PHARMACOKINETICS

WHAT THE BODY DOES TO THE DRUG

XENOBIOTIC

A compound to which the body is exposed that is foreign to the body.

Includes drugs, industrial and environmental chemicals

Pharmacodynamics – concentration – effect

Graded response

Quantal response Pharmacokinetics – dose - concentration

Routes of drug administrationRoutes of drug administration

Routes of Administration

PHARMACOKINETICS ABSORPTION

DISTRIBUTION

METABOLISM

EXCRETION

ABSORPTION

Describes the rate and extent to which a

drug leaves its site of administration

Pharmacokinetics

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

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 (from

snorting or sniffing the drug, with the drug depositing on the oral or nasal mucosa)

Drug Absorption -caveats

Orally

Drug 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

Drug Absorption -disadvantages

Rectually

Often irregular, unpredictable, and incomplete

Many drugs irritate the membranes that line the rectum.

Drug Absorption

Parenterally

Intravenous –directly into a vein

Intramuscular –directly into muscle

Subcutaneous –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.

Relatively quick route to the brain.*

*May even have a faster onset of effect than drugs administered intravenously.

Drug Absorption

Absorbed through the skin

Provides 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.

CHARACTERISTICS OF A DRUG FAVORING

ABSORPTION Low molecular size

Nonpolar

Uncharged

High lipid solubility

MECHANISMS OF SOLUTE TRANSPORT ACROSS MEMBRANESPassive diffusion

Facilitated diffusion

Active transport

Endocytosis

Passive Diffusion Concentration gradient Lipid-water partition coefficient Area, Thickness and Permeability

of the membrane Ionic, pH, charge gradient*

Ionic Transport

pH gradient

Drug’s acid dissociation constant

(pKa)

pKa – pH value at which one half of the drug is present in ionic form

pKa = pH + log (HA) (A-)

Henderson-Hasselbalch equation

Calculates the ratio of non-ionized to ionized drug at each ph

pH = log [A-] + pka (Acid) [HA] or = log [B] + pKa (Base) [BH+] Ka = dissociation constant A = molar concentration of the acidic anion HA = molar concentration of the undissociated acid B = molar concentration of the basic anion HB = molar concentration of the undisscociated base

1. Ionised drugs do not easily cross lipid 1. Ionised drugs do not easily cross lipid barriers such as the gut, placenta and barriers such as the gut, placenta and blood brainblood brain

2. Acidic drugs are well absorbed in the 2. Acidic drugs are well absorbed in the acidic medium of the stomach, basic drugs acidic medium of the stomach, basic drugs in the alkaline medium of the small bowelin the alkaline medium of the small bowel

Un-ionized Ionized

Pharmacologic effect Active InactiveSolubility Lipids WaterCross lipid barriers Yes No(gastrointestinal tract,

blood-brain barrier, placenta)

Hepatic metabolism Yes No Renal excretion No Yes

Drugs and ionisation: PractiseDrugs and ionisation: Practise

Acidic drugs (such as aspirin) will be Acidic drugs (such as aspirin) will be ionised in an alkaline urine and thus ionised in an alkaline urine and thus cannot be reabsorbed across the renal cannot be reabsorbed across the renal tubular membrane (alkaline diuresis)tubular membrane (alkaline diuresis)

pH trap (ion trapping) is significant for pH trap (ion trapping) is significant for some drugs, especially local some drugs, especially local anaesthetics in laboranaesthetics in labor

Factors Affecting GI Absorption

Gastric Emptying Time

Intestinal Motility

Food

Formulation Factors

“First Pass Effect”

PK DefinitionsPK Definitions

0 2 4 6 8 10 12

Time Postdose (hr)

100

1000

10000

Pla

sma

Co

nce

ntr

atio

n

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 & ResistanceDrug Levels & Resistance

BIOAVAILABILITY

Quantity of drug in systemic circulation

Quantity of drug administered

BioavailabilityBioavailability

BioavailabilityBioavailability

BioavailabilityBioavailability

Measuring bioavailabilityMeasuring bioavailability

time

LogConcentration

I.v. dose

Oral dose

AUC I.v.

