Cyprus International University

Faculty of Pharmacy
PHAR-210 Pharmacology I
Fall Semester, 2018
 
Instructor : Hakan Zengil, Ph.D.
Professor of Pharmacology
Graduated from Ankara University Faculty of Pharmacy, 1971
Professor in Pharmacology, 1990
Worked at Gazi University Faculty of Medicine 1980-2015
Academic Staff of CIU, 2017--

e-mail : hzengil@ciu.edu.tr
(please note the course and your registration number in your e-mails)

Office : ST-244
Office hours : 10:30-12:30 – anytime I am in Office (except Tuesdays)
 Contents of the Course PHAR-210

General Pharmacology

Autonomic Nervous System and Related Drugs

Autacoids and Related Drugs

  Purpose of the Course

This course is to prepare students for current ideas in the course contents.

The first part of the course, General Pharmacology,

is designed to acquaint students with the general aspects of pharmacology and
common terminology in pharmacological sciences, along with the basics of
drug pharmacokinetics and pharmacodynamics.

The second part, Pharmacology of Autonomic Nervous System (ANS),

deals with the anatomy and physiology of the peripheral nervous system which is
responsible with mainly involuntarily functions of our body. The neurotransmitters
of ANS and their receptors are targets for drug action to relieve several clinical
conditions, but also they involve the actions of many currently used drugs that
will be presented in the following courses, Pharmacology II and III.

The last part of this course, “Autacoids”,

dealt with local hormones that they are involved in many clinical conditions, and
many currently used drugs have direct or indirect effects on several autacoids.
 In the first part, General Pharmacology, drug names will only be used to give
examples about the currently discussed issue. The ANS and Autacoids sections,
you will be faced with many drug groups and drug names that you should learn
and memorize.

When you will graduate, when you are the head of your own pharmacy, you will
need all the drug and health information given to you during your pharmacology
classes that about medicinal issues, pharmaceuticals, wanted and unwanted
drug effects, drug-drug and drug-nutrient interactions.

In most parts of the World, Pharmacy is the first step healthcare unit, and the
pharmacist is the first healthcare professional for people to have healthcare
consultations and to reach the medicines and relief. Because of this you should
be familiar with health conditions and you should know medicines in all aspects.
 Grading
Student assessments will be based upon attendence to lectures, midterm and
final examinations. All students must participate in the following assignments:
Attendance - According to the rules of the ICU, students should be attended to
70% of theoretical lectures. Each students attendance at all class periods is
expected. Students are expected to be in their seats ready for the class and not
dealing with other material during the class.

Midterm and Final exams – will have multiple choice questions. The Midterm and
Final exam both will have a weight of 50% for overall grading.
 Finally

It is my hope that the Class will be a “teaching and understanding”

environment. Distractions such as cellular phones, beepers, side
conservations and sleeping in the class are not allowed and will not be
tolerated.

In order to respect the learning environment of classmates,

students should turn off their cellular phones and other electronic devices
while in class.
Continued disregard of this policy by any student may result in that
student being asked to leave the class.
General (Basic) Pharmacology
Hakan Zengil, Ph.D.
Professor of Pharmacology

CIU – 2018 Spring

 Recommended Reading

Goodman & Gilman’s The Pharmacological Basis of Therapeutics

(L.L. Brunton, J.S. Lazo & K.L. Parker; Editors of the 11th edition)

Rang & Dale’s Pharmacology (Rang, Dale, Ritter, Flower, Henderson) 8th
edition)

Katzung’s Basic and Clinical Pharmacology

Stockley’s Drug Interactions (I.H. Stockley)

 What is Pharmacology?

Pharmacology
Pharmacon + Logos
The Science of Drugs

Pharmacology: the study of drugs and their interactions with living

systems.

Physical and chemical properties

Biochemical and physiological effects
Knowledge of the history, source, and usage
Absorption, distribution, metabolism and excretion
All the effects...

Clinical Pharmacology: study of drugs on humans (patient and/or

volunteer)
 Pharmacology and related disciplines

Pharmacokinetics Pharmacodynamics
(what the body does (what the drug does
to the drug) to the body)

(Rang & Dale, 2012)

 What is a Drug ?

Drug = ???

Remedy Weapon / Shield

Consumption material
(Physician/Patient/Pharmacist/Drug Manufacturer)

A CHEMICAL COMPOUND !..

 How the population expose to chemicals ??

Voluntarily
Alcohol, Smoke (by active smoking), Psychoactive substances (abuse),
Cosmetics, Artificial chemicals added to the foods (color, smell or taste
modifiers), DRUGS

Involuntarily
Fossile fuels for providing energy, Disposal of waste materials,
Industrial chemicals (dyes, detergents, glues, etc.), Chemicals used in
agriculture (pesticides, herbicides, etc.), Smoke (by passive smoking),
Industrial accidents (Bhopal - methylisocyanide, Saveso - TCDD,
Minamata Bay - Hg), DRUGS

ADI & NOEL

Voluntarily transfer of drug choice
(by non-medical experts)
 Amateur prescriptions

«Motolin Air» with a nebuliser figure

«The pump used by elder people for shortness

of the breath» with the figure and price
Professional prescriptions (!)
 Drug

Definition by WHO
- A chemical substance used to change physiologic systems or pathologic
conditions for the benefit of human beings

surgical operation  General Anesthetics

physiologic event  Contraceptives
physical condition  Radiocontrast substances

- A chemical substance used to understand (diagnosis)

to prevent (prophylaxis) and
to treat (therapy) diseases
Ideal properties of the drugs

Safety / Quality / Efficacy

Reversible effect
Chemical stability
Reliable cost
 Classification of drugs

Chemical property : Quaternary ammonium substances

Indication : Analgesics

Site of action : Drugs affecting the heart

Mechanism of action : β-adrenergic receptor agonists

Prototype : Drugs with atropine-like action

Origine : Opium alcaloids

 Nomination of drugs

Chemical name : International Union of Pure and Applied Chemistry, UIPAC

Generic name : Committees of WHO
Trade (Brand) name : Manufacturer’s choice

Chemical : 1-cyclopropyl-6-fluoro-4-oxo-7-(1-piperazinyl)-1,4-dihydro-3-
quinolinecarboxylic acid
Generic : Ciprofloxacin
Trade : Ciprosin (Deva), Cipro (Biofarma), Ciproxin (Bayer), Siprosan (Drogsan)

Chemical name : ()-2-(p-isobutylphenyl) propionic acid

Generic name : Ibuprofen

Trade name : Advil (Wyeth), Artril, Dolven (Eczacıbası), Bebol (Wyeth), Biophen
(Ilsan), Brufen, Ibufen, Brufen Retard (Abbott), Gerofen (Munir Sahin), Nurofen
(Abdi Ibrahim), Pedifen (Atalay), Repozal, Siyafen (Gunsa), Rofren (Akdeniz),
Suprafen (Genbay), Temsofen (Tems), Ultrafen (Dinctas), Upren (Casel), Ibu-600
(YeniIlac) (∑19 as for 2014 April in Turkey)
 Drug nomenclature

British approved names (BAN) United States adopted names (USAN)

Adrenaline Epinephrine
Noradrenaline Norepinephrine
Dexamphetamine Dextroamphetamine
Ergometrin Ergonovin
Glyceryl trinitrate Nitroglycerin
Hyoscine Scopolamine
Isoprenalin Isoproterenol
Lignocaine Lidocaine
Paracetamol Acetaminophen
Pethidin Meperidine
Phenobarbitone Phenobarbital
Rifampicin Rifampin
 Preparation of Drugs

• Factory made
(Aspirin -Acetyl salicylic acid- 0,5 g 20 tablets in blister / box)

• Magistral drugs (prescriptions)

A drug for scabies
Rx.;
Benzylbenzoate 7.0 ml
Benzocaine 1.4 g
DDT 0.7 g
Ethyl alcohol QSP 70 ml
(Use only externally, apply to the affected areas b.i.d., after 24 h take a bath,
repeat in 10th day)
(DDT = dichlorodiphenyltrichloroethane)

