Introduction to pharmacology Part 2 ppt.pptx

Pharmacokinetics & Pharmacodynamics
Lecture-II
By: Muhammad Aurangzeb
BSN, MSPH, MSN
Lecturer-INS/KMU
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ZIAUDDIN ZEB COLLEGE OF NURSING DIR LOWER

Objectives
At the end of this lecture the students will be able to
• Define pharmacokinetics & Pharmacodynamics
• Discuss half life and bioavailability
• Describe factors affecting bioavailability
• Discuss various mechanisms through which drugs exert their
actions in the body
• Explain therapeutic index
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ZIAUDDIN ZEB COLLEGE OF NURSING DIR
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Pharmacokinetics
• Pharmacokinetics is the study of the absorption distribution,
metabolism and excretion of drugs, i.e. what the body does to
the drug (in Greek kinesis = movement).
• The process by which a drug is absorbed, distributed,
metabolized and eliminated by the body
• Once drug is administered it is absorbed, i.e. enters the
blood, is distributed to different parts of the body, reaches the
site of action, is metabolized and then excreted.
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Cont…
• Drugs may be transported across the membrane by passive
or active transport.
Passive transport:
• The drug moves across a membrane without any need for
energy.
Active transport
• It is the transfer of drugs against a concentration of drugs
against a concentration gradient and needs energy. It is
carried by a specific carrier protein.
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Pharmacodynamics
• Pharmacodynamics is the study of the effects of drugs on the
body and their mechanism of action, i.e. what the drug does
to the body
• The interactions of a drug and the receptors responsible for
its action in the body
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Pharmacokinetics
(The Life Cycle of a Drug)
• Absorption
• Distribution
• Metabolism/Degradation
• Excretion
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Absorption
• Absorption is defined as the passage of the drug from the site
of administration into the circulation. For a drug to reach its
site of action, it must pass through various membranes
depending on the route of administration .
• Absorption occurs by one of the processes i.e. passive
diffusion or active transport.
• Thus except for IV route, absorption is important for all other
routes of administration .
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Factors Affecting Drugs Absorption
Several factors influence the rate and extent of absorption of a
drug. They are:
1. Disintegration and dissolution time
2. Formulation
3. Particle size: small particle size is important for better
absorption of drugs
4. Lipid solubility: lipid soluble drugs are absorbed faster
5. Area and vascularity of the absorbing surface
6. Gastrointestinal motility
7. Presence of food: Drugs may form complexes with food,
such complexes are poorly absorbed e.g. Tetracycline
chelate Ca present in food, so absorption decreased. 8
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Cont…
8. pH and ionization: Ionized drugs are poorly absorbed while
unionized drugs are lipid soluble and are well absorbed.
Acidic drugs remain unionized in acidic medium of the
stomach and are rapidly absorbed, e.g. aspirin, barbiturates.
Basic drugs are unionized when they are reach the alkaline
medium of intestine from where they are rapidly absorbed,
e.g. pethidine, ephedrine
9. Metabolism: Some drugs may be degraded in gut, e.g.
nitroglycerin, insulin.
10. Diseases: The disease of the gut like malabsorption and
achlorhydria result in reduced absorption of drugs.
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Slow Absorption
• Orally (swallowed)
• Through Mucus Membranes
– Oral Mucosa (e.g. sublingual)
– Nasal Mucosa (e.g. insufflated)
• Topical/Transdermal (through skin)
• Rectally (suppository)
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Faster Absorption
• Parenterally (injection)
– Intravenous (IV)
– Intramuscular (IM)
– Subcutaneous (SC)
– Intraperitoneal (IP)
• Inhaled (through lungs)
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First Pass Metabolism
• First pass metabolism is the metabolism of the drug during its
passage from the site of absorption to the systemic
circulation. It is also called presystemic metabolism or first
pass effect.
• Drugs given orally may be metabolized in the gut wall and in
the liver before reaching the systemic circulation. The extent
of FPM differs from drug to drug.
• FPM may result in partial to total inactivation of the drug.
When it is partial, it can be compensated by giving higher
dose of particular drug, e.g. nitroglycerin, salbutamol.
