Unit 1(g. ph) -n

Specific Objectives:

At the end of this lesson students will be able to :
 Define: Pharmacology ,drugs
 Identify branches of pharmacology

 Lists out sources of drugs
 Describe dosage forms of drugs and drug naming systems
 Identify routes of drug administration

 Describe pharmacokinetic and pharmacodynamic processes of

drugs
 Discuss steps in new drug development process

I. INTRODUCTION
 The term ‘pharmacology’ is derived from two Greek

words:
’Pharmacon‟ -which means ‘a drug‟ and
„Logos’ - meaning ‘a reasonable’ or ‘rational discussion’
 Pharmacology can be defined as the study of drugs and

their interaction with living system
[study of Action and Effect of drugs on physiological

system]

or

 The science of substances used to prevent, diagnose, and

treat disease.

 Mainly includes pharmacokinetics and

Pharmacodynamics
 It also includes history, source, physicochemical,

properties of drugs dosage forms and method of

administration.
 It is a discipline devoted to patient therapy through the
use of drugs
 Utilizes concepts from human biology, pathophysiology,
and chemistry

History of Pharmacology
 One of the oldest form of healthcare, practiced in virtually

every culture dating to antiquity

 Applying products to relieve suffering has been recorded
throughout history , but
 Modern pharmacology began in the early 19th century
through the isolation of specific active agents from their
complex mixtures

Subdivision / branches of pharmacology
1.

Pharmacodynamics:



The study of the biological and therapeutic effects of
drugs and molecular mechanism of action
(what the drug does to the body”)

2.

Pharmacokinetics:
Study of drug movement in and alteration of drug by the body
It deals with drug disposition
(absorption, distribution, metabolism and excretion
(ADME) of drugs (“what the body does to the drug”)

3. Pharmaco-therapeutics:
 It deals with the proper selection and use of drugs for

the prevention and treatment of disease, drug adverse
and toxic effects contraindications , precautions as well
as drug interactions

4.Toxico dynamics:
 It is the study of poisonous effect of drugs and other

chemicals with emphasis on detection ,prevention ,and
treatment of poisonings
 Many drugs in larger doses may act as poisons

5.

Clinical Pharmacology:



It is scientific study of drugs in man.



Includes :
 Pharmacokinetics,

 Pharmacodynamics ,
 Evaluation of efficacy and safety of drugs as

well as
 Comparative trials with other forms of

treatment

6. Pharmacogenetics:


Is the study of the genetic variations that cause
individual differences in drug response
(concerned with unusual i.e. idiosyncratic drug responses
that have hereditary basis)

 Genetic variation in any of subcellural steps involved in

pharmacokinetics could lead to idiosyncratic drug
responses.

1. Transport [ Absorption, Plasma protein binding]

2. Transducer mechanisms[receptors, enzyme induction or
inhibition]
3. Biotransformation
4. Excretory mechanism (renal and biliary transport)
Examples of Pharmacogenetic disorders; Less enzyme

or defective proteins, increased resistance to drugs
,disorders due to unknown etiology.

Drug
 The term drug is derived from the French word ‘drogue‟

which means ‘a dry herb‟.
 Are chemical substances which change the function of

biological system by interacting at molecular level;

 May be chemicals administered to achieve a beneficial

therapeutic effect on some process within the patient
or

 For their toxic effects on regulatory processes in

parasites infecting the patient.

 Can also be defined as any substance that is used

for the prevention, diagnosis or treatment of
disease.

Sources of drugs
Drugs are obtained from………

.Naturally

1. Minerals: Liquid paraffin, magnesium sulfate,
magnesium trisilicate, kaolin, etc.
2. Animals: Insulin, thyroid extract, heparin and
antitoxin sera, etc.

3. Plants:

Morphine, digoxin, atropine, castor oil,
etc.

4. Micro organisms: Penicillin, streptomycin and
many other antibiotics

5. Synthetic source: Aspirin, sulfonamides,
Paracetamol, zidovudine, etc.
6. Semi –synthetic forms:Ampicillin, Cloxacillin,...

Drug components and dosage forms
 Dosage form - is the form by which drugs

prepared so that it’s convent for administration to
the patient
 Most pharmaceutical dosage forms constitute two

components.
 These are: Active ingredients

Additives (pharmaceutical exciepients)

 Active ingredients:

Are the main components of the dosage form, which is
responsible for the both desired and undesired
pharmacological effects
Additives (pharmaceutical exciepients):
Are substances other than active ingredients
(medicaments) in the formulation which don't have any
pharmacological action

Used to give a particular shape to the formulation to

increase the stability and/or to increase palatability and
elegance of the preparation.
Classification of Dosage Forms:
 Basically dosage forms/types of preparations

are classified in three major classes
 These are: Solid, Semi-solid ,liquid preparations

miscellaneous forms

and

Solid Dosage forms:

 This class include:


Internal: Which are intended to be administered
orally or parenterally or to be used in mouth
cavity
E.g.: Powders, Tablet, Capsules, Pills, and Lozenges



External: used topically (applied on the skin),dusting
powders

1.Tablet:
 Is a hard, compressed medication in round, oval or square

shape
A coating may be applied to:
1- Hide the taste of the tablet's components.
2- Make the tablet smoother and easier to swallow .
3- Make it more resistant to the environment.

4- Extending its release so that duration of action

 Different types of tablets

1-Buccal and sublingual tablet:


Medications are administered by placing them in the mouth,
either under the tongue (sublingual) or
between the gum and the cheek (buccal).



Dissolve rapidly and absorbed through the mucous
membranes of the mouth,



Avoid the acid and enzymatic environment of the stomach and
the drug metabolizing enzymes of the liver.
Examples: Nitroglycerine tablet (Sublingual)

2- Chewable tablet:
 They are tablets that chewed prior to swallowing.
 Are designed for administration to children,

geriatrics ,and to increase rate of dissolution
E.g. Vitamin products, antacids(MTS)

Hard gelatin capsule

2.Capsule:

Soft gelatin capsule

 It is a medication in a gelatin container.

 Advantage: Mask the unpleasant taste of its contents.

The two main types of capsules are:
1- Hard-shelled capsules- Which are normally used for
dry, powdered ingredients,
2- Soft-shelled capsules- Primarily used for oils and for
active ingredients that are dissolved or suspended in
oil.

3.Lozenge:
 It is a solid preparation consisting of sugar and gum,
 Used to medicate the mouth and throat for the slow

administration of cough remedies.
4.Pills:

 Are oral dosage forms which consist of spherical

masses prepared from one or more medicaments
incorporated with inert excipients

5.Powder (Oral):
Two kinds of powder intended for internal use.
1-Bulk Powders -Are multidose preparations
 They contain one or more active ingredients,
 Contain non-potent medicaments such as antacids

 The powder is usually dispersed in water

2-Divided Powders- are single-dose presentations of powder
( a small sachet)
 Intended to be issued to the patient as such, to be taken

with water.

