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80 Cards in this Set
- Front
- Back
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Define Drug Selectivity
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Ability to affect one tissue, cell type, organ
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What does drug selectivity depend on?
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"DDRR"
Dose, Distribution (of drug), Receptor Distribution, Receptor Selectivity |
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Chemical Chirality (enantiomer) Influences
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Pharmaceutical Action, Toxicity, Metabolism of Drugs
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Define Partial Agonist
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Bind receptor but have only partial efficacy at receptor relative to full agonist
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Physiological Antagonist
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2 drugs produce opposite effects through dif. receptor systems. ex. = 2 drugs that have opposing effects on blood pressure.
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Chemical Antagonist
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Doesn't require a receptor. Chemical interaction of 2 substances
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Kd
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Drug affinity to receptor = how well it binds. The lower the better
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Pharmacological Antagonist: Competitive
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Higher agonist concentration can out-compete antagonist concentration because binding occurs at same site.
Can be Reversible (overcome by increasing amts. of agonist conc.) or Irreversible (cannot be overcome, body must make new receptors) |
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What is the most likely culprit in a drug overdose?
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competitive, irreversible pharmacological antagonist
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Pharmacological Antagonist: Non-Competitive
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Independent of dose and affinity of agonist.
Eliminates available receptors Take away the drug and the effect is reversed. |
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Potency
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Amt. of drug needed to make a given intensity of effect
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Affinity
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Drug: Receptor Tightness.
High = binds well Low = Ligand doesn't bind well and may not activate receptor |
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Intrinsic Activity is the same as what?
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Receptor Efficacy. Emax = extent to which bound ligand activates receptor. High Intrinsic Activity (IA) = Ligand produces large effect, Low IA = Ligand produces small effect.
NOTE- Antagonist have NO Intrinsic Activity |
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Receptor Specificity
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Lingand binds only one receptor. This creates competition between ligands.
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Receptor Saturability
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Limited binding sites means receptors can become saturated. Excess ligand may cause side effects
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Full Agonist
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Drugs thats bind and produce the full maximum effect (Emax)
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Full Agonist will be where on a dose-response curve?
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It will have the highest line
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Partial Agonist will be where on a dose-response curve?
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Partial agonist cannot produce fill intrinsic activity = line will be below Emax.
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Potency
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Amt. of drug needed to produce a given effect.
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How can you tell if a drug is more potent?
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1. More left of a dose-response curve
2. Smaller EC50 or Kd 3. High Affinity of receptor for drug 4. High Intrinsic Activity More potent = smaller dose needed |
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Law of mass Action
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Magnitude of drug effect is directly proportional to the number of occupied receptors (Potency related to affinity)
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EC50
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Dose concentration of a drug that produces 50% of a max effect
EC50 = Kd |
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Clinical Efficacy Depends on:
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1. Receptor-Efficacy (ability to reach Emax)
2. Drug's ability to reach relevant receptors (route, absorption, distribution, clearance) |
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Effect of a Pharmacological Antagonist: Competitive?
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Shifts curve to the right, decreasing potency (=more agonist conc. requires to achieve same effect)
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Effect of a Pharmacological Antagonist: Non-Competitive?
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Reduces Efficacy (Emax) that will go away over time.
Potency can also be decreased, so curve can shift to the right. |
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effect on a dose-response curve by Pharmacological Antagonist: Irreversible?
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EC50 and Kd stay the SAME
Emax Decreases with increasing irreversible non-competitive inhibitor |
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A 100mg tablet has 30% bioavailabilty due to the first pass effect. How much of the tablet makes it into the systemic circulation?
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30mg
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First pass drugs have a high what?
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Extraction Ratio
ER = Ci-Co/Ci |
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Process by which most drugs cross membranes?
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passive diffusion
Must have high lipid solubility and dissolve...inc. lipid solubility = inc. diffusion Must be NON-IONIZED to cross membrane |
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whats the partition coefficient?
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For passive drug diffusion. Dependent on solubility. RATIO of drug in lipid vs. water phase
Controlled by altering chemical side groups |
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HIGHER PC (partition coefficient) means what?
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its more lipid soluble = the faster it will traverse lipid membranes = the greater the portion of it thats already in the lipid phase
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Ionization has what effect on drugs?
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the Greater the ionization, the slower it can pass through membranes due to increased polarity
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Whats the effect of pH on ionization?
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Low pH = lots of H+ = ACIDIC = weak BASE ionized
High pH = lots of -OH floating around = BASIC = weak ACID ionized |
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Where are weak basic drugs absorbed the best?
