UNIT – I General Pharmacology.pptx

UNIT-I
PRESENTED BY: Patil Divakar Rajendra
Assistant Professor
M. Pharm ( Pharmaceutics )
P. S. G. V. P. Mandal’s College of Pharmacy, Shahada
Dist. Nandurbar (MH)

INTRODUCTION TO PHARMACOLOGY:
 DEFINITION OF PHARMACOLOGY:
Pharmacology is the study of the therapeutic value (Standard vs Test) and/or
potential toxicity of chemical agents on biological systems.
 It targets every aspect of the mechanisms for the chemical actions of both
novel traditional and novel therapeutic agents.
 Two important and interrelated areas are:
i. Pharmacodynamics (what drug does with the body) is the study of the
molecular, biochemical and physiological effects of drugs on cellular systems
and their mechanisms of action.
ii. Pharmacokinetics (what body does with the drug) deals with the absorption,
distribution, and excretion of drugs
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A BRIEF HISTORY OF PHARMACOLOGY
 Pharmacology is the science of drugs (Greek pharmakos, medicine or drug; and
logos, study).
 It is the study of substances that interact with living systems through chemical
processes, especially through binding to regulatory molecules and activating or
inhibiting normal body processes.
 History of Pharmacology, Knowledge of drugs and their use in disease is as old as
history of mankind.
 Primitive men gathered the knowledge of healing and medicine by observing the
nature, noticing animals while ill and by personal experiences after consuming certain
herbs and berries as remedies.
 Hippocrates (460B.C.-377B.C.) also known as The Father of Medicine. He was the
first to attempt to separate the practice of medicine from religion and superstition,
developed his pledge of proper conduct for doctors.
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 I will use treatment to help the sick according to my ability and judgment, but
never with the view to injury and wrong doing…Into what's ever houses I
enter, I will enter to help the sick”
 Eberus papyrus describes more than 700 drugs in extensive pharmacopeia of
that civilization. Included in this are: beer, turpentine, berries, poppy, lead, salt
and crushed precious stones etc.(Egyptian remedies).
 Dhanvantari: an early Indian medical practitioner and one of the world‘s first
surgeons., regarded as the source of Ayurveda. He perfected many herbal
based cures and natural remedies and was credited with the discovery of the
antiseptic properties of turmeric and the preservative properties of salt which
he incorporated in his cures.
 Susruta Samhita Ancient Hindu Medical Text Describes 760 herbs.
 Charka Samhita describes more than 65O drugs of animal, plant and mineral
origins are used.
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 Paracelsus (1493-1541):
pioneered the use of chemicals and minerals (zinc) in medicine. Vigorously
opposed polypharmacy or the prescription of multiple ingredients in a single
medicine.
 Willow bark was used to treat fever and pains.
 Extract of foxglove plant, used to treat dropsy (congestive heart failure) in
1785. Contains digitoxin and digoxin; today called digitalis and its was William
Withering who discovered digitalis.
 Synthetic organic chemistry was born in 1828, when Friedrich Wohler synthe-
sized urea from inorganic substances and thus demolished the vital force theory.
 Pedanius Dioscorides:
 He personally researched each plant and its uses. About 65 AD, he wrote De
Materia Medica, "Regarding Medical Matters",on the "preparation, properties,
and testing of drugs.“
 five volume book on the uses of over 1,000 plants and minerals.
 For nearly 1500 years, De Materia Medica was the supreme authority on
medicine and pharmacology in western civilization.
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SOME HISTORICAL LANDMARKS
 Morphine: Friedrich Serturner (1805)
 Atropine : Grieger & Hessie (1833)
 Histamine: Vogt (1907)
 Sulfanilamide: P. Gleno (1908)
 Oxytocin: Abel (1919)
 Insulin : Banting & Best (1922)
 Penicillins: A. Flemming (1928)
 Sulfonamides: Domagk (1932)
 Cortisone: Edward C. Kendall
 Streptomycin: Waksman (1944)
 Chloramphenicol: Bartz (1948)
 Tetracycline: Duggar (1948)
 Lithium: Cade (1950)
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SCOPE OF PHARMACOLOGY
A. History
It is of intellectual interest to know how drugs are discovered and developed. Often
in the past, this was based on folklore or intelligent observation (e.g. digitalis leaf,
penicillin). Nowadays, new drugs are mostly developed by the organic chemist
working with a pharmacologist, increasingly from basic knowledge about key
molecular targets. Usually some sort of biological screen is used to select among
organic molecules for optimum pharmacological activity.
1. Francois Magendie (1783-1855), a French physiologist laid down the dictum
"Facts and facts alone are the basis of science." Experimental procedures with
animals are the testing grounds for determination of drug action.
2. Claude Bernard (1813-1878), investigated the plant extract curare and proposed
a site of action for this agent.
3. Rudolph Buchheim (1820-1879). In 1847 Buchheim established the first
laboratory devoted to experimental pharmacology in the basement of his home in
Dorpat which is known as the cradle of experimental pharmacology.
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4. Oswald Schmiedeberg (1838-1921). In 1872 set up an institute of
pharmacology in Strasbourg, France (Germany at that time) which became a
mecca for students who were interest in pharmacological problems.
5. J.N. Langley (1852-1925 and Sir Henry Dale (1875-1968) pioneered
pharmacology in England, taking a physiological approach.
6. John J. Abel (1857-1938) established the first chair of pharmacology in the
U.S.A. (U. Michigan, 1891) after training in Germany. Able went to Johns
Hopkins in 1893, and trained many U.S. pharmacologists. He is known as "The
Father of American Pharmacology".
7. The Second World War was the impetus for accelerated research in
pharmacology (the war time antimalarial program) in the U.S., and introduced
strong analytical and synthetic chemical approaches.
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B. Chemistry –
Chemical structures of drugs can provide information about mechanism of
action, pharmacokinetics, stability, and metabolic fate.
1. Structure -Activity Relationship – A modification of the chemical structure
of a drug may accentuate or diminish its pharmacological effects, often providing
clues as to the mechanism of action. A picture of the biological reactive site
(receptor) can be developed in such studies. Also, drugs are metabolized by body
systems, which may convert the parent drug to a more active or a less active
form. The drug structure can be modified to enhance or diminish the rate of
metabolic conversion.
2. Sites of Action - The organ or cellular target of drug action.
3. Drug Receptors - Macromolecules in cells or cell membranes with which
drugs interact to exert their effects. Usually the interacting forces are reversible
ionic and Van der Waals bonds of relatively low energy, but sometimes covalent
bonds are formed (e.g. organophosphate insecticides).
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C. Pharmacodynamics -
 This the effect of the drug on the body.
 It is the study of the relationship of drug concentration and the biologic effect.
 To study site of action and mechanism of action at the level of the organ,
functional system, or tissue.
 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.
 Patient factors that are age, weight, sex, diet, race, genetic factors, disease
states, trauma, concurrent drugs, etc affect drug responses
D. Pharmacokinetics -
The effect of the body on the drug. To produce its characteristic effects, a drug
must be present in appropriate concentrations at its sites of action. Thus, it is
important to know the interrelationship of the absorption, distribution, binding,
biotransformation, and excretion of a drug and its concentration at its locus of
action.
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1.Absorption - A drug must be absorbed and achieved in adequate concentration
at its site of action in order to produce its biological effects. Thus, when a drug is
applied to a body surface (e.g. GI tract, skin, etc.) its rate of absorption will
determine the time for its max concentration in plasma and at the receptor to
produce its peak effect.
2. Distribution - The blood, total body water, extracellular, lymphatic and CSF
are involved in drug movement throughout the body. Depending upon its
chemical and physical properties, the drug may be bound to plasma proteins or
dissolved in body fat, delaying its progress to its sites of action or excretory
mechanism.
3. Metabolism - This is how certain drugs are handled by the body in
preparation for their elimination and includes the fate of drugs biotransformation
(e.g. hydrolysis, conjugation, oxidation-reduction).
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E. CLINICAL PHARMACOLOGY AND THERAPEUTICS
4. Excretion - The kidney is the most important organ for drug excretion but the
liver, lung and skin are also involved in drug elimination. Drugs excreted in feces
are mostly derived from unabsorbed, orally ingested drugs or from metabolites
excreted in the bile and not reabsorbed by the intestine. The physical and chemical
properties, especially the degree of ionization of the drug, are important in the rate
of excretion.
5. Biological Factors Modifying Pharmacokinetic Aspects - Normal variations
occur in population pharmacokinetic constants (absorption rates, elimination
rates). Other factors include age, weight, obesity, edema, concurrent diseases,
other drugs (various interactions including effects on protein binding or metabolic
rate), diet, dose interval and route of administration, genetic variations in
elimination rate.
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1. Indications and Therapeutic Uses - Emphasis is placed on the therapeutic use
of drugs for the treatment of disease in clinical pharmacology, internal
medicine and therapeutics. There are specific clinic disorders or disease entities
for which a given drug may be prescribed and the physician must weigh the
potential benefit of drug use against the risks of adverse effects.

