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312 Cards in this Set
- Front
- Back
- 3rd side (hint)
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What is toxicology?
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The area pharmacology concerned with the undesirable effects of chemicals and biological systems.
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What are drugs?
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Substances that act on living systems at the chemical, molecular level
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What are drug receptors?
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The molecular components of the body with which a drug interacts to bring about its effects.
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What is pharmacodynamics?
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The actions of a drug on the body, including receptor interactions, dose response phenomenon, and mechanisms of therapeutic and toxic action.
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What is pharmacokinetics?
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The actions of the body on the drug, including absorption, distribution, metabolism, and elimination.
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What are the four forms of permeation?
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1. Aqueous diffusion.
2. Lipid diffusion. 3. Transport by special carriers. 4. Endocytosis, pinocytosis |
None
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What are the five determinants of drug distribution?
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1. Size of the organ.
2. Blood flow. 3. Solubility 4. Binding 5. Ion trapping |
None
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What is first -- pass effect?
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When a significant amount of the drug agent is metabolized in the gut wall, portal circulation, and liver before it reaches the systemic circulation
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What is first ordered drug elimination?
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When the rate of elimination is proportionate to the concentration of the drug. These drugs have a characteristic half-life of elimination, that is constant regardless of the amount of drug in the body.
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What is a zero order elimination?
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When the rate of elimination of a drug is constant regardless of its concentration.
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What is the volume of distribution?
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The ratio of the amount of a drug in the body to its concentration in the plasma or blood.
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What is Clearance?
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the ratio of the rate of elimination of a drug to its concentration in plasma or blood.
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What is a half life?
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the time it takes for the amount or concentration of a drug to fall to 50% of an earlier measurement. For 1st order drugs it is constant regardless of concentration, but for zero order kinetics it is not.
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What is bioavaliablity (F)?
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The fraction or percentage of the administered dose of a drug that reaches the systemic circulation.
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What is the area under the curve (AUC)?
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The graphic area under a plot of a drug concentration in plasma versus time after a single dose of a drug or during a single dosing interval. It is used to calculate the bioavailability of a drug given by any route other than IV.
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What are Peak and Trough Concentrations?
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The max and min drug concentrations in plasma or blood measured during cycles of repeated dosing.
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What is minimum effective concentrations (MEC)?
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the plasma concentration below which a patient's response is too small for therapeautic benefit.
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What is the first pass effect?
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The elimination of drug that occurs after administration but before it reaches the systemic circulation
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What is steady state?
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The condition in which the average total amount of drug in the body does not change over multiple dosing intervals
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What is extraction?
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The fraction of a drugn in the plasma that is removed by an organ as it passes thorugh that organ
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What is bioequivalence?
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The equivalence of blood conc. of two preparations of the same drug measured over time. ie. show comparable bioavailability
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What is biodisposition?
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The process of drug absorption, distribution, and elimination. Synonym of Pharmacokinetics
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What are three important drugs which follow zero-order rather than first-order kinetics?
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ethanol, aspirin, phenytoin
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What are 4 general mechanism by which drugs effects are produced?
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Interaction with receptors, alteration of the activity of enzymes, antimetabolite action, nonspecific chemical or physical interactions
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What is volume of distribution (Vd) and how is it calculated?
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the hypothetical volume of total body fluid into which a drug appears to distribute.
Vd = amt of drug administered (mg)/initial plasma conc. (mg/L) |
None
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What is the Henderson-Hasselbalch equation?
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pH = pKa + log [unprotonated species]/[protonated species]
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Does an acid or a base have a low pKa?
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Acid
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What physical factors influence drug absorption?
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Blood flow to the absorption site; total surface area available for absorption; contact time at the absorptive surface
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What is therapeutic equivalence?
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Drugs which have comparable efficacy and safety.
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What factors affect bioavailablity?
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first pass metabolism, solubility of the drug, chemical instability; nature of the drug formulation
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What is a class I drug?
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A drug given at a dose which is less than the binding capacity to albumin, maintains a high bound-drug fraction.
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What is a class II drug?
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A drug given at a dose which is higher than the binding capacity of albumin, a large portion of the drug is in the free state.
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What are first order kinetics?
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When the rate of drug metabolism is directly proportional to the concentration of free drug such that a constant fraction of drug is metabolized per unit time. The drug concentration is much less than the Michaelis constant Km.
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What are zero-order kinetics?
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When the rate of drug metabolism remains constant over time and the catalyzing enzyme becomes saturated due to the drug concentration being much greater than Km. This results in a constant amount of drug being metabolized per unit time.
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What is Phase I metabolism?
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The conversion of lipophilic molecules to more polar molecules by introducing or unmasking polar functional groups often by using the P450 system. This may/may not change the drug's activity.
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What is the generalized oxidation equation of Phase I conversion catalyzed by P450?
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Drug + O2 + NADPH + H --> changed drug + water + NADP+
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What is cytochrome P450 (CYP)?
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Many families of heme-containing isozymes which reside in the SER of cells and catalyze the Phase I oxidative metabolism of drugs. Specific isozymes are responsible for the metabolism of specific drugs.
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What are inducers of P450?
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Certain drugs which are capable of increasing the synthesis of one or more CYP isozymes and thus increasing the metabolism of themselves or other drugs (ie. phenobarbital, rifampin, carbamazepine)
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What are inhibitors of P450?
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Drugs which either compete for the same isozyme as another drug or inhibiting other CYPs thus leading to reduced metabolism of other drugs.
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What are Phase I reactions which do not involve P450?
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amine oxidation, alcohol dehydrogenation, and hydrolysis
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What is Phase II metabolism?
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Conjugation reactions with endogenous substrates to make metabolites from Phase I even more water soluble and able to be excreted by the kidneys
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What is ion trapping?
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The manipulation of the pH of the urine to increase the ionized form of an undesirable drug and thus minimize its back-diffusion in the kidneys and increase its clearance.
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What is the equation for a drug's half life?
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t1/2 = (0.693 Vd)/ CL
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What is the equation for a drug's renal clearance?
