PHARM EXAM 1

Guiding Principles of Pharmacotherapy

• Every medication should have a justifiable and documented indication for its use.
• Medications should be used at the lowest dosage and for the shortest duration to achieve the desired outcome.
• Monotherapy is preferred when a patient is adequately treated with a single drug.
• Newly approved medications should only be used if they have clear advantages over older medications.
• Lifestyle modifications should be made before using medications, when indicated.
• The selection of a medication regimen should be based on evidence from controlled clinical trials.
• The timing of drug administration should be considered as a possible influence on drug efficacy, adverse effects, and interactions with other drugs.

Preclinical Research

• Purpose: to discover toxicity
• Involves In Vitro and In Vivo studies
• Required to follow Good Laboratory Practices (GLP) requirements
• GLP requirements address study conduct, personnel, facilities, equipment, written protocols, operating procedures, study reports, and quality assurance oversight.

Clinical Research

• Involves designing clinical trials with protocols, inclusion/exclusion criteria, control groups, drug regimens, and data collection and analysis methods.
• Clinical research phase studies include:
  • Phase 1: Safety and dosage (20-100 participants)
  • Phase 2: Efficacy and side effects (up to several hundred participants)
  • Phase 3: Efficacy and monitoring of adverse reactions (300-3,000 participants)
  • Phase 4: Safety and efficacy (several thousand participants)

The Investigational New Drug Process

• Involves submitting toxicity data from animal studies, manufacturing information, human studies, and investigator information to the FDA.
• Researchers can ask for FDA assistance at any point in the process.

FDA Review

• The FDA review team has 30 days to review the original IND submission.
• The FDA responds to IND applications in one of two ways: approval to begin clinical trials or clinical hold to delay or stop the investigation.
• The FDA can place a clinical hold for specific reasons, including unreasonable or significant risk to participants, unqualified investigators, misleading materials, and inadequate information about the trial's risks.

New Drug Application

• Purpose: to demonstrate that a drug is safe and effective for its intended use in the population studied.
• Includes all information from preclinical data to Phase 3 trial data, as well as reports on all studies, data, and analyses.
• Also includes proposed labeling, safety updates, drug abuse information, patent information, and directions for use.

FDA Approval

• The FDA review team decides if the NDA is complete and then reviews it within 6 to 10 months.
• Once approved, the FDA finalizes labeling, which accurately and objectively describes the basis for approval and how best to use the drug.
• May require additional studies prior to approval for marketing.

Pharmacokinetics

• The movement of drugs through the body.
• Involves administration, absorption, distribution, metabolism, and excretion (ADME).
• Administration routes include enteral, parenteral, and other routes.

Absorption

• Factors influencing absorption: pH, blood flow, total surface area, contact time, and expression of P-glycoprotein.
• Bioavailability: IV vs oral (%), first pass hepatic metabolism, solubility, chemical instability, and nature of drug formulation.
• Bioequivalence vs. therapeutic equivalence (generics).

Absorption from the GI Tract

• Passive diffusion: no energy required, can be saturated, may be inhibited by competing compounds.
• Facilitated diffusion: carrier proteins, energy dependent, can be saturated, may be inhibited by competing compounds.
• Active transport: energy dependent, can move against concentration gradient, can be saturated, may be inhibited by competing compounds.
• Endocytosis: transport of exceptionally large molecules.

Permeation and Flux

• Fick's Law: describes passive movement of molecules down their concentration gradient.
• Flux (J) = (C1 - C2) · (Area · Permeability coefficient) / Thickness.

pH and Drug Absorption

• Henderson-Hasselbalch equation: log (protonated)/(unprotonated) = pKa - pH.
• For acids: pKa = pH + log (concentration [HA]/concentration [A-]).
• For bases: pKa = pH + log (concentration [BH+]/concentration [B]).
• The protonated form of an acid is uncharged, while the protonated form of a base is charged.
• Weak acids at acid pH will be more lipid-soluble because they are uncharged.

