general pharma.pptx

3rd year
General Pharmacology
By DR AWAIS IRSHAD

1.1 Pharmacology- An Introduction
The word pharmacology is derived from two Greek words, pharmacon meaning a drug, and logos
meaning an opinion or reason. It can be defined as
“The science which deals with the history, source, physical properties, chemical properties, compounding,
biochemical effects, physiological effects, mechanism of action, absorption, distribution,
biotransformation, excretion, therapeutic and other uses of drugs, is called pharmacology.”
“The study of a substance that interacts with the living system through chemical processes especiallyby
binding to regulatory molecules and activates or inhibits normal body processes”
“The science of substances used to prevent, diagnose and treat disease.”
Drug:
The word drug comes from Drogue meaning a dry herb. A drug can be defined as:
“A substance, material or product used for the purpose of diagnosis, prevention and relief of symptoms or
cure of disease.”
WHO defines drug as:
“A substance, material or product used or intended to be used to modify or explore the physiological
processes or pathological states for the benefit of the recipient.”
General Features of a Drug:
• Variability in molecular size
• Variability in shape
• Variability in chemical nature
• Variability in lipid/water partition coefficient
• Variability in degree of ionization
• Physical Properties
• Variability in molecular size
Smaller sized molecules are easily absorbed than larger molecules. Normally the molecular
weight is between 100-1000 but may be higher or lower. Streptokinase is an example of large
molecular weight drug while lithium or nitric oxides are of small molecular weight.
• Variability in shape

Drugs may be globular or linear in structure. Their shape is modified according to the receptor on
which they act.
• Variability in chemical nature
Tertiary compounds are lipid soluble while the quaternary compounds are water soluble. Tertiary
compounds can cross the membranes easily as compared to the quaternary compounds. This is
because of the fact that the quaternary compounds are ionized.
• Variability in lipid/water partition coefficient
Lipid soluble drugs (having higher lipid water partition coefficient) are more retained in the body
while water soluble drugs are easily excreted out.
• Variability in degree of ionization
Polar or ionized forms of drugs are lipid insoluble. Non polar drugs are water insoluble or lipid
soluble. Ionized forms of drugs can pass through the specific places i.e. through channels like
Na+ and K+ channels.
• Physical Properties
Drugs may be solids, liquids or gases. Examples include halothane and nitrous oxide, both of
which are gases.
Solubility of gases is greater than that of liquids, while solubility of liquids is greater than that of
solids.
Rational Drug Therapy
Administration of the right drug indicated for the disease in right dose through an appropriate route for
the right duration.
Rational drug therapy applies to the doctor.
Drug Abuse
Drug when used for non medical purposes is known as drug abuse. It is the wrong use of a drug other
than for the disease e.g. addiction of certain drugs, like morphine, nicotine.
Misuse of Drug:
Drug that is not required by the patient i.e. drug therapy that is not justified. If violate the quantity or
duration of the required drug, it is known as misuse.
History of Drug Development
Drug Development in Ancient Civilizations:

Egyptian- Medical Papyrus 1600 B.C
Ebers Papyrus 1550 B.C
China- Shen Nung
India- Ayurvedic medicine
Ancient Greek Culture- Hippocrates 460-377 B.C
Galen 130-201 A.D
Roman- Theophrastus 372-287 B.C
Dioscorides 57 A.D
Persians
Drug Development during the Middle Ages
Paracelsus (1493) is known as grandfather of science of pharmacology. According to him:
• Most body reactions are chemical in nature
• One must never use a combination of drugs.
• Every drug is a poison; it is the dose that matters.
Development in chemistry
Development in botany
• Opium poppy
• Cinchona bark- for malaria
• Digitoxin from Digitalis purpura- for edema due to cardiac failure
• Castor oil- for constipation
• Atropa belladonna- source of atropine and thiosine
• Hyoscyamus Niger- source of thiosine
Morphine was isolated as a pure compound in 1805.
Claude Bernard in 1856 found Curare
Fleming in 1928 found Benzyl penicillin which became the first antibiotic.
Modern Drug Development

• Salicylic acid- anti-inflammatory, synthesized from phenol in 1800 by Kolbe and Lautemann.
• Acetyl salicylic acid (aspirin) was synthesized from salicylic acid in 1899 by Dreser.
• Prontosil, therapeutically inactive dye is transformed in the body to an antibacterial sulfonamide,
was developed by Domagk in 1935.
• Acetazolamide and thiazide are diuretics
• Sulfonyl ureas are anti diabetic.
• H1 antihistamines were developed by Bovet in 1944
• Beta adrenoreceptors were discovered by James Black in 1960
• H2 antagonists (Cimetidine for peptic ulcer) were developed in 1970,
• Immunoglobulins and gene therapy
1.2 Branches and Divisions of Pharmacology
Pharmacology is the science of drugs. It is the study of chemical substances that interact with the living
things by chemical processes, especially by binding to regulatory molecules, i.e. receptors.
In 1847, Rudolph established the first institute of pharmacology.
Drug:
The word drug comes from a French word ‘Drogue’ meaning a dry herb. It can be defined as:
“Substance or material that is used or intended to be used to modify or explore physiological processes or
pathological states, for the benefit of the recipient.”
Branches of Pharmacology:
Following are the important branches of Pharmacology:
• Pharmacokinetics
• Pharmacodynamics
• Therapeutics
• Chemotherapy
• Toxicology
• Clinical Pharmacology
• Pharmacy
• Pharmacognesy
• Pharmacogenetics

• Pharmacogenomics
• Pharmacoepidemiology
• Comparative Pharmacology
• Animal Pharmacology
• Pharmacoeconomics
• Posology
1. Pharmacokinetics:
The word Pharmacokinetics is derived from two words, Pharmacon meaning drug and kinetics meaning
putting in motion. It can be defined as:
“The branch of pharmacology that deals with the absorption, distribution, metabolism and excretion of
drugs and their relationship with the onset, duration and intensity of the drug effect.”
What the body does to the drug is pharmacokinetics. For example, the absorption, distribution,
metabolism and excretion of Paracetamol is included in Pharmacokinetics.
2. Pharmacodynamics:
Pharmacodynamics is the branch of Pharmacology that deals with the mechanism of action of drug and
the relation between the drug concentration and its effect.
It is the study of physical and chemical effects of drugs on body, parasites and microorganisms.
What the drug does to the body is pharmacodynamics. For example, adrenaline acts on adrenal receptors,
stimulates adenyl cyclase system producing effects such as cardiac stimulation and hyperglycemia is
studied in Pharmacodynamics.
3. Therapeutics:
The branch of pharmacology that deals with the art and science of treatment of disease. It is the
application of pharmacological information together with the knowledge of disease, for the prevention
and cure of the disease.
4. Chemotherapy:
Chemotherapy refers to the treatment of diseases by chemicals that kill the cells, especially those of
microorganisms and neoplastic cells. It is classified into two divisions:
• Antibiotics
Includes the choice of drugs most potent against the organism or least toxic. Examples include
Erythromycin given for gram positive organisms and Aminoglycans for gram negative organisms.
• Antineoplastics
Examples include:

Methotrexate, which is an anticancer drug. It inhibits the dihydrofolate reductase and interferes with
the DNA synthesis and repair.
Vinca alkaloids, which bind tubulin of microtubules, and arrest mitosis in metaphase.
5. Toxicology:
Toxicology is the branch of pharmacology which includes the study of adverse effects of drugs on the
body. It deals with the symptoms, mechanisms, treatment and detection of poisoning caused by different
chemical substances.
The main criterion is the dose. Essential medicines are poisons in high doses and some poisons are
essential medicines in low doses.
6. Clinical Pharmacology:
Clinical pharmacology is the scientific study of drugs in man. It includes pharmacokinetic and
pharmacodynamic investigations in healthy or diseased individuals. It also includes the comparison with
placebos, drugs in the market and surveillance programmes.
The main objectives are:
• Maximize the effect of drug
• Minimize the adverse effects
• Promote safety of prescription
Aims include:
• Generate optimum data for use of drug.
• Promote usage of evidence based medicine.
7. Pharmacy:
Pharmacy is the branch of Pharmacology and is the art and science of compounding by dispensing drugs,
preparing suitable dosage form for administration to man and animals. The health profession blends
health science with chemical science and effective use of drugs.
8. Pharmacognosy:
Pharmacognosy is the identification of drugs by just seeing or smelling them. It is a crude method no
longer used. Basically it deals with the drugs in crude or unprepared form and study of properties of drugs
from natural sources or identification of new drugs obtained from natural sources.
9. Pharmacoeconomics:
Pharmacoeconomics deals with the cost of drugs. In this discipline the cost of one drug is compared with
another for same use. The cheap drugs are preferred.

10. Pharmacogenetics:
Branch of pharmacology dealing with the genetic variations that cause difference in drug responseamong
individuals or population.
Example includes succinyl choline which is a skeletal muscle relaxant used in general anesthesia. It is
metabolized by pseudocholine esterase and has short duration of action. The presence of enzyme is
determined by the gene and lack of this is recessively inherited. This may lead to respiratory paralysis,
apnea and death. Halothane in some patients may lead to malignant hyperpyrexia. G6PD deficiency may
lead to hemolysis on administration of antimalarial drugs.
11. Pharamcogenomics:
Pharmacogenomics is the broader application of genomic technologies to new drug discovery and further
characterization of older drugs.
Recombinant DNA technology involves the artificial joining of DNA of one specie to another. E. coli is
mostly used. In this way we can get huge amounts of drug in purified form which is less antigenic.
Examples include GH, interferon and vaccines.
12. Pharmacoepidemiology:
Pharmacoepidemiology deals with the effects of drugs on a large population. The effects may be good or
harmful. It is conducted in three ways:
• Observational cohort studies
• Case control studies
• Phase trials
a. Cohort studies:
Patients receiving drugs are collected and followed up to determine the outcomes. It is prospective
(forward looking) research, however, is time consuming and lengthy.
b. Case Control Studies:
These are retrospective studies. They reverse the direction of scientific logic from forward looking to
backward looking.
c. Phase Trials:
These include different phases:
• Human pharmacology (20 to 50 subjects), pharmacokinetics and pharmacodynamics of the drug
are observed in either healthy volunteers or diseased subjects. These studies are carried out by
experienced staff and in such premises where facilities are available.
• Therapeutic exploration (50 to 300 subjects), drugs are compared with placebos
• Therapeutic confirmation (250 to 1000 subjects), safety, efficacy of drugs is compared with the
drugs already present

• Therapeutic use (2000 to 10000 subjects), the opinion of physicians prescribing the drugs is
collected regarding dosage and efficacy. Surveillance programmes are lengthy when conducted
outside hospitals.
13. Comparative Pharmacology:
Branch of pharmacology dealing with the comparison of one drug to another belonging to the same or
another group.
14. Posology:
Posology deals with the dosage of drugs. Example includes paracetamol given as one tablet of 500mg
thrice a day.
15. Animal Pharmacology:
Animal pharmacology deals with the different properties of drugs in animals. A vast variety of animals
are utilized including rabbits, mice guinea pigs, etc. Drugs are given to the animals and all parameters
(their behavior, activities, vital signs, etc.) are recorded. Any change is noted down. If found to be useful
in animals, then the drug is tested on humans.
1.3 Scientific Sources of Drug Information
The scientific sources of drug information include:
• Textbooks
• Medial publications
• Pharmacopoeia
• Monographs (writings on one topic, single document)
• Professional seminars (USP conventional and European council meetings)
• Databases, CDs
Miscellaneous Sources:
• Mail brochures
• Library catalogues
• Advertisements
• Displays
• Pharmaceutical representatives