AUC oral

Bioavailability =

AUC oral/AUC i.v.

Bioavailability (f)

f = dose(IV) x AUC (PO)/dose(PO) x AUC (IV)

DISTRIBUTION

Delivery of drug from systemic circulation to tissues

Pharmacokinetics

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

Distribution

The movement of drug from the blood to and from the tissues

Drug Distribution4 Body Membranes that Affect Drug

Distribution

1. Cell membranes

2. Walls of the capillary vessels in the circulatory system

3. Brain-blood barrier

4. 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.

PATTERNS OF DRUG DISTRIBUTION Mainly in the vascular system

ex. Dextran, highly bound to plasma protein

apparent Vd = 3-5 L in adults (approx plasma volume)

PATTERNS OF DRUG DISTRIBUTION Uniformly distributed throughout the body

water

ex.ethanol, sulfonamides

Vd = 30-50 L corresponding to total body water

PATTERNS OF DRUG DISTRIBUTION Concentrated specifically in one or more

tissues that may or may not be the site of action

Vd – very large values

ex. Chloroquine – 1000x in the liver

Tetracycline – bone and developing teeth

PATTERNS OF DRUG DISTRIBUTION Non-uniform distribution in the body

- highest concentrations usually in the liver, kidney and intestine

- distribution varies with lipid solubility, ability to pass thru membranes

Factors Affecting Drug Distribution

Affecting Rate of Distribution Membrane Permeability Blood Perfusion Affecting extent of distribution Extent of plasma protein binding Regional differences in pH Lipid solubility Available transport mechanisms Intracellular Binding

Membrane Permeability

Capillary permeability Renal capillary permeability

large pores Brain capillaries

Blood Perfusion Rate

Greatest blood flow – brain, kidneys, liver and muscle

Highest perfusion rate – brain, kidneys, liver, heart

Protein Binding

Extensive plasma protein binding – lower Vd; stay in central blood compartment

Slight change in the binding of highly bound drugs – significant change in clinical response

Only free drug are active

Acidic drugs (e.g. barbiturates) bind to Acidic drugs (e.g. barbiturates) bind to albumin albumin

Basic drugs (e.g. opioids, local Basic drugs (e.g. opioids, local anaesthetics) bind to alpha 1 acid anaesthetics) bind to alpha 1 acid glycoproteinglycoprotein

The process is reversibleThe process is reversible Binding sites are non-selective for Binding sites are non-selective for

similar drugs and thus one can displace similar drugs and thus one can displace anotheranother

Drugs Binding sites for acidic agents

Vit. C, salicylates, sulfonamides, barbiturates, penicillins, tetracyclines, probenecid

Albumin

Binding sites for basic agents

Quinine, Streptomycin, chloram, digitoxin, coumarin

Globulins, 1, 2, β1, β2

Percent Unbound for Selected drugs

Drug % Unbound

Caffeine 90

Digoxin 77

Gentamicin 50

Theophylline 85

Phenytoin 13

Diazepam 4

Warfarin 0.8

Phenylbutazone 5

dicumarol 3

? Volume of container? Volume of container

Injecteddose

10 mg.

Sampledconcentration

1 mg. l-1

Volume = injected dose/ sampled concentration = 10 litres

? Volume of container? Volume of container

Injecteddose

10 mg.

