Principles of Pharmacokinetics

1. DR.KIRAN RAJAGOPAL DA DNB
ANAESTHESIOLOGIST

3.  Pharmacokinetics denotes the effects of
biologic systems on drugs.
 The major processes involved in
pharmacokinetics are
Absorption,
Distribution,
Elimination.

4.  Pharmacokinetics allows us to understand
the profile of drug concentration over time
Adjust the dosing

5. Membrane transfer
Drugs need to cross cell membranes in order to produce
their effects
Such transfer occurs more readily with a:
 low degree of ionization
 low molecular weight
 high lipid solubility
 high concentration gradient
MEMBRANETRANSFER

6. Membrane transfer
 Pharmacokinetic processes usually occur at a rate
proportional to the concentration gradient at the time
 As the process continues, the concentration gradient falls,
thus progressively slowing the rate of change
 This results in an exponential relationship between
concentration and time.
EXPONENTIAL PROCESS
•Exponential processes•Exponential processes

7.  There are two ways in which an exponential function can be described.
 If a specified time period is set, the decline is defined by the fraction by
which the concentration has been reduced during this interval. This is the
elimination rate constant (k), expressed as time-1.
 A given fractional reduction in concentration is set, and the time taken
to achieve this level is found. If a 50% reduction in concentration is used,
the time taken is the half-life (t1/2); this will be constant whatever
starting drug concentration is used.

8.  This is the point at which the elimination of drug would have
been completed if the process had continued at its initial
rate
 It corresponds with a reduction in concentration to 37% of
the original value.

9.  A constant fraction Of
a given drug is
metabolized in a given
time period

10. Elimination rate constant k
 Fraction of drug eliminated per unit of time is
a constant in first order kinetics
 If 10% of drug is eliminated per min ,rate
constant is 0.1 min
-1
Elimination half life
 Time necessary to eliminate 50% of drug
from body
t1/2= 0.693
k

11.  Constant amount of drug is metabolized per
unit of time
 Occurs when the plasma concentration of
drug exceeds the capacity of metabolizing
enzymes
 Alcohol, aspirin,phenytoin – Zero order
Kinetics at therapeutic doses

12. ABSORPTION
DISTRIBUTION
METABOLISM
CLEARANCE

13.  Transfer of a drug from its site of administration to the
systemic circulation
 Absorption depends on
 Drug solubility
 Blood flow to site of absorption
 Area of absorbing surface available

14.  Rapid increase in the drug concentration as directly injected
into systemic circulation.
 Bioavailability is 100% mostly in i.v administered drug.
 But for drugs like fentanyl – pulmonary endothelium uptake
is more. So some amount may be metabolised and reduce
their absolute bioavailability

15.  Safest and most convenient method. But not
significantly utilised in anaesthetized patients.
 Absorption rate is dependent of gastrointestinal tract-
gastric emptying into small intestine , where the surface
of absorption is greater
 The active metabolism of drug by small intestinal
mucosal epithelium enters the portal circulation first
than systemic circulation.Thus undergoes extensive
first pass metabolism and bioavailability is reduced

16.  Sublingual administration- directly absorbed into systemic
circulation.Thus first pass metabolism is bypassed and
bioavailability is raised.
 Eg. Nitroglycerine/ fentanyl

17.  Few lipophilic drugs – sufficient enough to penetrate intact
skin. Available as drug patches.
 The time taken to achieve therapeutic level limits its
practical use and preferred for maintainance therapy.
 Eg: fentanyl, opioids, scopolamine, NTG

18.  Absorption is dependent upon the drug dose administered
and blood flow to the area
 I.M administration will be absorbed more than S.C
 Subcutaneous administration – due to variability of blood
flow, variation in onset of drug action is seen. Prolonged
duration the drug will be seen. Eg. Insulin & heparin

19.  Intrathecal- direct injection into the site of action(spinal
cord)- reduces the limitations of drug absorption/distribution
compared to any other route of administration
 In rest two techniques- local anaesthetics has to be absorbed
through dura/ nerve sheath to reach the site of action.
 Expertisation of techniques is must than other routes
discussed above

20.  Large surface area of pulmonary alveoli available for
exchange with large flow of blood in pulmonary
capillaries makes this route to be a attractive
method to administer drugs

21. ABSORPTION
DISTRIBUTION
METABOLISM
CLEARANCE

22.  Body is composed of no:of compartments
representing theoretical spaces with
calculated volumes.

23.  Drugs are not distributed uniformly throughout the body.
The speed with which a drug reaches a particular tissue is
largely dependent on its local blood flow.
 Similar tissue types are often grouped together into various
‘compartments’ depending on their blood supply.
 The capacity of each compartment to act as a reservoir for
the drug is determined by a combination of its size and
affinity for the drug