Drug-Receptor Interactions and Pharmacodynamics

• Pharmacokinetics: the movement of drugs through the body
• Pharmacodynamics: the body's biological response to drugs

Drug-Receptor Interactions:

• Drugs act as signals, receptors are signal detectors
• The magnitude of the cellular response is proportional to the number of drug-receptor complexes
• Not all drugs exert effects by interacting with a receptor
• Receptor: any biologic molecule to which a drug binds and produces a measurable response (e.g. enzymes, nucleic acids, structural proteins)

Agonist, Antagonist, and Partial Agonist:

• Agonist: converts an inactive receptor to an active receptor, produces a measurable response
• Antagonist: blocks the receptor, keeping it in an inactive state and preventing it from binding and being converted to an active state
• Partial Agonist: similar to agonist, but with fewer activated receptors

Signal Transduction:

• The drug-receptor complex triggers a response
• Major receptor families:
  • Transmembrane ligand-gated ion channels
  • Transmembrane G protein-coupled receptors
  • Enzyme-linked receptors
  • Intracellular receptors
• Characteristics of signal transduction:
  • Signal amplification
  • Desensitization and down-regulation of receptors

Signal Transduction Receptor Families:

• Examples:
  • Acetylcholine, Nicotine, Chantix (transmembrane ligand-gated ion channels)
  • Dopamine, Epinephrine (transmembrane G protein-coupled receptors)
  • Insulin (enzyme-linked receptors)
  • Estrogen, Glucocorticoids, Paclitaxel, Trimethoprim, Erythromycin (intracellular receptors)

Dose-Response Relationships:

• Graded dose-response relationship
• Magnitude of the drug effect determined by:
  • Receptor sensitivity to the drug
  • Drug concentration at the receptor site
  • Dose of drug administered
  • Pharmacokinetic profile (absorption, distribution, metabolism, elimination)

Potency and Efficacy:

• Potency: a measure of the amount of drug necessary to produce an effect (EC50)
• Efficacy: the magnitude of response a drug causes when it interacts with a receptor, dependent on the number of drug-receptor complexes formed and the intrinsic activity of the drug

Intrinsic Activity:

• Full agonist: binds to a receptor and produces a maximal biologic response
• Partial agonist: has intrinsic activity greater than zero but less than one, cannot produce the same Emax as a full agonist
• Inverse agonist: has intrinsic activity less than zero, reverses the activation state of receptors
• Antagonist: binds to a receptor with high affinity but has zero intrinsic activity
  • Competitive antagonist: binds at the same site as the agonist in a reversible manner
  • Irreversible antagonist: binds covalently at the receptor, permanent binding
  • Allosteric antagonist: binds to a different site to prevent activation by agonist
  • Functional antagonist: action at a different receptor to create effects that are functionally opposite

Quantal Dose-Response Relationships:

• Therapeutic index (TI): the ratio of the dose that produces toxicity in half the population (TD50) to the dose that produces a clinically desired or effective response (ED50)

Pharmacogenomics

• Aims to predict how an individual may respond to a drug based on their genetics
• Over 250 drugs have been identified with pharmacogenomic implications, and over 40 are rated with the highest level of evidence (level A) for changing prescribing

Genotype and Phenotype

• Alleles: variant forms of genes, denoted with *
• SNP: single nucleotide polymorphism
• Haplotype: a group of inherited variations
• Genotype: an individual's collection of genes
• Phenotype: an observable trait
• Pharmacogenomics uses genotype results to predict a phenotype

Genotype-Phenotype

• Must evaluate individual alleles and interpret functional status
• Functional status is based on the level of activity associated with the allele:
  • Increased
  • Normal
  • Decreased
  • No
• The combination of alleles is used to predict the overall phenotype based on standardized translations

CYP2D6

• Metabolizes opioids, including codeine, tramadol, hydrocodone, and oxycodone
• Ultrarapid metabolizers (UMs) have higher concentrations of tramadol metabolite (O-desmethyltramadol) and codeine metabolite (morphine) than normal metabolizers (NMs), which may lead to increased risk of toxicity
• CPIC guidelines recommend against tramadol or codeine use in UMs
• Poor metabolizers (PMs) have significantly reduced metabolism to active compounds, which leads to decreased efficacy
• CPIC guidelines recommend against use in PMs

CYP2C9

• Metabolizes ~15% of drugs, including warfarin and NSAIDs
• 6 alleles are defined as Tier 1 (must test) variants
• A scoring system is used to determine the total activity score and to translate the genotype to phenotype
• Clinically relevant differences in allele frequencies exist between African Americans and Europeans

