Introduction to pharmacology

1. Pharmacokinetic
Pharmacodynamic
& Factors affecting drug
response &Adverse drug
reaction
 By dr. Ahmed S. Ali & Prof Magda Hagras

2. Introduction to Pharmacokinetic
(PK) principles
Topics
 ًWhat is pharmacokinetics?
 Variables affecting absorption &
Bioavailability
 Drug distribution &Protein binding.
 Metabolism : Phase 1 & Phase II reactions ;
enzyme induction & inhibition.
 Elimination
 SDL : ROUTES OF ADMINISTRATION
*** = you must know

3. ***What is pharmacokinetics ?
PK deals with the processes to which
drug is subjected within the body i.e
Absorption , Distribution, ,
Metabolism & Excretion (ADME).
 PK deals with variables affecting the above processes.
 It includes a mathematical description of these process
 PK concerned with optimization of pharmacotherapy: i.e optimal dose, dosing interval in
individual basis , avoiding drug interaction.
‫الدواء‬ ‫حركية‬
=
‫الجسم‬ ‫داخل‬ ‫الدواء‬ ‫حركة‬ ‫يصف‬ ‫علم‬
‫مجاالت‬ ‫وتشمل‬ ‫وإخراجه‬ ‫وايضه‬ ‫وتوزيعه‬ ‫الدواء‬ ‫امتصاص‬ ‫على‬ ‫تؤثر‬ ‫التى‬ ‫العوامل‬ ‫فهم‬ ‫الى‬ ‫ويهدف‬
‫التطبيق‬
:
‫التوافر‬ ‫ودراسات‬ ‫االدوية‬ ‫بين‬ ‫التداخل‬ ‫ومنع‬ ‫تعاطيها‬ ‫وطريقة‬ ‫الجرعات‬ ‫مقدار‬ ‫ضبط‬
‫الحيوى‬
.

4. Summary of PK process (ADME)
***
A : Absorption, the movement of drug from the site of
administration to the blood circulation.
– The term commonly used to describe the rate and extent of drug input is
bioavailability. Drugs administered by intravenous routes exhibit
essentially 100% bioavailability.
D = Distribution, the process by which drug diffuses or is
transferred from intravascular space to extravascular space
(body tissues).
M = Metabolism, the chemical conversion or transformation of
drugs into compounds which are easier to eliminate.
E = Excretion, the elimination of unchanged drug or metabolite
from the body via renal, biliary, or pulmonary processes.

5. Some Factors Affecting Drug
Absorption (oral route )
 Mechanism of transport
– Most drugs absorbed by
passive diffusion ) few
drugs requires active
transport
 Lipid soluble
(unionized ) drugs ,
usually well absorbed
Many Other factors ( see bioavailability )
ATP
ADP
+ Pi
A-
BH+
The diagram explains the active transport & effect of ionization
Active
transport
**Ionized
drug poorly
absorbed
HA HA

6. *** Bioavailability :Fraction of a drug that reaches
systemic circulation
It is affected by rate and extent of drug absorption after a particular
route of admin’n
Amoxicillin shows very good bioavailability after oral
administration

7. √Some factors affecting oral absorption or
Bioavailability
 F actors related to the drug
– Physiochemical properties
– Stability
– Lipid solubility
– Mol wt
 Factors related to the formulation
 Syrup ready for absorption > tablet
 Sustained release tab. slow absorption
 Factors related to the patient
o Physiological : age related change in Gastric pH, motility , gastric
emptying time
o Pathological : certain disease e.g. diarrhea , vomiting
 Remember pH = Pka + log (ionized/ unionized )

8. drug distribution
 Distribution allows the drug to reach the site of action e.g.
cardiac muscles, CNS, lung and sites of biotransformation

9. Drug Distribution
 ***Distribution is the process by which the drug
reversibly leaves the blood stream and enters the
extra cellular fluids.
 *Drugs may distribute into any or all of the
following compartments:
– Plasma
– Interstitial Fluid
– Intracellular Fluid;
…

10. Some Factors affecting drug distribution
1. Drug Chemical structure Mol.wt , polarity, lipid solubility
2. Binding to blood components (, RBC, plasma albumin)
3. Age : body composition ( water, lean body & fat )
4. Physiological state : pregnancy.( reduced albumin , larger
amount of body fluids
5. Rate of blood flow
6. Capillary permeability ( see next figure )
7. Diseases
• Liver disease ( low plasma protein levels )
• Renal impairment ( uraemia, low albumin )
• Diabetes ( increase free Fatty acid )
• Cystic fibrosis ( increase blood volume )

