General Pharmacology - Final.pptx

General Pharmacology
Sewasew Amsalu (MD)

Learning Objectives
• Define the terms Pharmacology, Pharmacokinetics,
Pharmacodynamics.
• List the various routes of administration of drugs.
• List factor effect on pharmacokinetics.
• Describe some factors that dedicate of the dose.
Sewasew Amsalu (MD)

Sewasew Amsalu (MD)

The word pharmacology is derived from the Greek
words pharmacon (drug or poison) and logos (science).
Pharmacology deals with the fate and actions of drugs at various
levels (molecular, cellular, organ, and whole body) in any animal
species.
Study of drugs, their actions, dosage, therapeutic uses, adverse
effects
.
Sewasew Amsalu (MD)

What is Pharmacology?
• Integrated medical science involving chemistry,
biochemistry, anatomy, physiology, microbiology, and
more
• Study of drugs, their actions, dosage, therapeutic
uses, adverse effects
• Drug therapy is directly linked to the pathophysiology
of a particular disease.
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1. Pharmacodynamics - how
the drugs act on the body?
2. Pharmacokinetics - how
the body act on the drugs?
3. Drug Indications and Application
4. Drug Interactions
5. Unwanted (adverse) effects
Object of Pharmacology
Sewasew Amsalu (MD)

Disciplines of Pharmacology
• Pharmacodynamics: drug induced responses.
What the drug does to the body .
• Pharmacokinetics: drug amounts at different sites after administration.
what the body does to the drug
(We will discuss this in more detail later in this unit)
• Pharmacotherapeutics: drug choice & application
• Toxicology: body’s response to drugs
• Pharmacy :The preparation, etc of therapeutic drugs
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As per WHO Scientific group
“Any Substance or product that is used and intended to be used to
modify or explore the physiological system or pathological state
for the benefit of the recipient “
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• Drug
Word “Drug” comes from a French word “Drogue” which means
“a dry herb”. It is the single active chemical entity present in a
medicine that is used for diagnosis, prevention, treatment/cure
of a disease.
The drugs are chemical substances which are
applied to or introduced into a living organism to
treat, prevent or diagnose of diseases, and as well
as to change some physiological functions (e.g.
reproduction).
Sewasew Amsalu (MD)

Sources of Drugs
• 50% of Drugs have synthetic or SS origin.
• 25% are received from plants and they include:
• alkaloids,
• glycosides,
• vitamins,
• bioflavonoids, etc
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Natural Drugs: these are the drugs which comes from certain natural
sources. They are further categorized as follows:
• Minerals Drugs
• Animal Drugs
• Plant Drugs
• Microorganism Drugs
Semi synthetic Drugs: these are the natural drugs with slight
modification.
Synthetic drugs: these are the drugs which can be synthesized by various
chemical processes.
Sewasew Amsalu (MD)

Drug Nomenclature and Classification
• Each drug has a generic name, a trade name, and a chemical name
• Generic name: unique, official, simple name for a specific drug
• For example, acetaminophen
• Trade, proprietary, or brand name
• For example, Tylenol
• Chemical name: chemical component
• For example, N-(4-hydroxyphenyl) acetamide
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Examples of Drug Nomenclature
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PHARMACODYNAMICS
WHAT DRUGS DO TO THE ORGANISM
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Pharmacodynamics:
(1) How the drugs act on the body?
(2) The mechanism of action of drug and its
effects.
The mechanism of action represents the interaction between
drug molecules and biological structures of the organism.
The effect represents the final results from the drug action.
The effect can be observed and measured, but not the action.
Sewasew Amsalu (MD)

PHARMACODYNAMICS
• The part of pharmacology that concerned with the biocemical
and physiological EFFECTS of drugs and their MODE OF ACTION
• The effect of the drug on the body.
• It includes the dose-effect relationship, factors modifying drug
effects, dosage, drug toxicity
• Most drugs exert effects on several organs or tissues, and have
unwanted as well as therapeutic effects.
• There is a dose-response relationship for wanted and unwanted
(toxic) effects.
Sewasew Amsalu (MD)

Site & Mechanisms Of Drug Action
•Therapeutic and toxic effects of drugs result from their
interactions with molecules in the patient.
•Most drugs act by associating with specific macromolecules
in ways that alter the macromolecules’ biochemical or
biophysical activities.
•This idea, more than a century old, is embodied in the term
receptor: the component of a cell or organism that
interacts with a drug and initiates the chain of events
leading to the drug’s observed effects.
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•Target/site of drug action (e.g.
genetically-coded proteins
embedded in neural
membrane)
•The drug–receptor complex
initiates alterations in
biochemical and/or molecular
activity of a cell by a process
called signal transduction
Receptors
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• Most of the drugs act by interacting with a cellular component
called receptor. Some drugs act through simple physical or chemical
reactions without interacting with any receptor.
• Receptors are protein molecules present either on the cell surface
or with in the cell e.g. adrenergic receptors, cholinoceptors, insulin
receptors, etc
• Many drugs are similar to or have similar chemical groups to the
naturally occurring chemical and have the ability to bind onto a
receptor where one of two things can happen- either the receptor
will respond or it will be blocked.
Sewasew Amsalu (MD)

