Pharm Exam 1

Question 1

Describe the responsibilities of the FDA

Answer 1

• Regulate drugs in the context of their therapeutic uses
• Maintain safety and effectiveness
• 2017 FDA:
  
  • Includes food products, drugs, devices, biological materials, tobacco
  • Federally approved commissioner

Question 2

Recognize the federal definition of a drug and how it differs from the scientific definition

Answer 2

Scientific Definition:

• “natural or synthetic substance which (when taken into a living body) affects its functioning or structure, and is used in the diagnosis, mitigation, treatment, or prevention of a disease or relief of discomfort.”

Federal Government Definition:

• “article intended for use in the diagnosis, cure, mitigation, treatment or prevention of disease” and “articles (other than food) intended to affect the structure or any function of the body”

Question 3

Recognize that federally-defined drugs are regulated by the CDER, while dietary supplements are not and consequences of this differential regulation to consumers

Answer 3

Center for Drug Evaluation and Research (CDER) -> Regulation of Federally-Defined Drugs

1. Pre-market Drug Approval Process (Safety and Efficacy Testing)
2. Quality Control for Drug Manufacturing
3. Oversight of Marketing and Advertising
4. Post-Approval Surveillance of Drugs

Question 4

Define the term dietary supplement and recognize how dietary supplements differ from regulated drugs in terms of FDA regulation

Answer 4

Substances NOT considered “Drugs” by the Federal Government -> NO FDA/CDER Regulation

• Alcohol (Treasury/Taxes)
• Tobacco (FDA)
• Dietary supplements

Question 5

What does it mean in terms of FDA oversight?

Answer 5

FDA Oversight

• Less stringent manufacturing guidelines
• Less pre-approval safety testing
• No requirement for efficacy testing as long as required labeling/wording guidelines are followed (includes statement that claims have not been evaluated by the FDA)

No-FDA oversight

• No safety as found with Pharmaceutical companies
• FDA looking for issues before AND after release
• No efficacy testing

Dietary Supplements

• “products taken by mouth that contain a dietary ingredients”
• Dietary ingredients: vitamins, minerals, herbs/botanicals (not tobacco), amino acids, metabolites, constituents, extracts
• Regulated by CFSAN (center for food safety and applied nutrition)
• Just like drugs, dietary supplements…
  
  1. can have therapeutic benefit
  2. can be toxic
  3. can produce unwanted interactions with medications

Question 6

Understand the drug development and approval process, including when an IND application and an NDA are submitted to the FDA

Answer 6

IND application: submitted AFTER Preclinical Testing and BEFORE Clinical Trials in Humans

• “Investigational New Drug Application”
• 30 Day Safety Review
• 1/10 IND Approvals make it to Market

NDA Submission to the FDA: Submitted AFTER Phase 3 Clinical Trials and BEFORE Drug Approval and Phase 4 Clinical Trials

• 12 Months
• Approval to the Market and Phase 4 Clinical Trials

Blockbuster Drugs: Generate > $1B annual revenue

Question 7

Describe and distinguish among Phase I-IV clinical trials

Answer 7

Phase I

• Healthy volunteers
• Dosing and Toxicity

Phase II

• Therapeutic Effects
• Small population with Target disease

Phase III

• Therapeutic Effects and toxicity
• Large populations
• Well-controlled

NDA to the FDA (12 Months)

Phase IV

• After NDA/FDA Approval
• Drug Use in the general population
• Surveillance for Low-incidence Toxicity

Question 8

Descirbe what it means for a sutudy to be double-blind and placebo-controlled and why this is important when examining the clinical usefulness of drugs

Answer 8

Use in Phase 3 clinical trials

Double-Blind Design

• Neither subject nor experimenter aware of treatment conditions during the course of the trial
• Treatment code retained by a 3rd party and only revealed upon completion of the trial or upon emergence of serious toxicity
• Reduces likelihood of experimenter or subject bias

Placebo control

• Placebo: inert substance provided in place of the drug (usually drug vehicle)
• Comparison with placebo permits examination of natural course of disease without drug treatment
• Placebo effect: patients respond to placebo 10-20% of the time

Question 9

Describe Phase IV post-market surveillance of drug safety, the role of the MEDWATCH program, and the potential outcomes, including black box labeling

Answer 9

• Once Drugs Hit Phase Four and the general Population -> issues come out, out of drug company control
• MEDWATCH - voluntary medical products reporting program
  
  • medication withdrawal from the market
  • change in Recommended Use Parameters
  • Recalls of Manufacturing
  • Altered Labeling
• Black Box - Serious potential effects, but some benefits exist
  
  • Serious or even life-threatening adverse effects

Question 10

Describe treatment INDs

Answer 10

“Permit use of a promising medication prior to FDA approval of NDA for eligible patients”

Treatment* *INDs* *(Treatment Investigational New Drugs)

• Established in 1987 at the height of the AIDS epidemic
• For patients with life-threatening conditions for which no effective treatment alternatives exist
• Permits use of a promising medication prior to FDA approval (before completion of Phase 3 clinical trials) for eligible patients
• Companies apply for treatment IND status