Pharmacopoeia:
Pharmacopoeia is an official book published legally in a country for the manufacturing of drugs. A
pharmacopoeia describes:
• Standard of drugs
• Physical properties
• Tests for identity/purity/potency/efficacy
Common pharmacopoeias include:
• USP (Unites States pharmacopoeia)
• BP (British pharmacopoeia)
• European pharmacopoeia
• International pharmacopoeia
• Martin Dale extra pharmacopoeia
Compendium:
Compendium is the comprehensive collection of knowledge in a field.
Essential Drugs:
Drugs which satisfy health care needs of a large population and are available readily all the time in
that particular area, are known as essential drugs.
WHO has provided a model list of essential drugs which includes 300 items and is updated every two
years.
Formularies:
Formularies are the lists of licensed medicines containing information about formulas for
manufacturing as well as information regarding compounding and testing of drugs.
1.4 Routes of Drug Administration
The path taken by the drug to get into the body is known as the route of drug administration. A drug may
be in ionized or unionized form.
Classification:

• Enteral
• Parenteral
• Inhalation
• Topical
• Enteral Route:
Enteral route is through the alimentary canal. It might be:
• Oral
• Sublingual
• Per rectum
• Oral Route:
Oral route is the most common route of drug administration. It is mostly used for the neutral
drugs. It may be in the form of tablets, capsules, syrup, emulsions or powders.
Advantages:
• It is convenient
• It is the cheapest available route
• It is easy to use
• It is safe and acceptable.
Disadvantages:
• Less amount of drug reaches the target tissue.
• Some of the drug is destroyed by gastric juices e.g. adrenaline, insulin, oxytocin
• Absorption has to take place which is slow, so is not preferred during emergency.
• It might cause gastric irritation
• It might be objectionable in taste.
• It might cause discoloration of teeth e.g. iron causes staining, tetracyclines below 14 cause brown
discoloration so are not advisable during pregnancy.
First Pass Effect:

First pass effect is the term used for hepatic metabolism of drug when absorbed and deliveredthrough
portal blood. Greater the first pass effect, less amounts of the drug reach the systemic circulation.
• Sublingual Route:
Sublingual route involves tablets placed under the tongue or between cheeks or Gingiva. The
drug should be lipid soluble and small.
Advantages:
• Rapid absorption takes place.
• Drug is dissolved easily
• Drug enters the blood directly
• Less first pass effect.
• Spitting out of the drug removes its effect
Disadvantages:
• This method is inconvenient.
• Irritation of the mucous membrane might occur
• Person may swallow the drug
• Might be unpleasant in taste.
Examples of drugs given by this route include nitroglycerin, isoprenaline and oxytocin Nifedipine
used for the treatment of hypertension in emergency is given by sublingual route.
• Rectal Route:
Drugs in solid forms such as suppositories or in liquid forms such as enema are given by this
route. This route is mostly used in old patients. Drugs may have local or systemic actions after
absorption.
Advantages:
• This route is preferred in unconscious or uncooperative patients.
• This route avoids nausea or vomiting
• Drug cannot be destroyed by enzymes.
• This route is preferred if drug is irritant.
Disadvantages:

This route is generally not acceptable by the patients.
Locally acting drugs include glycerin and Bisacodyl suppository
Systemic acting drugs include Indomethacin (anti inflammatory) and aminophyllin
(bronchodilator)
Retention enema is diagnostic and is used for finding the pathology of lower intestines.
Drugs given by rectal route have 50% first pass metabolism.
• Parenteral Route:
Parenteral route includes:
Injections:
• Intra muscular
• Intra venous
• Intra-arterial
• Intra-cardiac
• Intra-thecal
• Intraosseous- into bone marrow
• Intrapleural
• Intraperitoneal
• Intra-articular
• Intradermal (Intracutaneous)
• Subcutaneous route (Hypodermic)
Hypospray or jet injections
Advantages:
• Parenteral route is rapid.
• It is useful for uncooperative patients
• It is useful for unconscious patients

• Inactivation by GIT enzymes is avoided
• First pass effect is avoided
• Bioavailability is 100%
Disadvantages:
• Skill is required
• It is painful
• This method is expensive
• It is less safe.
Classification:
• Site of Release:
Site of release may be intradermal, intraperitoneal, intrapleural, intracardiac, intra-arterial,
intrathecal (into meninges of spinal cord), intra-articular (into joint cavity).
• Subcutaneous:
Subcutaneous route might be used for the arm, forearm, thigh and subscapular space.
The volume used is 2ml. Insoluble suspensions like insulin and solids might be applied
by this route.
Advantages:
• Absorption is slow and constant
• It is hygienic
Disadvantages:
• It might lead to abscess formation
• Absorption is limited by blood flow
Examples of drugs given by subcutaneous route include insulin, adrenaline and norplant.
• Intramuscular route:
Intramuscular route might be applied to the buttock, thigh and deltoid. The volume used
is 3 ml.
Advantages:

• Absorption is rapid than subcutaneous route.
• Oily preparations can be used.
• Irritative substances might be given
• Slow releasing drugs can be given by this route.
Disadvantages
Using this route might cause nerve or vein damage.
• Intravenous injections:
Intravenous injections might be applied to the cubital, basilic and cephalic veins.
Advantages:
• Immediate action takes place
• This route is preferred in emergency situations
• This route is preferred for unconscious patients.
• Titration of dose is possible.
• Large volume of fluids might be injected by this route
• Diluted irritant might be injected
• Absorption is not required
• No first pass effect takes place.
• Blood plasma or fluids might be injected.
Disadvantages:
• There is no retreat
• This method is more risky
• Sepsis-Infection might occur
• Phlebitis(Inflammation of the blood vessel) might occur
• Infiltration of surrounding tissues might result.
• This method is not suitable for oily preparations
• This method is not suitable for insoluble preparations

• Intraarterial route:
This method is used for chemotherapy in cases of malignant tumors and in angiography.
• Intradermal route:
This route is mostly used for diagnostic purposes and is involved in:
Schick test for Diphtheria
Dick test for Scarlet fever
Vaccines include DBT, BCG and polio
Sensitivity is to penicillin
• Intracardiac route
Injection can be applied to the left ventricle in case of cardiac arrest.
• Intrathecal route:
Intrathecal route involves the subarachnoid space. Injection may be applied for the
lumbar puncture, for spinal anesthesia and for diagnostic purposes. This technique requires
special precautions.
• Intra-articular route:
Intra-articular route involves injection into the joint cavity. Corticosteroids may be injected
by this route in acute arthritis.
• Intraperitoneal route:
Intraperitoneal route may be used for peritoneal dialysis.
• Intrapleural route:
Penicillin may be injected in cases of lung empyma by intrapleural route.
• Injection into bone marrow
This route may be used for diagnostic or therapeutic purposes.
Hypospray/Jet Injection:
This method is needleless and is subcutaneous done by applying pressure over the skin. The drug solution
is retained under pressure in a container called ‘gun’. It is held with nozzle against the skin. Pressure on the
nozzle allows a fine jet of solution to emerge with great force. The solution can penetrate the skin and
subcutaneous tissue to a variable depth as determined by the pressure. Mass inoculation is possible but the
method is expensive, definite skills are required and cuts might result.

• Inhalation:
Inhalation may be the route of choice to avoid the systemic effects. In this way drugs
can pass directly to the lungs. Drugs used involve volatile drugs and gases. Examples
include aerosols like salbutamol; steam inhalations include tincture and Benzoin
Advantages:
• Rapid absorption takes place.
• Rapid onset of action takes place.
• This route has minimum side effects.
• No first pass effect takes place.
• This method is easy.
• Fewer doses are required.
Disadvantages:
• Special apparatus is required.
• Irritation of the respiratory tract may take place.
• Cooperation of the patient is required.
• Airway must be patent.
• Topical route:
Drugs may be applied to the external surfaces, the skin and the mucous membranes.
Topical route includes:
• Enepidermic route
When the drug is applied to the outer skin, it is called enepidermic route of drug
administration. Examples include poultices, plasters, creams and ointments.
• Epidermic route (Innunition):
When the drug is rubbed into the skin, it is known as epidermic route. Examples
include different oils.
• Insufflations:

When drug in finely powdered form is blown into the body cavities or spaces with
special nebulizer, the method is known as insufflations.
• Instillation
Liquids may be poured into the body by a dropper into the conjunctival sac, ear,
nose and wounds. Solids may also be administered.
• Irrigation or Douching
This method is used for washing a cavity e.g. urinary bladder, uterus, vagina and
urethra. It is also used for application of antiseptic drugs.
• Painting/Swabbing
Drugs are simply applied in the form of lotion on cutaneous or mucosal surfaces
of buccal, nasal cavity and other internal organs.
Time of Action using Different Routes of Administration
Drugs take different time durations after injection using different routes to perform their actions. Some of
the approximate time intervals are given below:
Route of Drug Administration Delay time forAction
Intravenous route 30-60 seconds
Intraosseous route 30-60 seconds
Endotracheal inhalation 2-3 minutes
Sublingual route 3-5 minutes
Intramuscular route 10-20 minutes
Rectal route 5-30 minutes
Ingestion 30-90 minutes
This time delay is important, oral route has controlled release time, thus depot or reservoir preparation
may be made e.g. penicillin for rheumatic fever.
Usage of drug depends on its physical properties, chemical properties, speed of action, need and bypass
effect.
1.5 Dosage Forms
Dosage Forms given Orally
• Liquid preparations- mixtures, suspensions, emulsions, linctuses, elixirs, syrups, tinctures,
spirits, aromatic water
• Solid preparations
Dosage Forms given Rectally

Suppositories, enemas
Dosage Forms given Parentally
Injections (ampoules, vials, infusions)
Through respiratory passages
Gases, vapors, steam inhalations, aerosols, sprays, nebulizers
Topically given (External application, skin, mucous membranes)
Creams, ointments, liniments, lotions, pastes, poultices, dusting powders, lozenges, eye, ear and
nasal drops, mouth washes, glycerin, paints, gargles, solutions, vaginal douches, pessaries
Oral Route:
Mixtures:
It is a liquid preparation consisting of one or more drugs dissolved in aqueous vehicle, usually flavored,
meant for internal administration. E.g. carminative mixture
Suspension:
Mixtures of insoluble or sparingly soluble drugs in water or other vehicle, in which particles of insoluble
drugs are kept in suspended state, with the help of a suitable suspending agent. E.g. kaolin suspension,
dijex suspension
Emulsions:
Mixtures containing two immiscible liquids made miscible with the help of emulsifying agents. E.g. castor
oil emulsion.
Linctuses:
Thick viscous liquid preparations containing sucrose and medicines with demulcent, expectorant and
sedative properties. They are used for cough. E.g. codeine linctuses
Elixirs:
Pleasantly flavored and sweetened liquid preparation containing high proportion of alcohol or glycerin or
propylene glycol. E.g. paracetamol elixir
Syrups:
Concentrated aqueous solution of sucrose or other sugars to which medicines or flavoring agents may be
added. E.g. codeine phosphate syrup
Tinctures:

Alcoholic or hydrochloric solutions containing comparatively low concentration of active principlesof
crude drugs. They are generally prepared by percolation or maceration. E.g. tincture cardamom compound.
Tablets:
Compact products containing medicines in compressed form, discoid in shape but may be round or long,
cylindrical or triangular. E.g. aspirin tablet, co trimoxazole
Capsules:
Capsules consist of a medicine enclosed in a shell. Shell is made of gelatin. This is convenient for
medicines having unpleasant taste. Capsules are usually cylindrical. E.g. capsule amoxil.
Pills:
Spherical or ovoid masses containing one or more medicaments (medicines). They are smaller in size and
contain smaller quantity of drug.
Powders:
Mixtures of two or more medicines in finely divided forms. Minimum weight is 120 mg. e.g. atropine
powder, ORS.
Granules:
Preparations of medicines usually in the form of small irregular particles 2-4 mm in diameter. E.g. eno
granules.
Rectal Route
Suppositories
Solid preparations meant for rectal route administration. E.g. glycerin suppository.
Enemas:
Aqueous, liquid, oily solutions or suspensions for rectal route. They are anti inflammatory, having
anthelmintic, purgative and sedative effect. They are also used for x-ray examination of the large gut. E.g.
pregnisolone
Parenteral Route:
Injections:
Sterile solutions intended for parenteral administration given for those drugs that cannot be given orally
or are inactivated in the body. They produce rapid and prolonged effect. E.g. hydrocortisone injections.
Inhalation Route

Aerosol Inhalation:
Aerosol inhalation consists of solution of medicine in a mixture of inert propellants held under pressure in
aerosol dispenser, consisting of metering valve. E.g. salbutamol aerosol inhalation
Inhalations:
Liquid preparations composed of volatile ingredients when vaporized are brought into contact with the
lining of the respiratory tract. E.g. benzoic inhalation.
Sprays:
Preparations of medicines in aqueous, alcohol or glycerol containing media applied through nose or throat
by atomizer. E.g. lignocaine spray.
Topical Route
Lotions:
Liquid preparations used for external application to skin but not rubbed into skin. Usually contain alcohol
or glycerin. E.g. calamine lotion.
Creams:
Viscous emulsions of semisolid consistency. Creams may be of oil in water (aqueous creams) or water in
oil (oily cream) type. E.g. betamethasone cream.
Ointments:
Liquid/semi liquid preparation meant for external use containing substances possessing analgesic,
soothing or stimulating properties. E.g. sulphur ointments.
Liniments:
Liquid or semi liquid preparation meant for external application e.g. turpentineliniment.
Paste:
Semisolid preparation for external application consisting of medicine mixed with soft paraffin or liquid
paraffin or with non greasy base made with glycerol, mucilage or soap. It has antiseptic properties,
soothing effect and is protective. E.g. zinc, coal tar paste.
Poultices:
Thick pasty preparation used externally for reducing inflammation and pain. E.g. kaolin poultice.
Dusting powder:
Mixture of two or more substances in finely powdered form. It is applied externally but not on open
wound. E.g. boric, zinc, starch, dusting powder.

Eye Drops:
Sterile solutions or suspensions for instillation into eyes. They contain substances with antiseptic,
anesthetic, anti inflammatory, anti microbial, mydriatic or micotic properties. E.g. chloramphenicoleye
drops, pilocarpine.
Eye Lotions:
Solutions for washing or bathing eye. E.g. sodium bicarbonate eye lotion.
Eye Ointment:
Semisolid soft preparation for application to conjunctival sac or lid margin.
Ear Drops:
Liquid preparations instilled into the ear. E.g. chloramphenicol.
Lozenges:
Solid dosage forms of medicines for slow dissolution in mouth. They consist of medicines mostly in
flavored bases. E.g. strepsils.
Paints:
Liquid preparations meant for skin, mucous membranes containing volatile solvent which evaporates
quickly to leave a dry film of medicine. They contain glycerin which prolongs their effect. E.g. gum paint,
throat paint.
Gargles:
Aqueous solutions usually in concentrated form, used after diluted for prevention or treatment of throat
infections. They are usually thrown out of mouth but aspirin gargles and saline gargles can be swallowed.
Mouth Washes:
Aqueous solutions in concentrated form with deodorant, antiseptic, local analgesic, astringent properties.
They are thrown out of mouth after rinsing. E.g. Listerine mouth wash.
Pessaries:
Solid bodies for vaginal administration containing drugs for local actions. E.g. nystatin pessaries.
1.6 Sources of Drugs
Drugs are obtained from six major sources:
• Plant sources

• Animal sources
• Mineral/ Earth sources
• Microbiological sources
• Semi synthetic sources/ Synthetic sources
• Recombinant DNA technology
• Plant Source:
Plant source is the oldest source of drugs. Most of the drugs in ancient times were derived from
plants. Almost all parts of the plants are used i.e. leaves, stem, bark, fruits and roots.
Leaves:
a. The leaves of Digitalis Purpurea are the source of Digitoxin and Digoxin, which are cardiac
glycosides.
b. Leaves of Eucalyptus give oil of Eucalyptus, which is important component of cough syrup.
c. Tobacco leaves give nicotine.
d. Atropa belladonna gives atropine.
Flowers:
• Poppy papaver somniferum gives morphine (opoid)
• Vinca rosea gives vincristine and vinblastine
• Rose gives rose water used as tonic.
Fruits:
• Senna pod gives anthracine, which is a purgative (used in constipation)
• Calabar beans give physostigmine, which is cholinomimetic agent.
Seeds:
• Seeds of Nux Vomica give strychnine, which is a CNS stimulant.
• Castor oil seeds give castor oil.
• Calabar beans give Physostigmine, which is a cholinomimetic drug.
Roots:
• Ipecacuanha root gives Emetine, used to induce vomiting as in accidental poisoning. It also has
amoebicidal properties.
• Rauwolfia serpentina gives reserpine, a hypotensive agent.
Reserpine was used for hypertension treatment.
Bark:
• Cinchona bark gives quinine and quinidine, which are antimalarial drugs. Quinidine also has
antiarrythmic properties.
• Atropa belladonna gives atropine, which is anticholinergic.
• Hyoscyamus Niger gives Hyosine, which is also anticholinergic.
Stem:

Chondrodendron tomentosum gives tuboqurarine, which is skeletal muscle relaxant used in general
anesthesia.
2. Animal Source:
• Pancreas is a source of Insulin, used in treatment of Diabetes.
• Urine of pregnant women gives human chorionic gonadotropin (hCG) used for the treatment of
infertility.
• Sheep thyroid is a source of thyroxin, used in hypertension.
• Cod liver is used as a source of vitamin A and D.
• Anterior pituitary is a source of pituitary gonadotropins, used in treatment of infertility.
• Blood of animals is used in preparation of vaccines.
• Stomach tissue contains pepsin and trypsin, which are digestive juices used in treatment of peptic
diseases in the past. Nowadays better drugs have replaced them.
3. Mineral Sources:
i. Metallic and Non metallic sources:
• Iron is used in treatment of iron deficiency anemia.
• Mercurial salts are used in Syphilis.
• Zinc is used as zinc supplement. Zinc oxide paste is used in wounds and in eczema.
• Iodine is antiseptic. Iodine supplements are also used.
• Gold salts are used in the treatment of rheumatoid arthritis.
ii. Miscellaneous Sources:
• Fluorine has antiseptic properties.
• Borax has antiseptic properties as well.
• Selenium as selenium sulphide is used in anti dandruff shampoos.
• Petroleum is used in preparation of liquid paraffin.
4. Synthetic/ Semi synthetic Sources:
i. Synthetic Sources:
When the nucleus of the drug from natural source as well as its chemical structure is altered, we call it
synthetic.
Examples include Emetine Bismuth Iodide
ii. Semi Synthetic Source:
When the nucleus of drug obtained from natural source is retained but the chemical structure is altered,
we call it semi-synthetic.

Examples include Apomorphine, Diacetyl morphine, Ethinyl Estradiol, Homatropine, Ampicillin and
Methyl testosterone.
Most of the drugs used nowadays (such as antianxiety drugs, anti convulsants) are synthetic forms.
5. Microbiological Sources:
• Penicillium notatum is a fungus which gives penicillin.
• Actinobacteria give Streptomycin.
• Aminoglycosides such as gentamicin and tobramycin are obtained from streptomycis and
micromonosporas.
6. Recombinant DNA technologies:
Recombinant DNA technology involves cleavage of DNA by enzyme restriction endonucleases. The
desired gene is coupled to rapidly replicating DNA (viral, bacterial or plasmid). The new genetic
combination is inserted into the bacterial cultures which allow production of vast amount of genetic
material.
Advantages:
• Huge amounts of drugs can be produced.
• Drug can be obtained in pure form.
• It is less antigenic.
Disadvantages:
• Well equipped lab is required.
• Highly trained staff is required.
• It is a complex and complicated technique.
1.7 Active Principles of Crude Drugs
Active Principal:
Chemical constituents present in crude animal or vegetable preparations responsible for biological activity
are called active principles.
Important active principles include:
• Alkaloids
• Glycosides
• Saponins
• Fixed and volatile oils
• Fats
• Waxes
• Gums
• Resins

• Oleoresins
• Gum resins
• Balsams
• Tannins
• Neutral principles
• Alkaloids:
Alkaloids are the nitrogenous compounds having complex structure.
Source:
They are obtained from plants.
Taste:
They are bitter in taste.
Biological activity:
Alkaloids are biologically very active compounds.
Nature:
Alkaloids are basic in nature.
Reaction with acids:
With acids, alkaloids form salts.
Solubility:
Alkaloids are not soluble in water but are soluble in alcohol. Their salts are water soluble.
Physical State:
Alkaloids are mostly solids and rarely liquids.
Name:
English name ends in “ine”.
Examples:
Examples include :
a. Solids :
Atropine, hyosine, quinine, strychnine, codeine and theobaine.
b. Liquids :

Nicotine, lobeline and pilocarpine.
• Glycosides :
Glycosides are non-nitrogenous compounds having complex structure similar to the alkaloids.
Source:
Glycosides are obtained from plants
Biological activity:
Glycosides are biologically very active.
Portions:
Glycosides are hydrolyzed by enzymes and acids into two portions:
• Sugar portion- Glycone ( has pharmacokinetic properties)
• Non sugar portion- Aglycone (has pharmacodynamic properties).
If sugar portion is glucose, glycosides are known as glucosides.
Name:
English name ends in “in”.
Examples:
Examples include cardiac glycosides such as digitoxin and digoxin, gitoxin and gitalin.
3. Fixed/ Volatile Oils:
a. Fixed Oils:
Fixed oils are the esters of higher fatty acids.
Source:
Fixed oils are obtained from plant as well as animal sources.
Solubility:
They are not soluble in water but are soluble in alcohol, chloroform and ether.
Fixed oils are bland and non-irritating.
They leave a greasy mark on paper.
Distillation:
Fixed oils decompose on distillation.
Chemical Reactions:

With alkalies, they form soaps.
Pharmacological Actions:
They serve as nutrients and emolients (soften the skin).
b. Volatile Oils:
Volatile oils contain liquid hydrocarbons. Chemically they are phenols, alcohols or ketones.
Solubility:
They are slightly soluble in water.
They impart smell and taste to water.
They are highly aromatic compounds.
Pharmacological Actions:
They have many pharmacological actions like:
• Carminatives- Cardamom oil
• Diuretics- Sandalwood oil
• Expectorants- Balsam of tolu
• Counter irritants- turpentine oil
• Antiseptics- clove oil
Physical State:
They are usually solids like camphor, thymol and menthol, but may be liquids as well, like oil of
Eucalyptus (Eucalyptol).
Differences Between Volatile and Fixed Acids
Fixed Oil Volatile Oil
Source: Plant and animal Plants only
Volatility: Non volatile Volatile
Distillation: Decompose Can be distilled
Nature: Greasy and thick in consistency Thin and non greasy
Solubility in water: Completely insoluble Slightly soluble
Action: Non irritant, soothing when applied to
skin and mucosa
Mild irritant to skin and mucosa
Activeness: Not much active Quite active
Rancidity: Get rancid with time Do not get rancid
Nutritional value: Have nutritional value No nutritive value
Examples: castor oil, cod liver oil, olive oil ANISE, camphor, eugenol, methanol
4. Fats:

Fats are the fixed oils. These include the triglycerides.
Physical State:
They are solids at room temperature.
Sources:
Fats are obtained from plants as well as animal source.
Examples:
Examples include theobroma, lard and wool fat.
5. Saponins:
Saponins resemble glycosides and are the emulsifying agents.
Sources:
These are obtained from the plants.
Reaction:
Saponins are neutral in reaction.
Toxicity:
Saponins are toxic and cause hemolysis of RBC’s.
With water:
With water, saponins form a clear solution which makes soap like foam on shaking.
Examples:
Examples include Senegin and Quillaia Sapotoxin.
6. Waxes:
Waxes are the esters of fatty acids with monohydric alcohol. They are the complex mixtures and are used
in the formation of ointments, topical preparations.
Examples include bees wax (Cera alba).
7. Gums:
Gums are the exudates of plants. They are carbohydrates, amorphous and transparent compounds which
form viscous solution with water. This viscous solution is known as mucilage.
Examples include gum acacia and gum tragacanth.

8. Resins:
Resins are the solid and brittle oxidized volatile oils which form soaps with alkalies. They are soluble in
alcohol.
Examples include colophonium and podophyllum.
9. Oleoresins:
Oleoresins are the resins dissolved in volatile oils. E.g. Copaiba.
10. Gum Resins:
Gum resins are the combination of gums and resins and are the exudates of plants. Examples include
Myrrh and Asafetida.
11. Balsams:
Balsams are the resins in combination with benzoic acid with or without cinnamic acid. Examples include
Benzoin, Peru and Tolu.
12. Tannins:
Tannins are the non nitrogenous compounds which are precipitated by metallic salts and alkalies. They
are mucous and leave a blue inky color with iron. They are hydrolyzed to tannic acid. They act as
astringents which harden the mucous membrane by coagulation of proteins.
13. Neutral Principles:
Neutral principles do not confer to any special group and include Santonin and Aloin.
1.8 Absorption of Drugs
Absorption:
Absorption is the process by which drug molecules cross biological membranes. Absorption is the process
usually associated with oral drugs and their absorption through the GIT. It also occurs by subcutaneous,
intra muscular and transdermal routes of administration of drugs. However, the absorptive process does
not occur during direct injection of drug by intravenous or intra arterial injection.
Biological Membrane:
Biological membranes consist of a lipid bilayer separating different compartments, with protein
molecules acting as enzymes, channels or carrier proteins.
Drugs have to cross the biological membranes to get absorbed.
Processes Determining Absorption:

Absorption, distribution and excretion of drugs overlap in the processes determining them. These
processes include:
• Passive Transport
• Simple diffusion
• Filtration/ Aqueous diffusion
• Bulk flow
• Active Transport
• Primary active transport
• Secondary active transport
• Pinocytosis
• Phagocytosis
• Specialized Transport involving facilitated diffusion
Simple Diffusion:
Most of the drugs are absorbed by simple diffusion, which is the movement of molecules down the
concentration gradient i.e. from higher concentration to lower concentration. This type of transport occurs
mostly for the lipid soluble drugs.
Non-specific:
This type of transport is non-specific i.e. no carrier proteins are required.
Energy Expenditure:
No energy is required for this type of transport.
Factors:
1. Concentration Gradient Across Membrane:
Fick’s law of diffusion explains the concentration gradient across the membrane. It is stated as the
flux of molecules per unit time is equal to the concentration gradient times the area times the
permeability coefficient divided by the thickness.
Flux (molecules/unit time) = (C1- C2) x Area x Permeability coefficient
-----------------------------------------------------
Thickness
Where permeability coefficient is the motion of drug molecules across the membrane.
Thus Flick’s law indicates that the movement of molecules is directly proportional to the concentration
gradient, area and the permeability coefficient and is inversely proportional to the thickness of the
membrane.
• Molecular/ Particle Size:

Molecular size is the size of a single molecule. The particle size is different for differentpreparations
of the same drug. More the particle size, slow is the diffusion and absorption.
Therefore, if we want to have slower time of absorption, we can make the particle size larger.
• Membrane Surface Area:
More the surface area of the membrane, more is the absorption. Stomach and intestinal lining is the
main area of absorption for the oral drugs. Thus the absorption is greater in the small intestine due to
the large surface area.
• Lipid Water Particle Coefficient:
Membranes have a thin water layer on them. Therefore, part of the drug must dissolve in the water
film, while most of the remaining portion is lipid soluble. If the lipid water particle coefficient is
large, more diffusion will occur due to greater lipid solubility. In cases of small lipid water particle
coefficient, less diffusion will occur due to the less lipid solubility.
• Ionization of Drugs:
Most of the drugs are either weak acids or weak bases. Therefore they are part ionized and part
unionized. The ionized portion is charged, which attracts water molecules, thus forming large
complexes. These complexes cannot cross the membranes because they are less lipid soluble. This is
why the ionized part of the drugs cannot cross the membrane. Drugs are better absorbed in unionized
form.
Decreasing pH by one unit, 91% of acid would become unionized and 91% of base would become
ionized. Decreasing pH by two units, 99% of acid would become unionized.
Acidic drugs
AH ↔ A- + H+ (eq 1)
Acidic drugs on dissociation give anion and proton.
Basic drugs
B + H+ ↔ BH+ (eq 2)
Basic drugs on combining with a proton become an anion.
The existence of drugs as neutral or charged particles depends on the pH.
Acidic Medium
In acidic medium, lots of protons are present. Therefore, greater amount of acidic drug is unionized
(shift towards left of eq 1). Thus in acidic medium acidic drug is present more in unionized form,
which increases its absorption. This is why acidic drugs are better absorbed from the stomach.
Basic drugs get ionized in acidic medium (right shift of eq 2), thus this form is poorly absorbed.
Aspirin, an acidic drug is unionized in acidic medium of stomach, so is easily absorbed.

Basic Medium:
The opposite is true in case of basic medium. Acidic drugs are poorly absorbed while the basic drugs
are well absorbed. Quinidine and pyrimethamine are antimalarials and basic, so are ionized in stomach
and unionized in intestines, from where they are absorbed.
• Protonated/Unprotonated form:
Protonated form of acidic drugs is well absorbed while the protonated form of basic drugs is poorly
absorbed, due to the reasons given above.
• Ionization Coefficient:
Ionization coefficient is the pH at which the drug is 50% ionized and 50 % unionized. For acidic
drugs, pKa is lower, while that for basic drugs is higher.
• Henderson Hasselbalch Equation:
This can be stated as:
pKa – pH = log [P/UP]
where P is the protonated form while UP is the unprotonated form
If pH is lower than pKa the value will be positive indicating that the protonated form is more than the
unprotonated form.
For acidic drugs,
pKa – pH = log [AH/A-]
If pH is lower than pKa, AH will be more.
For basic drugs,
pKa – pH = log [BH+/B]
If pH is lower than pKa, BH+ will be more.
Drugs in Intestines:
For acidic drugs A- is more, so the drugs are present in ionized form in the intestines, thus are less
absorbed. But as the surface area of the stomach is small while that of intestines is very large, even
acidic drugs are more absorbed from the upper part of the intestine.
For basic drugs, B is more, thus are present in unionized form in the intestines and are absorbed in a
much greater quantity.
In short we can say that acidic drugs are better absorbed in the acidic medium while basic drugs are
better absorbed in the basic medium.
Ion trapping:

Most of the drugs are reabsorbed from the proximal tubules of kidneys. Acidic drugs are better
reabsorbed from acidic urine. This is an important fact, which can be manipulated to get desired
results, as is the case of poisoning with acidic drugs. If we make the urine alkaline (by administering
sodium bicarbonate), decreased reabsorption of acidic drugs take place, a phenomenon known as ion
trapping.
In case of poisoning with basic drug, urine can be made more acidic (by administering ammonium
chloride), by virtue of which the basic drug becomes ionized and is not reabsorbed, with the result
that more of it is excreted out.
Filtration:
Filtration involves the aqueous channels or pores through which hydrophilic drugs can pass. Filtration
occurs in the jejunum and proximal tubules of kidneys. It is absent in the stomach and the lining of
the urinary bladder.
Only certain ions like Na+ and drugs of low molecular weight, like ethanol and glycerol can undergo
filtration.
Bulk Flow:
The drug in this process passes through the pores between capillary endothelial cells. The passage is
independent of water and lipid solubility. Bulk flow is the phenomenon mostly seen with the intra
muscular and subcutaneous injections. Drug is injected in bulk form into the muscle. Drug molecules
along with the aqueous medium pass through the pores of endothelium, and diffuse into the blood.
This type of transport is independent of pH and pKa. Bulk flow does not occur in brain because of
absence of pores.
However, bulk flow is dependent on the blood flow, more the blood flow, more rapid is the
absorption. This is why the area is rubbed after intra muscular injections to increase the blood flow.
Active Membrane Transport:
Active membrane transport is for the drugs which cannot cross the lipid membrane and require
transport proteins. Their structure is similar to the endogenous substances undergoing active transport
like amino acids, sugars, neurotransmitters, which have the transport proteins. Active transport is the
carrier mediated transport.
The drug moves against the concentration gradient. Energy in the form of ATP is required for the
process to occur. Different drugs bind different proteins, thus their absorption is selective from
different areas, as well as their distribution.
Some drugs directly affect the brain like the Levo Dopa which utilize amino acid transporting
mechanism. Other examples include methyl dopa for hypertension and fluorouracil which is
anticancer drug.
Active transport mechanism is saturable and can be inhibited by competing drugs.

