UNIT I Part 2&3.pptx

Unit- I
Introduction to Pharmacology- Part-II
Pharmacokinetics – Absorption, Distribution,
metabolism, excretion
Ms. Kanchan Chouksey
Pharmacy, Medi-caps University, Indore
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BP 404 T Pharmacology I
Ms. Kanchan chouksey
 Unit I a. Introduction to Pharmacology
b. Pharmacokinetics
 Unit II a. Pharmacodynamics,
b. Adverse drug reaction,
c. Drug Interactions
d. Drug discovery and clinical evaluation of new drugs
 Unit III Pharmacology of drugs acting on Peripheral nervous system
 Unit IV Pharmacology of Drugs acting on Central Nervous system
 Unit V Pharmacology of Drugs acting on Central nervous system

Books
Text Books
 K.D. Tripathi A Text book of Pharmacology
 Sparsh gupta A textbook of Pharmacology
Reference Books
 Goodman and Gilman’s A Text book of Pharmacology
 Rang H.P., Dale M.M., A Text book of Pharmacology
 Lippincott A Text book of Pharmacology
Other Books
Sharma H.L. , Sharma K.K., A textbook of Pharmacology,
and many others

Receptor :
These are macromolecule or binding site
located on the surface or Inside the cell that
recognise the signal , molecule, or drug and
initiate the response
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chouksey

Agonist & Antagonist
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Agonist :
 Agonist facilitate the receptor response.
 An agonist is a mimetic of the natural ligand.
 It produces a similar biological effect as the natural ligand when it binds
to the receptor.
 It binds at the same binding site and leads in the absence of the natural
ligand , to either a full or partial response.
 In the latter case, it is called a partial agonist.
Ms. Kanchan
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The figure below shows the action of ligand,
agonist, and partial agonist:
Ms. Kanchan
chouksey

Antagonists:
 Antagonist inhibits receptor response.
 As there name implies, an antagonist inhibit the effects of the natural
ligand (hormone, neurotransmitter), agonist, partial agonist, and even
inverse agonists.
Ms. Kanchan
chouksey

Antagonist Types :
 Competitive Antagonist
 Non competitive Antagonist
A competitive antagonist binds to the same
site as the agonist but does not activate it,
thus blocks the agonist's action.
A non-competitive antagonist binds to an
allosteric (non-agonist) site on the
receptor to prevent activation of the
receptor.

Mechanism of Ligand, Agonist, Antagonist

The following terms are used in describing drug-
receptor interaction:
 Agonist- An agent which activates a receptor to produce an effect similar to that
of the physiological signal molecule.
 Inverse agonist -An agent which activates a receptor to produce an effect in the
opposite direction to that of the agonist.
 Antagonist- An agent which prevents the action of agonist on a receptor or the
subsequent response, but does not have any effect of its own.

Continue…
Partial agonist -
 An agent which activates a receptor to produce submaximal effect but
antagonizes the action of a full agonist.
Ligand -
 Any molecule which attaches selectively to particular receptors or sites.
 The term only indicates affinity or ability to bind without regard to functional
change: agonists and competitive antagonist are both ligands of the same receptor.

Graded dose–response relations
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chouksey
 As the concentration of a drug increases, its pharmacologic
effect also gradually increases until all the receptors are
occupied (the maximum effect).
 It is used to determine affinity, potency, efficacy

Affinity:
 A drug's affinity refers to the chemical forces that cause a substance to
bind its receptor.
 Intrinsic activity is a measure of the ability of a drug that is bound to
the receptor to generate an activating stimulus and produce a change
in cellular activity.
 Both agonists and antagonists can bind to a receptor.
Ms. Kanchan
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Continue…
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Potency :
Effective concentration (EC50) is the concentration of an agonist needed
to elicit half of the maximum biological response of the agonist.
Ms. Kanchan
chouksey
E.g., Highly potent drug -
fentanyl, alprazolam , evokes a
given response at low
concentrations
while a drug of
lower potency like diazepam,
ziprasidone, evokes the same
response only at higher
concentrations

Efficacy:
Efficacy is a drug's capacity to produce an effect
Ms. Kanchan
chouksey
E.g.-
1. Diuretic drugs : Furosemide
eliminates much more salt and
water through urine than
hydrochlorothiazide.
2. Analgesics : aspirin is less potent
as well as less efficacious than
Morphine
3. Sedative : Diazepam is less
efficacious than pentobarbitone

Drug Dependence, Tolerance & Addiction
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Drug Tolerance :
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 It refers to the requirement of higher dose of a drug to produce a given
response.
 Loss of therapeutic efficacy after prolonged/intensive use of a drug.
 Like sulfonylureas in type 2 diabetes , Beta-2 agonists in bronchial
asthma
 Example : Before X drug 500 mg Response
Tolerance 800mg Response