Implications of drug-receptor interaction
• Drugs can potentially alter rate of any bodily/brain
function
• Drugs cannot impart entirely new functions to cells
• Drugs do not create effects, only modify ongoing ones
• Drugs can allow for effects outside of normal
physiological range
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• Receptors Are Responsible For Selectivity Of Drug Action.
•Receptors Mediate The Actions Of Pharmacologic Agonists
And Antagonists.
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MOLECULAR
ASPECTS OF
SPECIFIC
DRUG ACTION
How drugs act?
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SITE OF DRUG ACTION:
• - A drug may act:
(i) Extracellularly e.g: osmotic diuretics, plasma expanders.
(ii) On the cell surface e.g.: digitalis, penicillin, catecholamines
(iii) Inside the cell e.g.: anti-cancer drugs, steroid hormones.
Main specific targets for drug actions are:
 DNA
 microbial organelles
 target macroproteins
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• receptors (> 150 types
with many subtypes)
• ion channels
• enzymes
• carrier molecules
 Target macroproteins
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SIGNAL TRANSDUCTION
• Drugs act as signals, and their receptors act as signal detectors. Many
receptors signal their recognition of a bound ligand by initiating a series of
reactions that ultimately result in a specific intracellular response.
• Cells have different types of receptors, each of which is specific for a
particular ligand and produces a unique response.
• The magnitude of the response is proportional to the number of drug–
receptor complexes:
• Drug + Receptor ←→ Drug–receptor complex →Biologic effect
Sewasew Amsalu (MD)

• The richest sources of therapeutically exploitable pharmacologic
receptors are proteins that are responsible for transducing extracellular
signals into intracellular responses.
• These receptors may be divided into four families:
1) ligand-gated ion channels,
2) G protein–coupled receptors,
3) enzyme–linked receptors, and
4) intracellular receptors
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Transmembrane ligand-gated ion channels
• Are responsible for regulation of the flow of ions across cell membranes
• The activity of these channels is regulated by the binding of a ligand to the
channel. Response to these receptors is very rapid, enduring for only a
few milliseconds.
For example,
• stimulation of the nicotinic receptor by acetylcholine results in sodium
influx, generation of an action potential, and activation of contraction
in skeletal muscle.
• Benzodiazepines, on the other hand, enhance the stimulation of GABA
receptor by GABA, resulting in increased chloride influx and
hyperpolarization of the respective cell.
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Transmembrane G protein–coupled receptors
• G protein–coupled receptors are the most abundant type of receptors,
and their activation accounts for the actions of most therapeutic agents.
• The extracellular domain of this receptor usually contains the ligand-
binding area (a few ligands interact within the receptor transmembrane
domain).
• Intracellularly, these receptors are linked to a G protein (Gs, Gi, and
others) having three subunits, an αsubunit that binds guanosine
triphosphate (GTP) and a βγsubunit .
• Work with a secondary messenger system
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Enzyme-linked receptors
• These receptors also have cytosolic enzyme activity as an integral
component of their structure and function
• Binding of a ligand to an extracellular domain activates or inhibits this
cytosolic enzyme activity.
• The most common enzyme-linked receptors (epidermal growth factor,
platelet-derived growth factor, atrial natriuretic peptide, insulin, and
others) are those that have a tyrosine kinase activity as part of their
structure
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4. Intracellular receptors
• differs considerably from the other three in that the receptor is entirely
intracellular, and, therefore, the ligand must diff use into the cell to interact
with the receptor
• This places constraints on the physical and chemical properties of the
ligand, because it must have sufficient lipid solubility to be able to move
across the target cell membrane.
For example,
• steroid hormones exert their action on target cells via this receptor
mechanism.
• the enzyme dihydrofolate reductase is the target of antimicrobials such
astrimethoprim, and the 50ssubunit of the bacterial ribosome is the target of
macrolide antibiotics such as erythromycin
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DOSE-RESPONSE
RELATIONSHIPS
(introduction)
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Graded dose–response relations
• As the concentration of a drug increases, the magnitude of its
pharmacologic effect also increases. The response is a graded
effect, meaning that the response is continuous and gradual.
• When a logarithm of dose as abscissa and responses as ordinate
are constructed graphically, the “S” shaped or sigmoid type curve
is obtained.
• The lowest concentration of a drug that elicits a response is
minimal dose, and the largest concentration after which further
increase in concentration will not change the response is the
maximal dose.
Sewasew Amsalu (MD)

•Affinity: ability of drug to bind to receptor, The affinity of a
drug is its ability to bind to the receptor.
•A drug, which is able to fit onto a receptor, is said to have affinity
for that receptor.
•The intrinsic activity of a drug is its ability after binding to the
receptor to produce effect.
•Intrinsic activity is a drug ability to stimulate receptor and cause
specific effect
•An agonist has both an affinity and efficacy whereas antagonist has
affinity but not efficacy or intrinsic activity.
Sewasew Amsalu (MD)

