREB binds to specific DNA sequences and activates the transcription of genes, leading to changes in protein synthesis. o Long-term signaling can result in synaptic plasticity, cell growth, or metabolic adjustments over a prolonged period*. 5. Provide the signaling pathway for rhodopsin, including the role of Gαt Rhodopsin Activation: o Rhodopsin is a GPCR located in the rod cells of the retina. o In response to light, rhodopsin undergoes a conformational change, activating the G-protein transducin (Gαt). Transducin Activation: o Gαt (the α subunit of transducin) binds GTP, activating the G-protein. Phosphodiesterase (PDE) Activation: o Activated Gαt activates PDE, which hydrolyzes cGMP to GMP.  Ion Channel Regulation: o The reduction in cGMP levels causes the closure of cGMP-gated ion channels, preventing the influx of Na+ and Ca2+ into the photoreceptor cell. o This results in the hyperpolarization of the photoreceptor and the transmission of the visual signal to the brain*. 6. Discuss the role of amplification in GPCR signaling Signal Amplification: o GPCR signaling involves a process of amplification, where a single ligand-bound receptor can activate multiple G-proteins. o Each activated G-protein can interact with its downstream eBectors in a catalytic manner, producing a large number of second messengers. o For example, a single activated Gαs can activate multiple adenylyl cyclase molecules, which in turn can generate many cAMP molecules. o Amplification ensures that a small extracellular signal results in a significant intracellular response, increasing the sensitivity of the signaling pathway. o Example: In the visual system, the activation of rhodopsin by a single photon can lead to the closing of thousands of ion channels, amplifying the light signal*. 7. Describe the role of beta-arrestin in GPCR signaling and adaptation Beta-arrestin in Desensitization: o Beta-arrestin binds to the phosphorylated GPCR after activation by a ligand, preventing further interaction between the GPCR and G- proteins. o This reduces the receptor’s ability to activate downstream signaling, a process known as desensitization. Beta-arrestin in Internalization: o Beta-arrestin promotes GPCR internalization by recruiting clathrin-coated pits, resulting in the receptor being pulled into the cell through endocytosis. o Once internalized, the receptor can either be: § Degraded: Leading to downregulation of receptor numbers on the cell surface. § Recycled: The receptor can be resensitized and returned to the cell surface for further signaling. Beta-arrestin in Alternative Signaling: o Apart from desensitization, beta-arrestin can also initiate G-protein-independent signaling pathways. o For example, beta-arrestin can activate MAPK (mitogen-activated protein kinase) pathways, leading to diBerent cellular outcomes, such as changes in gene expression or cell growth.  Importance in Drug Tolerance: o The role of beta-arrestin in desensitization and downregulation of GPCRs is crucial for the regulation of drug tolerance. o With prolonged exposure to a drug, the body adapts by desensitizing and downregulating receptors, decreasing the drug’s eBectiveness over time*.  Pharmacokinetics~ 25 1. Be able to identify the basic pharmacological Pharmaco-KINETICS terms and abbreviations used to describe What the · BODY does to the DRUG pharmacokinetics of drugs CADME) Pharmacokinetics (PK) is the study of how a drug Pharmaco-DYNAMICS moves through the body over time, involving its what the DRUG does to the BODY · absorption, distribution, metabolism, and (How the drug Changes body Dynamics elimination (ADME). o Example: Hydrocodone has a Tmax (time to maximum concentration) of 1.3 hours and a half-life of 3.8 hours【10†source】. Common abbreviations include: o Cmax: Maximum plasma concentration of the drug. AUC o Tmax: Time at which the drug reaches Cmax. o AUC: Area under the concentration-time curve, representing total drug exposure. o CL (Clearance): Rate at which the drug is eliminated from the body. o Vd (Volume of Distribution): Indicates the extent of drug distribution into body tissues【 10†source】. Low Vd 4-5 = in plasia High Vd -40 = in tissues 2. Understand and di3erentiate between the 4 phases of pharmacokinetics (ADME) factors that affects Absorption Absorption: · pH - > Acid in Acid - > Base in Base o The process of drug movement from its · Blood Flow - , blood flow , ↑ blood flow Contact time If contact time ↑ contact time administration site into the bloodstream. - · > , Surface · area - > If surface area ↑ surface o Oral drugs