Flashcards in Unit 1 Exam Deck (52):
What are the components of a dosage regimen or prescription?
-Component of absorption
=how much of the dose of the drug reaches its target in the body
Time to Peak Effect (Tmax or Cmax)
-Component of absorption
=how fast does the drug reach its target in the body
-duration of action
=how long the drug will stay at its target in the body
Side effects vs Extension effects
-Side effects: adverse reaction of drug at non-target system that is seen at therapeutic doses
-Extension effects: adverse reaction of drug at target system that is seen at higher-than-therapeutic doses
adverse reaction that is not a drug target and peculiar to an individual such as immunologic (allergic reactions) or metabolic (hepatotoxicity or blood dyscrasias)
What are the legal components of a prescription written in Colorado?
Identity of Prescriber
the symbol Rx
Drug name and strength
Direction to patient
Pharmaceutical Equivalents vs Bioequivalents vs Therapeutic Equivalents
-Pharmaceutical Equivalents: same active ingredients, same dosage information, same route administration, identical in strength of concentration
-Bioequivalents: pharmaceutical equivalents that display comparable bioavailability when studied under similar experimental conditions
-Therapeutic Equivalents: pharmaceutical equivalents given in same dosage regimen provide same efficacy with same safety which is very expensive to test for and not required by the FDA for generic drugs
What is the Controlled Substances Act?
Controlled substances have potential for abuse and are divided into 5 schedules. The DEA oversees control of manufacture and distribution of these drugs
What are the five schedules of controlled substances?
1. High abuse and dependence risk. No medical use. Cannot prescribe.
2. High abuse potential and dependence risk. Has medical use. Can prescribe, but cannot be refilled or telephoned in.
3. Moderate abuse potential. and dependence risk. Has medical use. Can prescribe, can be refilled up to 5x in 6 months, and can be telephoned to a pharmacist.
4. Low abuse potential and low dependence risk. Has medical use. Can prescribe, can be refilled up to 5x in 6 months, and can be telephoned to a pharmacist.
5. Limited abuse potential. Lowest dependence risk. Has medical use. Can prescribe, can be refilled up to 5x in 6 months, and can be telephoned to a pharmacist.
What levels of government regulate the prescription writing process?
1. Feds = what may be prescribed and who may prescribe controlled substances
2. States = who may prescribe (other than controlled substances)
3. Where laws or regulations differ, it is assumed that strictest laws will apply.
What are the phases of the new drug approval process?
1. In vitro studies
2. Animal Testing
3. Phase 1 Clinical Testing (usually has 20-100 patients. Done in healthy people. Answers if it is safe)
4. Phase 2 Clinical Testing (usually has 100-300 patients. Done in people with disease. Answers if it works in patients)
5. Phase 3 Clinical Testing (Usually has 1000-3000 patients. Answers if it works double blind.)
*Can get New Drug Application Approved
6. Phase 4 Clinical Testing (postmarketing surveillance)
*After 20 years patent expires and generic options can become available
FDA regulation of prescription drugs vs dietary supplements
-Drugs = tested for safety and efficacy
-Dietary Supplements = are not, manufacturers just have to say it is "reasonable" safe
-FDA can remove dietary supplements if deemed unsafe, but happens rarely because it is expensive and time consuming. Usually the FTC actually pulls the dietary supplement for making misleading claims.
-Dietary supplements cannot make health claims such as reducing risk of disease, but can make functional claims instead
Evaluate the routes of drug administration in regards to bioavailability and rate of onset effect.
1. Bioavailability: 100% in IV by definition. For other routes bioavailability approaches 100%. For oral administration it can vary between 0 and 100%. Oral bioavailability depends on it surviving the GI tract and crossing the membrane. For oral routes absorption is increased with liquid preparation or rapidly disintegrating tablets and decreased with enteric coats or sustained release preparations.
2. Rate of onset effect is determined primarily by route rather than drug characteristics for soluble formulations (IV=inhalation > IM > SC > oral). Rate of absorption is generally only of clinical importance for the first dose.