Sampledconcentration

0.1 mg. l-1

Volume = injected dose/ sampled concentration = 100 litres

Vd is proportional to body weight and Vd is proportional to body weight and thus, the loading dose can be based thus, the loading dose can be based on body weighton body weight

Varies with the very young, and very Varies with the very young, and very old old

Weight consideration

Centralcompartment

Peripheralcompartment

Peripheralcompartment

K12

K21

K elim

Dose

Central compartment

Intravascular space, highly perfused tissues

Rapid uptake of drug 75% of cardiac output; 10% of body mass Apparent volume can be calculated

METABOLISM

Active Drug Inactive drug Active Drug Active or toxic

metabolite Inactive Prodrug Active drug Unexcretable drug Excretable

metabolite

Pharmacokinetics

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

Drug Metabolism

Side effects are results that are different from the primary, or therapeutic, effect, for which a drug is taken.

First-pass metabolism drug-metabolizing enzymes in either the cells of the GI tract or the liver can markedly reduce the amount of drug that reaches the bloodstream.

BIOTRANSFORMATION

Phase I Phase II

PHASE I

Modify the chemical structure of a drug

OXIDATION

REDUCTION

HYDROLYSIS

Oxidative Reactions N- dealkylation – Imipramine, erythromycin O-dealkylation – Indomethacin,Codeine Aromatic hydroxylation – Phenytoin,

phenobarbital N- Oxidation – chlorpheniramine, Dapsone S- oxidation - Cimetidine, Omeprazole Deamination – Amphetamine, Diazepam

HYDROLYSIS

Ester Hydrolysis – Procaine, aspirin, Succinylcholine

Amide Hydrolysis – Lidocaine, Indomethacin

Epoxide Hydrolysis - Carbamazepine

REDUCTION

Nitro reduction – Chloramphenicol

Dehalogenation – Halothane

Carbonyl Reduction – Methadone, Naloxone

PHASE II Conjugate a drug to large polar molecules to :

Inactivate a drug

Enhance drug’s solubility

Enhance excretion rate

CONJUGATION REACTIONS

Glucoronidation – Acetaminophen, Morphine, Oxazepam

Sulfation – Acetaminophen, Steroids Acetylation – Sulfonamides, INH,

Clonazepam

Metabolism

Induction – drugs can cause an increase in liver enzyme activity thus increasing metabolic rates of some drugs

ex. Phenobarbitone – induce metabolism of itself, phenytoin, warfarin

Inhibition – inhibit metabolism of other drugs

Liver

Induction

Drug A induces the body to produce more of an enzyme to metabolized Drug B

This reduces the amount of Drug B and may lead to loss of Drug B’s effectiveness

Inhibition

Drug A inhibits the production of enzymes to metabolize Drug B

This increases the amount of Drug B in the body and could lead to an overdose or toxic effects

Extraction ratio = Ci - Co/ CiExtraction ratio = Ci - Co/ CiCi may be calculated by determining the Ci may be calculated by determining the

percentage of a drug absorbed, and thus percentage of a drug absorbed, and thus reaching the liverreaching the liver

Co may be calculated from the bioavailability Co may be calculated from the bioavailability Effect on clearance when hepatic blood Effect on clearance when hepatic blood

flow falls (e.g. hepatic disease, decreased flow falls (e.g. hepatic disease, decreased cardiac output and hypovolaemia)cardiac output and hypovolaemia)

Drug metabolism: Drug metabolism: Zero and first order kineticsZero and first order kinetics

The rate constant is the fractional change The rate constant is the fractional change in concentration in unit timein concentration in unit time

It is expressed as the elimination rate It is expressed as the elimination rate constant k, in units of hconstant k, in units of h-1-1

Thus, if 10% of the drug is removed per Thus, if 10% of the drug is removed per hour, then the rate constant is 0.1hhour, then the rate constant is 0.1h-1-1

T1/2 = natural logarithm of 2 (0.693)/kT1/2 = natural logarithm of 2 (0.693)/k Thus, k of 0.1 = T1/2 of 6.93 hoursThus, k of 0.1 = T1/2 of 6.93 hours

First order kinetics states that a fixed fraction First order kinetics states that a fixed fraction of the drug is metabolised in unit timeof the drug is metabolised in unit time

Or … the amount metabolised is proportional Or … the amount metabolised is proportional to the concentrationto the concentration

Or … amount metabolised = K * Or … amount metabolised = K * concentrationconcentration

K is the ‘clearance’ and has the unit of flow K is the ‘clearance’ and has the unit of flow (e.g. mls.min(e.g. mls.min-1-1 or litres.hr or litres.hr-1-1))

Why do we need to know the drug Why do we need to know the drug clearance?clearance?

