pharmacok 12 7 90 fall

PPHHAARRMMAACCOOKKIINNEETTIICCSS

DRUGSITEOF

ACTION

EFFECTS

BLOOD

SYSTEMICCIRCULATION

Drug must have necessary properties

to be transported From:

its site of administration To:

its site of action

The drug must be The drug must be capable of reaching capable of reaching

the site of actionthe site of actionmust remain at the site must remain at the site

of action long of action long enoughenough

The drug must

achieve

these

criteria without

inducing

unacceptable

toxicity in the patient

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

10 100 1000

Log scale dose (mg/kg)

50

100

0

% r

esp

on

se

Response changes with concentrationThe intensity of response is related to concentration of the

drug at the site of action

Response v Concentration

0.00

0.20

0.40

0.60

0.80

1.00

1.20

0.01 0.10 1.00 10.00 100.00 1000.00 10000.00 100000.00

Concentration

Resp

onse

Receptor Drug Molecule

No response

Linear response

Maximal response

(20-80%)

(semi-log)

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

افزایشقدرت انقباض قلب

تهوع اختلال بینایی

آریتمیقلبی مرگ

Dose -response

Therapeutic Index

• Therapeutic index = toxic dose/effective dose

• This is a measure of a drug’s safety– A large number = a wide margin of safety– A small number = a small margin of safety

Warfarin:A Small Therapeutic Index

Per

cent

of

Pat

ient

s

0

50

100

0 Log Drug Concentration

DesiredTherapeutic

Effect

UnwantedAdverseEffect

Penicillin:A Large Therapeutic Index

Per

cent

of

Pat

ient

s

0

50

100

0 Log Drug Concentration

DesiredTherapeutic

Effect

UnwantedAdverseEffect

•

PARAMETERS LD50 - ED50 & TD50

LD50 TD50ED50 ED50

Margin of safety (TI)

NSAID (IBUPROFEN) Wide TI

Normal dose = 400-3200 mg/day

(THEOPHYLLINE) BLOOD CONC = 10-20 µg/ml

below this conc (not much effect )above

20 µg/ml (serious toxicities)

How Do We Study Pharmacology?

General Concepts

Drug DoseAdministration

Drug Effect or Response

Pharmaceutical

Pharmacokinetics

Pharmacodynamics

Pharmacotherapeutics

Disintegrationof Drug

Absorption/distribution

metabolism/excretionDrug/Receptor

Interaction

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.

Drug is given into : eg: GUT (one body Compartment)

to move to its site of action eg: Brain (another compartment)

HOW?

PHARMACOKINETICS is the study of the kinetics of drug absorption and disposition.

ABSORPTION DISPOSITION

DISTRIBUTIONELIMINATION

EXCRETION METABOLISM

WHAT IS PHARMACOKINETICS?

PharmacokineticsPharmacokinetics The factors involved in a drug getting to and The factors involved in a drug getting to and

remaining at its sites of actionremaining at its sites of action

Passage of drugs across membranesPassage of drugs across membranesAAbsorptionbsorption- how the drug is taken into the body- how the drug is taken into the bodyDDistributionistribution -how the drug is moved into various -how the drug is moved into various

tissuestissuesMMetabolismetabolism --how the drug is changed into a form --how the drug is changed into a form

that can be excretedthat can be excretedEExcretionxcretion- how the drug is removed from the body- how the drug is removed from the body

Drug should be inactivated or excreted from the Drug should be inactivated or excreted from the body at a reasonable rate so its actions body at a reasonable rate so its actions

will be of appropriate duration.will be of appropriate duration.

Pharmacokinetic modelsPharmacokinetic models

“Standard “ Dose

Healthy volunteersPatients with average ability to :

ADME

Pharmacokinetics

Pharmaco dynamicsPharmaco dynamicsstudy the study the mechanismsmechanisms by which by which

drugs workdrugs workalso study endogenous agentsalso study endogenous agents

Receptors & spare RReceptors & spare RAffinity, Efficacy, PotencyAffinity, Efficacy, Potency

EC50, Emax, Kd, Bmax, ED50, TIEC50, Emax, Kd, Bmax, ED50, TIAgonist, antagonist ….Agonist, antagonist ….

PK/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.

Time

Co

nc

PK PD

Time

Eff

ect

Dose

Site of Action

Dosage EffectsPlasmaConcen.

Pharmacokinetics Pharmacodynamics

Pharmacodynamics (PD): What the drug does to the body

Pharmacokinetics (PK): What the body does to the drug

DRUG THERAPYGoal :

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

At the Right timeFor the Right duration

With MIN risk OF HARM

Routes of Drug DeliveryParenteral

(IV)Inhaled

Oral

Transdermal

Rectal

Topical

Parenteral(SC, IM)

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

patient’s 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 biologicalbarriers (mostly layers of cells) from the site of

administration to the blood stream.

