goodluck for exam

1. Zihnioğlu
BIOCHEMICAL
PHARMACOLOGY
AND TOXICOLOGY

2. Medicinal Chemistry
Medicinal Chemistry is an interdisciplinary
research area incorporating synthetic
organic chemistry, biochemistry,
pharmacology, molecular biology and
pharmaceutical chemistry in the search for
better drugs.

3. Medicinal Chemistry
• Primary objective－
design and discovery of
new compounds that are
suitable for use as drugs
• Team workers－
chemistry, biology,
biochemistry,
pharmacology,
mathematics, medicine
and computing, amongst
others

4. Toxicology
• Study of poisons and poisonous effects of
drugs
– Adverse effects
– Drug interactions
• Toxicology is the quantitative and qualitative
study of the adverse effects of toxicants on
biological organisms
• Toxicant is a chemical or physical agent that
produces adverse effects on biological
organisms.

5. Poisons are xenobiotics, but not all xenobiotics are poisonous.

6. XENOBIOTICS
Xenobiotics are compounds that are foreign to
the body.
Substance foreign (xenos = foreign) to life (bios)
It includes drugs, food additives, pollutants etc.
Understanding how xenobiotics are handled at
the cellular level is important in learning how to
cope with the chemical attack.

7. • Xenobiotics may be naturally occurring chemicals
produced by plants, microorganisms, or animals
(including humans).
• Xenobiotics may also be synthetic chemicals
produced by humans.
Xenobiotics

8. So Toxicology is the study of:
• How toxicants enter the organism
• How toxicants effect the organism
• How toxicants are eliminated from (leave) the
organism
• All substances are toxic if taken in the wrong
quantities
• Drugs
• Insecticides/herbicides
• Plant toxins
• Animal toxins
• Chemical weapon
• Radioactive elements
Chemical agents that cause toxicity include:

9. The science of Toxicology helps people make
informed decisions and balance
RISKS vs. BENEFITS
The study found the
highest levels of
pesticide residues in
peaches, apples,
pears…….
AND Spinach.

10. Measures of Toxicity
• Toxicity of chemicals is
determined in the
laboratory
• The normal procedure is to
expose test animals

11. Measures of Toxicity
• Toxicity is measured as clinical “endpoints”
which include
– Mortality (death)
– Teratogenicity (ability to cause birth defects)
– Carcinogenicity (ability to cause cancer), and,
– Mutagenicity (ability to cause heritible change
in the DNA)
• At this time we will discuss 2 measures of
mortality – the LD50 and the LC50

12. Measures of Toxicity:
The Median Lethal Dose
LD50
The amount (dose) of a chemical which produces death
in 50% of a population of test animals to which it is
administered by any of a variety of methods
mg/kg
Normally expressed as milligrams of substance per
kilogram of animal body weight

13. Measures of Toxicity:
The Median Lethal Concentration
LC50
The concentration of a chemical in an environment
(generally air or water) which produces death in
50% of an exposed population of test animals in
a specified time frame
mg/L
Normally expressed as milligrams of substance
per liter of air or water (or as ppm)

14. Effective Doses (EDs) are used to indicate the
effectiveness of a substance.
Normally, effective dose refers to a beneficial effect
(relief of pain). It might also stand for a harmful effect.
Thus the specific endpoint must be indicated.

15. Toxic Doses (TDs) are utilized to indicate doses
that cause adverse toxic effects.
The knowledge of the effective and toxic dose levels
aides the toxicologist and clinician in determining the
relative safety of toxic agents.

16. Effects of Toxicants
May or may not be reversible
• Dermatotoxic – affects skin
• Hemotoxic – affects blood
• Hepatotoxic – affects liver
• Nephrotoxic – affects kidneys
• Neurotoxic – affects nervous system
• Pulmonotoxic – affects lungs

17. You Know ?
• The household products implicated in
most poisonings are: cleaning solutions,
fuels, medicines, and other materials
such as glue and cosmetics.
• Certain animals secrete a xenobiotic
poison called venom, usually injected
with a bite or a sting, and others
animals harbor infectious bacteria.
• Some household plants are poisonous
to humans and animals.
92% of all poisonings happen at home.

18. Occupational and
Environmental Toxicology
• Environmental toxicants and water
pollutants) are substances harmful to the
environment and to humans.
• Environmental toxicants are both natural
and man made.
• Public perception that man-made ones are
more serious than natural ones - Reality:
both are serious.
• 5,000,000 yearly deaths worldwide due
• to bacterial toxicants (Salmonella, E. coli)

19. Occupations with high risk of cancer :
Health care workers, pharmaceutical and
laboratory workers, refinery workers, rubber
workers, furniture makers, and pesticide workers.
Occupational and
Environmental Toxicology
Many examples of diseases associated with specific
occupations were recorded in antiquity.

20. Occupational and
Environmental Toxicology
 Paracelsus - Miner’s Disease (1533) came from
inhaling metal vapors, foundation for the field of
chemotherapy.
 Hill (1761) linked tobacco (snuff) to cancer.
 Pott (1775) linked scrotal cancer and soot
(benzo(a)pyrene) in chimney sweeps.
 Radium dial painters, “aniline dye” workers (1900)
painters licked their brushes to pull it to a point.
 Shoe salesmen (1950s) shoe-fitting fluoroscopes:
radiation of feet in shoes of children and repeated
exposure for salesmen.
 Industrial chemical workers typically are exposed to a
greater number of carcinogens for longer periods of
time.

