Pharmacokinetics

Dr Bassi PU

University of Abuja

MBBS Lecture Series

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Definition of Terms

What is Drug�

Drug:

A chemical substance of a known structure, other than a nutrients or an essential dietary ingredient, which when administered in a living organism produces a biological effects

- any chemical substance which affects living systems

– Dutch word “droog” means dry

• used for treatment of disease, for the prevention of illness of pathologic states and for diagnosing disease condition.

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What is Medicine

- Medicine:

Is a chemical preparation, which usually but not necessarily contains one or more drugs, administered with the intention of producing a therapeutic effects, (Medicine usually contain other substances (excipients, stabilizers, solvents etc.)

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Note:

To count as drug the substance must be administered as such, rather than released by physiological mechanism

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• A pharmaceutical drug, also called a medication or medicine, is a chemical substance used to treat, cure, prevent, or diagnose a disease or to promote well-being.
• Traditionally drugs were obtained through extraction from medicinal plants, but more recently also by organic synthesis.
• Pharmaceutical drugs may be used for a limited duration, or on a regular basis for chronic disorders

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�What is Pharmacokinetics (PK)?�

• Means movement of drugs

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• Study of the relationship between dose, amount of drug

in the body and therapeutic or toxic effects of a drug

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• Pharmacokinetic data help us understand:
• dose and schedule (once a day vs. twice a day, etc)
• dose adjustments due to drug interactions and other issues.

ADME

Pharmacokinetics is generally broken down into four processes:

• Absorption
• Distribution
• Metabolism
• Excretion
• Metabolism and excretion are often combined and called elimination.
• LADME is also referred to, with the L standing for liberation.

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Processes that Determine Drug PK

• Absorption: how the drug enters the blood
• The amount of acid in stomach or amount of food changes the amount of drug absorbed
• This is why some drugs must be taken with or without food or can not be taken with antacids

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• Distribution: how the drug travels in the blood and how it goes into and out of other areas of the body

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• Metabolism: how the body changes a drug usually in intestine and liver

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• Drug Elimination: how the body gets the drug out:
• via kidneys through urine or
• via liver though stool

http://www.thebody.com/content/art875.html

Why study pharmacokinetics? �

You administer drugs (dose) because you seek a certain effect (response).

A complex chain of events links the administered dose to the observed response.

Pharmacokinetics determine the blood concentration from a prescribed dosing regimen.

More often the plasma concentration for analytical purposes

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Pharmacokinetics is essential for determining dosing regimens.

Getting the dose right

• Achievement of the correct dose for individual

patients is fundamental to clinical practice.

• Below a certain threshold concentration, the drug is inactive.
• Above a certain concentration, side effects appear.

•Therefore, the dose should be aimed to be

within the therapeutic window.

•The therapeutic dose can vary between

patients depending on a number of factors.

Mathijssen, R. H. J. et al. (2014) Determining the optimal dose in the development of anticancer

Agents. Nat. Rev. Clin. Oncol. doi:10.1038/nclinonc.2014.40

Importance of drug concentration

• Ideally, drug concentration should be measured at the receptor.
• Blood or plasma level is used as a measure to reflect the concentration.
• You need to identify the ideal concentration-time profile.
• Knowledge of individual pharmacokinetic parameters allows you to manipulate dosage regimens.
• You need to understand the pharmacokinetic characteristics of the drug and the physiological processes that are going on.
• Pharmacokinetics is based on the analysis of drug concentrations. In the graphic, after one or more doses ( ), the drug concentration in the desired matrix is measured (•).

Importance of Drug Concentrations

Linear PK Example.png

PK Definitions

0

2

4

6

8

10

12

Time Postdose (hr)

100

1000

10000

Plasma Concentration

3000

Cmax: Maximum concentration – may relate to some side effects

AUC: Area under the curve (filled area) = overall drug exposure

Cmin: minimum or trough concentrations: may relate with efficacy of HIV drugs

http://www.thebody.com/content/art875.html

Drug Levels & Resistance

Absorption

• Absorption is the movement of unchanged drug from the site of administration into the blood.
• Drug absorption is determined by:
• Physicochemical properties of the drug
• Formulation, for example, tablets, capsules or solutions
• Routes of administration

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Drugs must be in solution to be absorbed.

• Mechanisms of drug permeation
• Permeation: is the movement of drug molecules in to & within the biological environment. It involves several processes of drug transport across the cell membranes.