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CL = RPF x extraction ratio
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What is total body clearance?
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The sum of the clearances from the various drug metabolizing and eliminating organs.
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What abnormalities in patients will prolong a drug's half-life?
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diminished renal plasma flow or hepatic blood flow; decreased extraction ratio; decreased metabolism
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What is the equation for total body clearance?
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CLtotal = (k) Vd
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What is the equation for the steady state concentration?
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Css = rate of infusion/ CL
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Does doubling the infusion rate of a drug change the time needed to reach steady state?
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No, it only doubles the achieved steady state concentration
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How much of the steady state concentration is achieved in the time of one half-life for the drug?
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50% of the steady state concentration
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How many half-lives does it take for a drug to reach steady state?
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4 half-lives
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How long does it take for a drug to wash out of the system after reaching steady state?
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The same amount of time to reach steady state.
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What is a loading dose and how is it calculated?
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A single dose to achieve the desired plasma level rapidly, followed by an infusion to maintain the steady state (maintenance dose)
loading dose = (Vd)(desired steady state plasma conc.) |
None
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How do you change the drug dosing to reduce the amplitude of swings in drug concentration?
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use smaller doses at shorter intervals
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How much time does it take to reach 90% of the steady state on IV administration?
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3.3 x half-life
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What is Fick's Law of Diffusion?
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Rate of diffusion = (C1-C2) x (Permability coefficient/thickness) x area
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What are the three types of drug receptors?
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Type I: plasma membrane
Type II: cytoplasm Type III: nucleus |
None
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What is One-Compartment distribution?
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When a rapid equilibrium is achieved between plasma and tissue distribution following drug administration. Plasma concentration time profile declines mono-exponentially.
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What is Two-Compartment distribution?
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Rapid distribution of a drug to a central compartment followed by slow distribution to tissues/binding sites. This results in a bi-exponential plasma concentration time profile.
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What are characteristics of an active parent drug?
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very lipid soluble, less polar, less ionized, weak electrolyte, more able to penetrate cell membrane
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What are the characteristics of an inactive drug or drug metabolite?
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less lipid soluble, more polar, more ionized, strong electrolyte, less able to penetrate cell membranes
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What are the five important interactions with drugs that affect drug metabolism?
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Drug-Age interaction; Drug-Drug interaction; Drug-Endogenous substance interaction; Drug-Disease interaction; Drug-Genetic interaction
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How do liver and cardiac disease affect drug metabolism?
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Both slow metabolism by limiting the livers functionality and blood flow to the liver respectively.
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What are the chemical forces involved in drug binding?
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electrostatic forces; hydrogen bonding; van der waals forces; hydrophobic bonds
Note: most drug binding interactions are NOT covalent |
None
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What is a drug receptor?
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any component tat is receptive to interacting with drugs or endogenous substances and is capable of initiating a subsequent response
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What are drug binding sites?
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receptive components that can interact with or bind to substances but are not capable of initiating any subsequent response (eg. Albumin)
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What is the equation to calculate loading dose?
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LD = Css x Vd (L/kg) x Wt
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What kind of drugs bind to albumin?
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acidic drugs
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What kind of drugs bind to alpha1 glycoprotein in the serum?
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basic drugs
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Which drugs display two compartment pharmacokinetics?
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digoxin, lidocaine, and phenytoin
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How do you calculate Vd?
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dose/initial blood concentration
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What are some drugs which undergo only renal clearance?
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gentamicin, tobramycin, vancomycin
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What are some drugs which undergo only hepatic clearance?
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theophylline, warfarin, phenytoin, lidocaine
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What are some drugs which undergo both renal and hepatic clearance?
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digoxin, procinamide, penicillin G
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What are some drugs which follow zero order or dose dependent kinetics?
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at high doses: phenytoin, aspirin, and ethyl alcohol
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What is the use of digoxin?
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atrial fibrillation, atrial flutter, and CHF
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What are some of the pharmaocokinetic characteristics of digoxin?
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narrow therapeutic index, large Vd, high F, two compartment distribution profile
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What are some of the pharmaocokinetic characteristics of gentamycin/tobramycin?
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cleared exclusively by the kidney, tobramycin doesn't pass the GI tract so can only be given IV or IM
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What are some of the pharmaocokinetic characteristics of lidocaine?
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low F, eliminated primarily by the liver, two-compartment model of distribution
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What are some of the pharmaocokinetic characteristics of penicillin G?
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elimination is dependent on renal function,
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What are some of the pharmaocokinetic characteristics of phenytoin?
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approximates zero order kinetics of elimination, high F, eliminated primarily by the liver, two compartment model of distribution
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What are some of the pharmaocokinetic characteristics of propanolol?
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low F (extensive 1st pass metabolism), lipid soluble, large Vd
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What are some of the pharmaocokinetic characteristics of theophylline?
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narrow therapeutic index, approaches zero-order kinetics, high F, eliminated primarily by the liver
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What are some of the pharmaocokinetic characteristics of vancomycin?
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not absorbed orally, must be given IV, eliminated by the kidney
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What are some of the pharmaocokinetic characteristics of warfarin?
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long half life, highly protein bound so takes a while to reach therapeutic effect, high F, eliminated primarily by liver
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What is the use of gentamycin/tobramycin?
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aminogycoside antibiotic, treat bacterial infections esp. gram negative
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What is the use of lidocaine?
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local anesthetic and antiarrhythmic
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What is the use of penicillin G?
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antibiotic used as prophylaxis and treatment of gram positive bacteria
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What is the use of phenytoin?
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antiepileptic, stabilizes the inactive state of voltage gated sodium channels
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What is the use of propranolol?
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beta-blocker, used in treatment of hypertension
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What is the use of theophylline?
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methylxanthine drug used to treat respiratory dz such as COPD and asthma
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What is the use of vancomycin?
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glycopeptide antibiotic to treat gram positive bacteria
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What is the use of warfarin?
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anticoagulant
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What is the drug interaction concern with using procaine (novacaine) or procaine amide (pronetyl) in patients that are using sulfa drugs?
