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CLINICAL PHARMACOKINETICS -

1Dr. Jayesh Vaghela

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Introduction

• Application of pharmacokinetic concepts and principles in humans to design individualized dosage regimens,

- To optimize the therapeutic response of a medication

- To minimize the chance of an adverse drug

reaction

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PHARMACOKINETICS• Simply means, the science which deals with “ What the Body does to the drug ”

• Includes 4 stages –

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PHARMACOKINETICS

ABSORPTION

DISTRIBUTION

METABOLISM

EXCRETION

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Drugadministration

Crossesbiological membraneTransport

Absorption Enters

Systemic Circulation

Reaches body tissues

Distribution

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ABSORPTION

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BIOAVAILABILITY• DEFINITION :-

“ The Rate at which & the Extent to which the Active Concentration of drug is available at the desired site of action. ”

• Concept came into existence when an unusual incidence occurred in Australia in 1968.

• Phenytoin toxicity in Epileptic patients.

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BIOEQUIVALENCE Definition :

• If two or more dosage forms of the same drug reach the blood circulation at the same relative rate & same relative extent, they are called Bioequivalent preparations of the generic drug.

• Clinically important for the drugs having steep dose-response relationship,

• e.g. Zero order kinetics ( phenytoin, warfarin ) Narrow margin of safety ( Theophylline, Tetracycline )

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Measurement of Bioavailability

• Oral administration of 2 brand products of same drug

⇓Plasma concentration – Time curve is obtained

⇓3 characteristics noted & compared :

1) Cmax

2) Tmax

3) AUC

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Rate of Absorption

Extent of Absorption

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Calculation of AUC

Planimeter :- An instrument to mechanically measure the area of

plain figures

Cut & Weigh method :- Cut the area on rectilinear graph paper & weighing it by

analytical method

Mathematical :

- Trapezoidal rule

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Quantitative Evaluation of Bioavailability

Drug Bioavailability ( % ) = AUC ( Oral ) x 100

AUC ( I.V. )

AUC (oral) = AUC obtained after oral administration of

single dose

AUC (IV) = AUC obtained after IV administration of same

drug in the same dose.

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FACTORS AFFECTING DRUG ABSORPTION

&BIOAVAILABILITY

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Route of administration

Membrane physiology

Gastric emptying time

Intestinal transit time

Gastrointestinal pH

Disease states

Gastrointestinal contents

Blood flow through GIT

Age

Metabolism by Enzymes

PatientFactors

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Drug solubility

Particle size

pKa of drug

Dissolution rate

Polymorphism & Amorphism

Lipophilicity

Drug stability

Physico-chemicalFactors

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Disintegration time

Manufacturing variables

Dissolution time

Pharmaceutical ingredients

Nature & type of dosage form

Product age

Storage condition

Pharmaceuticalfactors

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A) Patient Factors :(1) Route of Administration :

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Absorption via G.I.T.

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Absorption Site

pHDrugs

absorbedExample

Stomach AcidicLipid solubleNon-ionized

Acidic/NeutralAspirin

Mouth

Lipid solubleNon-ionized

Basic/Neutral

Isosorbide

Small intestine Morphine

Colon Diazepam

Rectal Ergotamine

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Absorption via Parenteral Sites :

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Intravenous injection⇓

Direct in bloodstream⇓

Completely absorbed,Rapidly distributed

Intramuscular&

Subcutaneous injection⇓

Passive diffusion

Absorption : i.m. > s.c.

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Absorption via Lungs :•Rapid absorption of Lipid-soluble drugs

• From pulmonary epithelium & mucous membrane of trachea & lungs

•Ex. - General anaesthetics ( vapourized form )

- Salbutamol ( aqueous spray )

- Disodium cromoglycate ( suspended microfined particles)

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Absorption via Topical sites :

•Dermis – permeable for lipid-soluble drugs

◦Transdermal patches for – GTN, Scopolamine.