Primary Active Transport:
When the substance moves against the concentration gradient by the expenditure of energy, the
process is called primary active transport.
Secondary Active Transport:
When the substance moves against the concentration gradient by the energy stored by a substance
moving down the concentration gradient, the process is called secondary active transport.
Phagocytosis:
Phagocytosis is also known as cell eating. This type of transport is utilized by large molecular weight
drugs. This may be a two way process.
• Endocytosis- e.g. uptake of vitamin B12 along with intrinsic factor
• Exocytosis- e.g. anticancer drugs
Pinocytosis:
Pinocytosis, or cell drinking, requires expenditure of energy. Fat soluble vitamins, protein
molecules and folic acid enter the cells by this process.
Facilitated Transport:
Facilitated transport involves the drug moving down the concentration gradient by the help of
transport proteins. No energy expenditure is required. This type of transport is also specific and
saturable. The main objective is that lipid insoluble drugs become lipid soluble by combining with the
carrier. E.g. iron binds with apoferritin and certain catecholamines enter the nerve cells by this process.
Simple Diffusion Facilitated Diffusion Active Transport
Down concentration gradient Down concentration gradient Against concentration gradient
No energy required No energy required Energy required
No carrier protein involved Carrier proteins involved Carrier proteins involved
Non-specific Specific Specific
Non-saturable Saturable Saturable
Lipid soluble drugs Non-diffusible drugs Lipid insoluble drugs
1.9 Factors affecting Absorption
Related to Drugs:
• Lipid water solubility
Lipid water solubility coefficient is the ratio of dissolution of drug in lipid as compared to
water. Greater the lipid water solubility coefficient, more is the lipid solubility of the drug and
greater is the absorption. Less the coefficient, less is the lipid solubility and less is the absorption.

Water film exists on the membranes so part of the drugs must be water soluble to cross this water
film
Drugs with benzene ring, hydrocarbon chain, steroid nucleus and halogen groups in their
structures are lipid soluble.
• Molecular size
Smaller the molecular size of the drug, rapid is the absorption. There exist different processes
involved in absorption for different molecular sizes. Thos e with a large molecular size undergo
endocytosis or facilitated diffusion, while those with smaller molecular sizes utilize aqueous
diffusion or lipid channels.
• Particle size
Particle may be composed either of a single molecule or more than hundred molecules. Larger is
the particle size, slower will be the diffusion and absorption and vice versa.
• Degree of Ionization
Different drugs are either acidic or basic and are present in ionized or unionized form, which is
given by their pKa values. In the body, the ratio of the ionized and unionized forms depend on the
pH of the medium. Acidic drugs are unionized in the acidic medium and basic drugs are
unionized in the basic medium. Acidic drugs are better absorbed from the acidic compartment.
• Physical Forms
Drugs may exist as solids, liquids or gases. Gases are rapidly absorbed than the liquids, while the
liquids are rapidly absorbed than the solids. Thus the drugs in syrup or suspension form are
rapidly absorbed than the tablets or capsules. Volatile gases used in general anesthesia are quickly
absorbed through the pulmonary route.
• Chemical Nature
Chemical nature is responsible for the selection of the route of administration of drug. Drugs that
cannot be absorbed through the intestines are given by the parenteral route. Examples include
heparin which is large molecular weight, and cannot be given orally. Simililarly, benzyl penicillin
is degraded in the GIT, so is given parenterally.
Salt forms of drugs are better absorbed than the organic compounds when given orally. The
organic compounds are given by routes other than the oral or enteral route.
Drugs in inorganic form are better absorbed than organic forms e.g. iron in Fe+2 is better
absorbed than Fe+3, d-tubocurarine exists in ionized form and is a quaternary ammonium
compound. Neostigmine is also a quaternary ammonium compound.
• Dosage Forms

Dosage forms affect the rate and extent of absorption. A drug can be given in the form of tablets,
capsules or transdermal packets. Injections may be aqueous or oily. This changes the rate of
absorption. Examples include nitroglycerin which when given by sublingual route, disintegrates
rapidly but stays for a shorter duration. When it is given orally, it disintegrates slowly and stays
for longer duration. When given by transdermal route, the drug can cover an even longer duration.
• Disintegration:
Disintegration is the breaking up of the dosage form into smaller particles. When rapid is the
disintegration, rapid will be the absorption.
• Dissolution:
After disintegration, the drug dissolves in the gastric juices, which is called dissolution. It is
only then that the drug can be absorbed.
When these two processes occur rapidly, the rate of absorption increases.
• Formulation
When the drugs are formed, apart from the active form some inert substances are included. These
are the diluents, excipients and the binders. Normally they are inert, but if they interact, they can
change the bioavailability. Examples include Na+ which can interact to decrease the absorption.
Atropine is required by some patients only in amounts of 0.2 to 0.6 mg.
• Concentration
According to Fick’s law, higher the concentration more flux occurs across the membrane. The
rate is less affected than the extent of absorption.
Related to Body
• Area of Absorptive Surface
Area of absorptive surface affects oral as well as other routes. Most of the drugs are given orally
because of the large area of absorptive surface, so that greater absorption occurs. Intestinal
resection decreases the surface area leading to a decreased absorption. Similarly, when the
topically acting drugs are applied on a large surface area, they are better absorbed.
Organophosphate compounds are highly lipid soluble and poisoning can occur even by absorption
through skin.
• Vascularity
More the vascularity, more is the rate and extent of absorption and vice versa. In shock, blood
supply to the GIT is less so the oral route of drug administration is affected. The blood flow to the

peripheries is decreased, so absorption in those areas is diminished as well. Therefore,
intravenous route is preferred in case of shock.
Vasoconstrictors decrease the blood supply of an area, thus are useful to restrict the local
anesthesias so that they remain for a longer duration. Their wash away as well as their toxic
effects are decreased in this way.
Massage in intramuscular injections improves vascular supply to enhance absorption.
• pH
Acidic pH favors acidic drug absorption while basic pH is better for basic drugs.
• Presence of other Substances
Foods or drugs may interact with the drugs to alter their rate of absorption. Especially for the drugs
given orally, food can increase or decrease the absorption.
Antihyperlipidemic drugs like the statins are better absorbed when taken with the food.
Iron when given with milk has decreased absorption.
Vitamin C enhances the absorption of iron.
Phytates decrease iron absorption.
Milk decreases the absorption of tetracyclines.
Epinephrine when given with local anesthetics decreases their absorption.
Calcium salts when given with iron salts or tetracyclines interfere with their absorption
Aspirin is given with food while antibiotics are given in empty stomach. Liquid paraffin may
affect drug absorption. Some acidic drugs bind with cholestyramine to from a complex which is
not absorbed in GIT.
• GI Mobility
GI mobility must be optimal for absorption of oral drugs. It should be neither increasednor
decreased which may affect the rate or extent of absorption.
Different diseases or drugs may alter the mobility. Diarrhea causes rapid peristalsis, decreasing
contact time and thus the extent of absorption is affected more. Constipation affectsdisintegration
and dissolution so decreases motility.
• Functional Integrity of Absorptive Surface
Flattening and edema of mucosa decreaes absorption. Dysfunctional breach in the skin affects the
absorption of topical drugs.

Parasympathomimetic drugs can decrease drug absorption and parasympatholytic drugs can
increase absorption. Metodopramide prevents vomiting and accelerates gastric emptying. It
increases gastric emptying increasing drug absorption.
• Diseases
• Diarrhea
Already discussed.
• Malabsorptive syndrome
Decreases absorption
• Achlorhydria
Acidic medium for acidic drugs is affected.
• Cirrhosis
Cirrhosis affects portal circulation. Thus affecting metabolism of drugs.
• Emphysema
Emphysema affects the absorption of volatile gases through the pulmonary route.
• Lipodystrophy
Lipodystrophy decreases absorption. In diabetics, insulin might lose its affect.
Methods for Delaying Absorption
• Vasoconstrictors
When the drug is given by parenteral route, vasoconstrictors are added.
• Formulation
Clonidine is given by transdermal route. Drugs are also given in oily preparations. Slow releasing
(SR) preparations are also prepared.
Methods for Enhancing Absorption
• Formulation
Sublingually given drugs are rapidly absorbed. Aspirin is rapidly absorbed when water dissolved.
• Massage

1.10 Distribution of Drugs:
Drug enters the body by absorption. Inside the body, drugs move in the blood to different parts of the
body. Distribution of drugs can be defined as:
“The process by which a drug reversibly leaves the blood stream and enters the interstitium(extracellular
fluid) and/or the cells or tissues.”
The drugs are present in free or bound form and different processes or mechanisms affect their
distribution.
Compartments for Distribution:
• Plasma
• Interstitial fluid
• Intracellular fluid
• Transcellular fluid
Factors Affecting Distribution:
Factors affecting distribution of drugs include those related to the drug and those related to the body.
Factors Related to the Drug:
• Lipid Solubility
Greater the lipid solubility, more is the distribution and vice versa.
• Molecular size
Larger the size, less is the distribution. Smaller sized drugs are more extensively distributed.
• Degree of Ionization
Drugs exist as weak acids or weak bases when being distributed. Drugs are trapped when present
in the ionized form, depending upon the pH of the medium. This fact can be used to make the
drug concentrated in specific compartments.
• Cellular binding
Drugs may exist in free or bound form. Bound form of drugs exists as reservoirs. The free and
bound forms co-exist in equilibrium. Cellular binding depends on the plasma binding proteins.
Tissue binding:
Different drugs have different affinity for different cells. All cells do not bind the same drugs.

• Duration of Action
The duration of action of drugs is prolonged by the presence of bound form while the free form is
released. This leads to a longer half life and duration of action of drug.
• Therapeutic Effects:
Bisphosphonate compounds bind with the bone matrix cells and strengthen them. They are used
in the treatment of osteoporosis.
• Toxic Effects:
Chloroquinine can be deposited in the retina.
Tetracycline can bind the bone material. It may also get bound to the enamel of the teeth.
Factors Related to the Body:
• Vascularity
Most of the blood passes through the highly profused organs (75%) while the remaining (25%)
passes through the less profused areas. Therefore, most of the drugs go first to the highly profused
areas. They may get bound to these organs. They are then redistributed to the less profused areas
like the skin and the skeletal muscles. This phenomenon is common among the lipid soluble drugs.
Example includes thiopentone sodium which is used as general anesthetic. When given, it goes to
the brain producing its effects. It is then redistributed to the less profused organs. Because of high
lipid solubility, it is accumulated in the fatty tissue for longer duration. Thus the clearance of the
drug is slow, producing prolonged period of drowsiness (up to 24 hours).
• Transport Mechanism
Different drugs are taken up by different compartments of the body differently. Lipid soluble
drug move by passive transport which is non specific. Active transport occurs only where carrier
proteins are present.
• Blood Barriers
Different blood barriers exist. Blood brain barrier is present because of the delicacy of nervous
tissue to avoid chemical insult to the brain.
Structure:
Endothelial cells, pericytes and glial cells form the barrier through which drugs cannot pass
easily. Only selective passage takes place.
Transporters:

Certain efflux pumps or transporters exist through which drug can be effluxed as well. Example
includes p-glycoprotein.
Disruption:
• Disruption of barrier may occur, e.g. by inflamed meningitis. Drugs may pass which might be
toxic as well as beneficial i.e. during meningitis penicillin can pass which has beneficial effects.
• Placental Barriers
Trophoblastic tissue separates maternal blood from fetal blood. Different transporters are present.
Efflux transporters cause efflux back of the drugs from the fetus to the mother.
• Plasma Binding Proteins
Many proteins exist in the plasma. Plasma binding proteins include:
• Albumin
Albumin is the most abundant plasma protein. It has higher affinity for acidic drugs but the
capacity is low. Only two sites are present for binding drug molecules.
However, albumin can bind a large number of basic drugs but has lower attractive forces. Its
capacity for binding basic drugs is more but the affinity is less.
• Globulins
Globulins can bind hormones, vitamins, etc.
• Glycoproteins
Alpha glycoproteins mainly bind basic drugs. Their levels are increased during stress, trauma
and surgery. It is during these times that their more amounts are required.
• Lipoproteins
Lipoproteins also bind some drugs.
Free and Bound Forms of Drugs
When drug enters the body, it exists in:
• Free form
• Bound form
These two forms have certain effects on the pharmacokinetics and pharmacodynamics. Free forms are
metabolized and excreted because they can cross the glomerular membrane. Free forms of drugs are
therapeutically active.

