Pharmacokinetics and Pharmacodynamics

3. DEFINITION:-
Pharmacology may be defined as the study of Effect of a
drug (chemical) on the body (living system)
It is a study as how drugs can alter physiological or
biochemical function of a living organism
Why are drugs important for health and scientific
research?
“magic bullets”—agents that treat disease or produce
desirable effects but lack harm
‘maximize efficacy but minimize toxicity’’

6. Pharmacotherapeutics-
This deals with the clinical application of the drug in the prevention, treatment or
diagnosis of a disease

7. Clinical pharmacology- It deals with the protocols of clinical evaluation of
a new drug in healthy volunteers and patients.
Pharmacogenomics- Application of genomic technologies to new drug
discovery & further characterization of older drugs.
Posology- How medicine are dosed. It also depends on various factors
like age, climate, weight, sex.
Pharmacovigilance- WHO define the Pharmacovigilance (PV) as the
pharmacological science relating to the
detection, evaluation, understanding and prevention of adverse effects,
particularly long term and short term side effects of medicines.
Translational pharmacology- It is the process of turning appropriate
biological discoveries into drugs and medical devices that can be used in
the treatment of patients.

8. Deals with the natural drugs,
identification of medicinal plants,
drug extraction from plants,
composition and uses.
 Deals with composition, use and development of medicinal substance of
biological origin

9. Pharmacogenetics- Clinical testing of genetic variation that given rise to differing
response to drugs .It is the study of inherited differences in drug metabolism or drug
response in humans.
Eg.- Isoniazide(Anti tubercular)
Peripheral neuritis in slow acetylators
Hepatotoxicity in fast acetylators

10. Toxicology – is the study of harmful effects of chemical on
living organisms.
Experimental Pharmacology – deals with the study of
drug effects in laboratory animals.
Neuropharmacology – deals with effects of drugs on
Nerves.
Chemotherapy:- Deals with the effects of drugs upon
microorganisms and parasites without destroying the host cells.

11. Art & Science of compounding
& dispensing drugs
mainly concerned with
 Identification
 Preparation
 Standardization
 Storage
 Compounding
 Dispensing
Of drugs
Pharmacy

12. Types
Official Pharmacy
Extemporaneous
pharmacy

13.  is a word derived from a French word ‘Drogue’ which means dry
herb.
 Definition:-
Drug is any substance or product that is used or intended to
be used to modify or explore physiological systems or
pathological states for the benefit of the recipient.
 Are poisons if they used irrationally
Drugs

14. Categories
Non-prescriptive
Drugs/OTC:-
•These are safe
•Can be sold without the
prescription of Registered
Medical Practitioner
eg.-
Vitamins
Antacids
Minerals
Analgesics
Prescriptive Drugs:-
E.g.-Antibiotics
Anxiolytic

15. Every drug has at least three names—
1.Chemical name,
2.Generic name (non-proprietary or official),
3.Trade name(proprietary or brand).
The chemical name describes the atomic or molecular
structure of the drug. This name is usually too complex
and cumbersome for general use.
Nomenclature
Chemical name Generic name Brand name
Acetyl salicylic acid Aspirin Ecospirin(USV,india)
Disprin (Rickett,India)
P-Acetamino phenol Paracetamol Crocin(GSK,India)
Calpol
(Burroughs,India)

16. Name are assigned by USAN(united states adopted
name)
Only when the drug has been found to be of potential
therapeutic useful.
The generic names for drugs of a particular type (class)
usually have the same ending.
These names are used uniformly all over the world by an
international agreement through WHO.
For example:-
Beta-blockers-end in "lol."
Benzodiazepam-end ‘pam’
Proton pump inhibitors-end ‘prazole’
Generic name/NPN

17. • The is chosen by the pharmaceutical company that
manufactures or distributes the drug.
• Brand name are short & easy to recall
• A drug may have different brand name within a
country and in different country
Trade name/proprietary name/Brand
name

18. The WHO has defined Essential Drugs (medicines) as
"those that satisfy the priority healthcare needs of
the population. They are selected with due regard to
public health relevance, evidence on efficacy and safety,
and comparative cost effectiveness.
Drugs use in most common diseases & complaints
Drugs Intended to be available
within the context of functional health system
at all times and
in adequate amount
in appropriate dosage forms
at a affordable price
Essential drug

19. These are drugs used for diagnosis/treatment or
prevention of a rare disease or condition
Eg:-
Sodium nitrite,
fomepizole,
liposomal amphoterisin B,
miltefosine,
rifabutin, somatropin, digoxin antibody, liothyronine (T3).
Orphan drug

20. P drug (preferred or personal drug):-
A doctor can choose a preferred drug to treat a
particular disease.
He may choose his P-drug by comparing the efficacy,
safety, suitability and total cost of treatment with this
drug Vs other drugs used to treat.

21. This is an inert substance which is given in the
garb of a medicine.
It works by psychologically rather than
pharmacological means and often produces responses
equivalent to the active drug.
Some individuals are more suggestible and easily
respond to a placebo: and are called 'placebo
reactors'.
uses:-
1. As a control device in clinical trial of drugs (dummy
medication).
2. To treat a patient who, in the opinion of the
physician, does not require an active drug.
Placebo ‘‘I shall please ‘’

22. converse of placebo.
refers to negative psychodynamic effect evoked by
the pessimistic attitude of the patient, or by
loss of faith in the medication and/or the
physician.
Nocebo effect can oppose the therapeutic effect of
active medication.
Nocebo

23. DRUG USAGES
Drugs have 3 medical uses.
Therapeutic use:-Drugs are used to control,
improve or cure symptoms, conditions or diseases of a
physiological or psychological nature. E.g of the
therapeutic use of drugs include the following:
Antibiotics to kill the bacteria that cause an infection
Analgesics to control the pain and inflammation of
arthritis
Hormone replacement therapy for the symptoms of
menopause