Question 11

Define the term orphan drug

Answer 11

• Treat rare medical conditions (<200,000)
• Rarity of disease means costs/development exceeds profit -> federal incentive programs

Orphan Drugs

• Used to treat rare medical conditions (<200,000 cases in the U.S)
• Cost of drug development and manufacturing exceeds profit
• Orphan Drug Act (1983): provides incentive for orphan drug development
• FYI: 300+ Orphan drugs approved since 1983

Question 12

Define the term blockbuster drug

Answer 12

Drugs that generate > $1B in annual Revenue

Question 13

Describe the difference between first in class and me too medications

Answer 13

“First-In-Class” Medications:

• Targe novel mechanisms
• Innovative but more expensive to develop (require discovery of new mechanisms)

“Me-too” Medications:

• Modified versions of existing medications
• Cheaper to develop
• Improvements are often incremental
• Create market competition which can lower drug costs

Question 14

Understand the 2021 FDA Safety and Innovation Act established mechanisms that permit expedited review of promising medications

Answer 14

2012: FDA Safety and Innovation Act

• Established mechanisms for expedited review of promising drugs
• 73% of all drugs approved in 2016
• For drugs that demonstrate significant improvement over existing medications during preclinical testing

Question 15

Describe what is meant by a generic drug and when generic versions of a brand-name drug can be produced

Answer 15

• Generic Drug Production
  
  • New drugs are protected by a 20 year patent period -> begins upon INVENTION of the drug (filing of the patent)
    
    • Includes development time -> can last 15 years
  • Upon approval, drug companies get 5 years of exclusive marketing (7 years for orphan drugs)
  • Generic drug (Chemical “Clone”) can be produced after the patent period
• Creates competition in the market -> 80-85% lower price than “exclusive” brand names

Question 16

List how generic drugs can and cannot differ from original brand-name drugs

Answer 16

CANNOT Differ (Similarities)

• By Law (FDA):
  
  1. Pharmaceutically Equivalent - Same active ingredients, route of administration, potency/strength
  2. Bioequivalent - be delivered into the blood in the same time period as brand-names: no greater than 20% variation
  3. Therapeutically Equivalent - have the same indications, clinical effects, and safety policies
  4. Manufacture under the same FDA standards

CAN Differ (Differences)

• Cannot look the same, must look differently
• Can have different “inactive” ingredients, flavors, and formulations (esters, salts)

Question 17

Describe and distinguish between bioequivalence, therapeutic equivalence and pharmaceutical equivalence

Answer 17

Pharmaceutically Equivalent

• Have the same active ingredients, route of administrations, and potency/strength

Bioequivalent

• be delivered into the blood in the same time-period as brand-names: no greater than 20% variation

Therapeutically equivalent

• have the indications, clinical effects and safety profiles

Question 18

Describe the nomenclature of drugs in terms of their chemical, code, generic, official and trade names

Answer 18

• Chemical Name - “formal name of the drug based on its chemical structure”
• Code Name - short name provided by the pharmaceutical company for use during drug evaluation”
• Generic - non-proprietary name referring to drug or class of drugs, a.k.a., U.S. Adopted Name (USAN) - stays with drug regardless of manufacturer
• Official/Brand/Trade Name - Proprietary name provided by the manufacturer

Drugs manufactured by more than one company will have the same generic name but different brand/trade names

Question 19

Understand why some drugs require prescriptions and recognize which health professionals are permitted to prescribe drugs

Answer 19

• Prescription drugs = legend drugs
• require federally and state licensed health professional’s authorization for purchase
• Drugs “deemed unsafe for unsupervised use”
  
  • Habit forming
  • toxic
  • for medical conditions that are not easily diagnosed

Who can prescribe drugs?

• Anywhere:
  
  • Doctors of medicine
  • doctors of osteopathy
  • dentists
  • podiatrists
• Varies from state to state
  
  • in collaboration with a physician
    
    • physician assistants
    • nurse practitioners
  • limited drug types
    
    • optometrists
    • pharmacists
    • clinical psychologists

Question 20

Be familiar with the elements of a prescription and define common abbreviations used in prescription writing and recognize common errors related to prescription writing

• ad lib
• b.i.d
• b.d.s.
• h.s.
• non rep.
• n.p.o.
• p.o
• p.r.n.
• q.X.h
• q.d.
• q.i.d
• i.m
• i.v
• s.c., subc, SQ

Answer 20

• ad lib - at pleasure
• b.i.d - twice a day
• b.d.s.- twice a day
• h.s. - at bedtime
• non rep. - do not repeat (refill)
• n.p.o. - not by oral administration
• p.o - by mouth
• p.r.n. - as needed
• q.X.h - every X hours
• q.d. - every day
• q.i.d - four times a day
• i.m - intramuscular
• i.v - intravenous
• s.c., subc, SQ - subcutaneous

Common prescription Errors:

• Wrong drug dispensed
• Wrong dose dispensed
• Vague description of use parameters = wrong frequency/mode of administration
  
