Pharm Exam 1 Flashcards
Describe the responsibilities of the FDA
- 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
Recognize the federal definition of a drug and how it differs from the scientific definition
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”
Recognize that federally-defined drugs are regulated by the CDER, while dietary supplements are not and consequences of this differential regulation to consumers
Center for Drug Evaluation and Research (CDER) -> Regulation of Federally-Defined Drugs
- Pre-market Drug Approval Process (Safety and Efficacy Testing)
- Quality Control for Drug Manufacturing
- Oversight of Marketing and Advertising
- Post-Approval Surveillance of Drugs
Define the term dietary supplement and recognize how dietary supplements differ from regulated drugs in terms of FDA regulation
Substances NOT considered “Drugs” by the Federal Government -> NO FDA/CDER Regulation
- Alcohol (Treasury/Taxes)
- Tobacco (FDA)
- Dietary supplements
What does it mean in terms of FDA oversight?
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…
- can have therapeutic benefit
- can be toxic
- can produce unwanted interactions with medications
Understand the drug development and approval process, including when an IND application and an NDA are submitted to the FDA
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
Describe and distinguish among Phase I-IV clinical trials
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
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
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
Describe Phase IV post-market surveillance of drug safety, the role of the MEDWATCH program, and the potential outcomes, including black box labeling
- 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
Describe treatment INDs
“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
Define the term orphan drug
- 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
Define the term blockbuster drug
Drugs that generate > $1B in annual Revenue
Describe the difference between first in class and me too medications
“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
Understand the 2021 FDA Safety and Innovation Act established mechanisms that permit expedited review of promising medications
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
Describe what is meant by a generic drug and when generic versions of a brand-name drug can be produced
- 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
- New drugs are protected by a 20 year patent period -> begins upon INVENTION of the drug (filing of the patent)
- Creates competition in the market -> 80-85% lower price than “exclusive” brand names
List how generic drugs can and cannot differ from original brand-name drugs
CANNOT Differ (Similarities)
- By Law (FDA):
- Pharmaceutically Equivalent - Same active ingredients, route of administration, 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 same indications, clinical effects, and safety policies
- 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)
Describe and distinguish between bioequivalence, therapeutic equivalence and pharmaceutical equivalence
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
Describe the nomenclature of drugs in terms of their chemical, code, generic, official and trade names
- 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
Understand why some drugs require prescriptions and recognize which health professionals are permitted to prescribe drugs
- 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
- in collaboration with a physician
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
- 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
Define the term OTC drug and recognize that OTC drugs are subject to the same FDA regulation as prescription drugs
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
Describe the off-label use of prescription drugs
- 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
Describe concerns related to drug testing in pediatric populations and FDA actions to promote child testing
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
Understand and describe the scheduling of controlled drugs and recognize that this is overseen by the DEA
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)
Define the term, teratogen, and be familiar with the FDA categories for safety in pregnancy
Teratogen - “any substance that will harm a developing fetus or embryo”
Define the term: pharmacodynamics and distinguish pharmacodynamics from pharmacokinetics
Pharmacodynamics - Effects of Drugs on the Body
- Receptor-mediated responses
Pharmacokinetics - Effects of the body on drugs
- Absorption, Distribution, Metabolism, Elimination
Understand how the physical properties of drugs and receptors determine their interactions
-
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;
- binding
- selectivity
- affinity
- intrinsic activity/efficacy
- PHysical properties of the Drugs/Receptors (eg size, shape, charge) determines;
-
Lock and Key
- Drug is a Key -> fits the receptor, the Lock -> Receptor Activation, or Turning the Key, is a Biochemical Response (conformational change)
Define how the formation of covalent vs. non-covalent bonds determines drug-receptor interactions
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
Define the term selectivity and describe its relationships to drug dose and side effects
Selectivity - the number of receptors with which a drug interacts
- Higher drug concentrations -> lower selectivity
- Lower selectivity -> increased incidence of side effects
Define “affinity” and “Kd” and the relationship between the two
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
Define intrinsic efficacy and relate this concept to antagonist and various types of agonist drugs
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)
