Csf Test 2 Kuma

Front 1

clinical pharmacology goal

Back 1

Major goals in clinical pharmacology are to describe, quantitate and predict drug effects in humans.

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knowledge and requirements for clinical pharmacology

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Pharmacokinetics: the time course of a drug in humans
Pharmacodynamics: relationships between the dose or concentration of drug in the body and measured effects
Pharmacogenetics: a discrete inherited trait related to drug absorption and disposition, as well as response

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Drug approval process

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Pre-Clinical Laboratory and animal testing to determine biologic activity and safety. (2y)
Phase I First human administration to establish pharmacologic profile. (1y)

Phase II Clinical trials to assess drug activity, both safety and efficacy. (2y)

Phase III Extensive clinical trials in comparison with other compounds to confirm safety and efficacy. (3y)

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PK

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Types of studies: single and multiple doses, dose ranging (ie: dose esculations studies to determine therapuetic response changes and toxicities), bioavailability, and radioactive labeled.
Parameters of interest: Cmax and Cmin, F, Vd, T1/2, AUC, % recovery, and CL, renal, non-renal, and total.
Other considerations: food, renal or hepatic insufficiency, age, gender, race, pregnancy, drug interactions, and concomitant diseases.

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PD

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Types of studies: dose-ranging, open and controlled trials to establish preliminary safety and efficacy, and concentration-response.
Parameters of interest: lowest and highest useful dose or concentration, and maximum tolerated dose; formal modeling can be applied to determine maximum effect, and concentration that produces half maximal effect.
Other considerations: special populations (neonates, geriatrics), and concomitant diseases and drugs.

how disease states affect PD

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PK factors

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drug dose

biological fluid concentration
effect site concentration

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PD factors

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effect site concentration
phamacological effect

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Therapeutic window

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Between the upper and lower limits of drug concentration lies in the region of desirable concentration

based on probabilities
lots of variability with in patients

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Pharmacokinetics, Pharmacodynamics, and Rational Drug Development

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The objective of drug labeling is to advise the prescriber regarding safe and effective use
The basis of dosing recommendations for individual treatment should be the derived exposure-response relationship:
To guide practitioners when monitoring desired or adverse effects
To assist practitioners in optimizing the use of the drug in a variety of patients
To help practitioners appreciate the existence of interpatient variability in response, its causes, and ways to avoid adverse reactions

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Therapeutic Response Rates

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Asthma Beta-agonists, others 25-60

Solid cancers
Various 0-30

Depression SSRIs, tricyclics, others 60-80

Diabetes Sulfonylureas, others 25-50

Arthritis NSAIDs, COX-2 inhibitors, others 50-80

Migraine Triptans, NSAIDs, ergots 40-70

Schizophrenia Various 25-75

Major drug toxicity Various 2 million hospitalized patients/yr4th to 6th leading cause of death in the United States in 19941

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systemic concentration influenced by

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PK
ADME
compliance

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Pharmacologic site of action influenced by

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Systemic and cellular PK

drug transport and uptake
intracellular kinetics

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drug receptor influenced by

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PD
host factors
target factors

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Continuum of Pharmacotherapy

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Dose-->systemic concentration-->pharmacologic site of action-->drug receptor interaction-->therapeutic response

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Concepts of Applied Pharmacokinetics (Therapeutic Drug Monitoring)

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The objective is to promote optimum drug treatment, i.e., maximize efficacy and minimize toxicity
The notion of a therapeutic range is a probabilistic concept - not an absolute entity
Concentration information must be used in conjunction with other clinical information

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patients are trreated on ____ response not _____

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clinical
numbers

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Pharmacologic Characteristics of Drugs Applicable for Therapeutic Drug Monitoring

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Pharmacokinetic drug data are available
Significant interpatient pharmacokinetic variability exists
The drug has a narrow therapeutic index
The pharmacologic effect observed persists for a relatively long period of time (not a problem with tolerance)
The pharmacologic effect is related to the drug concentration

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Clinical Characteristics of Drugs Applicable for Therapeutic Drug Monitoring

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Clinical studies have documented the therapeutic range of the drug
Plasma concentration reflects the concentration at the site of action
Lack of effect is detrimental to the patient

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Analytical characteristics of Drugs Applicable for Therapeutic Drug Monitoring

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The drug assay is accurate, precise and specific, requires a small sample volume, yields results quickly, and is relatively inexpensive

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Reasons for Measuring Drug Concentrations

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To provide a basis for individualizing a patient’s drug dosing regimen.
To determine if a change in pharmacokinetic behavior (and therefore potentially therapeutic outcome) has occurred as a result of a change in physiologic status or concomitant drug therapy and why changes occured (ie: drug interactions, physiological actions)
To provide additional information useful in evaluating therapeutic response.

much more interested in failing patients

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Clinical scenarios that might warrant determination of drug concentrations

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Lack of initial response in a patient
Loss of response in a previously stable patient
Questionable patient adherence
Drug- or dose-limiting toxicity
Renal, hepatic, and/or gastrointestinal disease
Potential and/or known drug interaction

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Inappropriate Use of Measured Drug Concentrations

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Concentrations obtained in stable patients, responding appropriately to therapy, with no evidence of toxicity
Concentrations obtained too soon after initiation or a change in the dose regimen, or at incorrect times (not at Css yet and will give the wrong perameters
Repetitive measurement in patients with no change in physiologic status (nothing to be gained)

may want to measure to assess the level is at the desired level to determine patient compliance

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Drug Concentration Monitoring: A Multidisciplinary Process

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decision to treat--> drug and dose selection--> dose preparation--> dose administration--> blood samples (timing and collection)--> sample processing (at appropriate times)-->sample analysis-->PK analysis (clinical assesment, kinectic calculations, data interpretation, data application)--> dose recommendation

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at what time do we want to collect drug concentrations

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at the troughs (Cmin) because they are the most re-prducable

collect concetrations right before next dosing

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If a drug has a very long T1/2 life and CL does it matter when concentrations are measured?

