Introduction to pharmacology

1. INTRODUCTION TO
PHARMACOLOGY
By:
DEJENE
HAILU
Pharmacology for
medical laboratory
technology

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INTRODUCTION TO
PHARMACOLOGY
What is Pharmacology?
 Derived from Greek “pharmakon [drug], logos [Science ].
 Pharmacology is the science of drugs dealing with
pharmacokinetics and pharmacodynamics of drugs.
 Pharmacology studies the effects of drugs and
how they exert their effects.
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3. What are drugs?
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 A drug is any chemical or biological substance, synthetic or
non-synthetic, that when taken into the organism's body, will
in some way alter the functions of that organism.
 Drugs chemicals that are intended for treatment, diagnosis,
prevention and control of diseases
 Drugs are usually distinguished from endogenous
biochemicals by being introduced from outside the organism.

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DRUG NOMENCLATURE
 Many names are given to drugs often confusing.
 It is therefore necessary to know drug nomenclature.
The following is the drug name system
1)Chemical/Molecular/Scientific name: It depicts the
chemical/molecular structure of the drug
e.g. paracetamol
N-acetyl-p-amino-phenol

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2) Generic/ Approved Name: It is the official medical
name of the drug. Removes confusion of giving several
names to the same drug regardless of who
manufactures them e.g: paracetamol (Britain English)
or Acetaminophen (American English)
3) Trade/Brand Name: These are names given to the
drug by the manufacturing and marketing company. In
most cases one drug could have so many trade/brand
names e.g paracetamol has many trade names. Like :
Pacimol, Tylenol, Paramol, Panadol, Capol etc.
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6. Sources of Drugs
 Plants
 Microorganisms
 Animals
 Chemical synthesis
 Biotechnology
 Semi-synthetic: heroin, oxacilin,
Currently majority of the drugs used in therapeutics are
from synthetic source
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7. Sources of drugs
1-Plant sources
various parts of plants may be used as sources of
drugs e.g. Leaves of belladonna for atropine, Bark of
cinchona for quinine and quinidine.
2-Animal sources
Insulin from pancreas of different animals e.g.
cattle or pig
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8. 3-Mineral sources:
e.g. Magnesium sulphate and iodine
4-Microrganism:
Fungi and bacteria isolated from soil are important sources
of antibiotics e.g. penicillin
5-Synthetic drugs:
Many drugs are produced in the laboratory
e.g. sulphonamide, barbiturate, aspirin
6-Biotechnology:
Human insulin and growth hormone have successfully been
produced by genetic engineering
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9. Branches of pharmacology
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• Pharmacology is a vast science having major sub-
divisions:
Pharmacokinetics: deals with the action of body on the
drug [what the body do on the drug].
Pharmacodynamics: deals with action of drug on the
body [what the drug do on the body].

10. Pharmacokinetics
 Greek: Kinesis—movement
 What the body does to the drug.
 This refers to movement of the drug in and alteration of
the drug by the body; includes absorption, distribution,
binding/localization/storage, biotransformation and
excretion of the drug.
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11. PHARMACOKINETICS…
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PHARMACOKINETIC IMPORTANCE
1- To know the dose
2- To know the suitable route of administration
3- To know the dosage interval
4- To know the period of medication
 PHARMACOKINETIC comprises of: ADME
 Absorption
 Distribution
 Metabolism
 Excretion

