P H A R M A C O K I N E T I C S

The drug must be capable of reaching the site of action BLOOD DRUG
Drug must have necessary properties to be transported From: its site of administration To: its site of action

must remain at the site of action long enough EFFECTS

The drug must achieve these criteria without inducing SYSTEMIC unacceptable CIRCULATION toxicity in the patient

SITE OF ACTION

Dose
Dose is the amount of a chemical that gets inside of your body. Measured in mg of chemical/kg of weight The Dose Makes The Poison

Typical dose-response curve

100
% response

50

10

100

1000

Log scale dose (mg/kg)

The intensity of response is related to concentration of the drug at the site of action

Response changes with concentration

R e s p o n s e v C o n c e n t r a t io n
1 .2 0 1 .0 0 0 .8 0 Response 0 .6 0 0 .4 0 0 .2 0 0 .0 1 0 .0 0 0 . 1 0 1 . 0 0 1 0 . 0 0 1 0 0 . 0 0 0 0 0 . 0 0 0 0 0 1. 0 0 0 0 0 . 0 0 1 1 C o n c e n t r a t io n

Maximal response

Linear response (20-80%)

No response

(semi-log)

Receptor

Drug Molecule

A dose at which there is no measurable effect Upper dose where there is a maximal response

DOSE DOSAGE

Dose - Response
Effective dose ED50 - the dose producing the desired (therapeutic) effect in 50% of the test animals Toxic dose TD50 - the dose toxic to the specified organ in 50% of the test animals administered by the stated route Lethal dose LD50 - the dose lethal to 50% of test animals when administered by stated route

Dose -response
w

Therapeutic Index
Therapeutic index = toxic dose/effective dose This is a measure of a drugs safety
A large number = a wide margin of safety A small number = a small margin of safety

Warfarin: A Small Therapeutic Index

Percent of Patients
100 Desired Therapeutic Effect Unwanted Adverse Effect

50

0 0 Log Drug Concentration

Penicillin: A Large Therapeutic Index

Percent of Patients
100 Desired Therapeutic Effect Unwanted Adverse Effect

50

0 0 Log Drug Concentration

PARAMETERS
LD50
- ED50

& TD50

LD50 TD50 ED50 ED50

Margin of safety (TI)

NSAID (IBUPROFEN)
Wide TI Normal dose = 400-3200 mg/day

(THEOPHYLLINE)
BLOOD CONC = 10-20 g/ml below this conc (not much effect ) above 20 g/ml (serious toxicities)

How Do We Study Pharmacology?

General Concepts
Drug Dose Administration Disintegration of Drug Absorption/distribution metabolism/excretion Drug/Receptor Interaction Drug Effect or Response

Pharmaceutical Pharmacokinetics Pharmacodynamics Pharmacotherapeutics

Objectives
By the end of this session, students should be able to:
Define the four processes involved in pharmacokinetics Define parameters which can affect drug absorption drug distribution drug metabolism drug excretion Define half life, CL, Vd and bioavailability and describe the relevance of these to drug action Calculations

A young child given an intramuscular injection might ask "How will that 'ouch' get from there to my sore throat"?
The answer to this question is the basis of

pharmacokinetics.
eg: GUT (one body Compartment) to move to its site of action eg: Brain (another compartment)
Drug is given into :

HOW?

WHAT IS PHARMACOKINETICS?
PHARMACOKINETICS is the study of the kinetics of drug absorption and disposition. ABSORPTION DISPOSITION

ELIMINATION DISTRIBUTION EXCRETION METABOLISM

The factors involved in a drug getting to and remaining at its sites of action

Pharmacokinetics

A bsorption - how the drug is taken into the body D istribution -how the drug is moved into various tissues M etabolism --how the drug is changed into a form that can

Passage of drugs across membranes

E xcretion - how the drug is removed from the body

Drug should be inactivated or excreted from the body at a reasonable rate so its actions will be of appropriate duration.

be excreted

Pharmacokinetic models

Healthy volunteers Patients with average ability to : ADME

Standard Dose

Pharmacokinetics

Pharmaco dynamics study the mechanisms by which drugs work also study endogenous agents Receptors & spare R Affinity, Efficacy, Potency EC50, Emax, Kd, Bmax, ED50, TI Agonist, antagonist .

yPK/PD links PK with PD so that the time course of effect is described for a given dose regimen
PK along with PD tells the clinician how much, how often and how long to dose.

Conc

PK
Dose

PD
Time

Effect

Time

Pharmacodynamics (PD): Pharmacokinetics (PK):

What the drug does to the body What the body does to the drug

D osage

Plasm a C oncen .

