Pharmacology

1. Pharmacokinetics
Dr Rupesh Dalavi
PG Resident
NIMS&R,Jaipur.

2. What is P’cokinetics
▶ how the human body act on the drugs.
▶ Pharmacokinetics is the quantitative study of drug
movement in, through and out of the body.
▶ Intensity of effect is related to concentration of the drug
at the site of action, which depends on its
pharmacokinetic properties
▶ Pharmacokinetic properties of particular drug is important
to determine the route of administration, dose, onset of
action, peak action time, duration of action and
frequency of dosing

3. Relationship between Kinetic and
Dynamic

4. Pharmacokinetic process

5. Membrane transport
▶ Membrane transport is associated with transport
of solute particles across biological membrane
between polar-nonpolar/water soluble-lipid soluble
bilayer.
▶ Regulation of passage through the membrane is due to
selective membrane permeability.
▶ There are different transport proteins are available on the
surface of cells which mediates specific movement across
the bilayer.
▶ these proteins can be activated by cellular signalling
pathways, at the biochemical level,

6. Transport types
▶ Passive transport
1. Diffusion
2. Facilitated diffusion
3. Filtration
4. Osmosis
▶ Active transport
1. Primary active transport
2. Secondary active transport
3. Ponocytosis

7. Mechanism of transport

8. Facilitative transporters
▶ Move substrate of a single class
(uniporters) down a
concentration gradient.
▶ No energy dependent

9. Remember
▶ The drugs which are Unionized, low polarity and higher lipid solubility are
easy to permeate membrane.
▶ The drugs which are ionized, high polarity and lower lipid solubility are
difficult to permeate membrane.
Filtration

10. Osmosis

11. Active Transport(energy dependent)
▶ can move solutes against a concentration gradient.
▶ energy dependent
 Primary active transport:
• generate energy themselves (e.g. ATP hydrolysis)
 Secondary active transporters
• utilize energy stored in voltage and ion gated by a primary active
transporter (e.g. Na+/K+-ATPase)
• Symporters (Co-transporters)
• Antiporters (Exchangers)

12. Process of active transport

13. Pinocytosis
▶ It involves the invagination of a part
of the cell membrane and trapping
within the cell of a small vesicle
containing extra cellular
constituents.
▶ The vesicle contents can than be
released within the cell, or extruded
from the other side of the cell.
▶ Pinocytosis is important for the
transport of some macromolecules
(e.g. insulin through BBB).

14. Deference between Phagocytosis and
pinocytosis

16. Absorption
▶ Absorption is the transfer of the unchanged
drug from its site of administration to the
systemic circulation by crossing biological
membrane.
▶ Most of drugs are absorbed by the way of
passive transport.
▶ Intravenous administration has no absorption
because drug is directly reaches to systemic
circulation.
▶ Fraction of administered dose and rate of
absorption are important

17. Mechanism of drug absorption

18. Drug absorption
▶ If oral-----From stomach and intestine to portal circulation.
▶ If rectal-----from rectum to systemic circulation.
▶ If intramuscular-----from muscle to systemic circulation.
No absorption is needed if drug is taken intravenously.
So absorption is needed to reach the drug to at the site of
action and hence it have to cross the cell membrane.

19. Cell membrane consists of…
▶ Lipid bilayer
▶ Interseperated protiens

20. Drug transport process

21. Absorption of drug by passive diffusion
can be explained by Fick’s first law
▶ Rate of diffusion = (C1-C2) 🞩(A🞩PC)
T
Where,
C1- Higher concentration
C2- Lower concentration
A – Diffusion surface area
PC- Permeability coefficient
T – Thickness of membrane

22. Role of route of drug
administration
▶ When a drug is administered intravenously, the
entire dose is available in systemic circulation.
▶ Administration of a drug by any other route may result in less availability of
drug due to incomplete absorption.
▶ When a tablet or capsule is swallowed, it must dissolve before its absorption.
The process is called as dissolution.
▶ Once the drug is dissolve the drug will be absorbed by one of the mechanisms
mentioned earlier.