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the phase I metabolism of the procaine family drugs produces PABA which is a structural analog to sulfonamide and would competitively inhibit the antibacterial effect
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What is a wide therapeutic index?
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a drug with concentration ranges in which the probability of efficacy is high and toxicity is low
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What are some drugs with a wide therapeutic index?
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B-lactam antibiotics, H-2 antagonists
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What are some drugs with a narrow therapeutic index?
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digoxin, aminoglycosides
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When are dose adjustments best made and why?
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at steady state; minimizes potential for over/underdosing, assumes max and stable distribution
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Why are loading doses used?
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used with meds with long half lives which will take a long time to reach a therapeutic effect (steady state will still take ~4 half-lives), in patients with critical dz states which need the effect of the drug immediately
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What kind of drugs are given by continous infusion?
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drus which are not safe to give a bolus or loading dose, those drugs which require a maintenance of concentration, often meds with a short half-life
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What kind of medication interactions affect absorption?
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chelation, changes in stomach pH
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What kind of medication interactions affect distribution?
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competition for binding sites, changes in protein binding in disease states
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What kind of medication interactions affect metabolism?
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inducers/inhibitors of CyP450, and other metabolic pathways
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What kind of medication interactions affect elimination?
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competition for elimination pathways esp in kidney
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What are three types of medication interactions?
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drug-drug; drug-disease state; drug-nutrient
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What is the drug interaction between sucralfate and digoxin?
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sucralfate coats the stomach and decreases digoxin absorption
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What is the drug interaction between ciprofloxacin and aluminum hydroxide?
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chelation leading to decreased absorption of cipro
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What is the drug interaction between itraconazole and raniditine?
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raniditine decreases stomach pH and decreases absorption of itrazonazole
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What is the drug interaction between aspirin and warfarin?
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aspirin competes for protein binding sites of warfarin leading to increased free warfarin concentration and increased active drug and increased efficacy of warfarin
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What is the drug interaction between carbamazepime and oral contraceptives (OCP)?
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carbamazepime is a CyP450 inducer which leads to increased OCP metabolism and failure
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What is the drug interaction between saint john's wort and warfarin?
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st. Johns wort is a CyP450 inducer and leads to increased metabolism of warfarin
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What is the drug interaction between voriconazole and tacrolimus?
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voriconazole is a CyP450 inhibitor and leads to increased tacrolimus conc. And supratherapeutic effects
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What is the drug interaction between disulfiram and whiskey?
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disulfiram inhibits alcohol dehydrogenase and leads to increased alcohol concentrations and sickness
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What is the drug interaction between probenecid and ampicillin?
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probenecid blocks tubular secretion of ampicillin and leads to increased ampicillin concentrations
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What is the drug interaction between gentamicin and cyclosporine?
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both renally eliminated and nephrotoxic
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What is the drug interaction between ciprofloxacin and ensure nutrient supplements?
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divalent and trivalent cations of ensure bind to the cipro and result in chelation and decreased cipro absorption
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What is the drug interaction between phenytoin in a burn patient?
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decreased albumin, decreased bound phenytoin, increased free phenytoin and possible overdose
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What is the drug interaction between tobramycin in an ascitic patient?
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increased extracellular fluid, increased tobramycin Vd, possible supratherapeutic levels
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What is drug affinity?
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the propensity of a drug to bind to a receptor, typically expressed by its Kd value (k2/k1) or (rate to for DR complex/rate to break DR complex)
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What is the relationship btw Kd and affinity?
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inverse relationship since Kd is the conc of a drug that will occupy 50% of receptor population
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What does the fraction of receptors occupied by a drug depend upon?
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affinity and concentration of drug
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What does the total number of receptors occupied by a drug depend upon?
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fraction of the receptor population occupied and the number of receptors in the given tissue
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What is drug selectivity?
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a drug's ability to interact with one type of receptor versus other receptors; for any drug selectivity will decrease as dose is increased
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What is the drug-dose relationship?
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the correspondence btw the amt of drug and the magnitude of the response produced
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What is the simple occupancy theory of drug-dose response?
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the linear relationship btw the number of receptors occupied by a drug and the magnitude of response, only when all receptors are occupied is the max response achieved
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What is the modifiec occupancy theory of drug-dose response?
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the positive, though non-linear relationship btw the number of receptors bound by drug and the response created, the max response can be achieved without all receptors bound and different drugs have varying capacities to elicit a response
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What is drug efficacy?
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the intrinsic activity of a drug and it is the plateau or max response of a drug's dose response curve, a drug with greater efficacy is able to achieve a greater therapeutic benefit than a less efficacous drug
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What is drug potency?
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a measure of the amount of drug necessary to produce an effect of a given magnitude, measured by the conc of drug producing 50% of its max response (ED50); depends on a drugs affinity fo the receptor (Kd) and efficiency the drug-receptor complex is coupled to a response
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What are spare receptors?
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receptors that do not have to bind drug in order for the max effect to be produced, ie, Kd greater than EC50
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What are the effects of competitive antagonism?
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a change in ED50 results because more of the agonist is required to achieve 50% of the response, but the max response or efficacy of the agonist is not affected because large doses of the drug can overcome the effects of the competitive antagonist
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What are the effects of non-competitive antagonism?
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a decrease in the maximal response due to the loss of available receptors to interact with the agonist drug, however the remaining receptors would exhibit the same affinity Kd and so the ED50 would not change
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What are the effects of partial agonists on full agonists?
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since the partial agonists cannot achieve the same max response as the full agonists they can reduce the max response of full agonists when given together
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What are three means by which toxic effects can result from drugs?
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by the drug's action at the intended receptor but to an excessive degree; the drug's action at identical receptors but in different tissues or affecting different effector pathways; actions mediated by different types of receptors
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What is the quantal dose response relationship?
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the magnitude of the dose on the proportion of the poulation that responds, are useful in determining doses in which most of the population responds
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What is a pharmacologic antagonist?
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a drug that binds to its receptor without activating it
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What is a competitive antagonist?