12. Absorption
Absorption
Passage of a drug from its site of administration into
blood stream.
 is the transportation of the drug across the biological
membranes
There are different mechanisms for a drug to be
transported across a biological membrane:
 Passive (simple) diffusion
 Active transport
 Pinocytosis
 Facilitated diffusion
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13. SIMPLE (PASSIVE) DIFFUSION
• The major role for the transportation of the drugs across
the cell membrane is simple (passive) diffusion.
• The substances move across a membrane according to a
concentration gradient.
• The concentration gradient is the factor that determines
the route and rate of the diffusion.
 No energy is required.
 There is no special transport (carrier) protein.
 No saturation.
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14. ACTIVE TRANSPORT
 The transportation of the drug molecules across the cell
membrane against a concentration or an electrochemical
gradient.
 It requires energy (ATP) and a special transporter (carrier)
protein.
 There is «transport maximum» for the substances (the rate
of active transport depends on the drug concentration in
the enviroment).
e.g. levodopa and Methyl DOPA are actively absorbed from the
gut by the aromatic amino acid transporter.
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15. FACILITATED DIFFUSION
 Occurs by the carrier proteins.
 Net flux of drug molecules is from the high concentration
to low concentration.
 No energy is required.
 Saturable.
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16. Pinocytosis
 It is the process of transport across the cell in particulate
form by formation of vesicles.
 This is applicable to proteins and other big molecules, and
contributes little to transport of most drugs.
 The drugs which have MW over 900 can be transported by
pinocytosis.
 It requires energy.
 The drug molecule holds on the cell membrane and then
surrounded with plasma membrane and inserted into the
cell within small vesicles.
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17. FACTORS THAT AFFECT THE ABSORPTION OF THE
DRUGS
A) DRUG-RELATED FACTORS
 Molecular size
 Lipid solubility
 Degree of ionization
 Dosage form
 Chemical nature (Salt/organic forms, crystal forms,
solvate form etc.)
 Particle size
 Complex formation
 Concentration of the drug
B) SITE OF APPLICATION RELATED FACTORS
 Blood flow (at site of application)
 Area of absorption
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18. SITE of APPLICATION RELATED FACTORS
 Blood flow (at site of application):
 If the blood flow is high at the site of application, it
causes an increase in absorption rate.
 Area of absorption:
 If the surface area that allows the absorption of the
drug molecules is wide, then absorption rate from that
surface becomes high.
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19. Route Of Administration
Affects drug absorption, because each route has its own
peculiarities.
Oral Route
 Drug molecules are mostly absorbed from duodenum,
jejunum and upper ileum.
 Disintegration and dissolution are the two main processes
for the oral administered drugs before the absorption
process.
 The absorption rate and absorption ratio of the orally
administered drugs are closely related with the above two
parameters.
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20. Oral application.
 Unionized lipid soluble drugs (e.g. ethanol) are readily absorbed
from GIT.
 Acid drugs (aspirin, barbiturates, etc.) are predominantly unionized
in the acid gastric juice and are absorbed from the stomach.
 Acid drugs absorption from the stomach is slower, because the
mucosa is thick, covered with mucus and the surface is small.
 Basic drugs (e.g. atropine, morphine, etc.) are largely ioni-zed and
are absorbed only from the duodenum.
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Rout of
administration Advantage Disadvantage
oral route Safe
 convenient
economical
Slow onset
not for irritant drugs
not for vomiting pt.
Polar drug poorly absorbed
Distraction by gastric acid &
GI enzymes
Not for unconscious
IV Fast onset of action
Can be given for vomiting
patient
Can be given for
unconscious patient
Pain at the site of injection
Relatively costly
expertise is needed
Drug effect can’t be halted
Anal route Can be given for
unconscious patient
Absorption is not reliable
Not preferred by adults
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22. Bioavailability
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 Is the fraction of an administered dose of
unchanged drug reaching the systemic circulation
 By definition, when a medication is administered
via IV its bioavailability is 100%, However other
routes (such as orally), its oral bioavailability
decreases (due to incomplete absorption and First