11. *Effect of Blood flow on drug distribution
Blood flow to brain, liver, kidney
is greater than skeletal muscles,
Adipose tissues has lower blood
flow
Blood flow to the liver is important
for drugs subjected to significant
metabolism.
Discuss examples : diabetic foot,
meningitis, brain cancer

12. Influence of Capillary permeability on
drug distribution ( details are not requested
 ..
 Brain capillaries have a
dense-walled structure and
are surrounded by glial cells
(lipid). This prevents many
drug molecules from entering
the surrounding tissue
General body capillaries allow
drug molecules to pass freely into
the surrounding tissue

13. Binding of drugs to proteins to plasma
proteins
***Only free drug molecules can
penetrate biological membranes
and act at receptor site
 Many drugs bound to circulating plasma proteins such
as albumin
 albumin: binds many acidic drugs and a few basic
drugs
b-globulin and an a1acid glycoprotein have also been
found to bind certain basic drugs

14. Clinical significance of Protein Binding
Example : Consider a lower
dose of warfarin in a
patient with renal
impairment. Why ?

15. Drug - METABOLISM
 *** Drugs may converted to
less toxic/effective metabolites (this is usually occurs )
more toxic/effective metabolites ( sometimes occurs )
 Individual variation in drug metabolism may be
genetically determined
 Metabolism maybe induced or inhibited by other drugs;
foods or environmental factors
 liver is the main site
…

16. Many Factors affecting drug
metabolism
I. Genetic factors
o e.g. acetylation status
II. Liver disease
III. Other drugs
o hepatic enzyme inducers
o hepatic enzyme inhibitors
IV. Age ( extremes )
Impaired hepatic enzyme activity
o Elderly
o Children < 6 months (especially premature babies)
This may lead to reduced clearance and longer half life

17. Enzyme induction
is a process in which a molecule (e.g. a drug)
induces (i.e. initiates or enhances) the
expression of an enzyme.
Stimulate specific CYP
Enhance Metabolism of certain drugs
This leads to lower drug level Reduce pharmacological
effect ( therapeutic failure )
N.B enzyme induction involves protein synthesis .Therefore,
it needs time up to 3 weeks to reach a maximal effect

18. Enz Inhibiting Drugs
 It is the decrease of the rate of metabolism
of certain drug caused by another drug .
 This will lead to the increase of the concentration of the
target drug and leading to the increase of its toxicity
 Inhibition of the enzyme may be due to the competition
on its binding sites , so the onset of action is short may
be within 24h.
NB ; Inhibition = decrease of drug metabolism (
certain drugs )

19. Drug Metabolism (cont’d) ***
 Two Phases: I and II
– Phase I: conversion to
lipophilic cpds
– Phase II: conjugation
 Phase I involves the
cytochrome P-450 system
 Ultimate effect is to
facilitate elimination
Drug
Phase I
Phase II
Oxidation
Reduction
Hydrolysis
Activation/Inactivation
Conjugation Products
Glucuronidation

20. An Example of Phase I and II
Biotransformation: ( optional )
-OC2H5
CH3CON-
H
-OH
CH3CON-
H
-O-
CH3CON-
H
-OH
OH
COOH
HO
O
PHASE I
PHASE II
Phenacetin
Paracetamol
Glucuronic Acid
Conjugate

21. Factors affecting biotransformation
 race (CYP2C9; warfarin (bleeding) phenytoin
(ataxia) Losartan (less cleared but less activated as
well); also fast and slow isoniazid acetylators,
 age (reduced in aged patients & neonates)
 sex (usually little differences)
 species ( not clinically important);
 clinical or physiological condition e,g cystic
fibrosis.
 other drug administration (induction or inhibition)
 food (charcoal grill ++CYP1A)(grapefruit juice --
CYP3A)
 first-pass (pre-systemic) metabolism.

22. EXCRETION ( Overview ) -
It is important for drugs that mainly
eliminated by renal route
Renal elimination is greatly affected by
age & gender.
renal function by creatinine clearance
 apply the guidelines of dosing in view
of renal clerance

23. Ion trapping
Urine pH varies (4.5 - 8.0). Consider a barbiturate
overdose. Sodium bicarbonate may be given to make
the urine alkaline
Urine Rest of body
pH 8.0 pH 7.4
Non-ionized Non-ionized
Ionised Ionised
Barbiturate moves into urine - eliminated from body.