  • ***Poor handwriting and unclear abbreviations are common causes of error

Question 21

Define the term OTC drug and recognize that OTC drugs are subject to the same FDA regulation as prescription drugs

Answer 21

OTC Drugs

• Available Without a Prescription
• Same FDA regulations as legend drugs
• Easy-to-understand labeling
• Lower than prescription doses
• Same generic rules
• Some DEA restrictions of FDA OTC approvals because of abuse liability and use for drug synthesis

Question 22

Describe the off-label use of prescription drugs

Answer 22

• Prescribing outside of the scope of the FDA-approved indication label
• FDA permits health care providers to prescribe drugs outside of marketing indications based on professional judgment
• No pharmaceutical company marketing allowed

Question 23

Describe concerns related to drug testing in pediatric populations and FDA actions to promote child testing

Answer 23

Concerns:

• Dispensed off-label with doses extrapolated using formulas based on age/weight
• kids are NOT scaled down adults
• Kids have different pharmacokinetics (especially metabolism) and Pharmacodynamics

FDA has taken action to promote drug testing in kids

• Requirement for disclaimers when drugs have not been tested in kids
• Incentives pediatric testing of all drugs with intended use in kids (6-month exclusive marketing extensions)
• Encourages pediatric testing of approved medications frequently used in kids with potential penalties for non-compliance

Question 24

Understand and describe the scheduling of controlled drugs and recognize that this is overseen by the DEA

Answer 24

Controlled drugs:

• Have abuse potential
• Regulated by federal DEA and state departments
• Hold license to purchase/obtain drugs

Controlled drug act -> scheduling of drugs based on abuse potential and acceptable medical considerations

• Marijuana - states recognize use and do not prosecute (federal does not and will arrest)

Question 25

Define the term, teratogen, and be familiar with the FDA categories for safety in pregnancy

Answer 25

***_Teratogen_*** - "any substance that will harm a developing fetus or embryo"

Question 26

Define the term: pharmacodynamics and distinguish pharmacodynamics from pharmacokinetics

Answer 26

**_Pharmacodynamics_** - Effects of *_Drugs on the Body_* * Receptor-mediated responses **_Pharmacokinetics_** - Effects of the *_body on drugs_* * Absorption, Distribution, Metabolism, Elimination

Question 27

Understand how the physical properties of drugs and receptors determine their interactions

Answer 27

* **Receptor** - The component of a cell or organism that interacts with a drug and initiates the biochemical events leading to its effects * PHysical properties of the Drugs/Receptors (eg size, shape, charge) determines; 1. binding 2. selectivity 3. affinity 4. intrinsic activity/efficacy * **Lock and Key** * Drug is a Key -\> fits the receptor, the Lock -\> Receptor Activation, or Turning the Key, is a Biochemical Response (conformational change)

Question 28

# Define how the formation of covalent vs. non-covalent bonds determines drug-receptor interactions

Answer 28

**_Covalent Bonds:_** * **IRREVERSIBLE** * drug removal and/or receptor reactivation requires re-synthesis of the receptor, or enzymatic removal of the drug * Long-lived bond, non-competitive **_Non-Covalent Bonds_** * **REVERSIBLE** * **most drugs** bind via non-covalent bonds * Ionic, hydrogen, hydrophobic, Van der Waals

Question 29

Define the term selectivity and describe its relationships to drug dose and side effects

Answer 29

Selectivity - the number of receptors with which a drug interacts * Higher drug concentrations -\> lower selectivity * Lower selectivity -\> increased incidence of side effects

Question 30

Define "affinity" and "Kd" and the relationship between the two

Answer 30

***_Affinity_*** - between drug and receptor, describes **how readily and tightly** that drug binds to the receptor * **High affinity** = good drug-receptor interaction; LESS drug needed to produce a response * **Low affinity** = poor drug-receptor interaction; MOE drug needed to produce a response ***_Kd - Equilibrium Dissociation Constant,_* drug concentration** at which **50% of the receptor is bound by the drug** * Measures in molar concentration * Relationship -\> Kd value and affinity are **INVERSE**

Question 31

Define intrinsic efficacy and relate this concept to antagonist and various types of agonist drugs

Answer 31

***_Intrinsic efficacy_*** - the ability of a drug to activate a receptor and produce a physiological response when it binds the receptor * ***_Agonist_*** - bind to the receptor and **activate** it, produces a physiological response (**has intrinsic efficacy)** * ***_Antagonists_*** - bind to the receptor but do **NOT** activate it, **AND prevent activation** by endogenous chemicals or other drugs (**no intrinsic efficacy)**

Question 32

Understand the difference between full and partial agonist and competitive and irreversible non-competitive antagonists