pass metabolism)
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23. Bioavailability
Dose
Destroyed
in gut
Not
absorbed
Destroyed
by gut wall
Destroyed
by liver
to
systemic
circulati
on
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24. II. Distribution
Distribution is the transport of drug from systemic
circulation into site of action. After absorption of a
drug, it is usually distributed through the different
tissues and the body fluid compartment including
A- The plasma
B- The extracellular fluid
C- The intracellular fluid
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25. 25
• The Process
occurs by
the
diffusion of
Free Drug
until
equilibrium
is
established.
Distribution is a
Passive Process,
for which the
driving force is
the Conc.
gradient between
the blood and
Extravascular
Tissues
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26. DISTRIBUTION
Factors Affecting the Distribution of Drugs:
 Lipid solubility (diffusion rate)
 Ionization at physiological pH (dependent on pK)
 The Affinity of the drug to the tissue Proteins
 Blood Flow (Perfusion Rate)
 Binding to Plasma Proteins
 Disease like CHF, uremia, cirrhosis.
N.B Movement of a drug proceeds until an equilibration is
established between unbound drug in plasma and tissue fluids.
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27. Factors Affecting the Distribution of Drugs
4. Plasma Proteins:
 The most important protein that binds the drugs in blood is
albumin for most of the drugs.
 Especially, the acidic drugs (salicylates, vitamin C,
sulfonamides, barbiturates, penicillin, tetracyclines,
warfarin, probencid etc.) are bound to albumin.
 Basic drugs (streptomycin, chloramphenicol, digitoxin,
coumarin etc.) are bound to alpha-1 and alpha-2 acid
glycoproteins, globulins, and alpha and beta lipoproteins.
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28. Properties of plasma protein-drug binding
 Only the free (unbound) fraction of the drug circulating in
plasma can pass across the capillary membrane .
 Bound fraction serves as “drug storage”.
PLASMA
INTERCELLULAR FLUID
[DRUG]=1 mM [DRUG]=1 mM
[DRUG+PROTEIN]=9 mM
[TOTAL DRUG]=10 mM [TOTAL DRUG]=1 mM
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29. FACTORS AFFECTING DISTRIBUTION
5. Storage (Concentration-Sequestration) of
the Drugs in Tissues
◦ Stored drug molecules in tissues serve as drug
reservoir.
◦ The duration of the drug effect may get longer.
◦ May cause a late start in the therapeutic effect or
a decrease in the amount of the drug effect.
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30. Tissue storage
 Heart and skeletal muscles – digoxin (to muscle proteins)
 Liver – chloroquine, tetracyclines, digoxin
 Kidney – digoxin, chloroquine
 Thyroid gland – iodine
 Brain – chlorpromazine, isoniazid, acetazolamide
 Retina – chloroquine (to nucleoproteins)
 Iris – ephedrine, atropine (to melanin)
 Bones and teeth – tetracyclines, heavy metals (to
mucopolysaccharide of connective tissue)
 Adipose tissues – thiopental, ether, minocycline, DDT
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31. DISTRIBUTION
 Passage of the drugs to CNS:
 A BBB exists (except some areas in the brain) which limits the
passage of substances.
 Non-ionized, highly lipophilic, small molecules can pass into the
CNS and show their effects.
 Inflammation of the meninges of the brain increases
permeability of the BBB.
 Some antibiotics like penicillin can pass through the inflamed
BBB while it can’t pass through the healthy one.
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32. Placental barrier
 Placental membranes are lipid and allow free passage of
lipophilic drug, while restricting hydrophilic drugs.
 The placental P-gp also serves to limit foetal exposure to
maternally administered drugs.
 However restricted amounts of nonlipid soluble drugs,
when present in high concentration or for long periods in
maternal circulation, gain access to the foetus.
 Thus, it is an incomplete barrier and many drugs, taken by
the mother, can affect the foetus or the newborn.
 Penicillins, azithromycin, and erythromycin do not affect
the foetus and can be used during the pregnancy.
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33. Placental barrier
Passage of the drugs to fetus:
◦ Placenta doesn’t form a limiting barrier for the drugs to
pass to fetus.
◦ The factors that play role in simple passive diffusion,
effect the passage of drug molecules to the fetus.
Placental blood flow
Molecular size
Drug solubility in lipids
Fetal pH (ion trapping): fetal plasma pH: 7.0 to 7.2;
pH of maternal plasma: 7.4, so according to the ion
trapping rules, weak basic drugs tend to accumulate
in fetal plasma compared to maternal plasma.
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34. BIOTRANSFORMATION