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Bioavailability & Bioequivalence
• Bioavailability is the fraction of the drug that reaches the
systemic circulation following administration of any route. IV -
100% Bioavailability
• Bioequivalence: It is the study of comparison of
bioavailabilities of different formulation of the same drug.
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Bioequivalence
• Two drugs are said to be bioequilant if they have the same
bioavailability and efficacy provided, that they are
administered in the same molar doses at the same route of
administration.
Importance of bioequivalence
• It is necessary for generic substitution.
• Generic products are usually cheaper than brand product.
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Factors affecting bioavailability
• Physical properties of the drug (solubility)
• The drug formulation
• Gastric emptying time
• Condition of the GI tract
• pH in the stomach
• First –pass effect (morphine, isosorbide diniterate)
• Surface area for absorption
• Drug-drug interaction (antacid/ clarithromycin)
• Drug-food interaction
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Distribution
• After a drug reaches the systemic circulation, it gets
distributed to various tissues. It should cross several barriers
before reaching the site of action.
• Like absorption, distribution also involves the same process,
i.e. filtration, diffusion, and specialized transport.
• Various factors determine the rate and extent of distribution,
they are lipid solubility, ionization, blood flow and binding to
plasma proteins.
• Unionized and lipid soluble drugs are widely distributed
through out the body.
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Metabolism
• Metabolism or biotransformation is the process of
biochemical alteration of the drug in the body. Body treats
most of the drugs as foreign substance and tries to inactivate
and eliminate them by various biochemical reactions.
• Theses processes convert the drugs into more polar, water
soluble compounds so that they are easily excreted through
the kidneys.
• Some of the drugs are largely unchanged in urine, e.g.
furosemide, atenolol.
• Mainly drugs are metabolized in liver. Some are metabolized
in kidney, lungs, blood.
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Cont…
• The chemical reactions of biotransformation can take place in
two phases,
1. phase I (Non-synthetic reactions): convert the drug to more
polar metabolite by oxidation, reduction, or hydrolysis. If
the metabolites are not water soluble it undergoes phase II
reactions.
2. phase II (Synthetic reaction): In this reactions water soluble
substance present in the body like glucuronic acid, sulfuric
acid or an amino acid combine with the drug to form a
highly polar compounds to excreted by the kidneys. Large
molecules are excreted through the bile.
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Excretion
• The major organs of excretion are the kidneys, intestine,
biliary system and the lungs. Drugs in small amounts are
excreted in saliva, sweat, and milk.
• Renal excretion: Kidney is the most important organ of drug
excretion. Highly lipid soluble drugs are reabsorbed in in the
renal tubules, so their excretion is slow.
• Unabsorbed portion of the orally administered drugs are
eliminated through the feces. Large water soluble conjugates
are excreted in the bile.
• The lungs are the main route of elimination for gases and
liquids, e.g. GA , Alcohol.
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Plasma half-life (t1/2)
• Plasma half-life (t1/2) is the time taken for the plasma
concentration of a drug to be reduced to half itsvalue.
• Minimum dose is the smallest dose required to produce a
desired therapeutic effect of the drug.
• Maximum dose is the largest dose of the drug that can be
safely given to a patient without producing harmful effect.
• Toxic dose is the dose of the drug which produce
undesirable effects in majority of the patients
• Lethal dose is the dose of the drug which can cause
death. e.g. lethal dose of phenobarbitone is 6-10gm.
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Graph Show Half Life of Two Drugs
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Significance of Half Life
• It helps to know about the maintenance of dose.
• It helps to find the defect in distribution, metabolism or
clearance (to assess the disease).
• It gives an idea of the time to attain a steady state
concentration.
• It helps in calculating the total clearance.
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Factors affecting half-life
• Renal excretion
• Liver metabolism
• Protein binding
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Pharmacodynamics
• Pharmacodynamics is the study of actions of the drugs on the
body and their mechanism of action, i.e. to know what drugs
do and how they do it.
• Drugs produce their effects by interacting with the
physiological system of the organisms. By such interaction
drugs can only modify the rate of function of various systems.
