Exam 3 Learning Objectives

Question 1

Identify the portions of a concentration versus time curve that are associated with onset, duration, and intensity of
pharmacologic effect.

Answer 1

Peak: Intensity
Onset: Y-intercept
Duration: Y-Intercept to where line reaches MEC.

In-depth: For a drug whose pharmacologic effects aredirect and reversible, the onset occurs when the drug reaches the minimally effective
concentration, the duration lasts as long as the drug remains above the minimally effective concentration, and the intensity of effect is determined by the maximal concentration of drug achieved and when that maximum concentration is achieved.

Question 2

Provided a route of administration, identify barriers that may reduce the amount of drug that reaches the site of
action.

Answer 2

There are many barriers between the site of drug administration and the site of pharmacologic effect. These barriers can reduce the amount of drug that reaches the site of action, as well as the speed with which it reaches the site. These barriers include membranes that limit the movement of drug into certain tissues, as well as enzymes within
membranes that can metabolize the parent drug.

Also, tissue barriers, like the BBB, significantly reduce the amount of drug that enters the brain and the site of action. Drugs molecules can be designed to reduce the amount that enters the brain and reduce the frequency of adverse effects.

Question 3

Define disposition, pharmacokinetics and
pharmacodynamics.

Answer 3

Disposition: The fate of a drug when it enters the systemic circulation.

Pharmacokinetics: The study of absorption, biotransformation, and elimination of xenobiotics.

Pharmacodynamics: The study of the molecular, biochemical, and physiological effects of xenobiotics and their mechanisms of action.

Question 4

What is a xenobiotic?

Answer 4

A chemical that is normally foreign to the body, including drugs, occupational chemicals, and environmental compounds.

Question 5

Identify what percent of drugs currently fail in clinical trials due to problems with ADME.

Answer 5

In the past, about 40% of the attrition of new drug development was due to problems with the ADME characteristics of a drug. Due to improved preclinical ADME assessment, today,less than 10% of attrition in clinical trials of drugs is due to ADME.

Question 6

Identify the primary routes of administration.

Answer 6

Major Routes
1. Renal (urine)–> primary method
2. Biliary (feces)

Other Routes
1. Pulmonary (lungs)–> think alcohol
2. Salivary
3. Mammary (drug comes out of breast milk)

Question 7

Describe the four potential consequences of drug
metabolism (biotransformation) as it relates to pharmacologic activity.

Answer 7

Overview: The consequences of drug metabolism depend on whether the parent drug and/or metabolite are pharmacologically active. Thus, if the parent drug is active and the metabolite is inactive, co-administration of an inhibitor of the metabolism of the parent drug will prolong the pharmacological effect. On the other hand, if it is the metabolite that
is active, giving an inhibitor of the metabolism of the parent drug will decrease the pharmacologic effect.

Four Consequences:
1. Active drug–> Inactive metabolite
2. Active drug–> active metabolite
3. Inactive drug–> active metabolite
4. Active drug–> reactive metabolite

Question 8

Name the factors that determine drug absorption across a membrane.

Answer 8

1. Characteristics of the membrane
2. Mechanisms of passage across the membrane
3. Dwell time of the drug-membrane interface
4. Physiochemical characteristics of the drug-membrane interface
5. pH of the microenvironment
6. Surface area of the absorptive surface

Question 9

Identify the site in the GI tract where most drug absorption occurs.

Answer 9

The small intestine

Question 10

Describe the mechanisms by which drugs cross biological
membranes.

Answer 10

• Transcellular Transport
• Paracellular Transport
• Facilitated Diffusion
• Carrier-mediated Transport
• Phagocytosis or Endocytosis

Question 11

Differentiate the two forms of carrier-mediated absorption, facilitated diffusion and active transport.

Answer 11

Facilitated diffusion: a carrier mediated process that involves a transport protein which moves drug WITH a concentration gradient.

Active transport: A carrier-mediated process that requires energy that can move a drug AGAINST a concentration gradient.

Question 12

Describe the impact of efflux transporters on drug absorption from the small intestine.

Answer 12

Efflux transporters, like p-glycoprotein, can efficiently remove drugs from cells that have entered via passive diffusion. This can markedly reduce the amount of drug that accumulates in certain tissues, like the brain.

Question 13

Identify the mechanism by which nanoparticles cross
biological membranes.

Answer 13

Nanoparticles can only cross biological membranes via endocytosis.

Question 14

Describe the effect of drug distribution on the concentration versus time curve.