Site of A ction

E ffects

Pharm acokinetics

Pharm acodynam ics

DRUG THERAPY Goal : To Rapidly Deliver and Maintain therapeutic (non toxic) levels of drugs in the target tissues.

The drug will appear at the target organ :

How rapidly? In what concentration? For how long?

To Obtain : Right effect

At the

Right intensity

Right time For the Right duration With MIN risk OF HARM
At the

Routes of Drug Delivery

Parenteral (IV) Inhaled

Oral
Parenteral (SC, IM) Rectal

Transdermal Topical

HOW DO DRUGS GET INTO THE BODY?

Unless injected directly into the blood stream, drugs must be absorbed.

Absorption
Must be able to get medications into the patients body Drug characteristics that affect absorption:
Molecular weight, ionization, solubility, & formulation

Factors affecting drug absorption related to patients:

Route of administration, gastric pH, contents of GI tract

WHAT IS DRUG ABSORPTION?

The movement of drug molecules across biological barriers (mostly layers of cells) from the site of administration to the blood stream.
Site of Administration
DRU G

BIOLOGICAL BARRIER

Vascular System

THE TRANSPORT ACROSS THE MEMBRANES A. Passive diffusion and filtration B. Specialized transport

Passage of drugs across membrane

Cellular uptake inside vesicles

Highly ionized (sulphonic acids and Q ammonium compd) from GIT Low L-W PC but still go through

Levodopa and methyldopa

Ficks Law

at constant temp

R = Diffusion Rate
(flux molecules per unit time)

A (C2 C1) R = K --------------d

A = Surface area d = thickness of membrane > 1
K = Diffusion constant of compound (Temp dependent) Permeability coefficient

K
Function of :

Steric configuration M.Wt Lipid Solubility Ionization

IONIZATION decreases membrane permeability

Ionized forms of compounds have low lipid solubility Why?

non-ionized

forms of drugs are more soluble in lipids and absorbed better than water-soluble, ionized forms of drugs

Acidic drugs are ionized in basic environment Basic drugs are ionized in acidic environment

Many drugs are weak organic acids or bases (weak elctrolytes) Weak acids aspirin in intestines are mostly ionized (intestinal pH ranges from 6.6 to 7.5) Weak bases atropine in stomach are mostly ionized (stomach pH ranges from 1 to 2)

Weak acids Weak bases DISSOCOATE

R-COOH = R-COO- + H+ R-NH2 + H+ = R- NH3+ Degree of Ionization depends on : pH of Medium pKa of the molecule What is pKa?

Henderson-Hasselbach equation
pKa = pH at which 50% of a substance is ionized [A-] [HA]
WEAK acid

pH = pKa + log

pH = pKa + log

[B] [BH+]

WEAK base

pKa Dissciation constant

Henderson Hasselbach
pH - pKa [I] ---------------- = 10 [U] WEAK ACID
Benzoic Acid

Small changes in pH may greatly influence the Degree of drug ionization.

Henderson Hasselbach
pKa - pH [I] ---------------- = 10 [U] WEAK BASE

Aniline

Henderson Hasselbach

Morphine pKa = 8
Stomach pH = 2 Plasma pH = 7.4

Where & Why ?

Concen in blood may not be indentical to conc at the site of action

Basic Parameters
In the next few slides the basic concepts and paramaters will be described and explained. In pharmacokinetics the body is represented as a single or multiple compartments in to which the drug is distributed. Some of the parameters are therefore a little abstract as we know the body is much more complicated !

Pharmacokinetic Parameters

---------------------------Clearance Volume of distribution Half life Bioavailability

CONCEPT OF DRUG CLEARANCE (CL)

Quantifies ELIMINATION

Think of drug clearance as removal of drug from body by bodys garbage disposal systems!

DRUG CLEARANCE: Example:

Rate of Drug Elimination (Excretion rate) = 10 mg/hr [D]P (Concentration) = 4 mg/L

10 mg/hr CL = = 2.5 L/hr 4 mg/L Is the volume of body fluid cleared of drug per time unit (L/h, mL/min)

DRUG CLEARANCE:
CL is usually constant over a wide range of [D]P

CL

The rate of elimination is directly proportional to the drug conc

[D]P
This is a consequence of the fact that most drugs are eliminated from body by 1st order kinetics

Clearance (CL)
Blood, Plasma, Serum Which Particular fluid assay ?
Serum Clearance (CL) of 200 ml/min
In one minute all of the drug could have been eliminated from 200 ml of serum
----------------------------------------

Total Body Clearance (CL)

------------------------------------CL = CLren + CLhep + CLother
CL = (CLliver + CLg.i. tract + CLkidney + CLlung + ...)