Dusting powders:
 Are free flowing very fine powders for external use.
 Not for use on open wounds unless the powders are

sterilized

Semi-solid dosage forms:
 Semi-solid for internal use. E.g. Gels, Jellies
 External Semi-solids

Jellies

E.g. Ointments, Creams, Gels,

1- Ointments:
 Are semi-solid, greasy preparations for application to the

skin, rectum or nasal mucosa.
 May be used as emollients(having the quality to soften the

skin) or to apply suspended or dissolved medicaments to
the skin.

2- Gels (Jellies):
 Gels are semisolid systems
 Having a high degree of physical or chemical cross-

linking.
 Used for medication, lubrication and some

miscellaneous applications like carrier for

spermicidal agents to be used intra vaginally

Liquid dosage forms:
 Three different classes of liquids based on type
of preparations are: Solution, Suspension, Emulsion

a-Solution:
 Solutions are clear Liquid preparations containing one or more active

ingredients dissolved in a suitable vehicle.
b- Emulsion:
 Are stabilized oil-in-water/water- in – oil dispersions,
 Either or both phases of which may contain dissolved solids.

c-Suspension:


Liquid preparations containing one or more active ingredients
suspended in a suitable vehicle.

 May show a sediment which is readily dispersed on shaking

Syrup:
 It is a concentrated aqueous solution of a sugar, usually

sucrose.
 Flavored syrups are a convenient form of masking

disagreeable tastes.

Elixir:
 It is pleasantly flavored clear preparation of potent or

nauseous drugs.
 Contain a high proportion of ethanol or sucrose together

with antimicrobial preservatives

Linctuses:
 Are viscous, liquid oral preparations
 Usually prescribed for the relief of cough.
 Contain a high proportion of syrup and glycerol which have a demulcent

effect on the membranes of the throat.
 The dose volume is small (5ml)

Gargles:
 Are aqueous solutions used in the prevention or treatment of throat

infections.
 Prepared in a concentrated solution with directions for the patient to

dilute with warm water before use
Mouthwashes: Similar to gargles but are used for oral hygiene and to
treat infections of the mouth.

Rectal dosage forms:
Suppository:
 It is a small solid medicated mass,
 Usually cone-shaped ,
 It is inserted either into the rectum (rectal

suppository), vagina (vaginal suppository or
pessaries) where it melts at body temperature

or dissolve in body fluid(pessaries)

Enema:
 Is the procedure of introducing liquids into the rectum and colon

via the anus.
Types of enema:
1-Evacuant enema: used as a bowel stimulant to treat constipation
E.g. Soft soap enema & MgSo4 enema
2- Retention enema:
 Their volume does not exceed 100 ml.

E.g. Barium enema is used as a contrast substance in the
radiological imaging of the bowel( Local effect)

Transdermal patch or skin patch:

 Is a medicated adhesive patch that is placed on the

skin to deliver a specific dose of medication
through the skin and into the bloodstream.
 It provides a controlled release of the medicament

into the patient.
 The first commercially available patch was

scopolamine for motion sickness.

Inhaled dosage forms:
1- Inhaler :
 Inhalers are solutions, suspensions or emulsion of drugs in

a mixture of inert propellants held under pressure in an
aerosol dispenser.
 It is commonly used to treat asthma and other respiratory

problems

2- Nebulizer or (atomizer):
 Is a device used to administer medication to people in

forms of a liquid mist to the airways.
 Commonly used in treating asthma, and other respiratory

diseases.
 Usually reserved only for serious cases of respiratory

disease, or severe attacks.

Ophthalmic dosage forms:

1- Eye drops:
 Are saline-containing drops used as a vehicle to administer

medication in the eye.

2- Ophthalmic ointment & gel:
 These are sterile semi-solid preparations intended for

application to the conjunctiva or
eyelid margin.

Sterile products:
 Are products which intended for Parentral, administration or

ophthalmic use
 Could be administered through injection ,infusion
 In the form of drops used in eye

Drug nomenclature (naming system)
 Three basic drug names
1. Chemical Name
– Helpful in predicting a substances physical and chemical
properties
– Often complicated and difficult to remember or
pronounce
E.g. Chemical name for diazepam:
7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4benzodiazepin-2-one

 Generic Name
 Name is assigned by the U.S. Adopted Names Council
 Less complicated and easier to remember
 Only one generic name for each drug
 Less expensive

Used internationally in pharmacopeias

Non- proprietary name

 Trade Names
 Assigned by company marketing the drug
 Sometimes called proprietary, product or brand name
 A single drug may have multiple names
 Selected to be short and easy to remember
 Shorter and easier than generic name

Example:
Generic substance

Brand Name

 Aspirin -

Anacin, Bayer, Excedrin

 Diphenhydramine-

Benadryl, Caladryl, Allerdryl

 Ibuprofen-

Advil, Motrin, Midol

 Digoxin

Lanoxin

 Levothyroxine Sodium

Synthroid

 Warfarin

Coumadin

2.PHARMACOKINETIC PRINCIPLES
(DRUG DISPOSITION)

 Pharmacokinetics -is currently defined as the study

of the time

course of drug
Absorption, Distribution,Metabolism, and Excretion
 Examines the movement of a drug over time through the

body and metabolic alteration by enzymes
 These fundamental pathways of drug movement

and modification in the body control


Speed of onset of drug action,



The intensity of the drug's effect, and



The duration of drug action

 First, drug absorption from the site of administration

permits entry of the therapeutic agent (either directly or
indirectly) into circulatory system (Absorption)
 Second, the drug may then reversibly leave the

bloodstream and distribute into the interstitial and intracellular
fluids (Distribution)
 Third, the drug may be metabolized by the

liver, kidney, or other tissues (Metabolism)
 Finally, the drug and its metabolites are removed from the body

in urine, bile, or feces (Elimination)

Passage of drugs across membrane
Structure of biological membrane
 The absorption, distribution, and excretion involve

passage of a drug across cell membranes
 The plasma membrane consists of a bilayer of

amphipathic lipids
 Membrane proteins embedded in the bilayer serve as

receptors, ion channels, and transporters to
transduce electrical or chemical signaling pathways

Ways of drug passage across CM
1. Filtration [aqueous diffusion]



Size should be less than size of pore
Has to be water soluble E.g. Na+, Cl-, K+, Urea ...

