2. Introduction
The word pharmacology
– Pharmakon (drug) and logos (study)
Defined as the study of substances that interact with living
systems through chemical processes
Deals with drugs:
Biochemical and Physiological effects of drugs
Absorbtion, Distribution, Metabolism, Excretion
Use, adverse effect, drug interactions, and
contraindications.etc. )
2
3. Generally pharmacology is the study of pharmacokinetics and
pharmacodynamics of drugs
Pharmacokinetics : "what the body does to the drug“
Studies the ways in which drugs are modified within organisms
It deals with drug disposition (absorption , distribution ,
biotransformation & excretion)
Pharmacodynamics : " what the drug does to the body “
It deals with the study of the biochemical and physiological
effects of drugs and their mechanisms of action
3
4. Branches of pharmacology
Pharmacotherapeutics :
the study of safe and effective use of drugs in the diagnosis,
prevention and treatment of diseases.
applies the information gained from fundamental investigation and
observation to clinical medicine
Toxicology
is the science of poisons
deals with the undesirable effects of chemicals on living systems
study the adverse effects of drugs and poisonous effects of various
chemicals (house hold, environmental, industrial or homicidal
4
5. Drug
Drug (from French “drogue” – dried herb)
The term “drug” may be defined as any chemical substance which,
when reacts with biological systems, alters its functions but not
create a new function
Alternatively, it may be defined as any chemical substance that has
ability to modify the response of a living cell.
N.B. Drugs do not give new function to tissues or cells, they can
only modify processes
It is used in the prevention , mitigation, diagnosis and treatment of the
disease
The most important properties of an ideal drug are: effectiveness, safety,
and selectivity
5
6. Source of Drugs
• Plant sources (e.g. atropine , digitalis , ephedrine, and
morphine ) .
• Animal sources (e.g. insulin and heparin) .
• Mineral sources e.g. Mg salts & iron , aluminium , iodine. etc
• Microorganisms e.g. penicillin .
• Synthetic e.g aspirin
• Semi-synthetic e.g. homatropine, ipratropium
• Genetic engineering eg human insulin
6
7. Drug Nomenclature
• Chemical name: describes the chemical structure of the
drug given according to IUPAC rules
Example:
N-acetyl-p-aminophenol (paracetamol)
Acetyl salicylic acid (Aspirin),
2-(4-isobutylphenyl)propionic acid
7
8. It is too long and difficult to recognize and not used in
prescription writing
Used by the chemist and pharmacist during research
Trade name(s), Brand or proprietary name( s)
Given by the pharmaceutical companies
One drug may have more than one trade name
• Example: Bayer (Aspirin), Panadol , paramol, adol, tylol
(paracetamol) , Losec (Omeprazole)
8
9. Generic (official/non-proprietary) Name
• The approved official name or internationally accepted name of
drugs used in pharmacopoeias
• adopted by the United States Adopted Name (USAN) council
• Generic names are used uniformly all over the world by an
international agreement through the WHO
• One drug has only one generic name
Example: Aspirin, paracetamol/Acetaminophen, omeprazole
9
10. Routes of Drug Administration
• Drug can be applied in several routes
• It is important to know the route of administration because it
determines:-
On set of drug action
Duration of action
Intensity of drug action
Degree of localization of drug action
10
11. Route selection depends on;-
– Drug physical and chemical properties (Drug factor)
Ex. Solubility, ionization…
– Therapeutics objective (Patient factor)
E.g The desirability of a rapid onset
Restrictions to a local site
Patient preference ……
11
12. o May be classified into two:
– ENTRAL and PARENTRAL
o ENTRAL:
– Means “to do with the GI track”
– Administration of drugs through the alimentary tract
– Included all routes of administration that involve the GI
tract; oral, buccal, sublingual and rectal routes of
administration
12
13. o PARENTRAL:
– Means “not through the GI tract” and refers to all routes of
administration that do not involve the GI tract
– It commonly refers to injections such as IV, IM and SC but
also includes other like topical, vaginal and inhalational
routes.
13
14. First Pass Effect
• All drugs that are absorbed from the intestine enter
hepatic portal vein and pass through the liver before
they are distributed systemically.
• Some drugs are almost completely destroyed/
metabolized/ and other to some extent on their first
passage through the liver.
– This has been termed as Hepatic first pass effect
14
15. • Pharmacokinetic Processes
• May be defined as "what the body does to the drug“
• Is the study of drug movement in, through and out of the body;
and the alteration (metabolism) of the drug by the body.