24. Preventive use: Drugs are used to prevent the
occurrence of symptoms, conditions or
diseases. E.g of the preventive use of drugs
include the following
Vaccination for immunization against
childhood diseases
Drugs taken to prevent motion sickness prior
to flying on an aeroplane

25. Diagnostic use: Drugs are used by themselves or
in conjunction with radiological procedures and
other types of medical tests to provide evidence
of a disease process. E.g.Radiopaque dyes used
during x-ray procedures
Drugs given to stimulate cardiac exercise in
patients who cannot undergo regular exercise
stress testing

26. SOURCES OF DRUGSSOURCES OF DRUGS
Synthetic/semi-
synthetic sources
e.g.-
Aspirin,Paracetamol
Synthetic/semi-
synthetic sources
e.g.-
Aspirin,Paracetamol
Natural sourcesNatural sources
Plants sources
Animals sources
Mineral sources. e.g.-FeS04,MgS04
Microbiological sources.
Genetically engineered drugs.e.g.-Hepatitis B vaccine

27. 1. Natural drugs
A/ Plants sources
E.g. .Digoxin from Digitalis purpurea
.Atropine from Atropa belladonna
.Quinine from Cinchona officinalis
B/ Animals sources
E.g.. Insulin from pig
.Cod liver oil from Cod fish liver.
27

28. C/ Minerals sources
E.g.. Iron, Iodine, Potassium salts.
D/ Microbiological sources
E.g. .Penicillin from penicillium
notatum.
.Chloramphenicol from Streptomyces
venezuelae (Actinomycetes).
2. Synthetic drugs
- prepared by chemical synthesis in pharmaceutical
laboratories
Advantage:-
 More potent & safer
 Process is easier and cheaper
E.g.. Sulphonamides, quinolones,
barbiturates
28

29. 3. Semisynthetic drugs
- prepared by chemical modification of natural drugs.
E.g.. Ampicillin from penicillin G.
.Dihydroergotamine from ergotamine.
4. Biosynthetic drugs
- prepared by cloning of human DNA in to the bacteria
like E.coli.
E.g.. Human insulin.
29

30. Nature of Drugs
Physical nature of drugs:-
liquid e.g..-nicotine , ethanol
Gaseous e.g.- nitrous oxide
Solid e.g..-Aspirin , atropine

31. Dosage forms of Drugs
Solid
forms Semi-solid
form
Liquid
form

32. Solid dosage form
1. Powder:-finely divided form of drugs for external +
internal use
e.g.-ORS powder –dehydration,
boric acid
2. Effervescent powder:- powder drugs + NHCO3/citric
acid/tartaric acid
e.g.- Eno fruit salt
3.Granules:- small aggregates of powder
e.g.-Vitamin D3 granule

33. 4. Tablets:-
power form of drugs compresses under heavy pressure into
a round or disc like shape suitable for swallowing
Commonly used solid dosage form
Active substance + Excipients
o Ordinary Tabs:- uncoated compressed tab.e.g.-
paracetamol, aspirin tab.
o sugar coated tabs:- coated over by sugar to avoid bitter
taste.e.g.-Tab.metronidazole
o Film coated Tabs:-coated with thin layer of
polymer to masked unpleasant taste .e.g.-ceftum
(cefuroxime film coated Tab)

34. o Enteric coated Tab:- coating is resistant to gastric acid.
Dissolves at intestinal alkaline ph.
e.g.-diclofen-EC(diclofenac enteric coated tab)
o Sustained release Tab.- drug is released slowly over
specific prolonged period of time
advantages:-
 Increase the duration of action of the drug
 Decrease the frequency of drugs administration
 Improve patient compliance
E.g.- Diclonac-SR(Diclofenac sod. Sustained release)

35. o Chewable Tab:- suitable for large size tab.
e.g.- chewable albendazole tab
o Dispersible tab:- disintegrates rapidly when place in
liquid to form stable suspension
advantages:- 1.fast onset of action
2. useful for children and elderly who
find difficulty to swallow a
tab.
e.g.-disprin(dispersible aspirin tab.)
o Lozenge:- tablet contain drug with sugar and gum
and is ,meant for chewing or sucking for providing
local effects in mouth e.g.- strepsil,various cough

36. 5.Capsules:- solid form where ingredients are enclose in a
stable shell(gelatin/plant polysaccharides /modified form
of starch) and are meant for swallowing
e.g.-Tetracycline cap.,amoxicillin cap.
 Heard shelled:-contain dry powder e.g.-vit B complex
 Soft shelled:-active ingredient suspended in oil e.g.-vit-E
Spansule :- long acting capsules e.g.-ferrous sulfate
spansule
6.Pellets :- these are sterile sphere formed by compression
of drug powder which are implanted subcutaneously. Drugs is
slowly released for a long duration of time
e.g.-testosterone pellets

37. 7.Suppository:- solid dosage form,cylindrical or cone
shaped for introduction into rectum
e.g.- Bisacodyl suppository for constipation
pessary:- vaginal suppository.e.g.-nystatin
pessary for vaginal candidiasis
Bougie:- A urethral suppository

38. Semi solid dosage form
Ointment:- semisolid preparation contain a greasy base
meant for application to skin or mucosa.
e.g.- silver sulfadiazine ointment
cream:-semisolid emulsion for external application
Paste:-ointment but no greasy base.e.g.-toothpastes
Gel:-colloidal suspensions of a solid dispersed in a
liquid.e.g-contraceptive gels