Bound forms of drugs act as a reservoir. They are not metabolized or excreted and do not have therapeutic
or toxic effect. When the free form is used up, drug is released from the reservoirs. Thus both forms exist
in equilibrium.
Significance:
• Bound form acts as a reservoir, providing free form when required
• Drugs having higher plasma protein binding if given in normal doses, are only used in binding
plasma proteins, with the result that less free form is available for therapeutic effect. Thus drugs
having higher plasma protein binding are given in larger doses at the start. This is known as
loading dose. This is to ensure that enough free form of the drug is available. Higher plasma
protein binding drugs include warfarin and phenytoin while those having negligible plasma
protein binding include lithium, metronidazole and myxothiazol.
• Drug Interactions
If a number of drugs are simultaneously given, or drugs interact with endogenous substances, one
drug can be displaced by another.
Example includes interaction of sulphonamide with bilirubin, with the result that bilirubin is
displaced which may cause kernicterus in babies.
Drug interactions occur if both drugs bind to same protein and depend on:
• Affinity
Higher the affinity of the drug, more easily can it displace the other drug.
• Concentration
Higher concentration drug can displace the lower concentration drugs.
This phenomenon might be of consequence in the following situations:
• Volume of Distribution:
The volume into which the drug is distributed is known as the volume of distribution. If
drug can be distributed to different body compartments, it is diluted when goes to the
different compartment. If the drug has a small volume of distribution, it stays in the same
compartment producing toxic effects. (Explained separately)
Toxic effects are produced when more drug is present in free form than usual.
• Therapeutic Index
Therapeutic index is the safety margin, the range in which the drug is safe. If drug has a
large therapeutic index, then large concentrations of the drug are safe. If it has a small

therapeutic index, it may move out of the safe range and cause toxic effects. Thus the
drug displacement phenomenon is significant in low therapeutic index drugs.
• Disease States
Different diseases affect the distribution of drugs. Renal diseases cause hypoalbuminemia. Due to
less proteins, toxic levels of free drugs may be present. Uremic by-products are also produced
which compete with drugs.
Hepatic diseases cause decreased synthesis of proteins causing hypoalbuminemia. Free drugs may
be present in toxic levels and bilirubin by products increase as well.
Thus drug, whose doses have to be adjusted to produced desired effects (may be reduced even to
half).
• Drug Reservoirs
Drugs are stored and are released slowly which affects their pharmacokinetics and
pharmacodynamics. Drug reservoirs include:
• Plasma proteins
• Liver
• Adipose
• Bone
• Placenta
• Breast milk
• Transcellular fluid reserves
• Other body tissues- eye, kidneys, skeletal muscles, skin
• Volume of Distribution
The apparent or hypothetical volume in the body into which a drug distributes. Compartments:
First of all the drug enters the plasma which is approximately 4 liters. Heparin is a large
molecular drug, it does not cross blood vessel lining, thus volume of distribution is less.
Gentamicin, an antibiotic leaves the plasma to enter the interstitial fluid, its volume of distribution
is approximately 14 liters.
Some drugs like ethanol pass from the interstitial fluid to the intracellular fluid and enter the fluid
of the cells, thus have the volume of fluid approximately 42 liters.

We cannot measure the volume of distribution beyond the intracellular fluid. Drug does not stay
here but binds cell membranes, enzymes, nuclear proteins and transporting proteins. All of this
volume cannot be measured by any means.
Thus we say that the volume of distribution is the apparent volume. Each drug has different plasma
binding and cellular binding values.
Volume of distribution can be calculated as:
Vd = D/C
Where D is the dose while C is the concentration. Dose is the total amount of drug being given
while concentration is found from the plasma.
Significance:
• If we know Vf and the concentration required, we can calculate the appropriate dose.
• Drugs having large volume of distribution have to given in large loading doses, so that
binding proteins can be saturated first. Example includes chloroquinine, 4 tablets of which are
given at the start, then smaller doses are used subsequently.
• Relation with half life and duration of action.
Half life is prolonged when drug stays for a longer duration in different compartments.
Chloroquinine has a half life of 45 days, while that of gold is 1 year. Thus the duration of
action is prolonged.
Redistribution of Drugs:
The movement of drug from more perfused organs to less perfused organs is known as redistribution of
drugs. Initially the heart, liver, kidneys, brain and other highly perfused organs receive most of the drug,
during the first few minutes after absorption.
1.11 Bioavailability
Fraction of the dose of a drug contained in any dosage form that reaches the systemic circulation in
unchanged or active form administered through any route is known as bioavailability.
Drugs injected using intravenous route of administration have 100% bioavailability, while others have
much less bioavailability, because:
• All of the drug may not be adsorbed
• Metabolism of the drug might occur before reaching the site of action

Drugs not absorbed by the oral route are highly polar drugs, thus have low bioavailability.
Bioavailability = AUC (oral)/ AUC (I/V) x 100
Where AUC is the area under the curve
X-axis represents time, while y-axis represents the plasma concentration.
Bioavailability is the ratio of the area calculated for oral route of administration to the intravenousroute of
administration. It is determined by comparing the plasma levels of a drug after administration with plasma
drug level achieved by I/V injection.
Factors Affecting Bioavailability:
• Route of administration
Drugs given by intravenous route have 100% bioavailability. Exception includes prostaglandins,
which are inactivated/metabolized in the lungs, therefore, their bioavailability may be zero after
I/V injection. Those given by intramuscular route have bioavailability less than I/V route but
more than subcutaneous route, while subcutaneous route has bioavailability more than the oral
route. Only 10% of the dose of digoxin reaches systemic circulation after oral administration
because of lack of absorption and bacterial metabolism within intestines. Even some of the drugs
given by oral route may have 100% bioavailability but this is rare.
By rectal route, half of the drug undergoes first pass metabolism.
Chloramphenicol, an antibiotic, administered by intravenous route has bioavailability less than
oral route because it is present in pro form and has to be activated in the intestines.
Route Bioavailability Characteristics
Intravenous 100% Most rapid
Intramuscular 75≤100% Large volume may be injected
but painful method
Subcutaneous 75≤100% Smaller volume than IM, may
be painful
Oral 5≤100% Convenient, first pass
metabolism occurs
Rectal 30<100% Less first pass metabolism
than oral route
Inhalation 5<100% Rapid onset
Transdermal 80≤100% Usually slow absorption, lack
of first pass metabolism and
prolonged duration of action
• Factors affecting absorption

Factors affecting absorption may be classified as those related to the drug and those related to the
body. They have been discussed separately. If absorbance is decreased, bioavailability is
decreased and vice versa. For a drug to be readily absorbed, it must be hydrophobic yet have
some solubility in aqueous solution.
• First pass metabolism
Pre systemic metabolism en-route from the route of administration to the site of action is known as
the first pass metabolism. Most common site of first pass metabolism is the liver because after
absorption the drug administered by oral route enters the portal circulation to reach the liver. First
pass metabolism may also occur in the intestines, lungs adrenals or any other organ.
Significance:
• Drug undergoing first pass metabolism has low bioavailability, the dose must be adjusted
keeping this in mind.
• If a person is undergoing a liver disease, bioavailability may be increased, because most
drugs then enter systemic circulation in unchanged form. The dose must be decreased
otherwise toxic effects might result.
Drugs undergoing first pass metabolism and sites:
• Bronchial mucosa:
Prostaglandins, nicotine and isoprenaline
• Intestinal mucosa:
Chlorpromazine, levo dopa, tyramine, alpha methyl dopa, testosterone and progesterone
• Liver:
Glyceryltrinitrate, amitriptyaline, nortriptyaline, imipiramine, pentazocine, lignocaine,
propanolol, labetalol, cimetidine and pethidine.
Glyceryltrinitrate is administered sublingually, by oral route it has almost 0% bioavailability.
Lignocaine is a local anesthetic and antiarythmic drug, its bioavailability by oral route is also
0%.
Highly polar drugs also have 0% bioavailability. They are not absorbed from the intestine.
Examples include streptomycin and gentamicin.
Extraction Ratio:
The effect of first pass metabolism on bioavailability is measured by extraction ratio.
Extraction ratio = Clearance by liver/Hepatic blood flow

Where clearance is the amount of drug cleared from the unit plasma in unit time by liver.
Systemic bioavailability = Absorption x (1- Extraction ratio)
• Chemical Instability
Drug may be destroyed by the HCl or enzymes present in the GIT. Benzyl penicillin is not given
orally because it is destroyed by HCl. Parenteral route is generally preferred.
• Quality control
Quality control is related mainly to different brands. One drug might be manufactured by
different companies. These brands have different bioavailability although the drug is same. The
difference lies in the manufacturing process.
• Particle size:
Greater the size, smaller is the absorption. Size is inversely proportional to bioavailability.
Small particle size is important for absorption of corticosteroids, chloramphenicol and
griseofulvin.
• Diluents/Excipients
Inactive ingredients which do not have pharmacological action. These are important when the
drug is given in solid forms (tablets, capsules, pills). Drug before absorption must disintegrate
and dissolute. Disintegration and dissolution may differ with different brands. If dissolution
time is more, bioavailability will be less and vice versa.
These are added to:
• Increase bulk when dose is very low e.g. digoxin
• Adding stability, making drug resistant to environmental conditions
• Mask objectionable taste of drug
Excipients
Excipients are the inert substances added to the tablets or pills to increase their bulk because
sometimes the dosage is very small.
Diluents
Diluents are inert substances used in case of liquids. Commonly used diluents include lactate,
lactose, starch, sucrose, calcium phosphate.
Diluents and excipients may affect bioavailability of different brands. They may bind with
the active principle. Sometimes when the patient is taking one brand for a very long time,
suddenly bioavailability may change by changing the company.