21. How Xenobiotics Cause Toxicity
– Bind and damage proteins (structural, enzymes)
– Bind and damage DNA (mutations)
– Bind and damage lipids
– React in the cell with oxygen to form “free radicals”
which damage lipid, protein, and DNA
Some xenobiotics cause toxicity by disrupting
normal cell functions:

22. Types of Toxic Effects
Death - arsenic, cyanide
Organ Damage - ozone, lead
Mutagenesis - UV light
Carcinogenesis - benzene, asbestos
Teratogenesis - thalidomide

23. The power of EDUCATION

24.  The word pharmacology is derived from the
Greek words pharmacon (drug or poison) and
logos (science).
• The effect of drugs on the body and the effect of
the body on drugs
Pharmacology deals with the fate
and actions of drugs at various
levels (molecular, cellular,
organ, and whole body)
in any animal species.
Pharmacology
Pharmacognosy – study of characteristics of natural
drugs and their sources

25.  Pharmacodynamics - how the drugs
act on the body?
 Pharmacokinetics – how the body act
on the drugs?
 Drug Indications and Application
 Drug Interactions
 Unwanted (adverse) effects
Object of Pharmacology

26. What are drugs?
Chemical substances that are used in the
diagnosis, cure, mitigation, treatment, or
prevention of disease in humans, animals
and plants.

27. Drugs act by interfering with biological
processes, so no drug is completely safe.
therapeutic
effect
toxic
effectincreasing dose

28. Dose
 The amount of chemical entering the body
 This is usually given as mg of chemical/kg of
body weight = mg/kg
 The dose is dependent upon
The environmental concentration
The properties of the toxicant
The frequency of exposure
The length of exposure
The exposure pathway

29.  Pharmacology is the base of
Pharmacotherapeutics (the treatment of diseases
with drugs).
 It overlaps extensively with pharmacy - the
science of drug production.
Main branches
1. Basic (fundamental) pharmacology
2. Special (organ pharmacology)
3. Experimental (animal) pharmacology
4. Clinical pharmacology
5. Biochemical pharmacology
6. Immunopharmacology
7. Perinatal pharmacology
8. Geriatric pharmacology
9. Pharmacogenetics, etc.

30. Exposure:Duration
Acute : < 24 hr, usually 1 exposure
Subacute : 1 month repeated doses
Subchronic :1-3 month repeated doses
Chronic : > 3 month repeated doses
Over time, the amount of chemical in the
body can build up, it can redistribute, or it
can overwhelm repair and removal
mechanisms.

31. What is a “new” drug
• The term "new drug"
means …any drug the
composition of which
is such that such drug
is not generally
recognized, among
experts to evaluate
the safety and
effectiveness of
drugs.

32. Estimates of the number of possible drug molecules
average 1040. In contrast, the number of seconds
since the Big Bang is only 1017.
Why Is It So Difficult to Make Drugs?
If 10,000 chemists were to prepare 1 compound each per
second, it would take
10,000,000,000,000,000,000,000,000,000 years
to finish the job.

33. Sources of Drugs
• Natural products
– Plants
– Animals
– Minerals
– Bacteria and fungi
• Chemical development of natural products
– Synthesis of chemical makeup of a drug
– Manipulation of genetic information
Foxglove is used
to make digitoxin

34. New drugs from old poisons
The reductionist approach to medicine began with the
isolation of opium alkaloids
Where Did (Do) Our Drugs Come From?

35. • Ethnographies show that humans
are great botanical experimentors
• Perhaps human brains, drugs and
spices evolved together!

36. Examples of Natural Products as Leads & Drugs
Cardiac glycosides, morphine, quinine, salicylic acid, taxol,
camptothecin, penicillin, cyclosporin A, warfarin, artemisine….
O
HO
RO
N
R = H: Morphine
R = Me: Codeine
(pain killer)
HO
H H
OH
H
HO
H H
OH
HH
17-ethynylestradiol norethindrone
(the "Pill"; contraceptive)
Clarithromycin
(antibacterial)
O
O
O
OH
OMeHO
O
O
O
OMe
OH
O
HO
N
HO
O N
S
O
NH2
CO2H
HH
Ampicillin
(antibiotic)
N
O
O
OH
CO2H
Clavulanic acid
-lactamase inhibitor)
Augmentin
(antibiotic)
N
N
O
O
O
N
HN
N
N
H
H
N
N
O
O
O
O
O
O
N
O
OH
N
O
N
H
Cyclosporine A
1 2
3
4
56
7
89
10 11

37. Orphan Drug
• An orphan drug is one that is intended
for use in a few patients with a rare
disease or condition
– developing such a drug would be
prohibitively expensive, given the small
market
• Over 250 orphan drugs have been
approved by the FDA

38. Drug Naming
• Chemical Name - the name which is the precise description
of the drug’s chemical composition and molecular structure
e.g., N - (4 - hydroxphenyl)
• Generic Name - the name assigned to a new drug by the
manufacturer who first develops the drug and is not
copyrighted , e.g., acetaminophen
• Official name - the name officially assigned to a new drug
and listed in official compendiums (e.g., The United States
Pharmacopeia); frequently similar to or same as the generic
name, e.g., acetaminophen
• Trade or Brand Name - the name that is assigned to a new
drug by its manufacturer that sells the drug and is
coprighted
e.g., Tylenol  , Tempra  , Datril 

