PharmacokinetiPharmacokineticscs

DRUGSITEOF

ACTION

EFFECTS

BLOOD

SYSTEMICCIRCULATION

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

Definitions

• Pharmacokinetics is the study of the time course of the drug concentration in the body, i.e., "what the body does to the drug".

• Therapeutic drug monitoring is the measurement of the serum level of a drug and the coordination of this serum level with a therapeutic range.

• The therapeutic range is that range of serum drug concentrations which have been shown to be efficacious without causing toxicity in the majority of patients.

• Clinical pharmacokinetics deals with the application of pharmacokinetic principles to the safe and effective therapeutic management of drug dosage in an individual patient.

L = Liberation, the release of the drug from it's dosage form.

A = Absorption, the movement of drug from the site of administration to the blood circulation.

D = Distribution, the process by which drug diffuses or is transferred from intravascular space to extravascular space (body tissues).

M = Metabolism, the chemical conversion or transformation of drugs into compounds which are

easier to eliminate. E = Excretion, the elimination of unchanged drug or metabolite from the body via renal, biliary, or pulmonary processes.

Routes of Drug DeliveryRoutes of Drug DeliveryParenteral

(IV)Inhaled

Oral

Transdermal

Rectal

Topical

Parenteral(SC, IM)

Drug Absorption

Orally Rectually (drug embedded in a

suppository, which is placed in the rectum) Parenterally (given in liquid form by

injection with a needle and syringe) Inhaled –thru the lungs as gases, as

vapors, or as particulars carried in smoke or in an aerosol

Absorbed through the skin Absorbed through mucous membranes

Drug Absorption -caveats

OrallyDrug must be soluble and stable in

stomach fluid (not destroyed by gastric acids), enter the intestine, penetrate the lining of the stomach or intestine, and pass into the blood stream.

Drug Absorption -disadvantages May occasionally lead to

vomiting and stomach distress.

How much of the drug will be absorbed into the bloodstream cannot always be accurately predicted because of the genetic differences between people and because differences in the manufacture of the drugs.

The acid in the stomach destroys some drugs.

Drug Absorption -caveats

Rectually Rarely used unless patient is vomiting,

unconscious, or unable to swallow

Rectually Often irregular, unpredictable, and

incompleteMany drugs irritate the membranes

that line the rectum.

Drug Absorption -disadvantages

Drug Absorption

Parenterally Intravenous –directly into a veinIntramuscular –directly into muscleSubcutaneous –just under the skin

Drug Absorption

Parenterally Often produces a more prompt

response than does oral administration because absorption is faster.

Permits a more accurate dose because the unpredictable processes of absorption are bypassed.

Drug Absorption -disadvantages Parenterally Leaves little time to respond to an

unexpected drug reaction or accidental overdose.

Requires the use of sterile techniques.Once a drug is administers by injection, it

cannot be recalled.

Drugs that cannot become completely soluble before injection, cannot be injected intravenuously.

Drug Absorption

Inhaled Lung tissues have a large surface area

with large blood flow, allowing for rapid absorption of drugs.

Drug Absorption

Absorbed through the skinProvides continuous, controlled release of a drug from a reservoir through a

semipermeable membrane. Potentially minimizes side effects

associated with rapid rises and falls in plasma concentration of the drug contained in the patch.

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

Who took the largest dose of Tylenol?

65 kg 75 kg 10 kg 2.5 kg 300 mg 600 mg 100 mg 50 mg

Calculating Dose:

300 mg 62.5 kg = 4.8 mg/kg

50 mg 2.5 lb = 20 mg/kg

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

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

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)

Drug Concentrations in the Plasma

Drug Concentration in Plasma (Cp)

mcg/mL

50

40

30

20

10

Time since administration of drug(hours)

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

But what’s missing here

that is needed for this info to be of any use?