• Compression pressure
If tablets or pills are more tightly bound, the bioavailability is decreased.
• Moisture content/Binding agents
Moisture content may act in two ways:
• If the moisture content is more, disintegration time is less
ii. Sometimes some drugs when have more moisture, form lumps in the stomach, which decreases
their absorbance.
Thus moisture content may act both ways.
• Polymorphism
When the drug is chemically same but different in arrangement of molecules, the
phenomenon is known as polymorphism. Arrangement of molecules may be different with
different brands.
Disintegration time:
The time in which a solid dosage from administered orally releases the active drug for absorption is called
disintegration time.
Clinical Significance:
Bioavailability differs with the dosage forms. Drug in liquid form have more bioavailability than those of
solids, while gases have the highest bioavailability. This is why inhalation is used in bronchial asthma.
With the same brand, dosage form manufactured by different companies may differ in bioavailability.
Three terms are generally used:
• Bioequivalent:
If two similar drugs have the same bioavailability, they are called bioequivalent. If the two
similar drugs do not have the same bioavailability, they are called non-bioequivalent.
• Therapeutic equivalent
If two similar drugs perform the same effect, have same efficacy and toxicity, then they are called
therapeutically equivalent.
• Chemical Equivalent
If two drugs are manufactured according to the same principles and criterion layed down in
pharmacopoeia (official book published by country to manufacture drugs in that country), then
they are called chemically equivalent.

Two brands may be chemically equivalent but may not be bioequivalent and therapeutically
equivalent because they might differ in the factors mentioned above.
Sensitive Drugs:
• Antimicrobials
• Anticonvulsants
• Corticosteroids
• Cardio active drugs
• Oral antidiabetics
• Chemotherapeutic agents for cancer
If patient is stabilized on one brand, it should not be changed, because if the bioavailability is
decreased the drug will have less effect or if the bioavailability is increased, it might lead to
toxicity.
Antimicrobials:
Anti tuberculosis drugs have to be continued for six to nine months. Recurrence of disease might
occur on changing to brand with less bioavailability, although symptoms disappear after four
weeks. Bacteria may also become resistant.
Anticonvulsants:
Anticonvulsant dose is adjusted by starting from a lower dose to reach the state where patient is
free from fits. Drugs have to be continued for the whole life. If the brand is changed reappearance
of convulsions might occur due to decreased bioavailability. Phenytoin is a drug of low
therapeutic index. There exists small difference between toxic and therapeutic effects which must
be taken care of.
Cardio active drugs:
Cardio active drugs like digoxin have low therapeutic index. Small changes in plasma levels may
lead to toxicity.
Oral antidiabetic drugs:
Oral anti diabetic drugs have to be continued for the whole life. If bioavailability is increased, it
may lead to hypoglycemia and fainting. Decreased bioavailability may cause hyperglycemia and
diabetic complications.
Chemotherapeutics have low therapeutic index too. Plasma levels of corticosteroids matter as
well.
We have to adjust the dose so that therapeutic failure does not occur.

Therapeutic Index:
Therapeutic index represents the safety of a drug. Drugs having large therapeutic index and safer
and vice versa.
Therapeutic index = LD50/ED50 = TD50/ED50*
Where, LD50 is a dose which can kill 50% of the animals administered
ED50 is a dose which can save 50% of the animals
TD50 is the median toxic dose
ED50* is the median effectivedose
Drugs having low therapeutic index include:
Anticonvulsants, lithium, anticoagulents, corticosteroids and cardio active drugs.
Therapeutic Window:
Therapeutic window is the range between the high therapeutic index and low therapeutic index. Drugs
with low therapeutic index have a narrow therapeutic window.
Drugs having 100% bioavailability
Drugs having 100% bioavailability include chlordiazepoxide, diazepam, lithium, metronidazole,
phenobarbitol, salicylic acid, trimethoprin and valproic acid.
1.12 Plasma Half Life
Onset, duration and intensity of effect of drug depends on the rate of absorption, distribution and
elimination (biotransformation, excretion). In case of oral route, plasma concentration gradually rises and
reaches its peak value, then it begins to fall down. Drug requires a minimum effective plasma
concentration for the effects to start appearing. Once the level falls below the minimum effective plasma
concentration, the effect is over.
“Time required for the concentration of a drug to fall to half of its initial concentration after reaching its
peak.” For example, after intravenous administration, if maximum concentration is 16 mg and the half life
is 2 hours, after 2 hours 8 mg will be left, and so on.
Half life of a drug is directly proportional to the volume of the distribution and inversely proportionalto
the clearance.
Half life = 0.693 x Vd/ total body clearance
Alpha half life = plasma / distribution half life

Beta half life = tissue / elimination half life
Most of the drugs have alpha half life and remain in the plasma. Drugs having beta half life have two half
lives, one in the plasma and one in the tissues. They are highly distributed drugs. Their total time of
elimination Is more.
When the drug is absorbed and reaches the plasma, it is distributed to the tissues. Some drugs have high
volume of distribution and are distributed to various tissues, mostly adipose tissue. More time is required
for their elimination, thus have greater half life. More the clearance of a drug, shorter is the half life.
Thiopentone sodium is used as a general anesthetic. It is administered through intravenous route and has
very short duration of action (about 5 to 10 min). After administration, the drug immediately goes to the
brain, produces its effects, then leaves plasma to get deposited in the tissues. It is slowly released from
here. Once it leaves the brain, person regains consciousness but because it is deposited in the tissues,
person keeps on feeling drowsy. Elimination half life is about 7 to 10 hours. Alpha half life is about 2 to
5 minutes.
Plasma half life of some drugs:
Drug Half Life
Acetylcholine, GABA, catecholamines Milliseconds
Adenosine 10 seconds
Aspirin 15 minutes
Propanolol 4 hours
Digoxin 39 hours
Digitoxin 168 hours
Amiodarone more than 100 days
Factors affecting Half Life:
• Plasma protein binding:
Protein bound drug produces no effect and is not excreted because proteins are not filtered by
glomeruli. It is thus slowly released. Drugs having plasma protein binding have longer half life
( directly proportional). Acidic drugs bind albumin while basic drugs mostly bind globulins.
Example includes warfarin, an anticoagulant, having very long half life due to extensive protein
binding.
The bound drug:

• Is not distributed to tissues (stays in plasma)
• Has no pharmacological activity
• Is not metabolized (no biotransformation)
• Pharmacokinetic pattern
The rate of absorption, metabolism. Biotransformation and excretion are considered in
pharmacokinetic pattern. Most important pattern is the pattern of elimination of drug, consisting
of:
• Biotransformation
• Excretion
Pharmacokinetic pattern of drug elimination can be divided into:
• First order kinetics:
In first order kinetics, fixed fraction of drug is eliminated in unit time. If plasma
concentration of a drug is 100 mg and fixed fraction is 10%, after first hour 10 mg will be
eliminated, after second hour 9 mg will be eliminated, and so on.
• Zero order kinetics
In zero order kinetics, fixed amount is excreted in unit time. If plasma concentration of a drug
is 100 mg and fixed amount is 10 mg, after first hour 10 mg will be eliminated, after second
hour 10 mg, and so on. The capacity of body to eliminate drug is saturable, so also called
saturation kinetics.
Elimination is proportional to plasma concentration in first order kinetics, but not in zero
order kinetics. Half life is achieved early in zero order kinetics. Half life of drugs following
first order kinetics is not affected by dose of the drug, which is not the case with zero order
kinetics.
Most of the drugs follow the first order kinetics in therapeutic doses. When the dose is
increased, ultimately a point is reached where systems of metabolisms become saturated, then
only a fixed amount of the drug is excreted in unit time.
Significance:
Drugs which follow the first order kinetics have a constant half life. Drugs following zero order
kinetics do not have a constant half life. Their increased dose increases plasma concentration
which increases half life.
In toxic doses, drugs follow the zero order kinetics. Certain drugs follow zero order kinetics in
therapeutics after a small increase in dose. These include:

• Alcohol
• Phenytoin
• Salicylates
Doctor needs to be extra careful with these drugs and monitor their plasma levels. Alcohol stays
in blood because of zero order kinetics. Thus a dose of alcohol taken at night is still present in the
blood in the morning.
• Renal/hepatic diseases
Half life Is increased in kidney diseases because the elimination is less. Half life is also increased
in hepatic diseases because the metabolism is not taking place. Aminoglycosides get accumulated
in renal diseases as they are excreted through glomerular filtration.
• Active metabolites:
Some of the drugs when taken need to be converted to active metabolites. Thus they have longer
half life. Example includes diazepam, which is a sedative hypnotic. It has 72 hours long half life.
Aspirin has a half life of 15 minutes but salicylic acid has half life of 2 hours.
• Enterohepatic circulation
Some drugs are metabolized in the liver. They are conjugated with glucuronic acid and excreted
into the bile. In the intestines, the conjugate is broken down by the bacteria and enzymes. The
active drug is released and is reabsorbed. These drugs have a longer half life. Examples include
rifampicin, doxycycline, spironolactone and digitoxin.
Oral contraceptives undergo enterohepatic circulation, thus their dose must be adjusted. When
interference with the enterohepatic circulation occurs (gastritis or diarrhea), decreased
reabsorption and decreased half life is observed leading to therapeutic failure
• Volume of Distribution
Greater the volume of distribution, more is the half life.
Clinical Significance:
• Rate of elimination
Rate of elimination is the rate at which drug is eliminated from the body. Certain minimum
plasma levels of a drug have to be maintained for the effect to occur. Drugs having shorter half
lives are given in frequent doses. Drugs which are eliminated slowly, are given with less
frequency. About 90-95% of the drug is eliminated after four half lives.
• Duration of Action

Drugs having longer half life have more duration of action and vice versa. Ranitidine has a half
life of only 2 hours, but duration of action is about 12 hours. Although its concentration falls in the
plasma but binding to site of action is tight.
• Interval between doses
Drugs having short half life, the interval between the doses is kept short and are given frequently
to maintain minimum effective plasma levels.
• Time for steady state
When the drug is given by constant intravenous infusion or given repeatedly in fixed doses at
fixed intervals, plasma concentration of drug rises gradually, and if patient is still taking the drug
at fixed intervals and doses, it reaches a peak value and then plateau is reached.
This is because the amount of drug being administered is equal to the amount of the drug being
eliminated, which is called the steady state.
The amount of the dug in plasma becomes constant. This can only be reached when fixed doses
of drugs are given after regular intervals. At steady state, elimination kinetics = assimilation
kinetics.
After about five plasma half lives the steady state is achieved. Drugs having longer half lives take
longer time to reach the steady state. Drugs having longer half lives have no immediate effect.
For the drugs which need to be monitored, first sample is taken after the steady state has been
reached.
Lithium for bipolar disorder is an example. Plasma levels are maintained by repeated
examinations because the drug can be toxic. Its half life is about 24 hours, so the plasma levels
are checked after 5 days.
• Time for complete elimination
Drugs having short half lives have shorter time for complete elimination. 90-95% of the drug is
eliminated after four half lives.
Clinical Situations involving Increased Half Life
• Decreased renal plasma flow, e.g. heart failure, cardiogenic shock, hemorrhage.
• Increased volume of distribution
• Decreased excretion ratio as in renal diseases

• Decreased metabolism e.g. cirrhosis of liver.
Drugs having half life less than two hours:
Aspirin, ACTH, cephalosporins, chlorthiazide, heparin, lignocaine, methyl dopa, naloxone,
penicillin G (30min), dobutamine (I min), esmolol
Drugs having half life between two to five hours
Atropine, cimetidine, indomethacin, paracetamol
Drugs having half life between ten to twenty four hours
Amitriptyline, imipramine, practolol, theophylline
Drugs having half life greater than thirty six hours
Diazepam, digoxin, phenobarbitone, thyroxin, warfarin, piroxicam (48 hrs).
1.13 Biotransformation of Xenobiotics
“Enzymatic modification of the drug occurring within the living organisms or chemical transformation a
drug goes through in living organisms or biological fluids is known as biotransformation”.
Biotransformation occurs in those foreign agents to whom the body is exposed, which may be for
therapeutic, intentional, unintentional or recreational purposes. Once these agents gain entry, they
undergo chemical reactions or remain inert. Whenever these drug molecules are administered,
pharmacokinetic process occurs, first absorption sets into play, then distribution, metabolism and finally
elimination takes place.
Drug at site of administration
Absorption Distribution
Drug in plasma Metabolism
Drug metabolites Elimination
Biotransformation occurs only for the agents at physiological pH, having low molecular weight and less
complex. Highly lipophilic, non-ionized, high molecular weight, or agents complexed with tissue or
plasma proteins are not biotransformed easily.
Biotransformation is a process specifically to make agents more polar and excretable. If biotransformation
does not occur, drugs may have longer duration of action, and undesired effects are observed along with
desired ones. Biotransformation, in fact, is the inactivation of pharmacological action of drugs.

