DEPARTMENT OF PHARMACY 

Assignment on N-Oxidation and Drug Toxicity

Course Title: Toxicology

Course Code: PHAT-4106
  
Submission date: 9 sept. 2021

Oxidation Reaction
Addition of oxygen or removal of hydrogen
Normally the first and almost common step involved in the drug
metabolism
Majority of oxidation occurs in the liver and it is possible to occur in
intestinal mucosa , lungs and kidneys
Most important enzyme involved in this type of oxidation is cytochrome
P450
Increased polarity of the oxidized products (metabolites) increases their
water solubility and reduces their tubular reabsorption , leading to their
excretion in urine .
These metabolites are more polar than their parent compounds and
might undergo further metabolism by phase II pathways

Oxidation reaction catalysed by microsomal Enzymes

Require both molecular oxygen and reducing agent NADPH ,they are
referred to as mixed function oxidases (MFO)

MFO consists of 3 components

-cytochrome p450- heme protein ,transfer of oxygen atom

-Flavoprotein- NADPH dependent ,act as electron carrier ,catalyze the

reduction of cytochrome P450

-Phosphatidy choline – facilitate electron transfer

RH + O2 +NADPH + H+ ROH + H2O+NADP+

CYP450 oxidation cycle is given below -

Oxidation Reaction

- Oxidation of aromatic carbon atoms

- Oxidation of olefins (C=C)
- oxidation of Allylic carbon atom
- Oxidation of carbon – Hetero atom
- Oxidation of Carbon –Nitrogen
- N dealkylation
- Oxidation deamination
- N oxide formation
- N hydroxylation

Oxidative Reactions

N oxidation :
Aliphatic amine
Alicyclic amine

Drug Toxicity
Drug toxicity refers to the level of damage that a compound can
cause to an organism. The toxic effects of a drug are dose-
dependent and can affect an entire system as in the CNS or a
specific organ such as the liver.

Factors that may causes for drug Toxicity in human

body
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Types of Toxicity
1.Cytotoxicity
2. Carcinogenicity
3. Mutagenicty
4. Teratogenecity

Cytotoxicity
Cytotoxicity is an in vitro test to determine whether the medical
device will cause any cell death due to leaching of toxic substances
or from direct contact.

Types of cytotoxicity

Non covalent interactions Covalent interactions

-Lipid peroxidations - HEPATOTOXICITY

-Genaration of toxic reactive e.g. Paracetamol
ogygen species - NEPHROTOXICITY
-Reaction causing depletion of glutathione e.g. Amnioglycosides

-Modification of sulfhydryl groups

Carcinogenecity - The term "carcinogen" denotes a chemical

substance or a mixture of chemical substances which induce cancer
or increase its incidence. Substances which have induced benign
and malignant tumours in well performed experimental studies on
animals are considered also to be presumed or suspected human
carcinogens unless there is strong evidence that the mechanism of
tumour formation is not relevant for humans. Several radioactive
substances are considered carcinogens . Examples : inhaled
asbestos and tobacco smoke

Mutagenicity – Some drugs that can cause permanent changes to

the DNA of germ cells – egg cells and sperm cells – leading to
mutations ehich are inherited by a patients children . Example
Nitrogen mustard
Teratogenicity -Teratogenicity is defined as the observation of
any significant change in the function or form of a child secondary
to prenatal treatment .Some drug can cause defects in the
development of the fetus ,leading to groos abnormalities of the
baby . Depends on the different stages of organs develop at
different times during pregnancy
Example : Thialidomide

Mechanism
 On target adverse effetc Off Target adverse effect

drug binding in its intended Binding to a receptor that it was not

receptors intented

inappropriate posology
or inadequate kinetics or incorrect issues

Others mechanism

Harmful
immune
response

Production of
idiosyncratic
toxic
response
meatabolites

On target Adverse Effect

 Alterationo Dosing
f the Error

pharmacoki
netics
Ateltration
in the
pharmacod
ynamics

Exggeration in pharmacological
action

Subclass and Important details on target effects

Drug action on the same receptor but in different tissue than

tha target one

May Expose unknown functions of the biological target

Off target Effects – The drug interacts with unintended targets

indedd , few drugs are so selective that they interact with only one
molecular target
Example – The antihistamine terfenadine , Which also inhibits a
cardiac potassium cahnnel (hERG)

Idiosycratic Toxicity – Idiosyncratic drug reaction are rare

adverse effects for which no obvious mechanism is apparent .
Refelect unique individual genetic differences in the response to
the drug molecule ,possibly through variations in drug metabolism
or immune response

Measuring Toxicity - Toxicity can measured by the effect the

substance has on organism , a tissue or a cell . Therefore a
population –level measure of toxicity is often used , The
probability of an outcome for a population is then related to given
individual in population .

Lethal Dose (LD50) : one such population- level measure is the

median lethal dose ,LD50 (lethal dose 50%) .this is defined as the
dose required to kill half the members of a specific animal
population when entertaining animals body by a particular route .
LD50 is general indicator of a substances toxicity within a short
space of time ,It is a measure of acute toxicity .
paracetamol has an oral LD50 of 1,944 gm/kg in rats

Measuring Toxicity -

Toxic dose low – the lowest dose of a substance introduced by any

route ,other inhalation ,over any given period of time and reported
to produce any toxic effect in humans or to produce turmorigenic
or reproductive effects in animals .

Toxic concentration low - The lowest concentration of a

substance in air to which humans or animals have been exposed for
any given periods odf time that has produced any toxic effect in
humans or produced tumorigenic or reproductive effects in animals

Lethal dose low – The lowest dose ,other than LD50 of a

substance introduced by any route , other than inhalation ,which
has been reported to have caused death in humans or animals

lethal concentration low – The lowest concentration of a

substance in air which has been reported to cause death in humans
or animals

Avoiding Toxicity

- Banning dangerous drugs or strictly controlling their uses

- Drugs must go through both animal testing and small scale trials
on humans to detect unexpected effects
- To advise doctors not to prescribe toxic drugs to pregnant women

- Child proof containers have also been developed and clear

labeling is used to warn patients of risks

Treatment

The first line of defence

- Irrigation to remove drugs applied to eyes or skin

- Activated charcoal, which is swallowed and soaks up the drug
from the gut
- Ipecac Syrup ,which causes vomiting in order to empty the
stomach
- Cathartics ,laxatives which purge the drug from the gut

The second line of defence

-Changing urine pH to increases excretion of the drug into the

urine
- forced dieresis , where drugs are given to increase urine
production
- Haemodialysis , where the blood is passed through a machine to
remove the drug
- Exchange transfusion to replace the patients drug filled with
fresh blood

Thanks a Bunch