2. Passive(Simple) Diffusion [Direct penetration]


Transport from high to low concentration



Deriving force is concentration gradient across CM



Does not involve carriers,



Not saturable and show low structural specificity.
Majority of drugs are absorbed by this mechanism
But, the drug has to be lipid soluble




3. Carrier mediated absorption
a. Facilitated diffusion


Passive diffusion but facilitated



Does not require energy,



Can be saturated, and may be inhibited



E.g. Tetracycline, Pyrimidine, levodopa & amino acids into brain

b. Active transport


Use ATP & carrier proteins



Saturable and structurally specific



Against the concentration gradient, competitive inhibition

E.g. Penicillin secretion, alpha methyldopa, 5-fluoro uracil

4. Endocytosis & pinocytosis


Process by which large molecules are engulfed by the
cell membrane & releases them intracellularlly.
E.g. Proteins, toxins(botulinum, diphtheria),

norepinephrine

Fig.2a Mechanisms involved in the passage of drugs across CM

Fig.2b Mechanisms involved in the passage of drugs across CM

Fig.2c. Passage of drugs across membrane

Routes of Drug Administration
Two major classes of routes of drug administration,

A. Enteral routes- Administering a drug through
alimentary tract [Oral, sublingual, and rectal routes]
Is the simplest and most common means of administering
drugs
B. Parentral routes- Administering a drug through

other sites or non alimentary [ i.e. Injection, or local
application on skin and mucus membrane

Fig.1 Route of drug administrations

Fig. 2. Enteral routes of drug administration

Fig.3 Parentral and other
routes of drug administration

 The route of administration is determined

primarily by:
 Properties of the drug (water or lipid solubility,

ionization, etc.) ,
 Therapeutic objectives (the desirability of a rapid

onset of action or the need for long-term
administration or restriction to a local site)
 Patient characteristics (whether the patient is
conscious or not)

Enteral routes
I. Oral:
Provides many advantages to the patient such as


Oral drugs are easily self-administered and



Safe, more convenient and economical

 Need no assistance for administration
 Limit the number of systemic infections that could

complicate treatment
 Toxicities or overdose by the oral route may be overcome with

antidotes such as activated charcoal

 However ;the pathways involved in drug absorption

are the most complicated, and the drug is exposed to
harsh gastrointestinal (GI) environments that may
limit its absorption
 Some drugs undergo first-pass metabolism in the

liver,where they may be extensively metabolized
before entering the systemic circulation
E.g. Nitroglycerin

 Ingestion of drugs with food, or in combination with other

drugs, can influence absorption
 Action slower and thus not suitable for emergencies
 Unpalatable drugs difficult to administer

 Not suitable for uncooperative /unconscious, vomiting

patients
 Certain drugs are not absorbed sufficiently (polar

drugs) from GIT

II. Sublingual
 Placement under the tongue allows a drug to

diffuse into the capillary network and, therefore,
to enter the systemic circulation directly.
 Has several advantages including:


Rapid absorption,



Convenience of administration,



Low incidence of infection,



Avoidance of the harsh GI environment, and



Avoidance of first-pass metabolism`

III Rectal:
.

 Has advantage of preventing the destruction

of the drug by intestinal enzymes or by low pH in the
stomach
 Also it is useful if the drug induces vomiting when given

orally,
 If the patient is already vomiting, or if the patient is

unconscious
 Is commonly used to administer antiemetic agents

however

 Only fifty percent of the drainage of the rectal region

bypasses the portal circulation
 Absorption is slower, irregular, incomplete and often

unpredictable
 It is rather inconvenient and embarrassing

II. Parenteral
Parenteral:
 Par = beyond and enteral = intestine
 Drug directly introduced into tissue fluids or blood

without having to cross the intestinal mucosa
 Used for drugs that are poorly absorbed from the

tract ( heparin) and for agents that

GI

are unstable in the

GI tract ( insulin)
 Also used for treatment of unconscious patients under

circumstances that require a rapid onset of action

 Have the highest bioavailability and
 Are not subject to first-pass metabolism or harsh GI environments

 Provides the most control over the actual dose of drug delivered to the

body
 However, these routes are irreversible and may cause pain, fever, and

infections
 The three major Parentral routes are:


Intravascular (intravenous[ IV] or intra-arterial [ IA] ),



Intramuscular[IM], and



Subcutaneous [ SC]

 Other Parentral routes include: Intradermal ,Intrathecal,

Intrarticular, Interaperitonial

1. Intravenous (IV):


Is the most common Parentral route



Permits a rapid effect and a maximal degree of control
over the circulating levels of the drug; however



It is the most risky route



Injected drugs cannot be recalled by strategies such as
emesis or by binding to activated charcoal



May also induce hemolysis or possibilities of embolism



Expertise is needed to give injection

 Useful for compounds that are:


Poorly or erratically absorbed,



Extremely irritating to tissues, or



Rapidly metabolized before or during their absorption

from other sites.
 The rate of injection should be slow enough to:


Prevent excessively high local drug concentrations



Allow for termination of the injection if undesired
effects appear

2. Intramuscular (IM) :
 Drug is injected in one of the large skeletal muscles:

deltoid, triceps, gluteus maximus, rectus femoris
 Mild irritation can be applied and absorption is faster than SC

(high tissue blood flow)
 It can be given in diarrhea or vomiting
 By passes 1st pass effect

 Many vaccines are administered intramuscularly

N.B. The volume of injection should not exceed 10 ml

3. Subcutaneous (SC):


The drug is deposited in the loose subcutaneous
tissue( the layer of skin directly below the dermis and epidermis)

 Unsuitable for irritant drug administration and with

slow absorption rate
 Self injection is simple
 Oily solution or aqueous suspensions can be injected

for prolonged action
 Highly effective in administering vaccines and such medications

as insulin.

C. Others
1. Inhalation(Pulmonary administration)


Provides rapid delivery of a drug ,producing an effect
almost as rapidly as IV injection



Used for drugs that are gaseous (for example, some anesthetics)
or those that can be dispersed in an aerosol



This route is particularly effective and convenient for patients
with respiratory complaints (such as asthma, or COPD )

 Poor ability to regulate the dose
 Irritation of the pulmonary mucosa

2. Intranasal:
 Involves administration of drugs directly into the nose
 Nasal decongestants such as the anti-inflammatory

corticosteroid furoate
 Desmopressin is administered intranasally in the treatment

of diabetes insipidus;
 The abused drug, cocaine, is generally taken by intranasal

sniffing

3. Topical:
 Topical application is used when a local effect of the drug is

desired
 Application could be on mucous membranes, skin or the

eye
 For example, clotrimazole is applied as a cream directly to

the skin in the treatment of dermatophytosis

4. Transdermal:
 This route of administration achieves systemic effects by

application of drugs to the skin,.
 Most often used for the sustained (continuous) delivery of drugs,

such as the antianginal drug nitroglycerin, the antiemetic
scopolamine, and the once-a-week contraceptive patch
 (Ortho Evra) that has an efficacy similar to oral birth control pills
 The rate of absorption can vary markedly

I. Drug Absorption
 It is a process by which the drug leaves the site

of administration to circulatory system
 In case of IV or IA administration, drug

by passes absorption and enters the
circulation directly

Fig.4 The interrelationship of the absorption, distribution,

binding, metabolism, and excretion of a drug and its
concentration at its sites of action.

Factors affecting drug absorption and bioavailability
1. PH of absorption area-



Most drugs are either weak acids or weak bases.



Basic drugs are absorbed better at higher PH and



Acidic drugs are absorbed better at lower PH.