must pass through the , area gastrointestinal tract before entering circulation · Biovalibility()-IF , F 【10†source】. Distribution: o After absorption, the drug moves from the bloodstream to tissues and organs. o Factors aBecting distribution include § Blood flow § Membrane permeability § Protein binding Metabolism: o The chemical alteration of the drug, primarily in the liver, into more water-soluble metabolites for excretion. o Metabolism can activate (e.g., prodrugs) or inactivate drugs【7†source】. Excretion: o The process of removing the drug from the body, primarily through the kidneys (urine) or bile (feces). o For example, acetaminophen is eliminated via the kidneys within 24 hours【10†source】. 3. Know how cell membranes are constructed and how they influence the passage of drugs across the membrane Cell membranes: o Composed of a lipid bilayer with hydrophilic (water-attracting) heads facing outward and hydrophobic (water-repelling) tails facing inward. Drug passage: o Drugs with higher lipid solubility pass through cell membranes more easily than those with high water solubility【10†source】. o For instance, highly lipid-soluble drugs like volatile anesthetics cross membranes quickly【 7†source】. 4. Know the mechanisms through which drugs can cross biological membranes Passive diffusion: o Drugs move from an area of high concentration to low concentration without the need for energy. o Examples include small, non-ionized, lipid- soluble drugs crossing the membrane【 10†source】. Facilitated diffusion: o Carrier proteins assist the transport of larger or polar molecules across the membrane. o For example, glucose uses a carrier protein to cross cell membranes【10†source】.  Active transport: o Requires energy (usually from ATP) to move drugs against their concentration gradient. o ABC transporters (e.g., P-glycoprotein) actively pump drugs across membranes【10†source】. 5. Understand the chemical properties of drugs which influence their ability to cross biological membranes Polarity: o Polar molecules have an uneven distribution of Easily pass through membrane electrical charge, making them less able to pass · nonionized · non polar through the lipid bilayer. · Lipid soluble Ionization: o Ionized drugs (charged) are more water-soluble but less lipid-soluble, thus less likely to cross membranes. o Unionized drugs (uncharged) are more lipid- soluble and cross membranes more easily【 10†source】. Weak ACID Effect of pH: o Weak acids are absorbed better in acidic environments o Weak bases are absorbed better in basic environments. o Example: Ibuprofen is better absorbed in the Weak Base stomach (acidic environment) compared to the small intestine (basic environment)【10†source 】. 6. Know the advantages and disadvantages of di3erent routes of drug administration Oral administration: o Advantages: Convenient, economical, non- invasive. o Disadvantages: Subject to first-pass metabolism, slower onset, potential gastrointestinal irritation【8†source】. Intravenous (IV) administration: o Advantages: Rapid onset, precise dosing, bypasses absorption phase. o Disadvantages: Requires trained personnel, risk of infection【8†source】. Subcutaneous and Intramuscular administration: o Advantages: More consistent absorption than oral, avoids first-pass metabolism. o Disadvantages: Can cause pain and tissue damage, limited to small volumes. Topical and transdermal administration: o Advantages: Minimizes systemic side eBects, avoids first-pass metabolism. o Disadvantages: Absorption can be erratic, limited to high-potency drugs【8†source】. 7. Understand the importance of first-pass metabolism to the potency of orally administered drugs First-pass metabolism: o Drugs taken orally pass through the liver via the hepatic portal vein before entering systemic circulation. o A significant portion of the drug can be metabolized in the liver, reducing the amount of active drug that reaches its target o Example: Oral medications like propranolol undergo extensive first-pass metabolism, reducing their bioavailability【8†source】. 8. Describe how blood flow to tissues influences their distribution and the ways in which tissues can limit or enhance drug access Perfusion-rate limitation: o Tissues with high blood flow (e.g., brain, liver, Liver Bone Marrow , , Spleen , Kidneys , Glands kidneys) receive drugs more quickly, while poorly perfused tissues (e.g., fat) experience slower drug distribution【8†source】. Capillary permeability: BBB muscle , o Loose capillaries (e.g., in the liver) allow easier drug passage, while tight capillaries (e.g., in the brain) restrict drug entry. o The blood-brain barrier (BBB) limits drug distribution to the central nervous system【 9†source】. 