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a pharmacologic antagonist that can be overcome by increasing the dose of agonist
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What is an irreversible antagonist?
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a pharmacologic antagonist that cannot be overcome by increasing the dose of agonist
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What is a physiological antagonist?
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a drug that counters the effects of another by binding to a different receptor and causing opposing effects
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What is a chemical antagonist?
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a drug that counters the effects of another by binding the drug and preventing its action
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What are the characteristics of a intracellular receptor?
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bind to lipid soluble compounds (steroids), often alter gene transcription, are slow acting bc of the lag period to synthesize the protein, effects often persist for hours or days bc of the slow turnover of the proteins activated
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What are some endogenous substances which utilize tyrosine kinase receptors?
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insulin, epidermal growth factor (EDF), platelet derived growth factor (PDGF)
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What are some examples of substances which use ligand gated channel receptors to transmit signals?
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acetylcholine, GABA, excitatory aas (glutamate, aspartate, glycine)
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What is pharmacodynamic tolerance?
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desensitization phenomenon where a decreased response to a drug or hormone occurs slowly with time
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What is tachyphylaxis?
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rapid development of diminished responsiveness after drug administration
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What are some mechanisms which down regulate a receptors responsiveness to an agonist?
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agonist induced phosphorylation of the activated receptor and binding by beta-arrestin; receptor down regulation; post receptor adaptations
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What is homologous desensitization?
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when the desensitization of a receptor is restricted to the receptor activated by the agonist
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What is heterologous desensitization?
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when an agonist activation of one receptor subtype results in a decreased responsiveness to one or more other receptor subtypes; results in a more widespread effect on the system
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What is denervation supersensitivity?
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a compensatory enhancement of receptor-effector coupling or the number of receptors when there is lower activation such as loss of the agonist or innervation of the receptor
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What are the 8 parts of a prescription?
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Pt. Name; Date; Superscription (Rx); Inscription (name of drug, strength, drug form); Subscription (instructions for preparing or # units to dispense); Transcription (pt instructions for use); Refill info; Prescriber info/signature
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What drugs are classified in schedule I of the Controlled Substances Act?
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drugs with high potential for abuse and no accepted medical use in the US (LSD, heroine, mescaline)
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What drugs are classified in schedule II of the Controlled Substances Act?
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drugs with high potential for abuse that also have an accepted medical use; very likely to produce severe psychological and/or physical dependence (amphetamine, morphine, merperidine, secobarbital, fentanyl)
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What drugs are classified in schedule III of the Controlled Substances Act?
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drugs with lesser potential for abuse than those in schedules I and II, have potential to produce less serious dependence than those in schedule II (acetominophen with codeine, aspirin with codeine)
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What drugs are classified in schedule IV of the Controlled Substances Act?
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drugs will less abuse potential than those in schedule III; have potential for moderate dependence (diazepam, phenobarbital)
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What drugs are classified in schedule V of the Controlled Substances Act?
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drugs with lowest abuse potential; some may be sold in a pharmacy without a prescription (diphenoxylate with atropine, guaifenesin with codeine)
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What are the rules/regulations for prescribing a Schedule II drug?
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must be in writing with full name and address of pt; name, address and DEA number of prescriber; written signature, date, no refills
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What are the rules/regulations for prescribing a Schedule III/IV/V drug?
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written or verbal; name and address of pt; name, address, DEA # and signature of prescriber; date; up to 5 refills allowed to be used within 6 months
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What are the exceptions to emergency dispensing of schedule II drugs?
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may be verbal if: emergency, quantity of drug for the emergency period (no more than 72 hours); a written/signed prescription is delivered to the pharmacist within 7 days
may be faxed if: pt is in hospice and drug is for intractable pain; in an emergency but must be followed in 7 days by valid signed Rx |
None
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What are generic drugs?
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drugs reviewed and approved by FDA to be interchangable with brand name drugs, including dose, dosage form, route of administration, safety, quality, intended use and effectiveness
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Why are generic drugs less expensive?
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competitive market after expiration of patent drives down price, marketing costs less, research and development costs are much less since no animal or clinical studies are necessary only bioequivalence tests
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What are the Hatch Waxman amendments of 1984?
|
allowed generic firms to rely on findings of safety and efficacy of innovator drugs after expiration of patents
|
|
|
|
What is bioequivalence?
|
pharmaceutical equivalents whose rate and extent of absorption are not statistically different when administered to pts or subjects at the same molar dose under similar experimental conditions; if drugs have equal bioavailability they are bioequivalent
|
|
|
|
How are bioequivalence trials performed?
|
use 20-40 normal, healthy adults; 2x2 crossover design with single dose of the agent and measure the AUC and Cmax; the generic's 90% confidence interval must not be 20% greater or less than that of the branded agent
|
|
|
|
What pharm reference book has information on substitutions of branded drugs with generics?
|
Orange book - approved drug products with therapeutic equivalence evals
|
|
|
|
What are the two therapeutic equivalence codes?
|
A = substitutable; B = inequivalent substitution (only 3%)
|
|
|
|
What is pharmacogenomics?
|
the study of how an individual's genetic inheritance affects the body's response to drugs
|
|
|
|
What is a mutation?
|
an alteration in DNA sequence which is present only rarely (<<<1%) in the population
|
|
|
|
What is a polymorphism?
|
an alteration in DNA sequence which is present commonly (>1%) in the population
|
|
|
|
Which three CyP proteins of phase I metabolism are known to have polymorphisms in the population?
|
CYP2D6; CYP2C9; CYP2C19
|
|
|
|
What three phase II metabolism enzymes are known to have polymorphisms in the population?
|
thiopurine methyltransferase; N-acetyltransferase; uridine 5'-triphosphate glucuronosyltransferases
|
|
|
|
What drug classes does CYP2D6 metabolize?
|
20-25 % of all drugs: debrisoquine, sparteine, tricyclic antidepressants; antiarrhythmics, beta-blockers, neuroleptics
|
|
|
|
What drug classes does CYP2C9 metabolize?
