1. Pharmacokinetics

pharmacokinetics

movement of drug in the body, study of the kinetics of drug absorption, distribution, metabolism and excretion

what are the approaches of pharmacokinetics?

experimental and theoretical

pharmacodynamics

studies the biochemical and physiological effects of drugs on the body

clinical pharmacokinetics

utilizes the application of biopharmaceutics, pharmacokinetics, and pharmacodynamics to achieve optimum drug therapy in the individual patient

pharmacogenetics

The study of variability in drug response due to heredity

pharmacogenomics

study of the genetic basis of disease and pharmacodynamic impact of the drug in the patient

what does the recommended dose from the manufacturer include?

drug dose and frequency of doses, regimen if provided by what was found to be safe and efficacious in most of the patients in the clinical trials

why are plasma drug concentrations measured in patients

to determine whether a lack of response is due to subtherapeutic dosing or differences in drug response

what does a low plasma drug concentration indicate

the drug dose may be sub therapeutic due to the patient's pharmacokinetic profile

what does it mean if drug concentration are in the therapeutic range by the patient does not respond

the patient may have a genetic difference affecting receptor response

how can genetic differences affect drug therapy

they can alter receptor response, leading to reduced or absent therapeutic effects

what are the possible ranges of drug concentration in the body

sub therapeutic, therapeutic and toxic

why do some patients respond to drug treatment at lower doses

they are more sensitive to the drug and require lower plasma concentrations for effect

why do some patients require higher drug doses to achieve a therapeutic effect

they need higher plasma drug concentrations to respond to the treatment

what is the desired relationship between therapeutic and adverse drug concentrations

adverse effects should occur at concentrations higher than therapeutic levels

why are adverse effects a concern with potent drugs

adverse effects can occur at drug concentrations close to those needed for therapeutic effects

what clinical issue occurs when therapeutic and toxic drug concentrations are close together

there is a narrow therapeutic window, increasing the risk of toxicity

What is the general relationship between drug dose and pharmacodynamic response?

A higher drug dose generally produces a greater pharmacodynamic response.

Why is drug concentration in the body a better predictor of response than administered dose?

Drug concentration is more closely related to drug response than the amount of drug administered.

Why is the concentration of drug at the receptor site important?

It is more consistently related to the magnitude of the pharmacodynamic effect.

What is pharmacokinetics based on?

Measurement of drug concentrations in the body at various time intervals after a given dose.

In what types of biologic samples can drug concentrations be measured?

milk, saliva, plasma, urine, and other tissues

Why must analytical methods for drug measurement be sensitive, accurate, and precise?

To ensure accurate pharmacokinetic analysis and clinical drug monitoring.

Why must analytical drug measurements be validated?

To ensure that accurate and reliable information is generated.

What analytical methods are most commonly used to measure drug concentrations?

chromatographic and mass spectrometric methods

Why is chromatography used in drug concentration measurement?

It separates the drug from other substances that may cause assay interference.

What is the role of mass spectrometry in drug analysis?

It detects molecules or molecular fragments based on their mass-to-charge ratio.

invasive methods of sampling

blood, spinal fluid, synovial fluid, tissue biopsy, or other biologic material that requires parenteral or surgical intervention in the patient

noninvasive methods of sampling

urine, saliva, feces, expired air, or biologic material obtained with surgical intervention

what does the measurement of drug and metabolite concentration in biologic materials yield?

important information, such as the amount of drug

retained in, or transported into, that region of the tissue or fluid, the likely pharmacologic or toxicologic outcome of drug dosing, and drug metabolite formation or transport

what drug concentration is most related to safety and efficacy?

unbound concentrations

Why are distinctions between drug metabolites in different tissues and fluids important for initial pharmacokinetic modeling?

Because different metabolites may have varying activity and distribution, which affects accurate modeling of drug behavior in the body.

how is whole blood obtained

venous puncture and contains an anticoagulant such as heparin or EDTA

what are the components of whole blood

contains all the cellular and protein elements of blood

how is serum obtained

liquid obtain from whole blood after the blood is allowed to clot and the clot is removed

what are the components of serum

does not contain cellular elements, fibrinogen, or other clotting factors from the blood

how is plasma obtained

liquid supernatant obtained after centrifugation of non-clotted whole blood that contains an anticoagulant

what are the components of plasma

noncellular liquid fraction of whole blood and contains all the proteins including albumin

Why are drug concentrations more often measured in plasma rather than whole blood or serum?