23. Bioavailability
▶ The rate and extent of absorption of a drug is termed as
its bioavailability.
▶ When a graph of plasma concentration of a drug is plotted
against time, one gets a curve as shown as.
▶ The area under curve (AUC) of plasma concentration versus
time represents the total amount of drug reaching systemic
circulation.
▶ AUC will have a different shape depending on the route of
administration.
▶ AUC obtained after IV administration is consider 100% and is termed
as absolute bioavailability.
▶ The ratio of AUC of any other route of administration is compaited
with AUC of IV administration is termed as relative bioavailability of
that drug.

24. Calculation of bioavailability
Time
P
l
a
s
m
a
c
o
n
c
e
n
t
r
a
t
i
o
n
AUC=area under curve
F = Bioavailability
𝐹 =
𝐴𝑈𝐶 𝑝.𝑜.
𝐴𝑈𝐶 𝑖.𝑣.
× 100
0 5 10 15

25. Distribution
▶ Once a drug is absorbed in systemic
circulation, it can be carried throughout the body.
▶ Drug distribution is defined as it is an reversible transfer of drug
between one component(blood) to another component(Extra
vesscular/intera vescular tissue).
▶ Some molecules may be interacting with receptors on cell
membranes or inside of cells, while other molecules may move
back into the blood stream.

26. Distribution process

27. Significance
▶ Pharmacological action depends upon the concentration of
drug reach to the site of action.
▶ Thus distribution plays important role in
• Onset of action
• Intensity of action
• Duration of action MTC
MEC

28. Distribution depends upon
▶ The delivery of a drug from the blood stream to the site
of drug action depends on…
 Blood flow
 Capillary permeability
 Degree of binding to blood and tissue proteins
 Lipid solubility of drug

29. Why distribution is differ in brain as compared to other cell?

30. ▶ Blood flow to different organs of the body is not equal.
▶ The most vitally important organs of the body receive the greatest supply of blood.
These organs include the brain, liver, and kidneys.
▶ Skeletal muscle and bone receive less blood, and adipose tissue (fat) receives the
least.
▶ Blood flow is not the only factor responsible for drug distribution penetration
capacity of drug also plays important role in drug distribution
▶ few drugs exhibit good penetration of the central nervous system.
▶ The anatomical structure of the capillary network in the brain creates a significant
barrier to the passage of many drugs and is commonly referred to as the blood-brain
barrier.
▶ To readily penetrate into the brain, drugs must be fairly small and lipid soluble.
▶ This explains why the small and highly fat-soluble anesthetic gases quickly and
easily penetrate the brain to cause anesthesia, while other larger and water
soluble molecules like penicillin antibiotics penetrate the central nervous system
to a much lesser degree.

31. Factors Affecting Distribution
▶ Most drugs reversibly bind to plasma proteins in varying degree. Albumin is
the most abundant plasma protein with an greatest ability to bind drugs.
▶ Binding to plasma proteins affects drug distribution into tissues, because only
drug that is not bound is available to penetrate tissues bind to receptors, and
exert activity.
▶ Albumin acts as a reservoir for administered drug.
▶ Only free fraction of the drug is biologically active.
Free drug + Albumin Penetrate through tissue Bind to receptor Exert effect
Free drug Penetrate through tissue Bind to receptor Exert effect
Release the bloodstreem
Why serum albumin is checked in pathology lab before medication?

32. Factor cont…
▶ Other patient variables that can affect distribution include body composition,
cardiac decompensation (heart failure), and age of the patient.
▶ volume of distribution is the hypothetical volume required if the amount of
drug in the body was distributed throughout the body at the same
concentration measured in the blood.
▶
Dose administered IV
V = Plasma concentration
cardiac decompensation
Failure of the heart to
maintain adequate blood
circulation; symptoms
include shortness of breat
and edema.
Dosing of medications in infants and children requires special consideration. It is to be
noted that “children are not simply small adults” Bodies of children/infants contain a
high percentage of water and low percentage of muscle and fat. Especially in neonates,
albumin may be lower. All these variations can alter Vd significantly; hence dosage for
neonates/infants/children should be carefully adjusted.