9. Understand how drugs can be bound within the bloodstream and tissues to reduce their activity and delay their metabolism Plasma protein binding: o Drugs bind to plasma proteins such as albumin, making them temporarily inactive. o Only free (unbound) drugs can exert a pharmacological eBect and undergo metabolism. Clinical significance: o Drugs with a high degree (>90%) of protein binding, like warfarin, can have significant drug interactions if displaced from their binding sites 【8†source】【9†source】. 10. Explain how the Volume of Distribution (Vd) informs you about where drugs accumulate in the body e Vd = Volume of Distribution (Vd): o Represents the theoretical volume required to contain the total amount of drug at the same concentration as in plasma. o A high Vd indicates the drug is widely distributed in tissues, while a low Vd suggests it remains primarily in the bloodstream. o For example, amphetamine has a large Vd (>40 L), indicating it is extensively distributed into tissues【9†source】. 11. Know the two major phases of drug metabolism as well as the types of reactions that occur in each phase Phase I Phase I metabolism: o Includes oxidation, reduction, and hydrolysis reactions that make drugs more polar by adding or uncovering functional groups. o Example: Hydrolysis of aspirin into salicylic acid 【7†source】. Phase II metabolism: o Involves conjugation reactions, where the drug is coupled with an endogenous molecule (e.g., glucuronide) to increase solubility. Phase 2 o Glucuronidation is the most common Phase II reaction【7†source】. 12. Explain what CYP enzymes do and how they are involved in drug metabolism Cytochrome P450 (CYP) enzymes: o A family of enzymes, such as CYP3A4 and CYP2D6, responsible for metabolizing a wide range of drugs. o These enzymes perform oxidation reactions, making drugs more water-soluble for excretion 【7†source】【10†source】. · Inducers > induce warfarin - blocking ↓ warfarin Inducers = ↑ clotting Inhibitors 1 warfarin = ↑ Bleeding · warfarin = ↑ clotting #nhibitors-inhibitwarfarin block not 13. Know which organs are responsible for drug metabolism and elimination Liver: o Primary site for drug metabolism. ↑ TY = ↓C Kidneys: inversely proportional ↓T = ↑CL o Responsible for filtration and excretion of drugs in urine. Biliary system: o Involved in bile excretion, especially for drugs that undergo enterohepatic recycling【 9†source】. 14. Know the processes of hepatic, biliary, and renal elimination Hepatic elimination: o Involves biotransformation in the liver followed by secretion into bile. Biliary elimination: o Drugs excreted into bile can be reabsorbed via enterohepatic circulation, prolonging the drug's half-life Renal elimination: o Occurs via glomerular filtration, tubular secretion, and reabsorption in the kidneys 15. Understand the time course of drugs in the body in relation to ADME Absorption: The time for the drug to enter the bloodstream. Distribution: The time to reach various tissues. Metabolism: How long it takes the liver to process the drug. Excretion: The time required for the drug to be eliminated. zero order Key indicators: Cmax, Tmax, and half-life. 16. Know the di3erence between zero-order and first- · Phenoton (PHT) order elimination characteristics and be able to · Ethanol (ETOH) · Aspirin (ASA) determine the half-life of a drug Zero-order kinetics: constant amount over time o A constant amount of drug is eliminated per unit time, independent of plasma concentration. o Example: Alcohol elimination【9†source】. First-order kinetics: (0) o A constant percentage of drug is eliminated per unit time, proportional to its concentration. First order o Most drugs follow first-order kinetics under normal conditions【9†source】. Half-life (T1/2): o Time required for the drug concentration to decrease by half【9†source】. ↳ is constant First order 95% eliminated = 4-5 T 17. Understand how drugs accumulate in the body following continuous infusion, repeated dosing, and following a loading dose Continuous infusion: o Drug accumulates until steady-state concentration (Css) is reached, where the rate Administration = rate of elimination of administration equals the rate of elimination 【9†source】. Repeated dosing: o Drugs given at regular intervals will accumulate if dosing intervals are shorter than the half-life【 9†source】. Loading dose: o A higher initial dose given to rapidly achieve therapeutic concentration【9†source】. 