Clearance
Clearance also plays a role in determining the steady-state of a drug or toxicant:

concentration

Csteady-state = Rate of administration/ CL

CONCEPT OF DRUG CLEARANCE: INTRODUCTION TO Cl

Cl is a major determinant of [D]P at STEADY STATE ([D]PSS) INPUT STEADY STATE LEVEL (Kidney & Liver) OUTPUT

Clearance
Ability of organs of elimination (e.g. kidney, liver to clear drug from the bloodstream Volume of fluid which is completely cleared of drug per unit time Units are in L/hr or L/hr/kg Pharmacokinetic term used in determination of maintenance doses

Absorption
Must be able to get medications into the patients body Drug characteristics that affect absorption:
Molecular weight, ionization, solubility, & formulation

Factors affecting drug absorption related to patients:

Route of administration, gastric pH, contents of GI tract

Distribution
Membrane permeability
cross membranes to site of action

Plasma protein binding

bound drugs do not cross membranes malnutrition = albumin = free drug

Lipophilicity of drug
lipophilic drugs accumulate in adipose tissue

Volume of distribution

Drug Distribution
At any given time, only a very small portion of the total amount of a drug that is in the body is actually in contact with its receptors. Most of the administered drug is found in areas of the body that are remote from the drugs site of action.

Volume of Distribution
An abstract concept Gives information on HOW the drug is distributed in the body Used to calculate a loading dose

Drug Distribution
It takes time for a drug to distribute in the body Drug distribution is affected by elimination

Wide distribution often accounts for many of the side effects of a drug

Basic Parameters
In the next few slides the basic concepts and paramaters will be described and explained. In pharmacokinetics the body is represented as a single or multiple compartments in to which the drug is distributed. Some of the parameters are therefore a little abstract as we know the body is much more complicated !

THE BODY AS COMPARTMENTS --------------------------

1. Highly Vascular
PLASMA, RED CELLS LUNGS LIVER, BRAIN & SPLEEN

THE BODY AS COMPARTMENTS --------------------------

2. Low Vascular
FAT DEPOSITS

 Drugs may be deposited in fatty tissue which may become a resevior

low blood flow; cannot absorb or release quickly

bone & teeth may accumulate drugs which bind to calcium, tetracycline

Plasma Protein Binding

Many drugs bound to circulating plasma proteins such as albumin Only free drug can act at receptor site
Receptor Site Protein-bound drug

A bound drug has no effect!

Free Drug

Alter plasma binding of drugs

1000 molecules 99.9 1 % bound molecules free 90.0 100

100-fold increase in free pharmacologically active concentration at site of action.

Effective

TOXIC

Highly Protein Bound Drugs

> 95% bound
Thyroxine Warfarin Diazepam Frusemide Heparin Imipramine Amitriptylline

> 90% but < 95% bound

Glibenclamide Phenytoin Propranolol Sodium Valproate

Changes in plasma protein binding are significant for drugs which are greater than 90% bound to plasma proteins

Plasma Proteins that Bind Drugs

albumin: binds many acidic drugs and a few basic drugs This is more important quantitatively -globulin and an 1acid glycoprotein have also been found to bind certain basic drugs

A bound drug has no effect!

Amount bound depends on: 1) free drug concentration 2) the protein concentration 3) affinity for binding sites

[bound drug] % bound: ---------------------------------- x 100 [bound drug] + [free drug]

Binding % of some BDZs

Flurazepam Alprazolam Lorazepam Diazepam 10 % 70 % 90 % 99 %

No generalization for a pharmacological or chemical class

Pharmacokinetic Parameters

---------------------------Clearance Volume of distribution Half life Bioavailability

Volume of Distribution

The Volume of Distribution is the apparent volume into which a drug or toxicant distributes, and provides a proportionality constant between blood (or plasma) concentration and the amount in the body:
Volume of Distribution = Amount / Concentration

Volume of distribution Volume can range from about 3 liters (as is seen with Tolbutamide, which is distributed in blood only,

to about 50,000 liters (as is seen with Quinacrine, which distributes and binds to many tissues).

VOLUME OF DISTRIBUTION (VD) OF DRUGS

(Stir)

As a first approximation, the body behaves like a well-stirred beaker, i.e., chemicals are dispersed throughout the container (body) rather quickly.