• Potency: a measure of the amount of drug necessary to produce an
effect of a given magnitude.
• The concentration of drug producing an effect that is 50 percent of
the maximum is used to determine potency and is commonly
designated as the EC50.
• Efficacy: a measure of how well a drug produces a response
(effectiveness), shown by the maximal height reached by the curve.
•The efficacy of a drug is its ability to produce maximal response.
• This is the ability of a drug to elicit a response when it interacts with a
receptor.
• A drug with greater efficacy is more therapeutically beneficial than
one that is more potent Sewasew Amsalu (MD)

• ONSET – the period between the moment of drug introduction to the
organism and the beginning of its action
• DURATION OF DRUG ACTION – the period then specific effects of the
drug are maintained
• WIDENESS of therapeutic action (therapeutic window) – the
distance between minimum therapeutic and minimum toxic doses of
drug
Sewasew Amsalu (MD)

AGONISTS
• An agonist binds to a receptor and produces a biologic response.
• An agonist may mimic the response of the endogenous
ligand on the receptor, or
• It may elicit a different response from the receptor and its
transduction mechanism.
A. Full agonists-
• If a drug binds to a receptor and produces a maximal biologic
response that mimics the response to the endogenous ligand, it
is known as a full agonist
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• For example, phenylephrineis an agonist at α1-adrenoceptors, because
it produces eff ects that resemble the action of the endogenous ligand,
Norepinephrine.
B. Partial agonists
• Partial agonists have efficacies (intrinsic activities) greater than
zero but less than that of a full agonist.
• Even if all the receptors are occupied, partial agonists cannot
produce an Emax of as great a magnitude as that of a full
agonist.
• partial agonists produce a lower response, at full receptor
occupancy, than do full agonists.
Sewasew Amsalu (MD)

ANTAGONISTS
• Antagonists are drugs that decrease or oppose the actions of
another drug or endogenous ligand.
• An antagonist has no effect if an agonist is not present.
• Many antagonists act on the identical receptor macromolecule
as the agonist.
• Antagonists, however, have no intrinsic activity and, therefore,
produce no effect by themselves.
• Although antagonists have no intrinsic activity, they are able to
bind avidly to target receptors because they possess strong
affinity.
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A. Competitive antagonists
• If both the antagonist and the agonist bind to the same site on the
receptor, they are said to be “competitive.”
• The competitive antagonist will prevent an agonist from binding to its receptor
and maintain the receptor in its inactive conformational state.
• For example, the antihypertensive drug terazosincompetes with the
endogenous ligand, norepinephrine, at α1-adrenoceptors
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B. Noncompetitive antagonist
There are two mechanisms by which an agent can act as a noncompetitive
antagonist.
Direct receptors by covalent bond or allosteric receptors
• Competitive antagonists increase the ED50, whereas irreversible antagonists
do not (unless spare receptors are present).
• Thus, a fundamental difference between a competitive and
noncompetitive antagonist is that competitive antagonists reduce agonist
potency, whereas noncompetitive antagonists reduce agonist efficacy.
Sewasew Amsalu (MD)

Affinity Intrinsic Efficacy Selec-
activity tivity
Agonists + + ++ + +
(Morphine)
Antagonists + - - +
(Naloxon)
Partial
agonists
(Pentazocine) + + - +
Drugs
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QUANTAL DOSE–RESPONSE RELATIONSHIPS
• Reading Assignmet
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ROUTE OF DRUG ADMINISTRATION
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•Enteral administration, or administering a drug by mouth, is
the safest and most common, convenient, and economical
method of drug administration.
•When the drug is given in the mouth, it may be swallowed,
allowing oral delivery, or it may be placed under the tongue
(sublingual), facilitating direct absorption into the
bloodstream.
Sewasew Amsalu (MD)

A.ORAL ROUTE
It is the most common and acceptable route for drug administration.
Advantage
• Convenient - portable, safe, no pain,
• can be self-administered.
• Cheap - no need to sterilize (but must
be hygienic of course)
• Have a low risk of systemic infections
• overdose by the oral route may be
overcome with antidotes
DisAdvantage
• the low pH of the
• stomach may inactivate
some drugs.
• First-pass effect
• Sometimes inefficient
• Food
• Local effect
Sewasew Amsalu (MD)

Enteric-coated preparations:
• An enteric coating is a chemical
envelope that resists the action of
the fluids and enzymes in the
stomach but dissolves readily in the
upper intestine.
• Such coating is useful for certain
groups of drugs (for example,
omeprazole) that are acid
unstable.
Extended-release preparations
• Extended-release medications
have special coatings or
ingredients that control how fast
the
• drug is released from the pill
into the body.
• Having a longer duration of
action may improve patient
compliance, because the
medication does not have to be
taken as often.
Sewasew Amsalu (MD)