Drug Concentrations in the Plasma

Drug Concentration in Plasma (Cp)

mcg/mL

50

40

30

20

10

Time since administration of drug(hours)

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14

Therapeutic Concentrations

(Therapeutic Range)

Subtherapeutic Concentrations

Toxic Concentrations

0 2 4 6 8 10 12Time (hour)

Dru

g co

ncen

trat

ion

in b

lood

Onset and duration of drug action

0 2 4 6 8 10 12Time (hour)

Dru

g co

ncen

trat

ion

in b

lood

MEC

Onset and duration of drug action

0 2 4 6 8 10 12Time (hour)

Dru

g co

ncen

trat

ion

in b

lood

MTC

MEC

Onset and duration of drug action

0 2 4 6 8 10 12Time (hour)

Dru

g co

ncen

trat

ion

in b

lood

MTC

MEC

Onset and duration of drug action

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 oscillations in plasma concentration

Pla

sma

Con

cent

rati

on

Time

CONCEPT OF DRUG CLEARANCE:INTRODUCTION TO Cl

[D]PSS

Toxic Threshold

Therapeutic Threshold

Time (hrs)

[D] P

(m

g/L

) (Therapeutic Window)

Single Dose

Multiple Doses

[D]PSS = [D]P at steady state

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

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 Steady StateRate in = Rate out

F x Dose / Dosing Interval = SSC x CL

Dosage Plasma level

F = fraction of dose administered

Question

• What maintenance dose is required for drug A if;

• Target average SS concentration is 10 mg/L

• CL of drug A is 0.015 L/kg/hr• Patient weighs 75 kg

• Answer on next slide.

Answer

• Maintenance Dose = CL x CpSSav

• CL = 0.015 L/hr/kg x 75 = 1.125 L/hr

• Dose = 1.125 L/hr x 10 mg/L = 11.25 mg/hr

• So will need 11.25 x 24 mg per day= 270 mg

Example: Maintenance Dose Calculations

A target plasma theophylline concentration of 10 mg/L is desired to relieve acute bronchial asthma in a patient.

mean clearance = 2.8 L/h/70 kg. Since the drug will be given as an intravenous infusion, F = 1.

Dosing rate = CL × TC = 2.8 L / h / 70 kg × 10 mg / L = 28 mg / h / 70 kg

Therefore, in this patient, the proper infusion rate would be28 mg/h/70 kg.

If the asthma attack is relieved, the clinician might want to maintain this plasma level using oral theophylline, which might be given every 12 hours using an extended-release formulation to approximate a continuous intravenous infusion. Foral = 0.96

When the dosing interval is 12 hours, the size of each maintenance dose would be:

Maintenance dose =Dosing rate/F × Dosing interval

= 28 mg / h/ 0.96 × 12 hours

= 350 mg

If an 8-hour dosing interval was used, the ideal dose would be 233 mg; and if the drug was given once a day, the dose would be 700 mg.

Question

• What is the loading dose required for drug A if;

• Target concentration is 10 mg/L

• VD is 0.75 L/kg

• Patients weight is 75 kg

• Answer is on the next slide

Answer: Loading Dose of Drug A

• Dose = Target Concentration x VD• VD = 0.75 L/kg x 75 kg = 56.25 L• Target Conc. = 10 mg/L• Dose = 10 mg/L x 56.25 L• = 565 mg• This would probably be rounded to 560 or

even 500 mg.

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

Absorption –the process by which the drug moves into the body from external source

Distribution –the drug is distributed throughout the body (including fetus)

Metabolism –detoxification or breakdown of the drug into metabolites that no longer exert any effect

Elimination –metabolic waste products are removed from the body

PharmacokineticsPharmacokinetics in its simplest form describes the time course of a particular drug’s actions: the time to onset and the duration of effect.

Pharmacokinetics

PK/PD

Time

Co

nc

PK PD

Time

Eff

ect

Dose

Drug BodyDrug Body

Molecular size

Lipid solubility

Ionization

Absorption

Distribution

Elimination

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?

53

“7 Rights” of Safe Medication Administration

Right Drug Right Dose Right Time Right Route Right Patient Right Reason Right Documentation

WHY BE CONCERNED ABOUT HOW DRUGS GET INTO BODY?

• Bioavailability - % of dose that gets into body

• Bioequivalence - similarity between two formulations of same drug

• Speed of Drug Onset - how long it takes the drug to begin working

• Dosing Interval - how often the drug should be given

• Site of Action - whether the drug stays local or acts systemically

This issue importantly affects:

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

• 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?

• 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

Henderson Hasselbach

• pH = pKa + Log ---------------- [A-] [HA]

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

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

Henderson Hasselbach

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

[U]WEAK ACID

10pH - pKa

=

Benzoic Acid

Henderson Hasselbach

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

[U]WEAK BASE

10pKa - pH

=

Aniline

Moral of the story...Moral of the story...Moral of the story...Moral of the story...