Answer 14

If a drug readily crosses membranes and is widely distributed throughout the body, differences in tissue perfusion rate results in different time courses for drug in tissues. Overall, for time vs concentration curves the intensity may be offset to the right, if the drug is taking longer to distribute and reach MEC.

Question 15

Differentiate between perfusion rate limited and permeability rate limited distribution of drug into tissues.

Answer 15

Perfusion Rate Limited
* A drug that exhibits perfusion rate limited distribution is a compound that readily penetrates endothelial membranes so that the delivery rate of the drug to the tissue by perfusing blood is what deterines how quickly drug disappears in tissue.

Permeability Rate Limited
* A drug that exhibits permeability rate limited distribution is a compound that slowly passes across the endothelial membrane. As a consequence, drug is delivered to the site of tisses more quicly than the drug moves from blood into tissue.

Question 16

Differentiate between transvascular movement via convection versus diffusion.

Answer 16

Transvascular transport: The movement of drug molecules across vascular endothelial cells into the tissue interstitual space.

Convection: A transvascular transport process driven by a concentration gradient.

Overall:
Pressure serves as the driving force for convection, which is the means of transvascular transport for large molecules, such as monoclonal antibodies. Most drug molecules undergo transvascular transport via diffusion, for which the concentration gradient is the driving force of drug movement.

Question 17

Describe how differences in tissue pH may result in the trapping of ionizable drugs.

Answer 17

Drug trapping can result in significant differences in the drug concentration in tissues compared to blood. The inability of ionized drug to cross membranes can be used to enhance the urinary excretion of drugs by changing urine pH.

Question 18

Describe how plasma protein binding effects distribution and pharmacologic effect.

Answer 18

Drugs are often bound to plasma proteins which limits the distribution of drug into tissues–since only the free drug can cross endothelial membranes. SInce only the free drug can cross from blood to the site of action, and only free drug can bind with drug receptors, free drug is pharmacologically active species. Thus, changes in plasma protein binding can alter pharmacological effect.

Question 19

List 4 mechanisms by which drugs may gain access to the CNS.

Answer 19

1. If a drug is unionized and lipophilic, it gains access to CNS.
2. If exisiting transporters are used, such as glucose or amino acid transporters, drugs may gain access to CNS.
3. If the BBB is disrupted by microwaves, radiation, trauma, hypertension, or infection, the drug may gain access to the CNS.
4. If the drug is directly administered into the CNS via injection into CSF, the drug will gain access to CNS.

Question 20

Given a choice between 2 drug molecules, indicate which would be the best choice to use in a pregnant woman.

Answer 20

It would be best to choose the drug molecule that is most polar beause polar drugs usually do not cross the placenta.

Question 21

Name the primary routes by which drugs are excreted from the body.

Answer 21

The primary routes of drug excretion are renal and hepatic. Secondary routes, such as pulmonary, salivary, and mammary, and quantitatively insignificant but may have a clinical role in assessment of drug exposure.

Question 22

Identify the key processes and anatomical location involved in renal excretion.

Answer 22

The most imporant mechanisms of renal excretion are filtration (glomerulus), active tubular secretion (Proximal Convoluted Tubule), and tubular reabsorption (ascending loop). With rare exception, biotransformation in the liver is quantiatively insignificant.

Question 23

Describe how the physicochemical properties of a drug influence its filtration, secretion, and reabsorption by the kidney.

Answer 23

Glomerular filtration is largely influenced by molecular size and plasma protein binding.

Drugs that undergo tubular secretion exhibit saturation at high concentration and are subject to competitive interactions with other durgs that undergo transport by the same renal transporters.

Since most tubular reabsorption is passive, it is driven by the concentration gradient. Thus, increasing urine flow will decrease reabsorption (resulting in an increase in the amount of drug eliminated in urine) of drugs. The reabsorption of ionizable drugs is also sensitive to changes in urine pH.

WHen carrier-mediated reabsorption occurs, such as with vit C, the process is saturable. As a consequence, increasing the dose will increase the fraction of drug excreted in urine.

Question 24

Plot the relationship between molecular weight and renal clearance.

Answer 24

As molecular weight increases, renal clearance goes down.

Question 25

Plot the relationship between dose and urinary excretion rate for a drug that undergoes filtration only and one eliminated primarily through renal secretion.

Answer 25

Filtration: * As the dose increases, the urinary exretion rate increases. Renal secretion * As the dose increases, there is saturation at higher drug concentration. ATS is carrier mediated, so it is susceptible to competitive absorption.