2. Contraindications and Factors (e.g., liver disease) May Modify Drug
Action - where detoxification of the drug by the liver is important. It is
important to know that the presence of disease or organ pathology may
influence the actions of a drug. Conditions such as age, pregnancy,
concomitant administration of other drugs and disease may alter the patient's
response to a given drug.
3. Posology - Is an archaic term describing dosage regimens. Consideration of
dosage schedules is a part of pharmacokinetics.
4. Bioavailability: The fraction of drug administered which is actually absorbed
and reaches the systemic circulation following oral dosing. Preparations of the
same drug by different manufacturers may have a different bioavailability.
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5. Prescription writing: It is important that the physician write clear, error-free
directions for the drug provider (pharmacist) and for the patient. Physicians
must guard against prescribing too many drugs, or preparations of little value.
Drugs of unproven clinical value should be avoided, as well as potentially toxic
agents if drugs equally effective but less dangerous are available. Risk-benefit
and cost-benefit should be considered. Drugs may be prescribed by generic
name, since often a less expensive drug product can be obtained in this way. A
particular manufacturer may be specified if the physician has reason to believe a
better or more reliable preparation is available from that manufacturer.
6. Drug Nomenclature: In addition to its formal chemical name, a new drug is
usually assigned a code name by the pharmaceutical manufacturer. If the drug
appears promising and the manufacturer wishes to place it on the market, a
United States Adopted Name (USAN) is selected by the USAN Council which
is sponsored by:
i. The American Medical Association
ii. The American Pharmaceutical Association
iii. The United States Pharmacopoeial Convention 15

F. Toxicology
 The aspect of Toxicology deals with the adverse effects of chemical
agents.
 Toxicology is concerned not only with drugs used in therapy but also
with the other chemicals that may be responsible for household,
environmental or industrial intoxication.
1. Forensic Toxicology: Addresses medicolegal aspects of the use of
chemicals that are harmful to animals or man. Analytical chemistry and
fundamental toxicological principles are hybridized to underlie this
aspect of toxicology. Nonetheless accidental poisoning with drugs is a
health problem of major significance. More than 1/4 of the fatalities and
about 1/2 of all poisonings occur in children under 5 years of age. All
common household articles that are poisonous should be made
unavailable to children, and poisonous rodenticides and insecticides
should not be placed in the home.
2. Clinical Toxicology: Focuses on toxic events that are caused by or
are uniquely associated with drugs or other chemicals. 16

G. Pharmacovigilance
 The area of Pharmacovigilance that focuses on the effects of drugs on patient safety.
 It involves the characterization, detection, and understanding of adverse events associated
with drug administration, including adverse drug reactions, toxicities, and side effects
that arise as a consequence of the short- or long-term use of drugs.
 Adverse drug reactions, including drug-drug interactions, are estimated to be a major
cause of mortality of inpatients and also lead to significant increases in duration of
hospitalization. No drug is free of toxic effects. Some untoward effects of drugs are
trivial, but others are serious and may be fatal. Side effects often are predictable from
knowledge of the pharmacology of a particular drug.
 Examples of chemicals or drug-induced toxicities are given below:
1. Allergic reactions: The number of serious allergic reactions to drugs involving
antigen-antibody reactions is low but when they occur the physician must have sufficient
knowledge to manage these problems.
 2. Blood dyscrasias: These are very serious and sometimes fatal complications of drug
therapy. They include: agranulocytosis, aplastic anemia, hemolytic anemia,
thrombocytopenia and defects in clotting factors
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3. Hepatotoxicity and nephrotoxicity: Because many chemicals and drugs are
eliminated and metabolized by the liver and kidney, damage to these organs is
seen commonly.
4. Teratogenic effects: The thalidomide tragedy dramatically emphasized that
drugs may adversely influence fetal development.
5. Behavioral toxicity: This is a term used to describe suppression of normal
anxiety, reduction in motivation, impairment of memory and learning, distortion of
judgement, impairment of reflexes, adverse effects on mood, etc.
6. Drug dependence and drug abuse: The repeated administration of some
chemicals may lead to drug dependence. Drugs likely to be abused and upon
which drug dependence may develop are the various psychopharmacological
agents such as opiates, barbiturates, amphetamines, nicotine and ethanol.
7. Carcinogenesis: Carcinogenesis is a delayed type of toxicity with a latency of
many years.
8. Pharmacogenetic toxicities: Certain genetically-predisposed individuals have a
markedly toxic reaction to certain otherwise safe drugs. Examples are prolonged
apnea after succinylcholine, or malignant hyperthermia associated with anesthetics
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NATURE AND SOURCE OF DRUGS
19
Nature of drug
Semi-synthetic
(made by synthesis
from a naturally
occurring material)
Natural
(Obtained naturally)
Synthetic
(made by a chemical
process)