35. BIOTRANSFORMATION
The process of alterations in the drug structure by the
enzymes in the body is called “biotransformation (drug
metabolism)” and the products form after these reactions
are called “drug metabolites”.
Some drugs which don’t have any activity in vitro, may
gain activity after their biotransformation in the body.
These types of drugs are called “pro-drug” or “inactive
precursor”.
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36. cont’d…
Drug examples that gain activity after
biotransformation (pro-drugs):
Pro-drug effective
metabolite
Enalapril enalaprilat
Lovastatin lovastatin acid
L-Dopa dopamine
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37. Biotransformation
 Drug examples that is transformed to more active compounds
after biotransformation:
DRUG MORE ACTIVE
METABOLITE
Imipramine Desmethylimipramine
Codeine Morphine
Nitroglycerin Nitric oxide
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38. Biotransformation
 Drug examples that is transformed to less active
compounds after biotransformation:
 Drug examples that is transformed to inactive metabolites
after biotransformation
DRUG LESS ACTIVE
METABOLITE
Aspirin Salicylic acid
Meperidine Normeperidine
Lidocaine De-ethyl lidocaine
(dealkylated)
DRUG INACTIVE
METABOLITE
Most of the drugs Conjugated compounds
Ester drugs Hydrolytic products
Barbiturates Oxidation products
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39. Biotransformation
 The metabolites that are formed after biotransformation are
generally more polar, more easily ionized compounds compared to
the main (original) drug.
 So, these metabolites can be excreted from the body easily.
Organs in which biotransformation occurs:
 Liver** (the most important organ, the number and
variability of the biotransformation enzymes are the highest)
 Lungs
 Kidney (tubular epithelium, sulphate conjugation)
 Gastrointestinal system (duodenal mucosa)
 Placenta
 Adrenal glands
 Skin
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40. ENZYMATIC REACTIONS
The enzymatic reactions which the drugs are exposed to:
1. Oxidation
2. Reduction PHASE I
3. Hydrolysis
4. Conjugation PHASE II
DRUG X (inactive or less active**, same activity, higher activity) Y (generally inactive)
PHASE I PHASE II
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41. CONJUGATION REACTIONS
1. Glucuronidation
2. Methylation
1. N- methylation
2. O-methylation
3. N-acetylation
4. Sulfate conjugation (sulfation)
5. Glutathione conjugation
6. Conjugation with amino acids
7. Conjugation with ribose or ribose phosphates
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42. Glucuronidation
 These involve conjugation of the drug or its phase I meta-
bolite with an endogenous substrate to form a polar highly
ionized organic acid, which is easily excreted in urine or
bile.
 Conjugation reactions have high energy requirements.
 Glucuronic acid is a highly hydrophilic compound, so it
decreases the lipid solubility of the drug after conjugation.
 Glucuronosyl transferases catalyze the reaction.
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43. Characteristics of phase II products:
1) Product = conjugate
2) Usually are pharmacologically inactive.
3) Polar
4) More readily excreted in urine.
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44. Factors That Affect The Biotransformation of Drugs
1. Induction or inhibition of microsomal enzymes
2. Genetic differences
3. Age
4. Gender
5. Liver diseases
6. Environmental factors
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45. Induction or inhibition of microsomal enzymes
 Various drugs or environmental factors lead to increases in the
activity of these enzymes by increasing the synthesis of
microsomal enzymes.
 The importance of the enzyme induction is the increasing
metabolism rate of the drugs and the reduction in their activities.
 On the other hand, some drugs stimulate the enzymes that inhibit
themselves (biochemical tolerance).