• e.g. drugs may increase or decrease the secretions.
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Actions of Drugs
Thus drugs act by
1. Stimulation
2. Depression
3. Irritation
4. Replacement
5. Anti-infective or cytotoxic action
6. Modification of the immune status
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Cont…
• Stimulation is the increase in activity of the specialized cells,
e.g. adrenaline stimulates the heart.
• Depression is the decrease in activity of the specialized cells,
e.g. quinidine depresses the heart.
• Irritation: This can occur on all types of tissues in the body and
may result in inflammation, corrosion and necrosis of cells.
• Replacement: drugs may be used for replacement when there
is deficiency of natural substances like hormones ,metabolites
or nutrients ,e.g. insulin in diabetes, iron in anemia, vit C in
scurvy.
• Anti –infective and cytotoxic action: drugs may act by
specifically destroying infective organism, e.g. penicillin,
cytotoxic effect on cancer cells.
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Cont…
• Modification of immune status: vaccines and sera act by
improving our immunity while immunosuppressants act by
depressing immunity, e.g. glucocorticoids.
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Mechanisms of Actions of Drugs
Drugs may act by one or more complex mechanism of action.
Fundamental mechanism of drug action may be:
• Through receptor
• Through enzymes and pumps
• Through ion channel
• By physical action
• By chemical interaction
• By altering metabolic processes
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Cont…
Through receptor
• Drugs may interact with specific receptor in the body.
Through enzymes and pumps
• Drugs may act by inhibition of various enzymes, thus
altering the enzyme –mediated reaction, e.g. Captopril
inhibits Angiotensin Converting enzyme.
Through ion channel
• Drugs may interfere with the movement of ions across
specific channels, e.g. Ca channel blocker , K channel blocker.
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Cont….
Physical action
• The action of drug could result from its physical properties.
e.g. absorption –activated charcoal in poisoning.
Chemical interaction
• Drugs may act by chemical reaction.
• Antacids - Neutralize gastric acids
Altering metabolic processes
• Drugs like antimicrobial alter the metabolic pathway in the
micro organism resulting destruction of organism, e.g.
sulfonamides interfere with bacterial folic acid synthesis.
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Receptor
• A receptor is a site on the cell with which an agonist binds to
bring about a change. Receptors are proteins. They may be
present in the cytoplasm or on the nucleus.
Functions of receptors
• The receptor has to identify the compound, and when the
compound binds to the receptor, it has to convey the message
to bring about a response.
• Agonist: An agonist is a substance that binds to the receptor
and produce a response.
• Antagonist: An antagonist is a substance that binds to the
receptor and prevents the action of agonist on the receptor.
• Partial agonist: It binds to the receptor but has low intrinsic
activity that is, produce partial response. 32
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Drug synergism and antagonism
When two or more drugs are given concurrently ,the effect may
be additive, synergistic or antagonistic.
• Additive effect: the effect of two or more drugs get added up
and the total effect is equal to the sum of their individual
actions, e.g. Ephedrine with theophylline in bronchial asthma.
• Synergism: when action of one drug is enhanced or facilitated
by another drug the combination is synergistic. Here the total
effect of the combination is greater than the sum of their
independent effect. It is often called ‘potentiation’ or supra-
additive effect, e.g. acetylcholine + Physostigmine.
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Antagonism
• One drug opposing or inhibiting the action of another drug is
antagonism. Based on the mechanism, antagonism may be
• Chemical antagonism ,
• Physiological antagonism ,
• Antagonism at the receptor level
– Reversible
– Irreversible
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Cont…
• Chemical antagonism: Two substances chemically interact to
result in inactivation of the effect, e.g. Antacid like aluminum
hydroxide neutralize gastric acids.
• Physiological antagonism: Two drugs act at different sites to
produce opposing effect, e.g. Insulin and glucagon have
opposite effects on the blood sugar level.
• Antagonism at the receptor level
• The antagonist inhibits the binding of the agonist to the
receptor. Such antagonism may be reversible or irreversible.