• Officinal drugs Tinctura iodi

Iodine 7g
KI 3g
Alcohol (70%) 90 g
 Origin of Drugs

1) Natural sources
- Inorganic chemicals
- Minerals
- Free elements as Ferrium or Iodine
- Salts of several metals as Na, K, Ca, Mg, Fe, Co
- Radioactive substances (I125, I131)
- Plants (Morphine)
- Animals (Insulin)
- Microorganisms or fungi (Antibiotics)

2) Synthetic or Semisynthetic
- Penicillin  Methycillin
 Drug Forms

SOLID
Powders, Tablets, Granules, Coated tablets, Capsules
Vaginal tablets, Suppositories and Bougies

LIQUID
Solutions, Tincturas, Elixirs, Lotions, Enemas, Suspensions, Emulsions

SEMISOLID
Ointments (Merhem or Pomat in Turkish)
Creams
Danse ointments (Pat in Turkish)

CUSTOMIZED
Slow release tablets, Controlled release tablets (Oral Osmotic
Therapeutic System), Transdermal patchs, Aerosols, PC controlled
drug pumps, Liposomated drugs, ADEPT (Antibody-Directed
Enzyme Prodrug Therapy)
Package forms

BOX
BOTTLE
AEROSOL
BLISTER
CACHED
VITRELLA
AMPULE (Ampoule, Ampulla)
FLACON / VIAL

Excipients
To regulate disintegration, dissolution, improve stability
e.g. Lactose, methylcellulose
 Rational Use of Drugs

Patient/ Disease
Selection
Site of administration
Dose
RIGHT Interval
Monitoring
Documentation
+
Therapy cost
 Advers Reactions / Toxicity

• No Magic Bullets!
• Desired effect = therapeutic effect
• All other effects = side (adverse) effects

Systemic side effects at approved dosages

- Dry mouth, hyperthermia by anticholinergic drugs
- Tinnitus by Aspirin therapy (a sign for deafness)

Allergic, carcinogenic, teratogenic effects

- Embryotoxicity caused by Thalidomide
- Non-dose-dependent aplastic anemia caused by Chloramphenicol

Overdose
- toxicity
 Risk vs Benefit Ratio

Advers health effect vs risk of not using drugs in a disease condition

IATROGENIC DISEASES
(iatro = doctor)
Drug induced diseases
(Holland %17, Finland %37, Germany %33)

Primum nihil nocere (Hippocrates !..)

 Advers Reactions / Toxicity

PHARMACOVIGILANCE

Pharmaco = medicine
Vigilare = to watch
alert watchfulness; wakefulness;

WHO definition :
Pharmacovigilance (PV) is defined as the science and activities relating to the
detection, assessment, understanding and prevention of adverse effects or any
other drug-related problems.
 Why Pharmacovigilance ??

• It has been suggested that ADRs may cause 5700 deaths per year in UK.
(Pirmohamed et al, 2004)

• ADRs were 4th-6th commonest cause of death in the US in 1994.

(Lazarou et al, 1998)

125 Patients
24 Patients experienced ADRs (19%)
(59%) were avoidable
 Pharmacovigilance

No drug can be considered totally safe

Some problems are immediate
But some may arise years after or in subsequent generations

e.g. Diethylstilbestrol (DES) to prevent miscarriages (1930-1960)

increased risk of cervical and vaginal cancer in the female offspring of DES users
or
increased gynecomasty incidence in male offspring of oral contraceptives or
estrogen users during pregnancy
 Pharmacovigilance

Adverse effect:
Any response to drug that is noxious and unintended

- Advers Drug Reaction

Any undesirable medical event with exposure to a medicine at approved
usage principles

- Severe Advers Reaction

Conditions cause to death or vital danger, need to be hospitalized or
prolong to stay at hospital, cause transient or permanent disabilities or
congenital abnormalities

- Advers Event
Any undesirable medical event with known causal relationship with the
medicine
 Pharmacovigilance

Centers for Pharmacovigilance

(incorporated to the Ministry of Health)

Contact persons at every hospital and health center

 Pharmacovigilance

Spontaneous Reporting

Special report forms

via connect persons

to Center for Pharmacovigilance

 Pharmacovigilance

Which conditions should be reported ??

For all suspected reactions with new drugs (market life < 5 years)
For all severe and unexpected reactions with old drugs (market life > 5 years)
For all rebound reactions for all drugs

General prerequisites for reporting

An identifiable patient
One suspected reaction
One suspected medicine / medical device
An identifiable reporter
 PHARMACOKINETICS
(what the body does to the drug)
 Pharmacokinetics

Key concepts : Absorption , Distribution,

Key concepts (ADME) Metabolism, Excretion

The entry of drug molecules into systemic

Absorption circulation from the site of administration
Distribution of drug molecules between water,
Distribution lipid and protein constituents of the body
Conversion of drug molecules to more water-
Metabolism soluble products (metabolites) mainly by the
action of enzymes (biotransformation)
The removal of drug molecules and their
Excretion metabolites from the body

Blood drug CONCENTRATION profile by TIME

 SITE OF ACTION TISSUE
“RECEPTORS” RESERVOIRS
Bound Free Free Bound

BLOOD
COMPARTMENT

ABSORPTION Free Drug EXCRETION

Bound Drug

BIOTRANSFORMATION
 How Drugs Pass Over The Biologic Membranes ?

• Passive diffusion – through membranes

– through channels

• Carrier mediated transport

Active transport
Facilitated Diffusion
Pinocytosis
Masked transitions
Mosaic Membrane Model
Passive Diffusion
 Factors Affecting Passive Diffusion

• Concentration difference between two sides of the membrane

• pH of the medium
• Degree of ionization (pKa)
• Solubility in water
• Lipid/water partition coefficient
• Molecular weight
• Absorption area
• Properties of the biological membrane
• Perfusion rate
 Ionisation

Acidic drugs Basic drugs

k1 k1
AH A- + H + BOH OH- + B+
k2 k2

k1 AH = k2 A- H+ k1 BOH = k2 OH- B+

k1/k2 = Ka - log Ka = pKa pKa = 14- pKb

Henderson-Hasselbalch Equation

AH B
log -------- = pKa – pH log --------- = pH - pKa
A- BH+
Ionisation
 % Ionisation according to medium pH
(acidic drug; pKa = 5)

120

100
% Ionization

80

60

40

20

0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
pH of solution
 Ionisation

pKa values of some acidic and basic drugs

Acidic Drug pKa Basic Drug pKa

Cephalotin 2.5 Amphetamine 9.8
Aspirin 3.5 Diphenhydramine 8.3
Ibuprofen 4.4 Mepacrine 7.7
Acetazolamide 7.2 Aminopyrine 5.0
Pentobarbital 8.1 Diazepam 3.3
Phenytoin 8.3 Caffeine 0.8

(Atropin pKa = 9,3 ; GI absorption !...)

 Lipid / Water Partition Coefficient

Lipid / Water Partition Coefficient of some drugs

(Chloroform / Water ; pH = 7.4)

Ephedrin 0.015
Salicylic acid 0.2
Barbital 0.7
Phenobarbital 4.8
Pentobarbital 11.7
Tiopenthal 102
Packaging non-lipid soluble drugs into liposomes (Amphotericin)

** Barbiturates - close MWs and pKa values -

Barbital pKa = 7.8 L/W = 0.75
Secobarbital pKa = 7.9 L/W = 50
Secobarbital absorption 8 x Barbital
 Other factors modifying passive diffusion

• Solubility in water (e.g. BaSO4)

• Surface area of the absorption site

• Membrane properties
(unilayer / multilayer / keratinized / tight junctions)

• Molecular weight (Benzatinepenicillin)

• Estherification (medroxyprogesterone acetate, testosterone
propionate)

• Tissue perfusion rate

(Local anesthetic + adrenaline combinations)
 Non-lipid Diffusion

OUTSIDE Membrane INSIDE

Coutside Cinside

Electrolites, Neutral substances, ions charged oppositely to the channel

FACTORS INFLUENCING THE RATE OF TRANSFER :

Pore density, Pore diameter, Hydrostatic pressure difference, Viscosity (resistance),
Molecular weight & shape, Electrical charge
 Active Transport

Monosaccarides
Amino acids
Organic phosphates
Vitamin B group
Cardiac glycosides

Carrier specificity
Concentration gradient
Energy requirement
Competitive inhibition
Limited capacity kinetics
 Facilitated Diffusion