 Unlike the enzyme induction, some drugs can inhibit the
microsomal enzymes.
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46. ENZYME DRUG or SUBSTANCE THAT INDUCES THE ENZYME
CYP1A2
Cigarette smoke, grilled meat (barbecue), aromatic
polycyclic hydrocarbons, phenytoin
CYP2C9 Barbiturates, phenytoin, carbamazepine, rifampin
CYP2C19 NOT INDUCIBLE
CYP2D6 NOT INDUCIBLE
CYP3A4
Barbiturates, phenytoin, rifampin, carbamazepine,
glucocorticoids, griseofulvin,
INDUCERS
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47. Use of inducers result in
1. Increase the metabolism of the inducer.
2. Tolerance : Decreases the inducer’s pharmacological action.
3. Increase the metabolism of co-administrated drugs (drug
interaction)
E.g. Barbiturates and warfarin thrombosis.
Phenytoin and oral contraceptive ( the woman gets pregnant )
4. Increase tissue toxicity by metabolite.
E.g. Paracetamol , phenacetin .
5. As therapy.
E.g. Phenobarbitone (given to babies with physiological
jaundice to induce liver microsomal enzymes) and
hyperbilirubinemia.
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48. INHIBITORS
ENZYME DRUG or SUBSTANCE THAT INHIBITS THE
ENZYME
CYP1A2 Cimetidine, ethinyl estradiol, ciprofloxacin
CYP2C9
Amiodarone, isoniazid, co-trimoxazole, cimetidine,
ketoconazole
CYP2C1
9
Fluoxetine, omeprazole
CYP2D6
Amiodarone, cimetidine, fluoxetine, paroxetine,
haloperidol, diphenhydramine
CYP3A4
Ketoconazole, erythromycin, , isoniazid, Ca
channel blockers, red wine, grapefruit juice
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49. Use of inhibitors result in:
 Impede the metabolism and excretion of the inhibitor and
Co-administered drugs, thus increasing t1/2.
 Prolong the action of the inhibitor and co- administrated
drugs increased pharmacological activity
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50. Liver Diseases
 Especially, the metabolism of drugs with a “high hepatic
clearance” decreases in liver diseases.
 This leads to accumulation of drugs in the body which are
metabolized in liver, and eventually causes an increase in
the effect and adverse effects as well.
 On the other hand, transformation of pro-drugs into their
active forms occurs less in liver diseases.
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51. ENVIRONMENTAL FACTORS
 Especially pollutants can affect the microsomal enzymes.
 Induction of microsomal enzymes can occur with;
 DDT and some insecticides
 Benzopyrenes and other polycyclic aromatic hydrocarbons
(products of burned coal and petroleum products)
 Polycyclic hydrocarbons in the cigarette smoke can induce some enzymes like
CYP1A2 and CYP1A1 (For this reason, the metabolism rate of
chlorpromazine, theophylline and imipramine is significantly high in heavy
smokers).
 Diet (Cabbage and cauliflower can induce CYP1A1 and CYP1A2)
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52. ENVIRONMENTAL FACTORS
 Inhibition of microsomal enzymes can occur with;
 Carbon monoxide inhibits the microsomal enzymes.
 Grapefruit juice (some flavonoids in grapefruit juice can inhibit
CYP3A4)
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53. EXCRETION
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54. EXCRETION
Excretion is the passage out of systematically absorbed
drugs.
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55. RENAL EXCRETION
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56. Drug elimination
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 Elimination of drug from body occurs by
excretion and metabolism
 Drugs are eliminated from the body either
unchanged (parent compound), or as metabolites
 Excretory organs, excluding the lung, eliminate
polar compounds more efficiently than
substances with high lipid solubility
 Lipid soluble drugs are thus not readily
eliminated until they are metabolized to more
polar compounds
 Occurs through a number of routes: the major
organ kidney being and include others: bile,
intestine, breast milk, and lung.