• It deals with drug disposition (absorption , distribution ,
biotransformation & excretion)
• Describes the action of drugs in the body over a period of time
• This knowledge is essential to obtain the right effect at the right
duration with least risk
15
16. • Understanding and employing pharmacokinetic principles
can increase the probability of therapeutic success and reduce
the occurrence of adverse drug effects in the body
• The absorption, distribution, metabolism and excretion of a
drug all involve its passage across cell membranes
16
19. • Factors affecting the transfer of drugs across
membranes
• The characteristics of a drug that predict its movement
and availability at sites of action are
its molecular size and structural features
degree of ionization
relative lipid solubility of its ionized and non-ionized
forms
its binding to serum and tissue proteins
19
20. Processes of Drug Absorption
• Passive Diffusion
The drug can pass from one side of the cell membrane to the other
along its concentration gradient by virtue of its solubility in the lipid
bilayer
Small, uncharged molecules can pass through a lipid bilayer by
simple diffusion
drug that has a very high lipid–water partition coefficient will
rapidly diffusion across the cell membrane
• Filtration
describes the passage of substances through porous membranes
The pores in the cell membranes are minute and allow only few
substances with small molecular weight 20
21. • Facilitated Diffusion
The transport of substance down their conc. gradient
is protein carrier–mediated transport System
no energy input is required
• Active processes
The energy-dependent movement of compounds across
membranes
most often against their concentration gradient
involves the reversible binding of the molecule with a carrier
There are two types of active transport
21
22. • Primary Active Transport
• Active transport for which energy derived from ATP hydrolysis directly
moves molecules across membranes against their electrochemical
gradient
• Example: the Na/K-ATPase (pump three Na+ out of the cell against their
electrochemical gradient and two K+ into the cytosol against their
electrochemical gradient)
• Secondary Active Transport (coupled transport)
• The transport of one molecule across a biological membrane can be
coupled by the transport protein to the movement of another molecule
• If the movement of both molecules is in the same direction, the
cotransport is referred to as symport
Example: the uptake of amino acids and glucose from the diet 22
24. • If the molecules are being moved in opposite directions,
the cotransport is referred to as antiport
Example: antiport of sodium and calcium ions, which
plays an important role in cardiac muscle contraction
24
26. Summary of Process of Drug Absorption
26
Mechanism Direction Energy
required
Carrier Saturability
Passive Diffusion Along gradient No No No
Facilitated Diffusion Along gradient No Yes Yes
Active transport Against gradient Yes Yes Yes
27. • Endocytosis
• A process by which cells take up macromolecules and even other cells
• Two main types
Phagocytosis (cellular eating, phagosomes)
Pinocytosis (cellular drinking)
Phagocytosis
It is a process of engulfing solid materials
Important for protozoa and worms nutritional supply
It is defense in animal cells and carried out by specialized cells called
phagocytes
Phagocytosis does not concentrate and not clathrin-dependent
27
28. Pinocytosis
• A process by which liquid substances are engulfed by the cell
• There are two types of pinocytosis
1. Clathrin dependent (receptor-mediated endocytosis)
Process by which an external ligand binds to a receptor on the surface of
the cell is internalized by the help of clathrin protein
Provides a selective concentration mechanism that increases the efficiency
of internalization
2. Clathrin-independent endocytosis
Non-specific internalization of ECF independent of clathrin protein
Substances dissolved in the ECF can also be internalized
Does not concentrate ingested material
28
29. 1. Drug absorption
Is the movement of drug from its site of administration in to the
systemic circulation
Bioavailability is a term used to indicate the fraction of
unchanged drug reaching the systemic circulation following
administration by any route
•I.V. provides 100% bioavailability.
• Oral usually has less than I.V.
• Bio = (AUC oral / AUC IV) X 100
29
31. Factors modifying drug absorption
• Physicochemical properties of the drug
Lipid / water partition coefficient ;Lipid soluble drugs are readily
absorbed
For a drug to be readily absorbed it must be largely hydrophobic yet have
some solubility in aqueous solutions
• Area & vascularity of the absorbing surface
Intestinal microvilli increases surface area available for absorption
• Rate of general circulation
blood flow produced by vasoconstrictor agents , shock or others can
slow absorption
31
32. • Drug Formulation (ease of dissolution)
(solution > suspension > capsule > tablet)
• Rate of gastric emptying
rapid gastric emptying fast transit to intestine
• Presence of food in the stomach
presence of food delays absorption
• Route of administration
Absorption is excellent from pulmonary alveoli , followed by
the skeletal muscles , the subcutaneous tissues , intestine , skin
& stomach
32
33. Distribution
• After a drug is absorbed into the blood stream, it
rapidly circulates through the body.
• Once absorbed, most drugs do not spread evenly
throughout the body.
Drugs that dissolve in water (water-soluble drugs),
such as atenolol , tend to stay within the blood and
the fluid that surrounds cells (interstitial space).
Drugs that dissolve in fat , such as the anesthetic
drug halothane, tend to concentrate in fatty tissues.