Oral drugs are subject to first-pass effect which basically says that the drug will be subject to hepatic metabolism prior to entry into systemic circulation
What are the factors that determine a drugs ability to cross biological membranes?
1. Molecular size: smaller is better. Can't be bound to protein.
2. Lipid solubility: better if higher lipid solubility
3. Degree of ionization: better for unionized form of drug (not charged). Affected by tissue pH.
4. Concentration gradient: move from high to low concentration.
How does pH influence the ionization of weak acid/weak base drugs?
-Weak Acid: R-COOH <> R-COO- + H+
-Weak Base: R-NH4+ <> R-NH3 + H+
-If drug placed in pH lower than pKa will shift to the left. If drug places in pH higher than pKa will shift to the right.
-The unionized (uncharged) form can move through lipid membranes better.
pH = pKa + log([A-]/[HA])
What are the therapeutic consequences of the GI mucosa, blood-brain-barrier, and renal tubule cells?
These are all sites with right barriers that can limit the movement of certain drugs by requiring the drugs to pass through the cells instead of between them
Rate of distribution is rarely of clinical consequence. Really only important when giving the first dose of an IV drug because you are dumping all of it into the plasma compartment at one time. This can lead to having a concentration 4x the therapeutic target in the plasma which can cause toxicity until the drug distributes through the body and leaves the plasma to go to its target or to be eliminated. In order to avoid bolus toxicity you can either run the IV on a drip over time or push the drug 4 different times over a period of time.
Volume of Distribution
-Essentially a dilution factor
-It is an apparent volume that represents the relationship between the dose of a drug and the resulting plasma concentration (Cp)
-The distribution can be homogeneous throughout the body or concentrate in specific areas
Maintenance Dose vs Loading Dose
-MD/Tau = Cpss x CL
-LD = Cp x Vd
What are the general principles of drug metabolism?
-Drugs undergo enzyme-catalyzed chemical structure transformation after administration to the patient
-Liver is the primary site, but it can also occur in lungs, intestines, kidney, skin, placenta, and bacteria in gut.
-Oxidation is the most common pathway, but other types of chemical transformation can occur.
-Lipid-soluble compounds are generally converted to more polar compounds that are more readily excreted
-Generally metabolism is detoxifying process, but can also metabolize active drug into more active compound such as codeine to morphine
Phase I and Phase II metabolism reactions
1. Phase 1: inserts or unmasks a functional group on the drug that render molecule more water-soluble and the molecule can then undergo conjugation in Phase II reaction
2. Phase II: endogenous substrate combines with pre-existing metabolically inserted functional group on the drug forming a highly polar conjugate that is excreted via the urine
What types of reaction are involved in Phase I reactions and what enzymes are used?
1. Oxidation - P450 dependent or P450 independent (most common); Enzymes = NADPH, flavoprotein NADPH-cytochrome P450 reductase, and O2
2. Reductions (azo, nitro, carbonyl reductions); Enzymes = reductase
3. Hydrolysis; Enzymes = esterases or amidases
What types of reactions are involved in Phase II reactions and what enzymes are used?
3. Glutathione conjugation
4. Sulfate conjugation
Enzymes are all transferases (ie glucuronyl transferases, N-acetyltransferases)
Are Phase I or Phase II reactions more susceptible to inhibition/induction?
Are Phase I or Phase II reactions more likely to be saturated at high drug substrate levels?
Phase II - due to limited supply of reactants
Induction vs Inhibition
-Induction: increased drug metabolizing activity (increased clearance) via stimulation of the CYP450 system. Requires 48-72 hours to see onset of effect (relatively slow).
-Inhibition: decrease clearance of drug by inhibiting drug metabolizing activity typically in Phase I. Inhibition can occur as soon as sufficient hepatic concentration is reached (within hours).