Mechanisms of transport (absorption)

Transport and the Cell Membrane Transport?

• Transport is any process in which movement of matter and / or energy occurs from one part of a system to another
• If a substance can cross a membrane , the membrane is said to be permeable to that substance , if a substance is unable to pass ,the membrane is impermeable to it
• The plasma ( cell ) membrane is selectively permeable in that it permits some particles to pass through while excluding others
• Across the cell membrane without any assistance , substances can pass through if they are lipid soluble and if they are of small particle size.

After oral administration

• The small intestine is where the majority of drug absorption takes place. The small intestine has:
• - A much larger surface area - Surface area
• small intestine = 200 m²
• stomach = 1 m²
• - A much better blood supply - Blood flow (for perfusion rate-limited absorption)
• small intestine = 1000 mL/min through intestinal capillaries
• stomach = 150 mL/min

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After oral administration

• Better permeability - Permeability
• intestinal membrane>stomach
• The small intestine, which is more basic in pH, favours absorption of weakly basic drugs.
• Transit time in the small intestine is slower than in the stomach.
• GI transit
• Rate of gastric emptying is a controlling step for rapid absorption

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Cell Membrane

Following movement into the small intestine, the

drug must next cross the intestinal epithelial

membrane to reach the systemic circulation.

Drugs can cross cell membranes by:

• Passive diffusion
• Facilitated passive diffusion
• Active transport

Schematic representation of the cell (or plasma) membrane showing the phospholipid bilayer and embedded proteins

Passive diffusion

• Drugs diffuse across a cell membrane from a region of high concentration to one of low concentration until equilibrium is reached.
• Diffusion rate is directly proportional to the gradient. It also depends on physicochemical properties of the molecule including:
• Lipophilicity: Lipid-soluble drugs diffuse most rapidly.
• Size: Small molecules tend to penetrate membranes more rapidly than larger ones.
• Degree of ionisation

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Passive diffusion efficiency

Factors influencing rate of simple diffusion�

In general, the diffusion rate is higher when:

• the concentration gradient is greater
• when heat is applied
• when molecules are smaller: H2O is a polar molecule but uses simple diffusion because of its very small size, however, water molecules diffuse at 10,000 times slower than they would without a membrane being present.
• when movement occurs through a gaseous medium.

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Factors influencing rate of simple diffusion

• Chemical properties also influence the rate of simple diffusion.
• The hydrophobic nature of the interior of a plasma membrane means only small relatively non polar molecules such as O2 and CO2 can quickly permeate the membrane by simple diffusion.
• Non-Polar:Ethanol and glycerol are much larger than water but can still use simple diffusion to cross the lipid bilayer because they are non-polar.

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Facilitated passive diffusion

• Facilitated passive diffusion requires binding between the drug or molecule with a specific membrane- embedded channel or carrier proteins.
• It allows the entry of specific groups of molecules while excluding others.
• It is a passive process:
• Molecules move down their concentration gradient.
• Molecules cannot be transported against their concentration gradient.
• It is a saturable process.
• The availability of carriers limits the process.

Simple diffusion:Osmosis.

• Osmosis is defined as the net movement of a solvent, usually water, across a differentially permeable membrane from a weak or dilute solution (high water concentration, low solute concentration) to a strong solution (low water concentration, high solute concentration).
• More simply, osmosis is the net movement of free water molecules from a dilute solution through a partially permeable membrane to a concentrated solution.

Active transport

• Active transport is a selective process.

- It requires a structurally specific transporter to

transport drugs of a certain conformation.

• It requires energy expenditure.
• It can move molecules across the membrane against their concentration gradient.

- From a low concentration to a high concentration

• It is also a saturable process.
• Three types

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Barriers to absorption

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• An orally administered drug must survive additional encounters in the systemic circulation.

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• Exposure to metabolic enzymes
• Exposure to transporters

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• First-pass effect through the liver and hepatic portal system

Bioavailability (F)

• Bioavailability (F) refers to the extent of absorption of intact drug.: It is the proportion of administered drug available to produce a pharmacological response.
• It can provide useful information about the:
• -Dosage or dosage regimen of a given drug
• - Performance of a drug formulation compared to other formulations
• It is quoted as a percentage (43%) or a decimal (0.43) and has no units.
• Intravenous (IV) administration equals 100% bioavailability.
• For a non-IV dose, F ranges from 0 to 100%.