33
34. Distribution…
• Some drugs leave the bloodstream very slowly, because they
bind tightly to proteins circulating in the blood.
• Others quickly leave the bloodstream and enter other tissues,
because they are less tightly bound to blood proteins.
• The protein-bound part is generally inactive
• As unbound drug is distributed to tissues and its level in the
bloodstream decreases, blood proteins gradually release the
drug bound to them
• A highly plasma protein bound drug (e.g., ibuprofen) will
have a small Vd while a drug with high tissue protein
binding (digoxin) will have a large Vd.
34
35. • In plasma, acidic drugs tend to bind mainly to albumin
while basic compounds have greater affinity towards alpha
acid glycoproteins.
– Due to the limitation in both the number and the type of
binding sites
• 1) binding may be saturable
• 2) drugs may compete with one another for binding to the
same site.
• Drug distribution to CNS is affected by blood brain barrier
– Small and highly lipid-water partition coefficient drugs
can pass BBB
35
36. Biotransformation (Metabolism)
36
Many pharmaceuticals are lipophilic, which enables the drug to
pass across cell membranes.
Unfortunately, the same chemical property that enhances
bioavailability of drugs may also make renal excretion difficult.
Metabolism often converts lipophilic compounds into more
readily excreted hydrophilic products.
The rate of metabolism determines the duration and intensity of
a drug's action.
Liver is quantitatively the most important organ in metabolizing
drugs
37. Metabolism…
Phase I reactions (also termed nonsynthetic reactions) may occur
by oxidation, reduction, hydrolysis.
These reactions typically involve a cytochrome P450 (often
abbreviated CYP), NADPH and oxygen.
Results in drug inactivation (most of drugs), conversion of inactive
drug into active metabolite, conversion of active drug into active
metabolite, conversion to toxic metabolite.
Phase II (Synthetic) reactions: Functional group formed by phase I
is masked by natural conjugates such as glucuronic acid,
glutathione, sulphate, acetic acid, glycine or methyl group.
Sites on drugs where conjugation reactions occur include -COOH,-
OH), NH2, and -SH groups.
37
38. CYP (Cytochrome P450 ) Families
• Multiple CYP gene families have been identified in humans, and
the categories are based upon protein sequence homology
• Most of the enzymes are in CYP 1, 2, & 3 families .
• Frequently, two or more enzymes can catalyze the same type of
oxidation, indicating redundant and broad substrate specificity.
• CYP3A4 is very common to the metabolism of many drugs
• its presence in the GI tract is responsible for poor oral availability of
many drugs.
• Percentage of drugs metabolized by CYP3A4-5:33%, CYP2D6:23%,
CYP2C9:14%, CYP1A2:14%, CYP2C19:11%.
38
39. Factors affecting drug metabolism
• Enzymes induction (phenobarbitone, phenytoin)
• Enzyme inhibition (Cimetidine, erythromycin).
• important in predicting drug-drug interactions
• Genetics variation: Isoniazid (Slow/fast acetylators).
• Nutrition state: low protein diet can decrease glycine.
• Over dose: acetaminophen overdose causes hepatotoxicty
• Age: children (immature enzyme), elders (organ
degeneration)
• Gender: Diazepam metabolism is faster in women while
propranolol metabolism is faster in men.
• Disease state: kidney and liver failure
• Route of Administration: First pass hepatic effect
39
41. Excretion
• Drugs are eliminated from the body either unchanged or
converted to metabolites
• Excretory organs eliminate polar compounds more
efficiently than substances with high lipid solubility
• Lipid-soluble drugs are not readily eliminated until they are
metabolized to more polar compounds
• The kidney is the most important organ for excreting drugs
and their metabolites
41
42. • Substances excreted in the feces are principally
unabsorbed orally ingested drugs
drug metabolites excreted in the bile
Drug secreted directly into the intestinal tract and not
reabsorbed
• Excretion of drugs in breast milk is important
• because the excreted drugs are potential sources of
unwanted pharmacological effects in the nursing infant
• Excretion from the lung is important mainly for the
elimination of anesthetic gases
42
43. Renal Excretion
43
Renal excretion provides the most common mechanism of drug
excretion
this form of excretion relies on the hydrophilic character of a
drug or metabolite.
It is the result of three processes:
Filtration
active tubular secretion
passive re-absorption.
Changes in overall renal function generally affect all three
processes to a similar extent
44. In healthy persons, renal function is not constant
In neonates, renal function is low compared with body mass but
matures rapidly within the first few months after birth
During adulthood, there is a slow decline in renal function, ~1%
per year, so that in elderly patients a substantial degree of
functional impairment may be present.