Answer 32

***_Full Agonists:_*** * Fully activate receptors * Produce a maximal pharmacological effect when all receptors are occupied * *_Maximal intrinsic activity_* ***_Partial Agonists:_*** * Partially activate the receptor upon binding * Produce a sub-maximal pharmacological effect when all receptors are occupied * *_Intrinsic efficacy varies depending on*_ _*drug_**_,*_ _*but is always submaximal_* ***_Competitive Antagonists_*** * Compete with endogenous chemicals or agonist drugs for binding of the receptor * Reversibly bind to and occlude the agonist site on the receptor by forming *_non-covalent bonds_* * Can be displaced from the receptor by other drugs (effects are surmountable) ***_Irreversible Antagonists_*** * Receptor inactivation is not surmountable * Irreversibly bind to and occlude the agonist site on the receptor by forming *_covalent bonds_*

Question 33

Describe the difference between orthosteric and allosteric drugs and describe positive and negative allosteric modulators

Answer 33

**Orthosteric** (bind the *_primary agonist site_* on the receptor) vs. **Allosteric** (*_bind to secondary, allosteric site_* to positively or negatively regulate agonist binding and/or efficacy) * **Positive Allosteric Modulator (PAM)** - *_GREATER signaling,_* help affinity and efficacy of orthosteric agonist * **Negative Allosteric Modulator (NAM)** - *_DIMINISHED signaling,_* dampens affinity and efficacy of orthosteric agonist

Question 34

Understand that many receptors can exist in an active/signaling conformation in the absence of agonists and describe how inverse agonists work

Answer 34

In the **absence of an agonist**, receptors maintain a low level of "**constitutive**" signaling and exist in active or inactive (R\* or R) conformation * ***_Agonists_*** promote the active (R\*) conformation and increase cellular responses * ***_Antagonists_*** produce no conformational effects but prevent agonists from induce conformational changes * ***_Inverse agonists_*** promote the inactive (R) conformation and therefore eliminate baseline/constitutive signaling thereby producing effects opposite those of regular agonists

Question 35

Define what is meant by a biased agonist

Answer 35

***_Biased Agonist_*** - agonist-dependent selectivity for distinct signaling/second messenger pathways when binding to the same receptor (selective for a specific second messenger that the receptor can produce -\> agonist determines the pathway

Question 36

Understand the relationship between drug-receptor interactions and the pharmacological effects of drugs in terms of potency and efficacy

Answer 36

Receptor principles * Drugs **MIMICK** the actions of **Endogenous** chemicals at receptors * Drugs **BLOCK** the actions of **Endogenous** chemicals at receptors * Because the **SAME RECEPTOR TYPE** can be found throughout the body, a **VARIETY OF PHYSIOLOGICAL EFFECTS** can be produced, depending on the **LOCATION** "The magnitude of a drug's effects will be proportional to the degree of its interactions with a receptor" * ***_Potency_***: describes the **amount of drug required** to produce a specific pharmacological effect * Drugs with **higher affinities** for a receptor (ie, drugs that have a **lower Kd**) tend to be **more potent** * ***_Efficacy_***: describes the maximal pharmacological effect that a drug can produce * Efficacy is related to the **total number of receptors available** to bind a drug, also known as the **B_MAX** * Drugs with a **higher B_MAX tend to have higher efficacy**

Question 37

Describe the function of second messengers in cellular communication

Answer 37

"intracellular signaling molecules released by the cell to trigger physiological changes such as *_proliferation, differentiation,_* migration, survival, and *_apoptosis*_. Secondary messengers are therefore one of the initiating components of intracellular _*signal transduction_* cascades"

Question 38

Interpret dose-response curves in terms of the relationship between a drug and its pharmacological effects

Answer 38

Dose-Response Curve - Quantitative measure of the response to a drug at a given concentration * ***_Linear Phase_*** - Increasing effect as dose increases * ***_Plateau Phase_*** - Response reaches its height and eventually increased concentration illicits no greater response

Question 39

Distinguish between arithmetically and logarithmically plotted dose-response curves

Answer 39

**_Arithmetically_ - Hyperbolic Curve** **_Logarithmically_ - Sigmoidal Curve** * Uses **Log** of the Drug Concentration -\> captures an **ACTIVE LINEAR PHASE** and plateau phase * Threshold Dose and Ceiling Effect * Gives us E_MAX (maximal effect, measure of efficacy) and ED₅₀ (Effective Dose 50 - the dose of the drug that produces 50% of the maximal effects, measures potency

Question 40

Define the terms, effective dose 50 (ED₅₀) and E_MAX, and relate to drug potency and efficacy

Answer 40

* **E_MAX** * maximal effect * measure of efficacy * **_Efficacy_: determines** **clinical** **effectiveness** * Describes the **maximal effect that a drug can produce** * Represented by the **E_MAX** * **The greater the E_MAX, the more efficacious the drug** * **ED50 (Effective Dose 50)** * the dose of the drug that produces 50% of the maximal effects * measures potency * Potency: determines the drug dose that will be used clinically * Describes the **amount of drug required to produce a specific effect** * Represented by the ED50 * The l**ower the ED50, the more potent the drug**

Question 41

Rank drugs in terms of efficacy and potency based on their dose-response curves

Answer 41

Question 42

Relate drug effects to receptor binding: How does affinity (KD) relate to potency (ED₅₀)? How does E_MAX relate to B_MAX and intrinsic activity/efficacy?