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Bioavailability PK study

• To determine the bioavailability of a drug, you must carry out a pharmacokinetic (PK) study to obtain a blood/plasma concentration versus time plot for the drug in question.
• The area under the curve (AUC) is equal to the integral of the concentration-time curve after a single dose or in steady state.

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• Cmax = The peak plasma concentration of a drug after administration
• Tmax = The time to reach Cmax

Absolute and relative F

Absolute bioavailability : Assessed with reference to an intravenous dose with 100% F

Relative bioavailability: Comparison of F between formulations of a drug given by the same or different routes of administration

• Chemical equivalence indicates that drug products contain the same active compound in the same amount and meet current official standards; however, inactive ingredients in drug products may differ.

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• Bioequivalence indicates that the drug products, when given to the same patient in the same dosage regimen, result in equivalent concentrations of drug in plasma and tissues.

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• Therapeutic equivalence indicates that drug products, when given to the same patient in the same dosage regimen, have the same therapeutic and adverse effects.

Causes of Low Bioavailability

• Low bioavailability is most common with oral dosage forms of poorly water-soluble, slowly absorbed drugs.

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• Insufficient time for absorption in the gastrointestinal (GI) tract is a common cause of low bioavailability. (eg, if it is highly ionized and polar), time at the absorption site may be insufficient. In such cases, bioavailability tends to be highly variable as well as low.

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• Age, sex, physical activity, genetic phenotype, stress, disorders (eg, achlorhydria, malabsorption syndromes), or
• Previous GI surgery (eg, bariatric surgery) can also affect drug bioavailability.

Half-Life

• Half-life is the time taken for the drug concentration to fall to half its original value
• The elimination rate constant (k) is the fraction of drug in the body which is removed per unit time

Importance:

• It denotes how quickly a drug is removed from the plasma by biotransformation or excretion
• Since drug require a minimum conc. in the plasma to produce pharmacological action, a drug which is eliminated quickly requires more frequent dosing than a drug with a long half life.
• It thus indicates the duration of action of drug and therefore it determines the frequency of administration of dose of the drug for therapeutic effectiveness.

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C₀

C₀/2

t_1/2

t_1/2

t_1/2

Intravenous Bolus Injection

Half-Life

• Complete drug elimination occur in 4-5 half lives.
• After that drug will reach steady state concentration in the plasma. (drug administered=drug eliminated)
• 1-50 %
• 2-75%(50+25)
• 3-87.5%(50+25+12.5)
• 4-3.75%(50+25+12.5+6.25)

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Toxic level

Minimum

therapeutic level

Same drug, same route, different doses

Cp

time

Therapeutic window

Therapeutic Index

• Therapeutic Index =

TD50 or LD50

ED50

• The higher the TI the better the drug.
• TI’s vary from: 1.0 (some cancer drugs)

to: >1000 (penicillin)

• Drugs acting on the same receptor or enzyme system often have the same TI: (eg 50 mg of hydrochlorothiazide about the same as 2.5 mg of indapamide)

Steady-State

• Steady-state occurs after a drug has been given for approximately five elimination half-lives.
• At steady-state the rate of drug administration equals the rate of elimination and plasma concentration - time curves found after each dose should be approximately superimposable.

100

187.5

194

175

150

75

87.5

94

97

50

200

100

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Accumulation to Steady State

100 mg given every half-life

Drug distribution

• After entry into the systemic circulation, either by intravascular injection or by absorption from any of the various extravascular sites, the drug is subjected to a number of processes called as disposition processes.
• Disposition is defined as the process that tend to lower the plasma concentration of drug.
• The two major drug disposition processes are as :

1.Distribution: Which involves reversible transfer of a drug between compartments.

2.Elimination: Which causes irreversible loss of drug from the body. Elimination is further divided into two processes:

a) Biotransformation (metabolism)

b) Excretion

Drug distribution

• Drug distribution describes the reversible transfer of a drug from one location to another within the body.
• Blood flow to tissues: Good blood supply is vital for efficient drug delivery.

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• The distribution of a drug between tissues is dependent on vascular permeability, regional blood flow, cardiac output and perfusion rate of the tissue and the ability of the drug to bind tissue and plasma proteins and its lipid solubility. pH partition plays a major role as well.

Steps In Drug Distributions

Distribution of drug present in systemic circulation to extravascular tissues involves following steps:

1.Permeation of free or unbounded drug present in the blood through the capillary wall (occur rapidly) and entry into the interstitial/extracellular fluid (ECF)

2.Permeation of the drug present in the ECF through the membrane of tissue cells and into the intercellular fluid.