Drug tolerance may be:
Natural
 The species/individual is inherently less sensitive to the drug.
E.g. rabbits are tolerant to atropine, Hyporesponsive people for Beta blocker.
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Acquired :
 This is a result of repeated use of drug in an individual was initially responsive for
the same drug.
 Body is capable of developing tolerance to most drugs, but the phenomenon is very
easily recognized in the case of CNS depressants.
 E.g.:
• CNS Depressant – like chlorpromazine ( sedative action ), Analgesics (Morphine) ,
Alcohol
Note : Higher dose is required for the effect of the same drug
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Cross tolerance
 One drug causes tolerance to other given drug but only when both has same
pharmacological activity
 It is the development of tolerance to pharmacologically related drugs
E.g.- alcoholics are relatively tolerant to barbiturates and general
anaesthetics
Why ?
Because frequent consumption of alcohol develops tolerance for
Barbiturates and General anesthetics ( Higher dose is required )
Ms. Kanchan
chouksey

Drug dependence :
 It is an altered physiological state produced by repeated administration of a
drug which necessitates the continued presence of the drug to maintain
physiological equilibrium.
 This has been earlier termed 'physical dependence’ but is now simply called
'dependence '
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chouksey

Continue…
 This is due to adaptation of the nervous system to function normally in the
presence of the drug, it has been also called 'neuroadaptation' .
 Drugs producing dependence are - opioids, barbiturates, alcohol
 Opioid dependence causes withdrawal symptoms, which makes it difficult to
stop taking them.
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chouksey

Drug addiction
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 A person is said to have developed 'drug addiction' when he/she believes
that optimal state of well being is achieved only through the actions or
the drug.
 The subject feels emotionally distressed if the drug is not taken.
 It often starts as liking for the drug effects and progresses to compulsive
drug use in some individuals who lose control and cannot stop taking the
drug, even if they known it to be harmful.

Continue…
 This was earlier termed 'psychological dependence'.
 However, to avoid confusion, the widely understood term 'drug addiction' is
used now.
 Drug addiction is a pattern of compulsive drug use characterized by
overwhelming involvement with the use of a drug.
 Amphetamines, cocaine, are CNS stimulants drugs which produce
addiction but Little/no dependence.
 Results : Feeling happy, Sexual arousal , fast heart beat , pupil dilation
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Tachyphylaxis
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 When some drugs administered repeatedly at short intervals, the cell
receptors get blocked up and pharmacological response to that drug
decreased.
 The decreased response cannot be reversed by increasing the dose this
phenomenon is called tachyphylaxis or acute tolerance
 E.g. ephedrine given repeated dose at short intervals in the treatment
of bronchial asthma may produce very less response due to
tachyphylaxis

Idiosyncrasy-
 Non-immunological hypersenstivity of drug in specific individual without
connection to pharmacological toxicity.
 Idiosyncrasy refers to genetically determined abnormal reactivity to a chemical.
 Idiosyncrasy is also called as allergy.
 An extraordinary response to a drug which is different from its characteristic
pharmacological action is called idiosyncrasy.
 E.g. small quantity of aspirin may cause gastric hemorrhage.
 E.g. some persons are sensitive to penicillin and sulphonamide because they
produce severe toxic effect.

Drug allergy (hypersensitivity)
 It is an immunologically mediated reaction.
 The symptoms may appear even with much smaller doses and have a
different time course of onset and duration.
 This is also called drug hypersensitivity.
 The target organs primarily affected in drug allergy are skin, airways, blood
vessels, blood cells and gastrointestinal tract.
Ms. Kanchan
chouksey

Continue…
 The drug or its metabolite acts as an antigen (AG)
 They induce production of antibody (AB)/sensitized lymphocytes.
 A particular drug can produce different types of allergic reactions in different
individuals, while widely different drugs can produce similar reaction.
 Example : Penicillin causes anaphylaxis, methyldopa cause hemolytic
anemia
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chouksey

Pharmacokinetics (The life cycle of a Drug)
 Pharmacokinetics is the quantitative study of drug movement in,
through and out of the body.
 Pharmacokinetics: Pharmakon - drug and Kinesis - motion
 The intensity of response is related to concentration of the drug at
the site of action.
 Pharmacokinetic - determine four pharmacokinetic properties determine
the onset, intensity & duration of drug action.

Pharmacokinetics :
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Pharmacokinetics: Membrane Transport, Absorption
and Distribution of Drugs
All pharmacokinetic processes involve transport of the drug across biological
membranes.
Biological membrane:

Biological membrane:
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 Biological membranes carry out functions that are indispensable for life.
 They provide a barrier against the extracellular environment.
 They also give shape to the cell, creating a matrix for insertion of proteins,
storing and transmitting energy, receiving and amplifying signals,

Structure of Biological membrane Composition:
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Biological membrane Composition:
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All Biological membrane are composed of mainly lipid and protein
molecule:
Three major types of lipids in cell membrane are:
 Phospholipid -The most abundant.
 Cholesterol- responsible for stabilizing the membrane.
 Glycolipid- found at the external surface of the membrane.

