Intravenous Infusion

 Advantage for giving a drug by IV infusion is that it allows precise control of plasma drug
concentration to fit the individual needs of the patient.
 Disadvantage is it causes greater risk of toxicity

At steay state the rate of drug leaving the body is equal to the rate of drugs entering the body

One Compartment Model Drugs

 Drugs given by constant IV infusion follows a zero order inpute process in which the drug is
directly infused into the systemic blood circulation.

First order input – zero order output

Loading Dose Plus IV Infusion One Compartment Model

 Instant at a higher concentration

 If an IV loading dose of R/k is given, followed by an IV infusion, steady state plasma drug
concentration are obtained immediately and maintained.

Pharmacokinetics of Oral Absorption

 Absorption occurs when drug reaches the systemic circulation, or sometimes when it reaches
the portal vein blood stream.

Drug Absorption fro the Gastrointestinal tract

 1. Physicochemical properties of the drug and the environment in the small intestine
 2. Dosage form used
 3. Anatomy and physiology of the absorption site

Basic Principles of Physiologically Based Absorption Kinetics

 Provide a quantitative mechanistic framework by which scaled drug specific parameters can be
used to predict the plasma and importantly tissue concentration time profiles of drugs following
oral administration

Main advantage

 They can be used to extrapolate outside the studied population and experimental conditions

Absorption phase

 Rate of drug absorption is greater than rate of drug elimination

Significance of absortion rate constant

 Immediate release dosage forms, the absorption process is first order due to the physical
nature of drug diffusion
 Controlled release drug products, the rate of drug absorption may be more appropriately
describe as zero order rate constant

First order absorption model

 The maximum plasma concentration after oral dosing is Cmax and the time needed to reach the
maximum concentration is tmax. The tmax is independent of dose and is dependent on the rate
constants for absorption ka and elimination k. At Cmax sometimes called peak concentration,
the rate of drug absorbed is equal to the rate of drug eliminated.

Lag Time

 The time delay prior to the commencement of first order drug absorption

Onset Time

 Represents latency, that is the time required for the drug to reach minimum effective
concentration

Flip flop of ka and k

 Ka and k, the terminal phase of an oral absorption curve is usually represented by k, whereas
steeper slope is represented by k
 Ka and k obtained by the method of residuals have been interchanged. Flip flop or the reversal
or the rate constants, may occur whenever ka and k are estimated from oral absorption data.
 Most of the drugs observed to have flip flop characteristics are drugs with fast elimination.
 Drugs with large k are usually considered to be unsuitable for oral drug product due to their
large elimination rate constant, corresponding to a very short elimination half life. An extended
release drug product may slow the absorption of a drug such that the ka is smaller than the k
and producing a flip flop situation.

Wagner-Nelson Method

 Estimates the loss of drug form the GI overtime, whose slope is inversely proportional to ka

Loo-Riegelman Method

 Does require that the drug be given intravenously as well as orally to obtain all the necessary
kinetic constants.
Ka and k

 A drug with a rate of absorption slower than its rate of elimination will not be able to obtain
optimal systemic drug concentrations to achieve efficacy.

Multiple Dosage Regimens

 After single dose drug administration the plasma drug level rises above and then falls below the
minimum effective concentration (MEC) resulting in a decline in therapeutic effect. To treat
chronic disease, multiple dosage IV infusion regimens are used to maintain the plasma drug
levels within the narrow limits of the therapeutic window to achieve optimal clinical
effectiveness. These drugs may include antibacterial, cardiotonics, anticonvulsants,
hypoglycemic, antihypertensive, hormones and others.

Dosage regimens

 Established for each drug to provide the correct plasma level without excessive fluctuation and
drug accumulation outside the therapeutic window.

Two Main Parameters

 Size of the drug dose

 Frequency of drug administration

Drug Accumulation

 To calculate a multiple dosage regimen for a patient or patients, pharmacokinetic parameters

are obtained from the plasma level time curve generated by single dose drug studies.
 Pharmacokinetic parameters and knowledge of the size of the dose and dosage interval
 Complete plasma level time curve the plasma level may be predicted at any time after the
beginning of the dosage regimen.

Superposition

 Assumes that the early doses of drug do not affect the pharmacokinetics of subsequent doses.
Therefore, the blood levels after the second, third, or nth dose will overlay or superimpose the
blood level attained after the (n-1)th dose.

Basic Assumptions

 1. That the drug is eliminated by first order kinetics

 2. That the pjharmacokinetics of the drug after a single dose are not altered after taking multiple
dose.
Repetitive intravenous injections

 The maximum amount of drug in the body following a single rapid IV injection is equal to the
dose of the drug. For a one compartment open modl, the drug will be eliminated according to
first order kinetics.

Early or Late Dose Administration during Multiple Dosing

 When one of the drug doses is taken ealier or later than scheduled, the resulting plasma drug
concentration can still be calculated based on the principle of the superposition.