Question 26

Plot the relationship between molecular weight and percent of drug excreted in bile.

Answer 26

As the molecular weight increases, the more of the dose in the bile.

Question 27

Describe the impact of enterohepatic recirculation on drug half-life in the body.

Answer 27

EHC can lead to a longer half-life for drugs that undergo this process. After being excreted into the bile and then into the intestines, the drug can be reabsorbed, leading to repeated exposure to the systemic circulation. This prolongs the time it takes for the drug concentration in the bloodstream to decrease, effectively extending its half-life.

Question 28

Name the primary organ involved in drug metabolism.

Answer 28

The liver is the primary organ involved iin drug metabolism. * Smooth endoplasmic reticulum of liver cells * High concentration of drug metabolizing enzymes * First organ exposed to compounds that are absorbed in the gut. * Involved in many processes (residence time, dosing frequency, etc) leading to adverse drug effects (may form toxic metabolite).

Question 29

Describe and differentiate the two phases of drug metabolism.

Answer 29

Phase I: Chemical modification (biotransformation) including oxidation, hydroxylation, etc to introduce new functional group or expose a group for Phase II reactions. Phase II: Biotransformation of xenobiotics that involves conjugation with a polar group (sulfate, glucuronic acid) yielding a polar metabolite that can be more readily excreted in the bile or the urine. These pathways are sometimes referred to as conjugation reactions and can be influenced by the availabilty of the co-substrate (e.g. sulfate or activated sulfate).

Question 30

Match the primary substrates, inhibitors, and inducers of CYP3A4, CYP2D6, and CYP2C9.

Answer 30

CYP3A4 * Substrates: midazolam, indinavir * Inhibitors: ritonavir, ketoconazole * Inducers: rifampin, St. John's Wort CYP2D6 * Substrates: codeine, quinidine * Inhibitors: fluoxetine, quinidine * Inducers: clinical relevance? CYP2C9 * Substrates: s-warfarin, ibuprofen * Inhibitors: fluconazole, amiodarone * Inducers: rifampin, secobarbital

Question 31

Given a specific CYP450, identify the family, subfamily, individual gene, and allelic variant component.

Answer 31

CYP450- cytochrome P (superfamily) ex. CYP2D61 2-Family D-Subfamily 6- Individual gene 1- allelic variant component

Question 32

Differentiate between the mechanism of reversible and irreversible CYP450 inhibition.

Answer 32

Reversible Inhibition * Reversible inhibitors compete with other substrates for occupany of the active site of the same CYP enzyme. * Nitrogenous compounds that can serve as the sixth axial ligand for iron in the heme are especially potent inhibitors of CYP450. Irreversible Inhibiton * Mechanism-based inhibitors (sometimes called suicide inhibition or suicide substrates) are metabolized to reactive species which covalently bind to the heme or binding site residues on the CYP450 protein. * This covalent binding renders CYP450 inoperable and new CYP450 must be synthesized for restoration of normal metabolism.

Question 33

Explain why an enzyme inducer may increase the metabolism of drugs metabolized by different cytochromes P450.

Answer 33

An enzyme inducer may increase the metabolism of drugs by induction cross-talk, which is characterized by hitting multiple CYP450s resulting in greater drug clearance and a broader number of drugs impacted.

Question 34

Provided a reaction, name the Phase II metabolic process (i.e., sulfation, glucuronidation).

Answer 34

* Chair conformation- likely from UGT--> glucuronidation * S with Oxygens attached--> sulfation

Question 35

Explain why genetic variation in metabolism often is not the most important factor in determining variation in drug concentrations and, ultimately, clinical response.

Answer 35

While genetic variation can be important as a determinant of variability of drug metabolism, other sources of variability (diet, other drugs, disease, and environmental exposures, etc) are often more important than genetic variation.

Question 36

Define toxicology.

Answer 36

The study of adverse effects of chemical or physical agents on living systems.

Question 37

Provided a substance, determine if it is properly denoted as a toxin or a toxicant.

Answer 37

Toxin: A poisonous substance produced by living cells. Toxicant: A man-made chemical introduced into the environment that produces toxic effects on living cells.

Question 38

Provided a specific activity/intervention, indicate whether the activity/intervention is an example of descriptive, mechanistic, or regulatory toxicology.

Answer 38

Descriptive: An area of focus in toxicology which is concerned with determining the toxic responses to agents. Mechanistic: An area of focus in toxicology concerned with determining why (or how) agents provoke a toxic response. Regulatory: An area of focus in toxicology concerned with assessing the risks of toxic substances and determining how that risk is best managed.