2. Area of absorbing surface

Small intestine has microvillus;



It has absorption surface 1000 times that of stomach

3. Particle size of the drug and formulation

4. Gut motility (contact time at absorption area)

Faster is the motility, lower is the absorption
E.g. Diarrhea, food in the stomach both decrease drug absorption

5. Blood flow to GIT


Blood flow to the intestine is higher and so absorption is high
from intestine

6. Presence of other agents:
 Vitamin C enhances the absorption of iron from the GIT
 Calcium present in milk and in antacids forms insoluble complex with

some antibiotics( decrease its absorption)

7. Enterohepatic recycling:
8. First-pass hepatic metabolism
9. Pharmacogenetic factors:

10. Disease states:

Bioavailability(F):
 Fraction of administered drug that reaches the systemic

circulation/site of action in chemically unchanged form
following non-vascular administration or
 Amount of drug available in the circulation/site of action
 It is expressed in percentage

N.B. When the drug is given IV/IA, the bioavailability is
100%

Plasma level (mg/Li)

A

MTC
B

MEC
C
Time (hr)

Fig.3 Plasma –drug level curves following administration of three
formulations (A, B, C) of the same drug.
Formulation A; has quick onset, short duration of action and has
toxic effects.
Formulation B; has longer duration of action and is non-toxic
Formulation C; in adequate plasma level and therapeutically ineffective.
Note: MTC-Minimum toxic concentration.
MEC-Minimum effective concentration

II. Drug distribution
 Is the process by which a drug reversibly leaves the

blood

stream & enters the interstitium and/or

cells of the tissues
 Cardiac output, regional blood flow, capillary

permeability, extent of plasma protein and specific
organ binding, regional differences in pH,
transport mechanisms available and tissue
volume determine the rate of delivery

 Liver, kidney, brain, and other well-perffused organs

receive most of the drug

[First phase]

or central

compartment whereas
 Delivery to muscle, most viscera, skin, and fat is slower

[Second phase] or peripheral compartments

Fig. 4 Factors that affect drug concentration at its site of action

Factors affecting rate of drug distribution
A. Blood flow
 The rate of blood flow to the tissue capillaries varies widely as a result

of the unequal distribution of cardiac output to the various organs
 Blood flow to the brain, liver, and kidney is greater than that to the

skeletal muscles; adipose tissue, bone lower rate of blood flow
B. Plasma protein binding

Drug molecules may bound reversibly to plasma proteins such as
Albumin, Globulin, Lipoproteins, α1 Acid Glycoprotein's...

 Binding is relatively nonselective to chemical structure



Bound drugs are pharmacologically inactive, while
free drugs leave plasma to the site of action ( are pharmacologically
active)

 Acidic drugs bind principally to albumin, basic

 Drugs frequently bind to other plasma proteins, such as

lipoproteins and 1-acid glycoprotein (1-AGP),
N.B. Protein binding acts as temporary store of
drugs(reservoir)

Albumin:
 Is the most important contributor to drug binding -

Has a net negative charge at serum pH
 Basic, positively charged drugs are more weakly

bound
 Disease states (E.g., hyperalbuminemia,

hypoalbuminemia, uremia, hyperbilirubinemia) change in plasma protein binding of drugs

α1 Acid Glycoprotein:
 α1-AGP is a determinant of the plasma protein binding of

basic drugs, chlorpromazine, imipramine, and
nortriptyline
 There is evidence of increased plasma α1-AGP levels in

certain physiological and pathological conditions, such as
injury, stress, surgery resulting in ______????

A drug with a higher affinity may displace a drug with
weaker affinity
Increases in the non–protein-bound drug fraction (i.e.,
free drug)

An increase in the drug‟s intensity of pharmacological
response, side effects, and potential toxicity
(Only a limited number of drugs) , but
 Depends on the volume of distribution (Vd) and the therapeutic

index of the drug (TI)

C . Capillary permeability
 Determined by capillary structure and by the chemical nature of

the drug
 In the brain, the capillary structure is continuous

no slit

junctions
 Liver and spleen a large part of the basement membrane is

exposed due to large, discontinuous capillaries

Large

plasma proteins can pass
 Also

,can be influenced by agents that affect capillary

permeability (E.g., histamine) or capillary blood flow
rate (E.g., norepinephrine)

Blood-brain barrier[BBB]
 Ionized or polar drugs generally fail to enter the CNS
 While lipid-soluble drugs readily penetrate into the CNS

Placental Barrier
 Does not prevent transport of all drugs but is selective

Blood-Testis Barrier
 Found at the specialized Sertoli–Sertoli cell junction
 This barrier may prevent Cretan chemotherapeutic agents

from reaching specific areas of the testis

D. Drug structure:


The chemical nature of a drug strongly influences its ability
to cross cell membranes

E. Affinity of drugs to certain organs:


Drugs will not always be uniformly distributed to and
retained by body tissues

Eye: Chlorpromazine and other phenothiazines bind to
melanin and accumulate

Retinotoxicity

Chloroquine concentration in the eye can be
approximately 100 times that found in the liver.

 Adipose tissue (Fat): DDT, chlordane

 Bone: TTC, lead, and the antitumor agent cisplatin
 Liver : Chloroquine,
 Thyroid gland :Iodine
 Lung: Basic amines (E.g., antihistamines, imipramine,

amphetamine,methadone, and chlorpromazine

F. Presence of back transporter proteins
 Like P- glycoprotein (Pgp), multidrug resistance–associated

protein (MDRP), and breast cancer resistance protein (BCRP);
 Are located in many tissues E.g. in the placenta

Function as efflux transporters, moving endogenous and
exogenous chemicals from the cells back to the systemic
circulation
Protect the fetus from exposure to unintended chemicals

III. Biotransformation/metabolism of drug
 Alteration of drug structure and/activity by action

of enzymes
 Main site of biotransformation: Liver

 Other tissues include the:

 Gastrointestinal tract,
 The lungs, the skin, and
 The kidneys

Enzymes Responsible for Metabolism of Drugs

 Microsomal enzymes:


Present in the smooth endoplasmic reticulum of the liver, kidney
and GIT

E.g. Glucuronyl transferase, dehydrogenases ,
hydroxylases and cytochrome P450 enzymes
(primarily found in the liver and GI tract)
CYP3A4, CYP2D6, CYP2C9/10, CYP2C19, CYP2E1, and
CYP1A2
 Non-microsomal enzymes:
 Present in the cytoplasm, mitochondria of different organs

E.g. esterases, amidase, hydrolase

Therapeutic consequences of metabolism:
 Increase in solubility of drugs
 Activation of pro drugs (converted to active drug)

E.g. L-dopa (inactive)

dopamine(active)

 Inactivation of active drugs

E.g.Phenobarbital(active) hydroxypentobarbital(inactive)]
 Alteration of activity

E.g. [Codeine(Less active)

Morphine( more active)

 Decreseasing/increasing toxicity of the drug

E.g.- Metabolism of
acetaminophen

Fig. Metabolism of acetaminophen (AC) to hepatotoxic metabolites. (GSH,
glutathione; GS, glutathione moiety; Ac*, reactive intermediate.)