57. Excretion of Drugs (cont’d)
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 The kidney is the most important organ for
elimination of drugs and their metabolites
Primary organ of removal for most
drugs, especially those that are water
soluble and nonvolatile
 Three principle processes by which the kidney
eliminates drugs:
Glomerular filtration
Tubular secretion
Tubular reabsorption

58. Metabolism and Elimination
 Half-lives and Kinetics
 Half-life:
Plasma half-life: Time it takes for plasma
concentration of a drug to drop to 50% of initial level.
Whole body half-life: Time it takes to eliminate half of
the body content of a drug.
 Factors affecting half-life
Age
Renal excretion
Liver metabolism
Protein binding
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59. SET BY: DEJENE HAILU
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PHARMACODYNAMICS

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PHARMACODYNAMICS
What the drug does when it gets there.
It deals with the biochemical and physiological
effects of drugs and their mechanisms of action
 A thorough analysis of drug action can provide the
basis for rational therapeutic use of a drug
Mechanisms of Action- the ways by which drugs
can produce therapeutic effects
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61. PHARMACODYNAMICS: Mechanism of action of a
drug
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 Once the drug is at the site of action, it can modify the rate
(increase or decrease) at which the cells or tissues function
by interacting with receptors.
A drug cannot make a cell or tissue perform a function it
was not designed to perform
Mechanisms of Action :
• Receptor interaction
• Nonspecific interactions
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62. What is Pharmacodynamics (PD)
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• PD deals with
– Interaction of drugs with receptors and understanding
the molecular mechanisms by which a drug acts
– Relationship between drug concentration and magnitude
of the response
Why we study it ??
To understand how the drugs produce its therapeutic and
toxic effects.

63. Drug-receptor interaction
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• Begins all the pharmacodynamic process.
• Receptors are biological macromolecules to which a ligand can bind and
produce a measurable response.
They include
 Regulatory proteins, which mediate the actions of endogenous
chemical signals such as neurotransmitters
 Enzymes, which may be inhibited by binding a drug (eg,
dihydrofolate reductase)
 Transport proteins (eg, Na+/K+ ATPase, the membrane receptor
for cardioactive digitalis glycosides)
 Structural proteins (eg, tubulin, the receptor for colchicine, and
anti-inflammatory agent).

64. Drug-receptor interaction
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• Largely determine the quantitative relations between dose of
drug and pharmacologic effects.
• Responsible for selectivity of drug action.
• Mediate the actions of both pharmacologic agonists and
antagonist
• Many toxic chemicals produce their effect by interaction with
receptors.
• Drugs only modify an already existing biochemical processes.

65. Drug-receptor interaction
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• Involve formation of chemical bonds
- Hydrogen 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
 The formation of D-R complex depends on drug affinity for the receptors. But
the Pharmacological response depends on intrinsic activity

66. Dose-response relationship
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 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
A- Graded : Relates dose to intensity of effect e.g. blood
pressure. Reponses measured in usual units eg, B.P, Blood sugar levels
etc. It can take fraction.
B- Quantal :% of population responding to drug. Responses are
recorded as either positive or no response and can not take fractions.

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Two factors that determine the effect of a drug on
physiologic processes are affinity and intrinsic activity.
A- Affinity is a measure of the tightness that a drug binds to
the receptor.
B- Intrinsic activity is a measure of the ability of a drug
once bound to the receptor to generate an effect activating
stimulus and producing a change in cellular activity.
Affinity & intrinsic activity

68. Agonist & partial agonist
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 Agonist::A drug which binds to a receptor and
activates it, producing pharmacological response
(contraction, relaxation, secretion, enzyme
activation, etc.). Intrinsic activity =1
 Partial agonist : A drug which binds to a
receptor and activates it, producing a
pharmacological response but less than full
agonist Intrinsic activity <1 but not zero

69. AGONIST and ANTAGONISTS
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 AGONIST: A drug is said to be an agonist when it
binds to a receptor and causes a response or effect. It
has intrinsic activity = 1
 ANTAGONISTS: A drug is said to be an antagonist
when it binds to a receptor and prevents (blocks or
inhibits) a natural compound or a drug to have an
effect on the receptor. An antagonist has NO activity.
Its intrinsic activity is = 0

70. Partial agonist
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Fuall agonist vs partial agonist
0
0.2
0.4
0.6
0.8
1
1.2
1.00 1000.00
log Concentration
%
of
maximal
responses
full agonist
partial
agonist

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PHARMACOLOGICAL ANTAGONISTS
A pharmacological antagonists can either be
Competitive and non-competitive
1. Competitive
They compete for the binding site
• Reversible
2. Non-competitve
Bind elsewhere in the receptor (Channel Blockers).