Membrane transport :
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Membrane transport of drugs/nutrients :
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Continue…
 All of the lipids are described as being amphipathic as they have a
hydrophilic (water- loving) end and a hydrophobic (water-hating) end to
the molecule.
 The proteins within the membrane are largely concerned with the
transport of molecules across the membrane.
Ms. Kanchan
chouksey

Continue…
Drugs are transported across the membranes by:
(a) Passive diffusion
(b) filtration : for low molecular weight ( less than 100)
(c) Specialized transport
(d) Active transport
Ms. Kanchan
chouksey

Passive diffusion:
 The drug diffuses across the membrane in the direction of its concentration
gradient (high to low).
 The membrane playing no active role in the process.
 This is the most important mechanism for majority o f drugs.
 The drugs moves from high concentration to low concentration untill the
equilibrium is maintained between extracellular and intracellular fluid
 It does not require energy and depends on concentration.
Ms. Kanchan
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Continue…
 Lipid soluble drugs diffuse by dissolving in the lipoidal matrix of the
membrane the rate of transport being proportional to the lipid
 Water partition coefficient of the drug.
 A more lipid-soluble drug attains higher concentration in the membrane and
diffuses quickly.
 Also, greater the difference in the concentration of the drug on the two sides of
the membrane, faster is its diffusion.
Ms. Kanchan
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Continue..
b) Filtration : for molecule of low molecular weight (less than 100) through 7 Å pores of membrane
(1micrometer = 10000 Aangstrom)
Example : Urea , ethylene glycol (additives)
c) Bulk flow : Passage across capillary wall which pore size of 40Å.
d)Active transport:
 Require energy (ATP)
 It work against concentration gradient ( Higher to lower concentration)
 Example : Methyldopa, Levodopa
e) Facilitated diffusion : through carrier proteins
f) Endocystosis ( outside to inside) and exocytosis( Inside to outside) through pinocytosis, phagocytosis
Ms. Kanchan
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Active transport :
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chouksey

Filtration
 Filtration is passage of drugs through aqueous pores in the membrane or
through paracellular spaces.
 This can be accelerated if hydrodynamic flow of the solvent is occurring under
hydrostatic or osmotic pressure gradient, e.g. across most capillaries including
glomeruli.
Ms. Kanchan
chouksey

Specialized transport
 This can be carrier mediated or by vesicular transport.
 Endocytosis & Exocytosis-
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ABSORPTION
 Absorption is the transfer of a drug from the site of administration to the
bloodstream.
 The rate and extent of absorption depend on the environment where the drug
is absorbed, chemical characteristics of the drug, and the route of
administration (which influences bioavailability).
 Routes of administration other than intravenous may result in partial
absorption and lower bioavailability

Factors influencing drug absorption:
 Lipid solubility of drug
 pH of the medium ( stomach & intestine)
 pKa of the drug
Ms. Kanchan
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Lipid solubility of the drug
 Drugs which are lipophilic easily cross the membrane
 Drugs which are lipophobic / Hydrophilic have problem crossing membrane
 This is the major source of variation in drug diffusion or absorption
 Only non ionized drug ( non-polar) diffuse across the cell membrane
 Non polar drugs are lipid soluble
 Polar drugs are water soluble , they cannot absorbs biological membrane
 Lipid soluble = Non ionized molecule( NaCl)
 Hydrophillic = Ionized molecule (Na+, Cl-)
Ms. Kanchan
chouksey

Effect of pH on drug absorption :
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chouksey
 Acidic drug better absorbed in acidic media.
 Basic drug better absorbed in basic media.
 Acidic drugs ( aspirin) are better absorbed in stomach in acidic media.
 Basic drugs better absorbed in intestine ( alkaline media).

