illustration parameters of Pharmacokinetics

1. Basic Pharmacokinetics

2. Learning
objective
What is
pharmacokinetics ?
Relation between
Pharmacokinetics
and
pharmacodynamics.
Define properties of
Pharmacokinetics
Application of
Pharmacokinetics
and principles in
biomedical field

3. Pharmacokinetics :
• Pharmacokinetics: refers to what the body does to a drug

4.  4 Pharmacokinetic
properties :
1)Determine the onset
2)Intensity
3)Duration of drug action
which includes:
A
D
M
E

5. Route of
Administration:
Enteral ???????
Sublingual / buccal
Parenteral
Topical
Trandermal
Rectal

6. Absorption
of drugs:
Transfer of the from the
site of administration to
the blood stream The
rate and extent of
absorption depend on :
• Environmental of drug
absorbed
• Chemical characters of drug
• Rout of administration

7. A) Mechanism of
absorption
of drugs from GIT
Passive diffusion
Drug transfer from high concentration to low
concentration
Don't involve carrier , is not saturable
Majority of drugs are absorbed by this mechanism

8. A) Mechanism of
absorption of drugs
from GIT
Facilitated Diffusion

9. A) Mechanism of
absorption of
drugs from GIT
Active transport

10. A) Mechanism
of absorption
of drugs from GIT
Endocytosis and Exocytosis

11. Factors
Influencing
absorption
Blood flow to the
absorption site :
Intestine receive much
more blood than stomach
so intestine is favored
over the stomach.
Total surface area
available for absorption:
Surface rich in Brush
borders containing
microvilli Intestine has
surface area about 1000
fold Making absorption of
drug across the intestine
more efficient
Expression of P-
glycoprotein :
is transmembrane
transporter protein
responsible for
transporting molecules
including drugs.

12. B) Bioavailability (F)
Rate and extent to which an administered
drug reaches the systemic circulation
Example :
bioavailability of digoxin is estimated to be
0.7 or orally administered tablets , 250
mcg (0.25 mg) o digoxin is given orally, the
effective or absorbed dose can be
calculated by multiplying the administered
dose by F
Amount of drug absorbed = (f) ( dose )
= (0.7) ( 250) = 125mg

13. Factors that influence
bioavailability:
I. First pass hepatic metabolism :
• Drug enter the portal circulation before entering the
systemic circulation . if the drug is metabolized by liver or
gut wall during this initial passage , the amount of
unchanged drug entered circulation is decreased
• First pass metabolism by intestine or liver limits efficacy
of many oral medication
• {For example 90% of nitroglycerine is cleared during first
metabolism so it is administered by sublingual ,
transdermal , intravenous route }

14. Factors
that influenc
e bioavailabil
ity
2) Chemical instability :
Some drug like Penicillin G are unstable in the pH of gastric content
, Others such as insulin are destroyed in GIT by degradative enzyme
3) Solubility of the drug:
Very hydrophilic drugs are poorly absorbed because the inability
to cross lipid rich cell membranes .Paradoxically drugs lipophilic
are poorly absorbed because they are insoluble in aqueous body
fluid cannot gain access to the surface of the cells
4) Nature of drug formulation :
Drug absorption may be alter by other aspects .Particle size Salt
Form Crystal polymorphism Enteric coatings Excepients

15. I.Drug Distributi
-on
• Cardiac output
• Local blood flow
• capillary permeability
• Tissue volume
• degree of binding of drug to plasma and tissue
• lipophilicity
Drugs reversely leaves blood
stream and enter to
extracellular fluid and tissue
for drugs administered IV
absorption is not factor the
initial phase is distribution
phase , it is depend on

16. Factors affecting
drug distribution?
• Blood flow :

17. Factors affecting drug
distribution?
• Capillary permeability :

18. In brain , capillary structure are continuous and
there are no slit junction. To enter the brain the
drugs pass through endothelial cells of CNS
capillaries or undergo active transport
Example :
levodopa lipid soluble drugs readily
penetrate the CNS because they dissolve
in endothelial cell membrane
By contrast , ionized or polar drugs are generally failed to enter
CNS because they cannot pass through endothelial cell that
have no slit junction

20. Factors
affecting drug distribution?
• Binding drugs to plasma protein and tissue:
I. Binding drugs to plasma protein

21. Factors
affecting drug distribution?
Binding to tissue proteins :
Acrolein the metabolite of CP * Cyclophosphamide* can cause
hemorrgaic cystitis because of accumulation in bladder.