SOURCE OF DRUGS
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Source
of drug
Plant source
Mineral
Semi-
synthetic or
synthetic
source
Recombinant
DNA
technology
Micro-
biological
sources
Animal
source

ESSENTIAL DRUGS CONCEPT
 In pharmacology, a drug is a chemical substance, typically of known
structure, which when administered to a living organism, produces a
biological effect.
 This concept was introduced by WHO in 1977
 Essential medicines, as defined by the World Health Organization (WHO),
are the medicines that "satisfy the priority health care needs of the
population". These are the medications to which people should have access at
all times in sufficient amounts. The prices should be at generally affordable
levels.
 The selection criteria of essential drugs depends on:
1. A better supply of drugs.
2. More rational prescribing.
3. Procurement of good quality at low cost.
4. Easiest storage, dispensing and distribution.
5. Focused training and drug information.
6. More experience with fewer drug and better recognition of adverse drug
reaction.
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SELECTION CRITERIA
1) Adequate data on safety & efficacy about the drug.
2) Based morbidity pattern on of disease in the country incidence & prevalence
disease in one country.
3) Availability in dosage form of suitable strength for which adequate quarility in
terms of Bioavailability can be assured.
4) Stability under climate conditions.
5) In case of two or more similar medicines, choices should be made basis of :
 Relative efficacy
 Safety & quality
 Price & availability
6) Influenced by comparative P’kinetic properties and local facilities for
manufacture and storage should considered.
7) Preferably single active ingredient.
8) Fixed dose combination includes only when:
 Dose of each ingredient meets the requirement of a defined population group
 Proven advantage in therapeutic effect, safety, or decreasing the emergency of
drug resistance.
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NEED OF ESSENTIAL DRUG
1. Therapeutic jungle > 60,000 drugs.
2. Irrational fixed drug dose combinations.
3. Me too drugs (similar to drugs already in market).
4. Sub- Standard & spurious drugs.
5. Costs of drugs.
6. Irrational prescription of tonic, multivitamins.
7. limited health budgets.
8. Source of information.
9. Iatrogenic diseases: (Result of diagnostic & therapeutic proceding
undertaken on a patient)
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ROUTES OF DRUG ADMINISTRATION
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 Often there is a great choice in selecting the route by which a drug should be
given to patients. However, the condition of the patient and knowledge of
advantages and disadvantages of various routes are of prime importance in
making the selection of best suiting route.
1. Following are the different ways by which a therapeutic agent could be given
to patients.
1 Enteral
2 Parenteral
3 Inhalation
4 Topical or Local
1. ENTERAL
a. ORAL OR PER OS (P.O.)
Oral route is the most common route of administration. It is safe,
convenient, cheap and does not require the services of a skilled personnel.
However, it has certain disadvantages.
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 Some drugs are unpalatable and cause irritation of the intestinal tract
resulting in nausea, vomiting and diarrhea, in particular if these are given
before meal.
 Some drugs are destroyed by intestinal enzymes e.g. insulin is destroyed by
intestinal enzymes.
 In case of emergency, when quick action of a drug is desired this route is not
suitable.
 This route is not suitable in the cases of unconscious patients.
 There is a necessity for cooperation on the part of patient.
 Absorption may be slow, unpredictable and irregular because of the presence
of variable amounts of food at various stages of digestion and acidity and
alkalinity of the digestive juices might have a great impact on absorption of
drugs.
 A very important factor is that blood from intestinal tract passes via portal
vein to the liver where the drug may be metabolized to a great extent before
being distributed to the site of action. Thus oral route is not recommended
for drug undergoing extensive FIRST PASS EFFECT.
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First Pass Effect
It is defined as the loss of drug as it passes through the gastrointestinal membranes
and the liver, for the first time, during the absorption process after oral
administration. This is also known Pre-Systemic elimination.
 Drugs interaction may occur if two drugs are given concurrently.
b. Sublingual
 The tablet is placed under the tongue and absorption form oral mucosa is rapid
and uniform. This route has special importance for certain drugs. For example
nitroglycerine is effective when given sublingually but ineffective when
administered orally. The reason is that the drug has very high lipid solubility.
 Also the drug being very potent needs few molecules to be absorbed in order to
produce the therapeutic effect. The major advantage of this route is that
venous drainage from mouth (bucal cavity) is poured into the superior vena
cava and the drug is saved from first-pass effect. It nitroglycerine is given by
oral route, the hepatic first-pass effect is sufficient to preclude the appearance
of any intact nitroglycerine in the systemic circulation.
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c. RECTAL ADMINISTRATION
 The drug may be given rectally for systemic effect when the patient is either
unconscious or vomiting. However, absorption from rectum is irregular and
incomplete and may cause irritation of rectal mucosa: Also 50% of the drug
absorbed from rectum passes through liver before entering the systemic
circulation thus first-pass effect cannot be fully avoided.
 The drugs administered reactally are in the form of suppositories e.g.
Ergotamine for the treatment of migraine. Another form of preparation for
rectal administration is the ENEMA i.e. a solution or suspension of the drug in
water or some other vehicle. Suppositories may also be given for local
treatment of rectal conditions e.g. benzocaine is used to relieve pain and
itching caused by hemorrhoids
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Advantages of rectal Administration:-
 Drugs could be given by this route in vomiting, motion sickness,
migraine or when the patients is unable to swallow the medication.
This route is also suitable for drugs that are irritant to the stomach
e.g. aminophylline, indomethacin. This route is of particular value
in case of children.
Disadvantages of Rectal Administration:-
 The patient may be embarrassed.
 Inflammation of rectum may occur due to repeated administration.
 The absorption is irregular specially when rectum is not empty.
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2. PARENTERAL (Par-beyond enteral-intestine)
The term parenteral administration implies the routes through which the drug
directly reaches the body fluids, by passing the preliminary process of transport
through the intestinal wall or pulmonary alveoli which is an essential process
when drugs are taken orally, inhaled or administered rectally. Following are the
Parenteral routes:
i. Subcutaneous (S/C)
ii. Intramuscular (I/M)
iii. Intravenous (I/V)
iv. Intraperitoneal (I/P)
v. Intradermal
vi. Intra Medullary
vii. Intrathecal
viii. Intra-articular
ix. Intra-cardiac
x. Intra arterial
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The Parenteral administration has certain advantages over oral
route.
i) Drug is neither invaded nor destroyed by digestive enzymes.
ii) A higher concentration of drug in blood may be achieved because the hepatic
metabolism of drug due to First-Pass effect is avoided.
iii) Absorption is complete and predictable.
iv) In emergency this method is particularly useful. If the patient is unconscious,
uncooperative or vomiting, the Parenteral therapy becomes necessary.
However, there are certain disadvantages of the parenteral therapy which
are as under:
a) It is expensive because all the parenteral preparations should be sterilized.
b) Asepsis must be maintained to avoid infection.
c) An intravascular injection may accidentally occur when it is not actually
intended.
d) Pain may accompany or follow the injection.
e) It requires the services of a professionally skilled personnel because it is
difficult for the patient to perform the injection himself. 31