39. -:Liquid dosage forms:-
1.syrups:- concentrated sugar solution containing the
drugs + flavoring agents. Administer bitter,
unpalatable drugs.e.g.-cough syrups(Grilinctus-
BM,Benadril)
2.liquors:- aqueous solution of medically substance
which are either gases or are volatile.e.g.-liquor
ammonia
3.Linctus:- viscous syrupy liquids preparation which
should be sipped slowly to allow it to trickle down the
throat.e.g.-cough linctus
4.Mixture :- preparation containing one or more
soluble /insoluble ingredient for oral use.e.g.-Mgso4
mixture for constipation

40. 5.Emulsion:-mixture of 2 immiscible liquids
e.g.-cod liver oil emulsion
6.Suspension:-one or more insoluble ingredient
homogeneously distributed in liquid.e.g.-antacid
suspension
7.Elixir:- clear, Pleasants flavored liquid of potent drugs
dissolve in water and ethanol e.g.-promethazine elixir for
cough
8.Liniment :- liquid or semifluid preparation to be rubbed
on skin e.g.-liniment turpentine
9.Lotion :- without rubbing.e.g.-zinc calamine lotion

41. 10.Spray:- drug is delivered in the form of fine
droplets .e.g.-diclofenac(on skin)
11.Enema:- liquid preparation to be administered into
rectum
evacuation enema:- to evacuate the bowel content
e.g.-soap and water enema
retention enema:- the drug containing fluid is
retained in the rectum.e.g.-prednisolone enema for
ulcerative colitis
12.Injections:- sterile solution /suspension of drugs in
suitable solvent + preservatives meant for parental use
eg.- injection solution:-regular insulin
injection suspension –lente insulin

42. Depot Injection :- Longer acting injectable
preparation
Ampule:- small,sterile,sealed glass container
containing drugs solution for injection
it contain single dose of drug
e.g.- atropine ,adrenaline
• Vial :- small,sterile,glass bottle closed with a stopper
containing drugs in powder form/ aqueous solution/
suspension for injection
It contains single or multiple doses of a drug
e.g.- lignocaine,

43. -:Transdermal adhesive
patches :-
Device in the form of adhesive patches
Deliver drugs into circulation for systemic effect
Thickness is 0.2-0.4 mm

44. Drug is delivered at the skin surface by diffusion
Site:- chest , abdomen, lower back, buttock ,mastoid
region
 e.g.- scopolamine – motion sickness
Nitroglycerine- angina
estrogen- HRT
fentanyl- analgesia

45. I. Local:
Means drug reaches the lesion directly
1. Application: e.g. Creams, Ointments,
Inhalers
2. Injection: e.g. Intra-articular, Intrathecal
Routes of Drug Administration
II. Systemic: Means drug reaches the
lesion through the blood

46. 1. Enteral
Systemic Routes
2. Parenteral
3. Others

47. 1. Oral
Enteral Routes
2. Sublingual
3. Rectal

48. 1. Intradermal
Parenteral Routes
2. Subcutaneous
3. Intramuscular
4. Intravenous

49. 1.Inhalational
2.Nasal
3.Transdermal
Other Routes

50. Local
Routes of Drug Administration
Systemic
Enteral OthersParenteral

51. pharmacokinetics
Pharmacokinetics and Dosage Regimens Determine:
How much drug is in the body at any given time
How long it takes to reach a constant level of drug
in the body during chronic drug administration
How long it takes for the body to rid itself of drug
once intake of drug has stopped

52. Pk principles
In practical therapeutics, a drug should be able to
reach its intended site of action after administration by
some convenient route.so,drug should be
 absorbed into the blood from its site of administration
distributed to its site of action, permeating through the
various barriers that separate these compartments
After bring about its effect, a drug should be eliminated
at a reasonable rate
-by metabolic inactivation or
-by excretion from the body, or by a combination of
these processes

53. Drug at site
of
administration
Drug in
plasma
Drug /
metabolites
in tissues
Drug /
metabolites in
urine, feces, bile
Absorption
Distribution
Elimination
Metabolism
Kidney
Liver

54. 1,000
500
250
125
1 32
Half-life (plural half-lives)
t1/2
Half-life
What is the percentage of drug left after 4.5
hours if its half-life is 1.5 hours?
Question
Conc

55. absorption
The transfer of substances from sites of administration to
sc.
Drugs get absorbed to systemic circulation after crossing
different barriers
-orally mucous membrane of gut
capillary membrane of BV
-injections capillary membrane of BV

56. Mechanisms by which Drugs Cross
Biological Membranes……..Cont
Passive Diffusion:
• Vast majority of drugs cross membranes by passive
diffusion
• Most lipid soluble drugs readily move across
membranes (lipid diffusion)
• Drug moves across membranes according to
concentration gradient
• No carrier is involved
• Not saturable
• Low structural specificity

57. Mechanisms by which Drugs Cross
Biological Membranes……..Cont
Passive Diffusion…cont:
• Water-soluble drugs (MW 20,000 – 30,000) cross
membrane through aqueous channels or pores
(Aqueous diffusion)
• Drugs bound to large molecules such as albumin do
not penetrate aqueous pores
• The capillaries of the brain and testes are
characterized by absence of pores that permit
aqueous diffusion of many drug molecules into the
tissues (protection)

58. Mechanisms by which Drugs Cross
Biological Membranes……..Cont
Active transport:
• Involves specific carrier protein
• A few drugs that closely resemble the structure of
naturally occurring metabolites (structural
specificity)
• Involves energy expenditure
• Drugs can move against concentration gradient
• Saturable

59. Mechanisms by which Drugs Cross
Biological Membranes……..Cont
Endocytosis and Exocytosis:
• For large molecules
• Substance is engulfed by the cell membrane and
carried into the cell by pinching off of the newly
formed vesicle inside the membrane
• The substance can then be released inside the cytosol
by breakdown of the vesicle membrane
• Iron and vitamin B12
• Exocytosis is a reverse process for the excretion of
some substances outside the cell