This step is rate limiting and depend upon two major factors:

a) Rate of Perfusion to the ECF

b) Membrane Permeability of the Drug

Factors affecting Drug Distributions

1. Tissue Permeability of Drugs

a) Physicochemical Properties of drug like:

• Molecular size,
• pKa,
• o/w Partition Coefficient

b) Physiological barriers to diffusion of drugs

2. Organ/tissue size and perfusion rate

3. Binding of drugs to tissue components.

a) Binding of drug to blood components

b) binding of drug to extra cellular components

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Factors affecting Drug Distributions

4. Miscellaneous

a) Age b) Pregnancy

c) Obesity

d) Diet

e) Disease states

f) Drug interactions

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Tissue Permeability of Drugs

• The tissue permeability of a drug depends upon the physicochemical properties of the drug as well as the physiologic barriers that restrict diffusion of drug into tissues.

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• Physicochemical Properties of drugs of the drug
• Molecular size, 
• pKa 
• o/w Partition
• Co Efficient.

Physiological barriers to Distribution of Drugs 

• Simple Capillary Endothelial Barrier 
• Simple Cell Membrane Barrier 
• Blood Brain Barrier 
• Blood – CSF Barrier 
• Blood Placental Barrier 
• Blood Testis Barrier

a) Physicochemical Properties of the Drug

• Important physicochemical properties that influence its distribution are
• molecular size,
• degree of ionization,
• partition coefficient.

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Molecular Size

• Almost all drugs having molecular weight less than 500 to 600 Daltons easily cross the capillary membrane to diffuse into the extracellular interstitial fluids.
• However, penetration of drugs from the extracellular fluid into the cells is a function of molecular size, ionization constant and lipophilicity of the drug.
• Only small, water-soluble molecules and ions of size below 50 Daltons enter the cell through aqueous filled channels whereas those of larger size are restricted unless a specialized transport system exists for them.

Degree of Ionization

• The degree of ionization of a drug is an important determinant in its tissue penetrability.
• The pH of the blood and the extravascular fluid also play a role in the ionization and diffusion of drugs into cells.
• A drug that remains unionized at these pH values can permeate the cells relatively more rapidly.
• Since the blood and the ECF pH normally remains constant at 7.4, they do not have much of an influence on drug diffusion unless altered in conditions such as systemic acidosis or alkalosis.

• Most drugs are either weak acids or weak bases and their degree of ionization at plasma or ECF pH depends upon their pKa. All drugs that ionise at plasma pH (i.e. polar, hydrophilic drugs), cannot penetrate the lipoidal cell membrane and tissue permeability is the rate-imiting step in the distribution of such drugs.
• Only unionized drugs which are generally lipophilicity, rapidly cross the cell membrane.
• Among the drugs that have same o/w partition coefficient but differ in the extent of onization at blood pH, the one that ionizes to a lesser extent will have greater penetrability than that which ionizes to a larger extent; for example, pentobarbital and salicylic acid have almost the same Ko/w but the former is more unionized at blood pH and therefore distributes rapidly.
• pKa, o/w Partition Coefficient In case of polar drugs where permeability is the rate- limiting step in the distribution, the driving force is the effective partition coefficient of drug.
• It is calculated by the following formula: Effective Ko/w = (Fraction unionsied at pH 7.4) (Ko/w of unionsied drug)

Physiological barriers to Distribution of Drugs

Physiological barriers to Distribution of Drugs: 

• Simple Capillary
• Endothelial Barrier 
• Simple Cell Membrane Barrier 
• Blood Brain Barrier 
• Blood – Cerebrospinal fluid Barrier 
• Blood Placental Barrier 
• Blood Testis Barrier

Simple Capillary Endothelial Barrier

• The membrane of capillaries that supply blood to most tissues.
• All drugs, ionised or unionised, with a molecular size less than 600 Daltons, diffuse through the capillary endothelium and into the interstitial fluid.
• Only drugs that bound to that blood components can’t pass through this barrier Because of larger size of complex.

Plasma protein binding (1) �

• A drug's efficiency can be affected by the degree to which it binds to the proteins in the blood.

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• The drug binds to specific sites on plasma proteins, which results in sequestering of the drug, making it unavailable to its site of action.