i) SUBLINGUAL
 The tablet is placed under the tongue and absorption form oral mucosa is rapid
and uniform. This route has special importance for certain drugs. For example
nitroglycerine is effective when given sublingually but ineffective when
administered orally. The reason is that the drug has very high lipid solubility.
32
subcutaneous injection in the mouse
A diabetic patient making subcutaneous
injection

 This method is particularly useful when continuous presence of the drug in the
tissues is needed over a long period. The usefulness of this method is enhanced
by the use of depot preparations from which the drug is released more slowly
than it is from simple solution e.g. long-acting insulins. Another form of the
depot preparation is subcutaneous implant.
 In this case, a sterile pellet is implanted into subcutaneous tissue instead of
injecting drug solution e.g. hormones are administered in this way. If a
vasoconstrictor agent is incorporated in a drug solution, it retards the absorption
e.g. adrenaline is combined with local anesthetics to prolong the local
anesthesia.
ii) Intramuscular:-
 Injection is injected deep into the muscle tissue. In humans, the best site is
deltoid muscle in the shoulder or the gluteus muscle in the buttocks.
This method is suitable for the irritating substances that cannot be given by
subcutaneous route.
The speed of absorption from site of injection is dependent on the vehicle used,
absorption is quick from aqueous solutions and slow from oily preparations.
Absorption is complete, predictable and faster than subcutaneous route. 33

34
Intramuscular injection in deltoid
and gluteal muscles
Intramuscular injection in
gluteal muscles

iii) Intravenous:-
o Drug solution in injected directly into the lumen of a vein so that it is diluted
in the venous blood.
o The drug is carried to the Heart and circulated to the tissues.
o Drugs in oily vehicle or those that cause haemolysis should not be given by
this route.
o Since the drug is introduced directly into blood, the desired concentration of
the drug is achieved immediately which is not possible by any other
procedure.
35
Intravenous Administration

This route is of prime importance in emergency. Also certain irritant drugs
could be given by this route. Also this is the only route for giving large
volume of drugs e.g. blood transfusion.
However, there are certain disadvantages of this procedure.
1. Once the drug is injected nothing can be done to prevent its action.
2. I/v injection requires technical skill to minimize the risk of leakage of
irritant solution into the surrounding tissues.
3. Air embolism may cause serious problems.
iv) Intraperitoneal:-
 The peritoneum offers a large absorbing surface area from which drugs enter
circulation rapidly but primarily by way of portal vein. Hence First-Pass
effect not avoided.
 This is probably the most widely used route of drug administration in
laboratory animals. In human, it is very rarely employed due to the dangers
of infection and injury to viscera and blood vessels.
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V) Intradermal:-
Drug are injected into papillary layer of skin. For example tuberculin injection
for montoux test and BCG vaccination for active immunization against
tuberculosis. (BCG: Bacille Calmette-Guerin)
Administering Intradermal Injections:-
1. Check physician's order
2. Prepare equipment:
Draw up 0.1ml of the medication in a 1cc syringe - ones called a
TB/tuberculin syringe.
Collect medication, procedure gloves, alcohol wipe, and cotton ball
3. Cleanse the site with an alcohol pad going in a circular motion
4. Hold the skin taut
5. Hold the needle at a 15 degree angle to the skin with the bevel facing up.
6. Insert the needle through the skin, just below the epidermis into the dermis.
7. Inject the fluid, making a bubble just below the skin
8. Remove the needle
9. Dispose of used syringe and needle in a Sharps container
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vi) Intra Medullary:-
The needle is introduced into marrow cavity and effects are similar to those
following intravenous injection. This route is used when veins are not
available specially in children. In adults the injection is made into marrow
cavity of sternum and under 3 years of age into that of tibia or femur.
vii) Intrathecal:-
 Blood brain barrier often prevents the entry of certain drugs into the central
nervous system. Also the blood CSF barrier prevents the approach of drugs to
the meninges.
 Thus when local and rapid effects of drugs on meninges are desired the drugs
are injected into Subarachnoid (between arachnoid mater and pia mater) space
and effects of the drugs are then localized to the spinal nerves and meninges
 e.g. intrathecal injection of streptomycin in tuberculosis and meningitis used to
be used by this route but with the invention of third generation cephalosporins
it is not used any more to treat these conditions.
 The injection of local anaesthetics for the induction of spinal anaesthesia is
given by this route. (the three membranes covering the brain and spinal cord
from outside to inward are dura mater, arachnoid mater and pia mater)
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viii) Intra articular:-
It is also known as intra synovial. Sometimes drugs are injected into the joint
cavity to localize their action at the site of administration e.g. Hydrocortisone
acetate in the treatment of rheumatoid arthritis. Local anesthetic is added to
minimize pain of injection. Strict aspesis must be maintained to avoid joint-
infection.
ix) Intra Cardiac:-
In cardiac arrest intracardiac injection of adrenaline is made for resuscitation.
x) Intra-arterial:-
 Sometimes a drug is injected directly into an artery to localize its effects in a
particular tissue or organ. However, the therapeutic value of such practice is
doubtful.
 Infact in human the use of this technique is restricted to the injection of
radio-opaque media for diagnostic purposes. A competent person is required
to inject the drug intra arterially. However, there is no fear of first-pass effect
when the drug is given by this route. 42