|
15% of all drugs: tolbutamide (hypoglycemia/anti-diabetic); warfarin; phenytoin; and NSAIDs
|
|
|
|
What drug classes does CYP3A4 metabolize?
|
~50% of all drugs, inhibited by grapefruit juice (bioflavonoids and furanocoumarins)
|
|
|
|
What drug classes does N-acetyltransferase 2 (NAT2) metabolize?
|
isoniazid (peripheral neuropathy); hydralazine (lupus); sulfonamide (hypersensitivity rxns)
|
|
|
|
What is phase I of clinical drug testing?
|
determine the pharmacodynamic parameters of a drug: test on small sample of healthy humans to assess safety and dosage
|
|
|
|
What is phase IIA of clinical drug testing?
|
test the desired clnical effect and safety of the drug tested on small sample of humans with the disease the drug is intented to treat
|
|
|
|
How can pharmacogenomics improve clinical trials?
|
determine who would be good responders, smaller clinical trials necessary, reduce the # of failed trials, greater chance of obtaining statistically significant results
|
|
|
|
How could pharmacogenomics improve the treatment of schizophrenia?
|
by being able to determine who would be a good candidate for use of clozapine and ensure avoidance of the fatal side effect of agranulocytosis
|
|
|
|
Where is the location of the Abl gene?
|
on chromosome 9q34
|
|
|
|
Where is the location of the Bcr gene?
|
on chromosome 22q11
|
|
|
|
What disease results from the translocation t(9,22) of the bcr-abl genes?
|
chronic myelogenous leukemia (CML) forming the philadelphia chromosome (short chromosome 22)
|
|
|
|
What drug is used to treat chronic myelogenous leukemia?
|
imatinib (Gleevec) inhibits the Bcr-Abl tyrosine kinase and reduces the proliferation of cancerous white blood cells
|
|
|
|
What is the Her2-Neu gene?
|
human epidermal growth factor receptor 2 which is amplified in 25-30% of breast cancer pts
|
|
|
|
What drug is used to treat breast cancer patients with Her2 amplification?
|
transtuzumab (Herceptin) which is a humanized monoclonal antibody directed against Her2
|
|
|
|
What is the use of erythropoeitin (Epogen)?
|
used to treat chronic kidney failure and stimulate RBC production; contraindicated in pts with uncontrolled HTN
|
|
|
|
What is the use of tissue plasminogen activator (Activase)?
|
thrombolytic agent used in pts who have had a heart attack or stroke; risk of excessive bleeding
|
|
|
|
What is the use of tumor necrosis factor alpha (Etanercept)?
|
used to treat rheumatoid arthritis
|
|
|
|
What is the use of nerve growth factor (NGF)?
|
attempted in the treatment of alzheimer pts, but developed neuropathies
|
|
|
|
What is the use of trastuzumab (herceptin)?
|
is a humanized monoclonal antibody against epidermal growth factor receptor 2 (HER2/Neu) expressed in 25-30% of breast cancers, slows the dz progression and improves survival
|
|
|
|
What is the use of cetuximab (Erbitux)?
|
chimeric MAb against epidermal growth factor receptor (EGFR), used to treat solid tumors associated with colorectal cancer
|
|
|
|
What is the use of bevacizumab (Avastin)?
|
humanized MAb against vascular endothelial growth factor (VEGF), used in treating colorectal and lung cancers, reduces tumor angiogenesis and growth
|
|
|
|
What are the advantages and disadvantages to use of adenovirus as a viral delivery vector?
|
advantage: can be readily generated, infects most cells; disadvantage: very immunogenic causing inflammation, infection only for a few months, virus doesn't integrate into genome
|
|
|
|
What are the advantages and disadvantages to use of adeno-associated virus (AAV) as a viral delivery vector?
|
advantage: small, infects many cell types, no immune response, persists in vivo, may integrate into genome; disadvantage: difficult to generate sufficient for infection
|
|
|
|
What are the advantages and disadvantages to use of retrovirus as a viral delivery vector?
|
advantage: generated at high titer, readily integrates into dividing cells, long lasting effects; disadvantage: only integrates into dividing cells, unpredictable integration
|
|
|
|
What are the advantages and disadvantages to use of lentivirus as a viral delivery vector?
|
advantage: infects nearly all cell types even neurons, transgene expression persists; easy to generate; harmful HIV genes removed; disadvantage: site of integration is upredictable
|
|
|
|
What are the advantages and disadvantages to use of herpesvirus as a viral delivery vector?
|
advantage: infects neurons; disadvantage: large and difficult to use
|
|
|
|
What are two gene silencing treatment techniques?
|
Antisense oligonucleotide (ASO) and RNA interference (RNAi)
|
|
|
|
How do antisense oligonucleotides (ASO) function?
|
single stranded DNA like molecule complementary to selected mRNA binds to it and promotes its degradation
|
|
|
|
How does RNA interference (RNAi) function?
|
in cells double stranded RNA is recognized and degraded by an enzyme DICER and the pieces are used by RNA inducing silencing complex (RISC) to bind to complementary mRNA and degrade it. Short double stranded RNA is delivered via virus vectors to silence desired mRNAs
|
|
|
|
What is LD50?
|
the dose of a substance that kills 50% of the subjects
|
|
|
|
What are the major routes of toxic exposure?
|
oral (#1). Inhalation, dermal
|
|
|
|
What are some factors which will affect dose-response relationship with a toxin?
|
route of exposure, biotransformation, health/nutritional state, age, genetics
|
|
|
|
How is therapeutic index calculated?
|
LD50 or TD50/ ED50; the larger the value the safer the drug
|
|
|
|
What are some drugs which are known to be teratogenic?
|
thalidomide, tetracycline, cyclophosphamide, phenytoin, cocaine, ethanol
|
|
|
|
What are the most common causes of death due to acute poisoning?
|
airway obstruction, aspiration, respiratory arrest, hypotension, cellular hypoxia, hyperthermia, and seizures
|
|
|
|
When treating a possible acute poisoning what sure the initial considerations be?