Sublingual
• Placement under the tongue allows a drug to diff use into the capillary
network and, therefore, to enter the systemic circulation directly.
• Sublingual administration of an agent has several advantages, including rapid
absorption, convenience of administration, low incidence of infection, bypass
of the harsh gastrointestinal (GI) environment, and avoidance of first-pass
metabolism (the drug is absorbed into the superior vena cava).
• The buccal route (between cheek and gum) is similar to the sublingual route.
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Rectal
• Because 50 percent of the drainage of the rectal region bypasses the
portal circulation, the biotransformation of drugs by the liver is minimized
with rectal administration.
• Drugs can be given in the form of solid or liquid.
- Suppository: It can be used for local (topical) effect as well as systemic
effect, e.g. indomethacinfor rheumatoid arthritis.
- Enema: Retention enema can be used for local effect as well as systemic
effect. The drug isabsorbed through rectal mucous membrane and produces
systemic effect, e.g. diazepam for status epilepticus in children.
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Parenteral
• The parenteral route introduces drugs directly across the
body’s barrier defenses into the systemic circulation.
• Parenteral administration is used for drugs that are poorly
absorbed from the GI tract (for example, heparin) and for agents
that are unstable in the GI tract (for example, insulin).
• Parenteral administration is also used for treatment of unconscious
patients and under circumstances that require a rapid onset of
action.
• In addition, these routes have the highest bioavailability and are
not subject to first-pass metabolism or harsh GI environments.
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• Parenteral administration provides the most control over the
actual dose of drug delivered to the body.
• However, these administrations are irreversible and may cause
pain, fear, local tissue damage, and infections.
• The three major parenteral routes are intravascular (intravenous or
intra-arterial), intramuscular, and subcutaneous
Sewasew Amsalu (MD)

Intravenous (IV)
• IV injection is the most common parenteral route.
• For drugs that are not absorbed orally, such as the neuromuscular blocker
atracurium, there is often no other choice.
• IV delivery permits a rapid effect and a maximum degree of control over the
circulating levels of the drug.
• Drugs are administered as:
a) Bolus: Single, relatively large dose of a drug injected rapidly or slowly as a
single unit into a vein. For example, i.v. ranitidine in bleeding peptic ulcer.
b) Slow intravenous injection: For example, i.v. morphine in myocardial
infarction.
c) Intravenous infusion: For example, dopamine infusion in cardiogenic
shock; mannitol infusion incerebral oedema; fluids infused intravenously in
dehydration. Sewasew Amsalu (MD)

Intramuscular (IM)
• Drugs administered IM can be in aqueous solutions, which are absorbed
rapidly , or in specialized depot preparations, which are absorbed slowly.
• The muscles that are usually used are detoid,triceps, Gluteus,. Maximus,
rectus, femurs depending on the specie of animal
• Absorption of drug from gluteal region is slow especially in females due to
high fat deposition
• Deep I/M injections are less painful than I/M injections on arm due to high
fat content. Sewasew Amsalu (MD)

Subcutaneous (SC)
• This route of administration, like IM injection, requires absorption
via simple diffusion and is somewhat slower than the IV route.
• SC injection minimizes the risks of hemolysis or thrombosis associated
with IV injection and may provide constant, slow, and sustained
effects.
• This route should not be used with drugs that cause tissue irritation,
because severe pain and necrosis may occur.
Sewasew Amsalu (MD)

INTRATHECAL ROUTE
• Drug is injected into the subarachnoid space (spinal anaesthetics, e.g.
lignocaine; antibiotics, e.g. amphotericin B,etc.).
• The blood-brain barrier typically delays or prevents the absorption of
drugs into the central nervous system (CNS). When local, rapid effects are
needed, it is necessary to introduce drugs directly into the cerebrospinal
fluid.
• For example, intrathecal ampho tericin Bis used in treating cryptococcal
meningitis
Sewasew Amsalu (MD)

INTRA-ARTICULAR ROUTE
• Drug is injected directly into the joint space, e.g. hydrocortisone injection for
rheumatoid arthritis.
• Strict aseptic precautions should be taken. Repeated administration may cause damage
to the articular cartilage.
TRANSDERMAL ROUTE
The drug is administered in the form of a patch or ointment that delivers the drug into
the circulation for systemic effect.
For example, scopolamine patch for sialorrhoea and motion sickness, nitroglycerin
patch/ointment for angina, oestrogen patch for hormone replacement therapy (HRT).
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LOCAL ROUTES And inhalational routes
• Reading Assignment
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Pharmacokinetics
How does the human body
act on the drugs?
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PHARMACOKINETICS
(The Life Cycle of a Drug)
THE PART OF PHARMACOLOGY THAT CONCERNED WITH THE
ABSORBTION,
DISTRIBUTION,
METABOLISM (BIOTRANSFORMATION)
AND EXCRETION OF DRUGS
WHAT THE ORGANISM DOES TO THE DRUGS
Sewasew Amsalu (MD)