Acidic drugs are best absorbed from acidic environments

Acidic drugs are best absorbed from acidic environments

Basic drugs are best absorbed from

basic environments

Basic drugs are best absorbed from

basic environments

WHAT AFFECTS DRUG ABSORPTION?

• Rate of release of drug from pharmaceutical preparation

• Membrane permeability of drug

• Surface area in contact with drug

• Blood flow to site of absorption

• Destruction of drug at or near site of absorption

The rate of drug absorption will be affected by:

WHAT DETERMINES RATE OFRELEASE OF DRUG FROM

PHARMACEUTICALPREPARATION?

• Solutions: No Delay, Immediate Release

• Capsules & Tables: Delay (Dissolution) Followed by Rapid Release

• Creams, Ointments & Suppositories: No Delay, but Slow Release

A: DOSAGE FORM

WHAT DETERMINES RATE OFRELEASE OF DRUG FROM

PHARMACEUTICALPREPARATION?

Decrease Rate ofDissolution

• Binders• Lubricants

• Coating Agents

B: ADDITIVES (EXCIPIENTS)

Increase Rate of Dissolution

• Disintegrants

Variable Effects onRate of Dissolution

• Diluents• Coloring Agents• Flavoring Agents

WHAT DETERMINES RATE OFRELEASE OF DRUG FROM

PHARMACEUTICALPREPARTAION?

• Tablet Compression - Hard tablets dissolve more slowly

• Tablet Shape - Round tablets dissolve more slowly

•Tablet Size - Large tablets dissolve more slowly

C: MANUFACTURING PARAMETERS

WHAT DETERMINES RATE OFRELEASE OF DRUG FROM

PHARMACEUTICALPREPARATION?

• Enteric Coating - Dissolve in intestines, not stomach

D: DELAYED RELEASE PREPARATIONS

WHAT DETERMINES RATE OFRELEASE OF DRUG FROM

PHARMACEUTICALPREPARATION?

• Reservoir Diffusion Products - Drug diffuses from pill corethrough membrane shell

• Matrix Diffusion Products - Drug diffuses through matrixin which it is embedded

• Matrix Dissolution Products - Drug released as matrix dissolves• Osmotic Tablets - Drug pumped out of tablet by osmotic forces

• Ion-Exchange Products - Drug bound to resin exchanges with endogenous ions

E: SUSTANED RELEASE PREPARATIONS

WHAT DETERMINES MEMBRANEPERMEABILITY OF DRUGS?

• Presence of Aliphatic and Aromatic Structures

•Absence of Polar Groups

A: LIPOPHILICITY increases membranepermeability

WHAT DETERMINES MEMBRANEPERMEABILITY OF DRUGS?

• Weak acids in intestines are mostly ionized(intestinal pH ranges from 6.6 to 7.5)

• Weak bases in stomach are mostly ionized(stomach pH ranges from 1 to 2)

B: IONIZATION decreases membranepermeability

WHAT DETERMINES SURFACEAREA FOR ABSORPTION?

• Low Surface Area: eyes, nasal cavity, buccal cavity, rectum, stomach, large intestines

• High Surface Areasmall intestines, lungs

ANATOMY

WHAT DETERMINES WHETHER A DRUG IS DESTROYED

AT OR NEAR SITE OF ADMINISTRATION?

• Liver - hepatic enzymes (“first pass” effect)

• Colon - intestinal microflora

•Stomach - digestive enzymes and acids

BIOCHEMISTRY

WHAT ARE THE ROUTES OFADMINISTRATION FOR DRUGS?

• Oral

•Sublingual

•Rectal

ENTERAL

• Intravenous (IV)• Intra-arterial (IA)• Subcutaneous (SC)• Intradermal (ID)

• Intramuscular (IM)• Intraperitoneal (IP)• Lungs (Inhalation)

• Skin (Topical)

PARENTERAL

•Nose (Intranasal)• Eye (Opthalmic)

• Ear (Otic)• Vagina

• Urinary Bladder• Directly Into Target Tissue

High

WHAT ARE THE ADVANTAGES AND DISADVANTAGES OFORAL, IV, IM AND SC ADMINISTRATION?