22. Factors
affecting drug
distribution?
• Lipophilicity :

23. Factors
affecting drug
distribution?
• Volume of distribution :

24. Distribution into the
water compartments
in the body :
Plasma compartment
Extracellular fluid
Total body fluid

25. Distribution into the water
compartments in the body :
• Plasma compartment :
Heparin

26. Distribution into
the water compartments in the
body :
• Extracellral fluid :
Aminoglycoside

27. Distribution into the water
compartments in the body:
• Total body fluid :
(Larger Vd indicates greater distribution into tissue; a smaller Vd suggest
confinement to plasma or extracellular
)

28. Effect of Vd
on drug
half-life:
Vd has an important influence on
the half-life of a drug, because drug
elimination depends on the amount
of drug delivered to the liver or
kidney (or other organs where
metabolism occurs) per unit of time.
Delivery of drug to the organs of
elimination depends not only on
blood flow but also on the fraction
of drug in the plasma.

29. Effect of
Vd on
drug half-
life:
If a drug has a large Vd, most of the drug is in the
extraplasmic space and is unavailable to the excretory
organs. Therefore, any factor that increases Vd
can increase the half-
life and extend the duration of action of the drug.
[Note: An exceptionally large Vd indicates considerable
sequestration of the drug in some tissues or
compartments.]

30. Drug clearance through
metabolism:

31. Drug
clearance t
hrough met
abolism:
Once the drug enters body the
process of elimination begins.
There are three major route
elimination are hepatic metabolism
, bililary elimination and urinary
excretion.
Elimination is irreversible removal
of drug from body it
involves biotransformation (drug
metabolism ) and excretion.

32. Drug
clearance t
hrough met
abolism:
Excretion is removal of intact
drug from the body theses
elimination process decrease
plasma concentration
exponentially
Metabolism results inproducts
with increased polarity , which
allows the drug to be eliminated
Clearance estimates the volume
of the blood from which the
drug is cleared per unit of time

33. Total CL is a composite estimate
reflecting all mechanisms of drug
elimination and is calculated as
follows :
CL = 0.693*Vd /t1/2
t1/2 half life

34. A) Kinetic
metabolism
The fundamental difference between zero and
first-order kinetics is their elimination rate
compared to total plasma concentration.

35. Zero-Order
Kinetics:
undergo constant elimination regardless
of the plasma concentration, following a
linear elimination phase as the system
becomes saturated.

36. First-order
kinetics
Proportionally increases
elimination as the
plasma concentration increases,
following an exponential
elimination phase as the system
never achieves saturation.

37. Click to add text

38. Reaction
of
metabolis
m
The kideny cannot effeciantly excrete lipophilic
drugs that readily cross dell membranes and
are reabsorbed in the distal
convulated tubules.
Therefor lipid soluble agents are first
metabolized into more polar (hydrophilic)
substanses in the liver via two general sets of
reactions called
Phase 1
Phase 2

39. Phase One
• Converted lipophilic drugs into more polar molecules by
introducing or unmasking a polar function such as –OH , -NH2
. involve reduction , oxidation or hydrolysis
• Phase one may be increase or decrease , have no effect on
pharmacologic activity
• There are two type of phase one :
Phase one utilizing the P450 system
Phase one not involve P450 system

40. Phase I utilizing the P450
system :
• The phase I reactions most frequently
involved in drug metabolism are
catalyzed by cytochrome 450
• P450 is important to cataylze
endogenouse Cpd like (Steriods and
lipids ) and for biotransformation
exogeonus substances ( drugs ,
carcinogens )

41. Phase I reactions not
involving the p450 system
• These include include amine oxidation ( for
example , oxidation of catechole -amine or
histamine) , alcohol dehydrogeneration ( for
example , ethanol oxidation ) estrase ( for
example , metabolism of aspirin n the liver ),
hudrolysis ( for example procaine)

42. Phase II
A subsequent conjugation reaction with an endogenous substrate, such as
glucuronic acid, sulfuric acid, acetic acid, or an amino acid, results in
polar, usually more water-
soluble compounds that are often therapeutically inactive.