24. Tissue group Composition Bodymass% Cardiacoutput%
Vessel rich Brain,heart,liver,
kidney,endocringla
nds
10 75
Muscle Muscle,skin 50 19
Fat Fat 20 6
Vesselpoor Bone,ligament,cart
ilage
20

29. SLOWLY EQILLIBRATING
COMPARTMENTRAPIDLY
EQILLIBRATING
COMPARTMENT
Infusion
Elimination
V2 V3
Vcentral
K2 K3

30. First, the concentrations continuously decrease over time.
Second, the rate of decline is initially steep but continuously becomes less steep, until
a portion that is linear

31.  Begins immediately after injection of the bolus.
Very rapid movement of the drug from plasma to the rapidly
equilibrating tissues
 Movement of drug into more slowly equilibrating tissues and
return of drug to plasma from the most rapidly equilibrating
tissues.
 Primary mechanism for decreasing drug concentration is
elimination of drug from the body
 Plasma concentration is lower than tissue concentrations
 Relative proportion of drug in plasma and peripheral volumes of
distribution remains constant
 Drug returns from the rapid- and slow-distribution volumes to
plasma and is permanently removed from plasma by metabolism
or excretion
SLOW DISTRIBUTION PHASETERMINAL / ELIMINATION PHASE

32.  Apparent volume in which a drug is distributed
 It is a theoretical value expressed as the volume of
blood which would be necessary to contain the
entire drug present in the body, at the equilibrium
concentration (units litre /kg ).

33. 

34.  Vd= dose of drug administered
concentration in blood
Vd

35. Vd= Amount at specific time
Concentration at specific time

38.  CENTRALVOLUME OF DISTRIBUTION
 PERIPHERALVOLUME OF DISTRIBUTION
 VOLUME OF DISTRIBUTION AT STEADY
STATE

39. FatMuscles &
Connective Tissue
Elimination
V2 V3
Vcentral
K2 K3
Qelim

40.  Vi is the initial dilution volume
 Reflects the plasma volume of the heart,
great vessels , venous volume and also
uptake into lung parenchyma

41. FatMuscles &
Connective Tissue
Elimination
V2 V3
Vcentral
K2 K3
Qelim

42.  Distribution into periphery is represented as
additional volumes of distribution attached
to central volume
 Intercompartmental clearance
 More soluble a drug is in peripheral tissues
larger are the peripheral volumes of
distribution

43.  When a drug has been fully distributed throughout the body
& the system is at equilibrium, the volume within which the
drug is contained is called the volume of distribution at
steady state

44. Vd is influenced by
 Lipid solubility
 Plasmaprotein binding
 Molecular size

45.  Free drug cross cell membrane and reach site
of action
 Free drug is available for elimination and
clearance
 ALBUMIN AND α1ACID GYCOPROTEIN

46.  Barbiturates
 Benzodiazepines
 Pencillin

47.  Fentanyl
 Alfentanil ,Sufentanil
 Lidocaine
 Quinidine
 Bupivacaine
 Ropivacaine
 Verapamil
 Disopyramide
 Meperidine
 Propranolol

48. Albumin decreased
Elderly
Pregnancy
Neonates
Hepatic disease
Renal disease
Trauma
Surgery
@1acid glycoprotein increased
Age
Trauma
Surgery
Inflammatory diseases like chrons RA
Malignancy acute MI
@1 acid glycoprotein decreased
neonates

49. ABSORPTION
DISTRIBUTION
METABOLISM
CLEARANCE

50.  Pharmacologically active lipid soluble drugs
are converted into water soluble and often
pharmacologically inactive metabolites

51.  Liver is the most metabolically active tissue
 Gut wall, Lungs, Kidney and Plasma

52.  The smooth endoplasmic reticulum of the hepatocyte is the
principal site of metabolism in the liver
 The largest family of membrane-bound, nonspecific, mixed-
function enzymes is called the cytochrome p450 system
 It contains a haem-bound iron at the active site, responsible
for binding with and metabolising the drug, attached to a
protein chain

53.  It is so named because of its location (cyto = cell) and the fact
that the haem moiety absorbs coloured(chrome) light at a
wavelength of 450nm
 The enzyme catalyses the reaction whereby a molecule of
oxygen is split into its 2 atoms; one atom of oxygen is
“inserted” into the substrate and one atom is reduced
(combines with 2 hydrogen ions) into water, often called a
mono-oxygenase reaction

54.  Non-cytochrome p450 enzymes in the liver are also involved
in the metabolism of endogenous and exogenous
compounds including, esterases and flavin-containing mono-
oxygenases
 Examples of commonly used anaesthetic drugs metabolised
by cytochrome p450 are