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Weak bases are highly ionized in acidic pH = they are better absorbed where its basic, like the duodenum, over the stomach (acidic)
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Where is P-Glycoprotein (MDR1) Found?
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1. Intestinal Cells (with CYP3A4)
2. Hepatocyte mem. 3. Renal Proximal Tubular Cell 4. Brain Endothelial Cell |
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What is P-Glycoprotein (MDR1)?
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ABC trasporter that works in conjunction with liver after it makes drugs more ionized and aqueous
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Chemically Equivalent
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Same of amount of active ingredient but differs in bioavailability = it will yield a dif. amount of plasma conc. of active ingredient over time.
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Bioequivalent
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Rate and extent of absorption of a drug is not significantly different
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Bioequivalent Generic Drugs
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Do not have to go through all the same testing because they are not significantly different in terms of rate and extent of absorption.
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Parameters measured in bioavailability studies?
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1. Minimal Effective Conc. (MEC)
2. Minimal Toxic Conc. (MTC) 3. Peak conc. (C-Max) *Want this to be between MEC and MTC Half life also taken into consideration |
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How does plasma protein binding affect drug distribution?
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It will slow the rate at which the drug can cross the membrane...move out of the capillaries or be excreted by the kidneys
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What are the plasma proteins involved in drug binding?
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1. Albumin (prefers ACIDIC drugs)
2. Alpha 1-Acid Glycoprotein (AGG) (prefers BASIC drugs) |
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Is binding irreversible or reversible for the plasma proteins that bind drugs?
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reversible
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How would an increase in AGG (Alpha 1-Acid Glycoprotein) affect drug distribution?
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Decreased drug intensity and prolonged drug duration
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What is plasma protein binding's affect on Vd?
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Free and bound drug are not distinguishable in Vd.
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How would hypoalbuminemia affect drug action?
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intensity and duration altered. NOTE - Albumin decreases with age. (Increased drug intensity and decreased drug duration)
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When are binding interactions clinically significant?
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1. when >90% of drug is bound
2. Drug has a low TI 3. Drug has low hepatic extraction 4. Drug is given IV |
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Define Redistribution
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Because some drugs perfuse tissues more rapidly than others, a drug from a rapidly perfused tissue may be redistributed to a tissue with a slow perfusion rate. ex = thiopental
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Define First Order
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What most drugs follow.
Elimination rate dependent on drug concentration A Constant Fraction is eliminated per unit time (unlike zero order, in which a constant amt. is eliminated per unit time) |
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Define Zero Order
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Rare for drugs to follow this, but some examples are aspirin and ethanol
Elimination independent of drug conc. Constant amt. eliminated per unit time (unlike first order, where a constant fraction is eliminated per unit time) |
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Define Dose-Dependent Kinetics. What are the clinical implications?
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Kinetics change from first order to second order as the process becomes saturated.
Once enzymes are saturated, adding more of the drug produces disproportionate effect, leading to potential toxicity |
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Define Clearance
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Volume of blood "cleared" of drug my metabolism and/or excretion per unit time.Units = mL/min.
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Define Loading Dose
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Used when there is a need to obtain effective drug concentrations quickly.
Follow initial dose, and then administer maintenance doses |
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Define Therapeutic Window
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Range of plasma concentrations between minimal effective concentration and minimal toxic concentration
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Define Therapeutic Drug Monitoring
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Monitor blood concentration to ensure a drug's safety and effectiveness
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What is the usefulness of TDM; Therapeutic Drug Monitoring?
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1. Ensures therapeutic effects and avoids toxicity for narrow therapeutic window drugs
2. Helps individualize drug therapy 3. Evaluates patient compliance 4. Avoids Irreversible toxicities that develop only after long exposure to toxic levels 5. Evaluates changes in drug effectiveness due to elimination process changes 6. Useful for drugs lacking a clearly defined clinical end point |
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When might a Serum Drug Assay be Requested?
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1. Therapeutic confirmation
2. Suspected toxicity 3. Absence of therapeutic response 4. Drug Overdose 5. Poor dose-response correlation 6. Monitor active metabolites 7. Altered pharmacokinetics 8. Suspected Drug Interactions |
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Explain the relationship between half life (t1/2) and duration of effect
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Half life = time it takes for drug dose to decrease by 50%.