Biotransformation may convert drugs to active metabolites or inactive sometimes toxic metabolized
products.
Prodrugs:
Prodrugs contain parent drug compounds in inactive form. Active specie is required to be carried to the
site of action. Prodrugs carry maximum amount of specie to site of action. These prodrugs have minimum
biological activity, longer half life and low toxic activity. They undergo biotransformation to bring about
desired results.
Advantages of Prodrugs:
• More stable
• Better bioavailability
• Low side effects
• Less toxic
• Desirable pharmacokinetic profile.
• Increase concentration of drug at site of action.
• Increase duration of action of drug
Examples include:
• Chloral hydrate converted into trichloroethanol
• Phenacetin converted into paracetamol
• 6-metacaptoprine
• Cortisone converted into hydrocortisone
• Prednisone converted into prednisolone
• Clorazepate
• Dipivefrin
• Enalapril converted into enalaprilat
First pass Effect:
Presystemic metabolism of drug compounds, more commonly seen with oral drugs. Drugs are absorbed
from gut, enter portal blood, reach liver, are metabolized and delivered to general circulation.
Drugs undergoing first pass effect have low bioavailability, hence first pass metabolism contributes to
termination of activity of drug, along with biotransformation.

Drug Biotransformation:
Sites:
Liver is the main organ. Others include GIT, lungs, kidneys, skin, adrenals and blood (plasma).
Some of the drugs biotransformed at these sites include:
• Liver:
Meperidine, pentazocine, morphine, nitroglycerine, lidocaine, propanolol, paracetamol, prazosin.
• GIT:
Insulin, catecholamines, clonazepam, chlorpromazine, tyramine, salbutamol
• Lung:
Prostanoids
• Plasma:
Suxamethonium
Types of Biotransformation:
• Enzymatic
• Microsomal
• Non-microsomal
• Non-enzymatic (Hofmann Elimination)
Non Enzymatic Elimination:
Spontaneous, non-catalyzed and non-enzymatic type of biotransformation for highly active, unstable
compounds taking place at physiological pH. Very few drugs undergo non-enzymatic elimination. Some
of these include:
• Mustin HCl converted into Ethyleneimonium
• Atracurium converted into Laudanosine and Quartenary acid
• Hexamine converted into Formaldehyde
• Chlorazepate converted into Desmethyl diazepam
Enzymatic Elimination:

Biotransformation taking place due to different enzymes present in the body/cells is known as enzymatic
elimination.
Non-Microsomal Biotransformation:
The type of biotransformation in which the enzymes taking part are soluble and present within the
mitochondria. Examples include:
• Xanthine oxidase converting hypoxanthine into xanthine.
• Cytotoxic agent 6-mercaptocurine
• Monoamine oxidase involved in non-microsomal metabolism of catecholamines and
noradrenaline.
• Alcohol dehydrogenase responsible for metabolism of ethanol into acetaldehyde
• Tyrosine hydrolases enzymes
Microsomal Biotransformation:
Enzymes responsible are present within the lipophilic membranes of endoplasmic reticulum. After
isolation and putting through homogenization and fractionation, small vesicles are obtained, known as
microsomes. They possess all functional, morphological properties of endoplasmic reticulum i.e. smooth
and rough. Smooth ER is concerned with biotransformation and contains enzyme components while the
rough ER is mainly concerned with protein synthesis.
Enzymes isolated from ER possess enzymatic activity termed as microsomal mixed function oxidase
system.
Components:
• Cytochrome P450 (ferric, ferrous forms)
• NADPH (flavoprotein)
• Molecular oxygen
• Membrane lipids
Cytochrome P450:
Cytochromes are the heme proteins, present abundantly within the living kingdom. They have about
thousand known kinds. Only 50 of these heme proteins are found within the humans, which are divided
into 17 families and sub-families. Name is derived because it is a heme protein (abbreviation cyp) and
450 because it reacts with carbon monoxide and during the reaction absorbs light at 450 nm.
NADPH
NADPH is a flavoprotein, less abundant than cyp 450.

For every 10 molecules of cytochrome P450, only one NADPH cytochrome reductase is present.
Cytochrome P450 cycle, RH is parent drug, ROH is oxidized metabolite, e- is electron.
Biochemical Reactions:
• Phase I reactions
• Phase II reactions
Phase I reactions:
Phase I reactions are non-synthetic catabolic type of chemical reactions occurring mainly within the ER.
They are the reactions in which the parent drug is converted into more soluble excretable agents by
introduction or unmasking of functional component.

Example includes phenobarbitone, aromatic hydroxylation of which abolishes its hypnotic activity.
Similarly, metabolism of azathioprine produces 6-mercaptopurine.
Drug products, which are water soluble are excreted by the kidneys. Sometimes this is not true and phase I
compounds do not result in true inactivation and may act as functional components of phase II reactions.
Phase I reactions include:
Oxidation
Reduction
Hydrolysis
Oxidation:
Hydroxylation
• Hydroxylation of aromatic ring
e.g. phenobarbitone is converted into p-hydroxy phenobarbitone
• Aliphatic hydroxylation
e.g. Meprobamate is converted into hydroxymeprobamate
Dealkylation
Conversion of mephobarbitone into phenobarbitone
O-Dealkylation
Conversion of codeine into morphine.
N-oxidation:
Conversion of aniline into nitrobenzene
Sulfoxidation
Conversion of chlorpromazine into chlorpromazine sulfoxide
Deamination
Conversion of amphetamine into phenylactate.
Desulfuration
Conversion of parathion into paraoxon
Reduction

Chloramphenicol, dantrolene, clonazepam
Hydrolysis
Esters: procaine, suxamethonium and aspirin
Amides: procainamide, lidocaine
Consequences of Phase I reactions:
• Active drug may be converted into inactive metabolite. Active parent drug inactivation may
terminate biological activity.
• Active drug may be converted into active metabolite. E.g. morphine is converted into more active
metabolite.
• Prodrug may be converted into active metabolite
• Active drug may be converted into toxic metabolite
e.g. halothane used in general anesthesia, is converted into trifluoroacetylated compound or
trifluoroacetic acid, leading to hepatic toxicity.
5. Biotransformation of xenobiotics to mutagenic or carcinogenic agents.
6. Conversion of xenobiotics into harmless compound.
Phase II reactions:
Phase I metabolites if not readily excretable or contain component ends, combine with endogenous
substrates like glucuronic acid, sulphuric acid, amino acid or acetic acid, to undergo conjugation
reactions, yielding more excretable drug conjugates which are excreted by the kidneys. Phase II reactions
are said to by synthetic, occurring within cytosol, while some occur within mitochondria.
Phase II reactions lead to :
• Usually inactivation of drug
• Production of water soluble metabolites, which is the main aim of biotransformation.
• Usually detoxification reaction for xenobiotics (as some substances might be carcinogenic)
• There are some important exception, toxic metabolites may be produced by their activation, e.g.
methanol is converted into formaldehyde, which is toxic.
• Certain conjugation reactions may lead to the formation of reactive species responsible for the
hepatotoxicity of drugs.
• Products produced might be more potent e.g. M-6-P.

Reactions are mainly conjugate reactions. Normally phase I reactions are followed by phase II
reactions but in case of isoniazid (antituberculous drug), phase II reactions occur before phase I
reactions because N-acetyl moiety acts as an endogenous substrate for the conjugation reaction. This
is followed by phase I hydrolysis to isonicotinic acid.
Effects of Phase II reactions on drugs
• Lipid solubility is totally converted into solubility.
• Drugs are generally inactivated
• Sometimes drugs are activated e.g. minoxidil is activated to minoxidil-o-sulphate (a vasodilator).
Morphine is activated to morphine-6-glucuronide.
Type of
Conjugation
Endogenous
Reactant
Transferrase
(Location)
Types of
Substrates
Examples
Glucuronidatio
n
UDP glucuronic
acid
UDP
glucuronosyl
transferrase
(microsomes)
Phenols,
alcohols,
carboxylic
acids,
hydroxylamines
, sulfonamides
Nitrophenol,
morphine,
acetaminophen,
diazepam,N-
hydroxydapsone
, sulfathiazole,
meprobamate,
digitoxin,
digoxin
Acetylation Acetyl-coA N-acetyl
transferrase
(cytosol)
Amines Sulfonamides,
isoniazid,
clonazepam,
dapsone,
mescaline
Glutathione
conjugation
Glutathione (GSH) GSH-S-
transferrase
(cytosol,
microsomes)
Epoxides, arene
oxides,nitro
groups,
hydroxylamines
Acetaminophin,
ethacrynicacid,
bromobenzene
Glycine
conjugation
Glycine Acyl-coA
glycinetransferas
e (mitochondria)
Acyl-coA
derivativesof
carboxylic acids
Salicylicacid,
benzoic acid,
nicotinicacid,
cinnamicacid,
cholicacid,
deoxycholic acid
Sulfation Phosphoasenosyl
phosphosulfate
Sulfotransferrase
(cytosol)
Phenols,
alcohols,
aromatic amines
Estrone, aniline,
phenol,3-
hydroxy-
coumarin,
acetaminophen,
methyl dopa
Methylation S-
adenosylmethionin
e
Transmethylases
(cytosol)
Catecholamines,
phenols, amines
Dopamine,
epinephrine,
pyridine,
histamine,

general pharma.pptx

Empfohlen

Empfohlen

Weitere ähnliche Inhalte

Ähnlich wie general pharma.pptx

Ähnlich wie general pharma.pptx (20)

Mehr von FAZAIA RUTH PFAU MEDICAL COLLEGE ,KARACHI,PAKISTAN

Mehr von FAZAIA RUTH PFAU MEDICAL COLLEGE ,KARACHI,PAKISTAN (20)

Kürzlich hochgeladen

Kürzlich hochgeladen (20)

general pharma.pptx