Pharm 3 Therapeutics: Rational Dosing

• Therapeutics aims to achieve beneficial effects with minimal adverse effects
• Clinicians must determine the optimal dose of a medicine for each patient to achieve this goal

Rational Approach

• Pharmacokinetics and pharmacodynamics principles are combined
• This approach helps understand the dose-effect relationship

Pharmacodynamics

• Governs the concentration-effect relationship
• Concepts of maximum response and sensitivity determine the effect's magnitude at a concentration

Pharmacokinetics

• Deals with the dose-concentration relationship
• Input, distribution, and elimination determine how rapidly and long the target organ is exposed to a drug

Dose and Effect Relationship

• Separated into pharmacokinetic (dose-concentration) and pharmacodynamic (concentration-effect) components
• Concentration links pharmacokinetics and pharmacodynamics
• It focuses on target concentration for rational dosing

Pharmacokinetics Primary Processes

• Input
• Distribution
• Elimination

Pharmacology Hypothesis

• A relationship can exist between a drug causing either a beneficial or toxic effect, which depends on the drug concentration
• The target concentration reflects a balance between beneficial and adverse effects
• The time course of concentration at the site of action is important

Pharmacokinetic and Pharmacodynamic Parameters

• Shown for selected drugs in adults can vary greatly

Standard Drug Dose

• It is based on trials
• conducted on healthy subjects and patients
• who possess average ability to absorb, distribute, and eliminate the drug
• May need adjustments for individual patients, depending on:
• physiological processes like body size and organ function maturation
• pathological processes like heart failure and renal failure

Basic Pharmacokinetic Parameters

• Volume of distribution measures the apparent space in the body to contain the drug
• Clearance measures the body's ability to eliminate the drug

Volume of Distribution

• Volume of distribution relates the amount of drug in the body to the drug concentration in blood or plasma

Calculating Volume of Distribution

• The calculated volume may be an apparent volume
• Apparent volume is determined by comparing the volumes of distribution of drugs like digoxin or chloroquine with physical body volumes
• Volume of distribution can exceed any physical volume
• It is volume that is seemingly necessary to contain the amount of drug homogeneously at the concentration
• Drugs can have high concentrations in extravascular tissue if they are not homogeneously distributed
• Drugs that are completely retained within the vascular compartment have a minimum volume of distribution, equal to the plasma component

Clearance

• It is analogous to renal physiology clearance concepts
• Drug Clearance relates to the rate of elimination and the drug concentration
• It can be defined with respect to blood, plasma, or unbound in water

Organs of Elimination

• Kidney
• Lungs
• Liver

Total Systemic Clearance

• Sum the clearance at each organ to equal total systemic clearance

Kidneys and Liver

• Major elimination sites
• Renal clearance measures unchanged drug in the urine
• Liver drug elimination occurs via biotransformation to one or more metabolites, or excretion of unchanged drug into the bile, or both
• Pathways of biotransformation can often occur in the liver, which is difficult to measure, unlike measuring renal elimination
• Hepatic is often assume to be the difference between total system and renal clearance

Directly Proportional Elimination Constant

• Directly proportional to concentration
• The rate of drug elimination is directly proportional to drug concentration
• Clearance is constant over clinical concentration ranges (not saturable)

First-Order Elimination

• The rate of drug elimination is directly proportional to drug concentration
• It can be estimated by calculating the area under the curve (AUC) of the time-concentration profile after a dose
• It is calculated from the dose divided by the AUC
• It is a convenient calculation, but not the definition of clearance

Capacity-Limited Elimination

• For drugs such as phenytoin, and ethanol will not remain constant
• Depends on the drug concentration achieved
• The elimination can also be known as mixed-order, saturable, nonlinear, and Michaelis-Menten elimination
• Associated with either dose or concentration-dependent clearance

Drug Elimination Pathways

• Pathways become saturated by metabolism if the dose and concentration are high enough
• Blood flow to an organ does not limit elimination
• Mathematical equation expresses the relation between elimination rate and concentration

Maximum Elimination Capacity

• Vmax is the maximum elimination capacity
• Km is the drug concentration at which the rate of elimination is 50% of Vmax
• Elimination rate is almost independent of concentration at concentrations that are high relative to the Km, which is a "pseudo-zero order" elimination
• Steady state cannot be achieved if the dosing rate exceeds the elimination capacity
• Concentration will keep rising as long as dosing continues
• This is important for ethanol, phenytoin, and aspirin
• Clearance varies with concentration, so the AUC is avoided when calculating clearance for these drugs

Flow-Dependent Elimination

• Some drugs are cleared rapidly by the organ of elimination
• Most blood perfusing the organ is eliminated on the first pass
• Called "high-extraction" drugs
• Rate the drug is delivered to the organ as depends on
• blood flow to the organ
• plasma protein binding
• blood cell partitioning

Proteins

• Proteins, often large molecules used as therapeutic agents, have two aspects to their pharmacokinetics
• They all have the same pharmacokinetics with a half life of a weeks
• For some, the effect of the molecule is produced by binding to its target site
• Elimination may be determined by elimination of the target
• Target-mediated drug disposition occurs when the clearance of the molecule increases
• Half-life gets shorter
• Time course of the effect is often followed by changes in the time course of drug concentration

Half-Life

• The time required to change the amount of drug in the body by one-half during elimination is called half-life
• Simplest case is a single compartment, where:

t1/2 = (0.7 x V) / CL, 

• V is the volume of distribution
• CL the clearance.
• The constant .7 is an approximation of the natural logarithm of 2