61. Factors deciding Choice of Route
Type of desired effect: systemic or local
Physiochemical properties: solid or insoluble
 Rapidity of effect: oral, intramuscular (IM),
 intravascular (IV)
Condition of patient: conscious or unconscious,
vomiting
61

62. Classification of the Routes of Drug
Administration
 Enteral:
 Oral
 Sublingual Administration
 Rectal Administration
 Parenteral Injection:
 Intravenous (IV)
 Intramuscular (IM)
 Subcutaneous (SC)
 Intraarterial
 Intrathecal/intraventricular

63. Classification of the Routes of Drug
Administration……Cntd
Other Routes:
 Inhalation
 Intranasal
 Transdermal
 Topical Application:
 Mucous Membranes
 Skin
 Eye

64. Enteral Routes
The Oral (Per Os, PO):
• The most common route
• Most variable and requires the most complicated
pathway to tissues
• Some drugs are absorbed from the stomach
However, the duodenum is the major site of
absorption
• Absorbed drugs enter the liver through the portal
circulation before they are distributed in the
general circulation: First-pass metabolism
• First-pass metabolism by intestine or liver limits the
efficacy of many drugs e.g. Nitroglycerline

65. Enteral Routes……Cont
Advantages of the Oral Route:
• Most convenient
• Safe
• Economical

66. Enteral Routes……Cont
Disadvantages of the Oral Route:
• Needs patient cooperation
• Some drugs may become destroyed by
-the gastric acidity e.g. penicillin
-enzymes eg.insulin
-micro flora
• Irritant drugs need to be coated
• Presence of food may delay absorption
• First pass effect limits availability of some drugs
• Presence of GIT diseases may limit absorption

67. Enteral Routes……Cont
Sublingual Route:
• Placement of the drug under the tongue
• Drug bypasses the intestine and the liver and
therefore not inactivated by the metabolism (no
first-pass effect)

68. Enteral Routes……Cont
Rectal Route:
• 50% Bypasses portal circulation (Drug avoids
destruction by the liver enzymes)
• Good absorption
• Prevents drug destruction by low pH of the
stomach and intestinal enzymes
• Good for drugs that might induce vomiting if given
orally
• May be used for unconscious patients or if the
patient is vomiting (commonly used to administer
antiemitics)

69. Parenteral Routes
• Used for drugs poorly absorbed from the GIT
• Used for drugs unstable in the GIT
• Used for treatment of unconscious patients
• Used in circumstances that require rapid onset of action
• Only sterile solutions can be injected

70. Parenteral Routes…Cont
Intravenous Route (IV):
• The most common parenteral route
• Used for drugs not absorbed orally
• Avoids first-pass effect
• Permits rapid onset of effect
• May be used for irritant drugs
• May be used inject large volumes like iv fluids
• May be used to administer drugs over a long period
of time

71. Parenteral Routes…Cont
Disadvantages of the IV Route:
• Only used for sterile solutions
• Difficult to control an administered dose
• Possibility of bacterial contamination
• Possibility of hemolysis
• Possibility of adverse reactions by too rapid
delivery of high drug concentrations

72. Parenteral Routes…Cont
Intramuscular Route (IM) :
• Aqueous solutions are injected IM
• Used for depot preparations (oily preparations, or
special nonaqueous vehicles such as ethylene
glycol).
• Irritant drugs may be given IM.
• Deltoid, vastus lateralis and gluteus maximus
muscles are commonly used

76. Parenteral Routes…Cont
Subcutaneous Route (SC) :
• Only used for drug not irritating to tissues.
• May be used for:
– depot drugs (implants; silastic capsules containing the
contraceptive levonorgestrel)
– or sustain release drugs
• Absorption may be controlled through co-
administration of a vasoconstrictor (Epinephrine)

77. Parenteral Routes…Cont
Intraarterial (IA):
Occasionally used when a drug effect is
intended to be localized in a particular organ
or tissue (treatment of liver cancer;
diagnostic agents)

78. Parenteral Routes…Cont
Intrathecal:
Used for injection of certain drugs directly in
the cerebrospinal fluid (CSF) when rapid and
localized effect is intended in the meninges
or the cerebrospinal axis:
 methotrexate in acute leukemia
 treatment of brain tumor
 spinal anesthesia
 acute CNS infections

79. Other Routes of Drug Administration
Inhalation:
• Provides rapid delivery of drugs over the
large surface area of the mucous membranes
of the respiratory tract and pulmonary
epithelium
• For Drugs which are gases (general
anesthetics), or as aerosols.
• Convenient for patients with respiratory
complaints such as asthma.
• Rapid onset of effect (as the IV)

80. Other Routes of Drug Administration
Intranasal:
 Drugs taken by sniffing
 Desmopressin for the treatment of diabetes
insipidus (banned in USA in 2007, pills are the
alternative)
 Salmon calcitonin for treatment of ospeoporosis

81. Other Routes of Drug Administration
Topical application:
1. Mucous membranes:
 Drugs are applied on the mucous
membranes of the conjunctiva,
nasopharynx, oropharynx, vagina,
urethra, urinary bladder to produce a
local effect
 Good absorption to sites of action

82. Other Routes of Drug Administration
Topical application:
2. Skin:
 Drugs applied directly on the skin.
 Used when a local effect is desired.
 Absorption through the skin can be
enhanced by preparing the drug in a
cream or as an oily preparation.
 May be used for sustain release preparations (dermal
patches) to achieve systemic effects.
2. Eye:
 Used for ophthalmic drugs to produce local effects on
the eye