39. – Pharmacopeia of the US (official)
– National Formulary
– Hospital Formulary
– Modern Drug Encyclopedia and Therapeutic
Index
– Physician Desk Reference
– package inserts
– nursing journals/texts
Common Sources of Drug
Information

40. Properties of medications controlled by
standards of quality
purity: type and concentration of extraneous substances
in a drug
potency; the concentration of the active ingredient in a
drug
bioavailability: ability of a drug to be released from
dosage form and dissolved, absorbed, and transported
by the body to its site of action
efficacy: ability of a drug to perform its desired response
at its site of action
safety/toxicity: ability of a drug to be safe and nontoxic

41. Steps in Drug Approval Process
• Isolation or development of new chemical
• Animal studies
• Investigational New Drug approval
process
– Phase 1 - small numbers; healthy individuals
– Phase 2 - small numbers; subjects with
disease
– Phase 3 - large multicenter clinical trials
• New Drug Application
Details will be explained in subsequent lectures!!!

42. Drug Classifications
• Pharmacologic Classification
–Similar Characteristics
–Similar Chemical Make up
–examples: Penicillins, Beta Blockers
• Therapeutic Classification
–Used for similar effect
–May not have similar chemical make up
–Examples: Antihypertensives, Antibiotics

43. Drug Classification
’’according to their origin’’
• Natural compounds: materials obtained from both plant
and animal, e.g. vitamins, hormones, amino acids,
antibiotics, alkaloids, glycosides…. etc.).
• Synthesis compounds: either pure synthesis or
synthesis naturally occurring compounds (e.g. morphine,
atropine, steroids and cocaine) to reduce their cost.
• Semi-synthesis compounds: Some compounds either
can not be purely synthesized or can not be isolated from
natural sources in low cost. Therefore, the natural
intermediate of such drugs could be used for the synthesis
of a desired product (e.g. semi synthetic penicillins).

44. Drug Classification
’’according to their medicinal uses’’
No certain relation between chemical structure and
pharmacological activity therefore, it would be
unwise to arrange all drugs on the basis of their
structures or origin.
1.Pharmacodynamic agents: Drugs that act on
the various physiological functions of the body
(e.g. general anaesthetic, hypnotic and
sedatives, analgesic etc.).
2.Chemotherapeutic agents: Those drugs which
are used to fight pathogenic (e.g. sulphonamides,
antibiotics, antimalarial agents, antiviral,
anticancer etc.).

45. Infectious diseases: Born (transmitted) from person to
person by outside agents, bacteria (pneumonia,
salmonella), viruses (common cold, AIDS), fungi (thrush,
athletes foot), parasites (malaria)
Non-infectious diseases: disorders of the human body
caused by genetic malfunction, environmental factors,
stress, old age etc. (e.g. diabetes, heart disease, cancer.
Haemophilia, asthma, mental illness, stomach ulcers,
arthritis).
Non-diseases: alleviation of pain (analgesic), prevention of
pregnancy (contraception) , anesthesia.
Drug Classification
Drugs can treat different types of diseases:

46. CLASSIFICATIONS OF
MEDICATIONS
• Anticoagulants
• Anticonvulsants
• Antidiabetics
• Antidysrhythmics
• Antihypertensives
• Anti-infectives
• Antipsychotics
• Cardiac glycosides
• Corticosteroids
• Drotrecogin
• GI Agents
• IV fluids
• Narcotics
• Parenteral Nutrition
• Platelet Aggregation
Inhibitors
• Respiratory Medications
• Sedatives
• Vasoactive Agents

47. 47
Drug Misuse
• Drug misuse - Improper use of any
medication which leads to acute/chronic
toxicity
• Drug abuse - Inappropriate intake of a
substance

48. Therapeutic
(the desired
response to a drug)
Nontherapeutic
(an undesired response
to a drug)
Responses to Drugs

49. Therapeutic
(the desired response to a drug)
 Palliative : relieves the symptoms of a disease
but does not affect the disease itself
e.g., morphine sulphate for pain
 Curative: cures a disease or condition
e.g., penicillin for an infection
 Supportive : supports body functions until other
treatments or the body’s response can take over
e.g., dopamine (Inotropin) for low blood pressure

50. Therapeutic
(the desired response to a drug)
 Substitutive: replaces body fluids or substances
e.g., insulin for diabetes
 Chemotherapeutic : destroys malignant cells
e.g., vincristine (Oncovin) for Hodgkin’s
lymphoma
 Restorative : returns the body to health
e.g., vitamins

51. Why should I lose
time to send a
report of adverse
drug reactions?
Adverse Effect
• Any non-therapeutic response to the drug
therapy-consequences may be minor or
significant
Non-therapeutic
(undesired response to a drug)

52.  Drug allergy : an altered state of reaction to a drug
resulting from a previously sensitizing exposure to
the drug
1) mild or severe
mild: rash, angioedema, rhinitis, fever, asthma,
pruritis, lacrimal tearing, diarrhea, nausea and
vomiting
severe: sudden, severe bronchospasm,
vasospasm, severe hypotension, tachycardia
(anaphylaxis)
2) immediate or delayed
immediate: within minutes of exposure to the drug
delayed: 7 to 14 days after initial exposure to the drug
Non-therapeutic
(undesired response to a drug)

53.  Side effect ; an unintended, but usually
predictable, response to a drug which can be
harmless or injurous
 Idiosyncracy : an abnormal or peculiar response
to a drug
1) overresponse to the drug
2) underresponse to the drug
3) a different response to the drug than expected
4) an unexplained or unpredicted response to the drug
Non-therapeutic
(undesired response to a drug)