VOLUME OF DISTRIBUTION OF DRUGS: DEFINITION OF VD Add DRUG to Beaker Obtain Sample

Assay for C (Stir) Calculate Volume C = Amount Added Volume of Beaker Volume of Beaker = Amount Added C

VOLUME OF DISTRIBUTION OF DRUGS: DEFINITION OF VD Dose Body with DRUG Obtain Plasma Sample

Assay for CP

Calculate Volume (This volume is called VD)

By DEFINITION: VD = A/CP
(where A is amount of drug in body and CP is concentration of drug in plasma)

VOLUME OF DISTRIBUTION OF DRUGS: DEFINITION OF VD

WARNING: VD is a calculated value that should not be taken literally as representing some real volume!!!!!!
VD is: VD is not a real volume with 1. a calculated value, an independent existence. In 2. a reproducible value, this regard, the word volume 3. a clinically useful value. is used in a metaphorical sense.

Volume of Distribution (Vd)

The apparent volume of distribution: A theoretical volume only: NO PHYSICAL BASE NO PHYSIOLOGICAL BASE Volume in which drug appears to distribute Vd not physical volume. Vd is proportionality constant Vd = Dose(known)/Cp(known)

Volume of Distribution (Vd)

Vd = D / C
- Quantifies Distribution - Drug Concentration (C) mg/L Amount of drug in the body (D) mg

Volume of Distribution
Drugs are distributed unevenly between various body fluids and tissues according to their physical and chemical properties

For example, gentamicin Very good water solubility Very poor lipid solubility (do not enter cells)
Gentamicin stays mainly in blood and body water 0.25 L/kg

VOLUME OF DISTRIBUTION OF DRUGS: DETERMINANTS OF VD

Distribution into Body Compartments

Small VD

vs

Large VD

Restriction of Drug to Limited Areas of Body

Free Assess of Drug to Many Areas of Body

VOLUME OF DISTRIBUTION OF DRUGS: DETERMINANTS OF VD

Tissue Binding
CP

VD

A CP

VOLUME OF DISTRIBUTION OF DRUGS: DETERMINANTS OF VD

Plasma Protein Binding A CP

CP

VD

VOLUME OF DISTRIBUTION OF DRUGS: DETERMINANTS OF VD

Distribution into Fat

Cp

VD

A CP

Pharmacokinetic Parameters

---------------------------Clearance Volume of distribution Half life Bioavailability

Half life (t1/2) Half life is the time required to reduce the plasma concentration to half of its original value

t1/2 = 0.693/kel
Elimination rate constant

How long a drug is expected to remain in the body after termination of dosing?

Elimination rate constant Kel

= -----------

0.693 t1/2

CL ----- = Kel Vd

Fraction of the drug present at any time that would be eliminated in unit time.
If 2 g of the drug is present in the body and 0.1 g is eliminated every hour, then k = 0.1/2 = 0.05 or 5% per hour

Clearance = 10 L/hr Volume of Distribution = 100 L What is the Elimination Rate Constant (kel) ?

CL = kel x Vd kel = 10 Lhr -1 = 0.1 hr -1 100 L

10 % of the Volume is cleared (of drug) per hour kel = Fraction of drug in the body removed per hour

CL = kel x Vd
If V increases then k must decrease as CL is constant

Half Life
110 100 90
Concentration (m g/L)

80 70 60 50 40 30 20 10 0 0 1 2 3 4 5 6 7 8 9
Tim e (hours)

Half-life is the time taken for the concentration of drug in blood to fall by a half

Significance
Say a patient is taking a drug and has a toxic blood level of 16mg/L Say
The blood level you want is 2mg/L Drug half life is 8 hours How long will it take for the blood level to fall back to the level you want?

Significance
Half life = time taken for blood level to reduce by 50% Therefore: 16mg to 8mg = 8 hours 8mg to 4 mg = 8 hours 4mg to 2mg = 8 hours Total: 24 hours

Time Course of dru action

Distribution Half Life:
time for drug to reach 50% of its peak concentration

Elimination Half Life:

time for drug concentration to fall 50%

Steady State Concentration:

the level of drug achieved in blood with repeated, regular-interval dosing

12

Plasma Concentration

10 8 6 4 2 0

TOXIC RANGE

THERAPEUTIC RANGE

SUB-THERAPEUTIC

Dose

Time to Steady State

Time to steady state depends on half life

Tss = 4 x t Steady-state occurs after a drug has been given for approximately 4-5 elimination half-lives.
C
C p
a v

t
Fr al eo a sa st oh i s r c t d t e u l v t ehe ya f

Half - Life (t1/2)

t1/2 = ---------------CL
Both Vd and CL may change independently. Therefore t1/2 is not an exact index of drug elimination. Secondary pharmacokinetic parameter and depends on CL & Vd

