Investigating drug effects

Pharmacology

Drug: medicine, active substance, active ingredient, usually synthetic or plant-derived (not only drugs of abuse!).

Pharmacology: the science of medicines; investigates the fate of medicines, active substances within the organism.

The presence of active substances in the organism is influenced by absorption, distribution, metabolism and elimination of the substance.

Absorption and distribution

• Absorption: the active substance reaches the blood plasma.

• Distribution: the process when the substance leaves the blood and reaches different tissues and organs.

Theophrastus von Hohenheim

(Paracelsus)(1493-1541): „All things

are poison, and nothing is without

poison; only the dose permits

something not to be poisonous.”

„The dose makes the poison.”

Therapeutic window: plasma

concentration range of a substance,

where it evokes the therapeutic effect

without harmful side effects.

Metabolism and elimination

Metabolism

• Enzymatic biological transformation in the liver (less important in kidneys, lungs).

• Metabolism may help elimination in case of lipid-soluble (hydrophobic) substances. They are transformed into water-soluble (hydrophilic) metabolites, which can be eliminated through the kidneys.

Elimination

• The substance is cleared out, eliminated of the body.

• May occur after metabolism or without metabolism.

• Hydrophilic compounds are easily eliminated without metabolism.

• Elimination occurs mostly through the kidneys .

• In a lesser degree, the lungs, skin (sweat glands) and liver (bile) are also capable of eliminating foreign substances.

Administration and absorption of drugs

Local administration

• Mucosa • Skin • Eye

Systemic administration

• Enteral administration: ― Oral (mouth) ― Sublingual (under tongue) ― Rectal (suppository)

• Parenteral administration (injections): ― Intravenous ― Intramuscular ― Subcutaneous (under skin) ― Intraperitoneal (into abdominal

cavity)

What is a medicine?

• A compound or product interacting on the molecular level with human or animal organisms, causing the cure of an illness or the relief of symptoms.

• Licensing and registering medicines: European Medicines Agency (EMA), Food and Drug Administration (USA), national societies

Developing a human medicine

1. discovery, identification of the molecule

2. preclinical tests – in vitro and in vivo toxicological and pharmacological experiments on animals and human cell/tissue cultures

3. clinical tests – human phase I-II-III studies

4. registering, licensing of the medicament

5. phase IV and post-marketing (PMS) studies

Clinical (human) studies

Phase I.

20-40 healthy volunteers, usually young men

Aim: prove that the drug is relatively harmless

Phase II.

100 selected patients (no liver and kidney disorders)

Aim: determine the effectiveness, pharmacological profile, adjust daily dosage

Phase III.

Multicentre study on 5-8000 patients (international)

Blind and double-blind studies

Aim: detailed description of effect and side effects

Phase IV.

Monitoring effects and side effects when medicine is already on the market

Animal experiments

animal= biological model for humans

laboratory animal : animals raised under strictly controlled conditions, for the purpose of experiments (mouse, rat, rabbit, beagle dog, cat, primates)

Regulation of animal experiments

• European Council: Agreement 123 a

• European Economic Association: Directive 609/86

• European Union: Directive 2010/63

• national laws about animal protection

• experiments should be carried out by causing the less possible pain, suffering, deprivation or damage to the animal

• 3R principle: Replacement, Reduction, Refinement

Use methods which don’t use animals (e.g. in vitro tests).

Reduce the number of animals (more uniform animals, controlled conditions)

Refine the methods to need less animals.

Game presenting the mechanism of action of drugs of abuse

http://learn.genetics.utah.edu/content/addiction/drugs/mouse.html

Irwin’s activity test

• Rapid screening, testing method for the investigation of drug effects on the CNS, carried are on adult male mice.

• About 30 parametres are examined, scoring 0-8.

• Comparison of control and treated animals.

• For activities/characteristics present in control also, the standard score is 4 (this may increase or decrease after treatment). For activities or characteristics not present in control, standard score is 0.