Common examples of inducers
St. John's Wort
Common examples of inhibitors
HIV protease inhibitors
Describe how the kidneys excrete drugs
Excretion = loss of chemically unchanged drug from the body. Kidneys are the most important organ for excretion
1. Filtration: glomerular rate of 120ml/min, all drugs smaller than albumin will be filtered, only free drug is filtered (not protein bound), renal excretion affected by renal blood flow and renal function
2. Secretion: active tubule secretion, drugs transported from blood to urine at a rate of 120-600 ml/min, occurs with drugs that are stronger acids and bases via secretory mechanisms that are saturable, plasma protein binding does not appreciable affect rate of secretion, poorly developed process in neonates
3. Reabsorption: drugs that are lipid-soluble and uncharged would be cleared at rate of urine formation (1ml/min) but this is counteracted by drug metabolism making them more water soluble and less likely to be reabsorbed
-Drug metabolites in the liver are secreted into bile, stored in gallbladder, delivered to intestine via bile duct, hydrolyzed by bacterial enzymes back to the parent drug that is more lipid soluble, and undergo reabsorption from the gut
-Lengthens half-life of the drug, but some drug is still excreted through feces each time
-Clearance: the volume of plasma which is completely cleared of drug in a give period of time by the processes of kidney excretion and liver drug metabolism
-CL = Vd x Ke (Ke = fraction of drug eliminated per unit of time)
-Heaptic Clearance: for low extraction drug (metabolism not efficient) changes in blood flow do not significantly influence clearance. But for high extraction drugs, changes in blood flow will have a major influence on clearance.
-Renal Clearance: changes in renal function will alter clearance. Will necessitate dose changes to prevent accumulation aka "renal dosing."
Details about half-life
1. Time it takes for drug to be essentially eliminated or to reach steady state when drug is administered in 4-5 half-lives
-Half-life is dependent on both CL and Vd
-t1/2 = 0.693/Ke
Degree of Fluctuation
Degree of fluctuation between doses = 2^n, where n = # of half-lives in dosage interval (tau/half-life)
Zero Order Kinetics
-Process in which the rate of elimination of drug from the body is independent of the amount of drug in the body.
-The amount of drug removed per unit time is constant
-Most often occurs due to saturation of hepativ metabolic enzymes systems
-Enzyme saturation only occurs at therapeutic levels for a few drugs (aspirin, phenytoin, EtOH)
-These drugs don't have half-lives
First Order Kinetics
-Virtually all drugs are eliminated by first order kinetics
-Rate of elimination (mg/hr) is proportional to the concentration of drug in the plasma (mg/L)
-As drug is eliminated from the body, its concentration is constantly changing, therefore rate of elimination also changes constantly
Describe the features of a dose response curve
-Dose response curves are generated by giving increasing doses of drug and measuring the specified response to each dose
-Hyperbolic in shape
-Y-axis = efficacy (Emax)
-X-axis = ED50 = 1/potency
Describe the advantages of the log dose-response curve versus the dose-response curve.
An advantage of the log dose-response is that it allows for a wide range of doses to be plotted allowing easy comparison of different drugs
Potency on Log Dose-Response Curve
Potency: concentration (ED50) required to produce 50% of that drug's individual maximal effect. Provides information on how much drug will be required to produce a given effect.
Efficacy on Log Dose-Response Curve
Maximal effect or maximal efficacy (Emax): limit of the dose-response relationship on the y-axis, indicates the relationship between binding to the receptor and the ability to initiate a response. Most important determinant of drugs clinical utility.
Agonist = drug that activates its receptor upon binding and brings about the characteristic tissue response
1. Partial Agonist: occupy the same receptor as full agonist, but brings about less than maximum response even at full dosage levels. Will have lower Emax.
2. Full Agonist: occupy receptors and bring about a full or maximal response.
Antagonist = a drug that inhibits the action of an agonist, but has no effect in the absence of an agonist.
1. Competitive Reversible Antagonist: binds to same site as agonist thus blocking the agonist. Since it is reversible can add more agonist to out compete it. Emax of agonist unchanged. Potency of agonist decreased.
2. Noncompetitive Irreversible Antagonist: binds covalently at the active site blocking the agonist and limiting the number of receptors available. Emax reduced.