Drug concentrations are more often measured in plasma because plasma drug levels are in dynamic equilibrium with tissue concentrations and therefore best reflect changes in drug levels at tissue and receptor sites while avoiding interference from cellular components of whole blood

What are the differences between bound drug, unbound drug, total drug, parent drug, and metabolite drug concentrations in the plasma?

In plasma, bound drug is drug attached to plasma proteins, unbound drug is free drug responsible for safety and efficacy, total drug is the sum of bound and unbound drug, parent drug is the original administered compound, and metabolite drug refers to drug products formed by biotransformation

how is the plasma drug concentration-time curve created?

from blood samples taken at various time intervals after the drug product is administered

MEC

minimum effective concentration, reflects the minimum concentration of drug needed at the receptors to produce the desired pharmacologic effect

MTC

minimum toxic concentration, represents the drug concentration needed to just barely produce a toxic effect

What happens to plasma drug concentrations after a single extravascular dose?

Plasma drug concentrations rise to a maximum and then decline over time.

Why do plasma drug concentrations initially rise and then decline?

Drug absorption initially exceeds elimination, followed by elimination exceeding absorption.

What processes are involved in drug elimination from the body?

Drug absorption initially exceeds elimination, followed by elimination exceeding absorption.

What does the onset time of drug action represent?

The time required for the drug concentration to reach the minimum effective concentration (MEC).

How is the intensity of the pharmacologic effect related to plasma drug concentration?

Higher plasma drug concentrations produce greater pharmacologic effects up to a maximum.

How is the duration of drug action defined?

The time between onset of action and the decline of drug concentration back to the MEC.

therapeutic window

concentrations between the MEC and MTC

what therapeutic window is considered safer?

Drugs with a wide therapeutic window are generally considered safer than drugs with a narrow therapeutic window.

what is Cmax related to?

peak plasma level or maximum drug concentration is related to the dose, the rate constant for drug absorption, and the drug elimination constant

what is Tmax related to

time for peak plasma level, time of maximum drug concentration in the plasma and is a rough marker of average rate of drug absorption

what is AUC related to

area under the curve, related to the amount of drug absorbed systemically (bioavalible)

Why is measuring drug concentration in tissue biopsies difficult?

Only a small tissue sample is removed, making accurate measurement difficult.

Why may drug concentrations in a tissue biopsy not represent the entire tissue?

Blood flow and drug distribution can vary within different parts of the same tissue.

How can differences in blood flow affect tissue drug concentrations?

Areas with different blood flow may receive different amounts of drug.

What information can measurement of drug concentration in tissue biopsy material provide?

it can determine whether the drug reached the tissue and achieved the proper concentration.

How are drug concentrations in tissues usually determined?

They are generally estimated using pharmacokinetic models.

Why is measurement of drug in urine considered an indirect method of assessing bioavailability?

The rate and extent of urinary drug excretion reflect systemic drug absorption.

How can urinary drug excretion data be used clinically?

To determine renal versus nonrenal elimination and adjust drug doses in patients with impaired renal function.

What can measurement of drug in feces indicate after oral administration?

It may indicate unabsorbed drug or drug eliminated via biliary secretion.

Why are urine and feces collected in mass balance studies?

To account for the entire drug dose administered to the patient.

Why may fecal collection be used for some solid oral dosage forms?

To recover undissolved dosage forms and assay them for residual drug.

Why do saliva drug concentrations approximate free drug rather than total plasma drug concentration?

Only free (unbound) drug diffuses into saliva.

What factors influence the saliva/plasma drug concentration ratio?

the pKa of the drug and the pH of saliva

Why should salivary drug concentrations be used cautiously?

They are best used as a secondary indicator and may not reliably reflect total plasma drug concentration.

What is forensic science?