Reactions of drug metabolism
1. Phase I biotransformation Drug is changed to more polar metabolite by introducing or

unmasking polar functional groups like OH, NH2 etc..
 Increase, decrease, or leave unaltered the drug's pharmacologic activity



Consists of reactions:


Oxidation - Introduction of an oxygen and/or the removal of a
hydrogen atom or hydroxylation, dealkylation or demethylation of

drug molecule



Reduction - By the enzyme reductase
Hydrolysis -Splitting of drug molecule after adding water

N.B Phase I metabolites are too lipophilic and can be

retained in the kidney tubules
2. Phase II reaction/biosynthesis or [conjugation]
 Conjugation reaction with endogenous compounds

glucuronic acid, sulfuric acid, acetic acid, or an
amino acid
 Makes drugs most often therapeutically inactive, more

polar and water soluble and easily excreted

Examples of phase II reactions
I. Glucuronide conjugation

It is the most common
E.g. Phenobarbitone, chloramphenicol,
Morphine, sulphonamide, ASA etc
Note: Neonates are deficient in this conjugating system

II. Sulfate conjugation:


Transfers sulfate group to the drug molecules
E.g. phenols, catechols, steroids etc

III. Acetyl conjugation: INH, hydralazine, dapsone,

IV. Glycine conjugation:
E.g. salicylic acid, isonicotinic acid, p-amino salicylic acid
V. Methylation:
E.g. Adrenaline is methylated to
metanephrine by catechol-o-methyl transferase

Fig. Examples of phase II conjugation reactions in drug metabolism

Factors affecting drug biotransformation
 Genetic polymorphism
 Disease conditions especially of the major drug

metabolizing sites
 Age
 Predisposing factors to enzyme induction or inhibition

Regulation of the CYP Enzymes:
 CYP450 enzymes can be regulated by the presence of other drugs

or by disease states
Enzyme Inhibition:
 It is the primary mechanism for drug-drug pharmacokinetic

interactions
 The most common type of inhibition is simple competitive

inhibition
 A second type of CYP enzyme inhibition is mechanism based

inactivation (or suicide inactivation)

Enzyme Induction:
 It can be due to:


Synthesis of new enzyme protein or



Decrease in the proteolysis degradation of the enzyme

 The net result is the increased turnover (metabolism) of

substrate
 Most commonly associated with therapeutic failure due

to inability to achieve effective drug level in bld

Table 1 Liver enzyme inhibitors and CYP isoforms inhibited

Table 2. Liver enzyme inducers and CYP isoforms induced

IV. Drug Excretion
 Excretion is transport of unaltered or altered drug out of

the body
 Rate of excretion influences duration of drug action

Routes of Drug Excretion
 Minor route of excretion: Eye, breast, skin
 Intermediate route: Lung [volatile drugs like inhalational

anesthetics]
Bile [digoxin, rifampin]



Renal excretion- major route for most drugs & involves


Glomerular filtration



Active tubular secretion



Passive tubular reabsorption

Glomerular filtration:


Depends on the:


Concentration of drug in the plasma,



Molecular size, shape and charge of drug, and



Glomerular filtration rate

Note: In congestive cardiac failure, the glomerular filtration
rate is reduced due to decrease in renal blood flow.

Fig. Renal excretion of drugs.
Filtration of small non–protein-bound drugs occurs through glomerular
capillary pores.
Lipid-soluble and un-ionized drugs are passively reabsorbed throughout
the nephron. Active secretion of organic acids and bases occurs only in
the proximal tubular

Active tubular secretion:
 Primarily occurs in the proximal tubules

I. For anions
II. For cations
 Each of these transport systems shows low specificity and can

transport many compounds; thus,
 Competition between drugs for these carriers can occur within

each transport system
E.g. Probenecid, and penicillins, Acetazolamide, benzyl penicillin,
dopamine, pethidine, thiazide diuretics,

Tubular re -absorption:
 Occurs either by simple diffusion or by active transport
 Manipulating the pH of the urine
 Increase the ionized form of the drug in the lumen

 Minimize the amount of back diffusion, and hence, increase

the clearance of an undesirable drug.
E.g. A patient presenting with phenobarbital (weak acid),
overdose can be given bicarbonate, which alkalinizes the
urine and keeps the drug ionized, thereby decreasing its reabsorption

 If overdose is with a weak base, such as cocaine,

acidification of the urine with NH4Cl leads to protonation of
the drug and an increase in its clearance

Hepatobilary Excretion Conjugated drugs are excreted by hepatocytes in to the bile
 Certain drugs may be reabsorbed back from intestine after

hepatic excretion and this is known as enterohepatic
cycling
E.g. CAF, oral estrogen

Pulmonary excretion:
 Drugs that are readily vaporized, such as many inhalation

anaesthetics and alcohols are excreted through lungs
 The rate of drug excretion through lung depends on


The volume of air exchange,



Depth of respiration,



Rate of pulmonary blood flow and



The drug concentration gradient

Mammary excretion:
 Many drugs mostly weak basic drugs are

accumulated into the breast milk ???
 Therefore lactating mothers should be cautious of

furosemide, morphine, streptomycin etc

Summery Points:
 Route of drug administrations
 Pharmacokinetics –Def, Components ( in order)
 Factors affecting drug absorption

 Factors affecting drug distribution in the body
 Bioavailability
 Biotransformation, sites, enzymes , reaction phases ,

factors affecting
 Excretion , routes, steps

Review question
 A drug M is injected IV into a laboratory subject. It is

noted to have high serum protein binding. Which of the
following is most likely to be increased as a result?
A. Drug interaction
B. Distribution of the drug to tissue sites
C. Renal excretion

D. Liver metabolism

Pharmacokinetic variables and Dose
calculation
 Two models exist to study and describe the

movement of xenobiotics (Drugs) in the body with
mathematical equations
1. Classical compartmental models (one or two

compartments)
2. Physiologic models

Classical compartmental model:
 The body represented as consisting of one or two

compartments


A central compartment- representing plasma and tissues

that rapidly equilibrate with chemical(Liver, Kidney),


Peripheral compartments-represent tissues that more
slowly equilibrate with chemical???

 Assumes that the concentration of a compound in blood or

plasma is in equilibrium with concentrations in tissues, and

 Changes in plasma concentrations repesent change in

tissue concentrations
 Valuable in predicting the plasma chemical

concentrations at different doses ,but
 Have no apparent physiologic or anatomic reality, and
 Under ideal conditions, classic models cannot

predict tissue concentrations,

Fig. 1. Compartmental pharmacokinetic models
Where ka is the first- order extravascular absorption rate
constant into the central compartment (1),
kel is the first-order elimination rate constant from the central
compartment (1), and
k12 and k21 are the first-order rate constants for distribution of
chemical into and out of the peripheral compartment (2) in a twocompartment model.

One-Compartment Model:
 The simplest pharmaco-kinetic analysis
 Describe the body as a homogeneous unit
 Compounds rapidly equilibrate, or mix uniformly, between

blood and the various tissues
 Plasma changes assumed to reflect proportional changes in

tissues chemical concentration
 Is applied to xenobiotics (drugs) that rapidly enter and

distribute throughout the body



The data obtained yield a straight line when they are plotted
as the logarithms of plasma concentrations versus time
C0
Slope= Kel/ -2.303

C

LogC
1/2C0
Time

t 1/2

Time

Fig.2. Concentration versus time curves of chemicals exhibiting
behavior of a one-compartment pharmacokinetic model on a

linear scale (left) and a semilogarithmic scale (right).