3. Noncompetitive Allosteric Antagonist: binds to different site on the receptor than agonist, but inhibits receptor from responding to agonist. Decreases Emax. May also shift curve to the right (decrease in apparent potency) is spare receptors are available.
1. Physiological: activates or blocks a different distinct receptor that mediates a physiological response that is opposite to that of activation of the receptor for agonist. Ex. epinephrine is a physiological antagonist of histamine.
2. Chemical: does not involve receptor binding, antagonism occurs via inactivation of agonist itself by modifying it or sequestering it so it is no longer capable of binding to and activating the receptor. Ex. protamine is a chemical antagonist of heparin.
Dose Response Curve vs. Quantal Curves
-Dose-response curve: a number of increasing doses of a drug are given to the same subject and the increase in response for each dose is measured allowing for determination of the maximal effect of the drug.
-Quantal (Population Dose-Response Curve): characterize pharmacologic responses that are all-or-nothing events (not graded) in a population of subjects, generated arbitrarily by defining some specific therapeutic effect and then determining the minimum dose to produce this response in each member of the population. These are used to determine the therapeutic index and standard safety margin.
Therapeutic Index and Standard Safety Margin
-Therapeutic Index: compares midpoint in the population (ED50 and LD50). ED50 being the midpoint for the therapeutic effect and LD50 being the midpoint for the lethal effect. TI = LD50/ED50. The higher the TI, the safer the drug, clinically used drugs are >10-20.
-Standard Safety Margin: looks at the extremes in the population (ED50 and LD1). SSM = [(LD1/ED99)-1] x 100. More conservative measure than TI, more reliable if patient response to therapy of specific drug varies, takes into account the extremes, SSM can be negative.
What interventions are available prevent absorption of a poison?
1. Emesis. Can use drug such as Ipecac to stimulate this, but not commonly done.
2. Gastric Lavage. Most rapid and complete way to empty the stomach, but still only empties 30% of oral poisons. Best within 60 min of ingestion.
3. Charcoal. binds drug in gut to limit absorption. Effective, but difficult to administer and poorly accepted in children.
4. Osmotic Cathartics. Can give drug like Sorbitol which acts as an osmotic laxative to decrease time of toxin in GI tract. Indicated if toxin ingested less than 60 min prior.
What interventions are available to enhance elimination of a toxin?
1. Extracorporeal Removal such as hemodialysis. Has lots of complications and patient must really need this.
2. Enhanced Metabolism such as induction of cytochrome P450 metabolism is not realistic because it takes to long, but could also inhibit metabolism to block formation of toxic metabolites such as in methanol toxicity.
3. Enhance renal excretion. Can do forced diuresis or alkanize urine to flush toxins out more quickly. Previously popular, but unproven value.
4. Chelation of heavy metals. Combines aspects of enhancing elimination of the toxin and inactivating the toxin.
Describe the mechanism of acetaminophen overdose toxicity and its treatment.
-Acetaminophen is primarily metabolized through phase II reaction (glucuronic acid or sulfate) which becomes overloaded quickly. This causes more acetaminophen to be metabolized by a phase I reaction involving CYP2E1 which produces a toxic metabolite (Ac).
-Ac metabolite build-up leads to hepatocellular injury which progresses over multiple days.
-Treatment: activated charcoal and gastric lavage to remove residual drug within 4 hours. Supportive therapy as needed. Primarily focus on increasing detoxication through the use of N-acetylcysteine. N-acetylcysteine recommended within 12-36 hours of ingestion as this drug is thought to serve as a precursor for glutathione synthesis.
Describe methanol and ethylene toxicities and their treatment.
-Methanol and ethylene glycol are well absorbed orally and are not toxic until they are metabolized by alcohol dehydrogenase in the liver.
-Methanol is metbolized to formaldehyde formic acid and causes severe acidosis and retinal damage.
-Ethylene glycol is metabolized to oxalic acid and causes acidosis and nephrotoxicity,
-Primary treatment method focuses on inhibiting toxication. Ethanol (or Fomepizole) can be given as a competitive inhibitor of alcohol dehydrogenase to saturate the enzyme and limit the toxicity.