Choline, Vit B12

Carrier specificity
Competitive inhibition
Energy requirement (!)
Limited capacity kinetics
 Pinocytosis

Colloidal substances
Receptor-linked-endocytosis (peptide hormones)
Immunoglobulins in the milk / intestinal epithelium in neonates
 Principles for choosing drug administration route

Consider the importance of the following

• Target concentration in blood

• Rapidity of onset
• Duration of effects
• Magnitude of effects
• Amount delivered Route for administration Time until effect
• Patient characteristics intravenous 30-60 sec
intraosseus 30-60 sec
inhalation 2-3 min
endotracheal 2-3 min
sublingual 3-5 min
intramuscular 10-20 min
subcutaneous 15-30 min
peroral 30-90 min
 Biologic barriers according to the selected route

Route Barriers

Peroral (p.o.)
sublingual
rectal mucous or serous epithelium
intravaginal surrounding the cavity
intranasal +
inhalation vascular endothelium

intraconjunctival mucous membrane of conjunctiva

+
corneal epithelium

percutaneous keratinized epithelium of skin

subcutaneous (s.c.) vascular or lymphatic endothelium

intramuscular (i.m.)

intraarterial (i.a.) No barriers for absorption

intravenous (i.v.)
 Routes For Drug Administration

LOCAL
Percutaneous (Epidermal), intracutaneous, intranasal, intraconjunctival,
intrathecal, intraperitoneal, intrapleural, intracardiac, intrauterine,
intravaginal, intrauretral, intraarticular

SYSTEMIC
Enteral, Parenteral, Transdermal, Inhalation, Intraosseus, Endotracheal
 Percutaneous Administration

Skin is not much permeable / mainly epidermis

Hair follicles, sweat and sebaceous glands (0.1% of whole area)

Lipid/water partition coefficient

Humidity

Stratum corneum thickness (scrotum < mastoid < hairy skin <...)
(psoriasis, skin ulcers, wounds, etc.)

Slow systemic absorption (lipid soluble drugs only; eg. estrogen, opioids)

Excipients / Corticosteroids
Acute Dermatosis Lotions / Creams

Chronic Eczema Ointments (with mineral hydrocarbon

Psoriasis based non-hydrophyllic excipients)

Talk or starch based powders // Water based emulsions

 Intracutaneous Administration

intradermally with suitable needles

Local anaesthetics
Substances for allergy tests
Vaccines
 Intraconjunctival Administration

Intraconjunctival
administration
 Intraconjunctival Administration

Eye / eyelid infections / glaucoma

Myosis / Mydriasis

Collyr / Ointment / Ocular implant

( 10l liquid)

Some systemic absorption through “nasolacrimal channel”

(eg. timolol for glaucoma may precipitate
bronchospasm in asthma)

Reducing systemic side effects (Dorzolamid for glaucoma)

Intravitreal injection
(Ranibizumab in age-dependent macular
degeneration)
 Intrathecal Administration

L 3-4 / L 4-5 Subarachnoid space

Specific gravity / patient position

BOS drainage

Meningitis treatment (several antibiotics)

Spinal anesthesia (e.g. Bupivacaine, Opioids)
Serious muscle spasms (Baclofen)
Childhood leukemias (e.g. Methotrexate)
 Intranasal Administration

• Nasal mucosa or paranasal sinuse diseases

(local : decongestants, hemostatics)
(systemic : antidiuretic hormon, gonadotropin releasing hormone, calcitonin)

• goutte / spray / ointment / powder (insuflation ; snuff, pulverized

tobacco)

• Lipid pneumonia
 Intraperitoneal Administration

• Local / Systemic

• passes through liver first

• Antibacterials, anticancer substances

• Site of administration

• Paracentesis (the surgical puncture of a body cavity in order to

draw off excess fluid)

• Bladder rupture
 Intrapleural Administration

• Antibacterials, anticancer substances

• Dorsal axcillary line / 7th intercostal space

• Aspiration of excess fluids from the area

 Intracardiac Administration

• Into the myocardium or one of the cardiac cavities

• Parasternal 4th intercostal space on the left

 Intrauterine Administration

• Oxytocine hormone administration into myometrium after cesarian section

• Some contraceptives, spirals

• Drug administration to amnion fluid or cervics for medical abortus

 Intravaginal Administration

Bacterial or fungal infections

Atrophic vaginitis
Contraception

ovule / tablet / cream / gel

 Intrauretral Administration

• Bougies

• Solutions for bladder irrigation

 Intraarticular Administration

• Romatoid Arthritis

• Antibacterials / Corticosteroids

Drawbacks :
• Infections
Crystal Synovitis
Tendon rupture
 Routes for Systemic Administration

• ENTERAL
Oral (peroral; per os; p.o.)
Sublingual
Rectal

• PARENTERAL

• TRANSDERMAL

• INHALATION

• INTRAOSSEUS

• ENDOTRACHEAL (TRANSTRACHEAL)
 Peroral Administration

Properties of the absorption site

Stomach Intestine

pH 1-3 5-7

Surface area 1 m2 200 m2

Perfusion rate 150 ml/min 1 lt/min

Permeability poor high

Membrane thicki mucus covered very thin

Peroral Administration

Disintegration
Dissolution

Passive diffusion
(Atropine)
Active processes
(L-DOPA)
 Peroral Administration

Factors influencing disintegration and/or dissolution

- Particular size (surface area)

Spironolakton (100 mg) / Spironolakton A (25 mg)

- Molecular properties
Cortisol acetate 5 crystal forms at different solubility rate
Anhidr forms are more soluble than crystals (as for Ampicilline)
Amorph forms are more soluble than crystals (as for Chloramphenicol
palmitate)

- Formulation (inactive ingredients)

Phenytoin toxicity outbreak (Australia, 1968) CaSO4  Lactose
Change in Phenytoin Excipients Results in Epidemic Toxicity

F Bochner, Proc Aust Assoc Neurol, 1973

 Peroral Administration

Gastric acid secretion

- pH / Ionisation

- Gastric irritation (vomiting, ulcers)

- Decomposition via acid hydrolysis

 Peroral Administration

Presence of food

- Gastrointestinal passage rate

- Gastric emptying

- Physical/chemical complexes

hunger period
 1 hr before – (eating time) – 2 hrs after 
 Sublingual Administration

SUBLINGUAL / BUKKAL TABLETS

Lipid soluble drugs only (eg. Glyceryl trinitrate, buprenorphine)

Small surface area
Rapid absorption

Factors influencing absorption rate : pKa, salivary pH, lipid solubility

No gastric or hepatic first-pass effect

 Rectal Administration

• Excellent route of administration of medications for the patient who :

– Vomiting / nausea
– Refuses or not able to take medication PO
– Difficulty in swallowing a medication
– Infants – fever or pain medications
– Useful if unable to get IV access (eg diazepam in status epilepticus)
– Direct effect on large bowel

• local / systemic

• ointment, suppository, enema

• partial first-pass effect (lower or middle hemorroidal veins go through V. cava

inferior)

• Defecation / emptying enemas

irritant excipients may stimulate defecation
 Parenteral Administration

- Rapid onset of activity

- No gastrointestinal loss
Bioavailability % 100
- Unconscious or noncompliant patients, vomiting or diarrhea
- Injectable solutions, emulsions, suspensions
- Asepsis at the site of injection
-Water soluble, pyrogen-free, sterile, isotonic, pH
-Does not precipitate by blood elements, does not haemolyse erythrocytes
- First-pass effect at lungs
(except intraarterially administered drugs)

Requirements
 Intraarterial (i.a.) Administration

• Antineoplastic drugs
• Radioopaque substances for angiography
 Intravenous (i.v.) Administration

Peripheral veins (Antecubital vein)

Bioavailability %100

Slow injection

Caution for : suspensions, lipid excipients, hemolytic drugs,

drugs with solubility problems!..
 Intramuscular Administration

Deltoid, Gluteus, Vastus lateralis muscles

Factors influencing absorption rate

pKa, lipid solubility, osmolality,
perfusion rate at the injection site
Massage / friction

Attention to the drugs with solubility problems

(Chlordiazepoxide, Diazepam)

Dorsogluteal muscle * caution for the underlying sciatic

nerve and major blood vessel of gluteal trunk

Thickness of the gluteal fat in obese patients !..