 A curve of one compartment type can be described by the

expression :
C = C0 x e-Kel x t

on Linear scale

Log C= -Kel/2.303 X t + logC0

on logarithmic

scale
C = Blood or plasma chemical concentration over time t,
C0 = Initial blood concentration at time t = 0, and
kel = First-order elimination rate constant( dimension t-1)

Two-Compartment Model:
 Implies more than one dispositional phases
 The chemical requires a longer time for its concentration

in tissues to reach equilibrium with the concentration in

plasma, and
 The semilogarithmic plot of plasma concentration versus

time yield a curve
 A multicompartmental analysis of the results is necessary

Distribution phase,(decrease more rapidly)

C

Slope= β/ -2.303

LogC
1/2C

Elimination phase(decrease slowly)
t 1/2

Time
Time
Fig.3 Concentration versus time curves of chemicals exhibiting behavior
of a two-compartment pharmacokinetic model on a linear scale
(left) and a semilogarithmic scale (right

 The curve described by multiexponential mathematical
equation :
C= A x e-α x t + B x e-β x t
where A and B are proportionality constants and α and β are the first-order
distribution and elimination rate constants, respectively

Physiologic models:
 Consider the movement of xenobiotics based on known or

theorized biologic processes and
 Are unique for each xenobiotics
 Allows the prediction of tissue concentrations

Advantages:
 Provides [Tx] time course in any organ
 Estimation of effect of changing physiological parameters

on tissue [Tx]
Disadvantages: More information needed , Mathematics
difficult,

First order Kinetics
 Elimination rate proportional to total amt in the

body
 Semi log plot of [Tx] vs time is straight line
 Vd, Cl, T1/2, Ke or β are independent of doses
 Tissue [Tx] decrease by Kel or β like plasma [Tx]

Zero-order kinetics
 Saturation of metabolism
 An arithmetic plot of plasma concentration versus time yields

a straight line
 Non linear kinetics (Constant amount of drugs

eliminated per unit time)
 Clearance slows as drug concentration rises
 A true T1/2 or kel does not exist, but differs depending upon

drug dose

Saturation Pharmacokinetics:
 As the dose of a compound increases, its Vd or its rate of

elimination(Kel )may change ,because
Biotransformation,
Active transport processes, and
Protein binding have finite capacities and can be
saturated
 The rate of elimination is no longer proportional to the

dose and the transition from first-order to saturation
kinetics (Zero-order)

First-order Toxic kinetics

Saturation- Toxic kinetics
First-order

First-order

First-order

No change

Fig. Vd, Cl and T1/2 following first-order pharmaco kinetics (left )
and changes following saturable pharmacokinetics (right)

Characteristics of saturation phrmaco kinetics:
 Vd, Cl, T1/2, Kel change with dose
 Non proportional changes in response to increasing dose
 The composition of excretory products changes

quantitatively or qualitatively with the dose,
 Competitive inhibition by other chemicals that are

biotransformed or actively transported by the same
enzyme system occurs,

Volume of distribution [Vd]:
 Hypothetical volume of fluid in to which the drug is

disseminated
 Correctly called the apparent volume of distribution,

because
 It has no direct physiologic meaning and does not refer to a

real biological volume
 Represents the extent of distribution of chemical out of

plasma and into other body tissues

E.g. Apparent Vd of amiodarone is 400 lit
 Drugs that are extensively bound to plasma

proteins, but are not bound to tissue compartments,
- Vd approximately equals to plasma volume
 If the drug is highly lipid soluble, its volume of

distribution will be very high because it will

concentrate in the adipose and other lipid tissues
and its concentration in the plasma will be very low

Effect of large Vd on half-life of a drug:


If the Vd for a drug is large, most of the drug is in

the extraplasmic space and unavailable to the
excretory organs.
 Therefore, any factor that increases the volume of

distribution can lead to an increase in the half-life
and extend the duration of action of the drug.

 Vd

relates the amount of the drug in the body to the

concentration of the drug (C) in the plasma
Vd = D /Co ; D-total amount of drug in the body
Co- plasma concentration of the drug at
zero time
 Described in units of liters or liters per kilogram of body weight

N.B. Maximum actual Vd= Total body water( 42 lit)
 Apparent Vd= The theoretical volume of body fluid in to which

a drug is distributed
 May not correspond to anatomical space

Example :

A 23-year-old, 90-kg female is seen in the emergency
department 2 hours after the ingestion of 50 of her
brother's Theo-Dur (300 mg) tablets. Her initial

theophylline serum concentration is 40 mg/L.
Q. Estimate a peak serum concentration knowing that
theophylline has a Vd of 0.5 L/kg, F = 1 (100%
bioavailable).

Calculation:

Vd = Dose IV/C0 = Dose(other route)xF
Co
Where: F= fraction of drug available to systemic cir

C0= Initial peak plasma concentration
Thus C0= Dose X F / Vd
Co = 50 x 300 mg x 1 = 0.333 mg/ml
o.5 L/ Kg x 90 Kg

Review Question
 An agent is noted to have a very low calculated volume of

distribution (Vd). Which of the following is the best
explanation?
A. The agent is eliminated by the kidneys, and the patient

has renal insufficiency
B. The agent is extensively bound to plasma proteins
C. The agent is extensively sequestered in tissue
D. The agent is eliminated by zero-order kinetics

Clearance:
 Is the volume of fluid containing chemical that is cleared

off a drug per unit of time.
 Describes the rate of chemical elimination from the body

 Has the units of flow (ml/min)

Example:
A clearance of 100 mL/min means that 100 mL of blood
or plasma containing xenobiotic is completely cleared in
each minute.

 Clearance characterizes the overall efficiency of the

removal of a chemical from the body i.e
High values of clearance indicate efficient and rapid

removal,
Low clearance values indicate slow and less efficient

removal

 Total body clearance is defined as the sum of clearances by

individual eliminating organs:
Cl = Clr + Clh + Cli . . .
Where- Clr-renal, Clh -hepatic, and Cli- intestinal clearances
respectively
 After IV , bolus administration, total body clearance is defined as

Cl = Dose IV/AUC0-∞
Where –Dose IV is the IV dose at time zero
AUC0-∞ is the area under the chemical concentration
versus time curve from time zero to infinity

 Can be estimated by creratinien clearance

Cr cl= UxV/C
U -is the concentration of creatinine in urine (mg/mL);
V - is the volume flow of urine (mL/min);
C - is the plasma concentration of creatinine (mg/mL
 If the volume of distribution and elimination rate constants

are known Cl can also be calculated

Cl = Vd × kel - for a one-compartment model ,first order
process

For flow dependent elimination
CL = Q.(Ca- Cv) = Q.E
Ca
Where Q- is blood flow,

Ca- is the concentration entering the organ, and
Cv -is the concentration leaving the organ,
E- is drug extraction by the organ

Note: Clearance is an exceedingly important pharmaco
kinetic concept

Half-Life( t1/2):
 Is the time required for the blood or plasma concentration

of a drug to decrease by one-half,(50%)
t1-t2= Lnc1 –LnC2 = t1/2= Ln2 = 0.693
Ke
Ke
Ke
 t1/2 is influenced by both Vd for a chemical and the rate

by which the chemical is cleared from the blood (Cl)
 If Vd and Cl are known:

t1/2 = (0.693 × Vd)/Cl

 For a fixed Vd, T1/2 decreases as Cl increases,

Half life in minute

 For a fixed Cl, as the Vd increases, T1/2 increases

Fig.2 The dependence of T1/2 on Vd and Cl

NB. Values for Vd of 3,18, 40 L represent approximate volumes of
plasma water, extracellular fluid and total body water, respectively

Fig. Elimination of a hypothetical drug with a half-life of 5 hours.
The drug concentration decreases by 50% every 5 hours (i.e., t1/2 5 hrs).
The slope of the line is the elimination rate (ke).