24. There are Many Routes of Drug Delivery
Parenteral
(IV)
Inhaled
Oral
Transdermal
Rectal
Topical
(SC, IM)

25. Half-life
 Another important
property of first order
kinetics is the half-life of
elimination( t 1/2.)
 The half-life is the time
taken for the plasma
concentration to fall to
half its original value.
Thus if Cp = concentration
at the start and Cp/2 is the
concentration one half-life
later then

26. Topics
1. What is Pharmacodynamic (PD)?
2. What are receptors ??
3. Ligands- receptors interaction ?
4. Major receptor families ?
5. Dose response curve
6. Agonist & Antagonist (types) Partial agonist
7. Potency & Efficacy
8. Therapeutic index &Therapeutic range
9. Desensitization and Tachyphylaxis
Optional further reading ( during summer vacation slides 20 -28 SDL )
1. Spare Receptors
2. Details of about types of receptors

27. What is Pharmacodynamic (PD)
PD deals with
– Interaction of drugs with receptors.
– Relationship between drug concentration and
magnitude of the response
In fact targets for drug action include
: receptors, enzymes, carriers, ion
channel

28. What are receptors ?
Receptors are biological molecules to
which a drug can bind and produce a
measurable response
Many are protein molecules , some are
DNA
 Some receptors are activated by endogenous transmitters
& hormones.
 Many toxic chemicals produce their effect due to
interaction with receptors
 NB : Drugs only modify an already existing biochemical processes

29. Explain Ligands (drugs) - receptors interaction ?
 Involve formation of chemical bonds
- H bonding other weak electrostatic interaction
- Usually interaction is reversible
- Few cases , strong covalent bonds are formed ( Toxic substances )
 Drug – receptor interaction initiates the action of the drug.
 Drug + Receptor D-R complex
biological response
Drugs usually exhibit high degree of specificity ( Key and Lock ) at certain
concentration

30. What are the major receptor families ?
1. Ligand – gated ion channels
2. G-Protein coupled receptors
3. Enzyme –linked receptors
4. Intracellular receptors

32. Desensitization , Tachyphylaxis & Tolerance
Some drug when given continuously or repeatedly their
effect are gradually decreases.
 If decrease of drug effect develops in very short
time we call it tachyphylaxis or desensitization
 If occurs during several days or weeks we call it
Tolerance
Many different mechanisms can give rise to this type of
phenomenon.
Change in receptors ; Loss of receptors; Exhaustion of mediators
Increased metabolic degradationPhysiological adaptation

33. Dose response relationship
 The intensity and duration of a drug’s effects are a
function of drug concentration at the effect site
 Two types of Dose-response relationship
 Graded : Relates dose to intensity of effect
e.g ……………………………………………….
 Quantal :Relates dose to frequency of effect (All-or-none
pharmacologic effect )
e.g………………………………………………..

34. Agonist & partial agonist
Agonist : A drug which binds to a receptor and
activates it, producing a pharmacological response
(contraction, relaxation, secretion, enzyme activation,
etc.).
Partial agonist : A drug A drug which binds to a
receptor and activates it, producing a pharmacological
response but less than full agonist

35. Antagonist
competitive
o bind reversibly to the
receptors
o Their effect Can be
overcome by
increasing the
concentration of
agonist
o Example………
A drug which binds to the receptors in common with an
agonist, without causing their activating
non competitive
 bind irreversibly to the
receptors.
 Their effect Can’t be
overcome by increasing the
concentration of agonist
 Example…………….

36. Potency & Efficacy ***
Potency
is related to the amount of drug needed to produce a
given effect.
 In graded dose-response potency of drugs are compared using EC50
(The dose producing 50 % of the maximum effect )
Efficacy
Is the maximum effect an agonist can produce
(Emax)
Its More clinically important than potency .

37. Potency & efficacy ***
 drug A or B are
more potent than
drug C.
 Drug A has higher
efficacy than drug
B
Quiz : Compare A &
C ?
Drug A
Drug B
Drug C
0
2
4
6
8
0 10 20 30
Ln concenteration
%
Response

38. Therapeutic Index
TI = TD50 /ED50
 It represents an estimate of the relative safety of
the drug.
 For example penicillin has a high therapeutic index as compared to
digoxin which have a low therapeutic index
 Therapeutic range is clinically more important
examples Gentamicin, vancomycin, phenytoin, and digoxin are drugs
with a narrow therapeutic range
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