Question 39

Differentiate between local versus systemic, immediate versus delayed, and reversible versus irreversible toxic responses.

Answer 39

Local vs Systemic * Local: effect exhibited at portal of entry * Systemic: site distant from portal of entry Immediate vs Delayed * Immediate: seconds to hours * Delayed: days to years Reversible vs Irreversible * Reversible: effect abates after stopping exposure * Irreversible: effect persists after stopping exposure.

Question 40

Given a case of a toxic exposure, determine which of the three phases of toxic responses are ongoing.

Answer 40

Exposure--> Environmental factors Disposition--> In the body Toxicodynamics--> cellular responses

Question 41

Given a case of toxic exposure, identify three means by which toxic responses may be mitigated.

Answer 41

* Prevent/reduce exposure * Enhance elimination from body * Block/repair cellular effects

Question 42

Identify the three levels of risk-benefit analysis that occur related to drug therapy.

Answer 42

* FDA--> evaluates benefits/risks for the population (accessibility) * Provider--> evaluates the benefits/risks for a patient (applicability) * Patient--> evaluates the benefits/risks in terms of personal values (acceptibility) In-depth description: Assessment of the risk:benefit ratio for drug therapy needs to be conducted at three levels. The FDA holds responsibility to determine if the risks of accessibility to the drug outweigh the overal risks in the population. The approval of a drug for the market does not mean its use is wise for a specific patient, only that the treatment option should be widely available. Using information for the specific patient combined with published data about the rsponse of patients in general to the drug in question, a health care provider must determine the applicability of the data available to a particular patient. Does the combination of risk factors and likelihood of patient benefit indicate the drug to be a good choice for this particular patient? Finally, the patient must determine the acceptibility of the risk versus the benefit for them personally. Sometimes data does not indicate that one drug is better than another and personal preference, or patient specific tolerability issues, may be the deciding factor.

Question 43

State the three elements of information needed for application of an Investigational New Drug with the Food and Drug Administration.

Answer 43

1. Animal pharmacology and toxicity 2. Manufacturing information 3. Clinical protocol and investigator information Investigational new drug Application: An application to begin to administer a drug to human subjects.

Question 44

Differentate the No Observable Adverse Effect Level and Minimal Anticipated Biological Effect Level for determining the first dose in man for an investigational drug.

Answer 44

NOAEL: The highest dose of an agent that does not produce an adverse effect. MABEL: The lowest dose of an agent that still produces a biological effect.

Question 45

Identify the primary reasons adverse drug events are often not detected until after the drug is approved and marketed for a period of time.

Answer 45

1. Rare events happen that were not previously seen in patient numbers in clinical trials. (ex. Stevens Johnson Syndome, Thrombocytopenia, Serious liver injury, PCN induced anaphylaxis) 2. Common events over a long duration of time may yield different results than the patients during the duration of clinical trials (Ex. Refoxib has higher risk of suicidal behaviors for those under 25 year of age rather than over 65)

Question 46

Provided key information about a potential pharmaceutical excipient (such as its presence on the GRAS list) determine whether or not preclinical toxicology studies are needed for its inclusion in a dosage form.

Answer 46

To determine whether preclinical toxicology studies are needed for a potential pharmaceutical excipient, consider the following key factors: 1. GRAS Status: If the excipient is on the Generally Recognized as Safe (GRAS) list, it suggests that the substance is considered safe for its intended use based on a long history of safe consumption or scientific evidence. However, GRAS status does not automatically exempt it from preclinical testing in pharmaceutical formulations. 2. Intended Use: Evaluate the specific role of the excipient in the dosage form. Excipients used in drug formulations, especially for novel or sensitive populations (like pediatrics or geriatrics), may require additional safety data. 3. Route of Administration: The method of delivery (oral, intravenous, etc.) can influence the need for toxicology studies. Some routes may have more significant exposure or risk profiles than others. 4. Dose and Exposure: Assess the concentration of the excipient in the final dosage form. Higher concentrations or prolonged exposure could necessitate further toxicological assessment. 5. Existing Data: Review any existing toxicological data from similar excipients or from studies on the specific excipient in question. If substantial safety data is available, preclinical studies might not be necessary. 6. Regulatory Guidelines: Consult regulatory guidelines from agencies such as the FDA or EMA, which may provide specific recommendations regarding the need for toxicology studies based on the excipient’s characteristics and intended use. 7. Formulation Context: Consider the overall formulation context, including interactions with active pharmaceutical ingredients (APIs) and other excipients, which could influence safety profiles. If, after evaluating these factors, there is sufficient evidence of safety and no significant concerns regarding toxicity, preclinical toxicology studies might not be necessary. However, if any uncertainty exists, it is prudent to conduct the studies to ensure patient safety.