SAFETYHigh Low Oral > SC > IM > IV

Oral > SC > IM > IV

CONVENIENCELow

DelayedImmediate

WHAT ARE THE ADVANTAGES AND DISADVANTAGES OFORAL, IV, IM AND SC ADMINISTRATION?

BIOAVAILABILITYHigh and Reliable Low and/or Variable IV > IM = SC > ORAL

IV > IM > SC > Oral

ONSET OF ACTION

LowHigh

LowHigh

WHAT ARE THE ADVANTAGES AND DISADVANTAGES OFORAL, IV, IM AND SC ADMINISTRATION?

INTERACTIONS WITH FOODRisk No Risk Oral > IV = IM = SC

Oral > IM = SC = IV

COMMERCIAL AVAILABILITY OF DOSAGE FORMS

VOLUME OF DRUG Oral = IV > IM > SC

WHY CONSIDER OTHER ROUTES OFADMINISTRATION?

• Sublingual - Rapid absorptionthat bypasses liver

• Rectal - Great for patient thatis vomiting or cannot (will not)

swallow medication

Pharmacokinetic Parameters

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

ClearanceVolume of distribution

Half – lifeBioavailability

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)

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 = (CLliver + CLg.i. tract + CLkidney + CLlung

+ ...)

Dose / Area under the curve (AUC)e.g. mg / (mg.h /L) = L/h

Clearance

Clearance also plays a role in determining

the steady-state concentration of a drug or toxicant:

Csteady-state = Rate of administration/ CL

Cl is a major determinant of [D]P at STEADY STATE ([D]P

SS)

INPUT

OUTPUT

STEADY STATE LEVEL

(Kidney & Liver)

Elimination

Drugs leave the body through: Kidneys Lungs Bile Skin

Elimination

Drugs leave the body through: Kidneys:1) Excrete most of the products of body

metabolism2) Closely regulate the levels of most of

the substances found in body fluids• Psychoactive drugs are often reabsorbed out of the kidneys, so the liver has to enzymatically transform the drugs so with minimal reabsorption they can exit in urine.

Elimination

Drugs leave the body through: Lungs

Only occurs with highly volatile or gaseous agents

Elimination

Drugs leave the body through: Skin

Small amounts of a few drugs can pass through the skin and be excreted in sweat.

Pharmacokinetics

Distribution –the drug is distributed throughout the body

Drug Distribution Body Membranes that Affect Drug

Distribution1. Cell membranes2. Walls of the capillary vessels in

the circulatory system3. Brain-blood barrier4. Placental barrier

Drug Distribution1st Body Membrane that Affects

Drug Distribution Cell membranes

Permeable to small lipid (fatty) molecules

Drug Distribution2nd Body Membrane that Affects

Drug Distribution Walls of the capillary vessels in

the circulatory systemDoes not depend on lipid solubility

Only drugs that do not bind to plasma proteins

pass through capillary pores.

Drug Distribution3rd Body Membrane that Affects

Drug Distribution Brain-blood barrier

The rate of passage of a drug into the

brain is determined by two factors:

(1) the size of the drug molecule and

(2) its lipid (fat) solubility.

Drug Distribution4th Body Membrane that Affects

Drug Distribution Placental barrier

Oxygen and nutrients travel from the

mother’s blood to that of the fetus,

while carbon dioxide and other waste

products travel from the blood of the

fetus to the mother’s blood.

Fat-soluble substances (including all

psychoactive drugs) diffuse rapidly and

without limitation.

Distribution

Distribution is the process by which a drug diffuses or is transferred from intravascular space toextravascular space (body tissues). These spaces are described mathematically as volume(s) ofdistribution.

In the simplest of terms, a drug's volume of distribution is that volume of bodily fluid into which a drugdose is dissolved.

Volume of distribution = Dose / drug concentration

Central volume (Vc)

The central volume of distribution (Vc) is a hypothetical volume into whicha drug initially distributes

upon administration. This compartment can be thought of as the blood in vessels and tissues whichare highly perfused by blood.

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.

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

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

1. Highly Vascular PLASMA, RED CELLS

LUNGS

LIVER, BRAIN & SPLEEN

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

2. Low Vascular FAT DEPOSITS

One, two, and three compartment pharmacokinetic models. Fortunately many of the processes involved in drug movement around the body are not saturated at normal therapeutic dose levels. The pharmacokinetic - mathematical models that can be used to describe plasma concentration as a function of time can then be much simplified. The body may even be represented as a single compartment or container for some drugs. For other drugs a two or three compartment model is found to be necessary.