◦Applied on mucous membranes – Oxytocin, Vasopressin

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(2) Membrane Physiology :•Nature of Cell membrane :

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Drug transport process

DRUGS ARE TRANSPORTED ACROSS THE MENBRANE

PASSIVE DIFFUSION AND FILTRATION

SPECIALIZED TRANSPORT

CARRIER MEDIATED

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Diffusion

Higher conc.

Lower conc.M

EMBRANE

Lipid soluble

Lipid insoluble

DIFFUSION

FILTRATION

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Carrier mediated transport• Facilitated

MEMBRANE

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• Active transport

AAMEMBRANE

ATP ADP

e.g.- levodopa30-Dec-13

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Active transport

PRIMARY◦Energy obtained directly

from ATP

◦Eg. Na+ K + ATPase

SECONDARY◦Energy obtained from

movment of other solute (Na+)

◦Eg- SERT, DAT

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• Primary Active transport

AAMEMBRANE

ATP ADP

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• Secondary Active Transport

AAMEMBRANE

Na+ K

+ ATPase

ATP ADP

Na+ K + ATPase

H+ H+GLUCOSE

Na+

K+

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Pinocytosis / Cell Drinking

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• Uptake of fluid solutes

E.g.- Sabine polio vaccine (orally administered)

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• Pore transport / Convective Transport :

◦Absorption occurs through narrow, aqueous filled channels or pores in the membrane structure

◦Ex.

- Water, Sugars, Urea.

- LMW drugs

• Ion-pair formation :

Ionized drug + opposite charged ion

⇩Ion pair ( Neutral )

⇩Diffuses more easily through membrane

e.g. – Quaternary Ammonium Compounds30-Dec-13

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(2) Age :

Infants :

◦ High gastric pH

◦ Less intestinal surface & blood flow

Elderly :

◦ Achlorhydria

◦ Less intestinal blood flow

◦ Altered gastric emptying

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(3) Gastric Emptying Time• Volume of Ingested Material • Bulky material tends to empty

more slowly than liquids

• Type of Meal • carbohydrates > proteins > fats

• Body Position • Lying on the left side decreases emptying rate,

• Right side promotes it

• Drugs• Anticholinergics • Narcotic analgesics • Ethanol

• Reduction in rate of emptying

• Emotional state • Anxiety promotes,• depression retards it

• Disease states • Hypothyroidism retards it,• Hyperthyroidism promotes it.

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(4) Intestinal Transit Time

• Delayed Time is desirable for –

A) Drugs that dissolve or release slowly from their dosage form (sustained release products)B) Drugs that dissolve only in intestine (enteric coated formulations)C) Drugs absorbed from specific sites in the intestine (Vit B)

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(5) Presence of food

FOOD INCREASES THE ABSORPTION OF ..

Chloroquine

Carbamazapine

Griseofulvin

To be taken before meals

To be taken after

meals

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(6) Metabolism by Enzymes

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Physicochemical Factors

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Solid dosage form

Solid drug particles

Drug in solution at absorption site

Drug in the body

Dissolution is rate

limiting step for

lipophillic drugs

e.g. Spironolactone Permeation is rate

limiting step for hydrophilic

drugse.g. Neomycin

1) Drug solubility & dissolution rate :

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2) Particle size and effective surface area:

◦Dissolution rate of solid particles surface area∝◦Smaller particle size → greater surface area → higher

dissolution rate

◦e.g. Bishydroxycoumarin

Digoxin

Griseofulvin

Two types of surface area ◦ 1) Absolute surface area◦ 2) Effective surface area (More important)

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1) Disintegration

Oral Administration of Drug

To fine particles

Tab or Cap

2) Dissolution

Drug in solution

Powders &Suspensions

Solutions

Available for absorption in GIT

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3) Polymorphism & Amorphism :◦Depending upon internal structure, forms of solid may

be – Crystalline or

Amorphous form

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1. Polymorphism:

- Differ from each other in physical propertiese.g. Solubility, Density

- Ex.- RiboflavinPolymorph 3 is more watersoluble than polymorph 1.