54.  Tolerance: decreased physiologic response to
the repeated administration of a drug which
necessitates an increased dosage of the drug to
maintain a therapeutic effect
 Acummulation: the build up of a drug when the
body cannot biotransform (metabolize) and/or
excrete one dose of the medication before the
next is administered
Non-therapeutic
(undesired response to a drug)

55.  Drug dependence : reliance on or need to take a
drug or substance
Two types of drug dependence;
1) Physiologic dependence : state of physiologic
adaptation to a drug that manifests itself by
intense physical disturbance when the drug is
withdrawn
2) Psychologic dependence: state of emotional
reliance on a drug to maintain a sense of well-
being manifested by a mild desire to craving for
the drug
Non-therapeutic
(undesired response to a drug)

56. Drug interaction:
Changing the effect of one drug by the
administration of another drug(s)
 can either increase or decrease the
effect of each drug
 can either be beneficial or detrimental
Non-therapeutic
(undesired response to a drug)

57. Type of drug interactions ;
1) Summative:
Drug interaction in which the combined
effects of two drugs equal the sum of each
drug acting individually
1 + 1 = 2
e.g., codeine (analgesic) + aspirin (analgesic)
= better pain control
Non-therapeutic (undesired response to a drug)

58. Type of drug interactions (cont.) ;
2) Synergistic :
Drug interaction in which the combined effects of
two drugs is greater than the sum of each drug
acting individually
1 + 1 = 3 or more
e.g., propranolol (beta blocker) + hydralazine
(vasodilator) + hydrochlorothiazide (diruetic) =
better B/P control (work in different ways)

59. Type of drug interactions (cont.) ;
3) Potentiative:
Drug interaction in which the concurrent
administration of one drug increases the
effect of the other drug
1 + 1 > 2
e.g., probenecid (blocks excretion of
penicillin) + penicillin = higher blood levels of
penicillin

60. Type of drug interactions (cont.) ;
4) Antagonistic
Drug interaction in which the combined effects of
two drugs is greater than the sum of each drug
acting individually
1 + 1 = 3 or more
e.g., propranolol (beta blocker) + hydralazine
(vasodilator) + hydrochlorothiazide (diruetic)
= better B/P control (work in different ways)

61.  iatrogenic: adverse drug effects inflicted
unintentionally as a result of treatment
Types of iatrogenic responses ;
1) blood dyscrasias ; e.g., agranulocytosis, aplastic
anemia, thrombocytopenia, bone marrow depression
2)hepatic toxicity : e.g., biliary obstruction, hepatitis-like
syndromes, hepatic necrosis
3)renal damage: e.g., glomerular damage
4)Teratogenic: e.g., fetal malformations
5)dermatologic : e.g., acne, psoriasis, eczema,
maculopapular rashes, erythema multiforme
Non-therapeutic
(undesired response to a drug)

62. Drug-dose response
Depends on three factors;
1. Plasma levels of a drug
2. Biological Half-life
3. Therapeutic index

63. Drug-dose response
1. Plasma levels of a drug
1) Onset of action or latent period ; interval between the time
a drug is administered and the first sign of its effect
2) Termination of action : point at which a drug effect is no
longer seen
3) Duration of action: period from onset of a drug action to the
time when a drug response is no longer perceptible
4) Minimal effective concentration: lowest plasma
concentration that produces the desired drug effect
5) Peak plasma level: highest plasma concentration attained
from a dose of a drug
6) Toxic plasma level: plasma concentration at which a drug
produces serious adverse effects
7) Therapeutic range: range of plasma concentration of a drug
that produces the desired effect without toxicity (the range
between minimal effective concentration and toxic level)

64. Drug-dose response
2. Biologic Half-Life
The time interval required for the
body’s elimination processes to
reduce the plasma concentration of
the drug in the body by one-half

65. 3.Therapeutic Index (TI)
Relates to drug’s margin of safety, the ratio of
effective dose to a lethal dose
Drug-dose response
1)Lethal dose (LD): the dose of a drug at which it is
lethal in 50% of laboratory animals tested
2)Effective dose (ED): the dose of a drug which is
therapeutically effective in 50% of laboratory
animals tested
3)TI = LD divided by ED
The closer the therapeutic index is to 1, the more
lethal the drug

66. DRUG THERAPY
• The processes of drug therapy are very
complex!!!
• It is important to understand the disease
processes
• Precise Diagnosis!!!!
• Advances in the understanding of the
detailed events underlying the pathology
of diseases have allowed the development
of drugs with spesific targets.

67. “7 Rights” of Safe Medication
Administration
• Right Drug
• Right Dose
• Right Time
• Right Route
• Right Patient
• Right Reason
• Right Documentation

68. DRUG THERAPY
Four main processes in drug therapy;
1.Pharmaceutical process
Is the drug getting into the patient?
2.Pharmacokinetic process
Is the drug getting its site of action?
3.Pharmacodynamic process
Is the drug producing the required
pharmacological effect?
4.Therapeutic Process
Is the pharmological effect being translated into
a therapeutic effect?