Pharmacokinetics is the quantitative study of
drug movement in, through and out of the body.
Intensity of effect is related to the concentration
of the drug at the site of action, which depends
on its pharmacokinetic properties.
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All pharmacokinetics processes involve transport
of the drug across biological lipid membrane.
Passive diffusion
through lipid
Filtration Carrier transport
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I. ABSORPTION
• Absorption is the process by which the drug enters in to the systemic
circulation from the site of administration through biological barrier.
• In case of intravenous or intra-arterial administration the drug bypasses
absorption processes and it enters into the circulation directly.
• For IV delivery, absorption is complete. That is, the total dose of drug
administered reaches the systemic circulation (100% bioavailability).
• Depending on their chemical properties, drugs may be absorbed from the
GI tract by passive diffusion, facilitated diffusion, active transport, or
endocytosis
Sewasew Amsalu (MD)

•I.V. administration requires no absorption
Sewasew Amsalu (MD)

• The vast majority of drugs gain access to the body by this mechanism.
• Water-soluble drugs penetrate the cell membrane through aqueous
channels or pores, whereas lipid-soluble drugs readily move across most
biologic membranes due to their solubility in the membrane lipid bilayers
Sewasew Amsalu (MD)

Factors Affecting Absorption of drug
Aqueous solubility.
• Drugs given in solid form must dissolve in the aqueous biophase before they
are absorbed.
• For poorly water soluble drugs (aspirin, griseofulvin) the rate of dissolution
governs the rate of absorption.
• If a drug is given as water solution, it is absorbed faster than the same given
in solid form or as a oily solution.
• Very hydrophilic drugs are poorly absorbed because of their inability to
cross the lipid-rich cell membranes.
• Paradoxically, drugs that are extremely hydrophobic are also poorly
absorbed, because they are totally insoluble in aqueous body fl uids
and, therefore, cannot gain access to the surface of cells.
Sewasew Amsalu (MD)

Concentration.Passive transport depends on the concentration gradient. A
drug given as concentrated solution is absorbed faster than dilute solution.
Area of absorbing surface.If the area is larger, the absorption is faster.
• small intestine has large surface area than stomach due to intestinal microvilli.
Vascularity of absorbing surface.Blood circulation removes the drug
from the site of absorption and maintains concentration gradient across the
membrane. Increased blood flow hastens drug absorption.
• greater blood flow increases bioavailability
• Intestine has greater blood flow than stomach
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• Dosage forms (depending on particle size and disintegration, ease of
dissolution).
(solution > suspension > capsule > tablet)
Sewasew Amsalu (MD)

Route of administration affects drug absorption,
because each route has its own peculiarities.
Oral application. Unionized lipid soluble drugs (e.g.ethanol) are
readily absorbed from GIT.
Acid drugs (aspi-rin, 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.
Sewasew Amsalu (MD)

Presence of fooddilutes the drug and retards absorption.
• Certain drugs form poorly absorbed complexes with food
constituents, e.g. tetracyclines with calcium present in milk.
• Food delays gastric emptying. Most drugs are absorbed better if taken on
an empty stomach.
• Highly ionized drugs, e.g. amikacin, gentamicin, neostigmine, are poorly
absorbed when given orally.
• Certain drugs are degraded in the GIT, e.g. penicillin G by acid, insulin by
peptidases, and are ineffective orally.
• Enteric coated tablets (having acid resistant coating) and sustained
released preparations can be used to overcome acid ability, gastric
irritancy and brief duration of action.
Sewasew Amsalu (MD)

Intestinal absorption:
- duodenum (B1, Fe2+)
- ileum (B12, A, D, E, K)
- large intestine
(water, Na+, Cl-, K+)
Sewasew Amsalu (MD)

Drugs can also alter absorption by gut wall effect: altering motility
(atropine, amitriptyline, pethidine, methoclopramide) or causing mucosal
damage (neomycin, methotrexate, reserpine, vinblastine).
Alteration of gut flora by antibiotics may disrupt the enterohepatic
recirculation of oral contraceptives and digoxin.
S.c. and i.m. application
By these routes the drug is deposited in the vicinity of the capillaries.
Lipid soluble drugs pass readily across the whole surface of the capillary
endothelium, but very large molecules are absorbed through lymphatics.
Sewasew Amsalu (MD)

• Many drugs not absorbed orally are absorbed parenterally.
• Absorption from s.c. site is slower than that from i.m. site, but both are
generally faster and more predictable than p.o. absorption. Application
of heat and muscular exercise accelerate drug absorption by increasing
blood flow.
• Application of vasoconstrictors (e.g. adrenaline) retard absorption.
• Many depot preparations (preparations with long action), such as
benzatine benzylpenicillin and protamine zinc insulin can be given by
these routes.
Topical applications(skin, cornea, mucous membranes)
Systemic absorption depends on lipid solubility.
Only a few drugs significantly penetrate intact skin.
Sewasew Amsalu (MD)

• Nitroglycerine, hyoscine (scopolamine) and estradiol have been used
in this manner.
• Glucocorticosteroids(GCS) applied over extensive areas can
produce systemic effects and pituitary-adrenal suppression.
• Cornea is permeable to lipid soluble, unionized physo-stigmine but
not to highly ionized neostigmine.
• Similarly, the mucous membrane of the mouth,rectum and vagina
absorb lipophilic drugs, e.g. estrogen cream applied intravaginally has
producedgynecomastia in the male partner.
Sewasew Amsalu (MD)