Body before and after a rapid I.V. bolus injection, considering the body to behave as a single compartment. In order to simplify the mathematics it is often possible to assume that a drug given by rapid intravenous injection, a bolus, is rapidly mixed. This slide represents the uniformly mixed drug very shortly after administration.

Oral curve and beakers. We can picture oral administration as water flowing from one bucket (representing the GI tract) into a second beaker (representing the body). At first drug flows into the 'body' beaker and the level rises, as drug concentration rises, then after peaking the levels start to fall as elimination overtakes absorption.

Intravenous bolus injection with a two compartment model. Often a one compartment model is not sufficient to represent the pharmacokinetics of a drug. A two compartment model often has wider application. Here we consider the body is a central compartment with rapid mixing and a peripheral compartment with slower distribution. The central compartment is uniformly mixed very shortly after drug administration, whereas it takes some time for the peripheral compartment to reach a pseudo equilibrium.

WHY BE CONCERNED ABOUT WHERE DRUGS GO?

Where drugs go determines Where Drugs Act:

• Ciprofloxacin [Cipro®] penetrates the prostate gland andtherefore is effective in bacterial prostatitis, whereas

most antibiotics do not enter the prostate andare therefore ineffective in prostatitis.

• Fexofenadine [Allegra®] is largely excluded from the brainand therefore is a “nonsedating” antihistamine, whereas

most antihistamines freely enter the brain andcause marked drowsiness.

WHY BE CONCERNED ABOUT WHERE DRUGS GO?

Where drugs go influences Where Drugs Are Eliminated:

• Penicillin is actively transported into the proximal tubules andis therefore rapidly excreted by the kidneys.

• Inhalation anesthetics distribute to alveolar spaces andtherefore are eliminated by the lungs.

WHY BE CONCERNED ABOUT WHERE DRUGS GO?

Where drugs go influences How Long Drugs Last In the Body :

• Raloxifene [Evista®]) (for treatment of osteoporosis in postmenopausal women) is transported by the liver into the

intestines where it is reabsorbed (enterohepatic recirculation).This greatly increases the time raloxifene lasts in the body.

Pharmacokinetic Parameters

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

ClearanceVolume of distribution

Half – lifeBioavailability

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 OF DRUGS:DETERMINANTS OF VD

Plasma Protein Binding

CP

VD

CP

=A

VOLUME OF DISTRIBUTION OF DRUGS:DETERMINANTS OF VD

Distribution into Fat

Cp

VD

CP

=A

Volume of Distribution

• Gives information on HOW the drug is distributed in the body

• Used to calculate a loading dose

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!

Binding % of some BDZs

• Flurazepam 10 %

• Alprazolam 70 %

• Lorazepam 90 %

• Diazepam 99 %

No generalization for a pharmacological or chemical class

Pharmacokinetic Parameters

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

Volume of distributionHalf – life

Bioavailability

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)

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

Half - Life (t1/2)

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

CLIs the time it takes for the concentration to fall to half

of its previous value

Secondary pharmacokinetic parameter and depends on CL & Vd

A drug has a half life of A drug has a half life of 10 seconds10 seconds. You . You give a patient a dose of give a patient a dose of 6mg6mg. After . After 30 30 secondsseconds how much of the drug remains? how much of the drug remains?

A drug has a half life of A drug has a half life of 10 seconds10 seconds. You . You give a patient a dose of give a patient a dose of 6mg6mg. After . After 30 30 secondsseconds how much of the drug remains? how much of the drug remains?

TimeTime AmountAmount

0 sec0 sec 6 mg6 mg

10 sec10 sec 3 mg3 mg

20 sec20 sec 1.5 mg1.5 mg

30 sec30 sec 0.75 mg0.75 mg

Time Course of drug 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

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

Pharmacokinetic Parameters

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

Volume of distributionHalf – life

Bioavailability

Bioavailability

Dose

Destroyed in gut

Notabsorbed

Destroyed by gut wall

Destroyedby liver

tosystemiccirculation

0

10

20

30

40

50

60

70

0 2 4 6 8 10

Pla

sma

con

cen

trat

ion

Time (hours)