Intermittent intravenous infusion

 Method of successive short IV drug infusions in which the drug is given by IV infusion for a short
period of time followed by a drug elimination period, then followed by another short IV infusion.
In drug regimens involving short IV infusion, the drug may not reach steady state.

Loading Dose

 Since extravascular doses require time for absorption into the plasma to occur, therapeutic
effects are delayed until sufficient plasma concentrations are achieved.
 To reduce the onset time of the drug- that is the time it takes to achieve the minimum effective
concentrations- a loading (priming) or initial dose of drug is given.
 The main objective of the loading dose is to achieve desired plasma concentrations Cav, as
quickly as possible.
 As a general rule of thumb, if the selected dosage interval is equal to the drugs elimination half-
life, then the dose ratio calculated from Equation Dose ratio= DL/Do should be equal to double
the initial drug dose.

Dosage Regimen Schedules

 Predictions of steady state plasma drug concentrations usually assume the drug is given at a
constant dosage interval throughout a 24 hour day. Very often, however the drug is given only
during the walking hours.
 Ideally, drug doses should be given at evenly spaced intervals. However to improve patient
compliance, dosage regimens may be designed to fit with the lifestyle of the patient.
Nonlinear Pharmacokinetics
2 Active Process which are Saturable

Drug Excretion

1. Active tubular secretion – penicillin G

2. Active tubular reabsorption – water soluble vitamins

Saturation of carrier systems – deacrease in renal clearance (1) and deacrease in (2) half life
also increases

Linear models assumed that the pharmacokinetic parameters for a drug would not change
when different doses or multiple doses of a drug were given.

 This nonlinear pharmacokinetic behavior is also termed dose dependent

pharmacokinetics
 Due to a pathologic alteration in drug absorption, distribution and elimination.
 In most cases the main pharmacokinetic outcome is a change in the apparent
elimination rate constant
 Drugs demonstrate saturation or capacity limited metabolism in humans.

Examples of Drugs Showing Nonlinear Kinetics

Riboflavin GI Absorption saturable transport

Propanolol GI Absorption intestinal metabolism

Chlorothiazide GI Absorption drugs with low solubility in GI but relatively high

dose

Omeprazole GI Absorption saturable gastric GI decomposition

Phenylbutazone, ceftriaxone, phenytion, warfarin distribution saturable plasma

protein binding

Methicillin distribution cellular uptake

Imiprimine distribution tissue binding

Benzypenicillins distribution CSF transport

Methotrexate distribution saturable transport into or out of tissues

Para-aminohippuric acid renal elimination active secretion

Riboflavin, ascorbic acid renal elimination tubular reabsorption

Salicylic acid renal elimination change in the urine pH

Theophylline, valproic acid metabolism saturable metabolism

Acetaminophen metabolism cofactor or enzyme limitation

Carbamazepine metabolism enzyme induction

Propanolol, verapamil metabolism altered hepatic blood flow

Diazepam metabolism metabolite inhibition

Iodipamide biliary excretion biliary secretion

Cimetidine biliary excretion enterohepatic recycling

Drugs that demonstrate saturation kinetics usually show the following characteristics

1. Elimination of drug does not simple first order kinetics that is, elimination kinetics are
nonlinear.
2. Elimination half life changes as dose is increasd.
3. The area under the curve is not proportional to the amount of bioavailable drug
4. The saturation of capacity limited processes may be affected by other drugs that require
the same enzyme of carrier mediated system
5. The composition or ratio of the metabolites of a drg may be affected by a change in the
dose.

Inorder to determine whether a drug is following dose dependent kinetics.

The drug is given at various dosage levels and a plasma level time curve is obtained for each
dose

The curves should exhibit parallel slopes if the drug follows dose dependent kinetics

Alternatively the plot for the areas under the plasma level time curves at various doses should
be linear.

Drug metabolism

2 important causes

1. Capacity limited enzyme – phenytoin, alcohol

2. Enzyme induction decrease in plasma concentration – carbamazepine

Causes of metabolism

1. Solubility dissolution
2. Carrier mediated transport system
3. Pre systemic gut wall/ hepatic metabolism

Saturable Enzymatic Elimination Processes

 The elimination of drug by saturable enyzymatic process is described by Michaelis

Menten Kinetics. If Cp is the concentration of drug in the plasma, Vmax is the maximum
elimination rate and KM is the Michaelis constant that reflects th capacity of the enzyme
system.

Dependence Elimination Half life on Dose

Drugs that follow linear kinetics, the elimination half life is constant and does not chamge with
dose or drug concentration.