84. The process of drug absorption
• Absorption is the transfer of a drug from its site of
administration to the blood stream
• The rate and efficiency of absorption depend
on the route of administration
• For IV administration, absorption is complete as the
total dose reaches the systemic circulation
• Other routes result in partial absorption and thus
lower bioavailability

85. The Effect of pH on drug absorption
• Most drugs are either weak acids or weak bases.
• Acidic drugs (HA) release a H+
causing a charged
anion (A-
) to form in basic media:
HA H+
+ A-
A weak acid is defined as a neutral molecule that can reversely dissociate into
an anion (a negatively charged molecule) and a proton (a hydrogen ion)
Factores affecting drug absorption

86. The Effect of pH on drug absorption…Cont
• Weak bases (BH+
) can also release a H+; however,
the protonated form of basic drugs is usually
charged and loss of a proton produces the
uncharged base (B).
BH+
B + H+
A weak base is a is defined as a neutral molecule that can form a cation (a
positively charged molecule) by combining with a proton

88. Passage of unchanged drug through a
membrane
• A drug passes through membranes more readily if it
is unchanged as either weak acids or weak bases
• The effective concentration of the permeable form
of each drug at its absorption site is determined by
the relative concentrations of the charged and
uncharged forms
• The ratio between the two forms is determined by
the pH at the site of absorption and by its pka value

89. Determination of how much drug will be
found on either side of a membrane
Henderson-Hasselbalch equation:
pH = pka + log
For acids: pH = pka + log
For bases: pH = pka + log
• The equation is useful in determining how much
drug will be found on either side of a membrane
that separates two compartments that differ in pH
[non-protonated species]
[protonated species]
[A-
]
[HA]
[B]
[BH+
]

92. Ion Trapping
At steady state:
• An acidic drug will accumulate on the more basic
side of the membrane.
• A basic drug will accumulate on the more acid side
of the membrane.
• The phenomenon has obvious implications for the
absorption and excretion of drugs

94. Physical factors influencing drug
absorption
• Blood flow to the absorption site.
-Blood flow to the intestine is much greater than the flow to the
stomach
• Total surface area available for absorption.
-Intestine surface is rich in microvilli, it has a surface area about
1000 times that of the stomach.
• Contact time at the absorption surface.
-Speed of movement through the GIT (diarrhea).

96. Other factors affecting absorption
Dosage forms of the drugs
Drug solubility
Stress/pain
Food
Routes of administration
The presence of other drugs

97. Designated by:
By ‘F’
SerumConcentration
Time
Injected Dose
Oral Dose
bioavailability
Fraction of a drug that reaches systemic
circulation after a particular route of
administration

98. Bioavailability
Dose
Destroyed
in gut
Not
absorbed
Destroyed
by gut wall
Destroyed
by liver
systemic
circulation

99. Intravenous route of drug administration gives
100% bioavailability as it directly enters the
circulation.
“ F ” is equal to 1
Non i.v - ranges from 0 to 100%; value of “ F ” is
equal or less than 1
e.g. lidocaine bioavailability - 35% → due to
destruction in gastric acid and liver metabolism,
hence not given orally
The term bioavailability is used commonly for
drugs given by oral route.

100. Why less Bioavaililbity for drugs given other
than IV route?
Because they undergo …..
FIRST PASS METABOLISM

101. Hepatic ‘First-Pass’ Metabolism
Metabolism of drug in gut (liver) before drug
reaches systemic circulation
Drug absorbed into portal circulation, must pass
through liver to reach systemic circulation
Reduce the bioavailability of drug
Orally administered drugs will have high FIRST
PASS METABOLISM
Parenteraly administered drugs will bypass the
FIRST PASS METABOLISM to the major extent

102. Circulation
Membrane
permeability
Protein
binding
distribution
After a medication is absorbed, it is
distributedwithin the body to tissues and organs
and ultimately to its specific site of action
Rate and extent of distribution depend on the
physical and chemical properties of medications
and the physiology of the person taking the
medication

103. Apparent volume of distribution (aVd) :-is the
hypothetical volume of body fluid into which a drug is
uniformly distributed at a concentration equal to that
in plasma, assuming the body to be a single
compartment.

104. Factors affecting drug distribution / Vd
Physicochemical properties of the drug: Lipid soluble
and unionized form of drugs readily cross the cell
membrane and are widely distributed
e.g.. lignocaine, propranolol, tricyclic antidepressants
etc.
Drugs like heparin (strongest acid in the body) is
confined only to intravascular compartment as it
exists in ionized form.

105. Plasma protein binding:
Acidic drugs bind to albumin, Basic drugs bind to α1 acid
glycoprotein etc
Clinical importance of Plasma protein binding:
 Free form Bound form
Free form – Pharmacologically active
Bound form - Pharmacologically inactive,
acts as a “temporary store” of the drug

106. Plasma protein binding favours drug absorption.
Drugs which are highly bound to plasma proteins have
a low volume of distribution.
Plasma protein binding delays the metabolism of drugs.
Bound form is not available for filtration at the
glomeruli, hence delays its excretion.

107. Highly protein bound drugs have a longer duration of
action.
In cases of poisoning, highly plasma protein bound
drugs are difficult to be removed by Hemodialysis.

108. Plasma protein binding can cause displacement
interactions
More than one drug can bind to the same site on
albumin. The drug with higher affinity will displace
the one having lower affinity and may result in a
sudden increase in the free concentration of the drug

109. Disease states:
Eg: In CHF, the Vd of some drugs can increase due to
increase in ECF volume or it could decrease due to
reduced perfusion of tissues.
Fat: lean body mass ratio: If the ratio is high, fat acts
as a reservoir for certain drugs

110. Redistribution
Highly lipid soluble thiopentone → IV administration
immediately gets distributed to areas of high blood flow -
brain → general anaesthesia.
In few minutes, it re crosses the BBB gets distributed to
less perfuse tissues such as muscle, adipose tissue →
termination of action Thiopentone
Has a very short duration of action (5-10 min) and is used
for induction of general anaesthesia.