BIO

LO

GIC

AL

BA

RR

IER

Vascular SystemSite of Administration

DRUG

THE TRANSPORT ACROSS THE MEMBRANES

A. Passive diffusion and filtrationB. Specialized transport

Passage of drugs across membrane

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

Cellular uptake inside vesicles

Levodopa and methyldopa

Ficks Law at constant temp

• R = K ---------------A (C2 – C1)d

R = Diffusion Rate (flux – molecules per unit time)

A = Surface aread = thickness of membrane > 1

K = Diffusion constant of compound(Temp dependent) Permeability coefficient

K • Function of :

• Steric configuration

• M.Wt

• Lipid Solubility

• Ionization

• non-ionized forms of drugs are more soluble in lipids and absorbed better

than water-soluble, ionized forms of drugs

IONIZATION decreases membrane permeability

Ionized forms of compounds have low lipid solubility

Why?

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

• 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)

Many drugs are weak organic acids or bases (weak elctrolytes)

Weak acids Weak bases DISSOCOATER-COOH = R-COO- + H+

R-NH2 + H+ = R- NH3+

Degree of Ionization depends on : pH of Medium

pKa of the molecule

What is pKa?

pH = pKa + log [A-]

Henderson-Hasselbach equation

[HA]WEAK

acid

pH = pKa + log [B]

[BH+]WEAK

base

pKa = pH at which 50% of a substance is ionized

pKa Dissciation constant

Henderson Hasselbach

---------------- [I]

[U]WEAK ACID

10pH - pKa

=

Benzoic Acid

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


---------------- [I]

[U]WEAK BASE

10pKa - pH

=

Aniline


Morphine pKa = 8

Stomach pH = 2Plasma 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

----------------------------

ClearanceVolume of distribution

Half – lifeBioavailability

CONCEPT OF DRUG CLEARANCE (CL)

Think of drug clearance as removalof drug from body by body’s

garbage disposal systems!

Quantifies ELIMINATION

DRUG CLEARANCE:

Example:

CL = 10 mg/hr

4 mg/L= 2.5 L/hr

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

[D]P

This is a consequence of the fact that mostdrugs are eliminated from body by

1st order kinetics

The rate of elimination is directly proportional to the drug conc

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 concentration of a drug or toxicant:

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

OUTPUT

STEADY STATE LEVEL

(Kidney & Liver)

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

patient’s 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 drug’s 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

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

drug

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

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

Protein-bound drug

Free Drug

Receptor Site

A bound drug has no effect!

Alter plasma binding of drugs

1000 molecules

% bound

molecules free

99.9 90.0

100 1

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 drugswhich 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 10 %

• Alprazolam 70 %

• Lorazepam 90 %

• Diazepam 99 %

No generalization for a pharmacological or chemical class


----------------------------

ClearanceVolume of distribution

Half – lifeBioavailability

Volume of DistributionThe 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 distributionVolume 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).

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 (VD) OF DRUGS

(Stir)

VOLUME OF DISTRIBUTION OF DRUGS:DEFINITION OF VD

Add DRUGto Beaker

Calculate Volume

Obtain Sample

Assay for C

(Stir)

C = Amount Added Volume of Beaker

Volume of Beaker = Amount Added C


Dose Bodywith DRUG

Calculate Volume(This volume is called VD)

Obtain Plasma Sample

Assay for CP

By DEFINITION: VD = A/CP

(where A is amount of drug in body and CP is concentration of drug in plasma)


WARNING: VD is a calculated value that should not be taken literally as

representing somereal volume!!!!!!

VD is:1. a calculated value,2. a reproducible value,3. a clinically useful value.

VD is not a real volume with an independent existence. Inthis regard, the word “volume”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 distributeVd not physical volume.Vd is proportionality constantVd = 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

Restriction of Drug toLimited Areas of Body Free Assess of Drug to

Many Areas of Body

vs Large VDSmall VD


Tissue Binding

CP

VD

A

CP

=


Plasma Protein Binding

CP

VD

CP

=A


Distribution into Fat

Cp

VD

CP

=A


----------------------------Clearance

Volume of distributionHalf – life

Bioavailability

• Half life is the time required to reduce the plasma concentration to half of its original value

Half – life (t1/2)

Elimination rate constant

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

t1/2 = 0.693/kel

Elimination rate constant

0.693

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

Kelt1/2

= -----------CL

Vd 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

Clearance = 10 L/hrVolume of Distribution = 100 L

What is the Elimination Rate Constant (kel) ?

CL = kel x VdIf V increases then k must decrease as

CL is constant

Half Life

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

0

10

20

30

40

50

60

70

80

90

100

110

0 1 2 3 4 5 6 7 8 9

Time (hours)

Co

nce

ntr

atio

n (

mg

/L)

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

Dose

Pla

sma

Co

nce

ntr

atio

n

0 1 2 3 4 5 6 7 8 90

2

4

6

8

10

12

TOXIC RANGE

THERAPEUTIC RANGE

SUB-THERAPEUTIC

Time to Steady State• Time to steady state depends on half life

Tss = 4 x t½

Steady-state occurs after a drug has been given

for approximately 4-5 elimination half-lives.