Understand the difference between full and partial agonist and competitive and irreversible non-competitive antagonists
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
Describe the difference between orthosteric and allosteric drugs and describe positive and negative allosteric modulators
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
Understand that many receptors can exist in an active/signaling conformation in the absence of agonists and describe how inverse agonists work
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
Define what is meant by a biased agonist
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
Interpret dose-response curves in terms of the relationship between a drug and its pharmacological effects
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
Distinguish between arithmetically and logarithmically plotted dose-response curves
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 EMAX (maximal effect, measure of efficacy) and ED50 (Effective Dose 50 - the dose of the drug that produces 50% of the maximal effects, measures potency
Define the terms, effective dose 50 (ED50) and EMAX, and relate to drug potency and efficacy
-
EMAX
- maximal effect
- measure of efficacy
-
Efficacy: determines clinical effectiveness
- Describes the maximal effect that a drug can produce
- Represented by the EMAX
- The greater the EMAX, the more efficacious the drug
-
Efficacy: determines clinical effectiveness
-
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 lower the ED50, the more potent the drug
Rank drugs in terms of efficacy and potency based on their dose-response curves
Relate drug effects to receptor binding: How does affinity (KD) relate to potency (ED50)? How does EMAX relate to BMAX and intrinsic activity/efficacy?
Affinity (KD) vs potency (ED50)
- Affinity, Log Drug Concentration (KD) = Potency, Log Drug Dose (ED50)
EMAX vs BMAX and intrinsic activity/efficacy
- EMAX, the maximum effect/efficacy = BMAX and intrinsic activity/efficacy, all available receptors are bound and full intrinsic activity is achieved
Classify drugs as full, partial or inverse agonists according to their dose-response curves
Distinguish between quantal and graded responses and recognize when a response is graded vs quantal
Tell the difference between graded vs. quantal curves
Recognize the interpret quantal dose-response curves when plotted cumulatively or non-cumulatively
Cumulative
- % of individuals AT AND BELOW that dose
Non-Cumulative
- % of individuals AT A SINGLE DOSE
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)
Define tolerance (and tachyphylaxis) and sensitization, and depict them in terms of shifts in dose-response curves
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
Define absorption, distribution and elimination
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
Understand basic principles determining passage of drugs across biological membranes
-
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
- Lipid solubility
- When molecules are charged (anion or cations), they are very hydrophilic and do not readily diffuse across membranes
-
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
Define weak acid and weak base and predict shifts in the ionization states and membrane permeability of weak acids/bases with changes in pH
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
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
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
Describe Drug distribution and the factors that influence it
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(
Describe the renal and biliary excretion of drugs
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
Define biotransformation and its fundamental purpose
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)
Describe and distinguish between phase I and phase II reactions and recognize various types of reactions as being phase I or phase II
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
Define a prodrug and describe when it may be necessary to develop a prodrug
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
Understand the principle of drug dosing and what it meant by the term therapeutic window
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
Describe how changes in pharmacokinetics can influence dosing for active drug and prodrugs and drug efficacy/safety
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
- Absorption:
-
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
- Absorption
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
Understand how induction/inhibition of metabolic enzymes can alter drug effects
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
Define the term genetic polymorphism and describe how a genetic polymorphism can affect drug metabolism (cite the example of aldehyde dehydrogenase and alcohol metabolism)
-
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
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
-
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
- Example: acetaminophen (tylenol) overdose
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
- Normal tylenol dose (650 - 1000 mg)
- Higher tylenol dose
- completely saturation of transferase enzyme
- Cytochrome P450 (phase I)
- Toxic metabolite = NAPQE Phase II
- Cytochrome P450 (phase I)
- completely saturation of transferase enzyme
- Tylenol overdose (7.5-10 g in non-alcoholic)
- depletion of glutathione
- Causes liver damage
Understand the basic definition of clearance
- 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
Explain what it means for a drug to have a small or large volume of distribution
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
Be familiar with the basic responses of target organs in response to sympathetic and parasympathetic stimulation
Parasympathetic: Cranial + sacral
Sympathetic: thoracic + lumbar