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 metabolism Incomplete absorptionIncomplete absorption Enterohepatic cyclingEnterohepatic cycling & elimination into & elimination into

the bilethe bile

BiequivalenceBiequivalenceDrugs with comparable Drugs with comparable

BioavailabilityBioavailability

Therapeutic equivalenceTherapeutic equivalence

Drugs with comparable Drugs with comparable Efficacy & SafetyEfficacy & Safety

Bioavailability Affected by:

Dosage form Dissolution and absorption of drug Route of administration Stability of the drug in the GI tract (if oral

route) Extent of drug metabolism before reaching

systemic circulation Presence of food/drugs in GI tract

Example – same drug, 3 different formulations could have same

bioavailability

Time

Plasma conc

IV

Oral – not S/R

Oral - SR

bioequivalent

Two drug products are said to be bioequivalent if they

are pharmaceutical equivalent or pharmaceutical

alternatives, and if their rates and extents of

absorption do not show a significant difference.

Purpose of BE

Therapeutic equivalence (TE) Bioequivalent products can be

substituted for each other without any adjustment in dose or other additional therapeutic monitoring.

The most efficient method of assuring TE is to assure that the formulations perform in an equivalent manner.

Fundamental Bioequivalence

Assumption

When a generic drug is claimed bioequivalent to a

brand-name drug, it is assumed that they are

therapeutically equivalent.

Safety Concern

Generic Drugs

They’re cheaper, but do they work as well?

Safety Concern

Generic and brand-name drugs do exactly the same thing and are

completely interchangeable.

I would hesitate to substitute a generic for a brand-name drug for those patients who have been on the drug for years. However, I would not hesitate to suggest a doctor start a new patient on

the generic version.

Drug Switchability

The switch from a drug (e.g., a brand-name drug or its generic

copies) to another (e.g., a generic copy) within the same patient whose concentration of the drug has been titrated to a steady, efficacious and

safe level Individual Bioequivalence (IBE)

Post-approval meta-analysis for BE review

DRUG METABOLISMDRUG METABOLISM

Drug MetabolismDrug Metabolism(we’re still talking about (we’re still talking about

Pharmacokinetics)Pharmacokinetics)

CYP450

Biotransformation

Potentially toxic xenobiotic

Inactive metabolite

Relatively harmless

Reactive intermediate

DetoxificationMetabolic activation

Converting lipophilic to water soluble compounds

Xenobiotic

Reactive intermediate

Conjugate

Phase I - Activation

Phase II - Conjugation

Excretion

Lipophilic

(non-polar)

Water soluble(polar)

Metabolism –detoxification or breakdown of the drug into metabolites that no longer exert any effect

How Drug go out from body ?

Drug Elimination

Metabolism:conversion of one chemical

entity to another.

Excretion:Loss of drug or its

metabolites

DRUG METABOLISMDRUG METABOLISM

BiotransformationBiotransformationXenobiotic Xenobiotic metabolismmetabolism

Phase I Phase IIDRUG METABOLITE CONJUGATE

Expose or introduce a Conjugate the functional functional group that groups exposed or introduced can be conjugated by during Phase I biotransformation Phase II enzymes

Small in water solubility Large in water solubility

• Termination of Pharmacological activity or introduce toxicity

• The rate and extent to which a drug is metabolized determines the dose of the drug and the duration of the effect of the drug

Rate limiting/Affected by genetic and

environmental factors

Active/Inactive/Toxic/Mutagenic/Carcinogen

OH OGlucuronide

Two-phase biotransformation

Phase I (functionalization) reactions: Oxidation, Reduction, and hydrolytic reactions

(makes the drug more polar, but not necessarily inactive)

Phase II (conjugation) reactions: Conjugation to polar groups: glucuronidation,

sulfation, acetylation (most of these result in drug inactivation)

•Ultimate effect is to facilitate elimination

Phase I

• introduction of functional group

• hydrophilicity increases slightly• may inactivate or activate original compound• major player is CYP or mixed function oxygenase

(MFO) system in conjunction with NAD(P)H• location of reactions is smooth endoplasmic reticulum

Phase II

• conjugation with endogenous molecules(GSH, glycine, cystein, glucuronic acid)

• hydrophilicity increases substantially• neutralization of active metabolic intermediates• facilitation of elimination • location of reactions is cytoplasm

BIM

M11

8

Drug Metabolism - Phase II

• Conjugation reactions– Glucuronidation by UDP-Glucuronosyltransferase:

(on -OH, -COOH, -NH2, -SH groups)

– Sulfation by Sulfotransferase:

(on -NH2, -SO2NH2, -OH groups)

– Acetylation by acetyltransferase:

(on -NH2, -SO2NH2, -OH groups)

– Amino acid conjugation

(on -COOH groups)– Glutathione conjugation by Glutathione-S-transferase:

(to epoxides or organic halides)– Fatty acid conjugation

(on -OH groups)– Condensation reactions

Cytochrome P450 (CYP) Mixed Function Oxidases (MFO)

• Located in many tissues but highly in liver ER• Human: 16 gene families• CYP 1,2,3 perform drug metabolism• >48 genes sequenced• Key forms: CYP1A2, CYP2C9, CYP2C19, CYP2D6,

CYP2E1, and CYP3A4• Highly inducible

– Alcohol CYP2E1– Dioxin/PCBs CYP1A– Barbiturates CYP2B

• CYP genes have multiple alleles (2D6 has 53, and 2E1 has 13)

METABOLISM (BIOTRANSFORMATION)------------------------------------

The processes by which foreign molecules (Xenobiotics) are

chemically altered by a living organism.

Result------------

• Water soluble metabolites

• Increased Excertion

• Reduced Biological Half-life

• Minimum Toxicity

Result------------

• More polar metabolites is formed

• Possible Increase in M. wt and Size

• Excretion & Elimination

Result------------

• Exposure time is shortened

• Possibility of accumulation is reduced

• Probable change in Biological activity

• Change in the duration of the biological activity

Metabolism

the major mechanism for terminating xenobiotic activity,

and is frequently the single most important determinant of the

duration and intensity of toxic responses to a xenobiotic.

Enzymatic, chemical, or stereo chemical change to an administered drug;

conversion of substance

Active to Less Active or Inactive (Most cases):» Hydroxylation of Pentobarbital

Active to Equivalent Activity:» Codeine to Morphine

Inactive to Active:

Carbon Tetrachloride - carcinogen

IMPLICATIONS FOR DRUG METABOLISMIMPLICATIONS FOR DRUG METABOLISM

1. Termination of drug action

2. Activation of prodrug

3. Bioactivation and toxication

4. Carcinogenesis

5. Teratogenesis

Transformation of Xenobiotics by Biological Systems

Sites of biotransformation

• where ever appropriate enzymes occur; plasma, kidney, lung, gut wall and

LIVER

• the liver is ideally placed to intercept natural ingested toxins (bypassed by injections etc) and has a major role in biotransformation

Skin BloodBrain

MetabolismMetabolism

• Amitriptylline is metabolized by CYP1A2

• Cimetidine inhibits CYP1A2

• Coadministration results in elevated Amitriptylline levels

Cimetidine, Ritonavir, amiodarone, diltiazem, ketoconazole

Inhibit CYP3A4

Cimetidine, Fluoxetine, amiodarone

Inhibit CYP2D6

Cimetidine, Ketoconazole, Omeprazole

Inhibit CYP2C19

Barbiturates, Carbamazepine, Phenytoin, pioglitazone, glucocorticoids, …

Induce CYP3A4 & 3A5

Phenobarbital, dexamethasone

Induce CYP2A6 & 2B6 & 2C9

Smoking , Omeprazole

Induce CYP1A1 &1A2

Aspirin, Ethanol

Phenytoin

Metabolism rate is constant

Drug Elimination Kinetics

Time

Log Concentrati

on100

12.5 6.25

3.13

1.56

0.78

0.39

25

50

• Most drugs are eliminated according to a First-Order Rate Process:– A constant fraction of drug is eliminated per unit of time –

– rate of elimination is proportional to the plasma concentration

– Blood concentration declines in linear fashion over time

First order kinetics

A constant fraction of drug is eliminated per unit of time.

When drug concentration is high, rate of disappearanceis high.

First order kinetics First order kinetics

First order kinetics First order kinetics

• The half life is independent of The half life is independent of dosedose

• The rate of elimination is directly The rate of elimination is directly proportional to the amount of proportional to the amount of chemical in the bodychemical in the body

Zero order kinetics

Rate of elimination is constant.

Rate of elimination is independent of drug concentration.

Constant amount eliminated per unit of time.