• The amount of drug entering the tubular lumen by filtration
depends on
the glomerular filtration rate
the extent of plasma binding of the drug
only unbound drug is filtered
44
45. • In the proximal renal tubule, active, carrier-mediated tubular
secretion also may add drug to the tubular fluid
Transporters such as P-gp and the multidrug-resistance–
associated protein type 2 (MRP2), localized in the apical brush-
border membrane, are responsible for
the secretion of amphipathic anions and conjugated metabolites
(such as glucuronides, sulfates, and glutathione adducts),
respectively
• Solute carrier transporters that are more selective for organic
cationic drugs are involved in the secretion of organic bases
•
45
46. • Membrane transporters, mainly located in the distal renal
tubule, also are responsible for any active reabsorption of drug
from the tubular lumen back into the systemic circulation
however, most such reabsorption occurs by non-ionic diffusion
• In the proximal and distal tubules, the non-ionized forms of
weak acids and bases undergo net passive reabsorption
The concentration gradient for back-diffusion is created by the
reabsorption of water with Na+ and other inorganic ions.
46
47. • The tubular cells are less permeable to the ionized forms of weak
electrolytes, passive reabsorption of these substances depends on the pH
• When the tubular urine is made more alkaline
weak acids are largely ionized and thus are excreted more rapidly and to
a greater extent
• When the tubular urine is made more acidic
The fraction of drug ionized is reduced, and excretion is likewise reduced
• Alkalinization and acidification of the urine have the opposite effects on
the excretion of weak bases
In the treatment of drug poisoning, the excretion of some drugs can be
hastened by appropriate alkalinization or acidification of the urine
47
48. Biliary and Fecal Excretion
• Transporters present in the canalicular membrane of hepatocyte
actively secrete drugs and metabolites into bile
• P-gp and BCRP (breast cancer resistance protein, or ABCG2)
transport a plethora (excess) of amphipathic lipid-soluble drugs
• MRP2 is mainly involved in the secretion of
conjugated metabolites of drugs (e.g., glutathione conjugates,
glucuronides, and some sulfates)
• drugs and metabolites present in bile are released into the GI tract
during the digestive process
48
49. • Because secretory transporters are expressed on the apical membrane of
enterocytes
direct secretion of drugs and metabolites may occur from the systemic
circulation into the intestinal lumen
drugs and metabolites can be reabsorbed back into the body from the
intestine
• Such enterohepatic recycling, if extensive, may prolong significantly the
presence of a drug (or toxin) and its effects within the body prior to
elimination by other pathways
For this reason, drugs may be given orally to bind substances excreted
in the bile
• In the case of mercury poisoning, for example, a resin can be
administered orally that binds with dimethyl mercury excreted in the
bile, thus preventing reabsorption and further toxicity
49
50. • Excretion by Other Routes
• Excretion of drugs into sweat, saliva, milk and tears is quantitatively
unimportant
• Elimination by these routes depends mainly on diffusion of the non-
ionized lipid-soluble form of drugs through the epithelial cells of the
glands and depends on the pH
• The concentration of some drugs in saliva parallels that in plasma
Saliva therefore may be a useful biological fluid in which to determine
drug concentrations when it is difficult or inconvenient to obtain blood
• Milk is more acidic than plasma
basic compounds may be slightly concentrated in this fluid
the concentration of acidic compounds in the milk is lower than in
plasma 50
51. • Clinical Pharmacokinetics
• The fundamental tenet (principle) of clinical pharmacokinetics is
a relationship exists between the pharmacological effects of a drug
and an accessible concentration of the drug (e.g., in blood or
plasma)
• This relationship has been documented for many drugs and is of
benefit in the therapeutic management of patients
• The importance of pharmacokinetics in patient care is based on
the improvement in therapeutic efficacy
the avoidance of unwanted effects that can be attained by
application of its principles when dosage regimens are chosen and
modified
51
52. Clearance
• Clearance is a proportionality constant describing the relationship
between a substance’s rate of elimination (amount per unit time) at a
given time and its corresponding concentration in an appropriate fluid at
that time
• volume of blood (plasma or serum) or other biological fluids from which
the drug is totally and irreversibly removed per unit time’’
The units for clearance are mL/min or L/hr
• It is the most useful parameter available for the evaluation of the
elimination mechanism and of the eliminating organs (kidney and liver)
• Clearance is parameter that relates the plasma or serum concentration
(Cp or Cs) to the rate of drug excretion (dX/dt)
Eg. Rate of renal excretion = Renal clearance x Plasma concentration52
53. Subsets of Clearance
• Systemic (Cls) or total body clearance (TBC): This is the sum of all