Answer 42

Affinity (K_D) vs potency (ED₅₀) * Affinity, Log Drug Concentration (K_D) = Potency, Log Drug Dose (ED₅₀) E_MAX vs B_MAX and intrinsic activity/efficacy * E_MAX, the maximum effect/efficacy = B_MAX and intrinsic activity/efficacy, all available receptors are bound and full intrinsic activity is achieved

Question 43

Classify drugs as full, partial or inverse agonists according to their dose-response curves

Answer 43

Question 44

Distinguish between quantal and graded responses and recognize when a response is graded vs quantal

Answer 44

Question 45

Tell the difference between graded vs. quantal curves

Answer 45

Question 46

Recognize the interpret quantal dose-response curves when plotted cumulatively or non-cumulatively

Answer 46

Cumulative * % of individuals AT AND BELOW that dose Non-Cumulative * % of individuals AT A SINGLE DOSE

Question 47

Define the terms, median effective, toxic, and lethal doses (ED50, TD50, LD50), determine their values from quantal dose-response curves and use them to calculate therapeutic index (TI) and margin of safety (MOS)

Answer 47

Question 48

Define tolerance (and tachyphylaxis) and sensitization, and depict them in terms of shifts in dose-response curves

Answer 48

***_Tolerance_*** - same dose of a drug produces **less** effect * **Tachyphylaxis** - immediate/rapid onset tolerance * Curves move to the **right** because more drug is needed to achieve the same effect ***_Sensitization_*** - same dose of a drug produces **more** effect * Curve moves to the **left** because less drug is needed

Question 49

Define pharmacokinetics and contrast with pharmacodynamics

Answer 49

**Pharmacokinetics** - "effects on the body on drugs" * absorption, distribution, metabolism, elimination **Pharmacodynamics** - "effects of Drugs on the Body" * Receptor-mediated

Question 50

Define absorption, distribution and elimination

Answer 50

***_Absorption_*** - transfer of drugs from site of delivery to the **BLOOD** ***_Distribution_*** - **MOVEMENT** of a drug from the blood to various sites in the body ***_Elimination_*** - **REMOVAL** of the drug from the body

Question 51

Understand basic principles determining passage of drugs across biological membranes

Answer 51

1. ***_Passive diffusion_*** * **ALMOST ALL DRUGS** * Down electrochemical gradient * No transport molecules involved * Molecules will diffuse down a concentration gradient * for uncharged molecules, diffusion depends on * Lipid solubility * More lipophilic = greater permeability * Higher ***_partition coefficient_*** the more lipid soluble * Size * smaller size = greater permeability * When molecules are charged (anion or cations), they are very hydrophilic and do not readily diffuse across membranes 2. ***_Special permeation Processes_*** * **VERY FEW DRUGS** * carrier mediated transport * _active transport_ - against its electrochemical gradient * _Passive transport_ - facilitated diffusion with the electrochemical gradient * Endocytosis and exocytosis

Question 52

Define weak acid and weak base and predict shifts in the ionization states and membrane permeability of weak acids/bases with changes in pH

Answer 52

The degree of ionization depends on the concentration of protons (H+): pH * ***_Weak Base_***: neutral compound that can form into a cation by combining with a proton * *_at Low pH_*: Most of a weak base will be charged and therefore LESS ABLE TO CROSS MEMBRANES * *_at High pH:_* Most of a weak base will be uncharged and therefore BETTER ABLE TO CROSS MEMBRANES * ***_Weak acid_***: neutral compound that can dissociate into an anion and a proton * *_at Low pH_*: Most of a weak acid will be uncharged and therefore BETTER ABLE TO CROSS MEMBRANES * *_at high pH:_* Most of a weak acid will be charged and therefore LESS ABLE TO CROSS MEMBRANES

Question 53

Define Pka and understand how it can be used to predict the predominant ionization state of a weak acid or weak base at a given pH

Answer 53

Use Pka value as a pH value and based on above/below that pH, and WA or WB, then decide ionization and solubility * **WA**: neutral when protonated (AH dissociates in basic conditions) * **Lower than pKa/pH** -\> more protons means more protonated (AH), *_soluble_*, membrane solubility * **Higher than pKa/pH** -\> less protons means more ionization (A-), *_insolubility_*, polarity, low membrane solubility * **WB**: polar when protonated (B protonated in acidic conditions) * **Lower than pKa/pH** -\> more protons means more protonated/ionization (BH+), *_insolubility_*, polarity, low membrane solubility * **Higher than pKa/pH** -\> less protons means more no ionization (B), *_soluble_*, membrane solubility

Question 54

Understand examples of weak acid/base diffusion across biological membranes in the kidney and GI tract and to cellular sites of action in the case of local anesthetic