3) Inhalation (or Pulmonary Absorption):
 Gaseous and volatile drugs may be inhaled. They are then absorbed by
pulmonary endothelium and mucous membrane of the respiratory tract and
reach circulation rapidly. Volatile or gaseous anaesthetics such as halothane,
enflurane and nitrous oxide are administered by this route.
 Bronchodilators are generally given from inhalers in aerosol form. Now
inhalers have been developed which allow the supply of accurately metered
doses of drugs. This development has greatly extended the scope of this
technique.
4) Local or Topical Application
a) Skin:
 Drugs applied locally on the skin are poorly absorbed through the epidermis.
However, dermis is permeable to many solutes.
 Thus systemic absorption of drugs occurs more readily through abraded,
burned or denuded skin.
 Inflammation and other conditions that enhance cutaneous blood flow also
promote absorption. 43

 Drugs are applied in the form of ointments, pastes, poultice and cream to the
skin for their local action.
 However, absorption through skin can be increased by suspending the drug in
an oily vehicle and rubbing the preparation into the skin. This method of
administration is called inunction.
b) Mucous Membranes:-
Drugs are applied onto the various mucous membranes for their local
action.
c) Mouth and Pharynx:-
Bitters are used for their reflex action to improve digestion. Boroglycerine
and gentian violet paint (as astringent) are used for their effects on buccal
mucosa.
d) Stomach & Intestine:-
Antacids (to neutralize secreted HCl) and emetics ( to induce emesis) are
used for their local effect.
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e) Rectum:-
Drugs are applied in the form of suppository or enemas e.g. glycerin
suppository for their local action. Drugs are employed for relief of itching
and pain in haemorrhoid.
f) Respiratory Tract:-
In infections of respiratory tract, tincture benzoin co steam inhalations give
relief from nasal congestion, phenyl ephrine nasal drops are also used for
nasal congestion.
g) Vagina:-
The drugs are used in the form of pessary or tablet to treat the vaginal
infections. Although this method can be applied for the drugs that are
absorbed through vaginal mucous membrane into the circulation, it is
restricted to the local treatment of vaginal conditions
45

h) Conjunctivae:-
Mydriatics ( to dilate pupil), miotics (to constrict the pupil),
local anaesthetics antiseptics and antibiotics are applied to the
conjunctivae for their local action.
i) Conjunctiva:
The delicate membrane lining the eyelids and covering the eye
ball.
46

 Agonist:
It is a drug that binds to the receptor, producing a similar response to
the intended chemical and receptor.
 Antagonist:
It is a drug that binds to the receptor either on the primary site, or on
another site, which all together stops the receptor from producing a
response.
47

 Properties of agonist:
1. Acute signalling
2. Desensitization
3. Sequestration
4. Resensitization
 Receptors can be activated either by endogenous or exogenous, leads to change
in the biological response.
 Type of agonist:
a) Full agonist
b) Partial agonist
c) Inverse agonist
48

49
 Full agonist
A full agonist has high efficacy, producing a full response while occupying a
relatively low proportion of receptors.
e.g. morphine mimics the action of endorphins at opioid receptors.
 Partial agonist:
A partial agonist has lower efficacy than a full agonist. A drug that binds to a
receptor at a site distinct from the active site.
e.g. Buspirone, is an anxiolytics drug, used to treat an anxiety disorder.
 Inverse agonist:
It is a drug that binds to the same receptor as an agonist but induces a
pharmacological response opposite to that of the agonist.
e.g. Flumazenil drugs acts as a inverse agonist for the GABA receptor &
produce anxiogenic effect.

 Properties of antagonist:
1. Site selective
2. Mimics with the natural ligand.
3. Reduces the response
4. Effect may be permanent or temporary
Type of antagonist
50
Reversible
Irreversible
competiti
ve
Non-
competiti
ve

COMPETITIVE ANTAGONISTS
 Competitive antagonists are ligands
that compete with agonists, usually for
a common binding site in a
receptor. Competitive antagonists bind
to receptors at the same binding site
(active site) as the endogenous ligand
or agonist, but without activating the
receptor. Agonists and antagonists
"compete" for the same binding site on
the receptor. Once bound, an antagonist
will block agonist binding.
51

NON-COMPETITIVE ANTAGONISTS
 An irreversible antagonist is a type of antagonist that binds permanently to
a receptor, either by forming a covalent bond to the active site, or alternatively
just by binding so tightly that the rate of dissociation is effectively zero at
relevant time scales.
52

IRREVERSIBLE ANTAGONISTS
 An irreversible antagonist is a type of antagonist that binds permanently to
a receptor, either by forming a covalent bond to the active site, or alternatively
just by binding so tightly that the rate of dissociation is effectively zero at
relevant time scales.
53

 Spare Receptors:
A drug can produce the maximal response when even less than 100% of the receptors are
occupied. The remaining unoccupied receptors are just serving as receptor reserve are called
spare receptors
 Addiction:
it is an inability to stop using a substance or engaging in a behavior even though it is causing
psychological and physical harm.
 Tolerance:
It is a person's diminished response to a drug, which occurs when the drug is used repeatedly
and the body adapts to the continued presence of the drug.
 Dependence:
Dependence means that when a person stops using a drug, their body goes through
“withdrawal”: a group of physical and mental symptoms that can range from mild (if the drug
is caffeine) to life-threatening (such as alcohol or opioids, including heroin and prescription
pain relievers)
54

 Tachyphylaxis:
It is the appearance of progressive decrease in response to a given dose after
repetitive administration of a pharmacologically or physiologically active
substance; the symptoms could appear also during treatment with
antidepressants.
 Idiosyncrasy:
refers to untoward reactions to drugs that occur in a small fraction of patients
and have no obvious relationship to dose or duration of therapy.
 Allergy:
It is the abnormal reaction of your immune system to a medication. Any
medication (over-the-counter, prescribed or herbal) is capable of inducing a
drug allergy. However, a drug allergy is more likely with certain
medications.
55

PHARMACOKINETICS
 Pharmacokinetics is the quantitative study of drug movement in, through and out
of the body.
 The intensity of response is related to concentration of the drug at the site of
action, which in turn is dependent on its pharmacokinetic properties.
Pharmacokinetic considerations, therefore, determine the routes of
administration, dose, latency of onset, time of peak action, duration of action and
frequency of administration of a drug.
 All pharmacokinetic processes involve transport of the drug across biological
membranes.
 So before discussing the absorption, distribution, metabolism and excretion of
drug we have to go through the anatomy and physiology of biological
membrane.
56

