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Dr. Henry's Objectives
Terms in this set (17)
4. Briefly outline the steps taken to develop and market a new drug.
a. Identification of a new compound
b. In vitro experimentation and animal testing
c. Clinical Testing
d. Phase I: small number of patients that are used to test the limits of a safe dosing range typically in health volunteers
Phase II: testing the drug with a relatively small number of patients to determine if the drug actually works or has the desired effect
Phase III: similar to phase II but with larger number of patients, usually these are well controlled studies which aim to demonstrate statistical significance as compared to control (placebo) patients
Phase IV: continued monitoring during actual clinical use
Describe and give examples of common receptors that serve as drug targets.
Intracellular receptors (1) Lipophilic, usually change gene activity/transcription
Intrinsic enzymatic activity receptors 2 single membrane protein
1. tyrosine kinases (i.e. insulin receptors, epidermal growth factor receptor)
2. serine/threonine kinases (i.e. transforming growth factor-beta receptors)
3. tyrosine phosphatases (i.e. CD45 receptors)
4. guanylyl cyclases (atrial natriuretic peptide receptors)
Receptors that directly associate with intracellular enzymes 3 associate with kinases or proteases and include receptors such as the interleukin-3 receptor, erythropoietin receptor, and leptin receptor.
Ligand-gated ion channels (4) the nicotinic acetylcholine receptor (nAchR).
7 membrane-spanning-receptors or 7MSR (5) g proteins, etc.
Be able to draw and label a ligand binding affinity curve and provide definition for the Bmax and Kd. Explain how one can use this plot to distinguish ligand binding affinities between two drugs
Kd = dissociation constant = [R]x[L]/[RL] = point at which ½ receptors are occupied with ligand and ½ free.
Bmax = full receptor occupancy/saturation
Articulate the difference between efficacy and potency. Be able to distinguish between potency and efficacy using a dose-response curve.
Potency: a measurement of drug dose used to compare the relative affinity and effectiveness of two or more drugs. This is most conveniently done by comparing the EC50 of two or more agents. Lower EC50 more potent
Efficacy: the maximal effect a drug can induce (Emax)
a drug that produces a lower maximal response as compared to the agonist as binding of the partial agonist to the receptor increases, the binding of the agonist decrease
can be represented as the ratio of the TD50/ ED50. The greater the ratio or the greater the window between the TD50 and the ED50, the safer the drug is for a patient.
Describe the biochemical steps (phase I and II), key physiological sites and "first-pass" effect as it relates to metabolism.
Biotransformation phase I and phase II
Phase I oxidative, reductive, and hydrolytic rxns to make a more polar molecule by putting on a functional group. Better phase II compound
Phase II reactions yield a more water soluble conjugated product that is transported into the bile caniculi and eventually into the bile duct to be excreted with the feces; or back into the blood to be excreted by the kidneys
gastrointestinal tract, lungs, skin, kidneys, and brain have relatively high levels of metabolizing activity and serve as key sites of biotransformation. Mostly Liver due to vasculature and enzymes
First pass when oral, has to pass through liver via portal vein. Exposed to metabolizing enzymes in the liver before distribution.
Describe the sites and factors that play an important role in the elimination of a drug.
Renal excretion of compounds represents the primary mechanism of drug elimination
Glomerular filtration rate
Binding to plasma proteins
Alkalinization or acidification of urine
Describe the difference between a drug with a V (volume of distribution) similar to blood volume versus a drug that has a V 100x blood volume.
The larger the volume of distribution, the greater the extent to which the drug distributes to extravascular tissue. V close to blood volume majority located in vasculature. Larger V majority is located in extravascular compartments.
V = Amnt drug in body/C
Define clearance and describe the difference between zero-order and first-order elimination kinetics. Explain the difference between capacity-limited elimination and flow-dependent-elimination in the context of zero and first order kinetics
CL = Rate of Elimination/C
Zero-order elimination: The process of elimination is independent of the drug concentration. The bodies capacity to eliminate the drug is saturated - capacity limited elimination. If dose is greater than elimination, could build to dangerous levels.
First-order elimination: Clearance is constant, system not saturated. Organ has excess capacity to eliminated. Limited by flow of blood to organ.
Understand the impact of predicting the initial plasma concentration (Cp0) using a one-compartment model and a two-compartment model.
V = amount of drug/concentration in blood
Cp0 = Dose (amount of drug)/V just reorganizing the other equation
Rate of elimination/clearance (k) = .693/t1/2
For a 2 compartment model, cannot do this. Initial dose will appear as an exponential decay of concentration
Use the accumulation factor to predict the ratio of the steady-state concentration to the initial dose.
Accumulation Factor = AF
For AF = 1/0.875 = 1.143 the drug will accumulate to a concentration of 1.143 as much as seen following the first dose
Define bioavailability and predict the impact of clearance, hepatic blood flow, and gut absorption on the bioavailability of a drug taken orally.
Bioavailability: the amount of drug that reaches the systemic circulation.
The absorption, metabolism, distribution and elimination of a drug will all impact the bioavailability of a drug.
F(bioavailability) = f(fraction absorbed in gut) x (1 - ER)
ER = CL/Q(hepatic blood flow)
Define the therapeutic window.
The concentration ranges between the minimum effective concentration for the desired result and the minimum effective concentration for the toxic effect.
Define steady-state concentration and the impact dosing rate and clearance have on the steady-state concentration. Explain why it takes 4-5 half-lives to reach a steady-state concentration.
elimination of a drug is equal to the bioavailability of the drug
C(SS) = Dosing Rate/CL
Following 4-5 half-lives, the amount of drug from the first dose is negligible. The time it takes to reach Css is independent of the dose or dosing rate but is dependent upon the half-life. The longer the half-life, the longer it will take to reach the Css.
Be able to calculate a loading dose and predict the impact of changing the volume of distribution and bioavailability on the loading dose. Describe why a loading dose may be needed therapeutically and the major disadvantages of giving a loading dose.
Useful when drugs have a long ½ life and a therapeutic concentration is needed before steady state can be reached. A large dose could have toxic implications. Smaller multiple doses over a period of time to avoid this. Also larger concentrations in specific areas before distribution could cause problems.
What are F, f, TC and Q?
Bioavailabillity = F
Extent of Absorption = f
Hepatic Blood Flow = Q
Target Concentration = TC
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