Elimination Half-Life

• Time required to attain 50% of steady state, or to decay 50% from steady-state conditions
• Drug accumulation during a constant-rate drug infusion, and the time course of drug elimination stopping an infusion after steady state
• Disease states affect both primary pharmacokinetic parameters such as volume of distribution and clearance
• A change in the elimination half-life does not necessarily reflect a change in drug elimination
• Patients with chronic renal failure have decreased renal clearance of digoxin and a decreased volume of distribution
• The increase in the digoxin elimination half-life is not as great as expected based on the change in renal function
• Multicompartment pharmacokinetics has a “half-life” greater than calculated equation

Drug Accumulation

• Accumulates until dosing is stopped with repeated doses
• It takes an infinite time to eliminate all of a given dose in theory
• Accumulation will be detectable if the dosing interval is shorter than four half-lives

Accumulation

• Accumulation is inversely proportional to the fraction of the dose lost in each dosing interval
• You can make an index of accumulation
• The accumulation factor predicts the ratio of the steady-state concentration to that seen at the same time following the first dose
• Peak concentrations at steady state with intermittent doses will equal to peak concentration after first dose multiplied by the accumulation factor

Bioavailability

• Fraction of unchanged drug reaching the systemic circulation via route
• Bioavailability is shown with the area under the drug blood concentration-time curve
• Intravenous bioavailability assumed is 1
• Oral bioavailability may be <100%

Reasons for Reduced Bioavailability

• Incomplete gut wall absorption
• First-pass elimination by the liver

Drug Absorption

• It may be incomplete
• Other hydroPHILIC drugs, such as atenolol, or lipophilic drugs, such as acyclovir, which contribute to low bioavailability

P-Glycoprotein

• Transporter associated with P-glycoprotein
• It pushes drugs out of the gut wall cells back into the gut lumen
• Inhibiting this P-glycoprotein by something such as grapefruit juice is associated and the gut wall metabolism may be associated with a substantially increased drug absorption.

First-Pass Elimination

• After absorption across the gut wall, portal blood delivers the drug to the liver before systemic circulation
• Liver and gut wall metabolize and reduce bioavailability
• Bioavailability is expressed by the extraction ratio

High Hepatic Blood Clearance

ER = CLliver/Q (hepatic blood clearance/hepatic blood flow)

Bioavailability of the Drug (F)

F = fx (1-ER)

Rate and Extent of Absorption

• Differ by administration and drug formulation site
• Dosage forms differ in intensity and clinical effect
• Differences in rate of absorption can impact drugs in single doses

Mechanism of Absorption

• Zero-order absorption when rate is independent of amount of drug and related to the rate of gastric emptying or controlled-release formulations
• First-order absorption is when the rate is proportion to and the absorption half lives describe this
• The rate is proportional to gastrointestinal fluid concentration
• After four absorption half-lives all drugs have been absorbed

Extraction Ratio

Effect of bioavailability doesn't affect systemic clearance but affects affect the extent of concentration Differences due to hepatic function and blood flow can mean drugs extracted by the liver have high variations in bioavailability between patients

Blood Extraction

• For drugs with high extraction ratios, bypassing elimination will result in substantial increases in availability
• Drugs poorly extracted by the liver will not be substantially changed
• Drugs can be administered in different routes to achieve different blood concentrations at the sites of action
• The first pass effect can be avoided with sublingual tablets and transdermal preparations
• Drugs absorbed by suppositories may bypass the liver, but not completely

Drug Metabolism by Inhalation

• Drugs administered by inhalation may also serve the potential for first pass loss and metabolism by non-gastrointestinal methods from the lungs

Time Course and Drug effect

• Principles of pharmacokinetics and those pharmodynamics provide an framework to understand the time course of drug effect
• Drug effects are immediately related to plasma concentrations, but this also means they don't parallel

Angiotensin-converting Enzyme Example

• Plasma level of blood concentration changes quickly, but the ACE inhibitation will only drop 30%
• High concentration is not needed for a effective result

Changes in Drug Effects

• Often delayed in relation to changes in plasma concentration
• Delay may reflect time required to distribute from plasma to site of action
• Distribution accounts for delay of minutes, rapid i.v. of CNS agent
• Some drugs cause a delay in effects as they bind tighly to receptors
• Common for longer delays is the turnover of a physiological substance that is involved in the drug effect
• Example, warfarin as an anticoagulant

Warfarin Action

• Decrease production of clotting but long half life so takes time to for warfarin drug effect to refelct
• Schedule dependent effects will reduce renal toxicity when taken in smaller intervals
• Cumulative effects are related to a cumulative action that is irreversable to it

Rational Dosage Regimen

• It is based on the assumption that there is a target concentration that will produce the desired therapeutic effect
• Consider the pharmacokinetic factors that determine the dose-concentration relationship and decide whether to start a regimen

Maintenance Dose

• Dose is given that will replace the drug eliminated since previous dose
• At steady state is reached when the rate of dosage going in is equal to the rate of elimination
• By finding the correct target rates we can make an effective maintenance dose

Target Concentration Intervention

• The clinical drug interpretation from rates of inputs and concentrations with variables helps make important and more effective medications
• If there is an abnormality we can test the functions of the organs to determine whether they are working
• Important that the half-life and drug doses come into play with determining best outcomes for concentrations and dosing in each particular patient
• Overall, it is important to consider as the patient's well-being is vital, by finding the best drug or concentration