2. Amorphism:

- Not having internal Crystalline structureMore water soluble than crystalline form

- Ex.- Novobiocin Amorphous form is more water soluble

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4) pH-Partition Theory :

• Absorption is governed by – Dissociation constant pKa of the drug. Lipid solubility of the un-ionized drug. pH at the absorption site.

Amount of drug that exists in un-ionized form and in ionized form is a function of –

pKa of drug, & pH of the fluid at the absorption site,

• It can be determined by Handerson-Hasselbach equation:30-Dec-13

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Handerson-Hasselbach equation

• For weak acids,

pH = pKa + log [ionized]

[un-ionized]

• For weak bases,

pH = pKa + log [un-ionized]

[ionized]

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Effect of pH on drug absorption:

• Acidic drugs (HA) release a proton (H+), causing a charged anion (A–) to form:

HA H⇔ + + A-

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• Weak bases (BH+) can also release an H+.

◦the protonated form of basic drugs is usually charged,

◦loss of a proton produces the uncharged base (B)

BH+ B + H⇔ +

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5) Drug stability :

◦A drug for oral use may be destabilized either during its shelf life or in the GIT.

◦Problems resulting in poor bioavailability of an orally administered drug are –

Degradation of the drug into inactive form Interactions with different components of drug itself or

that present in GIT.

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B) Pharmaceutical factors :Disintegration time :

Rapid disintegration

⇓Less disintegration time

⇓Rapid absorption

◦Ex.-

• Coated tablets – more disintegration time

slow absorption

• Fine dispersible tablets – less disintegration time

fast absorption30-Dec-13

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Manufacturing variables :

◦Method of granulation

◦Compression force

Pharmaceutical ingredients :

◦Vehicles

◦Diluents

◦Binders & granulating agents

◦Disintegrants

◦Lubricants

◦Surfactants

◦Buffers

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Nature & type of dosage form :

◦As a general rule, Bioavailability of different dosage forms in decreasing order is as following

◦Solutions > Emulsions > Suspensions > Capsules > Tablets > Enteric Coated Tablets > Sustained Release Products.

Product age & storage condition :

◦Ex. –

• Precipitation of the drug in solution

• Hardening of tablet

• Change in particle size of suspension

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Methods to Delay Absorption 1. Using Appropriate Dosage Form :

• Slow & Sustained absorption of drugs –

- Retard tablets ( pot. Chloride retard tablets )

- Depot injections ( Fluphenazine depot injectons )

- Subcutaneous implants ( testosterone pellets )

2. Changing Physical characteristics of drug :

• e.g. Procaine PnG

- Slightly water soluble

- When given i.v. slowly absorbed & action is prolonged ⇨

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Contd…3. Adding a Vasoconstrictor Drug :

- Noradrenaline + Local Anaesthetic ( Xylocaine )

⇓- Prolongs effect of local anaesthetic effect

- Reduces absorption into Systemic circulation &

systemic toxicity

4. Applying a Tourniquet :

- Tourniquet application injection of L.A. below it⇨⇓

Delays systemic absorption

Prolongs action of L.A.30-Dec-13

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Methods to Facilitate Absorption

• Addition of enzyme Hyaluronidase (breaks down intercellular matrix)

⇓Speeds absorption

• Increasing the local blood flow to the tissue

⇓Increased absorption

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DISTRIBUTION

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Drug may get Distributed into -

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Body water Various TissuesEthanol

I2 in Thyroid,Fluoride in bones,Vit A & CHQ in liver,Griseofulvin in keratin

Extracellular

Intracellular K+ ions, Sucrose

I- ions,d-TC,Gentamicin

Intravascular InterstitialMannitol,Dextran,Heparin

Digoxin,emetine

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Special Compartments for Drug Distribution