Answer 54

**Gastrointestinal Tract** * Aspirin is a weak acid with a pKa of 3.1 * In the stomach at low pH, it is primarily in the protonated/neutral form = readily absorbed * Once it diffuses into the blood where the pH is higher (7.4) it is deprotonated and trapped (not reabsorbed) * in the intestines where the pH is higher, it is less readily absorbed * in contrast, weak bases will be more readily absorbed at higher pH in the intestines **Elimination: removal of** **drug** **from the body** * Mechanisms of Drug elimination: renal excretion * Glomerular ultrafiltration * Reabsorption = retention vs. elimination * Kidney damage = reduced filtration and decreased drug elimination * Tubular reabsorption * across renal tubules cell layers * down chemical gradient * Requires lipid=solubility * pH-dependent * **Renal elimination of Wea Acids and Weak Bases** * All drugs filtered at the glomerulus * Lipid-soluble drugs are reabsorbed in renal tubules by passive diffusion * Ionized (charged) or hydrophilic drugs can't be reabsorbed and are therefore excreted in urine * ***_Alkalization of urine (increasing pH) will facilitate extraction of weak acids (eg. aspirin)_*** Local anesthetic will more readily reach their site of action when they are in their LIPID SOLUBLE (UNCHARGED) FORM * **Local anesthetics = WEAK BASES**

Question 55

Define bioavailability and how it varies with different routes of administration

Answer 55

***_Bioavailability_*** - fraction of the *_uncharged drug reaching the systemic circulation_* following administration * *_Depends on_* * Route of administration * Drug properties (lipophilicity, pKa, formulation) * physiological variables (pH, blood flow, enzymes) Effects of route of administration on absorption: * IV = 100% bioavailability * IM, SC, Inhaled = High Bioavailability but \< 100% * Oral = Low and inconsistent Bioavailability; Slower absorption * first pass effect * Requires lipid solubility * Bioavailability varies with GI motility, presence of food * GI tract = low pH, lots of enzymes

Question 56

Distinguish between enteral and parenteral routes of drug administration and recognize various routes of administration as enteral or parenteral

Answer 56

***_Enteral_***: administration into the systemic circulation via the alimentary (digestive) canal * *_Tablets_*, capsules, solutions, suspensions * Oral (PO): by mouth * Buccal: across membranes of the mouth * Sublingual (SL): under the tongue * Rectal (PR) by suppositories ***_Topical_***: administration by direct application onto the skin or associated membranes * *_Powders, creams, ointments, gels, sprays, patches_* * Dermal: onto the skin * Ophthalmic: onto membranes of the eye * Vaginal: onto the membranes of vagina * Intrauterine: onto membranes of the uterus lining ***_Parenteral_***: administration into the systemic circulation via routes other than alimentary canal * *_Solutions, emulsions, suspensions, aerosols, gases_* * Intravenous (IV) * Intramuscular (IM) * Subcutaneous (SC) * Inhalation * Intrathecal (IT): into spinal subarachnoid space * Epidural: into epidural space outside of dura mater * intrasynovial (Intra-articular): into the joint * Intraosseous: into the bone * Intraperitoneal (IP): into the abdominal cavity * Intra-arterial (IA): into arterial circulation * Transdermal: across the skin * Transmucosal: across the mucous membranes

Question 57

Describe the first pass effect and relate to various routes of administration

Answer 57

***_First Pass Effect_*** - Reduction of the concentration of a drug *_before it reaches systemic circulation_* Swallowed drugs are absorbed by the digestive tract and enter the hepatic portal system -\> liver metabolism reduces concentration ***_First Pass Metabolism_*** * *_Oral drug administration only_* * Avoid with parenteral and non-oral enteral routes * Up to 90% of orally administered drugs * *_Extraction Ration (ER):_* Fraction of drug removed by first pass effect

Question 58

Define extraction ratio in terms of first pass metabolism

Answer 58

Extraction ratio - fraction of drug removed by first pass metabolism

Question 59

Describe Drug distribution and the factors that influence it

Answer 59

Distribution - MOVEMENT of a drug from the blood (general circulation) to various sites in the body * To site of action, metabolism/elimination, storage * Reversible process; drugs can redistribute * Requires passage through endothelial cell layer Factors influencing Distribution * lipid solubility, drug size * Drug pKa and blood/tissue pH * Extent of blood perfusion * Extent of binding to plasma binding proteins (albumin, glycoproteins(

Question 60

Describe how the blood-brain barrier can determine the CNS effects of drug

Answer 60

* Tight junctions at CNS capillaries only allow VERY LIPID SOLUBLE drugs to enter the CNS * WIll or will not allow drugs to have CNS effects

Question 61

Describe the renal and biliary excretion of drugs

Answer 61

Renal Excretion: * Mechanisms of Drug elimination: renal excretion * Glomerular ultrafiltration * Reabsorption = retention vs. elimination * Kidney damage = reduced filtration and decreased drug elimination * Tubular reabsorption * across renal tubules cell layers * down chemical gradient * Requires lipid=solubility * pH-dependent Biliary Excretion: * Bile transported from the liver to the small intestine by way of the gallbladder * some is reabsorbed into the blood capillaries and then the bile salt is absorbed and circulated back to the liver by way of the capillaries of the digestive tract and hepatic portal vein * others gets excreted to the large intestine and eliminated in feces