69. Pharmaceutical process
Is the drug getting into the patient?

70. DRUG THERAPY
1. Pharmaceutical process
 Patient compliance or concordance with therapy
 Systemic availability ( Bioavailabilty )
 extent of absorption and the rate at which an
administered dose reaches systemic circulation in
its active form
 Drug formulations and route of administration
Two important factors that determine whether
or not a drug gets into the patient are;

71. Pharmaceutics
• Different dosage forms have different
pharmaceutical properties.
• Specific drugs may come in a number of
forms:
– Digoxin
capsule, tablet, liquid for swallowing, liquid
for injection
• Never change the route or form without
specific clinician’s order

72. Major categories of dosage forms:
 Solids: tablets, capsules, lozenges
 Liquids: syrups, solutions, emulsions,
and suspensions
 Semisolids: ointments, creams
 Gases or vapors

73. Common types of drug preparations
 Elixir: a sweetened and aromatic solution of
alcohol used as a vehicle for medicinal agents
 Extract: a concentrated form of a drug made from
vegetables or animals
 Solution: one or more drugs dissolved in water
 Spirit: a finely concentrated alcoholic solution of a
volatile substance
 Suspension: one or more drugs finely divided in a
liquid such as water
 Syrup: an aqueous solution of sugar often used to
disguise unpleasant-tasting drugs
 Tincture: an alcoholic or water-and-alcohol
solution prepared from drugs derived from plants

74. Common types of drug preparations
 Caplet:an oval-shaped tablet that is coated to
facilitate swallowing.
 Capsule:a gelatinous container to hold a drug in
powder, liquid, or oil form
 Pill:one or more drugs, mixed with a cohesive
material, in oval, round, or flattened shapes
 Powder: a finely ground drug or drugs; some are
used internally, others externally
 Suppository:one or several drugs, mixed with a firm
base such as gelatin, and shaped for insertion into
the body; the base dissolves gradually at body
temperature releasing the drug

75. Common types of drug preparations
 Tablet: a powdered drug compressed into a
hard, small disc; some are readily broken
along a scored line; others are enteric-coated
to prevent them from dissolving in the
stomach
 Lozenge (troche); a flat, round, or oval
preparation that dissolves and releases a
drug when held in the mouth
 Fluid extract: an alcoholic solution of a drug
from a vegetable source; the most
concentrated of all fluid preparations

76. Common types of drug preparations
 Paste: a preparation like an ointment, but
thicker and stiffer, that penetrates the skin
less than an ointment
 Aerosol spray or foam; a liquid, powder, or
foam deposited in a thin layer on the skin by
air pressure
 Cream: a nongreasy, semisolid preparation
used on the skin
 Gel or jelly: a clear or translucent semisolid
that liquefies when applied to the skin

77. Common types of drug preparations
 Liniment: an oily liquid used on the skin
 Lotion: an emollient liquid that may be a clear
solution, suspension, or emulsion used on the
skin
 Ointment; a semisolid preparation of one or
more drugs used for application to the skin
and mucous membranes
 Transdermal patch; a semipermeable
membrane shaped in the form of a disk or
patch that contains a drug to be absorbed
through the skin over a lengthy period of time

78. Routes of Administration
• Depends upon:
– Drug characteristic
– Desired responses
– The action of the medication on the body
– The physical and emotional state of the patient
• Each route has advantages/disadvantages
DRUG THERAPY
1. Pharmaceutical process

79. Routes of Administration
1. Enteral
Enteral refers to anything involving the
alimentary tract (from the mouth to the rectum).
DRUG THERAPY
1. Pharmaceutical process
2. Parenteral
Any route other than enteral is considered
parenteral.
 Parenteral means next to, or beside the
enteral. It refers to any sites that are
outside of or beside the alimentary tract

80. Routes of Administration
DRUG THERAPY
1. Pharmaceutical process
2. Parenteral
Any route other than enteral is considered
parenteral.
Parenteral means next to, or beside the
enteral. It refers to any sites that are outside of
or beside the alimentary tract

81. Routes of Administration
1. Enteral
There are 4 enteral routes of administration;
 Oral (PO)
 Buccal (Buc)
 Sublingual(SL)
 Rectal (PR)

82. Oral Route
 Medication is taken by mouth (example:
swallowing a caplet or syrup)
 By mouth or oral medications are very
convenient, do not need to be measured, less
expensive, systemic, and safe
 The downside is that they do not work as
quickly as parenterals
 Some drugs cannot be taken orally because
they are not as effective
Routes of Administration; Oral

83. Advantages
 Safer
 More convenient
 Easier to store
 May be more readily
available in pharmacies
 Generally less expensive
 May be available in
immediate-release or
extended-release dosage
forms
 Easier to self-administer
 Generally do not require
additional administration
supplies
Disadvantages
 hepatic first-pass effect
 effect too slow for
emergencies
 presence of food retards
absorption
 possible enzymatic
degradation/acid degradation
 May not be appropriate for
children or elderly patients
 May be difficult for patients to
swallow
 Have to be broken down,
absorbed, and then distributed
to the body
Routes of Administration; Oral

84. First Pass Effect
Drugs that are absorbed via the GIT are
circulated to the liver first via the hepatic portal
vein
Liver then acts as a filter
Only part of the drug is circulated systemically
The combination of processes is termed the
‘First Pass’ effect

85. First Pass Effect

86. “First Pass Effect”
• Routes that bypass the liver:
–Sublingual Transdermal
–Buccal Vaginal
–Rectal* Intramuscular
–Intravenous Subcutaneous
–Intranasal Inhalation
* Rectal route undergoes a higher
degree of first-pass effects than the
other routes listed.