individual organ clearances that contribute to the overall elimination of
drugs
• Renal clearance (Clr): The clearance of drug (a fraction of total clearance)
for a drug that is removed from the blood (plasma/serum) by the
process of renal excretion
• Metabolic clearance (Clr): The clearance of drug (a fraction of total
clearance) for a drug that is removed from the blood (plasma/ serum) by
the process of metabolism
• Hepatic clearance (Cl h): The clearance of drug (a fraction of total
clearance) for a drug that is removed from the blood (plasma/serum) by
the process of hepatic metabolism
53
54. The time of peak plasma concentration (t max)
• The time required to reach maximum drug
concentration after drug administration
• The peak time can be used :
to determine comparative bioavailability and or
bioequivalence
to determine preferred route of drug administration
and the desired dosage form for the patient
to assess the onset of action
54
56. • Maximum (peak) plasma concentration Cpmax:
• The peak plasma conc. Cpmax occurs when time is equal to tmax
used to determine the comparative bioavailability or
bioequivalence between two products
used to determine the superiority between two different dosage
forms or two different routes of administration
may correlate with the pharmacological effect of a drug
56
57. The area under the plasma level–time curve (AUC)
• is a measurement of the extent of drug bioavailability
• AUC reflects the total amount of active drug that reaches the systemic
circulation
• Elimination Half-Life (t1/2): The time required for drug blood levels to be
reduced by 50%
• Therapeutic effects are prolonged for drugs with longer half life and vice versa
• Absorption Half-Life (t1/2): The time required for 50% of the drug to be
absorbed from the site of administration to the systemic circulation
• Therapeutic effects are delayed for drugs with longer absorption t1/2
• To reduce the onset time of the drug, a loading or initial dose of drug is given
The main objective of the loading dose is to achieve desired plasma
concentrations, as quickly as possible
57
58. Steady State Concentration (Css)
• Drugs are administered in such a way as to maintain a
steady state of a drug in the body
• At steady state just enough drug is given in each dose to
replace the drug eliminated since the preceding dose
• Thus, calculation of the appropriate maintenance dose is
the primary goal
• It takes approximately three to five half-lives to reach
steady-state concentrations during continuous dosing
• In three half-lives, serum concentrations are at
approximately 90% of their ultimate steady-state values
58
60. • Pharmacodynamics
• The study of the physiological effects of drugs on the body
or on microorganisms or parasites within or on the body
• Often summarized as the study of what a drug does to the
body
• The majority of drugs:
Mimic or inhibit normal physiological/biochemical/
pathological processes
Inhibit vital processes of parasites and microbial organisms
60
61. • Mechanisms of Action of the Drugs
• The following are the main modes of actions.
1. Physical
– Based on physical properties of drugs
• Bulk purgative, Osmotic diuretic
• Physical barriers (demulscents)
• Adsorbents (kaolin, charcoal)
2. Chemical
– Based on chemical properties of drugs.
• Antacids neutralize gastric HCl
• Oxidizing/reducing agents (methylene blue in
methemogobinemia, cyanide poisoning with nitrites in
erythrocytes)
61
62. 3. Through Enzymes
Enzyme inhibition
- Alternative substrate
- Competitive or non-competitive
- Removal of co-factors
- ACEIs,, PDEIs,, Dopa decarboxylase inhibitors
4. Through Transporters
• Transport substrates back and forth and regulate their
concentration
- Pgp (ABC transporters) in the intestinal lumen, bile
duct and kidney
- Inhibited by drugs e.g., verapamil, probenicid
• Uptake mechanism for neurotransmitters (cocaine, SSRIs) 62
63. 5.Through specific target molecules (Receptors)
Definition:
• The component of a cell or organism that interacts with a drug
and initiates the chain of events leading to the drugs observed
effects
• In this sense, receptors are those components of a cell that
serve as sensing elements of chemical signals (such as
hormones and neurotransmitters)
63
64. Properties of Receptors
1. Sensitivity
• Receptors exhibit sensitivity, i.e. a small amount of drug / ligand is
required to sensitize the receptor and produce response
– There is a signal amplification system
2. Selectivity
• The molecular size, shape, and electrical charge of a drug determine
whether - and with what affinity it will bind to a particular receptor
• Receptors interact only with molecules that are complementary to them
64
65. 3. Specificity
• The response obtained at a given receptor remains the same in spite of the
difference in the type of agonist
• Orphan receptors
• Receptors for which no ligand has been discovered but they have a similar
structure to other identified receptors and whose function can only be
presumed
Nature of Receptors
1. Most receptors are proteins,
• Because the structures of polypeptides provide both the necessary
diversity and the necessary specificity of shape and electrical charge.