Question 62

Define half-life and use half-life to calculate drug elimination over time

Answer 62

Half life (t1/2) T1/2 is the time required to decrease the amount of drug in the body by 50% * 50% of drug is lost in one half-life * 75% is lost in two half lives * 87.5% is lost in three half lives * 93.75% is lost in four half-lives

Question 63

Define biotransformation and its fundamental purpose

Answer 63

***_Biotransformation_*** - metabolism of a drug with the fundamental purpose of facilitating **elimination** via the kidneys * Make polar metabolites that cannot be reabsorbed and are secreted * ***_Site_*** ***_of reaction_***: primarily but not exclusively in the **LIVER** (also in some other organs such as skin and lungs and in many cases, e.g. hydrolysis, in the blood)

Question 64

Describe and distinguish between phase I and phase II reactions and recognize various types of reactions as being phase I or phase II

Answer 64

***_Phase I Reactions_*** * Making a **drug more polar by introducing or unmasking functional groups** * ***_Hydrolysis reactions_*** * Catalyzed by **ESTERASES** * Cleavage of ester or amide bonds in a molecule via a reaction involving the introduction of water * ***_Oxidation reactions:_*** * oxidases, dehydrogenases, oxygenases * involves the loss of electrons from the drug upon introduction of molecular oxygen * The most important Phase I oxidation reaction involves **CYTOCHROME P450 ENZYMES** * Alcohols (ethanol, methanol) are oxidized by a different family of enzymes that include **ALCOHOL AND ALDEHYDE DEHYDROGENASES** * *_Purposes of Phase I reactions_* * Exposure or introduce functional groups on a drug * Make a drug more hydrophilic * Provide site on a drug for phase II reactions * In most, but not all cases, metabolism results in drug inactivation * *_The cytochrome P450 System_* * Binds to drugs and catalyze oxidation reactions * most common phase I metabolic reactions * Three "families" of cytochrome P450s * CYP1, CYP2, CYP3 * Each cP450 enzyme can metabolize many different drugs * A single drug can be metabolized by many different cP450 enzymes * ***_CYP3A4_***: **MOST COMMON METABOLIC ENZYME INVOLVED IN DRUG INTERACTIONS** ***_PHASE II REACTIONS_*** * *_CONJUGATION_* * The transfer of endogenous substances to functional groups catalyzed by enzymes call transferases to form polar conjugates which are easily eliminated

Question 65

Define a prodrug and describe when it may be necessary to develop a prodrug

Answer 65

***_Prodrug_*** - a medication/compound that is metabolized into a pharmacologically active drug * Changes in absorption, distribution, metabolism and elimination * Improved bioavailability (proportion entering circulation, able to have an effect)for drugs that poorly absorb into the GI tract

Question 66

Understand the principle of drug dosing and what it meant by the term therapeutic window

Answer 66

**Therapeutic Window:** * *_Target drug concentration_* where enough is administered to reach/maintain optimal effects, while staying below the threshold for toxicity **Phases** * loading - reach window * Maintenance - periodic administration to stay within therapeutic window

Question 67

Describe how changes in pharmacokinetics can influence dosing for active drug and prodrugs and drug efficacy/safety

Answer 67

***_Pharmacokinetic Factor_*** * **Cause of change** * Absorption: * Compromised organ system (ex. gastric bypass) * pH changes * Distribution * Blood flow (ex. conditions, pathology -\> altered organ perfusion) * Impaired blood-brain barrier * Metabolism * Enzyme issues (ex. drug inhibition, pollutants) * Poor liver function (eg. damage) * Elimination * impaired kidney function * pH changes change absorption/distribution * **Dosing influence** * Absorption * need higher doses because little is absorbed * Distribution * need higher doses because little is absorbed * Metabolism * less dosing because they are poorly metabolized and accumulating * Elimination * less dosing because they are poorly eliminated and accumulating ***_Prodrug - "trojan horse"_*** * Metabolism enzymes are responsible for activating of drug * Problem: * poor enzymatic activity/metabolism may mean drug is never activated * Metabolism that works too well could mean toxic effects for patients

Question 68

Distinguish between intrinsic and idiosyncratic drug toxicity

Answer 68

* ***_Drug toxicity_*** - can occur acutely (single exposure) or emerge with repeated use * ***_Intrinsic toxicity_*** * **Reproducible - all patients at risk** * **Dose-dependent** - overdose * sensitivity varies from patient to patient * Result of action at **target receptor** (extensive effects) or effects at **other receptors** (off-target effects) * ***_Idiosyncratic_*** * Not widely reproducible - **occurs in** **small** **patient subset** * **Low incidence** * occurrence is the result of interaction with **specific patient attributes** * includes **Hypersensitivity**/allergic reactions

Question 69

Understand how induction/inhibition of metabolic enzymes can alter drug effects

Answer 69

***_Induction_*** * *_Increased enzymatic activity_* (MORE metabolism -\> **LOWER drug levels**) * Notorious inducing agents include * some medications: Sedatives, anti-seizure medications, rifampin * many environmental pollutants: polycyclic aromatic hydrocarbons * Some foods: cruciferous vegetables, charcoal-broiled foods * Chronic alcohol consumption * cigarettes ***_Inhibition_*** * *_DECREASED enzymatic capacity_* (LESS metabolism -\> higher drug levels, **ACCUMULATION**) * Notorious inhibiting agents include * Grapefruit juice * Medications: macrolide antibiotics, azole antifungal drugs

Question 70

What is the most commonly involved drug interaction metabolic enzyme?