88. Routes of Administration
2. Parenteral
 Medication is injected directly into the body,
bypassing the gastrointestinal system for
absorption and distribution
 The most common parenteral medications are
given IV, IM, or SC
 Very-small–gauge needles are used, and the
length depends on the site being injected
Benefit: speed of action
 Parenteral drugs work within a few minutes
 Important for emergency situations, for those
who are combative, or for those who are
unable to swallow

89.  Intraventricular; injected into the brain cavities, or ventricles (e.g.,
antibiotics or chemotherapy agents)
 Intravesicular; injected directly into the urinary bladder
 Intravitreal; injected directly into the vitreous body of the eye
 Intradermal; injected into the top layers of the skin
 Subcutaneous; injected into the tissue immediately under the skin
 Intramuscular; injected directly into muscle
 Intravenous; injected directly into the vein
 Implant; temporary or permanent medical device inserted into the
body that slowly releases medication
 Intra-articular; injected directly within the joints
 Intracardiac; injected directly into the heart
 Intraperitoneal; injected directly into the abdominal or peritoneal
cavity
 Intrapleural; injected into the sac (pleura) surrounding the lungs
 Intrathecal; injected within the cerebrospinal fluid surrounding the
spinal cord
Parenteral routes of administration; Injection.

90. Advantages
 Fast absorption and distribution
 Convenient for those who can’t take oral medication
 Varied rate of delivery, from a couple of seconds to
several hours
Disadvantages
 Action can be immediate
 No way to reverse the amount of drug administered
 Little or no way to reverse any adverse effects
 Very invasive, Can be very painful
 Poses an opportunity for bacteria and infection to
enter the body-through a significant portal to the
bloodstream
Parenteral routes of administration; Injection.

92. Intravenous Administration (IV)
• Involves injection of drugs directly into
bloodstream
• Drugs act rapidly
• Administered through established IV line or
direct injection into the vein (in emergencies)
• Used for intermittent or continuous
infusions

93. Intravenous Administration

94. Subcutaneous Administration (SQ)
• Injection of drugs under the skin
• Used for small volume (1 ml)
• Absorption is slower
• Drug action is usually longer
• Drugs that are irritating to tissues
cannot be given SC
• Common sites:
upper arms, abdomen, thighs

95. A diabetic patient
making subcutaneous
injection
subcutaneous injection
in the mouse

96. Intradermal Administration (ID)
• Use 26-27 gauge needle
• Apply traction to skin near site
• Place needle with bevel upward
• Inject small wheel at site and
withdrawal needle
• Do not massage
• Maximum volume = 0.1ml

97. Intramuscular Administration (IM)
• Involves injection of drugs into muscle
• Absorption is more rapid due to blood
supply
• Incorrect injection techniques may damage
blood vessels and nerves
Photo Source: Lippincott, Williams & Wilkins, Connection, Image Bank, http://connection.lww.com/products/smeltzer9e/imagebank.asp

98. Intramuscular injection in deltoid and gluteal
muscles

99. Inraperitoneal Injection

100. Pulmonary Administration
 large contact surface (surface area > 30 m2 )
 extensive blood supply (2000 km of capillaries)
 thin membrane separating air from blood

101. Pulmonary Administration
Inhalation:
 medication is inhaled through the
mouth and absorbed in the lungs
-using an asthma inhaler
 Inhalants (INH) are used to treat
lung diseases
 Onset of action is very quick
Formulations:
Powders
Aerosol solutions
Nebulised solutions

102. Topical routes of administration
 Topical (TOP) preparations effects range
from systemic to localized for rashes
 There are agents to fight skin infections,
inflammation, and UV rays of the sun
 They work at the site of action and
systemically
 An advantage is easy application
 A downside is that they might cause a
reaction
 Medication is administered externally to
the skin or mucous membranes-rubbing
an anesthetic gel onto a sore gum

103. Topical: Intranasal Formulations
 Medication is inhaled through the nose and
absorbed into the bloodstream, or medication is
sprayed into the nose for local effects
 Most nasal sprays are used to treat colds and
allergies
 The latest generation of nasal sprays includes
antihistamines, which can treat allergic reactions that
result in nasal congestion at the site of the reaction
Saddle-nose deformity

104. Topical:Ophthalmic; Eye Drops
 Medication is administered through the eye
 Eyedrops are applied for irritation or inflammation
of the conjunctiva
 Doctors often use eye solutions to treat ear
conditions, but ear solutions cannot be used to
treat eye conditions because:
• All eye agents are sterile
• The eye is aqueous with water-based secretions

105.  Medication is administered
into the ear
 Eardrops are delivered into
the ear canal to treat an
infection
 Otic preparations are not
necessarily sterile because
they treat the ear canal and do
not penetrate a sterile
environment
 Most ear treatments are for:
infections, water in the ears,
and to solve ear wax buildup
Topical: Otic; Ear Drops

106.  A patch is applied to the skin, where it
delivers medication to the bloodstream-a
nicotine patch is applied to the skin
Topical: Transdermal
Advantages of transdermal route;
 Easy to store,
 Convenient to use
 Can remain on the body for a long time
 More convenient than taking a tablet on a daily basis
-better compliance
-bypasses GI tract (including liver)
Disadvantages of transdermal route;
 May cause skin irritation
 May pull on body hair

108. Conventional Dosage Forms

109. • Intravenous; 30-60 seconds
• Endotracheal; 2-3 minutes
• Inhalation; 2-3 minutes
• Sublingual; 3-5 minutes
• Intramuscular; 10-20 minutes
• Subcutenous; 15-30 minutes
• Rectal; 5-30 minutes
• Oral; 30-90 minutes
• Transdermal (topical); various
(minutes - hours)
Routes of Administration; Response Time