Subcutaneous (S.C.) Administration

Outside skin layer of humerus or femur

+ hyaluronidase / + vasoconstrictors

massage / friction

painful ; s.c. > i.m.

Maximum volume 2 ml

solid pellets for s.c. administration

(e.g. estradiol)
 Transdermal Administration

ointments
(Nitroglycerine)
Patches
(Nitroglycerine, Kinidine, Estrogen, Testosterone, Fentanyl, Nicotine)

individual skin properties !

 Administration by Inhalation

Local / systemic
(beclometasone propionate, salbutamol)

Inhalation / Expiration
Gaseous / Aerosol drugs / solid (silicosis)
Nebulizers for asthma
Absorption via perialveolar capillaries
(large surface area and blood flow)
(trapping by nasal fluid)

Caution for substances irritant to pulmonary epithelium

No hepatic first-pass effect

Nebulizers ~10% absorption

Depends on type of inhaler and how used
 Intraosseus Administration

infusion into proximal tibia

distal femur
distal tibia

absorption is as rapid as i.v. administration

children under 5 years of age !..

- unconscious / unresponsive patients

- Patients under risk of death due to cardiac arrest or circulation failure
- Drugs that cannot be administered intravenously
Aerosols
Particle size determines absorption

> 5 microns drug may be deposited in nasopharnyngeal region, some

swallowed following ciliary movements

= 2-5 micron deposited in tracheobronchial region, cleared by

mucociliary action, some swallowed and GI absorbed

< 1 micron penetrate to alveolar sacs, absorbed into blood

 Endotracheal Administration

Intubated patients

Only the following drugs can be applied directly into the

endotracheal tube
Atropine
Adrenaline
Diazepam (except children)
Lidocaine
Naloxon (Naltrexone)
Vasopressine

absorption is as rapid as i.v. administration

 Bioequivalency and Bioavailability

EQUIVALENCY
CHEMICAL EQUIVALENCY
PHARMACEUTICAL EQUIVALENCY
THERAPEUTIC EQUIVALENCY
(80-125% of original is acceptable)

BIOAVAILABILITY
bioavailability is a measurement of the rate and extent to which a drug reaches at
the site of action
ABSOLUTE BIOAVAILABILITY (%)
RELATIVE BIOAVAILABILITY

in vitro : Dissolution rate

in vivo : Comparison of drug concentration-time variables
(Cmax, Tmax, AUC)

AUCpo * Dose iv AUCA * DoseB

Fa = -------------------------- Fr = --------------------------
AUCiv * Dose po AUCB * DoseA
Comparison of different formulations

Burkitt, Australian Prescriber, 2003

 Bioavailability

FACTORS INFLUENCING BIOAVAILABILITY

I- Pharmaceutical
II- Physiologic / Biologic
 Factors Influencing Bioavailability

I- Pharmaceutical Factors
A- Physicochemical properties of the drug
(solubility, ionisation, etc.)

B- Factors related to the dosage form of the drug

(disintegration, dissolution, particular size, ingredients other than the
active substance, etc.)

C- Factors related to the manufacturing methods

(immediate release, modified release, compress pressure for tablets,
coat material, etc.)
 Factors Influencing Bioavailability

II - Physiologic / Biologic Factors

A- pH, mucus, biliary salts, etc. at gastrointestinal channel
B- Factors influencing the passage (duration of gastric emptying,
duration of intestinal passage, enterohepatic circulation, presence of
food, quality and quantity of food, etc.)
C- Absorption surface area at the gastrointestinal channel and perfusion
rate of the area
D- First-pass effect, enzyme induction/inhibition by secondary drugs,
individual variations in metabolic activity (phenotype, age,etc.)
E- Pathologic conditions such as malabsorption syndrome or
achlorhydria (absence of sufficient amount of hydrochloric acid in
presence of a suitable stimulation)
 Factors Influencing Bioavailability

Suspension / tablet
 Factors Influencing Bioavailability

Four Chloramphenicol preparations from different manufacturers

Factors Influencing Bioavailability
 Factors Influencing Bioavailability

Five Phenytoin preparation from different manufacturers

Factors Influencing Bioavailability
 Factors Influencing Bioavailability

Partikül Büyüklüğü
 Factors Influencing Bioavailability

Disintegrator support
 Factors Influencing Bioavailability

Disintegrator support
DRUG DISTRIBUTION
 Drug Distribution

Movement of drug from blood to other sites of the body

Body compartments for drug distribution

INTRACELLULAR  27-29 lt / 70 kg (ethanol, phenytoin)

EXTRACELLULAR  9-12 lt / 70 kg (gentamycine)
PLASMA  3-3,5 lt / 70 kg (heparin, Evans Blue)

Interstitial fluid
Lymph
Transcellular water (cerebrospinal, intraocular, peritoneal, pleural, synovial, digestive)
 Compartment Models

One compartment model, i.v. administration

One compartment model, p.o.. administration

Vd = Volume of distribution, Ka = absorption rate constant

C = concentration, Ke = elimination rate constant
Compartment Models
 Compartment Models

Two compartment model, p.o. administration

 Compartment Models
Two compartment model, p.o. administration
 Physiologic Model

Intestine Stool

Kidneys Urine

Lungs Expiration

Liver
Blood
Muscle

Brain

Adipose tissue
 Factors Influencing Drug Distribution-I

ION TRAP

BASIC DRUG pKa = 6

1. COMPARTMENT 2. COMPARTMENT
pH = 5 pH = 7

M] M]
log -------- = pH –pKa = 5-6 = -1 log -------- = pH –pKa = 7-6 = 1
I] I]

M] 10 M] 10
-------- = 0.1 = --------- -------- = 10 = ---------
I] 100 I] 1

110 / 121 (% 91) 11 / 121 (% 9)

 Factors Influencing Drug Distribution

pH differences between the compartments

Compartments pH
Plasma 7.4
Extracellular 7.4
Intracellular 7.0
Cerebrospinal fluid 7.3
Breast milk 6.7
Bile 7.8 – 8.6
Saliva 6.2 – 7.2
 Factors Influencing Drug Distribution-II

DIFFERENT BINDING RATIOS AT ADJACENT COMPARTMENTS

I. COMPARTMENT II. COMPARTMENT

% 5 binding %75 binding

Free 19 19 Free
--------- = ------ ------ = ----------
Bound 1 57 Bound

20 / 96 76 / 96
(%21) (%79)
 Factors Influencing Drug Distribution-III

PERMEABILITY DIFFERENCES BETWEEN TISSUES

Penicylline / Tiopenthal /// Brain / Muscle

 Factors Influencing Drug Distribution-III

Passage of drugs from blood to cerebrospinal fluid

is often permeability rate-limited
 Lipid / Water partition coefficients (in order) : T > P > B > S > S ]
 Factors Influencing Drug Distribution-IV

PERFUSION RATE OF TISSUES

Perfusion Rate
(% of cardiac output)
Tissues which perfused rapidly
- Adrenal gland 1
- Kidneys 24
- Thyroid gland 2
- Abdominal tissues and liver (V.portae) 20
- Liver (A. hepatica) 5
- Heart 4
- Brain 15
Tissues which perfused slowly
- Skin 5
- Muscle (at rest) 15
- Connective tissue 1
- Adipose tissue 2
 Factors Influencing Drug Distribution-IV

PERFUSION RATE OF TISSUES

Perfusion Rate % of body weight Blood flow
(% of cardiac output) (lt/kgtissue/min)

Tissues which perfused rapidly

- Adrenal gland 1 0.02 5.5
- Kidneys 24 0.4 4.5
- Thyroid gland 2 0.04 4.0
- Abdominal tissues and liver 20 2 0.75
(V.portae)
- Liver (A. hepatica) 5 2 0.2

- Heart 4 0.4 0.7

- Brain 15 2 0.55
Tissues which perfused slowly
- Skin 5 7 0.05
- Muscle (at rest) 15 45 0.03
- Connective tissue 1 7 0.01
- Adipose tissue 2 15 0.01
Redistribution
 Binding Sites
Protein binding allows part of the drug to be stored and released as needed

Functional and non-functional binding

Serum albumine
- high-affinity (bilirubin) and low-affinity (BDZ) binding sites for drugs (binds
Warfarin, Barbiturates, Benzodiazepins, NSAIDs, Phenytoin, Penicillines,
Tolbutamide, etc)
α1-acid glycoprotein
- acute phase protein / concentration increase in inflammatory diseases, MI, cancer
(binds β-blockers, Bupivacaine, Imipramine, Prazosin, Verapamil)

Lipoproteins
- (binds triglycerides, phospholipids, cholesterol, etc.)