Question 47

Name the five categories of preclinical studies typically completed in the development of a new drug.

Answer 47

1. Acute Studies--> effect of the single dose on at least 2 species. 2. Repeated Dose Studies--> Length depends on anticipated therapy of at least 2 species 3. Genetic Toxicity--> Determine likelihood compound is mutagenic or carcinogenic 4. Reproductive Toxicity--> Needs depend on target population, multiple species. 5. Carcinogenicity--> Only for compounds in chronic or recurring conditions.

Question 48

What is GRAS?

Answer 48

GRAS-->Generally Regarded as Safe GRAS is a group of compounds whose safety in humans has been established through careful study or widespread use. If needed in a drug formulation as excipients, specific toxicology data is **not** needed for these compounds.

Question 49

Given a patient response to drug, identify the nature of the adverse reaction (side effect, augmented response, or toxic response).

Answer 49

Side Effect: Off-target effects of a drug that are bothersome but do not meaningfully impact the health of a patient. Effects are usually self-limiting but may decrease patient compliance. Examples would include nausea, headache, and dry mouth. Augmented response: An exaggerated response to a drug due to an excessive dose or greater than usual sensitivity to the drug. These responses are an extension of the expected pharmacologic action and will occur in most patients given a large enough dose. Toxic response: Responses that are not expected based upon the targeted pharmacologic effect and put the patient's health at serious risk. May or may not be dose dependent. Examples include rashes, organ injury, and cardiac arrhythmias.

Question 50

Given the mechanisms by which a drug provokes a toxic response, provide potential interventions to prevent or minimize the toxic response.

Answer 50

Pharmaceutical companies often acoid drug candidates that possess reactive functional groups known to be assicuated with toxic organ injury.

Question 51

Given a cell type that experiences genomic damage, identify the likely clinical outcome.

Answer 51

Somatic cells * Cancers * Depends on route of exposure Germ cells * Birth defects * Childhood cancers Developing embryo * Miscarriages * Stillbirths * Birth defects * Occasional childhood cancers

Question 52

Provided a specific gestational stage for a woman, identify whether a teratogen is likely to result in: 1) embryo death, 2) major congenital anomalies, or 3) functional defects and minor anomalies.

Answer 52

Embryo death * 1-2 weeks Major congenital anomalities * 3-8 weeks Functional defects and minor anormalities * 9-38 weeks

Question 53

State the criteria for classification of an agent as a teratogen

Answer 53

Criteria for classification as a teratogen: 1. Exposure results in a characteristic set of malformations 2. Effect occurs with exposure at specific stage of development 3. Effect is dose-dependent

Question 54

Define drug-induced hypersensitivity.

Answer 54

A low frequency serious adverse drug reaction with an immunological etiology to an otherwise safe and effective therapeutic agent.

Question 55

State the 4 key characteristics of DIHR

Answer 55

Rare, unpredictable, complex, and potentially fatal.

Question 56

Distinguish between the two types of DIHR.

Answer 56

1. Immediated Hypersensitivity reactions occur within one hour of the last dose, are type I immunologically, and are IgE mediated. 2. Delayed Hypersensitivity reactions occur one hour after the last dose, is Type IV or III, and is T cell mediated.

Question 57

State the two primary reasons most people who claim to have an allergy to penicillin actually tolerate the drug.

Answer 57

1. 10% of the population claim to have a PCN allergy, but 90% can tolerate the drug 2. 50% of ppl with IgE-mediated PCN allergy lose sensitivity within 5 years; 80% by 10 years.

Question 58

State the two phases of delayed hypersensitivity reactions.

Answer 58

1. Sensitization Phase 2. Effector Phase

Question 59

Identify the most common organ effected by delayed hypersensitivity reactions.

Answer 59

The skin

Question 60

State the time frame at which most drug eruptions occur.

Answer 60

1-3 weeks after exposure.

Question 61

Describe how DRESS is differentiated from other DIHR.

Answer 61

DRESS: Drug Reaction with Eosinophilia and Systemic Symptoms distinguished by involvement of internal organs as well as the skin. The DRESS reactions happen in about 2-8 weeks after the start of therapy. There is a higher eosinophil count in the bloodstream.