110. DRUG THERAPY
Four main processes in drug therapy;
1.Pharmaceutical process
Is the drug getting into the patient?
2.Pharmacokinetic process
Is the drug getting its site of action?
3.Pharmacodynamic process
Is the drug producing the required
pharmacological effect?
4.Therapeutic Process
Is the pharmological effect being translated into
a therapeutic effect?
√

111. Pharmacokinetic process
Is the drug getting its site of
action?

112. Pharmacokinetics (PK)
 The study of the disposition of a drug
 The disposition of a drug includes the
processes of ADME
 Absorption
 Distribution
 Metabolism
 Excretion
 Toxicity
Elimination

113. Pharmacokinetics
• Based on the hypothesis that the action of
a drug requires presence of a certain
concentration in the fluid bathing the target
tissue.
• In other words, the magnitude of response
(good or bad) depends on concentration of
the drug at the site of action

114. ADME
the process by which a
drug moves from its
site of administration
to the systemic
circulation
the reversible
transfer of a drug to
and from the
systemic circulation
any chemical alteration
of a drug by the living
system to enhance
water solubility and
hence excretion
the irreversible transfer
of a drug from the
systemic circulation

115. Pharmacokinetics: Drug Absorption
Absorption; describes the rate and extent at which a
drug leaves its site of administration.
Bioavailability; is the extent to which a drug reaches
its site of action, or to a biological fluid (such as
plasma) from which the drug has access to its site of
action.
% Absorption = % first pass effect + % bioavailability
So bioavailability is not the same as absorption

116. Absorption
 Absorbed largely from small
intestine
•Some Sublinqual absorption
•Rectal Absorption (suppository)
•Some Absorption from stomach
(rare)
 Molecules need to be near the
intestinal mucosa to be absorbed
 Compound should be soluble in
gut contents or in vehicle
 Crystals are not well absorbed
 Gummy stuff is not well absorbedTaken from TNO Pharma Web

117. Intestinal Wall Structure
Epithelium
Central capillary network
Intestinal wall epithelial cells have many finger-like
projections on their luminal surface called microvilli which
form the brush border membrane
Brush Border
Membrane
Epithelial
Cell (enterocyte)
Microvilli
Apical surface
Basolateral surface

118. Drug properties
• Molecular weight, shape and size
• Water solubility (basic property)
• Lipid solubility
• Ionization

119. Molecular weight, shape and size
• Small molecules – more chance of crossing
membrane
Selective
permeability

120. Mechanisms of Drug Transport
Transcellular transport
 Passive diffusion
 Carrier-mediated transport
 Facilitated diffusion
 Active transport
 Ion-pair transport
 Endocytosis or
Pinocytosis
Paracellular transport
 Bulk flow
 Filtration

121. Factors Affecting Drug Absorption
• Routes of drug administration
• Dose, Concentration, and Rate of
administration
• Dosage forms
• Physical and chemical properties of drugs
• Physiological Factors
121

122. MOUTH
INTESTINE
BLOOD
Gut wall
Metabolism
STOMACH
pH ~1
Relative SA ~1
pH ~ 7
Relative SA ~ 600
Liver
Portal vein

123. 1) Formulation; route of administration
2) Drug solubility: Ability of a drug to breakdown
and dissolve
 drugs that are readily soluble are absorbed more
rapidly
e.g., liquids, elixirs, syrups
 drugs that are not readily soluble are absorbed
less rapidly
e.g., enteric-coated tablets
Factors Affecting Drug Absorption

124. 3) pH
a) Effect of ionization on drug absorption
 Drugs that do not ionize, which are lipid soluble
and water insoluble, pass with ease across cell
membranes (use passive diffusion) and,
consequently, are absorbed relatively rapidly
 Drugs that ionize, which are lipid insoluble and
water soluble, pass with difficulty across cell
membranes (use active transport) and,
consequently, are absorbed relatively slowly
Factors Affecting Drug Absorption (Cont..)

125. 4)
5)
pH
b) Effect of an acidic or basic environment on
drug absorption
 a weak acidic drug in an acidic medium (such as
the stomach; pH = 1.4) does not ionize and, thus,
is absorbed better in this environment
 a weak basic drug in a basic medium (such as
the intestines; pH = 6 - 8) does not ionize and,
thus, is absorbed better in this environment
Blood flow to the site of administration
 relatively blood rich site enhances absorption of
drugs
 relatively blood poor site delays absorption of
drugs
Factors Affecting Drug Absorption (Cont..)

126. 6) Nature of the absorbing surface through
which the drug must traverse
 Number of cell layers in the absorbing surface
 Surface with few cell layers enhances
absorption of drugs
 Surface with many cell layers delays
absorption of drugs
 Size of the absorbing surface
 Relatively large surface area enhances
absorption of drugs
 Relatively small surface area delays
absorption of drugs
Factors Affecting Drug Absorption (Cont..)

127. 7) Drug Concentration
 Drugs administered in high concentrations tend to
be more rapidly absorbed
 Drugs administered in low concentrations tend to
be less rapidly absorbed
 Idea of priming and maintenance dose of a drug
utilizes this phenomena
a) priming (or loading) dose ;adminstration of a
drug in a large dose that temporarily exceeds the
body’s capacity for excretion of the drug
b) maintenance dose ; administration of a drug in
smaller doses after a priming (or loading) dose in
order to replace only the amount of the drug
excreted since the previous dose
Factors Affecting Drug Absorption (Cont..)