Specific binding globulins

-(binds thyroxine, steroids, etc.)

Other
- (some antimalarial drugs bind to lymphocytes)
 Binding Affinity

k1
DRUG + PROTEIN DRUG - PROTEIN COMPLEX
D P k2 DP

k1 DP
ka = ----- = -------------
k2 D P

ka = affinity constant for binding

 Kinetics Of Drug-protein Binding

Relationship between protein concentration and binding ratio

Ka (in order) A > B > C
 Conditions Altering Binding Site Concentrations in Blood

Causes of Hypoalbuminemia
Ageing, Severe malnutrition, Severe burns, Hepatic cirrhosis, Cystic fibrosis,
Bacterial pneumonia, Hepatic abscess, Multiple myeloma, Nephrotic
syndrome, Acute pankreatitis, Renal failure, Pregnancy, Severe traumas
Causes of Hyperalbuminemia
Exercise, Hypothyroidizm
Causes of -1 acid glycoprotein concentration decrease
Nephrotic syndrom, Oral contraceptives
Causes of -1 acid glycoprotein concentration increase
Ageing, Celiac disease, Crohn disease, Myocardial infarct, Stress,
Renal failure, Rheumatoid arthritis, Surgical operations, Severe traumas
Causes Of Hypolipoproteinemia
Hyperthyroidism, traumas
Causes Of Hyperlipoproteinemia
Diabetes, Hypothyroidism, Nephrotic syndrome
 Results of a decrease in binding ratio

If binding occurs 10 points less...

Normal New % increase

binding (%) binding (%) in free conc.
20 10 12
50 40 20
80 70 50
90 80 100
98 88 500
99.8 98 1000

Slight changes in binding of tightly bound drugs can be significant

 Diseases influencing binding ratio

Changes in drug binding in some clinical conditions

Hemodialysis / Cephazoline 84 %  22 %
Severe renal insufficiency / Phenytoin 90 %  80 %
Nefrotic syndrom / Prednisolone 74 %  65 %
Hepatic insufficiency / Digitoxin 97 %  93 %
 Binding

BINDING SITES OTHER THAN SERUM ALBUMINE

Lipoproteins Weak basic drugs

1-acid glycoprotein Weak basic drugs

Erythrocytes Propranolol, Quinidine

Membrane ATPase Digoxin

Specific carrier globulins Vit B12, Thyroxine, Corticosteroids

 Sequestration (Accummulation)

Basophilic materials Acridine substances (Mepakrin)

Keratin containing tissues Arsenic

Retina (nucleoproteins) Chloroquine

Iris of the eye (melanine) Ephedrine, Atropine

Bone Pb, Sr, Tetracyclines, Florine

Thyroid Iodine

Brain tissue Chlorpromazine

Chloroquine Liver (x1000)

Adipose tissue Anesthetic gases, Tiopenthal,

DDT
 Relationship Between Binding and Toxicity

I – SATURATION OF THE BINDING SITES

Serum Albumine (MW = 67.000 D)

 43 g / lt = 0.64 mM

1-acid glycoprotein
0.4 – 1.0 g / lt = 0.015 mM

Transcortin
0.03 – 0.07 g / lt = 1 M
 Relationship Between Binding and Toxicity

II – REDUCTION IN BINDING SITES

Hypoalbuminemia

Endogenous binding inhibitors

Free fatty acids, metabolic acidosis, urea  cyanates

Drug interaction
Warfarin x Acetyl salisilic acid
 Volume of Distribution (VD)

APPARENT VOLUME OF DISTRIBUTION

Volume of fluid required to contain the total amount of drug in the

body at the same concentration as that in the plasma

total amount of drug in body Dose

Vd = ------------------------------------- = -----------
plasma concentration C0
Apparent Volume of Distribution at i.v. Administration
 % Binding and Volume of Distribution

Protein binding ratio and Vd for some drugs

DRUG BINDING (%) Vd (lt / kg)

Warfarin 97 0.2
Diazepam 95 2.0
Propranolol 95 4.0
Digoxine 27 6.0
Chlorpromazine 95 15
Haloperidol 92 20
Nortryptilline 92 40
Lithium 0 1.0
Ceftriaxon 92 0.2
Cefoxitin 70 0.15
Cefuroxim 35 0.15
Ceftizoksim 30 0.2

*Binding outside the plasma compartment or distribution into body fat

increases VD.
 % Binding and Elimination Half Life

Protein binding ratio and t1/2 for some drugs

DRUG BINDING (%) t1/2 (hour)

Furocemide 95 1
Propranolol 95 4
Diazepam 96 30
Phenytoin 95 35
Warfarin 97 35
Digitoxin 98 150
 % Binding and Elimination Half Life

Protein binding ratio and t1/2 of sulphonamides

DRUG BINDING (%) t1/2 (hour)

Sulphatiazol 55 3
Sulphapyridine 30 8
Sulphametoxazol 60 15
Sulphametoxypyridazin 85 40
Sulphametoxypirazine 65 70
Sulphadoxine 95 150
 Blood Brain Barrier

Brain; %2 of total body weight

%16 of cardiac output

Dansity of capillaries :
Cortex 1000 capillaries/mm2
White matter 300 capillaries/mm2

Blood Brain Barrier (BBB)

Tight junctioned capillary endothelium + surrounding astrocytic sheat do not
allow water soluble substances to enter brain tissue.
 nucleus
Basal
membran
Tight
junction

fenestrae

astrocyte
Peripheral capillaries Brain capillaries

 tight junctioned endothelium

 no pores at the basal membrane
 glial sheat consisting of tightly joined monolayer astrocyte cells
 membrane pumps which are organized to transfer chemicals back to
the capillary lumen
 very little pinocytotic activity
 BBB

Enzymes supporting BBB

Dopa decarboxylase
Pseudocholinesterase
CYP450
MAO-B
Renin
Angiotensin Converting Enzyme

Peptides increasing BBB permeability

Bradykinin
Enkephalins
 Transfer of chemicals at brain capillaries

 Pasif diffusion
Small, free lipophyllic drugs only
 Carrier mediated transport
D-glucose, aminoacids

Carrier Localisation Function

GLUT-1 KBB, KBOSB Glucose uptake

PHT1 KBOSB Small peptides and histidine uptake

System L KBB Zwitterion amino acids such as L-Leu, L-Phe, L-Trp

System A KBB Small neutral aminoacids

 Blood - CSF - Barrier

Choroid plexus (CSF production area)

Fenestration in capillary endothelium

Similarities with brain capillaries ( tight junctions and monolayer choroid

epithelial cells)

Permeability properties mostly resembles BBB

 Membrane pumps to transfer chemicals back into the capillary lumen

 P-glikoprotein (P-gp)
• At the luminal side of the capillaries
 Organic anion transfering polipeptide (OATP)
• Both influx and efflux
Organic cation transfering polipeptide (OCTP)
Breast cancer resistant protein (BCRP)
Multipl drug resistance associated proteins (MRP)

(McNamara & Leggas, 2009)

 Factors deteriorating BBB

Infections (meningitis) Hyperosmolarity

Trauma Ionizing radiation
Inflammation, Ischemia Cytotoxic agents
Hypertonic solutions HIV
Alcohol (high concentration) Some cancers
 Periventricular Areas Deficient of BBB

Pineal gland Subfornical organ

(melatonin) (Regulation of body fluids)

Neurohypophysis Labia teminalis vascular organ

(oxytocin and vasopressin) (Control of peptides)

Area postrema Eminentia media

(CTZ) (Control of anterior hypophysis)