33. Metabolism
▶ While the drugs are getting distributed in different parts of body, there are
chemical changes in their structures due to interaction with various enzymes
or due to other chemical reactions.
▶ The process of chemical change is called as biotransformation or metabolism.
▶ Liver is major site for drug metabolism
▶ The purpose of metabolism is to convert the drug into more water soluble
compounds.
▶ The kidneys cannot efficiently excrete highly fat-soluble drugs that readily cross
cell membranes because they are reabsorbed in the last stages of filtration. These
compounds must first be metabolized in the liver to more water-soluble
compounds and then removed.
▶ There are two types of metabolic processes which drugs undergo.
1. oxidation-reduction reactions or hydrolysis.
2. conjugation reactions.

34. oxidation-reduction reactions or hydrolysis.
▶ In the first type of reaction drugs are made more polar through
oxidation-reduction reactions or hydrolysis.
▶ These reactions use metabolic enzymes, most often those of the
cytochrome P450 enzyme system, to catalyze the biotransformation.
▶ In enzyme-catalysed reactions, the rate of reaction is accelerated by
presence of enzymes.
▶ Since the quantum of enzymes is limited, metabolism is considered as a saturable
process.
▶ Once enzymes are saturated, blood levels of drug increase exponentially which may
lead to toxicity.
Ex. metabolism of alcohol or phenytoin.

35. conjugation reactions.
▶ In this type of reaction the drug undergoing change is joined with another substance,
such as glucuronic acid, sulfuric acid, acetic acid, or an amino acid.
▶ Glucuronidation is the most common conjugation reaction.
▶ The result of conjugation is a more water-soluble compound that is easier for the
kidneys to excrete.
▶ Some agents are initially administered as an inactive compound (prodrug) in order to
improve availability or reduce side effects.
Eg. Leodopa/carbidopa – dopamine in the treatment of Parkinson’s disease

36. Factors Affecting Metabolism
1. Genetic factor will result in poor tolerance of certain drugs.
Eg. Many asians and native americans have difficulty metabolizing drugs
that require acetylation, such as ethanol. These individuals will exhibit a
low tolerance of such drugs, and can suffer adverse drug reactions at a
much higher rate than the average population.
▶ Age is another important variable, Organ function gradually declines with
age and the elderly may poorly tolerate to drugs. Also those who are very
young due to immaturity of organs system.
▶ Drug interactions may occur between two drugs that are metabolized by
the same enzyme systems in the liver. Because there is a limit on available
enzymes for metabolism, excess drug will remain active and free to exert
an effect elsewhere in the body.

37. Excretion
▶ When a drug is taken into and distributed throughout the body and is getting
metabolised, there has to be some way by which it is excreted; otherwise its
concentration along with its metabolites will continue to rise with each successive
dose.
▶ The complete removal of drug from the body is termed as its elimination.
▶ Elimination of the drug includes its metabolism and excretion through kidneys and to
a lesser degree into bile.
▶ Excretion in urine is one of the most important mechanisms of drug removal.
▶ When drugs have not been converted to water soluble compounds in the liver, they
are likely to be reabsorbed into blood at the end of filtration process and will cycle
through the body again.
▶ If they are water soluble, they will be excreted in urine.

38. Steady state
Factor affecting on excretion
▶ The complete elimination of a drug from the body is dependent
on normal liver and kidney function.
▶ The kidney is the major organ of excretion in the form of urine
▶ liver also contributes to elimination through metabolism and
excretion into the feces via the bile.
▶ Age is also an important factor in drug excretion in elder persons
kidney and liver function is slightly reduced.