43. Drug clearance by the
kidney

44. Renal elimination of a
drug :
1) Glomerular filtration
2) Proximal Tubular
secretion
3) Distal tubular
reabsorption

45. Excretion by
Other Routes:
1)
Drug excretion may also occur via the intestine
, bile, lungs, and breast milk, among others.
2) Drugs that are not absorbed after oral
administration or drugs that are secreted directly
into the intestines or into bile are excreted in
the feces.

46. Excretion by Other Routes
3) The lungs are primarily involved in the elimination of anesthetic gases
(for example, desflurane). Elimination of drugs in breast milk may expose
the breast-feeding infant to medications and/or metabolites being taken by
the mother and is a potential source of undesirable side effects to the infant.

47. Total body (systemic)
clearance
• CL total is the sum of all clearances from the drug-
metabolizing and drug eliminating organs. The kidney
is often the major organ of excretion. The liver also
contributes to drug clearance through metabolism
and/or excretion into the bile.
• Total clearance is calculated using the following
equation:
• CL= CL hepatic +CL renal + CL pulmonary + Cl other
• where CL hepatic+ CL renal are typically the most
important
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48. Pharmacokinetics
Modelling

49. One Compartmental Model
When the drug is rapidly distributed to all parts of the
body, the body is considered behaving as
one compartment, and the drug follows the one-
compartment model

50. Two Compartmental Model
While when the drug distribution to
some organs is faster than
its distribution to other​
organs, the body behaves as
two different compartments, and
the drug follows the two-compartment
model.
1= central ( blood and well perfused
organs) * liver , kideny*
2= peripheral ( poorly perfused tissue
)
* muscle *

51. Pharmacokinetics
and
pharmacodynamic

52. Three parameters
affecting on
Pharmacodynamics
Exposure :
is related to a measure of drug
amount at a particular site in the
body from which it elicits a response.
Commonly used exposure measures
are dose of a drug and plasma
concentrations (Cp)

53. Three
parameters affecting
on Pharmacodynamics
Response
A response (R)refers to a direct measure of
the pharmacologic observation. For example,
measure of diastolic blood pressure (DBP) at
some time point is considered as a
response.
R(t) = Response at time, t :Diastolic blood
pressure

54. Three para
meters affe
cting on Ph
armacodyn
amics
Effect
Effect, refers to a change in the biological response
from one time to another. In other words, an effect is a
derived or calculated value from an observed
response. For example, change from baseline in
diastolic blood pressure is the effect.
E= Effect :Change from baseline in DBP at 8 weeks
To further illustrate, let us consider the DBP
measured at the beginning of a clinical trial in a
subject as 92 mm Hg, denoted as R(t= 0), and DBP
measured at the end of 8 weeks of the trial,

55. Design dosage
regimen
To initiate drug therapy, the clinician must select
• Appropriate route of administration,
• Dosage and dosing interval.
Selection of a regimen depends on various patient and drug fa
ctors, including how rapidly therapeutic levels of a drug must be
achieved.
Therapy may consist of a single dose of a drug, for example, a
sleep-inducing agent, such as zolpidem.

56. Fixed-dose/fixed-
time regimens • Administration of a drug by
fixed doses rather than by
continuous infusion is often
more convenient.
• fixed doses of IV or oral
medications given at fixed
intervals result in time-
dependent fluctuations in the
circulating level of drug, which
contrasts with the smooth
ascent of drug concentration
with continuous infusion

57. Multiple IV Injections
Drug A in continues infusion
Drug B Twice daily injection
Drug C once daily injection

58. Multiple oral
administration