Domperidone (an antiemetic dopamine receptor antagonist) does not pass the
BBB but does access to CTZ and can be used to prevent neusea caused by
antiparkinson dopamine agonists !..
Methylnaltrexone bromide (a μ-receptor antagonist) has very limited GI
absorption and does not pass the BBB and can be used to treat opioid-
induced constipation.
 Binding Ratio and CSF Access

Drug % binding CSF / BLOOD Vd (lt/kg)

Sulfamethoxypyridazine 90 0,10 0,25

Sulfamethoxazole 60 0,30 0,20

Sulfadiazin 40 0,60 0,35

Sulfapyridin 30 0,78 0,30

Sulfanilamid 10 0,90 0,20

CSF protein content is ≈ 1/500 of the blood

 Maternal-Fetal Distribution

Passive diffusion (placenta villus epithelium and fetal capillary endothelium)

Some active transport and a little pinocytosis

Maternal / fetal equilibrium 40 min

(Labours requiring anesthesia)

Fetal pH a little bit more acidic (weak bases cross easily)

Feta salicylat and valproate concentrations are higher than maternal ones.
Small molecule, liposolubl, non-ionized, unbound molecules cross rapidly
maternal concentration

* Placental surface area increases progressively by pregnancy duration

* Placental membrane thickness reduces accordingly
* Placental blood flow increases near delivery
* Placenta has some enzymes to metabolize chemicals.

Exposure to a single dose or chronic exposure / Term

Teratogenic drugs
Thalidomide, Diethylstilbestrole
 FDA PREGNANCY CATEGORIES (since1983)

• A Any proven risk with controlled studies

• B animal studies show no risk; inadequate human data.
• C animal studies show risk, inadequate human data.
• D human data show risk, benefit may outweigh risk.
• X animal or human data positive for risk. Use unwarranted.
(ACEI, Anticancer agents, Phenytoin, Valproic acid, Carbamazepine, Lithium,
Vit A, Estrogens, Androgens, Progestins, Varfarin, Misoprostol, etc)

Vitamins (at Recommended Daily Allowances)

A Vit B1 (thiamine), B2 (riboflavin), B6 (pyridoxine), B9 (folic acid)
C Vit C (ascorbic acid), B3 (niacin), Vit K
X Vit A
 ELIMINATION

BIOTRANSFORMATION
(METABOLISM)
&
EXCRETION
 Drug Biotransformation
(Drug metabolism)

• Enzyme-catalyzed conversion of drugs to their inactive metabolites, more

soluble forms, or a more potent metabolite

• Main purpose: To detoxify and inactive drugs and other foreign

substances

• Liver (main site), kidneys, lungs, plasma, intestinal mucosa

• Metabolites are usually more water soluble and excreted by kidneys

• Prodrugs are biotransformed to active drugs

– Prodrug is absorbed better than biotransformed forms

• First-pass effect
 Biotransformation

Phase I Reactions Oxidation

Reduction
Hydrolysis

Phase II Reactions Conjugations

NH2 Acetylation or conjugation with glycine or glutamine

PAS

OH Conjugation with glucuronic acid

COOH Conjugation with glucuronic acid

 Biotransformation

Sequential enzymatic reactions

hydroxylation conjugation

Benzene Phenol Phenolglucuronide

 Biotransformation

Active Drug Reaction

Amphetamine  CYP-450-catalysed oxidation (deamination)
Diazepam  CYP 2C19 (N-demethylation)
Noradrenaline  Vanilmandelic acid

Prodrug Active metabolite

L-DOPA Dopamine
Azathioprine Mercaptopurine
Prednisone Prednisolone
Enalapril Enalaprilat
Zidovudine Zidovudine triphosphate
Cyclophosphamide Phosphoramide mustard
Phenacetine Paracetamol
Sulindac Sulphide derivative
(reductases of bacterial flora - 500 times more potent)
Risperidone 9-hydroxyrisperidone
Codeine Morphine (CYP 2D6-catalysed O-demethylation)
 Biotransformation

CYTOCHROME P-450 ENZYME FAMILIES

CYP 1A1 CYP 2A6 CYP 3A4

CYP 1A2 CYP 2B6 CYP 3A5
CYP 1B1 CYP 2C8 CYP 3A7
CYP 2C9
CYP 2C19
CYP 2D6
CYP 2E1

(http://medicine.iupui.edu/flockhart)
Human P450 isoenzymes : availability and function
 CYP ENZYMES

Intestine Liver
CYP3A % 82 % 40
CYP2C9, CYP2C19 % 16 % 25
CYP1A2 %10
CYP2E1 % 9
CYP2A6 % 6
CYP2D6 <%1 % 2
CYP2B6 <%1
 CYP450 Izozymes and Their Substrates

CYP 1A2 (Chromosome 15)

Location : Liver tissue
Substrates : Caffeine, Theophylline, Paracetamol, Estradiol,
Verapamil, Ondansetron, Fluoxamine,
Induced by : Smoking, PAHs, Omeprazole, Broccoli, Brussel sprouts
Inhibited by : Fluvoxamine, Fluoroqinolones,

CYP 2C9, 19 (Chromosome 10; polymorphic)

(2C9 1-3% Caucasians PM)
(2C19 3-5% Caucasians PM , 15-20% Asians PM)

Location : mostly in liver

Substrates : Taxol, Phenytoin, Diclofenac, Diazepam, Imipramine,
Lansoprazole, Omeprazole, Sildenafil, Tolbutamide
No specific inductor (Induced by Phenytoin, Carbamazepine (2C19),
Inhibited by : Fluvoksamine, Sulfaphenazole (2C9),
Omeprazole (2C19)
 CYP450 Izozymes and Their Substrates

CYP 2D6 (Chromosome 22; polymorphic)

(PM 5-10% Caucasians; 4% Blacks; 1% Orientals; 1 % Asians)
Location : mainly in liver
Substrates : Propranolol, Codein, Debrisoquine, Captopril, Venlafaxine,
Fluoxetine, Ondansetron, Tamoxifen, Lidocaine, Risperidone,
Inhibited by : Quinidine, TAD, SSRIs, Amiodaron, Cimetidine, Ritonavir
Induced by : Rifampin, Dexamethasone

CYP 2E1 (Chromosome 10)

Location : mainly in liver and peripheral lymphocytes
Substrates : Paracetamol, Chlorzoxazone, industrial chemicals (such as
benzene, vinyl chloride, carbontetrachloride, etc.)
Inhibited by : diethyl-dithiocarbamate, disulfiram
Induced by : Ethanol (alcoholics), Isoniazid
 CYP450 Izozymes and Their Substrates

CYP 3A3 and 3A4 (Chromosome 7)

Location : Liver, intestine
Substrates : Nifedipine, Nitrendipine, Quinidine, Taxol, Erythromycin,
Warfarin, Cyclosporine, Verapamil, Testosterone,
Sildenafil, Buspirone, HMG CoA Reductase inhibitors,
Indinavir, Haloperidol,
Induced by : Barbiturates, phenytoin, rifampicin, Efavirenz
Inhibited by : Grapefruit juice alkaloids, Klaritromycin, Indinavir
Eritromycin, Klaritromycin, Triacetyloleandromycin
(NOT Diritromycin and Azitromycin)
 CYP450 Izozymes and Their Substrates

P450AROM (CYP 19A1; over, placenta, breast tissue)

Androstenedione, Testosterone
(inhibitor : Letrazole)

P450C-21 (CYP 17 2B1; adrenal cortex zona fasiculata)

17-Hydroxyprogesterone
(deficiency causes congenital adrenal hyperplasia)

P45017 (CYP 17A1; adrenal cortex, testes, over theca cells)

Pregnenolone
(inhibitor : Abiraterone)
 Conjugations (PHASE II)
Glucuronidation (microsomal)
UDP-glucuronosyltransferase (microsomal) // UDP-glucuronic acid

Sulphation
sulphotransferases // adenozin 3-phosphate-5-phosphosulphate

Methylation
O-methyl transferase, N-methyl transferase, C-methyl transferase
// S-adenosyl-L- methionine