Example: Alcohol

Velocity Of Metabolism Of A Drug

0 5 10 15 20 25 30 35 40 45 50 55 600

10

20

30

40

50

60

70

80

first order metabolism

zero order metabolism

[Drug] mM

Vel

ocity

(ng/

g tis

sue/

min

)

Kmx2.pzm

Velocity Of Metabolism Of A Drug

0 5 10 15 20 25 30 35 40 45 50 55 600

10

20

30

40

50

60

70

80

first order metabolism

zero order metabolism

[Drug] mM

Vel

ocity

(ng/

g tis

sue/

min

)

Kmx2.pzm

Aspirin, Ethanol

Phenytoin

Metabolism rate is constant

Zero order kinetics Zero order kinetics Why?Why?

Paracetamol Metabolism

N-acetylcysteine

• Supplies glutathione

• Dosage for NAC infusion - ADULT– (1) 150mg/kg IV infusion in 200ml 5% dextrose over 15 minutes,

then– (2) 50mg/kg IV infusion in 500ml 5% dextrose over 4 hours, then– (3) 100mg/kg IV infusion in 1000ml 5% dextrose over 16 hours

• Side-effects– Flushing, hypotension, wheezing, anaphylactoid reaction

• Alternative is methionine PO (<12 hours)

Metabolism

Factors affecting drug metabolism

• Drug metabolism can be affected by:

– First pass effect

– Hepatic blood flow

– Liver disease

– Drugs which alter liver enzymes

Main site of drug metabolism = LIVER

The phenomenon of

“first pass effect”

or

“first pass metabolism”

and its clinical relevance

Some drugs are ineffective when given orally – examples: nitroglycerine, nor-adrenaline, insulin

Drug Admin: Formulation

• First Pass EffectBlood from the gastrointestinal tract passes through the liver before entering any other

organs. During this first pass through the liver, a fraction of the drug (in some cases nearly all) can

be metabolized to an inactive or less active derivative. The inactivation of some drugs is so

great that the agents are useless when given orally.

(e.g.. lidocaine)

Factors affecting drug metabolism

• Genetic factors– e.g acetylation status

• Other drugs– hepatic enzyme inducers– hepatic enzyme inhibitors

• Age– Impaired hepatic enzyme activity

• Elderly• Children < 6 months (especially premature babies)

Factors affecting biotransformation

• age (reduced in aged patients & children)

• sex (women slower ethanol metabilizers)

• species (phenylbutazone 3h rabbit, 6h horse, 8h monkey, 18h mouse, 36h man); biotransformation route can change

• clinical or physiological condition

• other drug administration (induction (not CYP2D6 ) or inhibition)

• food (grapefruit juice --CYP3A)

• first-pass (pre-systemic) metabolism

Factors Influencing Activity and Level of CYP Enzymes

Nutrition 1A1;1A2;2E1; 3A3; 3A4,5

Smoking 1A1;1A2

Alcohol 2E1

Drugs 1A1,1A2; 2A6; 2B6; 2C; 2D6; 3A3, 3A4,5

Environment 1A1,1A2; 2A6; 1B; 2E1; 3A3, 3A4,5

Genetic Polymorphism

1A; 2A6; 2C9,19; 2D6; 2E1

Red indicates enzymes important in drug metabolism

Pharmacogenetics

–drug transporters

–drug metabolizing enzymes

Succinylcholine

● Used during anesthesia to induce muscle Used during anesthesia to induce muscle paralysisparalysis

● Paralysis usually lasts minutes, but in some Paralysis usually lasts minutes, but in some individuals, it may last up to one hourindividuals, it may last up to one hour

● Due to altered kinetics of Due to altered kinetics of pseudocholinesterase pseudocholinesterase

Isoniazid

● Used in the treatment of tuberculosisUsed in the treatment of tuberculosis● Observed variation in the amount of unchanged Observed variation in the amount of unchanged

isoniazid in the urineisoniazid in the urine● Differences were due to an individuals ability to Differences were due to an individuals ability to

convert isoniazid to acetylisoniazid.convert isoniazid to acetylisoniazid.● Caused by mutations in the Caused by mutations in the N-acetyltransferase-2 N-acetyltransferase-2

enzyme (NAT2) on chromosome 8enzyme (NAT2) on chromosome 8● Some individuals develop isoniazid toxicity Some individuals develop isoniazid toxicity

manifested as peripheral neuropathymanifested as peripheral neuropathy