Answer 70

**CYP3A4** is the metabolic enzyme most commonly involved in drug interactions

Question 71

Define the term genetic polymorphism and describe how a genetic polymorphism can affect drug metabolism (cite the example of aldehyde dehydrogenase and alcohol metabolism)

Answer 71

* ***_Genetic polymorphisms_*** - normal variations in the nucleotide sequences of genes that result in functional differences in the encoded protein * no effect * altered activity * eliminated activity * ***_Manifestations_*** * individual differences in drug metabolism * Familial differences in drug metabolism * Ethnic differences in drug metabolism

Question 72

Define the term pharmacogenetics and cite the example of how genetic polymorphisms is VKORC1 and CYP2C9 can alter responsiveness to warfarin

Answer 72

* ***_Pharmacogenetics_*** - the study of genetic variations that *_leads to differing drug responses_* * GOAL: develop pharmacogenetic diagnostic testing to permit individualized treatment (individual drug selection or dosing) in the identified, genetically variable populations * Genetic variations in ***_CYP2C9_*** **reduces warfarin metabolism** = *_increased bleeding risk_* * genetic variations in the ***_VKORC1_*** subunit **reduces warfarin sensitivity** = *_increasing clotting risk_*

Question 73

Understand how individual attributes (eg. age, disease) can influence drug metabolism)

Answer 73

**Children** * *_Kids are NOT simply scaled down adults_* * many metabolic systems are slow to develop * Kids also have differences in drug receptors, distribution and elimination * **Best** **source of info for child dosing = *_drug insert_*** * If necessary, child dosing for certain drugs can be determined based on age and weight * Remember, a fetus or breast-feeding child can be exposed to drugs that the mother is taking ***_Elderly_*** * *_Drug effects change as people get older_* * Reduced metabolism * reduced kidney function (elimination) * altered distribution (Body composition changes) * average senior citizen is taking 4 prescription drugs, 2 OTC drugs + dietary supplements at the same time = risk for drug interactions

Question 74

Understand how increasing drug dose can affect metabolism in a way that can increase the risk of hepatoxicity through NAPQE formation and describe the example of acetaminophen (Tylenol) overdose

Answer 74

* **_High drug concentrations_ = deficiencies or changes in metabolic pathways** * *Metabolic enzymes can be saturated* * *Substrates for phase II reactions can be depleted* * Example: acetaminophen (tylenol) overdose * regular strength = 325 mg/tab * Extra strength = 500 mg/tab ***_Toxic doses consume available glutathione, causing_*** ***_buildup_*** ***_of toxic NAPQ1. NAPQ1 is usually a minor product of acetaminophen metabolism. However, alcohol can increase acetaminophen toxicity by inducing CYP450 enzymes_*** * Inhibition = decreased enzymatic capacity * less metabolism = drug accumulation 1. Normal tylenol dose (650 - 1000 mg) 2. Higher tylenol dose 1. completely saturation of transferase enzyme 1. Cytochrome P450 (phase I) 1. Toxic metabolite = NAPQE Phase II 3. Tylenol overdose (7.5-10 g in non-alcoholic) 1. depletion of glutathione 2. Causes liver damage

Question 75

Describe the effects of chronic alcohol consumption on tylenol metabolism and the risk of hepatotoxicity

Answer 75

Chronic alcohol consumption induces CYP enzymes that convert Tylenol to NAPQE in the liver * Increased risk for hepatoxicity * Risk for hepatotoxicity at Tylenol doses as low as 4 g * risk in moderate drinkers is unclear * recommended OTC doses are safe

Question 76

Understand the basic definition of clearance

Answer 76

* Clearance = a way to collectively quantify all of the processes that make active drug disappear from the body * Two ways to understand * Rate of elimination relative to drug concentration * Amount of plasma that would have to be cleared in order to account for disappearance of drug

Question 77

What are the three important clinical pharmacokinetic parameters?

Answer 77

Clearance Half-life Bioavailability

Question 78

Explain what it means for a drug to have a small or large volume of distribution

Answer 78

if there is a small distribution the drug is only concentrated in one or two areas, such as the blood and VRG = vessel-rich groups However; over time the distribution increases and the drug is the spread to muscles, adipose tissues, etc throughout the body

Question 79

Afferent and efferent divisions of the peripheral nervous system

Answer 79

**_Afferent Division_** Somatic sensory visceral sensory Special sensory **_Efferent Division_** Somatic motor Autonomic motor (sympathetic, parasympathetic, Enteric)

Question 80

Be familiar with the basic responses of target organs in response to sympathetic and parasympathetic stimulation

Answer 80

Parasympathetic: Cranial + sacral Sympathetic: thoracic + lumbar