Membrane transport:
 In cellular biology, membrane transport refers to the collection of mechanisms that regulate the
passage of solutes such as ions and small molecules through biological membranes, which are
lipid bilayers that contain proteins embedded in them.
 It is flexible, fragile and transparent barrier that contains all cell contents and separate them from
surrounding environment. It is selective barrier that controls flow of material into and out of cell,
maintains environment for cellular activities and plays role in communication among cells and
between external environments.
Structure of the Biological Membrane:
 The Lipid Bilayer The basic structural framework of the plasma membrane is the lipid
bilayer, two tail-to-tail arranged layers of lipids.
 Lipid bilayer is made up of three types of lipid molecules - phospholipids, cholesterol, and
glycolipids.
 The bilayer arrangement occurs because the lipids are amphipathic, which means that they
have both polar and nonpolar parts.
 In phospholipids, the polar part is the phosphate containing “head,” which is hydrophilic.
The nonpolar parts are the two long fatty acid “tails,” which are hydrophobic. 57

 Because “like seeks like,” the phospholipid molecules orient themselves in the
bilayer with their hydrophilic heads facing outward.
 The hydrophobic layer present inside plasma membrane makes it relatively
impermeable to water soluble materials
58
Fig: The Lipid Bilayer

 The plasma membrane also contains number of proteins present in it which are
called Membrane proteins. Membrane proteins are of two types:
a. Integral proteins: These extend into or through the lipid bilayer among the
fatty acid tails and are firmly embedded in it. Most integral proteins are
Trans membrane proteins, which mean that they pass through entire lipid
bilayer and protrude into both the cytosol and extracellular fluid.
b. b. Peripheral proteins: These are not as firmly embedded in the membrane
and are associated loosely with the polar heads of membrane lipids or with
integral proteins at the inner or outer surface of the membrane.
Mechanisms of Drug Transport:
Transport across the plasma membrane:
Plasma membrane is a semipermeable membrane and transport across plasma
membrane occurs by two methods: 59

1) Passive Process
In passive processes, a substance moves down its concentration or electrical gradient
to cross the membrane using only its own kinetic energy (energy of motion). There is
no input of energy from the cell. E.g. Simple diffusion.
2) Active Process:
In active processes, cellular energy in the form of ATP (Adenosine Triphosphate) is
used to move the substance “uphill” against its concentration or electrical gradient.
E.g. Active transport.
1. Passive Processes:
A) Diffusion: It is a passive process in which random mixing of particles in
a solution occurs because of particles kinetic energy. If a particular solute
is present in higher concentration in one area and in low concentration in
another area of a solution, then solute molecule will diffuse toward area
of lower concentration i.e. they will move down their concentration
gradient. Similarly a substance may diffuse through plasma membrane if
there is concentration difference across plasma membrane. Diffusion is
of 3 types:
a) Simple diffusion
b) Facilitated diffusion
Channel mediated facilitated diffusion
Carrier mediated facilitated diffusion
c) Osmosis 60

a) Simple diffusion:
 Simple diffusion is a passive process in which substances move freely through
the lipid bilayer of the plasma membranes of cells without the help of
membrane transport proteins.
 Nonpolar, hydrophobic molecules move across the lipid bilayer through the
process of simple diffusion. E.g. oxygen, carbon dioxide, nitrogen gas, fatty
acids, steroids and fat-soluble vitamins (A, D, E, and K).
 Small, uncharged polar molecules such as water, urea, and small alcohols also
pass through the lipid bilayer by simple diffusion.
 Simple diffusion through the lipid bilayer is important in the movement of
oxygen and carbon dioxide between blood and body cells, and between blood
and air within the lungs during breathing.
 It is also the route for absorption of some nutrients and excretion of
some wastes by body cells.
61

b) Facilitated diffusion:
 Solutes that are too polar or highly charged move through the plasma
membrane by a passive process called facilitated diffusion.
 In this process, an integral membrane protein assists a specific substance
across the membrane. Facilitated diffusion is of 2 types:
Channel mediated facilitated diffusion: In this process, the solute moves
down its concentration gradient across plasma membrane through a
membrane channel. The membrane channel allows passage of small inorganic
ions that are too hydrophilic to pass through lipid bilayer. E.g. K+ ion
channels, Cl- ion channels, Na+ ion channels and Ca2+ ion channels
63

Carrier mediated facilitated diffusion:
In this diffusion a carrier or transporter moves solute down its concentration
gradient across plasma membrane. The solute binds to a specific carrier on one
side of membrane and is released on the other side after carrier undergoes a
change in the shape. Glucose, Fructose, Galactose and some vitamins move
across plasma membrane by carrier mediated facilitated diffusion.
64
Fig: facilitated diffusion

c) Osmosis:
It is a type of diffusion in which there is net movement of solvent thorough
selective permeable membrane. It is also a passive process. On living system
is defined as movement of water from area of higher water concentration to
area of lower water concentration through plasma membrane. During osmosis
water molecule pass through plasma membrane either by simple diffusion or
through an integral protein aquaporin which acts as water channel.
65

2. ACTIVE PROCESSES:
a) Active Transport: The charged or polar solutes that have to move against their
concentration gradient cross the plasma membrane by a process called active
transport. It is called so because energy is required to move solute against their
concentration gradient. The energy required is provided by ATP. Solutes which
are actively transported include Na+, Ca2+, H+, K+, I-, Cl-, amino acids and
monosaccharides. Active transport is of 2 types:
i) Primary Active Transport
ii) Secondary Active Transport
i) Primary Active Transport: In this type of transport, the energy required is
provided by hydrolysis of ATP which changes the shape of carrier protein and
thus the carrier protein pumps the substance across plasma membrane against
its concentration gradient. E.g. Na+- K+ pump which expels Na+ out
of cell and brings K+ ions inside the cell.
66

b) Secondary Active Transport:
 In this transport, the energy stored in Na+ or H+ ion concentration gradient is
used to drive the substances across the membrane against their own
concentration gradient.
 Because Na+ or H+ ion concentration gradient is maintained by primary
active transport, so the secondary active transport indirectly uses the energy
obtained from hydrolysis of ATP.
 In secondary active transport, a carrier protein simultaneously binds to Na+
and another substance and then changes its shape so that both substances cross
the membrane at the same time.
 If these transporters move two substances in the same direction, they are
called symporters (sym = same); and if transporter moves two substances in
opposite direction, then they are called antiporters (anti = against).
 E.g. Na+/Ca2+ antiporters, Na+/glucose symporters.
67