|
airway, breathing, circulation, dextrose (ABCDs); cervical spine protection
|
|
|
|
What toxics are often the cause of cholinergic or anticholinesterase syndrome?
|
organophosphate and carbamate insecticides
|
|
|
|
What are symptoms of cholinergic or anticholinesterase syndrome?
|
Muscarinic overstimulation leading to parasympathetic overdrive: bradycardia, miosis, abdominal cramps, incontinence, hypotension etc; Nicotinic overstimulation initial muscle cramps, later weakness and paralysis, respiratory distress
|
|
|
|
What toxins are often the cause of anticholinergic syndrome?
|
atropine, scopolamine, tricyclic antidepressants, antihistamines, jimson weed
|
|
|
|
What are symptoms of anticholinergic syndrome?
|
block of muscarinic receptors leading to sympathetic overdrive: mydriasis, tachycardia, hyperthermia, abdominal distention, urinary retention etc. and nonspecific central effects
|
|
|
|
What toxins are often the cause of hemoglobinopathy syndromes?
|
carboxyhemoglobinemia: inhalation of excessive CO or methylene chloride; methemoglobinemia: oxidation of ferrous 2+ iron of hemoglobin to ferric state
|
|
|
|
What are symptoms of hemoglobinopathy syndromes?
|
hypoxia, headache, coma, nausea, cardiac disfunction, acidosis, death
|
|
|
|
What are symptoms of and drugs which produce narcotic overdose ?
|
pinpoint pupils, respiratory depression and hypotension due to heroine, oxycodone, morphine, merperidine; IV naloxone given to counteract effects
|
|
|
|
What are symptoms of and drugs which produce sympathomimetic excess?
|
nervousness, agitation, tremor, dehydration, hypertension, tachycardia, and seizures; cocaine, amphetamines, MAOI's
|
|
|
|
What are physical signs of opiate withdrawl syndrome?
|
mydriasis, piloerection, rhinorrhea, and lacrimation; not associated with seizures
|
|
|
|
What are physical signs of non-opiate withdrawl syndrome?
|
hallucinations, tachycardia, hyperpyrexia, seizures
|
|
|
|
What drugs produce the toxic sign of AV block?
|
digitalis glycosides
|
|
|
|
What drugs produce the toxic sign of sinus bradycardia?
|
digitalis, beta-blockers, calcium channel blockers
|
|
|
|
What drugs produce the toxic sign of metabolic acidosis?
|
aspirin, methanol, ethylene glycol
|
|
|
|
What drugs produce the toxic sign of GI dysfunction?
|
iron poisoning
|
|
|
|
What drugs produce the toxic sign of seizures?
|
intoxications, withdrawls, CNS infections,
|
|
|
|
What drugs are given to acutely control seizures?
|
diazepam and lorazepam, not phenytoin
|
|
|
|
What is an antidote for iron?
|
deferoxamine
|
|
|
|
What is an antidote for acetaminophen?
|
acetycysteine
|
|
|
|
What is an antidote for atropine and organophosphates?
|
2-PAM chloride
|
|
|
|
What is an antidote for opiates?
|
naloxone
|
|
|
|
What is an antidote for carbamates?
|
atropine
|
|
|
|
What is an antidote for anticholinergic poisoning?
|
physostigmine
|
|
|
|
What are the 5 steps involved in neurotransmission?
|
1. Neurotransmitter synthesis, 2. vesicular storage, 3. synaptic release, 4. binding of NT to receptor, 5. termination of NT action
|
|
|
|
What are the pre-synaptic mechanisms by which drugs can enhance or decrease neuronal transmission?
|
inhibition of enzymes in production of NTs, inhibition of vesicular transport of NTs, inhibition or promotion of NT vesicular release, pre-synaptic (type I) augmentation of NT reuptake
|
|
|
|
What are the post-synaptic mechamisms by which drugs can enhance or decrease neuronal transmission?
|
agonistic or antagonistic binding to post-synaptic NT receptors, modification of enzymatic metabolism of the NT in the synapse, post-synaptic (type II) augmentation of NT reuptake
|
|
|
|
Are drugs that act pre-synaptically or post-synaptically more selective in their effects? Why?
|
post-synaptic drugs because they mimic or inhibit the effects of the NT at a single receptor rather than affecting the many other pathways and receptor interactions my affecting pre-synaptically.
|
|
|
|
What neurotransmitters are in the biogenic amines class?
|
dopamine, serotonin, norepinephrine, epinephrine, acetylcholine
|
|
|
|
What neurotransmitters are in the amino acid class?
|
glutamate, glycine, GABA
|
|
|
|
What neurotransmitters are in the peptide class?
|
SP, Ang II, LHRH, FSH, vasopressin, oxytocin, neuropeptide Y
|
|
|
|
What neurotransmitters are in the nucleotide class?
|
ATP, ADP
|
|
|
|
What neurotransmitters are in the gas class?
|
NO, CO
|
|
|
|
What are the 4 main therapeutic manipulations of cholinergic transmission?
|
1. interfere with vesicular release SNARE (botox); 2. post-synaptic receptor agonism and antagonism; 3. block NT degradation with acetylcholinesterase inhibitors; 4. presynaptic receptor inhibition of synaptic release
|
|
|
|
What are the 8 main therapeutic manipulations of adrenergic transmission?
|
1. competition for synthetic enzymes (Metyrosine); 2. inhibition of storage (Reserpine); 3. inhibition of synaptic release (Guanethidine); 4. receptor agonists/antagonists (phenylephrine); 5. autoreceptor agonists; 6. reuptake inhibitors (cocaine); 7. NT releasers (ephedrine); 8. inhibition of degradating enzymes (MAO inhibitors)
|
|
|
|
What is the effect of the drug Metyrosine?
|
competes with tyrosine for tyrosine hydroxylase, preventing tyrosine in adrenergic neurons from being transformed to DOPA and decreases the production of catecholamines
|
|
|
|
What is the effect of the drug reserpine?
|
blocks the vesicular dopamine transporter and results in the depletion of catecholamines in adrenergic neurons
|
|
|
|
What is the effect of the calcium channel blockers in adrenergic neurons?