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Cont…
• Reversible competitive antagonism: The agonist and
antagonist compete for the same receptor. By increasing the
concentration of the agonist, the antagonism can be
overcome. It is thus reversible antagonism. Ach and atropine
compete at muscarinic receptor. The antagonism can be
overcome by increasing the concentration of Ach at the
receptor.
• Irreversible antagonism: The antagonist binds so firmly by
covalent bonds to the receptor that it dissociate slowly or not
at all. It block the agonist the blockade cannot be overcome
by increase the dose of agonist hence it is irreversible
antagonism, e.g. Adrenaline and phenoxybenzamine at alpha-
adrenergic receptor.
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Drug Effectiveness
• Dose-response (DR) curve
– Shows the relation
between drug dose and
magnitude of drug effect
• Drugs can have more than one
effect
• Drugs vary in effectiveness
– Different sites of action
– Different affinities for
receptors
• The effectiveness of a drug is
considered relative to its
safety (therapeutic index)
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• Effective dose (ED50) = dose at which 50% population shows
response
• Lethal dose (LD50) =dose at which 50% population dies
• TI = LD50/ED50, an indication of safety of a drug (higher is
better)
ED50 LD50
Therapeutic index
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ED50 = effective dose in 50% of population
100
50
0
DRUG DOSE
0 X
ED50
% subjects
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• Relative strength of response for a given dose
– Effective concentration (EC50) is the concentration of an
agonist needed to elicit half of the maximum biological
response of the agonist
– The potency of an agonist is inversely related to its EC50
value
• D-R curve shifts left with greater potency
Potency
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• Maximum possible effect
regardless of the dose in
relation to other agents
• Indicated by peak of D-R
curve
• Full agonist= 100% efficacy
• Partial agonist =50% efficacy
• Antagonist = 0% efficacy
Efficacy
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• Decreased response to
same dose with repeated
(constant) exposure
• or more drug needed to
achieve same effect
• Right-ward shift of D-R
curve
Tolerance
(desensitization)
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Trachyphylaxis
• Trachyphylaxis is the rapid development of tolerance. When
some drugs are administered repeatedly at short interval,
tolerance develops rapidly and is known as tachyphylaxis or
acute tolerance.
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Mechanisms of Tolerance
• Changes in drug availability at site of action (decreased
bioavailability)
• Decreased absorption
• Increased binding to depot sites
• Changes in drug-receptor interaction
• Down regulation of receptors
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Drug-drug Interactions
• Pharmacokinetic and pharmacodynamic
– With pharmacokinetic drug interactions, one drug affects
the absorption, distribution, metabolism, or excretion of
another.
– With pharmacodynamic drug interactions, two drugs have
interactive effects in the site of action.
– Either type of drug interaction can result in adverse effects
in some individuals.
– In terms of efficacy, there can be several types of
interactions between medications: cumulative, additive,
synergistic, and antagonistic.
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Response
High
Low
Time
Drug A
Drug B
The condition in which repeated administration of a drug may
produce effects that are more pronounced than those produced
by the first dose.
Cumulative Effects
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Response
High
Low
Time
A B
A + B
The effect of two chemicals is equal to the sum of the effect of
the two chemicals taken separately, e.g., aspirin and motrin.
Additive Effects
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Response
Hi
Lo
Time
A B
A + B
The effect of two drugs taken together is greater than the sum of
their separate effect at the same doses, e.g., ampicillin and
gentamicin in treating bacterial infection
Synergistic Effects
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Response
High
Low
Time
A B
A + B
The effect of two chemicals taken together is less than the sum of
their separate effect at the same doses
Antagonistic Effects
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Nurses Responsibilities
• Ensure the correct drug is administered by the right route
and in the right dose.
• History of allergy should be taken particularly before
parenteral administration of the drugs.
• Monitor the adverse effect.
• Drugs should be kept in safe place.
• Check the prescription, drug label and the patients name
before the administration of drugs.
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References
• Goyal RK, Parikh RK, Patel MM. A Text book of Hospital
Pharmacy.13th edition. Ahmedabad: BS Shah Prakashan;
2015. 101-123.
• Nand P, Khar RK. A Textbook of Hospital and Clinical
Pharmacy. Delhi: Birla publishers; 2009. 53-70.
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