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No because Cmin and Cmax have very similar levels there is not much fluctuations

this would be something like a slow release product

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TDM: data collection

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History of drug administration
Drug, dose, dosage forms, routes of administration, times of administration, compliance, inpatient or outpatient
Time of sampling (relative to previous doses)
Present and previous measured concentrations
Clinical status of the patient
Weight, age, height, gender, medical problems, smoking, ethnicity, concurrent diseases
Concurrent drug therapy
Interacting drugs, assay interferences
Laboratory data
Renal function
Hepatic function
Protein binding
Active metabolites
Assay method
Matrix (plasma, serum)
Reproducibility, sensitivity, specificity
Usual pharmacokinetic parameters
Bioavailability, absorption rate constant, volume of distribution, protein binding, total and renal clearance

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Cornerstones of Monitoring Drug Therapy

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Understand the desired therapeutic outcome of drug therapy and the anticipated length of therapy
Assess the potential efficacy of the drug vs. other possible therapies for the patient
Determine monitoring parameters that will indicate optimal therapeutic outcome
Determine monitoring parameters that will indicate adverse drug reactions

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The Clinical Pharmacist and Applied Pharmacokinetics

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Educator
Physicians, nurses, patients, etc.
Collaborator
Physicians, nurses, technicians
Negotiator
To get things done correctly
Detective
When results do not make sense

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Concepts of Applied Pharmacokinetics (Therapeutic Drug Monitoring)

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The objective is to promote optimum drug treatment - to maximize efficacy and minimize toxicity
The notion of a therapeutic range is a probabilistic concept - not an absolute entity
Concentration information must be used in conjunction with other clinical information

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Steps of clinical pharmocolgy

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identify problem
goal
range
adjust
capitalize

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A patient receiving vancomycin 1g IV q12h (8 am and 8 pm) as 1-hour infusions has a trough (pre-dose concentration) drawn at 7:30 pm and a 2-hour post dose concentration obtained at 10 pm. The trough comes back as 11.1 mg/L and peak is 9.5 mg/L. How do you explain these levels?

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mixed up the samples
must interpret numbers

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When you see a higher thatn expected level in a patient what do you expect?

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CL has decreased

Css=Ro/CL

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Questions to ask yourself in every patient

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AFTER you have answered these questions you are ready to look at and interpret the measured levels:
Is the drug at steady state?
Was the correct dose administered?
Was the dose given as scheduled?
Is the patient compliant with therapy?
When did the drug infusion begin and end?
When was the blood sample drawn in relation to the dose?
Is this a drug with multicompartmental distribution?
From what site was the sample drawn?
Is the patient acutely or chronically ill? Stable organ function? Are concentrations likely to be at steady state?
What do I estimate the concentrations will be?

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Are the measured concentrations similar to what you estimated they would be?

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IF YES,
is the level in the appropriate range and/or close to your target concentration?
is the patient appropriately responding to therapy?
is the patient experiencing any drug-related adverse effects or toxicities that may be related to the drug level?
is there any reason to modify the regimen?
are any additional levels required and when should they be obtained?

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Are the measured concentrations similar to what you estimated they would be? in no

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IF NO,
go back and ask yourself all of the previous questions again!
is the level in the appropriate range and/or close to your target concentration?
is the patient appropriately responding to therapy?
is the patient experiencing any drug-related adverse effects or toxicities that may be related to the drug level?
is there any reason to modify the regimen?
are any additional levels required? When should they be obtained?
if the regimen needs to be modified, how soon does it need to happen and what is the most appropriate way to do it?

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Quantitative Framework for Optimizing Drug Therapy

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all centered around the patient

expected responses and measured responses

expected concentration and measured concentrations

dosing regimen

therapuetic goals

PK goals

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The Pharmacokinetic Consult: Information to Communicate

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a brief statement of the problem or question leading to the consultation

a summary of subjective and objective criteria influencing drug disposition and effects

recommendations for possible changes in drug therapy and follow up evaluations

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problem orriented approach: subjective

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Data include how the patient feels, or what can be observed about the patient
Data are generally descriptive in nature, and cannot be confirmed
Obtained by listening and observing

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problem oriented approach: objective

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The patient’s documented history
Results of various tests, procedures, and assessments: vital signs, physical examination findings, results of laboratory tests, radiographs, CT scans, ECGs
Current medications

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problem oriented approach assesment

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The use of subjective and objective data to assess therapy or develop a therapeutic plan
Etiology
Assessment if therapy is warranted
Assessment of current and/or new therapy
Drug, dose, duration
Compliance
Response to therapy
Assessment of adverse reactions

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problem oriented approach plan

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Diagnostic
Therapeutic
Current therapy - continue, modify, discontinue
Drugs to be avoided
Goals of therapy
Therapeutic and toxicity monitoring parameters
Patient education

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Applied Pharmacokinetics: What not to do!

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data supporting the clinical value of measuring plasma drug levels are still limited, and it is not uncommon that therapeutic drug monitoring leads to “treatment” of the plasma level rather than the patient