2. Receptors have two functional domains:
– A ligand-binding domain and an effectors domain
65
66. Types of receptors
• Based on molecular structure and their signal transduction mechanism ,
receptors may be grouped into the following types, or superfamilies
1. Ligand-gated ion channels
• These are membrane proteins with a ligand-binding (receptor) site in the
extracellular domain associated with an ion channel
• Binding of a ligand on the extracellular domain modulates the
opening/closure or conductance of the ion channel, Examples
• Nicotinic acetylcholine,
• Gamma-aminobutyric acid type A (GABAA)
• 5-hydroxytryptamine type 3 (5-HT3) receptors
66
67. 2. G-protein-coupled receptors
• They are membrane receptors that are coupled to intracellular
effectors systems via a G-protein
• Binding of an extracellular ligand on cell-surface receptor
activation of the receptor/ conformational changes in the receptor/
The receptor in turn triggers the activation of a G-protein
located on the cytoplasmic face of the plasma membrane
– The activated G-protein then changes the activity of an effectors
element, usually an enzyme or ion channel
67
68. Effectors controlled by G-proteins
– Adenylate cyclase (AC) / cAMP:
– Phospholipase C / inositol trisphosphate (IP3) / diacylglycerol
(DAG)
– Ion channels (e.g. potassium and calcium channels, thus affecting
membrane excitability, transmitter release, contractility, etc.).
– Phospholipase A ( thus the formation of arachidonic acid and
eicosanoids)
3. Kinase-linked and related receptors
• These receptors comprise an extracellular ligand-binding domain
linked to an intracellular domain by a single transmembrane helix
68
69. • Binding of a ligand results in change in receptor conformation
receptor molecules to bind to one another/ receptor dimerization/
which in turn brings together the protein kinase domains
autophosphorylation of tyrosine residues which become
enzymatically active phosphorylate additional downstream
signaling proteins
69
70. 4. Intracellular Receptors
– These are receptors for ligands which have sufficiently lipid-
soluble to cross the plasma membrane
• E.g. Thyroid hormone, Steroid hormones, Vitamin D,
Retinoic acid
– These receptors may be located in the cytoplasm or inside the
nucleus
• The receptor-mediated regulation of DNA transcription
• Receptors consist of a conserved DNA-binding domain attached to
variable ligand-binding and transcriptional control domains
• Effects are produced as a result of altered protein synthesis.
70
72. Action, Effect and clinical use
• Drug Actions are the biochemical and physiological mechanisms
by which the chemical produces a response in living organisms
• Drug effects are the observable consequence of a drug action
• Clinical uses are the diseases in which the drug is prescribed and
the practical aspects of their use
• Adverse Effect
• Any noxious or unintended reaction to a drug that is administered
in standard doses by the proper route of administration for the
purpose of prophylaxis, diagnosis or treatment
• Most ADRs are related to dose of the drug administered
72
73. • Dose related ADRs are often predictable
• Few ADRs are not related to the dose and are often unpredictable
Side effects
• May be defined as predictable dose related pharmacological effects that
occur within the therapeutic dose range and that are undesirable in a
given therapeutic situation
• Side effects are extension of the pharmacological effect of the drug either:
1. At the same tissue and same receptor: -Examples
• hypotension, headache, flushing produced by nitrates
• hypotension with antihypertensives
• haemorrhage with Warfarin
• hypoglycaemia with insulin
73
74. 2. Different tissues but same receptor: -Examples
• Bone marrow depression by the antineoplastic drug
methotrexate
3. On different receptors: -Example
• Non selective beta blockers indicated for arrhythmia may cause
bronchoconstriction.
• Distinction between a side effect and therapeutic effects may
sometimes depend on the clinical indication
74
75. Types of ADR
Type A ADRs
– These are dose related ADRs which are determined by the
pharmacological properties of the drug molecule
– They are often predictable
• Over dosage toxicity
– Refers to the toxic effects of drugs when taken in excess
– Over dosage toxicity is related to the pharmacological property
of the drug
– It is a direct extension of the drugs pharmacological action and
is predictable
75
76. Type B ADRs
– These are rare and often unpredictable
– These are not extension of the pharmacological activity of the drug
– They are often not related to the dose
– Occur in few individuals due to their susceptibility genetic d/ce
– Classified in to two:
• Hypersensitivity reactions and Idiosyncratic reactions
• Idiosyncrasy is an abnormal reactivity to a chemical that is peculiar to a
given individual: Example
– Slow and fast acetylators exist due to polymorphisms in N-acetyl
transferase
– Serious hemolytic anemia when an antimalarial primaquine is used
by black males due to deficiency of erythrocyte glucose-6-phosphate
dehydrogenase
76
77. Type C ADRs
– These are associated with long-term use of the drug.
– Often involve dose accumulation.
– They are well known and can be anticipated
• E.g. ocular toxicity by antimalarials
Type D ADRs
– These reactions refer to carcinogenic and teratogenic effects.