111. Drug reservoirs or tissue storage
Tetracyclines : bones, teeth
Thiopentone, DDT : adipose tissue
Chloroquine : liver, retina
Digoxin : heart
Clinical importance of drug storage: Because of
such storage, repeated exposure to some
chemicals like DDT in small quantities may lead
to chronic toxicity

112. Blood Brain Barrier (BBB)
The capillary boundary that is present between
the blood and brain is called BBB
Barbiturates, diazepam, volatile anesthetics,
amphetamine etc – cross BBB

113. Meningitis, encephalitis - increase the permeability of
the BBB
eg. penicillin in normal conditions has poor
penetration through BBB, but its penetrability
increases during meningitis and encephalitis.

114. Placental Barrier :
The lipid membrane between the mother and fetus is
called placental barrier.
Unionized and lipid soluble drugs can freely cross the
placental barrier. e.g.. anesthetics, alcohol, morphine
etc.
Quaternary ammonium compounds cannot cross the
placental barrier.

115. METABOLISM
Mechanism by which a drug interacts with and is
processed by the body.
Process by which a drug is converted by the liver to
inactive compounds (deactivated) through a series of
chemical reactions. Also called biotransformation

116. First Pass Metabolism Occurs Primarily in the Liver and Gut

117. After medications are metabolized, they exit the body through:
Kidneys – most common (in urine)
Liver
Bowel
Lungs
Exocrine glands
Bile
Breast milk
Elimination of a drug is usually affected by:
Renal filtration
Secretion
Reabsorption
The mechanism by which a drug leaves the body

118. Renal clearance
Is the sum total of three renal process
Rcl=RF+S-R
Drug clearance
-is the measure of the ability of the body to
eliminate drug
-it is the apparent volume of blood that is cleared of
drug per unit time
CL= rate of elimination/plasma concentration

119. Common terms
Onset: The time after administration when the
body initially responds to the drug
Peak Plasma Level: The highest plasma level
achieved by a single dose when the elimination
rate of a drug equals the absorption rate
Drug Half-Life (Elimination half-life): The time
required for the elimination process to reduce the
concentration of the drug to one-half what it was
at initial administration

120. 120
PHARMACODYNAMICS
Pharmacodynamics can be defined as the study of the
biochemical and physiological effects of drugs and their
mechanisms of action.
How do drugs act?
1. Most drugs must bind to a molecular target in order
to produce their actions.
- most drug targets are protein molecules.
- protein targets for drug binding.
a- receptors
b- ion channels
c- enzymes
d- carrier molecules (transporters).

121. 121
a) Ion channels
 minute pores present in the cell membrane.
 common ion channels are of Na+, K+, Ca+2
and Cl –
 are selective – for particular ion species
have gating properties
. Ligand – gated channels – activated by
binding of a chemical ligand.
. Voltage – gated channels – open when the
cell membrane is depolarized.

122. 122
Ion – channels:
Blockers
. Calcium channel blockers.
e.g. diltiazem
. Sodium channel blockers.
e.g. phenytoin, carbamazepine, lidocaine

123. 123
b) Enzymes
 Biocatalysts present in the cell
 Common target enzymes: cholinestrase (ChE) ,
monoamine oxidase (MAO), cyclooxygenase, (cox)
angiotensin converting enzyme (ACE) etc.
• Inhibitor – normal reaction inhibited
- competitive inhibitor
e.g. captopril – acting on ACE
normal reaction inhibited
- non – competitive and irreversible inhibitor.
e.g. aspirin – acting on COX.
• Activator.
E.g. nitroglycerine activates guanylyl cyclase

124. 124
c) Carrier molecules (transporters).
- The transport of ions and small organic molecules
across cell membranes generally requires a carrier
protein, because permeating molecules are often
too polar.
 Normal transporter
Transport glucose and aminoacid, transport Na+1
and Ca+2
out of cells.
Uptake of neurotransmitters precursor (e.g.choline).
 Inhibitor
 Na+
/K+
/ 2Cl-
– cotransporter
e.g. diuretics – transport blocked (furosemide)
 Selective serotonine reuptake inhibitors (SSRI)
e.g. fluoxetine


125. d)receptors
A receptor is a protein, which is embedded in a cell
membrane that facilitates communication between the
outside and the inside of a membrane
It is the initial site of action of a biologically active agent
such as neurotransmitter, hormone, or drug (all referred to
as ligands)

126. 126
d) Receptors
 A macromolecular component of an organism that
interacts with a drug and initiates the chain of events
leading to the drug’s effect.
Receptors are responsible for selectivity of drug action.
(Size, shape, electrical change of drug determines binding to a
receptor.)
Receptors mediate the actions of both pharmacologic agonists
and antagonists.
Function as regulatory proteins & components of chemical
signaling mechanisms that provides targets for important drugs.
Receptors largely determine the quantitative relations between
dose or concentration of drug and pharmacologic effect.

127. 127
Chemical bonds established during
interactions between drug and its receptor
*Ionic bond
*Hydrogen bond
*Hydrophobic interaction
*Covalent bond is responsible for irreversible
interaction.