72. non competitive
competitive
bind irreversibly to the receptors.
bind reversibly to the receptors
Their effect Can’t be overcome
by increasing the concentration of
agonist
Their effect Can be overcome by
increasing the concentration of agonist
Calcium channel blockers
Example atropine is a competitive agonist
for acetylcholine
A-Pharmacological Antagonists
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73. Other Antagonists
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FUNCTIONAL ANTAGONISTS
1. Physiologic Antagonists: A drug that binds to a non-
related receptor, producing an effect opposite to that
produced by the drug of interest.
• Its intrinsic activity is = 1, but on another receptor.
 Glucocorticoid Hormones  Blood Sugar
 Insulin  Blood Sugar
• Action of adrenaline counteracts that of histamine at
bronchioles.

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2. Chemical antagonists
• A chelator (sequester) of similar agent that interacts
directly with the drug being antagonized to remove it
or prevent it from binding its receptor.
• A chemical antagonist does not depend on interaction
with the agonist’s receptor (although such interaction
may occur).

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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 .

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 Is the ratio of the LD50 (Lethal dose that kills 50 %of
animals tested)to the ED50(is the amount of drug that
produces a therapeutic response in 50% of the people
taking it)
 It represents measure of relative safety of the drug.
 For example penicillin has a high therapeutic index as
compared to digoxin which have a low therapeutic index
 Therapeutic index is clinically more important parameter

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Therapeutic Index

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

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FACTORS MODIFYING THE DOSAGE AND
ACTION OF DRUGS
Drugs effect varies from person to person
Factors which influence the effect of drug:
Sex
Body Weight
Age
Disease status
Genetics/race
Drug interactions
Emotional state
Tolerance
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DRUG INTERACTIONS
 A drug interaction may be beneficial or harmful
 A drug interaction may be either pharmacokinetic or
pharmacodynamic
A.PHARMACOKINETIC DRUG INTERACTIONS:
 Interaction during absorption e.g. chelation
 Interaction during distribution e.g plasma protein binding
 Interactions during biotransformation -two mechanisms:
 Enzyme induction –accelerated
biotransformation
 Enzyme inhibition-delayed metabolism
 Interactions during excretion
 Competition for secretion; probenced and penicillin
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B. PHARMACODYNAMIC INTERACTIONS
1. COMBINED EFFECT OF DRUGS
i. Synergism - the effect of two drugs are greater than the effect
of the summation of their individual actions (1 + 1> 2)
ii. Additive effect- action of two or more drugs is equivalent to
the summation of their individual actions (1 + 1= 2)
iii. Potentiation effect- net effect of one drug used together with
other non therapeutic substance is greater than the individual
effects of the drug (1+0 >1)
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Pregnancy Considerations
 Drugs may cross the placenta
 Drugs may cross into breast milk
 Drugs may be teratogenic
 Teratogen - drugs or substances that blocks
normal growth of the fetus and causes one or
more developmental abnormalities
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83. Pediatric and Geriatric
Considerations:
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Pediatric Considerations
  Oral absorption
  topical absorption -
thinner skin
  Plasma protein
concentration
  Free protein-bound drug
  Elimination/metabolism
Geriatric Considerations
  Oral absorption
  Plasma protein
concentration
  Muscle mass,  body
fat
  Liver/renal function
 Multiple diseases
 Multiple drugs
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DEVELOPMENT AND EVALUATION OF NEW
DRUGS
Drug development comprises of two steps:
1. Preclinical development
 Experimentation ( invitro and invivo)
 Aims is to explore the drug’s efficacy and safety before it is
administrated to patients
 Varying drug doses are tested on animals (invivo and/or in
vitro systems
 Intact animals are essential for the acute, subacute, and
chronic toxicity tests
 Tests teratology and carcinogenicity
2. Clinical development
Through four phases
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B. Clinical development:
Efficacy of drug is tested on humans in 4 phases
Phase - I: usually conducted in healthy volunteers to
test the tolerable dose and duration of action
Phase - II: comprises small scale trials on patients to
determine dose level and treatment offers
Phase - III: It involves randomized control trials on
moderately large number of patients and is done in
multiple centers
Phase – IV : Post marketing surveillance
 Reports about efficacy and toxicity received from different
medical centers
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