Warfarin

• Consists of S-enantiomer (more active) and R-enantiomer
• S-enantiomer is metabolized to inactive metabolite
• If decreased enzyme activity occurs, a lower dose is needed to achieve target effects
• Also affected by VKORC1 genetic polymorphisms- can also allow a lower dosage if allele is present
• CPIC guidelines include a dosing algorithm for genotype-based recommendations rather than phenotype-based recommendations

NSAIDs

• Metabolized to inactive metabolites
• Intermediate metabolizers (IMs) and PMs have higher exposure to NSAID concentrations, which may or may not be clinically significant for association to adverse effects
• CPIC guidelines recommend PMs receive 25% to 50% of the lowest starting dose and IMs receive the lowest starting dose
• Alternative agents or dose reduction may be recommended for certain NSAIDs

METABOLISM-REACTIONS-P450

• Voriconazole-CYP2C19 genotype interaction
• Genetic variations influence the activity of CYP2C19, the primary enzyme responsible for metabolizing voriconazole
• Ultrarapid metabolizers are at increased risk of subtherapeutic levels and decreased efficacy
• Poor metabolizers are at increased risk of supratherapeutic troughs, which may cause adverse events

Drug Transporters

• Membrane-bound proteins that move drugs across biologic membranes
• Located throughout the body, but the most important locations include the liver, kidney, intestine, and BBB
• Promote influx or efflux of drug molecules
• Genetic factors can impact transporter expression and affect efficacy and toxicity of a drug

ATP-Binding Cassette Transporters

• These transporters bind adenosine triphosphate (ATP) and use the energy to drive the transport of molecules across the membrane
• P-glycoprotein is the most widely studied, but there are no clinical recommendations for PGP variation

Solute Carrier Transporters

• There are ~350 known solute carriers (SLC) transporters
• SLC transporters do not require ATP to transport molecules across the membrane
• The three most common types are OATPs, OCTs, and OATs

OATP1B1

• Hepatic transporter that moves drugs from the blood into the hepatocyte, particularly statins
• Decreased expression of OATP1B1 prevents drugs from entering the cell and results in increased plasma concentrations and increased adverse effects
• CPIC guidelines recommend lower simvastatin doses or alternative agents in patients with poor SLCO1B1 function

OATP1A2

• Intestinal influx transporter that moves drug molecules from the intestinal lumen into the endothelial cells of the intestine, which then allows the drug to get into the blood and be absorbed
• Genetic polymorphisms that result in decreased activity reduce the ability of the drug to get through the intestine to the blood and result in decreased absorption and lower drug concentrations
• In addition to genetic polymorphisms, other substances can inhibit transporters and cause a similar effect

Signal Transduction Characteristics

• Signal amplification allows for a maximal response with only a fraction of total receptors occupied, due to "spare receptors".

• Desensitization and downregulation of receptors occur due to prolonged agonist stimulation, resulting in diminished response.

  • Tachyphylaxis: phosphorylation renders receptors unresponsive to the agonist.
  • Downregulation: receptors are internalized within the cell and unable to interact with the agonist, requiring a finite time before they can be activated again (refractory).

• Repeated exposure to an antagonist can lead to upregulation, where receptor reserves are inserted into the membrane, increasing the number of available receptors.

Dose-Response Relationships

• Graded dose-response relationship: the effect of a drug increases as the concentration increases, until all receptors are occupied.
• Potency: the amount of drug necessary to produce an effect, measured by EC50 (the concentration producing 50% of the maximum effect).
  • A smaller EC50 indicates a more potent drug.
• Efficacy: the magnitude of response a drug causes when interacting with a receptor, dependent on the number of drug-receptor complexes formed and intrinsic activity.
  • Emax: the maximum efficacy, assuming the drug occupies all receptors.
• Therapeutic Index (TI): the ratio of the dose producing toxicity in half the population (TD50) to the dose producing a clinically desired response (ED50), measuring the safety of a drug.
  • A larger TI indicates a wider safety margin.

Clinical Usefulness of TI

• Warfarin: a small TI, with bioavailability critically altering therapeutic effects.
• Penicillin: a large TI, with bioavailability not critically altering therapeutic effects.

Pharmacogenomics

• Pharmacogenomics: the study of how genetic variation affects drug response, allowing for personalized medicine.
• Genomic medicine: the study of how genes affect health.

