Unit 1(g. ph) -n

UNIT-ONE GENERAL PHARMACOLOGY

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……… ۱ .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

and

miscellaneous forms

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)

2.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.

Soft gelatin capsuleHard gelatin capsule

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 E.g. Ointments,

Creams, Gels, Jellies

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-1,4-

benzodiazepin-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

GI tract ( heparin) and for agents that 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%

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-toxicFormulation C; in adequate plasma level and therapeutically ineffective. Note: MTC-Minimum toxic concentration. MEC-Minimum effective concentration

Time (hr)

A

B

C

MTC

MEC

Pla

sma l

eve

l (m

g/L

i)

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(inacti

ve)]

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 glomerularcapillary 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 two-compartment 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

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).

Slope= Kel/ -2.303

t 1/21/2C0

C0

LogC

TimeTime

C

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

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

Distribution phase,(decrease more rapidly)

Elimination phase(decrease slowly)

Slope= β/ -2.303

1/2C t 1/2

LogCC

Time Time

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/CU -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,

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

Half

lif

e i

n m

inu

te

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

Elimination:

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

250 185 65 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______________ = __ 1__________

Fraction lost in one dosing interval 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.

Fig. Representative plasma concentration–time

relationship after a single oral dose of a hypothetical drug.

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

Fig. Representative plasma concentration–time curve (AUC)

after single dose of oral(Blue) and IV( Red) of a

hypothetical drug.

P

lasm

a c

on

cen

trati

on

Time ____________

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): 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

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

Pla

sma l

eve

l of

the d

rug

C max

C min

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 extended-release 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