55. Phase 1 reactions
 Phase 1 reactions are classified into oxidation, reduction and
hydrolysis
 During these reactions, certain groups are added so that the
drug can undergo the second phase to produce conjugation
products
 If the metabolites of phase1 reactions are sufficiently water
soluble in nature, they can be readily excreted at this point
PHASE 1 REACTION

56.  Most common of the phase 1 reactions
 Involves the initial insertion of a single oxygen atom onto the
drug molecule.
 Phase 1 oxidative reactions catalysed by cytochrome p450
include hydroxylation, epoxidation, dealkylation,
deamination and dehalogenation reactions.
 Classes of drugs demonstrating oxidative metabolism
include paracetamol, codeine, ropivicaine, omeprazole and
phenothiazines

57.  Reduction reactions are the second type of phase 1 reactions.
 They are also catalysed by the p450 system and often take place
under anaerobic conditions. Examples of drugs subject to
reduction include
a) Prednisone, a prodrug which is reduced to the active
glucocorticoid prednisolone;
b) Warfarin, which is inactivated by the transformation of a ketone
group to a hydroxyl group
c) Halothane which undergoes both oxidation and reduction
reactions depending on the oxygen tension present in the liver.

58.  Hydrolysis is the final phase 1 reaction.
 Unlike the other two reactions, hydrolysis is catalysed by
esterases and amidases and not by the cytochrome p450
reactions.
 Amide local anaesthetic agents undergo hepatic hydrolysis
by amidases.
 Ester hydrolysis also occurs in extra hepatic sites;
 Remifentanil is rapidly degraded by non-specific tissue and
plasma ester hydrolysis

59.  Phase 2 conjugation reactions involve the attachment of
ionised groups to the drug
 Increases their water solubility, allowing excretion in the bile
and urine.
 These reactions include glucuronidation, sulphation,
acetylation and methylation
 Most phase2 reactions inactivate drugs or the active
metabolites formed from phase 1 reactions

60.  Glucuronidation is an important metabolic pathway for
many anaesthetic drugs.
Eg. Propofol ,morphine ,midazolam
 Sulphation reactions are responsible for the metabolism
of about 40% of paracetamol.
 40% by glucuronidation.
 A small amount undergoes n-hydroxylation to n-acetyl-
p-aminobenzoquinoneimine (NAPQI) which is toxic

61. ABSORPTION
DISTRIBUTION
METABOLISM
CLEARANCE

62.  Volume of plasma from which drug is
completely and irreversibly removed in a
given time interval
 Unit – ml/min

63. Clearance = Rate of elimination of drug
Plasma drug concentration
 Clearance depends on
The drug
Blood flow
Condition of the organs of elimination

64.  Two processes contribute to drug clearance:
Systemic (out of the tank)
Intercompartmental (between the tanks)

66. Q is the blood flow to metabolic organs,
Cin is the concentration of drug delivered to metabolic organs,
Cout is the concentration of drug leaving metabolic organs.
The fraction of inflowing drug extracted by the organ is
Cin − Cout
Cin this is called the extraction ratio (ER)

67.  HEPATIC CLEARANCE
 RENAL CLEARANCE
 TISSSUE CLEARANCE
 DISTRIBUTION CLEARANCE

68.  The total clearance is the sum of each
clearance by metabolic organs

69.  LOADING DOSAGE
 Propofol concentration required for induction is 0.5mg/dl
andVd is 4L/KG
So loading dose=0.5×4=2mg/kg

70.  MAINTENANCE DOSAGE

71.  Time necessary for the plasma drug
concentration to decrease by 50% after
discontinuing a continuous infusion of a
specific duration
 No constant relation to drugs elimination half
time
 For propofol-40 min for 8 hr infusion

72.  Decrement time is the time required to
decrease the concentration by a certain value
after a continuous infusion of a certain
duration
e.g. context-sensitivie half-time is
decrement time for 50% decrease

73. Age
 In elderly small central volume of distribution leads tohigher
peak concentrations after bolus or during the early part of
infusions
 Decrease in lean body mass and increase body fat
lipophilic drugs accumulate in peripheralVd
increases duration of effect
 Liver volume ,blood flow and hepatic metabolic capacity
decreases
decreased clearance

74. Cyt p450 inhibited by
Ketoconazole ,
protease inhibitors- ritonavir
indonavir
antibiotics-
erythromycin,clarithromycin
SSRI
Cyt p 450 induced by
Rifampicin
glucocorticoids carbamazepine
barbiturates

75.  Miller 8th edition
 Barash 7th
 Katzung pharmacology
 Continuing education in anaesthesia, critical
care & pain | volume 7 number 1 2007
 Continuing education in anaesthesia, critical
care & pain | volume 4 number 3 2004