Pharmacogenomics Implementation

• CPIC: the Clinical Pharmacogenomics Implementation Consortium, providing peer-reviewed, evidence-based clinical guidelines.
• PharmGKB: a database providing information on the impact of genetic variation on drug response.
• AMP: the Association for Molecular Pathology, publishing recommendations on variations to include in testing panels.
• FDA: providing a "table of pharmacogenetic associations" for genetic variations affecting drug response.

Pharmacogenomics Terminology

• Alleles: variant forms of genes, denoted with *.
• SNP: single nucleotide polymorphism.
• Haplotype: a group of inherited variations.
• Genotype: an individual's collection of genes, often used to predict a phenotype.
• Phenotype: an observable trait.

Genotype-Phenotype

• Evaluating individual alleles and interpreting functional status.
• Functional status is based on the level of activity associated with the allele: increased, normal, decreased, no, or unknown.

Drug Metabolizing Enzymes

• Metabolizing a wide variety of xenobiotic chemicals, including drugs, pollutants, and endogenous chemicals.
• Primary role: transforming compounds into more hydrophilic, polar entities to enhance elimination from the body.
• Can result in active or inactive metabolites, and are affected by gene polymorphisms.

Drug Transporters

• Membrane-bound proteins that move drugs across biologic membranes.
• Most important in the liver, kidney, and blood-brain barrier.
• Influx and efflux of drug molecules, with genetic factors impacting transporter expression and affecting efficacy or toxicity.
• Two general families: solute carrier (SLC) transporters and ATP-binding cassette (ABC) transporters.
• OATP1B1: moves drugs from blood to hepatocyte, with decreased expression preventing drugs from entering cells and increasing plasma concentrations.

CYP450 Inducers and Inhibitors

• CYP450 inducers: increasing the expression of CYP450 enzymes, such as PARC GPS.
• CYP450 inhibitors: decreasing the expression of CYP450 enzymes, such as PACMAN-G.

Guiding Principles of Pharmacology

• A justifiable and documented indication is necessary for every medication.

Rationale for Medication Use

• Medication should be used at the lowest dosage for the shortest duration of time to achieve the desired outcome.
• Monotherapy is preferred when adequate.
• Newly approved medications should be used only if there is a clear advantage over older medications.

Evidence-Based Medicine

• The selection of medication should be based on evidence obtained from controlled clinical trials when possible.

Drug Administration and Efficacy

• The timing of drug administration can influence drug efficacy, adverse effects, and interactions with other drugs and food.
• Medication regimens should be simplified as much as possible to enhance patient adherence.

Patient Factors and Adherence

• A patient's perception of illness or the risk and benefits of therapy can affect adherence and treatment outcomes.
• Careful observation of a patient's response to treatment is necessary to confirm its efficacy, prevent, detect, or manage adverse effects, assess compliance, and determine the need for drug dosage adjustments or discontinuation of drug therapy.

Medication Selection and Lifestyle Modifications

• Medication should not be given by injection when giving it by mouth would be just as effective and safe.
• Lifestyle modifications should be made, when indicated, before medications are used.

Medication-Related Adverse Effects

• Medication can cause a disease, sign, symptom, syndrome, or abnormal lab tests.

Cost-Effective and Convenient Care

• When a variety of drugs are equally effective and safe, the drug that results in the lowest healthcare cost or is more convenient for the patient should be chosen.
• Patients' societal effects should be considered.

Addressing Failure of Medication

• Possible reasons for failure of medication include:
  • Inappropriate drug selection
  • Poor adherence
  • Improper drug dose or interval
  • Misdiagnosis
  • Concurrent illness
  • Interaction with food or drugs
  • Environmental factors
  • Genetic factors

Drug Development Process

• The drug development process involves five steps: discovery and development, preclinical research, clinical research, FDA review, and post-market drug safety monitoring.

Step 1: Discovery and Development

• Examines molecular compounds.

Step 2: Preclinical Research

• Aims to discover toxicity in vitro (outside the body) and in vivo (in people or animals).
• Required to follow Good Laboratory Practices (GLP) requirements.