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• Competition for plasma protein binding sites can sometimes occur when another drug is given in combination with your drug of interest, resulting in displacement of the drug and increasing its

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• unbound concentration in the blood plasma. Such competition can be very significant clinically

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Example

• Consider the anticoagulant Warfarin as an example.
• It is approximately 98% protein-bound. So, for each 5 mg dose, only 0.1 mg of the drug is free.
• The patient takes a normal dose of aspirin at the same time, which occupies 50% of binding sites; the aspirin displaces some of the Warfarin.
• If 96% of the Warfarin dose is protein-bound, 0.2 mg of Warfarin is now free. The dose has been effectively doubled.

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Common blood proteins: Common blood proteins that drugs bind to are:

• Human serum albumin: Most concentrated protein in blood plasma : Acidic drugs

-α1 – acid glycoprotein : Basic drugs

• α, β‚ and γ globulins: Steroid hormones

Plasma protein binding (2)

• Drug binding to plasma proteins is generally reversible and rapid.
• The extent of binding is determined by quantifying the free drug fraction (fu).
• The extent of binding can vary widely among drugs.
• The unbound fraction of some drugs:
• Is dependent on the concentration of plasma proteins
• Can be altered in disease states that produce hypoalbuminemia
• An example of this type of drug is phenytoin

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Plasma albumin: This table shows examples of the extent of plasma albumin binding to various drugs:

Volume of distribution (1)

• The volume of distribution (Vd), or apparent volume of distribution, is: A theoretical volume that the total amount of drug administered would need to occupy to provide the same concentration as in blood plasma, if it were uniformly distributed
• The volume of fluid a drug would occupy if the total amount in the body was in solution at the same concentration as the plasma
• An equilibrium concept that relates the amount of drug in the body (A) to either the plasma or blood concentration (C): Vd = D/C
• Example: A patient is administered an intravenous analgesic at a dose of 75 mg.

A few minutes later, a blood sample is taken and the concentration of the analgesic in the blood is 0.65

μg/mg.

What is the volume of distribution (in litres) of the analgesic?

• Vd = D/C = 75mg / 0.65 μg/mg = 75,000 μg / 0.65 μg/mg = 115,385 ml = 115.4 litres

Volume of distribution (2)

• Volume of distribution provides little information about the specific pattern of distribution.
• Each drug is uniquely distributed in the body:

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• Volume of distribution can be: Increased by renal failure or liver failure, Decreased in dehydration

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Fat

Extracellular fluid

Specific tissues

Real water distribution

• The body is composed of 'real' compartments that contain 'real' volumes of fluid:

Distribution of Water in the Body for a 70kg Person.

Examples:

Heparin: A High molecular weight drug binds to plasma proteins excessively. Volume of distribution of about 4 litres. This correlates very well with the plasma volume.

• Volume of distribution for this drug considered a 'real' volume The volume occupies 'real space‘ in the plasma volume.
• Heparin unable to transport out of the vascular system

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Atracuronium: Neuromuscular blocking agent of low molecular weight drug but is hydrophilic. Volume of distribution of about 11 litres.

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• Equivalent to the volume in the extracellular compartment of the body
• Very polar compound
• Atracuronium unable to transport across cell membranes and remains in the extracellular fluids

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More examples (1)

• A minority of drugs that diffuse to intracellular fluid have a volume of distribution equivalent to TBW volume.

• The majority of drugs, drugs that bind strongly to tissues, have volumes of distribution higher than total body water.

More examples (2)

Clinical usefulness

The volume of distribution reflects the size of the distribution space, thereby giving you an idea of the localisation of the drug in the target organ.

With a large volume of distribution, you will need a higher dose to load.

With a low volume of distribution, you will need a lower dose to load.

Volume of distribution is used to calculate the loading dose.

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Thank you

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References

1. Dawes M, Chowienczyk PJ . Pharmacokinetics in pregnancy. Best Practice & Research Clinical Obstetrics and Gynaecology. Vol. 15, No. 6, pp. 819±826, 2001. doi: 10.1053/beog.2001.0231, available online at http://www.idealibrary.com.

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2. Further Reading: Loebstein R, Lalkin A & Koren G. Pharmacokinetic changes during pregnancy and their clinical relevance. Clinical Pharmacokinetics 1999; 33: 328±343. 826 M. Dawes and P. J. Chowienczyk

3. Hibernia College Dublin Ireland: Clinical Pharmacology and the Role of

Pharmacometrics, ADMEL 2014 CPD Lecture Series

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