C

t

Cpav

Four half lives to reach steady state

Half - Life (t1/2)

t1/2 = ----------------0.693 . Vd

CLBoth 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

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 Penicillin-G 30 minDigoxin 40 hr Digitoxin 7 days


----------------------------Clearance

Volume of distributionHalf – life

Bioavailability

An Important Concept:BIOAVAILABIITY

The fraction of

the administered

dose that reaches

the systemic circulation

of the patientS

erum

Con

cent

rati

on

Time

Injected Dose

Oral Dose

0

10

20

30

40

50

60

70

0 2 4 6 8 10

Pla

sma

con

cen

trat

ion

Time (hours)

Bioavailability (AUC)o

(AUC)iv=

i.v. route

oral route

BioavailabilityBioavailabilityExtent of absorption of a drug following its

administrationby routes

other than IV injection

BioavailabilityBioavailability 100 mg Oral , 70 mg absorbed 100 mg Oral , 70 mg absorbed

unchangedunchangedBioavailability = 70 % Bioavailability = 70 %

Iv admin = 1Iv admin = 1Oral admin < 1 Oral admin < 1

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

Gut wall, gut, liver metabolismGut wall, gut, liver metabolismIncomplete absorptionIncomplete absorptionEnterohepatic cyclingEnterohepatic cycling & elimination into the & elimination into the

bilebile

Factors influencingFactors influencing

BioavailabilitBioavailabilityy First Pass hepatic metabolismFirst Pass hepatic metabolism

Lidocaine, propranololLidocaine, propranolol, , Morphine, Morphine, PentazocinePentazocine

Solubility of drugSolubility of drug Chemical instabilityChemical instability

Penicillin G in gastric acid, Penicillin G in gastric acid, insulininsulin Nature of drug formulationNature of drug formulation

Particle size – salt form Particle size – salt form

Example – same drug, 3 different formulations could have same bioavailability

Time

Plasma conc

IV

Oral – not S/R

Oral - SR

Time Course• Steady State Concentration:

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

BUCKET with a HOLEWater level = DRUG Elimination

Example: Oral DoseExample: Oral Dose

A single A single oral doseoral dose will give you a single will give you a single peak plasma peak plasma concentrationconcentration

The drug The drug concentration then concentration then continuously declinescontinuously declines

Repeated doses result Repeated doses result in oscillations in in oscillations in plasma concentrationplasma concentration

Pla

sma

Con

cent

rati

on

Time

Important PointImportant Point

The pharmacokinetic The pharmacokinetic profile of a drug also profile of a drug also

depends on its mode of depends on its mode of administration …administration …

Example: Intravenous Example: Intravenous InfusionsInfusions

Plasma Plasma concentration rises concentration rises until until

elimination = inputelimination = input Faster infusions get Faster infusions get

more drugs on more drugs on board, but does not board, but does not change the time to change the time to achieve a steady achieve a steady statestate

Pla

sma

Con

cent

rati

on

Time

Slow Infusion

Fast Infusion

Time at whichsteady state is achieved

T1/2 = 12 h

Multiple dosing معین- - زمانی فواصل ثابت دوز مکرر

4

دارو عمر نیمه ساعت 24

قرص یکروزی

4

SS

6

قرص دوروزی SS2

1

Effect of Dose:Increasing the dose gives:

Higher plasma concentrationLarger peak to trough variation

Dose = 30mg

Time

Cp

Dose = 60mg

Pain relief

Example: DihydrocodeineBetter to give

30mg every 4 hoursthan

60mg every 8 hours

Effect of dosage interval:Increasing the dose interval gives:

Lower plasma concentrationsLarger peak to trough variation

Time

Cp

Dose interval= 12 hours

Dose interval= 8hours

Peak

Trough

E.g. gentamicin

Giving a dose every12 hours may avoid

toxicity

0

1

2

3

4

5

6

7

0 5 10 15 20 25

Time

plasma conc

toxic

effective

0

1

2

3

4

5

6

7

0 5 10 15 20 25

Time

plasma conctoxic

Cumulation and use ofloading doses

effective

Loading Dose = Vd x plasma conc

Dose

Pla

sma

Co

nce

ntr

atio

n

0 1 2 3 4 5 6 7 8 90

2

4

6

8

10

12

TOXIC RANGE

THERAPEUTIC RANGE

SUB-THERAPEUTIC

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.

0

1

2

3

4

5

6

7

0 5 10 15 20 25

Time

plasma conc

At Steady StateRate in = Rate out

F x Dose / Dosing Interval = SSC x CL

Dosage Plasma level

F = fraction of dose administeredCpss = Dose Rate/ CL2 x Cpss = 2 x Dose Rate/ CL

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

pharmacok 12 7 90 fall

Documents

plasma protein

steady state

weak base

gastric ph

plasma proteins

steady state

basic concepts

gastric acid