B) Transport in vesicles:
Vesicles are small spherical sacs which transport a variety of substances within
cell. They also transport material to inside and outside the cell. The transport is
done by Endocytosis and Exocytosis. Both endocytosis and exocytosis use
energy supplied by ATP, so it is also an active process.
 Endocytosis: (Endo = within) In endocytosis, the material moves into cell by
a vesicle formed from plasma membrane. Endocytosis is of 3 types:
 Receptor mediated endocytosis is a highly selective type of endocytosis in
which cell takes up specific ligand. A vesicle is formed when a specific ligand
binds to receptors on plasma membrane
 Phagocytosis (Phago = eat) is a form of endocytosis in which cell engulfs a
large solid particles such as worn out cell, whole bacteria or virus.
 Pinnocytosis (Pinno = drink) is a type of endocytosis in which a tiny droplet
of extracellular fluid is taken to form vesicles and all solutes dissolved
in extracellular fluid are brought into the cell.
68

 Exocytosis: In exocytosis, vesicle move material out of the cell.
It occurs generally in neurons and secretory cells. Neurons
release neurotransmitter and secretory cells of digestive systems
secrete enzymes. In some cases, waste products are also
released by exocytosis.
 Transcytosis: In transcytosis, vesicles are used to move
substance into, across and then out of the cell. In this vesicles
undergo endocytosis on one side, move across the cell and
undergo exocytosis on other side of the cell
69

ABSORPTION OF DRUGS
Transfer of drug from the site of administration to the systemic circulation.
1. Sites of absorption through the GI tract
2. Factors that modify absorption in the GI tract
3. Bioavailability
4. Other sites of drug administration/absorption
1) Mouth
2) Stomach
3) Small intestine
4) Large intestine
70

1) Mouth:
a. Small amount of surface area but good blood flow – best for potent drugs.
b.Transfer by passive diffusion – good for lipid soluble drugs.
c. pH = 6. Weak base drugs have better absorption.
Nicotine pKa 8.5
d. Can bypass first pass effect.
71
Perticulars Mouth GI tract
pH 6 1-5
Ionization more less
Absorption 4 times faster

2) Stomach:
a. Moderate surface area – more than mouth, less than small intestine.
b. Good blood supply.
c. Drugs absorbed in the stomach will experience first pass effect.
d. Transfer by passive diffusion.
e. Low pH (1-2) – ionization - Drugs that are weak acids will be
absorbed better than weak base drugs.
f. Ion trapping: Accumulation of weak base drugs in the stomach.
3) Small intestine
a. The primary site for most drugs.
b. Large surface area - Folds, villi and microvilli and high blood
perfusion rate.
c. pH = 5-8.
d. Passive diffusion.
e. Absorption can also take place by active transport, facilitated
diffusion, endocytosis and filtration.
72

4) Large intestine
a. Not important for drug absorption, if the drug is absorbed effectively in
small intestine.
b. Can be a site of absorption for incompletely absorbed drugs.
c. Less absorption then small intestine – less area and solid nature of contents.
d. Rectum can be used for drug administration.
 For drugs that cause irritation to the stomach
 After GI surgery
 Children
 Partially avoids liver first pass effect: The half of blood flow goes into liver, the
half of blood flow enters the systemic circulation directly.
73

2. Factors that modify absorption in the GI tract.
1) Drug solubilization
2) Formulation factors
3) Concentration of drug at the absorption site
4) Blood flow at the absorption site
5) Surface area of absorption
6) Route of administration
7) Gastric emptying
8) Food
9) Intestinal motility
10)Metabolism of drug by GI tract 74

 Hydrophilic drugs - poorly absorbed - inability to cross the lipid-rich cell
membrane.
 Hydrophobic drugs - poorly absorbed - insoluble in the aqueous body fluids -
cannot gain access to the surface of cells.
1) Drug solubilization – break down of drugs into smaller and more absorbable
particles.
75

2) Formulation factors – materials added to the drug during processing can
affect the solubilization of the drug.
a. Fillers – add bulk to the tablet
b. Disintegrators – cause tablet to break down into granules
c. Binders – hold tablet together
d. Lubricants – prevent tablet from sticking to machinery
 Formulation factors - not clinically important if the drug is absorbed effectively
and may have important influence on drug absorption for these drugs which are
not effectively absorbed in the GI tract - influence drug’s bioavailability.
76

3) Concentration of drug at the absorption site
 Passive diffusion
 Driving force – the concentration gradient.
 The higher the concentration of the drug, the faster the rate of absorption.
4) Blood flow at the absorption site
 maintain concentration gradient – driving force
77

5) Surface area of absorption
 small intestine
6) Route of administration
 GI tract – first pass effect
7) Gastric emptying
 small intestine – primary site of drug absorption
 Anything that delays/accelerates gastric emptying will
decrease/increase drug absorption.
 For all drugs - acidic, basic or neutral substances.
8) Food
 High fat food – delay gastric emptying – slow absorption .
78

9) Intestinal motility
 depends on whether the drug is completely absorbed under normal
condition.
 a. Completely absorbed early upon entry into the small intestine,
increasing intestinal motility will not significantly affect absorption.
 b. Not completely absorbed before entry into the small intestine
increasing/ decreasing intestinal motility will slow down/facilitate drug
absorption.
10) Metabolism of drug by GI tract
a. Drug metabolizing enzymes in the GI tract
b. Proteases in the GI tract
c. Microbes in the GI tract - metabolize certain drugs
- Drug metabolites are not usually absorbed.
79

81
Factors affecting bioavailability
A. First Pass hepatic metabolism
B. Solubility of drug
C. Chemical instability
D. Nature of the drug formulation

 4. Other sites of drug administration/absorption.
1). Lung – gases, liquid droplets or solid particles
 Advantages:
 The drug can have local effects - Epinephrine for asthma.
 The drug can have systemic effects - general anesthetics
 Large surface area, limited thickness of pulmonary membrane and high blood
flow allow for almost instant absorption by diffusion
 Avoid first pass effect
 Disadvantages:
 Administration is cumbersome - must use specific machines or equipment
 Patients must be able to inhale with certain timing and depth in order to get
full effects of drug
 Impaction may occur, if drug particles size is too large to pass through the
bronchi and reach the alveoli.
86

2) Skin –
 Most drugs that are incorporated into creams or ointments
are applied to the skin for local effect.
 Drug absorption through the skin - Passive diffusion –
lipid solubility
87

88
Drug Distribution
Transfer of drug from systemic circulation to tissues
Interstitial fluid
Blood – plasma
Intracellular
Capillary endothelium cells

89
Drug Distribution
A. Factors that affect drug distribution
1) Regional blood flow
2) Capillary permeability
3) Rate of transfer from interstitial fluid into tissues
4) Binding to plasma proteins
B. Barriers to drug distribution

90
Drug Distribution
A. Factors affecting distribution:
1) Regional blood flow – unequal distribution of cardiac output
Perfusion rate: blood flow to tissue mass ratio
• Higher: heart, kidney, liver, lung and brain
• Moderate: muscle and skin
• Low: adipose tissue
• The perfusion rate affects the rate at which a drug reaches the equilibrium in
the extracellular fluid of a particular tissue.
• The greater the blood flow, the more rapid the drug distribution from plasma
into interstitial fluid. Therefore, a drug will appear in the interstitial fluid of
liver, kidney and brain more rapidly than it will in muscle and skin.