The application of science to personal injury, murder, and other legal proceedings.

In what situations are drug measurements useful in forensic investigations?

when overdose, poisoning or drug abuse is suspected

Which biologic samples are commonly analyzed in forensic drug testing?

tissues, blood, urine, saliva, and hair

What does the presence of social drugs in blood, urine, or saliva indicate?

short-term drug abuse

Why can short-term drug abuse be difficult to prove using blood or urine samples?

Because many drugs are eliminated rapidly from the body.

why are hair samples useful in forensic drug analysis

they provide information about past drug exposure

What analytical methods are commonly used for drug detection in hair samples?

gas chromatography couple with mass spectrometry

Why is plasma drug concentration related to pharmacologic or toxic effects?

Because drug effects depend on drug concentration at receptor sites in tissues.

Why is measuring plasma drug levels an objective method of monitoring therapy?

Plasma perfuses tissues, so plasma drug levels reflect tissue drug concentrations.

Why is plasma drug monitoring important given patient variability?

Pharmacokinetic differences can affect whether therapeutic plasma levels are achieved.

How can plasma drug monitoring distinguish overdosing from hypersensitivity?

By determining whether high effects are due to high drug levels or increased receptor sensitivity

Why are pharmacokinetic models important when interpreting plasma drug levels?

They help relate plasma concentrations to pharmacologic response accurately.

Why are plasma drug levels alone insufficient for dosage adjustment?

Without timing, dose, and route information, plasma levels cannot be properly interpreted.

How does monitoring plasma drug concentrations help optimize therapy?

It allows dosage adjustments to maintain effective and safe drug levels.

Why should therapeutic decisions not be based solely on plasma drug concentrations?

Clinical judgment and patient observation are also essential.

When may pharmacodynamic response be more important than plasma drug concentration?

When drug effects are better reflected by physiologic measurements.

Give an example of a pharmacodynamic measure used instead of plasma drug levels.

ECG monitoring for digoxin or prothrombin time for anticoagulants.

Why may plasma drug concentrations not predict response for irreversible drugs?

Because their effects persist even after plasma concentrations decline.

How is toxicity monitored for cancer chemotherapy drugs?

By monitoring pathophysiologic parameters and side effects rather than plasma levels.

What factors determine the onset, intensity, and duration of a pharmacologic effect?

The drug dose and the pharmacokinetics of the drug.

How does increasing drug dose affect receptor site concentration and pharmacologic response?

Increasing the dose increases drug concentration at the receptor site and increases the response up to a maximum.

What is the shape of the dose-response curve when plotted on a linear scale?

A hyperbolic curve with a plateau at the maximum response.

What type of curve results when dose-response data are plotted on a log-linear scale?

a sigmoid curve

Why is the 20%-80% range of the log dose-response curve clinically important?

It represents the linear portion of the curve and typically includes the therapeutic dose range.

What is drug tolerance, and how is it demonstrated pharmacodynamically (PD)?

Drug tolerance is a quantitative decrease in receptor sensitivity and is demonstrated by a reduced pharmacologic effect after repeated exposure to the same drug.

For which classes of drugs has tolerance been well described?

Organic nitrates, opioids, and other drugs.

How do dosage and frequency of administration affect drug tolerance?

The magnitude of drug tolerance increases with higher doses and more frequent administration

What is cross-tolerance?

Cross-tolerance occurs when tolerance to one drug reduces responsiveness to another drug acting on the same receptor.

Why does tolerance not develop uniformly to all drug effects?

Different pharmacologic and toxic effects may involve different mechanisms or receptor sensitivities.

what are the two main mechanisms of drug tolerance?

Pharmacokinetic (PK) tolerance and pharmacodynamic (PD) tolerance.

how does pharmacokinetic (PK) tolerance develop?

Through enzyme induction that increases hepatic drug clearance with repeated exposure.

How does pharmacodynamic (PD) tolerance develop?

Through cellular or receptor alterations that reduce drug response despite similar drug concentrations

What is acute tolerance (tachyphylaxis)?

A rapid development of tolerance occurring after one or a few doses due to receptor sensitivity changes or cofactor depletion.