Drugs that follow nonlinear kinetics, the elimination half life and drug clearance both change
with dos or drug concentration.
Mixed Drug Elimination

 Drugs may be metabolized to several different metabolites by parallel pathways. At low

drug doses corresponding to low drug concentration at the site of the biotransformation
enzymes, the rates of formation of metabolites are first order.
 With higher doses of drug more drug is absorbed and higher drug concentrations are
presented to the biotransformation enzymes.
 At higher drug concentrations, the enzyme involved in metabolite formation becomes
saturated, and the rate of metabolite formation becomes nonlinear and approaches
zero order

Zero Order Input and Nonlinear Elimination

 If drug is given by constant IV infusion and is eliminated only by nonlinear

pharmacokinetics, then the following equation describes the rate of change of the
plasma drug concentration

First Order Absorption and Nonlinear Elimination

 The relationship that describes the rate of change in the plasma drug concentration for
a drug that is given extravascularly, absorbed by first order absorption, and eliminated
only by nonlinear pharmacokinetics.

Chronopharmacokinetics and time dependent pharmacokinetics

 Chronopharmacokinetics broadly refers to a temporal change in the rate process of a

drug.
 The temporal changes in drug absorption or elimination can be cyclical over a constant
period of time. Chronopharmacokinetics is an important consideration during drug
therapy.
 Time dependent pharmacokinetics generally refers to a noncyclical change in the drug
absorption or drug elimination rate process over a period of time.
 Time dependent pharmacokinetics lead to nonlinear pharmacokinetics. It may be the
result of alteration in the physiology or biochemistry in an organ or a region in the body
that influences drug disposition. May be due to autoinduction or autoinhibition of
biotransformation enzymes. Repeated dose of carbamazepine induce the enzymes
responsible for its elimination thereby increasing the clearance of the drug.
 Autoinhibition may occur during the course of metabolism of certain drugs. In this case
the metabolites formed increase in concentration and further inhibit metabolism of the
parent drug.
Circardian rhythms and Influence on Drug Response

 Circardian Rhythm are rhythmic or cyclical changes in the plasma drug concentration
that may occur daily, due to normal changes in body functions.
 Some well known circardian physiologic parameter are core body temperature (CBT),
heart rate (HR) and other cardiovascular parameters. This fundamental physiologic
factors can affect disease states, as well as toxicity and therapeutic response to drug
therapy.
 Example fluorouracil, aminoglycosides and verapamil

Clinical Focus

 Hypertensive patients are sometimes characterized as “dippers” if their nocturnal blood

pressure drops below their daytime pressure. Non dipping patients appear to be at an
increased risk of cardiovascular morbidity. Blood pressure and cardiovascular events
have a diurnal rhythm, with a peak of both in the morning hours and a decrease during
the night.

Clinical and Adverse Toxicity Due to Nonlinear Pharmacokinetics

 The presence of nonlinear or dose dependent pharmacokinetics, whether due to

saturation of a process involving absorption, first pass metabolism, binding or renal
excretion, can have significant clinical consequences. Dose estimation may result in
disproportionate increases in adverse reactions but sufficient therapeutics benefits.

Bioavailability of Drugs that Follow Nonlinear Pharmacokinetics

 Bioavailability of drugs that follow nonlinear pharmacokinetics is difficult to estimate

accurately.
 Drugs that follow linear pharmacokinetics follow the principle of superposition. The
assumption in applying the rule of superposition is that each dose of drug superimposes
on the previous dose.
 Consequently, the bioavailability of subsequent doses is predictable and not affected by
the previous dose. In the presence of saturable pathway for drug absorption,
distribution, or elimination, drug bioavailability will change within a single dose or with
subsequent doses.

Nonlinear Pharmacokinetics Due To Drug Protein Binding

  Protein binding may prolong the elimination half life of a drug. Drugs that are protein
bound must first dissociate into the free or nonbound form to be eliminated by
glomerular filtration. The nature and extend of drug protein binding affects the
magnitude of the deviation from normal linear or first order elimination rate process

Physiologic Drug Distribution and Protein Binding

Physiologic Factors of Distribution

 After a drug is absorbed systematically from the site of administration, the drug
molecules are distributed throughout the body of the systemic circulation.
 The location, extent and distribution are dependent on the drugs physicochemical
properties and individual patient characteristics such as organ perfusion and blood flow.
 The drug molecules are carried by the blood to the target site for drug action and to
other tissues as well, where side effects or adverse reactions may occur.
 These site may e intra or extra. Drug molecules are distributed to eliminating organs,
such as the liver and kidney and to the noneliminating tissues, such as brain, skin and
muscles.
 A substantial portion of the drug may be bound to proteins in the plasma or in the
tissues.
 Lipophilic drugs are deposit in fat, from which the drug may be slowly released.
 The volume of blood pumped by the heart per minute- the cardiac output – is the
product of the stroke volume of the heart and the number of heartbeats per minute
 An average cardiac output is 0.08 L/69 left ventricular contractions (heart beats)/min,
or approximately 5.5 L/min in subjects at rest. The cardiac output may be five to six
times higher during exercise.
 Left ventricular contractions may produce a systolic blood pressure of 120mm Hg, and
moves blood at a linear speed of 300 mm/s through the aorta.