 In general it takes five half lives‘ to either reach steady state for

repeated dosing or for drug elimination once dosing is stopped.
Example:
 A 45year- old man a known chronic alcoholic was admitted to the

hospital for ingestion of about 2.5 lit of solvent containg 30%
Volume by volume of methanol.
Q. What is t1/2 of methanol during dialysis if the patient
had serum methanol of 265 mg/ dl at the start of dialysis
and 65 mg/dl after 5.5 hrs?

Calculation:
 Using the following formulas

Kel= (1/t) LnC1/C2)=0.26 /hr
t1/2=Ln2 /Kel= 2.7 hr

 limination:
E
 Includes biotransformation, exhalation, and excretion
 For one-compartment model occurs through a first-order

process; i.e
 Constant fraction of xenobiotics is eliminated per unit time

( the amount of drug eliminated at any time is proportional to
the amount of the chemical in the body at that time) ;

Only at chemical concentrations that are not sufficiently high
to saturate elimination processes


 The equation for a monoexponential model

C = C0 x e-Kel x t

Transformed to a logarithmic equation that has the general form of a
straight line,
Log C= -Kel/2.303 X t + logC0

Where:
-Log C0 represents the y-intercept or initial concentration
-( kel/2.303) represents the slope of the line =Log(C1-C2)/(t2-t1)

- The first-order elimination rate constants( Proportion of a drug
removed per unit time (kel = –2.303 × slope)

 The fraction of dose remaining in the body over time (



C/C0) is calculated using the elimination rate constant by
rearranging the equation for the
C/C0 = Anti log [(–kel/2.303) × t]

Tab.1 Elimination of four different doses of a chemical
at 1 hour after administration
Dose mg

Chemical
remaining (
mg)

Chem.
Eliminated
(mg)

Che.
Eliminated
(% of dose)

10

7.4

2.6

26

30

22

8

26

90

67

23

26

Drug Accumulation:
 Accumulation is inversely proportional to the fraction of the dose

lost in each dosing interval.
 The fraction lost is 1 minus the fraction remaining just before the

next dose.
 The fraction remaining can be predicted from the dosing interval

and the half-life.
 A convenient index of accumulation is the accumulation factor(AF)

AF =

1______________ =
Fraction lost in one dosing interval

__ 1__________
1 – Fraction remaining

Q. For a drug given once every half-life, what is the
accumulation factor?

Bioavailability:
 Bioavailability is the fraction of administered drug that

gains access to the systemic circulation in a chemically
unchanged form.
 Bioavailability of drugs given orally and some other routes

may not be 100% because of one of the following reasons:



Incomplete extent of absorption and
First-pass elimination

 The systemic bioavailability of the drug (F) can be

predicted from the extent of absorption (f) and the
extraction ratio (ER):
F= f (1-ER)

Where

ER = Cl Liver/Q
Q- is hepatic blood flow, normally about 90 L/h in a

person weighing 70 kg

Example: Morphine is almost completely absorbed
(f = 1), so that loss in the gut is negligible.
 However, the hepatic extraction ratio for morphine

is 0.67,
Q. What is bioavailability of morphine?

Determination of bioavailability:
 Is determined by comparing plasma levels of a drug after a

particular route of administration with plasma drug levels
achieved by IV injection
 By plotting plasma concentrations of the drug versus time,

one can measure the area under the curve (AUC).
 Thecurve reflects the extent of absorption of the drug.

For other routes
F= Dose(IV) x (AUC0-∞)other
Dose( other) x (AUC0-∞)other

Fig. Representative plasma concentration–time relationship
after a single oral dose of a hypothetical drug.

Plasma concentration

Time ____________
Fig. Representative plasma concentration–time curve (AUC) after
single dose of oral(Blue) and IV( Red) of a hypothetical drug.

Clinical Implications of Altered Bioavailability
 Some drugs undergo near-complete presystemic

metabolism and thus cannot be administered orally.
E.g. Lidocaine, nitroglycerin
 Other drugs underging very extensive presystemic

metabolism but; can still be administered PO using much
higher doses than those required IV.
E.g. IV dose of verapamil would be 1 to 5 mg, compared to
the usual single oral dose of 40 to 120 mg.

Steady State Concentration(Css):

Plasma level of the drug

 Is plasma level of a drug where drug elimination is
in equilibrium with that absorbed (rate in=rate out)
 It takes at least four to five half live’s to reach Css

C max

C min

Time (multiple of t ½)
Fig. Steady state plasma concentration after repeated administration

Dosage regimen:
 Is a systematic way of drug administration or
 It is the one in which the drug is administered:


In suitable doses,



By suitable route,



With sufficient frequency that ensures maintenance of
plasma concentration within the therapeutic window
without excessive fluctuation and drug accumulation for
the entire duration of therapy.)

Two major parameters that can be adjusted in
developing a dosage regimen are:
1. The dose size:
 It is the quantity of the drug administered each time.
 The magnitude of therapeutic & toxic responses depend upon

dose size.
 Amount of drug absorbed after administration of each dose is

considered while calculating the dose size.
 Greater the dose size greater the fluctuation between Css,max &

Css,min (max. and min. steady state concentration) during each
dosing interval & greater chances of toxicity.

Points to be considered while selecting dose of a

drug to a patient

A. Defined target drug effect when drug treatment is
started
B. Identify nature of anticipated (expected) toxicity
C. Other mechanisms that can lead to failure of drug

effect should also be considered;
E.g. Drug interactions and noncompliance

D. Monitoring response to therapy, by physiologic

measures or by plasma concentration measurement
2. Dose frequency:
 It is the time interval between doses.
 Dose interval is inverse of dosing frequency.
 Dose interval is calculated on the basis of half life of

the drug.

 When dose interval is increased with no change in

the dose size ,Cmin, Cmax & Cav decrease, but
 When dose interval is reduced, it results in greater

drug accumulation in the body and toxicity.
N.B.


By considering the pharmacokinetic factors that

determine the dose-concentration relationship, it is
possible to individualize the dose regimen to achieve the
target concentration

Fig. Temporal characteristics of drug effect and
relationship to the therapeutic window (e.g., single
dose, oral administration)

There are two types of dosing:
 Constant ; and
 Variant dosing

Variant dosing includes;
1. A loading dose:


Is one or a series of doses that may be given at
the onset of therapy with the aim of achieving the
target concentration rapidly.

2. Maintenance dose:


Dose given at an adjusted rate to maintain a
chosen steady state concentration .