91
Tissue Perfusion rate
(ml/min/100g tissue)
Lung 400
Kidney 350
Muscle 5
Skin 5
Adipose tissue 3
Blood perfusion rates in adult humans
Drug Distribution

92
2) Capillary permeability
Drug transfer through capillary – filtration
a. Capillary structure: Capillary size and fenestrae size
Liver: larger fenestrae - greater filtration potential
Brain: smaller fenestrae – lower capillary permeability
Liver – slit junction
Brain – tight junction -blood-brain barrier

93
3) Rate of transfer from interstitial fluid into tissues
Passive diffusion, active transport and endocytosis.
Passive diffusion - the most common and quickest means
Interstitial fluid
Blood – plasma

94
4) Binding to plasma proteins - reversible
Interstitial fluid
Capillary endothelium cells
Blood
Cells and tissues
A + P = AP

95
a. Consequence of drug binding to plasma proteins:
Cannot go to its receptor at the site of action
Cannot be distributed to body tissues
Cannot be metabolized by enzymes
Cannot be excreted from the body
b. Bound drugs are pharmacologically inactive.
c. Drug binding to plasma protein will delay the onset of drug action.
d. Drug binding to plasma proteins will decrease the intensity of drug
action.
e. Drug binding to plasma proteins may prolong drug action.
Reservoir of non-metabolized drug in the body
Surmin – trypanosomiasis – A single IV injection may be effective for
three months.
Warfarin – 97% bound to plasma proteins and 3% free.
f . Types of plasma proteins:
1) Albumin:
• The primary serum protein responsible for drug binding
• 68 kD with pI = 5
• The strongest affinity for weak acid and hydrophobic drugs.
• 1 or 2 selective high affinity binding sites for week acid drugs

96
2) Lipoproteins:
• Lipid-soluble drugs
• The binding capacity is dependent on their lipid content.
• Binding ability of lipoproteins is VLDL > LDL > HDL.
• Patient – more free drug available for absorption in patients with high HDL
than patients with high LDL.
3) alpha1-acid glycoprotein:
• Alpha1- globulin
• 44KD
• One high affinity binding site and binds only basic drugs
• Plasma concentration - inducible by acute injury, trauma, and stress.
• The half time: 5.5 days.
• Patient with trauma taking a basic drug – side effect
More plasma proteins
Less free drug available

97
Drug Distribution
2. Barriers to drug distribution:
1) Blood-brain barrier
MEMBRANE
CNS
Tight junction
passive diffusion
Carrier-mediated transport
Tight junction
Small fenestrae
Endothelial cells
Interstitial fluid
Polar or ionized
Lipid soluble drug
X

98
2) Placental transfer
Placenta - Not a barrier – most drugs
• Fenestrae – MW cut off 600
• MW < 600 – free transfer
• MW > 600 – restricted
• Lipid soluble drugs - passive diffusion.
• May have profound affects on fetal development.
3) Blood testicular barrier
Regulates the passage of steriods
Prevents chemotherapeutic agents from reaching the testis

111
Drugs are removed from the body or drugs are transferred from the internal to the
external environment
1.Sites for drug excretion:
1)Kidney - Urine
2)Liver – Bile
3)Skin
4)Lung
5)Milk
Excretion of Drugs

112
Excretion of Drugs
Glomerular
filtration
Active
secretion
Passive
Reabsorption
(unionized, lipid soluble)
2. Renal excretion
1) Glomerular filtration
• Drugs from glomerulus into the renal tubules
• Pressure – blood flow - 20% of blood volume is filtered at
the glomerulus
• Drug transport is dependent on
a. Size - MW cut off = 5000
> 75,000 – restricted
b. Charge - charged substances are filtered slower
c. Shape – globular proteins are filtered slower
• Lipid soluble drugs – also by passive diffusion

113
Excretion of Drugs
Glomerular
filtration
Active
secretion
Passive
Reabsorption
2. Renal excretion
2) Active secretion
• Active transport systems:
Organic acids/Anions
Organic bases/Cations
• Relatively non-specific
Anion/acid system – penicillins, phenobarbital, uric acid,
et al.
Cation/base system – morphine,
catecholamines, histamine, et al.
• In some cases can remove protein-bound drugs from
the blood
• Possess all the characteristics of active transport
(e.g. saturation, energy requirement, competition,
unidirectional – accumulation and excretion

114
Excretion of Drugs
Glomerular
filtration
Active
secretion
Passive
Reabsorption
2. Renal excretion
2) Active secretion
3) Passive reabsorption
• Formation of concentration gradient of drug in
tubular filtrate
• Transfer of unionized, lipid soluble drugs back
to the blood by pass diffusion – passive
reabsorption
• Excretion of ionized, lipid-insoluble drugs
• More ionization – more secretion
• pH of urine = 4.5 – 8
• Acidification of urine causes reabsorption of
weak acids - Ammonium chloride or ascorbic
acid– decrease pH – enhance excretion - forced
acid diuresis
• Forced alkaline diuresis - - Bicarbonate –
increase pH – ionization of weak acids – faster
excretion

115
3. Secretion from the liver:
• Liver - Metabolizing enzymes
• Drugs are filtered from liver capillaries into interstitial fluid – liver has larger fenestrae
which will allow the filtration of most drugs
• Drugs in interstitial fluid are transported into hepatocytes by
a. Passive diffusion
b. Carrier-mediated transport
• Drugs are actively transported from the hepatocytes into the bile capillaries by 4 active
transport systems
a. Acids
b. Bases
c. Neutral compounds
d. Bile acids
• Lipid insoluble or ionized drugs – excretion
• Enterohepatic cycling: Liver Bile intestine
a. Lipid soluble – reabsorption from intestine to bile – transport back to the liver
b. Prolong drug action
c. Conserve endogenous substances – VD3, B12, folic acid, estrogens.

116
4. Pulmonary excretion
• Gasses and volatile liquids Simple diffusion from the blood into the airway.
5. Sweat and saliva
• Drugs or drug metabolites
• Passive diffusion
• Drug taste after i.v. administration
• Side reaction of the skin.
6. Milk
• Passive diffusion
• Milk pH 6.5 – ion trapping of weak bases
• Plasma protein binding decreases drug concentration in milk
• Not very important for mother, but may be important for infant.

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