For effective drug therapy you need to For effective drug therapy you need to

be able to maintain the effective be able to maintain the effective

concentration (Ceff) that produces the concentration (Ceff) that produces the

desired effect desired effect Thus, we need to calculate the Thus, we need to calculate the

maintenance dose maintenance dose

Why do we need to know the drug Why do we need to know the drug clearance?clearance?

Maintenance dose = clearance * Maintenance dose = clearance *

effective concentration (Ceff)effective concentration (Ceff)e.g. if clearance is 3 l.hre.g. if clearance is 3 l.hr-1-1 and Ceff is 10 and Ceff is 10

mg.lmg.l-1-1

Maintenance dose = 30 mg.hrMaintenance dose = 30 mg.hr-1-1

We can thus predict the effect of changes We can thus predict the effect of changes in clearance and Ceff on maintenance in clearance and Ceff on maintenance dosedose

CLP =___rate of elimination (mg/min)______ plasma concentration of drug (mg/ml)

CLEARANCE

Number of Percent of Drug Percent of Drug Half-lives Remaining Removed

0 100   01 50 502 25 753 12.5 87.54 6.25 93.755 3.125 96.875

Number of Percent of final Half-times steady state concentration

0 01 502 753 87.54 93.755 96.875

The context sensitive half lifeThe context sensitive half life

Definition:Definition:

The time for the plasma The time for the plasma concentration to fall by half concentration to fall by half following steady state infusion and following steady state infusion and constant blood levels.constant blood levels.

Usually after several hours infusion.Usually after several hours infusion.

FACTORS AFFECTING DRUG METABOLISM

Genetic variation

Environmental determinants

Disease Factors

Age

Sex

Cultural

Metabolism

Genetic –people have different amounts of enzymes that metabolize drugs

Metabolism

Physiological –if more than one drug is present in the body, the drugs may interact with one another either in a therapeutically beneficial way or in a way that can adversely affect the patient.

Metabolism

Environmental –current mood, stress, and past experience with drug can affect metabolism (and toxicity)

RELATIVE HEPATIC CONTENT OF CYP ENZYMES

% DRUGS METABOLIZED BY CYP ENZYMES

ROLE OF CYP ENZYMES IN ROLE OF CYP ENZYMES IN HEPATIC DRUG METABOLISMHEPATIC DRUG METABOLISM

CYP Enzyme Examples of substrates

1A1 Caffeine, Testosterone, R-Warfarin

1A2 Acetaminophen, Caffeine, Phenacetin, R-Warfarin

2A6 17-Estradiol, Testosterone

2B6 Cyclophosphamide, Erythromycin, Testosterone

2C-family Acetaminophen, Tolbutamide (2C9); Hexobarbital, S- Warfarin (2C9,19); Phenytoin, Testosterone, R- Warfarin, Zidovudine (2C8,9,19);

2E1 Acetaminophen, Caffeine, Chlorzoxazone, Halothane

2D6 Acetaminophen, Codeine, Debrisoquine

3A4 Acetaminophen, Caffeine, Carbamazepine, Codeine, Cortisol, Erythromycin, Cyclophosphamide, S- and R-Warfarin, Phenytoin, Testosterone, Halothane, Zidovudine

Adapted from: S. Rendic Drug Metab Rev 34: 83-448, 2002

Adapted from: S. Rendic Drug Metab Rev 34: 83-448, 2002

Nutrition 1A1;1A2; 1B1, 2A6, 2B6, 2C8,9,19; 2D6, 3A4,5

Smoking 1A1;1A2, 2E1

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

Pharmacokinetics

Elimination –metabolic waste products are removed from the body

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: Bile

After most psychoactive drugs are processed by the liver they are usually less fat soluble, less capable of being reabsorbed, and therefore capable of being excreted 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.