Acetylation
N-acetyl transferase // Acetyl CoA

Conjugation with aminoacids

glycine, glutamine

Conjugation with Glutathione (glycine-cysteine-glutamate)

glutathione S-transferase
 Presystemic Elimination

First-pass effect
depends on the route of drug administration
enzymes at liver / GI flora / pulmonary epithelium
Gastric acid inactivates benzylpenicillin,
Proteolytic enzymes inactivate insulin

Gastrointestinal Hepatic Bronchial

-methyldopa Alprenolol Isoprenaline
Catecholamins Propranolol Nicotine
Chlorpromazin Oksprenolol
L-Dopa Lidocaine
Labetolol Nitrit compounds
Testosterone Nortriptyline

NO first pass by sublingual, intranasal, transdermal, and inhalation

 First Pass Metabolism with the Enzymes of GI Flora

CYP 3A4
Blocked by grapefruit juice
Plasma Simvastatin Concentration (ng/ml)

Administration of 40mg
Simvastatin with
Water
Grapefruit juice

Lilja et al., Br J Clin Pharmacology, 1994

 Induction of Microsomal Enzymes

Inductor causes de-repression on the constructive gene by an action on the

regulatory gene at “Ah locus” area of DNA.
The resultant rise in mRNA synthesis increases ribosomal enzyme synthesis

Types of induction : Phenobarbital type

Methylcholantrene type

Some potent inductors

Barbiturates Rifampin Griseofulvin
Carbamazepine Warfarin Isoniazid
Nicotine Phenytoin Chlorpromazine

Clinical usage
Neonatal Kernicterus (bilirubine encephalopathy)
To increase metabolic capacity in alcoholic circhosis
Vit D2 intoxication
 Enzyme Inhibition

Some potent inhibitors

Chloramphenicol MAO Inhibitors

Cimetidine Erythromicine
Bishydroxycumarine Disulfiram

Conditions and diseases reducing microsomal enzyme activity

Starvation
Hepatic cancer
Occlusion jaundice
Nutritional deficits
EXCRETION
 Renal elimination

RENAL

GLOMERULAR FILTRATION - Molecular weight

- Binding ratio
- Blood concentration

TUBULAR REABSORPTION - pKa and Urinary pH for ionising drugs

- Lipid solubility for nonionising drugs

TUBULAR SECRETION - Active transport

Modifiers: renal blood flow, blood drug concentration, MW, renal disorders, blood
and filtrate pH (related nutrition)
Penicillin active secretion // organic acids as Probenecid
 Excretion

LIVER – BILE - FAECES

humans produce 400-800 ml bile/day

drugs have MW > 250
• Radioopaque substances, Bile acids, Bilirubin,
glucuronic acid conjugates of drugs

• Enterohepatic circulation

• Factors modifying enterohepatic circulation

transfer rate to bile, gastrointestinal flora and biliary function, nutrients,
gastrointestinal passage rate, Cholestatic jaundice, etc.
 Excretion

PULMONARY
(via expiration)

Gaseous or volatile substances, Nitrogen protoxide, Alcohol,

Ammonium chloride, Paraldehyde
 Excretion

SALIVA and MUCUS

Iodine, Brom, Mercury, Bismuth, Lead, Lithium,

Amphetamin, Heroin,
Sulfonamides, Clonidine, Quinidine
Lidocaine, Procainamid

SWEAT – TEARS

Iodine, Brom, Mercury, Arsenic, Lead, Ferrous compounds,

Alcohol, Urea, Thiamine, Sulfonamids, Salicilic acid, Rifamycins

***Lens staining
 Excretion

BREAST MILK

Iodine, Bromide, Lithium, Alcohol, Nicotine, Penicillin, Acetylsalicylic

acid, Chloramphenicol, Morphine, Barbiturats, Caffeine, Estrogens,
Antitiroid uracil substances, Antraquinone substances

Factors modifying transfer of drugs to breast milk

- Maternal drug concentration
- Lipid solubility of drug
- pKa
- pH difference between blood and breast milk

Drugs contraindicated during lactation

Anticancer agents, Immunosuppressants, Ergo alkaloids, Lithium, Fluoroquinolones,
Misoprostol, Gold salts, Amphetamines, etc)
 Drug Transfer to a Nursing Baby via Breastfeeding

For acidic drugs

1 + antilog (pHmilk – pKa)

R milk / plasma = --------------------------------------
1 + antilog (pHplasma – pKa)

For basic drugs

1 + antilog (pKa – pHmilk)

R milk / plasma = --------------------------------------
1 + antilog (pKa – pHplasma)

Drug amount reaching the baby = Cave maternal blood x R milk/ plazma x 500 ml
 Biological half-life (Elimination half-life)

• Serum half-life (or elimination half-life) is the time necessary for the
concentration of the drug in the plasma to decrease 50%

t1/2 = 0.693 / ke

Ct = C0 e-ket

ln C = ln C0 – ket

ln = 2.303 log

ke
log C = log C0 - ------- t
2.303
 Elimination Kinetics

CLEARANCE

CL = The proportionality factor correlating the elimination rate and blood concentration
(Amount of distribution volume cleared from drug per unit time ; ml / minute)

Elimination rate
Clearance (CL) = ---------------------------
Blood concentration

Clearance (CL) = ke x VD

0.693 x VD
Clearance (CL) = ----------------
t1/2

Dose
Clearance (CL) = ------------
AUC
 Renal Clearance

Renal Elimination rate

Renal Clearance (CLRE) = ------------------------------------
Blood concentration

(Renal elimination rate = filtration rate + secretion rate – reabsorption rate)

EXAMPLE :
Volume of urine collected for 24 hr = 1440 ml
Curine = 0,22 g /ml
Cplasma at 12th hr = 3,3 ng/ml

1440 ml x 0,22 g /ml

CL RE = ----------------------------- / 3,3 ng/ml CL RE = 66,6 ml/min
24 hr
 Total Clearance

RENAL Clearance (CLRE) = kre x VD

PULMONARY Clearance (CLPUL) = k L x VD
HEPATIC Clearance (CLHEP) = km x VD
*
*
KLTOT = KLRE + KLPUL + KLHEP + KLTER + KLMILK + KLOTHERS

TOTAL CLEARANCE (CLTOT) = VD (kre + kL + km + ... )

 Blood Urea Nitrogen (BUN)

the last product of the protein metabolism

(partial tubular reabsorption)

Normal blood level = 10-20 mg / dl

>20 mg / dl indicates renal disfunction

*** Excessive protein consumption, reduction in renal blood flow,

hemorrhagic shock, gastric bleeding
cause increase in BUN
 Creatinine Clearance

CREATININE
MUSCULAR METABOLISM / CREATININE PHOSPHATE
(GLOMERULAR FILTRATION + TUBULAR SECRETION)

Age, Body Weight, Gender

RELATIONSHIP BETWEEN SERUM CREATININE CONCENTRATION AND CREATININE

CLEARANCE

BY EQUATIONS OR NOMOGRAMS
 Creatinine Clearance

DRAWBACKS

Prerequisites for using serum creatinine concentration in such

formulas or nomograms
- No hepatic disfunction
- Any muscular disorder (such as hypertrophy or dystrophy)
- Any drugs intake modifying muscular creatinine production
(such as Trimethoprim)
(for obese patients Lean body weight should be used)

*** enzymatic colorimetric method of Jaffe for measurement of serum creatinine

disadvantage of this method is false positive results with :
ketonemia or drugs such as ascorbic acid, barbiturates,
phenolsulfophytalein, some cephalosporins (sefoksitin, seforanid)
 Estimation of Creatinine Clearance by
Kampmann & Siersbaek-Nielsen Nomogram
 Creatinine Clearance

Cockcroft and Gault Formula

(140-age) x body weight * (kg)

CLCR = ---------------------------------------------- (Man)
(72 x CCR)

(140-age) x body weight (kg)

CLCR = ----------------------------------------- ------ (Woman)
(85 x CCR)

CCR = Serum Creatinine concentration (mg / dl)

CLCR = ml / minute

* “lean body weight”

 Estimation of Lean Body Weight (LBW)

Man LBW = 0.3281 BW + 0.33929 H – 29.5336

Woman LBW = 0.29569 BW + 0.41813 H – 43.2933

BW = Body weight; kg
H = Height; cm
 Creatinine Clearance

Jellife Method
(Age = 20 - 80)

98 – 0.8 (Age – 20)

CLcr = ------------------------------
CCR
 Graphics in Pharmacology

Concentration Effect

Time Concentration

Concentration – Time Graphic Concentration – Effect Graphic

 Treshold Concentrations

Concentration

MTC

MEC

Time

MEK = Minimum Effective Concentration

MTK = Minimum Toksic Concentration
 Elements of concentration-time graphics; duration of action

MTC

Peak Conc.