– Are dose independent
– These reactions are delayed in onset
77
78. Drug-Receptor Interaction
The occupancy Theory
• The effect produced by the drug is proportional to the amount of
drug-receptor complex (DR) formed;
• Spare Receptors
• In some systems, full agonists are capable of eliciting 50%
response with less than 50% of the receptor bound
because pool of available receptors exceeds the number required
for full response
• These extra receptors are known as spare receptors
• Economy of hormone or neurotransmitter secretion is achieved at
the expense of providing more receptors
78
79. • Why are there spare receptors?
Allow maximal response without total receptor occupancy:
increases sensitivity of the system
Spare receptors can bind (and internalize) extra ligand
preventing an exaggerated response if too much ligand is
present
Factors Governing Drug Action
• Intrinsic activity: Ability to produce a measurable change in
cellular activity
• Affinity: Strength of interaction between the two species
• Some ligands bind better than others
79
80. Dose-Response Relationships
a. Graded Dose-Response Relationships
• When the response of a particular receptor-effector system is
measured against increasing concentrations of a drug
the graph of the response versus the drug concentration is called
a graded dose-response curve
• The efficacy (Emax) and potency (EC50) parameters are derived
from these data
80
81. b. Quantal Dose-Response Relationships:
• The Plot of the fraction of the population that responds at each
dose of the drug versus the log of the dose administered
The median effective (ED50), median toxic (TD50), and median
lethal doses (LD50) are extracted from experiments carried out in
this manner
81
82. Therapeutic Index
• Ratio of medial effective dose to medial lethal dose (definition often
used in preclinical screening)
• Therapeutic index = Medial lethal dose
Medial effective dose
• Ratio of medial effective dose to medial toxic dose (definition used
clinically)
• Therapeutic index = Medial toxic dose
Medial effective dose
• Therapeutic index is a measure of drug safety. A large therapeutic
index indicates a clinically safe drug
82
83. Evaluation of Drug Effect
Efficacy
• Efficacy (often called maximal efficacy): is the maximal
effect (Emax) an agonist can produce if the dose is taken
to very high levels
• Efficacy is determined mainly by the nature of the
receptor and its associated effector system
• It can be measured with a graded dose-response curve
but not with a quantal dose-response curve
• By definition, partial agonists have lower maximal
efficacy than full agonists
83
85. Potency
• Potency denotes the amount of a drug needed to produce a given
effect
• In graded dose-response measurements, the effect usually chosen
is 50% of the maximal effect ( EC50)
Potency is determined mainly by the affinity of the receptor for
the drug
• In quantal dose-response measurements ED50, TD50, and LD50
are typical potency variables (median effective, toxic, and lethal
doses, respectively, in 50% of the population studied)
• Safety: The drug is said to be safe if it doesn’t cause a harmful
effect at therapeutic dose
85
86. Classification of Drugs according to its Interaction to the
Receptor
• Agonist is a drug capable of fully activating the effector
system when it binds to the receptor
• A partial agonist produces less than the full effect, even
when it has saturated the receptors
• In the presence of a full agonist, a partial agonist acts as an
inhibitor
86
88. Inverse Agonist
• an inverse agonist is a drug that binds to the same
receptor as an agonist but induces a pharmacological
response opposite to that of the agonist.
• A neutral antagonist has no activity in the absence of
an agonist or inverse agonist but can block the
activity of either.
• Inverse agonists have opposite actions to those of
agonists but the effects of both of these can be blocked
by antagonists.