Step 3: Clinical Research

• Researchers can ask for FDA assistance at any point in the process.
• FDA IND review team consists of:
  • Project Manager: Coordinates the team's activities and is the primary contact for the sponsor.
  • Medical Officer: Reviews clinical study information and data.
  • Statistician: Interprets clinical trial designs and data.
  • Pharmacologist: Reviews preclinical studies.
  • Pharmakineticist: Focuses on the drug's absorption, distribution, metabolism, and excretion processes.
  • Chemist: Evaluates a drug's chemical compounds.
  • Microbiologist: Reviews data for antimicrobial products.

FDA Approval

• FDA review team has 30 days to review the original IND submission.
• The process protects volunteers who participated in clinical trials from unreasonable and significant risk.
• FDA responds to IND application in one of two ways:
  • Approval to begin clinical trial.
  • Clinical hold to delay or stop investigation.

Step 4: FDA Review

• New drug application (NDA) purpose is to demonstrate that a drug is safe and effective for its intended use in the population studied.
• NDA includes:
  • Preclinical data to Phase 3 trial data.
  • Reports on all studies, data, and analyses.
  • Proposed labeling.
  • Safety updates.
  • Drug abuse information.
  • Patent information.
  • Data from studies conducted outside the United States.
  • Institutional review board compliance information.
  • Directions for use.
• FDA review: complete or not complete; if complete, 6-10 months to make a decision.

FDA Approval

• Finalize labeling.
• May require additional studies prior to approval for marketing.

FDA Advisory Committees

• Provide independent, expert advice and permit public comments.
• Includes a patient representative providing input from the patient perspective.

Step 5: Post-Market Drug Safety Monitoring

• Supplemental applications.
• INDs for marked drugs.
• Manufacture inspection.
• Drug advertising.
• Generic drugs.
• Reporting problems.
• Surveillance.

Drug Studies Evidence Levels

• Top 3:
  • Meta-analysis.
  • Systematic review.
  • Randomized controlled trials.

Pharmacokinetics: "ADME"

Absorption

• Entry of a drug from the site of administration into the plasma (input)
• Types of absorption:
  • Passive diffusion: no carrier, not saturable, low structural specificity, applies to most drugs
  • Facilitated diffusion: specialized transmembrane carrier proteins, no energy required, can be saturated
  • Active transport: carrier proteins, energy-dependent, can be saturated, selective
  • Endocytosis: for transport of exceptionally large molecules (e.g. B12)

Factors Influencing Absorption

• pH: most drugs are weak acids or weak bases, affect drug absorption
• pKa: measure of the strength of the interaction of a compound with a proton
  • Lower pKa = more acidic
  • Higher pKa = more basic
• Henderson-Hasselbalch equation: describes how protonated and non-protonated molecules move
• Blood flow to absorption site: higher blood flow = greater absorption
• Total surface area: greater surface area = greater absorption
• Contact time: longer contact time = greater absorption
• Expression of P-glycoprotein: a transmembrane transporter protein that reduces drug absorption

Distribution

• Leaves the bloodstream and is distributed to specific tissues and interstitial fluids
• Factors affecting distribution:
  • Blood flow
  • Capillary permeability
  • Liver capillary: large fenestrations allow drugs to move between blood and interstitium
  • Brain capillary: tight junctions prevent many substances from entering
• Protein binding: albumin is the major drug-binding protein, affects drug distribution and half-life
• Lipophilicity: affects drug distribution into the brain and other tissues

Metabolism

• Transformation of a drug by the liver or other tissues, changes the plasma concentration of the drug
• Kinetics of metabolism:
  • First-order kinetics: constant fraction of drug is metabolized per unit of time
  • Michaelis-Menten kinetics: rate of metabolism depends on the concentration of the drug
• Reactions of drug metabolism:
  • Phase I: usually involve reduction, oxidation, or hydrolysis
  • Phase II: most often glucuronidation, prepares the drug for elimination
• Enzymes involved in metabolism:
  • Cytochrome P450 system: heme-containing proteins, located primarily in liver and GI
  • Genetic variability: affects drug metabolism and response

Elimination

• Removal of a drug from the body (output)
• Routes of elimination:
  • Renal: kidneys are the primary source of elimination
  • Hepatic: bile is the primary route of elimination
  • Other: lungs, breast milk, sweat, tears, hair, and skin
• Factors affecting elimination:
  • Diminished renal or hepatic blood flow
  • Decreased ability to extract blood from plasma
  • Decreased metabolism
  • Drug interactions or hepatic impairment