Slow Absorption
• Orally (swallowed)
• through Mucus Membranes
– Oral Mucosa (e.g. sublingual)
– Nasal Mucosa (e.g. insufflated)
• Topical/Transdermal
(through skin)
• Rectally (suppository)
Sewasew Amsalu (MD)

Faster Absorption
• Parenterally (injection)
• Intravenous (IV)
• Intramuscular (IM)
• Subcutaneous (SC)
• Intraperitoneal (IP)
• Inhaled (through lungs)
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Fastest Absorption
• Directly into brain
– Intracerebral (into brain tissue)
– Intracerebroventricular (into brain
ventricles)
General Principle: The faster the absorption, the quicker the
onset, the higher the addictiveness, but the shorter the
duration Sewasew Amsalu (MD)

Bioavailability
• It is the rate and amount of drug that is absorbed from a given
dosage form and reaches the systemic circulation following non-
vascular administration.
• Bioavailability is the fraction of administered drug that reaches the
systemic circulation.
• Bioavailability of a drug injected i.v. is 100%, but is frequently lower
after oral ingestion, because:
a)The drug may incompletely absorb
b)The absorbed drug may undergo first pass metabolism in
intestinal wall and/or liver, or be excreted in bile.
Sewasew Amsalu (MD)

•The route of administration largely determines the latent
period between administration and onset of action.
•Drugs given by mouth may be inactive for the following
reasons:
a) Enzymatic degradation of polypeptides within the lumen of
the gastrointestinal tract e.g. insulin, ACTH.
b) Poor absorption through gastrointestinal tract e.g.
aminoglycoside antibiotic.
c) Inactivation by liver e.g. testosterone during first passage
through the liver before it reaches systemic circulation.
Sewasew Amsalu (MD)

Bioavailability
• What determines Absorption and bioavailability?
• Physical properties of the drug (hydrophobicity, pKa, solubility)
• The drug formulation (immediate release, delayed release, etc.)
• If the drug is administered in a fed or fasted state
• Gastric emptying rate
• Circadian differences
• Interactions with other drugs
• Age
• Diet
• Gender
• Disease state
Sewasew Amsalu (MD)

II. DISTRIBUTION
• Is the process by which drugs leave blood circulation
and enters the interstitium and/or the cells of the
tissues.
• Penetration of a drug to the sites of action through
the walls of blood vessels from the administered site
after absorption
• They are virtual spaces in which the drug is evenly
distributed.
Sewasew Amsalu (MD)

• Once a drug has gained access to the blood stream, it gets
distributed to other tissues that initially had no drug,
concentration gradient being in the direction of plasma to
tissues.
Sewasew Amsalu (MD)

•Drug distribution is the process by which a drug reversibly
leaves the bloodstream and enters the interstitium
(extracellular fluid) and then the cells of the tissues.
•The processes of distribution of a drug from the systemic
circulation to organs and tissue.
Sewasew Amsalu (MD)

Body fluid compartments
The total body water as a percentage of body mass varies from 50% to
70%, being rather less in women than in man.
Body water is distributed into the following main compartments:
1. Plasma (5% of body mass)
2. Intestinal fluid (16%)
3. Intracellular fluid (35%)
4. Transcellular fluid (2%)
5. Fat (20%)
Sewasew Amsalu (MD)

• Movement of drug proceeds until
an equilibrium is established
between unbound drug in plasma
and tissue fluids. Subsequently,
there is a parallel decline in both
due to elimination.
• Once a drug enters the body, from
whatever route of administration, it
has the potential to distribute into
any one of three functionally distinct
compartments of body water or to
become sequestered in a cellular
site
Sewasew Amsalu (MD)

Apparent volume of distribution (Vd)
The volume into which the total amount of a
drug in the body would have to be uniformly
distributed to provide the concentration of the
drug actually measured in the plasma. It is an
apparent rather than real volume.
Sewasew Amsalu (MD)

Drugs extensively bound to plasma proteins are largely restricted to
the vascular compartment and have low Vd
(e.g. warfarin – 99% bound and its Vd is 0,1 L/kg).
Drugs sequestrated in other tissues may have Vd much more than
the total body water or even body mass, e.g. digoxin (6 L/kg) and
propranolol (3 to 4 L/kg) because most of the drug is present in other
tissues, and the plasma concentration is low.
Therefore, in case of poisoning, drugs with large Vd are not
easily removed by haemodialysis.
Sewasew Amsalu (MD)

Factors determining the rate of distribution of drugs
1. Protein binding of drug:
• Extensive plasma protein binding will cause more drug to stay in the
blood compartment .
• Therefore, drugs which bind strongly to plasma protein tend to have lower
distribution (Vd).
• The active concentration of the drug is that part which is not
bound, because it is only this fraction which is free to leave the
plasma and site of action.
• Low protein bound drug like thiopental sodium is short acting.
Sewasew Amsalu (MD)

•Free drug leave plasma to site of action
• binding of drugs to plasma proteins assists absorption
• protein binding acts as a temporary store of a drug
•protein binding reduces diffusion of drug into the cell and
there by delays its metabolic degradation
.
Sewasew Amsalu (MD)