88
90. • Antagonists
• Block the actions of endogenous regulatory molecules
• They interfere with the ability of an agonist to activate the
receptor
• An antagonist has affinity but no intrinsic activity
• Types of Antagonist
• Chemical antagonism – Chemical antagonist combines with
drug to produce insoluble, inactive complex. e.g., Protamine
sulphate neutralises action of heparin
• Indirect antagonism – antagonist act at a second downstream
molecule that links the action of the agonist to the final response
observed. e.g., beta blockers and tyramine
90
91. • Physiological (functional, variant) antagonism - the
“antagonist” has the opposite biological action by
acting on a different receptor. e.g., ACh and
Phenylephrine in blood vessels
• Pharmacokinetic antagonism – the antagonist
reduces free concentration of drug at target either by
reducing drug absorption or increasing elimination
• Receptor antagonism- blockade of the action of the
drug at receptor level
91
92. Scenarios of receptor antagonism
1. Competitive Antagonists
• Drugs that bind to the receptor in a reversible way
without activating the effector system for that
receptor
• The log dose-response curve is shifted to higher
doses but the same maximal effect is reached
• The effects can be overcome by adding more agonist
• Competitive antagonists increase the ED50
92
94. 2. None Competitive Antagonists
• Antagonist bind to the site other than the active site
• The effect cannot be overcome by increasing the
concentration of agonist
3. Uncompetitive Antagonist
• Antagonist bind to a site other than the active site but
only when agonist is bound
• The effect cannot not be overcome by increasing the
concentration of agonist
94
95. Receptor Regulation
• Sensitization or Up-regulation
1. Prolonged/continuous use of receptor blocker or antagonist
2. Inhibition of synthesis or release of hormone/ neurotransmitter
3. Denervation
• Desensitization or Down-regulation
1. Prolonged/continuous use of agonist
2. Inhibition of degradation or uptake of agonist
95
96. • Tolerance
– The gradual decreased in responsiveness to a drug that
occurs after repeated doses
– takes days or weeks to develop
– Increased doses are required to achieve the desired effect
• Tachyphylaxis
– is the phenomenon that describes decrease
pharmacological response to drugs which often develops
in the course of few minutes, with their continuous or
repeated administration
96
97. Drug interaction (DIs)
• Drug interaction is the modification of the action of one drug by another
• Alter effectiveness or toxicity of one or more drugs
• When drugs combine their effect may be:-
1. Additive (simple summation of effects)
• Effect of (DA+DB) = Effect of DA + effect of DB
• Between drugs that act at the same site (receptor)
2. Synergism
• The combined action of two or more drugs that is greater than the sum
of the 2 drugs acting independently
• Effect of (DA+DB) > effect of DA + Effect of DB
97
98. 3. Potentiation
• The enhancement of a drug’s effect by another drug
• Eg. promethazine may enhance the effect of morphine;
also alcohol and barbiturates
4. Antagonism (opposing action)
Pharmacological antagonism
Chemical antagonism
pharmacokinetics Antagonism
physiological antagonism
98
99. Mechanism of Drug interaction
1. Pharmaceutical interactions
• occur by chemical reaction or physical interaction when drugs are mixed
Eg. Charcoal and other drugs or TTC and antiacids
2. Pharmacodynamic interactions
• occur when different drugs each influence the same physiological
function
e.g. drugs that influence state of alertness or blood pressure
• Occur when different drugs with opposing actions, the result may be to
reduce the effect of the first
e.g. indometacin increases blood pressure in hypertensive patients
treated with an antihypertensive drug such as losartan
99
100. 3. Pharmacokinetic interactions
• occur when one drug affects the pharmocokinetics of another
by reducing its elimination from the body or by inhibiting its
metabolism
Useful Interactions
• Increased Effect
• Drugs can be used in combination to enhance their effectiveness
e.g. an anti platelet drug with a fibrinolytic in treating myocardial
infarction
the use of a β2 agonist with a glucocorticoid in the treatment of
asthma (to cause bronchodilation and suppress inflammation)
100
101. Prevent Resistance
• Anti TB drugs combination, ART drugs
• Combination of clavulanic acid, an inhibitor of penicillinase, with
amoxicillin
Minimize Side Effects
• low doses of two antihypertensive drugs may be better tolerated,
as well as more effective, than larger doses of a single agent
• The combination of a loop diuretic with a potassium-sparing
diuretic
• Isoniazid and pyridoxine combination to reduce peripheral
neuropathic risk of isoniazid
101
102. Adverse Interaction
1. Pharmaceutical Interaction
• Inactivation can occur when drugs are mixed(e.g. heparin with
gentamicin)
• interact in the lumen of the gut (e.g. tetracycline with iron, and
colestyramine with digoxin)
2. Pharmacodynamic Interaction
• Drowsiness caused by an H1-blocking antihistamine and by alcohol
• Antihypertensive drugs are rendered less effective by concurrent use of
non-steroidal anti-inflammatory drugs
because of inhibition of biosynthesis of vasodilator prostaglandins in the
kidney
102
103. 3. Pharmacokinetic Interactions
• drugs that influence gastric emptying (e.g. metoclopramide) can
alter the rate or completeness of absorption of a second drug
• Decreased efficacy can result from enzyme induction by a second
agent
carbamazepine and the antituberculous drug rifampicin are the
known enzyme inducers
• Inhibition of drug metabolism also produces adverse effects
Theophylline has serious (sometimes fatal) dose-related toxicities,
and clinically important interactions occur with inhibitors of the
CYP450 system
103
104. • Many drugs share a common transport mechanism in the proximal
tubules and reduce one another’s excretion by competition
Probenecid reduces penicillin elimination in this way
Aspirin and non-steroidal anti-inflammatory drugs inhibit secretion of
methotrexate into urine, as well as displacing it from protein-binding
sites
• Many diuretics reduce sodium absorption in the loop of Henle or the
distal tubule
Increased proximal tubular reabsorption of lithium in patients treated
with lithium salts can cause lithium accumulation and toxicity
• Digoxin excretion is reduced by spironolactone, verapamil and
amiodarone
104