|
prevent the signalling of the AP to be converted to a release of vesicles
|
|
|
|
What is the effect of the drug guanethidine?
|
prevents the SNAREs on vesicles from binding with the pre-synaptic membrane and catecholamine release
|
|
|
|
What is the effect of cocaine in adrenergic neurons?
|
inhibits reuptake of monoamines such as norepinephrine, dopamine, and serotonin.
|
|
|
|
What is the effect of tricyclic antidepressants in adrenergic neurons?
|
block the reuptake of monoamines
|
|
|
|
What is the effect of monoamine oxidase inhibitors (MAOIs)?
|
inhibit the degradation of monoamines in the pre-synaptic cytoplasm and increase catecholamine and other monoamine release
|
|
|
|
What are the three elements of the enteric nervous system?
|
sensory neurons that monitor the tension of the gut wall and chemical environment; motor neurons to control the muscles, vasculature, and secretions; interneurons to communicate btw sensory and motor
|
|
|
|
What are the two interconnected ganglia of the enteric nervous system?
|
submucosal (meissner's); myenteric (auerbach's)
|
|
|
|
What autonomic projections can modify the enteric nervous system function?
|
parasympathetic pre-ganglionic neurons; sympathetic post-ganglionic neurons
|
|
|
|
What three currents contribute to the SA membrane potential?
|
inward calcium current, inward funny current (induced by hyperpolarization); outward K+ current
|
|
|
|
Alpha-1: What tissue does this receptor distribute and what are its actions?
|
most vascular smooth m.(contracts causing increased vascular resistance), pupillary dilator m. (contracts causing mydriasis)
|
|
|
|
Alpha-2: What tissue does this receptor distribute and what are its actions?
|
adrenergic and cholinergic nerve terminals (inhibits transmitter release); some vascular smooth m. (contracts)
|
|
|
|
Beta-1: What tissue does this receptor distribute and what are its actions?
|
Heart (stimulates rate and force of contraction); justaglomerular cells (stimulates renin release)
|
|
|
|
Beta-2: What tissue does this receptor distribute and what are its actions?
|
respiratory, uterine, and vascular smooth m. (relaxes); liver (stimulates glycogenolysis); pancreatic B cells (stimulates insulin release); somatic motor nerve terminals (causes tremor)
|
|
|
|
Beta-3: What tissue does this receptor distribute and what are its actions?
|
fat cells (stimulates lipolysis)
|
|
|
|
Dopamine-1: What tissue does this receptor distribute and what are its actions?
|
renal and other splanchnic blood vessels (relaxes, reduces resistance)
|
|
|
|
Dopamine-2: What tissue does this receptor distribute and what are its actions?
|
nerve terminals (inhibits adenylyl cyclase and vesicular release)
|
|
|
|
What is the Alpha-1 adrenergic receptor signaling pathway?
|
Gq protein coupled to Phospholipase C (PLC) which forms DAG (activates PKC) and IP3 (releases stored calcium from SR)
|
|
|
|
What is the Alpha-2 adrenergic receptor signaling pathway?
|
Gi protein coupled to adenylyl cyclase inhibits cAMP formation preventing the activation of PKA which cannot phosphorylate N-type calcium channels (reducing vesicular release of NT) or MLCK (allowing it to remain active and promote smooth m. contraction)
|
|
|
|
What is the Beta-1 adrenergic receptor signaling pathway?
|
Gs protein coupled to adenylyl cyclase increases cAMP, which activates PKA to phosphorylate calcium channels (increasing calcium current in SA node and in the cell membrane and SR of myotomes)
|
|
|
|
What is the Beta-2 adrenergic receptor signaling pathway?
|
Gs protein coupled to adenylyl cyclase increases cAMP, which activates PKA to phosphorylate and inactivate MLCK (prevents smoot m. contraction)
|
|
|
|
What are the relative potencies of the direct acting sympathomimetics on Alpha-1 receptors?
|
Epi > NE >> Isoproterenol
|
|
|
|
What are the relative potencies of the direct acting sympathomimetics on Alpha-2 receptors?
|
Epi > NE >> Isoproterenol
|
|
|
|
What are the relative potencies of the direct acting sympathomimetics on Beta-1 receptors?
|
Isoproterenol > Epi >> NE
|
|
|
|
What are the relative potencies of the direct acting sympathomimetics on Beta-2 receptors?
|
Isoproterenol > Epi = NE
|
|
|
|
What are the cardiovascular effects of Epinephrine?
|
at low doses: beta receptors predominate causing peripheral vasodilation and ↓ diastolic BP (B2), ↑ CO, systolic BP, HR (B1); with higher doses alpha 1 predominates ↑ vascular resistance and total BP
|
|
|
|
What are the cardiovascular effects of Norepinephrine?
|
stimulates alpha-1 (↑TPR, diastolic BP); stimulates beta 1 (↑ HR, inotropy, systolic BP); rise in BP leads to barometric ↓HR
|
|
|
|
What are the cardiovascular effects of Dopamine?
|
stimulates D1 receptors at low conc (↓TPR); at medium conc stimulates B1 (↑inotropy, HR); at high conc stimulates A (↑BP, TPR)
|
|
|
|
What are the cardiovascular effects of Isoproterenol?
|
stimulates B2 (peripheral vasodilation, ↓diastolic BP); B1 (↑inotropy, HR, systolic BP); reflex tachycardic response to B2 receptor activation
|
|
|
|
What are two ways indirect acting sympathomimetic agents can increase the concentration of endogenous cateholamines?
|
release of stored catecholamines; blockade of reuptake transporters
|
|
|
|
What are two main types of drug interactions?
|
Homergic (2 drugs produce the same response, additively, supra-additively, or infra-additively) or Heterergic (only one drug of the pair produces the response, synergistically or antagonistically)
|
|
|
|
What is the interaction between thiazide diuretics and digitalis?
|
thiazide diuretics lead to the excessive loss of potassium in the urine and can cause hypokalemia this makes the heart more sensitive to digitalis and can make a normal dose of digitalis toxic and cause cardiac block and death
|
|
|
|
What is the interaction between warfarin and phenytoin?