128. 8) Dosage form of the drug
 Dosage forms with different formulations clearly
affect drug absorption
Depend on how well they can be dissolved –
Liberation process
Factors Affecting Drug Absorption (Cont..)

129. 9) Physicochemical Properties of Drug
 Acid or Base
 Degree of ionization
 Polarity
 Molecular weight
 Lipid solubility or...
 Partition coefficient (Kp)
Factors Affecting Drug Absorption (Cont..)

130. 10) Physiological Factors
 Gastric motility
 Gastric emptying time
 pH at the absorption site
 Area of absorbing surface
 Blood flow
 Presystemic elimination
 Ingestion with or without food
Factors Affecting Drug Absorption (Cont..)

132. Absorption Distribution
BLOOD TISSUES
The reversible transfer of a drug to and from
the systemic circulation
Pharmacokinetics:Distribution
Transportation of a drug in bodily fluids from
the bloodstream to various tissues of the
body and, ultimately, to its site of action

133. Pharmacokinetics:Distribution

135. Pharmacokinetics: Drug distribution
Distribution is influenced by:
a) Blood flow to target tissues
b) Ability of drug to exit blood vessels
 typical capillary - no barrier
 blood-brain barrier = tight junctions between
endothelial cells (only lipid soluble)
 placental barrier - only lipid soluble pass freely
c) Ability to enter cells
 must be lipid soluble, or have transporter
 most drugs act at receptors on cell surface (do
not enter)

136. Factors affecting drug distribution
• Factors  rate of distribution (how fast)
– Membrane permeability
– Blood perfusion
• Factors  extend of distribution (how much)
– Lipid solubility
– pH – pKa
– Protein binding
• Plasma protein binding
• Tissue protein binding
– Elimination processes

137. Phases of Distribution
First phase
 Reflects cardiac output and regional blood
flow.
 Thus, heart, liver, kidney & brain receive
most of the drug during the first few
minutes after absorption.
Second phase
 Delivery to muscle, most viscera, skin and
adipose is slower, and involves a far
larger fraction of the body mass.

138. Pharmacokinetics
Locus of
action
“receptors”
Bound Free
Tissue
reservoirs
Bound Free
Absorption Excretion
Biotransformation
Free drug
Systemic
circulation
Bound drug Metabolites

139. Plasma Protein – Drug Binding (PPB)
 Drugs can bind to macromolecules in the blood
– known as plasma protein binding (PPB)
 Only unbound compound is available for
distribution into tissues
 Acids bind to basic binding sites on albumin,
bases bind to alpha-1 acid glycoprotein
Drug
Free
Drug Protein
Rapid
Equilibrium
Bound
Drug
Factors Affecting Drug Distribution

140. Plasma Proteins
albumin
- primarily for acidic drugs
α1-acid glycoprotein
- for basic drugs
Lipoproteins
- for some drugs
The fraction of total drug in plasma that is
bound is determined by;
 the drug concentration,
 its affinity for the binding sites, and
 the number of binding sites.

141. Plasma Extracellular water
Plasma protein Tissue protein
drug
Drug – Protein Binding is reversible.

142. Plasma Protein – Drug Binding (PPB)
 A drug that exhibits a high degree of binding to
protein (mainly albumin) as it enters the
circulatory system does not leave much free drug
for distribution through the blood stream to the
drug’s site of action
 A drug that exhibits a low degree of binding to
protein (mainly albumin) as it enters the
circulatory system leaves more free drug for
distribution through the bloodstream to the drug’s
site of action

143. Plasma Protein – Drug Binding (PPB)
 Competition for binding sites
 some drugs bind to the same receptor site on
the albumin molecule and displace each other
and can lead to an increased level of free drug
in the bloodstream
 Hypoalbuminemia
 a decease of albumin in the blood results in
fewer albumin molecules for a drug to bind
with and can lead to an increased level of free
drug in the bloodstream
The degree of a drug’s propensity to bind to
protein can be influenced by the following:

144. • Drugs that bind to tissues (e.g., tetracycline
for bone; thiopental [Pentothal] for fat) leave
less free drug for distribution in the
circulation to the drug’s site of action
• Drugs that do not bind to tissues leave
more free drug for distribution in the
circulation to the drug’s site of action
Tissue – Drug Binding (PPB)
Factors Affecting Drug Distribution

145. • Row of capillary endothelial cells joined by
continuous tight intercellular junctions ; allows only
lipid soluble drugs to pass into the CNS
• Prevent distribution of drugs in the CNS
• Prevent distribution of drugs to the fetus
Blood Brain Barrier
Factors Affecting Drug Distribution
Placenta Barrier

146.  Cardiac output
(amount of blood pumped by the heart each minute)
a) low cardiac output prevents distrubtion of drugs
b) high cardiac output enhances distribution of drugs
 Regional blood flow
(amount of blood supplied to a specific organ or
tissue)
a) low regional blood flow deters distribution of drugs
b) high regional blood flow enhan ces distribution of
drugs
Cardiac Function
Factors Affecting Drug Distribution

147. Redistribution
 Termination of drug action is normally
by biotransformation, but may also occur
as a result of redistribution between
various compartments.
 Particularly true for lipid-soluble drugs
that affect brain and heart.

148. DRUG THERAPY
2. Pharmacokinetic process
Is the drug getting its site of action?
The study of the disposition of a drug; ADME
 Absorption
 Distribution
 METABOLISM
 Excretion