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130-Dec-13
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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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