Processes That Determine Urinary Excretion of Drug

1. Glomerular filtration

2. Tubular secretion

3. Tubular reabsorption

Drug excretion: Role of the Drug excretion: Role of the KidneysKidneys

Drug excretion: Role of the Drug excretion: Role of the KidneysKidneys

Glomerular filtration (GFR)Glomerular filtration (GFR)clearance = fraction unbound (FU) * clearance = fraction unbound (FU) *

GFRGFRif TOTAL renal clearance = the above, if TOTAL renal clearance = the above,

then the drug is principally excreted by then the drug is principally excreted by filtration (e.g. gentamicin) ANDfiltration (e.g. gentamicin) AND

clearance is proportional to GFRclearance is proportional to GFR

Drug excretion: Role of the KidneysDrug excretion: Role of the Kidneys Passive tubular reabsorptionPassive tubular reabsorption

clearance is clearance is less thanless than FU * GFR (due to FU * GFR (due to reabsorption)reabsorption)

e.g. aspirin and amphetamine (effect of e.g. aspirin and amphetamine (effect of pH of urine)pH of urine)

Active tubular secretion (ATS)Active tubular secretion (ATS)clearance is clearance is greater thangreater than FU * GFR (due FU * GFR (due

to secretion)to secretion)e.g. penicillin (inhibited by probenecid), e.g. penicillin (inhibited by probenecid),

digoxin (inhibited by quinidine)digoxin (inhibited by quinidine)

Renal Factors that Affect Urinary Drug excretion

Glomerular filtration rate Tubular fluid pH Extent of back-diffusion of unionized form Extent of active tubular secretion of the

compound Extent of tubular reabsorption

ADME - Summary

CLINICAL PHARMACOKINETICS

CLP =___rate of elimination (mg/min)______ plasma concentration of drug (mg/ml)

CLEARANCE

Clearance First Order Kinetic – constant fraction of

the drug in the body is eliminated

Saturation Kinetics – constant amount of drug is eliminated per unit time

CLEARANCE:Clinical Utility

Determines the maintenance dose (DM) required to achieve the target plasma conc at steady state

DM(mg/h) = Tconcn (mg/L) x Clearance (L/h)

Volume of Distribution

Actual volume in which drug molecules are distributed within the body

Vd = D/CO

Co = D/Vd

VOLUME OF DISTRIBUTION:Clinical Utility

Used to determine the loading dose (LD)

LD = Css x Vd

(mg) (mg/L) (L)

HALF-LIFE

Time it takes for plasma concentration or the amount of drug in the body to be reduced by 50%

t1/2 = (0.693 x Vd) / Cl

HALF-LIFE:Clinical Utility

Determines how long it takes to reach steady state after multiple dosing

CSS = Bioavailability x Dose Interval x Cl

STEADY STATE CONCENTRATION

Initial Concentration

Initial concentration = Loading Dose Vd

Dosing Rate

Dosing rate = Target conc’n x Cl / F

Oral Digoxin is to be used as maintenance dose to gradually digitalize a 69 kg patient with congestive heart failure.

A steady state plasma concentration of 1.5 ng/ml is selected as an appropriate target. Based on the patient’s renal function, the clearance of digoxin is computed at 1.6/ml/min/kg or 110ml/min.

How should the drug be given in this patient? Given:

Cl – 1.6ml/min/kg

F – 70%

Target conc’n = 1.5ng/ml

Dosing rate = 1.5ng/ml x 1.6ml.min/kg/0.7