Plasma protein binding (PPB). Most drugs possess
physicochemical affinity for plasma proteins. Acidic
drugs bind to plasma albumin and basic drugs
to α1-glycoprotein. Extent of binding depends on the in-
dividual compound. Increasing the concentration of a drug
can progressively saturate the binding sites. The clinical
significant implications of PPB are:
a) Highly PPB drugs are largely restricted to the vascular
compartment and tend to have lower Vd.
b) The PPB fraction is not available for action.
c) There is an equilibration between the PPB fraction of
the drug and the free molecules of the drug.
Sewasew Amsalu (MD)

d) The drugs with high physicochemical affinity for
plasma proteins (e.g. aspirin, sulfonamides,
chloramphenicol) can replace the other drugs
(e.g. acenocoumarol, warfarin) or endogenous
compounds (bilirubin) with lower affinity.
e) High degree of protein binding makes the drug long-
acting, because bound fraction is not available for
metabolism, unless it is actively excreted by the liver
or kidney tubules.
f) Generally expressed plasma concentrations of the drug
refer to bound as well as free drug.
g) In hypoalbuminemia, binding may be reduced and high
concentration of free drug may be attained (e.g. phenytoin).
Sewasew Amsalu (MD)

Tissue storage (Tissue binding)
Drugs may also accumulate in specific organs or get bound to
specific tissue constituents, e.g.:
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
Sewasew Amsalu (MD)

2.
Sewasew Amsalu (MD)

3.
Sewasew Amsalu (MD)

4. Physiological barriers to distribution:
There are some specialized barriers in the body due to which
the drug will not be distributed uniformly in all the tissues.
These barriers are:
a) Blood brain barrier (BBB)through which thiopental
sodium is easily crossed but not dopamine.
b) Placental barrier: which allows non-ionized drugs with
high lipid/water partition coefficient by a process of
simple diffusion to the foetus e.g. alcohol, morphine.
Sewasew Amsalu (MD)

III. METABOLISM (BIOTRANSFORMATION)
Metabolism includes chemical alteration of the drugs in the body.
• Most hydrophilic drugs (amikacin, gentamycin,neostigmine,
mannitol) are not biotransformated and are excreted unchanged.
• The mechanism to metabolize drugs is developed to protect the
body from toxins.
• The primary site for drug metabolism is the liver, other sites are the
kidney, intestine, lungs, and plasma.
. It is needed to render nonpolar (lipid-soluble) compounds
polar (lipid insoluble) so that they are not reabsorbed in the
renal tubules and are excreted
Sewasew Amsalu (MD)

Metabolism of drugs may lead to the following:
a) Inactivation. Most drugs and their active metabolites are converted to
less active or inactive metabolites, e.g.phenobarbital, morphine,
propranolol, etc
b) Active metabolite from an active drug. Many drugs are
converted to one or more active metabolites (e.g.diazepam,
amitriptyline).
c) Activation of inactive drug. Few drugs (so called prodrugs) are
inactive as such. They need conversion in the body to one or more
active metabolites (e.g. levodopa, benfothiamine, enalapril,
perindopril). Sewasew Amsalu (MD)

Enzymes responsible for metabolism of drugs
a) Microsomal enzymes: Present in the smooth endoplasmic
reticulum of the liver, kidney and GIT e.g. glucuronyl transferase,
dehydrogenase , hydroxylase and cytochrome P450
b) Non-microsomal enzymes: Present in the cytoplasm, mitochondria
of different organs. e.g. esterases, amidase, hydrolase.
Sewasew Amsalu (MD)

Types of biotransformation
• The chemical reactions involved in biotransformation are classified as
phase-I and phase – II (conjugation) reactions.
• In phase-I reaction the drug is converted to more polar metabolite. If this
metabolite is sufficiently polar, then it will be excreted in urine. Some
metabolites may not be excreted and further metabolized by phase –II
reactions.
• Phase-I: Oxidation, reduction and hydrolysis.
• Phase-II: Glucuronidation, sulfate conjugation, acetylation, glycine
conjugation and methylation reactions
Sewasew Amsalu (MD)

• CYP 3A4/5 carry out biotransformation of the largest number
(≈ 50%) of drugs.
• In addition to the liver, these isoforms are expressed in the
intestine (responsible for first pass metabolism at this site)
and the kidney too.
• Inhibition of CYP 3A4 by erythromycin, clarithromycin,
ketoconzole,itraconazole, verapamil, diltiazem, and a
constituent of grape fruit juice are responsible for unwanted
interaction with terfenadine. Rifampicin, phenytoin,
carbmazepine,phenobarbital are inducers of the CYP 3A4.
Sewasew Amsalu (MD)

FIRST PASS (PRESYSTEMIC) METABOLISM
This refers to metabolism of a drug during its passage
from the site of absorption into systemic circulation. All
orally administered drugs are exposed to drug metabo-
lism in the intestinal wall and liver in different extent.
•High first pass metabolism: propranolol, verapamil,
pethidine, salbutamol, nitroglycerine, morphine, lidocaine.
•Oral dose of these drugs is higher than sublingual or
parenteral dose.
•There is individual variation in the oral dose due to
differences in the extent of first pass metabolism.
•Oral bioavailability is increased in patients with severe
liver disease. Sewasew Amsalu (MD)