|
warfarin blocks the metabolism of phenytoin at its CYP450 leading to increased phenytoin levels
|
|
|
|
What do barbituates do to CYP450s?
|
they cause an increase in the production of CYP450s by enzyme induction and increase the metabolism of many drugs
|
|
|
|
What are the two types of nicotinic receptors and where are they located?
|
Nn - in autonomic ganglia; Nm - on membranes of skeletal muscles at neuromuscular junctions
|
|
|
|
What are the three types of muscarinic receptors and where are they located?
|
M1 (myenteric plexus); M2 (heart SA node; adrenergic neurons innervating the heart); M3 (pupillary sphincter, ciliary muscle, bronchiolar, GI, uterine, bladder, GI glands)
|
|
|
|
What are the two types of cholinesterases and where are they found?
|
Acetylcholinesterase (NM junction, cholinergic synapse; RBCs); Butyrylcholinesterase (plasma, glial cells, liver)
|
|
|
|
What does inhibition of cholinesterases cause?
|
increased Ach at all cholinergic synapses resulting in agonism of: muscarinic actions at autonomic effector targets and CNS; nicotinic actions at autonomic ganglia and motor end plates (these are very toxic bc of the wide spread effects)
|
|
|
|
What are the symptoms of irreversible cholinesterase inhibitors?
|
Salivation, Lacrimation; Urination; Diaphoresis (sweating); Gastrointestinal motility; Emesis (SLUDGE)
|
|
|
|
What is the treatment of severe organophosphate poisoning (irreversible cholinesterase inhibitors)?
|
1. artificial respiration; 2. suction of tracheal secretions; 3. anti-muscarinic agent (atropine); 4. reactivation of acetylcholinesterase with Pralidoxime Chloride (2-PAM)
|
|
|
|
What are the symptoms of atropine poisoning?
|
dry mouth, difficulty swallowing, flushed, mydriasis, blurred vision, tachycardia, high BP, hallucinations, psychosis
|
|
|
|
What is the treatment of atropine poisoning?
|
1. gastric lavage; 2. maintenance of circulation and resp; 3. lower body temp; 4. catherization; 5. mitotics; 6. barbituates for sedation;
|
|
|
|
What are the common routes of ocular pharmacological administration?
|
Topical; subconjuctival, retrobulbar; intraocular; intravitreal; oral; intravenous
|
|
|
|
What type of sympathetic/parasympathetic receptors are on the corneal epithelium of the eye?
|
β2 and M
|
|
|
|
What type of sympathetic/parasympathetic receptors are on the corneal endothelium of the eye?
|
β2 and undefined
|
|
|
|
What type of sympathetic/parasympathetic receptors are on the iris radial muscle of the eye?
|
α1 (dilation)
|
|
|
|
What type of sympathetic/parasympathetic receptors are on the iris sphincter of the eye?
|
M3 (miosis)
|
|
|
|
What type of sympathetic/parasympathetic receptors are on the trabecular meshwork of the eye?
|
β2
|
|
|
|
What type of sympathetic/parasympathetic receptors are on the ciliary epithelium of the eye?
|
α2/β2 (aqueous production)
|
|
|
|
What type of sympathetic/parasympathetic receptors are on the ciliary muscle of the eye?
|
β2 (relaxation); M3 (accommodation)
|
|
|
|
What type of sympathetic/parasympathetic receptors are on the lacrimal gland of the eye?
|
α1 (secretion); M2, M3 (secretion)
|
|
|
|
What type of sympathetic/parasympathetic receptors are on the retinal pigment epithelium of the eye?
|
α1/β2 (water transport)
|
|
|
|
Non-selective β-blockers
|
Propanolol; Nadolol; Timolol
|
|
|
|
Cardio selective β1 blockers
|
Metoprolol; Atenolol; Esmolol
|
|
|
|
Partial Agonist β-blocker
|
Pindolol
|
|
|
|
Non-selective α-blockers
|
Phenoxybenzamine (non-competititve); Phentolamine (competitive)
|
|
|
|
Selective α1 blockers
|
Prazosin; Doxazosin; Terazosin;
|
|
|
|
Non-selective β-agonist
|
Isoproterenol
|
|
|
|
Direct Sympathomimetics
|
Epinephrine (α1, α2, β1, β2); Norepinephrine (α1, α2, β1); Dopamine (α1, α2, β1)
|
|
|
|
β1- agonist
|
Dobutamine
|
|
|
|
Selective β2 Agonists
|
Albuterol; Turbutaline
|
|
|
|
Selective α1 Agonist
|
Phenylephrine
|
|
|
|
Selective α2 Agonist
|
Clonidine
|
|
|
|
Indirect acting Sympathomimetics
|
Amphetamine, Methamphetamine; Methylphenidate; Ephedrine; Pseudoephedrine
|
|
|
|
Nicotinic Agonists
|
Nicotine; Succinylcholine
|
|
|
|
Non-selective Cholinergic Agonists
|
Acetylcholine, Carbachol
|
|
|
|
Muscarinic Agonists
|
Methacholine; Bethanechol; Muscarine; Pilocarpine
|
|
|
|
Reversible Cholinesterase Inhibitors
|
Physostigmine; Neostigmine; Edrophonium; Tacrine; Galatamine; Rivastigmine
|
|
|
|
Irreversible Cholinesterase Inhibitor
|
Echothiophate
|
|
|
|
Acetylcholinesterase reactivator
|
Pralidoxime
|
|
|
|
Muscarinic Antagonists
|
Scopolamine; Atropine; Glycopyrrolate
|
|
|
|
What is the order from fastest to slowest route of elimination: organ/mechanism?
|
Plasma cholinesterase; Liver; Kidney
|
|
|
|
What is the order of muscles first affected by non-depolarizing drugs?
|
small muscles first (extraocular, hands, feet, head, neck) followed by larger muscles of limb and trunk (abdomen, extremities, diaphragm); recovery is in the reverse
|
|
