BASIC PHARMACOTOXICOLOGY

Eman SutrisnaDepartement of Pharmacology and Therapy

Medical School Unsoed

LEARNING OBJECTIVES

Student able to explain : Definition and field of

pharmacotoxicology Various of Pollutant, Toxic agents

and resourcers Application of the principles of

toxicology examination in drug development.

Assessment of Substant sefety in food

TOXICOLOGY

The study of poisoning and the harmful effect of chemicals on the living organism

THE FIELD OF TOXICOLOGY

Descriptive or experimental toxicology

Forensic toxicology Enviromental toxicology Occupational toxicology Clinical toxicology Ect…

THE CLASIFICATION OF TOXICOLOGY(The kind of Agents and the incidence time)

The toxicology of the drug The toxicology of the food The toxicology of the pesticide The toxicology of the industry The toxicology of the environment The toxicology of the accident The toxicology of the war The toxicology of the radiation

THE CLASIFICATION OF TOXICOLOGY(The type of Agents)

Metallic Pollutant Heavy metals Non Metallic Pollutant Air

Pollutant

VARIOUS TOXICANTS

Chemical Industrial Household

Agricultural Pesticides Natural toxicants

Mushrooms Plant toxin Snake/insect toxin Marine toxin

Heavy metal Pb Mercury Arsen Cadmium Iron

VARIOUS TOXICANTS

Drugs OTC free drugs Illegal Prescription

The drug which can cause harmdeath : Antihistamine Acetaminophene Carbon-monoxide Psychotropic : Barbiturates, chloral hydrate,

major tranquillizer, anti depressant tricyclic , karbamazepine

Teophilline Verapamil, digoxyne Narcotic : opiat ect

TOXICOLOGY EXAMINATION

Pharmacokinetic test Pharmacodynamic test The assessment of substance sefety

PRE CLINICAL TRIAL

Animal study Laboratory based To evaluate :

Active compound Performing pharmacological Toxicology Safety testing

CLINICAL TRIAL

Human study Phase I

Small number of subject (≤30) Healthy volunteer By clinical pharmacologist Determine metabolism of the drug in

human A safe dosage Extremly toxic effect in human

Phase II

Patient who have a target disease 100-200 subject By clinical pharmacologist Determine pharmacokinetic of the drug Additional toxic effect Preliminary information on the efficacy Dosage regiment

Phase III

Large number of patient (several hundred-thousands)

By clinical researcher To verifies phase I and II To make sure and proves that the

drug is more effective than previously available drugs

Phase IV

Post marketing surveillance. Conducted once the drug is

approved To gather information a long term

outcome Long term toxic reaction Neoplastic effect Terratogenic effect

SUBSTANCE SEFETY

IMPORTANT in toxicology NEL (No effect Level)/NOEL (No Observe

Effect level) the concentration of substance or drugs found in research that have no effect to cause dysfunction or damage of organ or death.

ADI (acceptable Daily Intake) the maximal concentration (mg/kgbw/d) of the substance can be daily in-taken for a long time and predicted no influent to human body

SUBSTANCE SEFETY

100 = safety factor 10 = the difference between animal and

human 10 = the difference among the human

ADI use to measure the additive or contaminant substance

MPC (maximal permissible concentration) the maximal concentration of the substance permitted in the foods

ADI= (NEL/100) mg/kgbw/d

SUBSTANCE SAFETY

Food factor = the average of food consumption every person (kg/person/d)

MPC= ADI x BW (kg) food factor (kg)

LEAD TOXICITY

HEAVY METALS

Heavy metals are natural constituents of the Earth's crust and are present in varying concentrations in all ecosystems

Metals differ from other toxic substances in that they are neither created nor destroyed by humans. Therefore, they tend to accumulate in the soils, seawater, freshwater, and sediments.

HEAVY METALS

Mercury is a contaminant of our water ways. Humans are exposed to mercury in the fish they eat as well as in the amalgam fillings in their teeth.

Arsenic is found naturally in high concentration in drinking water in various parts of the world.

Cadmium has been classified as a known human carcinogen.

Sources of Lead - environmental

Combustion of tetramethyl in gasoline Persistent lead-based paint (children with

Pica) Improperly glazed earthenware Lead piping (acid rain) Solder in food containers Automobile battery casing 

Mercury

MAJOR PHYSICAL AND CHEMICAL FORMS OF MERCURY

 INORGANIC Hg, Hg2++ Hg++ Metallic Mercurous Mercuric

 ORGANIC C6H5Hg+, CH3Hg+,  Phenyl Mercuric Methyl Mercuric

Human Exposure

Mercury Vapor Environmental - unimportant

Occupational - main source Electrical equipment, paints,

thermometers, laboratory Dental

Amalgam fillings - main source of background exposure

ORGANIC

Methylmercury important Environmental - main source is fish

Biomethylation - Hg (all forms) --> Hg++ --> CH3Hg and CH3HgCH3

Bioaccumulation in aquatic food chains Industrial, agricultural

By-product of plastic industry Fungicide in seed grain (also ethylHg) Misuse of treated grain (developing countries)

Cadmium

Cadmium is a natural element in the earth's crust. It is usually found as a mineral combined with other elements such as oxygen (cadmium oxide), chlorine (cadmium chloride), or sulfur (cadmium sulfate, cadmium sulfide).

All soils and rocks, including coal and mineral fertilizers, contain some cadmium. Most cadmium used is extracted during the production of other metals like zinc, lead, and copper.

Cadmium does not corrode easily and has many uses, including batteries, pigments, metal coatings, and plastics.

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