Duration of Effect could extend beyond point at which drug dose has decreased by 50% (its half life) A Larger half life will lead to an increased duration of effect as there is a greater conc. of drug in plasma for a longer period of time |
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Define Drug-Drug Interaction
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One drug can influence another's effect
Could be lethal, or can cause a loss of effect |
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Differentiate between Pkarmacokinetic and Pharmacodynamic drug-drug interactions
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Pharmacokinetic = Indirect = one drug produces an effect, and the second drug will act either as an inducer or inhibitor
Pharmacodynamic = Direct = Both Drugs have an effect and the overall effect is the sum of the effects. |
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What's the difference between Pharmacokinetic and Pharmacodynamic Genetic Polymorphisms?
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Pharmacokinetic = Kinetic Changes Lower Drug conc. at receptor site
VS. Pharmacodynamic Genetic Polymorphism = Decreased effect due to changes in receptor or post-receptor events ("pharmacoDYNAMICS = DEEPER mechanism of action) |
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Basis for Pharmacokinetic and Pharmacodynamic genetic polymorphisms?
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In some individuals, genetic polymorphisms cause different enzymes to be produced = effects of drug in these people are different.
Genetic Polymorphism of enzyme may decrease our ability to metabolize drug so it accumulates and causes toxicity |
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How can we ID pharmacokinetic or pharmacodynamic genetic polymorphisms in a patient population?
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Most drugs follow a unimodal curve. If we see a Bi-modal or Tri-modal curve, that means the drug characteristic may be being altered by a certain type of genes (genetic polymorphism) that part of the population has.
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What are some non-genetic factors that may impact drug response in patients?
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Drug-Drug interactions
Drug Allergy Tolerance Age, Weight, Sex Disease Route of Administration |
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Describe the different reactions patients can have to Succinylcholine
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Succinylcholine is used for temporary muscle blockage/relaxation. Normal Duration = minutes, however patients with mutations in the cholinesterase enzyme may see succinylcholine last HOURS (prolonged muscle relaxation and apnea)
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Describe the different reactions patients can have to Isoniazid
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N-acetyl Transferase mutations will decrease the ability to metabolize drug = toxicity due to accumulation. Differences in half life and plasma conc. are shown.
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What are the requirements for a drug allergy to occur?
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Sensitization and re-exposure
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Define Drug Tolerance
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A state of progressively decreasing responsiveness to a drug. A larger dose is required in order to achieve the same intensity or effect
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How is the drug dose-response different from the allergic-dose response in patients?
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There is no correlation between dose-response and allergic-dose response, because allergic dose response is an immunologic response and not simply a pharmacological response
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How does pharmacokinetic drug tolerance differ from pharmacodynamic drug tolerance?
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Pharmacokinetic = metabolic in nature = liver produces extra enzymes and metabolizes/eliminates drug faster
Pharmacodynamic = cellular-adaptive in nature = receptors adapt sensitivity or increase/decrease number of receptors |
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Define Additive Drug-Drug interactions
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Summative. Two drugs of similar properties and acting via same mechanism show exponential inc. in clinical effects when given together = effect of both is equal to sum of both effects
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Define Synergistic drug-drug interactions
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Joint effect of two drugs is greater than the sum of their individual effects. Act at different sites and one drug increases the effect of the other drug by changing its biotransformation, distribution, or excretion
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Define Potentiation drug-drug interactions
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A special case of synergism. When one of the drugs given has no clinical effect; typically, it inhibits a process that allows the other drug to produce a greater effect.
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Define Antagonistic drug-drug interactions
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When two drugs of similar properties show lessened or no clinical effect when given together
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Define Therapeutic Index
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An indication of how far from each other the therapeutic and lethal curves are from one another.
TI = LD50/ED50 |
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Define Margin of Safety
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The range of doses that produce the desired effect but do not kill a patient.
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Define Certain Safety Factor
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Certain Safety Factor = a ratio of the minimal dose that is lethal to 1% of the population to the minimal effective dose in 99% of the population
CSF = LD1/ED99 |
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Whats the difference between Therapeutic Index (TI) and Certain Safety Factor (CSF)
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TI = LD50/ED50
CSF = LD1/ED99 CSF = MUCH MORE STRINGENT THAN TI in determining drug safety |
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How predictable is the safety of a drug from the Therapeutic Index?
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Drugs with High TI are generally safe to use. CSF is a much more stringent examination of the safety of a drug.
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List Factors which cause biological variation with respect to drug effects
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Rate of drug absorption, rate of drug distribution throughout body, rate of clearance of drug, variance in the conc. of endogenous receptor ligand producing competition of the site, differences in the number of receptor sites, or in the function of their receptors due to the efficiency of receptor-effector coupling (drug-induced down regulation), variance in functional integrity of the biomechanical processes in the responding cell and physiologic regulation by interacting organ systems (age of pt., general health of pt.)
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