128. Agonists vs antagonists
After a medication binds to a receptor, the receptor helps to
communicate specifics about the medication to the inside of the
cell by generating a signal in the cell about the medication. A drug
must be a close mimic of the neurotransmitter
By binding to the receptor, medications can either augment or
block the signal normally brought about by binding of the
endogenous substance to the receptor
Medications that augment or enhance a signal normally
communicated in a cell are called agonist. Conversely,
medications that block the transmission of a signal normally
communicated in a cell are called antagonist

129. =
= =agonists
An agonist is a drug which produces a stimulation
type response. It activates or enhances cellular
activity once bound to the receptor. The agonist is a
very close mimic and fits with the receptor site and is
thus able to initiate a response
An agonist causes a particular effect by binding to the
correct receptor

130. ≠
≠ ≠
What are competitive antagonists and partial antagonists?
antagonist
Antagonist drug interacts with the
receptor site and blocks or depresses the
normal response for that receptor because
it only partially fits the receptor site and
can not produce an effect. However, it does
block the site preventing any other agonist
or the normal neurotransmitter from
interacting with the receptor site

131. 131
Response (effect) of drug Receptor
interaction
- If a drug has affinity for the receptor and if it is in close
proximity of the receptor site, then receptor occupancy takes
place. This drug, receptor interaction (coupling) leads to a variety
of response (effects) depending on the nature of drug molecules,
which are:-
1- Agonists:- are drugs that have the ability to activate
a receptor by binding to a receptor.
- have affinity for the receptors and
efficacy/ intrinsic activity.

132. 132
a) Full agonists:- bind to the receptor and elicit maximal
possible response.
b) Partial agonists:- have affinity for the receptors but sub
maximal efficacy.
- Competitively antagonize the effect of
a full agonists but in the absence of
the agonist they can produce some
responses (effect).
E.g. Succinylcholine for
acetylcholine.

133. 133

134. 134
2) Antagonists:- are drugs that antagonists or
block responses (effects) of the
concerned agonists.
- They have affinity for receptors but no
intrinsic activity.
- Antagonism can be produced:-
 Binding of an antagonist to the same site on the receptor
normally occupied by the agonist. The binding of the
antagonist blocks the agonist occupancy of the site.
 Binding of an antagonist to site different from that
normally occupied by the agonist (allosteric site). This
either provents the agonist from binding or prevents the
bound agonist from eliciting a response.

135. 135
Regulation of receptors
1) Down regulation of receptors
(Desensitization)
- Prolonged administration of an agonist leads to decrease in
number of receptors.
- cause decreased tissue sensitivity.
- leads to hypo activity (hyposensitivity) of receptors to an
agonist after prolonged treatment.
Mechanism of desensitization
- A conformational change in the receptor, resulting in
tight binding of the agonist molecule with out the
opening of the ionic channel.

136. 136
Tolerance – a more gradual decrease in responsiveness to
a drug, taking days or weeks to develop.
Tachyphylaxis – a rapid decrease in responsiveness to a
drug.
Drug resistance – loss of effectiveness of antimicrobial or
antitumor drugs.

137. 137
2) Upregulation of receptors (sensitization)
- Prolonged administration of an antagonist leads to
formation of new receptors causing increased tissue sensitivity.
- Leads to hyperactivity (super sensitivity) of receptors to an
against following sudden withdrawal of the antagonist after
prolonged treatment.
E.g. rebound hypertension, appearance of angina pectoris
or cardiac arrhythmias following sudden withdrawal of
propranolol.
Withdrawal effect – an effect due to sudden discontinuation of
the treatment.

138. 138
2.Some drugs don't bind to molecular targets, but act.
I. By reacting chemically.
e.g. antacids
II. By chelating
e.g. E D T A
III. Due to physical properties.
e.g. mannitol (osmotic diuretics.)

139. IV. By targeting DNA, cell wall constituents as well as
protein of bacteria, virus etc
e.g. Chemo therapeutic drugs
V. Being nutrients.
e.g. Vitamins
VI. Unknown mechanism.
139

140. Dose Response Relationships
Threshold (minimal) dose
Least amount needed to produce desired effects
Maximum effect
Greatest response produced regardless of dose used

141. Dose Response Relationships
Loading dose
Bolus of drug given initially to rapidly reach therapeutic
levels
Maintenance dose
Lower dose of drug given continuously or at regular
intervals to maintain therapeutic levels

142. 142
Therapeutic index
- an index for measuring safety of drugs.
- Therapeutic index (TI) = LD50
ED50
- LD50 = is the lethal dose that causes death in 50% a animal under
experiment.
- If TI is wide – the drug is safe.
- If TI is narrow – the drug is toxic.
Must be >1 for drug to be usable
Digitalis has a TI of 2
Penicillin has TI of >100

143. - Margin of safety = LD1
ED99
The therapeutic window
- a more clinically relevant index of safety
- describes the dosage range between the
minimum effective therapeutic concentration or dose,
and the minimum toxic concentration or dose
143

144. Some terms
Side Effects: non-desired effects of a drug
Drug Allergy: itching, burning, skin rash or severe reactions
(anaphylactic shock)
Efficacy – the ability of a bound drug to change the receptor in such a
way to elicit a tissue response.
Potency – the amount of drug we can use to produce the desired
effect. Potency is determined mainly by the affinity of the receptor for
the drug.
- doesn’t measure effectiveness.

145. Types of drug concentration– response relationship
A. Graded drug concentration-Response Relationships
As the dose of a drug is increased, the response (effect) of the
tissue or organ is also increased.
The efficacy (Emax) and potency (ED50) parameters are derived
from these data.
145

146. GRADED DOSE-
RESPONSE CURVE
146
QUANTAL DOSE-
RESPONSE CURVE

147. B. Quantal or all or none dose response relation ship.
The Plot of the fraction of the population that
responds at each dose of the drug versus the log of the
dose administered.
responses follow all or none phenomenon – that
means the individual of the responding system either
respond to their maximum limit or not at all to a dose
of drug and there is no gradation of response.
 population studies.
 relates dose to frequency of effect .
The median effective (ED50), median toxic (TD50) ,and
median lethal doses (LD50) are extracted from experiments
carried out in this manner.
147

148. 148
Median effective dose (ED50
):the dose at which 50% of individuals
exhibit the specified quantal effect.
Median toxic dose (TD50
) :the dose required to produce a particular
toxic effect in 50% of animals.
Median lethal dose (LD50
): is the lethal dose that causes death in
50% animal under experiment.