The amount is equivalent to daily excreted
dose

Maintenance Dose:
 It is the amount of drug prescribed or administered on a

continuing basis.
 Thus, calculation of the appropriate maintenance dose is a

primary goal.
 At steady state, the dosing rate ("rate in") must equal the rate of

elimination ("rate out").
Dosing Rate ss = Rate elimination ss
Dosing Rate ss = CL x TC ; Where CL= Clearance
TC= Target concentration

If intermittent doses are given, the maintenance dose is calculated from:
Maintenance dose = Dosing rate x Dosing interval

Example;
A target plasma theophylline concentration of 10 mg/L is desired to
relieve acute bronchial asthma in a patient.

If the patient is a nonsmoker and otherwise normal except for asthma the
mean clearance is 2.8 L/h/70 kg.
If the drug is given by intravenous infusion, F = 1.
Dosing rate = CL x TC
= 2.8L/h/70 Kg x 10 mg/L
= 28 mg/h/70 Kg

 To maintain this plasma level using oral theophylline,

which might be given every 12 hours using an extendedrelease formulation (Foral for theophylline is 0.96)
Q. When the dosing interval is 12 hours, what is the size of
each maintenance dose?

Calculation:
Maintenance dose= Dosing rate x Dosing interval
F
= 28 mg/h x 12 hrs
0.96
= 350 mg

Loading Dose:
 Is one or a series of doses that may be given at the onset of therapy

with the aim of achieving the target concentration rapidly.
 The appropriate magnitude for the loading dose is

Loading dose = Target Cp x Vdss
F
Vd ss= Volume of distribution at steady state
 It desirable if the time required to attain steady state by the

administration of drug at a constant rate is long relative to the
temporal demands of the condition being treated.

Example.
 In administration of digitalis ("digitalization") to a patient

with Cp = 1.5 ng/ml and Vdss= 580 liter , F= 0.7
Loading dose = 1.5 ng/ml X 580 liter =1243 μg ~ 1mg
0.7
 To avoid toxicity, this oral loading dose, which also could be

administered IV , would be given as an initial 0.5-mg dose
followed by a 0.25-mg doses 6 to 8 hours later, with careful
monitoring of the patient ...

Disadvantages of Loading dose administration:
 Sensitive individuals may be exposed abruptly to a toxic

concentration of a drug.
 If the drug has long half-life

It takes long time for the

concentration to fall if the level achieved was excessive
 Loading doses tend to be large, and they are often given

parentrally and rapidly; this can be particularly dangerous
if toxic effects occur as a result of action of the drug at sites
that are in rapid equilibrium with plasma

Factors Affecting dose and drug responses
 Individuals may vary considerably in their responsiveness

to a drug;
 Quantitative variations in drug response are in general

more common and more clinically important
 An individual patient is hypo reactive or hyper reactive

to a drug
 Intensity of effect of a given dose of drug is diminished or

increased in comparison to the effect seen in most
individuals.

 Decrease in response as a consequence of continued drug

administration, is called tolerance
 If diminishes rapidly after administration of a drug, the

response is said to be subject to tachyphylaxis.
 Four general mechanisms may contribute to variation in

drug responsiveness among patients or within an individual

patient at different times

1. Alteration in concentration of drug that reaches
the receptor:
 Patients may differ


In the rate of absorption of a drug,



In distributing it through body compartments, or



In clearing the drug from the blood.

 Some differences can be predicted on the basis of age,

weight, sex, disease state, liver and kidney function
 Other -active transport of drug from the cytoplasm

2. Variation in concentration of an endogenous receptor
ligand:

 Contributes greatly to variability in responses to

pharmacologic antagonists
E.g. Propranolol which is a -adrenoceptor antagonist
will markedly slow the heart rate of a patient whose
endogenous catecholamines are elevated (as in

pheochromocytoma) but will not affect the resting
heart rate

3. Alterations in number or function of receptors
 Change in receptor number may be caused by other

hormones;
E.g. Thyroid hormones increase both the number of
receptors in rat heart muscle and cardiac sensitivity
to catecholamines.

4. Changes in components of response distal to the

receptor
 Compensatory mechanisms in the patient that respond to

and oppose the beneficial effects of the drug.
E.g. - Compensatory increases in sympathetic nervous
tone and fluid retention by the kidney can contribute

to tolerance to antihypertensive effects of a vasodilator
drug

The impact of age
 Age is associated with changes in body composition, such

as:


A relative increase in body fat,



A decrease in drug clearance,



A higher sensitivity to pharmacodynamic

processes.

 Renal clearance is decreased due to a reduction in

renal functioning.
 The functioning of CYP enzymes tends to be lower

with increasing age,

 Dose adjustment based on age (Young‟s formula)

Child dose = Age (yr)

X Adult dose

Age + 12
 Based on the body weight (clerk‟s formula);

Child dose =Weight (pound) X Adult dose

150
Note: 1kg = 2.2 pound
 Based on body surface area:

Child dose = BSA of chiled x Adult dose
1.72
N.B. 1.72 is average BSA of an adult

The impact of gender:
 Males and females are not identical

E.g. Females respond rapidly even to lower concentration
of alcohol
Gender affects drug response in two ways
1.

Differences exist in pharmacokinetic properties
between men and women.
E.g. The clearance of drugs metabolized by CYP3A4 is
higher in women than in men



It has been suggested that this is caused by lower P-gp efflux
transporter activity in women.

2. Difference in pharmacodynamic actions of a drug
between genders.

E.g. Aspirin has a major role in the prevention of
myocardial infarction in men, in contrast many
women do not respond to aspirin therapy
 Special care should be exercised when drugs are

administrated during menstruation, pregnancy & lactation.

The impact of co-morbidity:
 Co-morbidities in liver and kidney organs may influence

drug response.
E.g. The risk of adverse drug reactions is increased in
patients with reduced kidney function who use drugs with

a narrow therapeutic window and which are excreted
unchanged by the kidney.
 Inflammation of meninges (meningitis)
 Under conditions of decreased tissue perfusion like heart

failure and shock,(hemorrhagic and cardiogenic )

The impact of environmental factors


Environmental factors, such as diet, smoking, hygiene,
stress and exercise, contribute to the variation in drug
response.

E.g. Grapefruit juice, which contains ingredients that
inhibit CYP3A4 enzymes,

The impact of body weight
 In obese people, the distribution of drugs throughout body

tissues differs from lean people

The impact of repeated administration and drug
accumulation
 If a drug is excreted slowly, its administration may build up a

sufficiently high concentration in the body to produce toxicity.
E.g. Digitalis, emetine

The impact of drug tolerance
 When an unusually large dose of a drug is required to elicit an

effect ordinarily produced by the normal therapeutic dose of the
drug, the phenomenon is termed as drug tolerance

The impact of co-prescribed drugs
 Polypharmacy, the use of multiple drugs by one

patient, is common.
 These drugs may influence each other resulting in

drug-drug interactions (DDIs).

The impact of genetic factors
 Genetic variation in the DNA encoding proteins can result

in a change in amino acid sequence in the protein or

differences in transcription rates.
 These deviations may result in the increased or reduced

effectiveness of drugs.
E.g. Acetylation of INH in slow and fast acetylators

Unit 1(g. ph) -n

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