18. Understand the relationship between the factors that can impact loading dose (e.g., Vd, F, etc.) Loading dose (LD): o Determined by Volume of Distribution (Vd) and bioavailability (F). o A drug with a large Vd requires a larger loading dose to reach the desired plasma concentration 【9†source】. x desired LD = F 19. Understand steady-state and how it can change depending upon drug dose administered, route of administration, and repeated dosing Steady-state concentration (Css): o Achieved when the rate of drug administration equals the rate of elimination. o Route of administration, dose, and dosing frequency all influence the time to reach steady state【9†source】. 20. Know the relationship between variables that determine steady state (e.g., CL, F, etc.) Key variables: o Clearance (CL): Rate at which the drug is removed from the body. o Bioavailability (F): Proportion of the drug that enters systemic circulation. o These variables determine how quickly steady state is reached【9†source】. Terms to Know Ed50: dose at which either produces mean 50% of the maximal response across subject; dose at which produces the desired response in the 50% of the subject tested EC50: eBective concentration 50% (outside body/sample)  Kd: Dissociation constant: concentration at which 50% of the drug is bound to the receptor and 50% unbound. Also can be thought as the drug concentration required to bind 50% of the receptor o Spare Receptors: EC50 ≠ Kd; No spare receptor: EC50 = Kd Emax: concentration at which the maximal eBect is produced (and can’t bind anymore) Bmax: concentration at which the maximal specific receptor binding is achieved Tmax: time where plasma concentration is at it’s maximum after administration pKa: the pH at which the drug is 50% ionized (water soluble) and 50% unionized (lipid soluble) C: plasma concentration Css: steady state when drug is given repeatedly or as a continuous infusion CLr: volume of plasma completely cleared of active drug by the kidney per unit of time Simple/Lipid DiQusion: passive transport moves directly through phospholipid bilayer (concentration) Carrier-Mediated Facilitated DiQusion: vis protein carrier specific for one channel; substrate binding causes shape change in transport protein (open/close door per solute) Channel-Mediated Facilitated DiQusion: via channel proteins for mostly ions selected on basis of size and charge (open door- as many ions that can fit through) Osmosis: diBusion through a specific channel protein (aquaporin) or through the lipid bilayer  Primary Active Transport: carrier moves a substrate against its concentration gradient using chemical energy - ABC Superfamily (ATP Binding Cassette) like sodium/potassium pump Secondary Active Transport: carrier moves a substrate against its concentration gradient using a cotransporter - symporter and antiporters like sodium/glucose linked transporter Enzyme Induction: enzyme induction is the upregulation (increased synthesis) of selective CPY450 enzymes resulting from drug exposure o Gradual process of increased enzyme production Enzyme Inhibition: enzyme inhibition is the result of a drug blocking the fxn of specific CYP450 enzymes o IMMEDIATE block activity = enzyme doesn’t work as well = ↑ DOA of drug Intrinsic Activity- the ability of the drug to interact with the receptor to produce its cellular eBect (agonist, partial agonist, antagonist) o Agonist- drug binds to a receptor & produces same eBect of endogenous ligand o Antagonist- drug binds to receptor & prevent agonist from exerting eBect o Modulator- ↑/↓ nrml activity lvl of receptor but don’t bind to site/location of endogenous ligand EQicacy- maximal therapeutic eBect a drug can produce regardless of dose (max eBect) Potency- amount of drug required to produce a given biological eBect AQinity- strength of bond (interaction) between a ligand (drug) and the receptor- "tightness" (hug)  Selectivity- receptors only respond to molecules with appropriate structural characteristics (lock and key) Therapeutic Index (TI)- experimental measure of drug safety relative to its eBicacy; use-limited toxic dose/eBective dose Ionized forms are water soluble and can't cross membranes Unionized forms are lipid soluble and can pass through membranes Zero Order Drug Elimination: constant amount of drug eliminated per unit of time. Rate is elimination is independent of drug plasma concentration, and can occur as the result of limited amount of degradation enzyme availability First Order Drug Elimination: rate of elimination is a constant percentage of total drug in the plasma. Measured in half-life