149. 149
Factors affecting response
1) Age
2) Body weight
-The concentration of a drug at the site of action depends on the ratio
between the body weight or surface area and the amount of drug
administered.
3) Sex
4) Psychological/ Emotional state
5) Pathological state
6) Physiological state
7) Time of drug administration.
8) Environment
9) Idiosyncratic – a different response for unknown reason(mostly due to
genetic variation) .
10)route of drug administration
11)drug interaction
12)tolerance

150. Drug – drug interaction that occurs inside the body are
of two types:-
I – Pharmacokinetic interaction
II – Pharmacodynamic interaction
I – Pharmacokinetic interaction
- It occurs by altering the concentration of one drug by the
other in the tissue or fluid.
1. Gastrointestinal absorption
 changes in gastrointestinal PH.
e.g. antacids/PPI/H2-antagonists
+ ketoconazole/digoxin/ampicillin/iron salts.
150

151.  Complex formation
*Irreversible binding of drugs in the GI tract
e.g. Tetracyclines,quinolone antibiotics +
ferrous sulfate (Fe+2
),antacids (Al+3
, Ca+2
,Mg+2
), dairy
products(Ca+2
)
151

152. 2. Distribution
- Displacement from tissue binding site.
e.g. - Phenylbatazone + wartarin
3. Metabolism
- Inducers
e.g. – Navirapine + oral contraceptives
- Rifampin + Nevirapine
- Inhibitors
e.g. – Ritonavir + sildenafil
- Ketoconazole + saquinavir/
anperenavir/ indinavir.
152

153. 4. Excretion
- Alteration of urine PH.
e.g. Phanobarbitone + NaHCo3
- Alteration of active tubular secretion
e.g. Probenecid + peincillin.
II – Pharmcodynamic interaction
- It occurs by modification of pharmacological
response of one drug by another without altering the
concentration of the drug in the tissue or tissue fluid.
1. Additive – Occurs when the combined effect of
two drugs is equal to the sum of the
effects of each agent given alone.
2 + 2 = 4
e.g H1antagonist + CNS depressant
153

154. 2. Potentiation:-
- a situation where by one drug enhance the
action another drug without having an effect
by itself.
e.g. 0 + 1 > 1
e.g. Caffeine +ergot alkaloid
3. Synergism
- when the combined effects of two drugs are
much greater than the sum of the effects of
each agent given alone.
e.g. 1 + 1 >>> 2
penicillin + aminoglycosides
154

155. 4.Antagonism
a)Pharmacological antagonism
- It is due to opposite effects of two drugs binding to
the same receptor. It can be competitive antagonism
or non – competitive antagonism.
Competitive antagonist
- Produce receptor blockade by competing with an
agonist for the same receptor. The binding of agonist
and antagonist is mutually exclusive, possibly
because both agents bind to the same receptor site.
- Reversibly bind to the receptor usually the
concentration of the agonist.
- The effect can be overcome by increasing the
concentration of the agonist.
155

156. E.g. diazepam (agonist) and flumazenil antegonist.
acetylcholine (agonist) and atropine.
d – tubocurarine (antagonist).
Non – competitive antagonist
- bind at different site from agonist binding site
brings conformational change.
- binding is irreversible. The irreversible mechanism
reduces the total number of receptors available for an
agonist action. The irreversible binding doesn’t last
forever.
156

157. b) Chemical antagonism
Occur when antagonist react chemically with agonist
and inactivate it independently from receptor interaction.
E.g. - Neutraliztion
- Antacids
-
157

158. c) Physiological antagonism
- It is due to opposite effects of two drugs on the
same physical function.
E.g. – Histamine and adrenaline
- Insulin and glucagon.
d) Physical antagonism
-It is due to physical properties of drugs.
E.g. activated charcoal in alkaloidal
posioning
158

159. C- Drug – herb interaction
e.g. Grape fruit juice + saquinavir / BDZ/ Ca+2
channel blocker (grape fruit juice is inhibitor)
159
B – Drug – food interaction
e.g. - MAOI + Tyramine
- TTC + milk

160. Adverse Drug ReactionsAdverse Drug Reactions
/ ADR // ADR /
Response to a drug that is noxious and unintended
and that occurs at doses used in humans for
prophylaxis, diagnosis, or therapy of disease, or for
the modification of physiologic function.
WHO
160

161. Allergic reaction
- an immunologically mediated adverse reaction to a chemical
resulting from previous sensitization to that chemical or to a
structurally similar one.
Tertogenecity
- some drug taken during pregnancy can cause congenital
abnormalities.
e.g. Thailodomide
CARCINOGENICITY
Certain drugs affect the genes and structural changes in the
chromosomes. The drugs that cause cancer are called as
carcinogenic drugs, for example, oral contraceptives increase the
incidence of benign liver tumors, vaginal adenocarcinoma in the
female offsprings of women who have taken
diethylstilboesterol(DES) during her pregnancy for abortion
purpose.
e.g.anticancer/antineoplastic drugs.
161

162. Definition of different terms
SIDE EFFECTS: There are undesirable and unavoidable
pharmacological effect of the drug, which occur at therapeutic
dose. e.g. Atropine causes dryness of mouth.
TOXIC EFFECTS: Toxic effects develop due to excessive
pharmacological action of drug, which may be due to overdose or
continuous use of drug for prolonged period.
IDIOSYNCRASY: It is genetically determined abnormal
reactivity to a drug.
Drug abuse: using drugs not for the intended purpose , but for
psychological or emotional effect.
162