MEC

Time to Peak

Duration of Action
 Pharmacokinetic properties of A > B: Therapeutic Significance?

9 9 9
8 8 8
7 7 7
6
6 6
5 Drug
5 A 5 Drug A Drug A
n

MEC
serumconcentration
tio

n
Drug B

tratio
tra

4 4 4 Drug B Drug B
en

n
c

e
n

c
o

n
mc

mco
3 3 3
ru

eru
se

s
2
2 2
1
1 1
MEC
0
0 0
0 5 10 15 20 25
0 5 10 15 20 25 0 5 10 15 20 25
Time after drug administered (hours)
Time after drug administered (hours) Time after drug administered (hours)
 Duration of Action for Prodrugs

Conc.

Drug

MEC

Metabolite

Time
Duration of Action
MEC = Minimum Effective Concentration
Relationship Between Dose and Duration of Action

2.3 D
TD = -------- log ------------
Ke Dmin
Repeated Drug Administration
constant interval – constant dose

MTC

MEC
 Repeated Drug Administration
constant interval – constant dose

K % = 40

100
60 + 100 = 160(40)
96 + 100 = 196(64)
117 + 100 = 217(87)
130 + 100 = 230(92)
138 + 100 = 238(95)
143 + 100 = 243(97)
146 + 100 = 246(98)
148 + 100 = 248(98)
149 + 100 = 249(99)
149 + 100 = 249(100)
149 + 100 = 249(100)
Repeated Drug Administration
constant interval – constant dose

Cmax

Cave

Cmin
 Loading Dose

Loading dose = Vd * desired plasma concentration

Loading dose

Drug administration rate = Cort x CLTOT

 Continuous i.v. infusion

ss İnfüzyon Hızı
C = ---------------
ort KLTOTAL
 Drug Development

Clinical development of medicines

Phase I Phase III

20 – 50 healthy volunteers 250 – 4000 more varied
to gather preliminary data patient groups – to
determine short-term safety
and efficacy
Animal experiments for
acute toxicity, organ
damage, dose dependence, Phase II
metabolism, kinetics, Phase IV
carcinogenicity, 150 – 350 subjects with
mutagenicity/teratogenicity Post-approval studies to
disease - to determine
determine specific safety issues
safety and dosage
recommendations

Preclinical
Phase IV Spontaneous
Animal Phase I Phase II Phase III
Experiments Post-approval Reporting

Development Post Registration

WHO Technical Seminar, 2008

 Drug Development

Screening process required by FDA that needs the following sequence

Animal studies to determine

• Toxicity
Acute, subacute and chronic toxicity– median lethal dose (LD50) the dose
lethal to 50% of animals tested (at least two different kinds of animals are
used)

• Therapeutic index – ratio of LD50 to median effective dose

• Modes of absorption, distribution, biotransformation, and excretion

 Drug Development

Human studies

Phase I - initial pharmacologic evaluation. Goals to analyze drug’s safety

and to identify tolerable dosages

Phase II – limited controlled evaluation. Designed to test drug’s effect on

the specific illness it was designed for. After completion of this phase,
a new drug application can be submitted to the FDA. If approved,
move to phase III

Phase III – extended clinical evaluation. large number of subjects are

used to determine therapeutic & side effects and tolerability

Phase IV – postmarketing surveillance

 Effect

Factors determining the strength of stimulus-response relation in any biological

organisation :
1. The nature and effectiveness of functions that transfer stimulus to response
(intrinsic activity)
2. Number (or density) of intermediate units (receptors)

Intrinsic activity: inherent ability to produce an effect

• Affinity –the tendency of a drug to form a combination with the receptors

• (Affinity = 1/KD; KD = dissociation constant)

• Efficacy – capacity to produce pharmacological response

• Potency- power to produce a pharmacologic response

Affinity & Efficacy need not be directly “proportional”

 Types of Receptors

Receptor : A macromolecular component of the organism that binds the drug and
initiates its effect. They mediate the actions of endogenous chemical signals such
as neurotransmitters, autacoids, hormones or growth factors

Chemical Bond: ionic, hydrogen, hydrophobic, Van der Waals, and covalent.

Saturable, Competitive, Specific and Selective, Structure-activity relationships,

Transduction mechanisms

Enzymes -
Ex: dihydrofolate reductase - receptor for methotrexate

Ion channels -
Voltage sensitive sodium channels - receptor for local analgesics

Transport proteins
Ex: Na+/K+ ATPase - membrane receptor for digoxin

Structural proteins
Ex: tubulin - receptor for colchicine
 Types of drug-receptor interactions

Agonist drugs: bind to and activate the receptor which directly or indirectly
brings about the effect.

affinity efficacy
Agonist (A) + R A-R complex Response
(Isoproterenol)

Antagonist drugs: bind to a receptor to prevent binding of other molecules

(competitively or not)

affinity
Antagonist (B) + R B-R complex No Response
(Atropine)

Partial agonist drugs: act as agonist or antagonist depending on the

circumstance
(Pindolol)
 Theories About Drug-Receptor Interaction

Receptor occupation theory (Hill-Clark, 1937)

Modified occupation theory (Ariens, 1954)
Biologic stimulus theory (Stephenson, 1956)
Rate theory (Paton, 1961)

Allosteric receptor theory

Two state receptor theory
Flux-carrier theory (MacKay, 1963)
Conformational perturbation theory (Belleau, 1964)
Receptor inactivation theory (Gosselin, 1968)
Mobile receptor theory ( Jacobs & Tallarida, 1976)
 Theories About Drug-Receptor Interaction

Hill-Clark theory (1937) (occupation theory) : the magnitude of the response is

directly related to fraction of the receptors occupied by the drug at equilibrium.
(General assumptions : proportionality; one-to-one binding; steady-state occupation; graded
response; whole receptors = max. effect; no change in the properties of other receptors)

Ariens (1954) : partial agonists and intrinsic affinity (General assumptions : two
independent parameters as affinity and intrinsic affinity; agonists has both; antagonists has
affinity but not intrinsic affinity; partial agonists has an intrinsic affinity of 0 to 1)

Stephenson (1956) : introduce a new parameter as “stimulus”. (General assumptions :

Emax can be obtained with the occupation of small percentage of receptors; different drugs
may produce same effects with occupying different percentage of receptors)

Paton (1961) (rate theory) : the observed effect is proportional to the rate of drug
receptor interaction (mainly dissociation rate constant). (General assumptions :
Agonist binds and produce an effect then rapidly dissociate from the receptor; antagonists
are much much slower in dissociation process)
effect [DR] [D] When [D] = Kd
= = [DR] = 0.5
Max. effect RT Kd + [D] RT
1.00

0.75
[DR]/R T

0.50

0.25
Kd
0.00
0 5 10 15 20

[D]
GRADED DOSE-RESPONSE CURVE
Graded Dose-Response Curve
Graded Dose-Response Curves For Three Drugs
Efficacy And Potency
 Intrinsic Activity and Affinity of a Drug

A B

A : a, b, c (equal pD2 , different Emax)

B : a, b, c (equal Emax , different pD2)
 Quantal (All-or-None) Dose Response Relation

m
• Mostly frequency distribution
(ratio of responding subjects to
total)

% of individuals responding
• Considers variability among Therapeutic Lethal or Toxic
patients in severity of disease
and responsiveness to drugs <Margin of safety>

ED50 LD50
• Measures and compares the
potencies of drugs

Dose (log)
Therapeutic Index – An Index of Safety

Hypnosis Death
 Safety Indices

LD50
Therapeutic Index = -----------
ED50

LD1
SF = ---------
ED99

LD1 _ - ED99
CSF = -----------------------
ED99
Thanks for Calm Hearing