Bioavailability
 Bioavailability is the rate and extent to which an administered drug reaches
the systemic circulation.
 Or Bioavailability is the rate and extent of drug absorbs from its dosage form
that reach to the systemic circulation.
 For example, if 100 mg of a drug is administered orally and 70 mg is absorbed
unchanged, the bioavailability is 70%.
Ms. Kanchan
chouksey

Objectives of Bioavailability studies:
Ms. Kanchan
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 Primary stages of development of a suitable dosage form
 Determination of influence of excipients (Stability and
solubility) and interaction with other drugs on the
efficiency of absorption

Factors affect Bioavailability:
Ms. Kanchan
chouksey

First-pass hepatic metabolism:
 When a drug is absorbed from the GI tract, it enters the portal circulation
before entering the systemic circulation.
 If the drug is rapidly metabolized in the liver or GIT wall during this initial
passage, the amount of unchanged drug entering the systemic circulation is
decreased.
 This is referred to as first-pass metabolism.
 Cytochrome P-450 enzymes metabolized many drugs.
Ms. Kanchan
chouksey

Continue…
 First-pass metabolism by the intestine or liver limits the efficacy of many oral
medications.
 For example, more than 90% of nitroglycerin (HF, HBP) is cleared during
first-pass metabolism.
 Hence, it is primarily administered via the sublingual or transdermal route
 Drugs with high first-pass metabolism should be given in doses sufficient
to ensure that enough active drug reaches the desired site of action.
Ms. Kanchan
chouksey

DISTRIBUTION
Drug distribution is the process by which a drug reversibly leaves the bloodstream and
enters the extracellular fluid and the tissues.
Phases of distribution:
First phase :
 Reflect cardiac output and blood flow –
 Thus heart , liver, kidney, and brain receive most of the drugs during the first few
minutes after absorption
Second phase:
 Deliver to muscle, skin, adipose is slower and involves a far large fraction of the
body mass.
Ms. Kanchan
chouksey

Drug reservoirs:
Body compartment where a drug can accumulate are reservoirs and have
dynamic effect on drug availability
1. Plasma proteins (albumins) as reservoirs (bind drug)
2. Cellular reservoirs:
 Adipose (lipophillic drug)
 Bone ( crystal )
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Drug Distribution:
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Drugs Binding primarily to albumin
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 Barbiturates
 Benzodiazepines
 Digitoxin
 Penicillins
 Streptomycin
 sulphonamindes

Volume of distribution:
 The volume of distribution Vd - is defined as the fluid
volume that is required to contain the entire drug in the
body at the same concentration measured in the plasma.
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Volume of distribution :
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Volume of distribution :
Ms. Kanchan
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100 mg
water
Vd= Amount of drug given
in body / Concentration of
drug in plasma
Vd= 100/20= 5 L
20mg / L
Concentration = Weight /
volume ( mg / L)

Ms. Kanchan
chouksey
 Drug metabolism is the term used to describe the
biotransformation of pharmaceutical substances in
the body so that they can be eliminated more easily.
 It is the enzymatic conversion from one chemical form of
a substance to another.
 Metabolism is an essential pharmacokinetic process
which converts lipid soluble or non-polar compounds to
water soluble or polar compounds that they are excreted
by various processes.
Metabolism or Biotransformation:

Phases of Metabolism
 Phase I: Non-synthetic reactions such as cleavage (e.g. oxidation,
reduction, hydrolysis), formation or modification of a function group.
 Phase II: Synthetic reactions such as conjugation with an endogenous
substance (e.g. sulfate, glycine, glucuronic acid).
Examples:
 Oxidation – phenytoin, barbiturates
 Hydrolysis- Aspirin
 Reduction- Benzodiazepines
Ms. Kanchan
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Drug metabolism pathway :
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Phase I and Phase II enzymes:
Phase I enzymes:
 Cytochrome P450, Esterase, Alcohol dehydrogenase
,Monoamine oxidase
Phase II enzymes:
 Uridine Diphosphate-glucuronosyl transferase (UDPGT)
(Catalyse the covalent addition of glucuronic acid with lipophilic
chemicals)
 Sulfo transferase ( sulphonation increases water solublity of
lipophilic drugs)
Ms. Kanchan
chouksey

Metabolic enzyme:
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Microsomal enzyme
 Found in smooth endoplasmic reticulum of liver cells.
 Example: CYP- 450, mono oxygenase
Non- microsomal enzymes:
 Found in cytoplasm and mitochondria of liver cells.
 Example: Alcholol dehydrogenase,

Excretion :
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chouksey

Drugs and their metabolites are excreted in:
1. Urine –
 Drug excretion in urine occurs via the kidney.
 It is the most important channel of excretion for majority of drugs.
2. Faeces –
 Apart from the unabsorbed fraction, most of the drug present in faeces is
derived from bile.
 Liver actively transports into bile organic acids
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Continue..
3. Milk –
 The excretion or drug in milk is not important for the mother.
 Most drugs enter breast milk by passive diffusion.
 As such. more lipid soluble and less protein bound drugs cross better.
 Milk has a lower pH (7.0) than plasma, basic drugs are somewhat more concentrated
in it.
Ms. Kanchan
chouksey

Enzyme Inducers and Enzyme inhibitors :
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Kinetics of drug metabolism and elimination:
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Questions
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chouksey

Thank You
Great God, Medi-Caps, All the attendees

UNIT I Part 2&3.pptx

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