Plasma Protein Binding :

Free Drug + Protein Drug-Protein Complex⇔

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Free Drug Protein bound Drug

Pharmacologically Active Inert

Can diffuse through capillary wall

Not accessible to capillary diffusion, metabolism or

excretion

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Proteins contributing to Drug Binding

Plasma Albumin :

• Most important contributor

• Binds to Acidic drugs - Warfarin

- Penicillin α1 Acid Glycoproteins :

• Binds to Basic drugs - Quinidine

- Imipramine

Tissue Proteins & Nucleoproteins :

• Digoxin

Miscellaneous binding proteins :

• Transcortin – corticosteroid binding protein30-Dec-13

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Clinical significance of PPB

Highly protein bound drugs

⇓Largely restricted to vascular compartment

Lower Vd

Difficult to be removed by dialysis

Hypoalbuminaemia ( e.g. Liver diseases )

• higher concentration of free drug

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Hyperalbuminaemia (e.g. M.I., Inflammation )

• higher concentration of Bound drug

Displacement reactions :

• drug having Higher affinity

⇓ displaces the drug having lower affinity

• e.g. – Sulfonamides & Vit K

⇓Displaces bilirubin

⇓Kernicterus in neonates

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Physiological Barriers to Drug Distribution

Blood Brain Barrier Blood – CSF Barrier CSF – Brain Barrier Placental Barrier

Significance : Prevent entry of the drug into organ & possible toxicity Contain P-glycoprotein which effluxes the drug from

organ to back into blood circulation. e.g.- GIT,

Brain, Kidney30-Dec-13

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Volume of Distribution

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Clinical example• Digoxin :

• In 70 kg patient,

• 500 μg dose →

plasma concentration of 0.78 μg/L

So, if 0.78 μg of digoxin is in 1 litre of plasma

⇓500 μg would require 641 L of plasma

⇓Not possible

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Apparent Volume of Distribution (aVd)

• Simply means,

“ the total space which should apparently be available in the body to contain the known amount of the drug ”

aVd = Total amount of drug in body ( mg/kg )plasma concentration of drug ( mg/L )

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Clinical significance

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If drug does not cross capillary membrane

- given by intravenous route

⇓ Vd = Plasma water i.e. 3 L

e.g. – Heparin, Insulin

High plasma protein bound

Less Tissue protein bound

e.g. – Tolbutamide

Reverse is true for drugs like Metoprolol

Low Vd value

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If Vd is much more than the actual body volume

⇓ Widely distributed in body (adipose tissue, etc.)

⇓ Difficult to remove by dialysis if toxicity occurs

e.g. – Digoxin, Imipramine.

Vd < 5 L drug within vascular compartment⇨e.g. – Heparin, Insulin, Warfarin

Vd ~ 15 L drug restricted to Extracellular fluid⇨e.g. – Aspirin, Tolbutamide

Vd > 20 L distributed in Total body water (Ethanol)⇨or penetration in tissues (Digoxin)

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Redistribution of drugsIV injection of Thiopentone

⇓Enters brain very rapidly (1 minute after injection)

(highly lipid soluble)

⇓General anaesthesia

⇓Being highly lipid soluble,

Diffuses back to circulation from Brain

⇓Redistributed to muscles & fat

Action is terminated

So, i.v. Thiopentone is ultra short acting30-Dec-13

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References

• Principles of Pharmacology, HL Sharma KK Sharma,

2nd Edition

• Applied Biopharmaceutics & Pharmacokinetics,

Leon Shargel, 5th Edition

• Lippincott’s Illustrated Reviews, Pharmacology 5th ed. - M. Clark, et. al., (Lippincott, 2012, )

• Goodman & Giman’s The Pharmacological Basis of Therapeutics, 12th edition

• Essentials of MedicalPharmacology, KD Tripathi, 6th Edition

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T h a n k y o u…

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