0.693 . Vd

First order kinetics (t1/2) remains constant because Vd and CL do not change with dose
Zero order kinetics
(t1/2) increases with dose because CL progressively decreases as dose is increased Aspirin 4 hr Digoxin 40 hr Penicillin-G Digitoxin 30 min 7 days

Pharmacokinetic Parameters

---------------------------Clearance Volume of distribution Half life Bioavailability

An Important Concept: BIOAVAILABIITY

The fraction of the administered dose that reaches the systemic circulation of the patient Serum Concentration

Injected Dose

Oral Dose

Time

70 60
Plasma concentration

Bioavailability= (AUC)o

(AUC)iv

50 40 30 20 10 0 0 2

i.v. route

oral route

4 6 Time (hours)

10

Bioavailability
Extent of absorption of a drug following its administration by routes other than IV injection

100 mg Oral , 70 mg absorbed unchanged Bioavailability = 70 %

Iv admin = 1 Oral admin < 1

Bioavailability

lidocaine bioavailability 35% due to destruction in gastric acid and liver metabolism

Gut wall, gut, liver metabolism Incomplete absorption Enterohepatic cycling & elimination into

First Pass hepatic metabolism Lidocaine, propranolol, Morphine, Pentazocine Solubility of drug Chemical instability Penicillin G in gastric acid, insulin Nature of drug formulation Particle size salt form

Bioavailabilit y

Example same drug, 3 different formulations could have same bioavailability

IV Oral not S/R Oral - SR

Plasma conc

Time

Time Course
Steady State Concentration:
the level of drug achieved in blood with repeated, regular-interval dosing

Water level = DRUG

BUCKET with a HOLE

Elimination

Example: Oral Dose

A single oral dose will give you a single peak plasma concentration The drug concentration then continuously declines Repeated doses result in

Plasma Concentration

Time

Important Point pharmacokinetic profile of a drug also depends on its mode of administration
The

Example: Intravenous Infusions

Plasma concentration rises until elimination = input Faster infusions get more drugs on board, but does not change the time to achieve a steady

Plasma Concentration

Fast Infusion

Slow Infusion

Time

Time at which steady state is achieved

T1/2 = 12 h

Multiple dosing

- -

 42 2 SS 1 SS

6 4

Effect of Dose: Increasing the dose gives: Higher plasma concentration Larger peak to trough variation Cp

Example: Dihydrocodeine Better to give 30mg every 4 hours than 60mg every 8 hours Dose = 60mg

Pain relief

Dose = 30mg

Time

Effect of dosage interval: Increasing the dose interval gives: Lower plasma concentrations Larger peak to trough variation

E.g. gentamicin Giving a dose every 12 hours may avoid toxicity Dose interval = 8hours

Cp

Peak Trough Dose interval = 12 hours Time

7 6 5 4 3 2 1 0 0 5 10 15 20
plasma conc

toxic

effective

Time

25

7 6 5 4 3 2 1 0 0 5 10 15 20
Cumulation and use of loading doses
plasma conc

toxic

Loading Dose = Vd x plasma conc

effective

Time

25

12

Plasma Concentration

10 8 6 4 2 0

TOXIC RANGE

THERAPEUTIC RANGE

SUB-THERAPEUTIC

Dose

Multiple dosing
In a medical/dental context some drugs are given as single doses but this is unusual. Most are given as a course of therapy, one or more doses per day for several days or weeks

Multiple dosing
On multiple dosing plasma concentration will rise and fall with each dose and body load will increase until

Rate in = Rate out

administration = elimination i.e. steady state is reached.

At each dose the level will oscillate through a range The objective is to achieve therapeutic levels quickly, to remain within the therapeutic window with acceptable variation at each dose and with a regimen which promotes compliance.

7 6 5 4 3 2 1 0

plasma conc

Time

10

15

20

25

At Steady State
Rate in = Rate out
F x Dose / Dosing Interval = SSC x CL Dosage Plasma level

Cpss = Dose Rate/ CL 2 x Cpss = 2 x Dose Rate/ CL F = fraction of dose administered

What is Steady State (SS) ? Why is it important ?

Rate in = Rate Out Reached in 4 5 half-lives (linear kinetics) Important when interpreting drug concentrations in TDM or assessing clinical response

Important Concepts
VD is a theoretical Volume and determines the loading dose Clearance is a constant and determines the maintenance dose CL = kel x VD CL and VD are independent variables k is a dependent variable