Clinical pharmacokinetics part 1 dr jayesh vaghela

1. 30-Dec-13 1

2. CLINICAL
PHARMACOKINETICS -
1
Dr. Jayesh Vaghela
30-Dec-13
2

3. 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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4. 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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Drug
administration
Crosses
biological membrane
Transport
Absorption
Enters
Systemic
Circulation
Reaches
body tissues
Distribution

6. ABSORPTION
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8. 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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9. 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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10. 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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12. 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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13. 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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Patient
Factors

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Physico-
chemical
Factors

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Pharmaceutical
factors

18. A) Patient Factors :
(1) Route of Administration :
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19. Absorption via G.I.T.
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Absorption
Site
pH
Drugs
absorbed
Example
Stomach Acidic
Lipid soluble
Non-ionized
Acidic/Neutral
Aspirin
Mouth
Lipid soluble
Non-ionized
Basic/Neutral
Isosorbide
Small
intestine Morphine
Colon Diazepam
Rectal Ergotamine

20. 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.

21. 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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22. 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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23. (2) Membrane Physiology :
• Nature of Cell membrane :
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24. Drug transport process
DRUGS ARE TRANSPORTED ACROSS
THE MENBRANE
PASSIVE DIFFUSION
AND FILTRATION
SPECIALIZED
TRANSPORT
CARRIER
MEDIATED
FACILITATED
DIFFUSION
ACTIVE
TRANSPORT
PRIMARY SECONDORY
PINOCYTOSIS
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25. Diffusion
Higher
conc.
Lower
conc.M
E
M
B
R
A
N
E
Lipid soluble
Lipid
insoluble
DIFFUSION
FILTRATION
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26. Carrier mediated transport
• Facilitated
M
E
M
B
R
A
N
E
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27. • Active transport
AA
M
E
M
B
R
A
N
E
ATP ADP
e.g.- levodopa30-Dec-13 28

28. 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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29. • Primary Active transport
AA
M
E
M
B
R
A
N
E
ATP ADP
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30. • Secondary Active Transport
AA
M
E
M
B
R
A
N
E
Na+ K +
ATPase
ATP ADP
Na+ K +
ATPase
H+ H+
GLUCOSE
Na+
K+
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31. Pinocytosis / Cell Drinking
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• Uptake of fluid solutes
E.g.
- Sabine polio vaccine (orally
administered)

32. • 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 Compounds
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33. (2) Age :
 Infants :
◦ High gastric pH
◦ Less intestinal surface & blood flow
 Elderly :
◦ Achlorhydria
◦ Less intestinal blood flow
◦ Altered gastric emptying
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34. (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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35. (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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36. (5) Presence of food
FOOD INCREASES THE
ABSORPTION OF ..
Chloroquine
Carbamazapine
Griseofulvin
FOOD DECREASES THE
ABSORPTION OF ..
Ampicilline
Aspirin
Captopril
Levodopa
Rifamicin
Tetracycline
To be
taken
before
meals
To be
taken
after
meals
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37. (6) Metabolism by Enzymes
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38. Physicochemical Factors
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39. Solid
dosage
form
Solid
drug
particles
Drug in
solution at
absorption
site
Drug in
the body
1) Drug solubility & dissolution rate :
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40. 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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41. 30-Dec-13 44
Oral Administration of Drug
To fine particles
Tab or Cap
Drug in solution
Powders &
Suspensions
Solutions
Available for absorption in GIT

42. 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 properties
e.g. Solubility, Density
- Ex.- Riboflavin
Polymorph 3 is more water
soluble than polymorph 1.
2. Amorphism:
- Not having internal
Crystalline structure
More water soluble than
crystalline form
- Ex.- Novobiocin
Amorphous form is more
water soluble

43. 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:
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44. 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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45. 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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46. • 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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47. 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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48. 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 absorption
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49. Manufacturing variables :
◦ Method of granulation
◦ Compression force
Pharmaceutical ingredients :
◦ Vehicles
◦ Diluents
◦ Binders & granulating agents
◦ Disintegrants
◦ Lubricants
◦ Surfactants
◦ Buffers
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50.  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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51. 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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52. 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.
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53. 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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54. DISTRIBUTION
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55. 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 Interstitial
Mannitol,
Dextran,
Heparin
Digoxin,
emetine

56. 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

57. 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 protein
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58. 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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59.  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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60. 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, Kidney
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61. Volume of Distribution
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62. 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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63. 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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64. 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

65.  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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66. Redistribution of drugs
IV 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 acting
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67. 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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68. T h a n k
y o u…
7130-Dec-13