IV. EXCRETION
Excretion is the passage out of systematically absorbed
drugs.
Drugs and their metabolites are excreted in:
urine (through the kidney)
•bile and faeces
•exhaled air
•saliva and sweat
•milk
•skin
Sewasew Amsalu (MD)

• Excretion of drugs means the
transportation of unaltered or altered
form of drug out of the body.
• The major processes of excretion
include renal excretion,
hepatobiliary excretion and
pulmonary excretion.
• The minor routes of excretion are saliva,
sweat, tears, breast milk, vaginal fluid,
nails and hair.
Sewasew Amsalu (MD)

• The kidney is responsible for excreting all water soluble
substances.
• Elimination of drugs via the kidneys into urine involves the three
processes of
Glomerular filtration,
Active tubular secretion, and
Passive tubular reabsorption
• The function of glomerular filtration and active tubular secretion is
to remove drug out of the body, while tubular reabsorption tends
to retain the drug.
Renal elimination of a drug
Sewasew Amsalu (MD)

Glomerular filtration.
• Glomerular capillaries have large pores.
• All nonprotein bound drugs (lipid soluble or insoluble) presented
to the glomerulus are filtrated.
• Glomerular filtration of drugs depends on their plasma protein
binding and renal blood flow.
• Lipid solubility and pH do not influence the passage of drugs into
the glomerular filtrate
Tubular reabsorption.
• Lipid soluble drugs filtrated at the glomerulus back diffuse in the
tubules because 99% of glomerular filtrate is reabsorbed, but
nonlipid soluble and highly ionized drugs are unable to do so
Sewasew Amsalu (MD)

Changes in urinary pH affect tubular reabsorption of partially ionized drugs:
•Weak bases ionize more and are less reabsorbed in acidic urine.
•Weak acids ionize more and are less reabsorbed in alkaline urine.
This principle is utilized for facilitating elimination of drugs in poisoning:
•Urine is acidified in morphine and atropine poisoning.
•Urine is alkalized in barbiturate and salicylate poisoning.
Sewasew Amsalu (MD)

Tubular secretion is the active transfer of organic acid and bases by two
separate nonspecific mechanisms, which operate in the proximal tubules:
•Organic acid transport for penicillins, probenecid,
salicylates, uric acid, sulfinpyrazones, nitrofurantoin,
methotrexate, drug glucuronides, etc.
•Organic base transport for thiazides, quinine,
procainamide, cimetidine, amiloride, etc.
Sewasew Amsalu (MD)

Many drug interactions occur due to competition
for tubular excretion, e.g.:
•Aspirin blocks uricosuric action of probenecid and sulfin-
pyrazone and decreases tubular excretion of methotrexate.
•Probenecide decreases the urine concentration of
nitrofurantoin, increases the duration of penicillin action
and impairs excretion of methotrexate.
•Quinidine decreases renal and biliary clearance of digoxin
by inhibiting efflux carrier P-gp.
Tubular transport mechanisms are not well developed
at birth. Duration of action of many drugs (penicillins,
cephalospoins, aspirin, etc.) is longer in neonates.
These systems mature during infancy.
Sewasew Amsalu (MD)

Reading Assignment
• Pulmonary Excreation
• Salivarry excreation
• Sweat excreation
Sewasew Amsalu (MD)

Plasma half live (t1/2) is the time in which the plasma concentration of a
drug declines by one half. Drug with long t1/2 can accumulate.
• Half life (t1/2) of a drug is the time taken for the concentration of
drug in the blood or plasma to decline to half of original value or the
amount of drug in the body to be reduced by 50%.
• Plasma t1/2 of some drugs: Adenosine < 2 sec
Dobutamine – 2 min
Benzylpenicillin – 30 min
Amoxicillin – 1 h
Paracetamol – 2 h
Atenolol – 7 h
Diazepam – 40 h
Ethosuccimide – 54 h
Digitoxin – 168 h
• Measure the duration of action
• Helps to determine dosing interval
Sewasew Amsalu (MD)

8. pregnancy and lactation
Sewasew Amsalu (MD)

Drug Interaction
• A drug interaction occurs when a patient’s response to a drug is
modified by food, nutritional supplements, formulation excipients,
environmental factors, other drugs or disease.
• Interactions between drugs (drug–drug interactions) may be
beneficial or harmful.
Sewasew Amsalu (MD)

Adverse Drug reactions
• An adverse drug reaction (ADR) is an unwanted, undesirable effect of
a medication that occurs during usual clinical use.
• The WHO defines an ADR as “a response to a drug which is noxious
and unintended and which occurs at doses normally used in man for
prophylaxis, diagnosis, or therapy of disease or for the modification of
physiologic function.”
Sewasew Amsalu (MD)

General Pharmacology - Final.pptx

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